SECTION 16 Cardiovascular disorders Section editor 16.1 Structure and function 3241 16.1.1 Blood vess 16.1 Structure and function 3241 16.1.1 Blood vessels and the endothelium 3241 Keith Channon and Patrick Vallance CONTENTS 16.1.1 Blood vessels and the endothelium  3241 Keith Channon and Patrick Vallance 16.1.2 Cardiac physiology  3253 Rhys D. Evans, Kenneth T. MacLeod, Steven B. Marston, Nicholas J. Severs, and Peter H. Sugden 16.1.1  Blood vessels and the endothelium Keith Channon and Patrick Vallance ESSENTIALS Anatomy of blood vessels The blood vessel wall consists of three layers:  the intima, media, and adventitia. Not all vessels have each layer, and the layers vary in size and structure between vessels. (1) The intima is made up of a single layer of endothelial cells on a basement membrane, beneath which—​depending on vessel size—​there may be a layer of fibroelastic connective tissue and an internal elastic lamina that provides both structure and flexibility. Embedded in the intima are pericytes. (2) The media is made up of smooth muscle cells, elastic laminae, and extra- cellular matrix. (3) The adventitia is the outermost part of the vessel, composed mainly of fibroelastic tissue but also containing nerves, small feeding blood vessels (the vasa vasorum), and lymph vessels. The adventitia is directly related to the surrounding perivascular adi- pose tissue. Function of particular constituents of blood vessels Endothelial cells are metabolically very active and exert a profound influence on vascular reactivity, thrombogenesis and coagulation, and the behaviour of circulating cells. Endothelial cells sense blood flow through transduction of shear stress (viscous drag), and align with the direction of blood flow through cytoskeletal functions. They produce key vasodilator mediators:  nitric oxide, prostanoids, and hyperpolarizing factors. Although the predominant influence of the healthy endothelium is as dilator, it also produces important vaso- constrictor factors, including endothelin, angiotensin-​converting enzyme, certain prostanoids, and reactive oxygen species such as superoxide anion. The endothelium synthesizes and releases prothrombotic and antithrombotic factors, with antithrombotic factors predominating under basal conditions. The healthy endothelium allows leucocytes to roll along its surface, but prevents cells from adhering fully to the vessel wall. Vascular smooth muscle cells provide the contractile function of the vessel wall, but may adopt a range of other phenotypes: they can enter a replicative state, undergo cell death through apoptosis, migrate into the intima, adopt a secretory phenotype that results in matrix deposition (including developing bone-​like features and cal- cification), and can contribute to inflammation within the vessel wall. The vessel is surrounded by adventitia and perivascular adipose tissue, which contain adipocytes, inflammatory cells, and fibro- blasts. Evidence suggests that there is continuous cross-​talk between the vascular wall and perivascular tissues. Perivascular adipose tissue secretes a wide range of adipocytokines, which have paracrine ef- fects on the vessel wall. The vessel and its perivascular adipose tissue are now considered to be closely interrelated, with perivascular adipose tissue playing important roles in vascular homeostasis and pathophysiology. Integrated responses of blood vessels Blood flow elicits an endothelium-​dependent dilator tone due to the production of nitric oxide, which provides a physiological counter- balance to the constrictor tone of the sympathetic nervous system. Veins differ from arteries and arterioles, and do not seem to be ac- tively dilated by continuous release of nitric oxide. Flow-​mediated dilatation is an autoregulatory property of blood vessels that tends to oppose classical myogenic autoregulation—​the process by which a blood vessel constricts in response to an in- crease in intraluminal pressure. There is a fourth-​power relationship between resistance to flow and the radius of a blood vessel, which means that relatively small changes in the thickness or contractile state of smooth muscle in small arteries and arterioles have big ef- fects on systemic vascular resistance. There are important interactions between the sympathetic ner- vous, renin–​angiotensin, and endothelin systems, with these acting in concert to control constrictor tone, and with the endothelin system providing a slowly modulating background constrictor tone. 16.1 Structure and function Section 16   Cardiovascula r disorder 3242 Additional endocrine signals that modulate vascular tone and func- tion include circulating cortisol and oestrogens. Pathophysiology Several clinical conditions associated with increased cardiovascular risk—​including atherosclerosis, hypertension, hypercholesterol- aemia, and diabetes—​are associated with reduced nitric oxide-​ mediated effects. Overproduction of nitric oxide may also contribute to disease, with induction of inducible nitric oxide synthase (e.g. in sepsis), leading to production of large amounts of nitric oxide and contributing to vascular paresis. Expression of adhesion molecules by the vascular endothelium is an important mechanism of cellular adhesion during inflammation and is also important in recruitment of monocytes in atherosclerosis. Impaired production and/​or func- tion of endothelial progenitor cells, particularly with ageing, may contribute to the pathogenesis of endothelial dysfunction in disease, particularly in atherosclerosis and vascular injury, where endothelial cell turnover is increased. Introduction Blood vessels range in size from microscopic capillaries to large ves- sels such as the aorta and vena cava, and vary in specialized func- tion from tissue to tissue. They deliver oxygen and nutrients, remove waste, control the passage of cells and macromolecules from the blood into the tissues, and are equipped to sense and respond to physical and chemical signals. There are three basic layers to blood vessels—​the intima, the media, and the adventitia (Fig. 16.1.1.1). The intima comprises a single layer of endothelial cells on a base- ment membrane, beneath which—​depending on vessel size—​there may be a layer of fibroelastic connective tissue and an internal elastic lamina that provides both structure and flexibility. Embedded in the intima are pericytes—​intriguing cells of smooth muscle cell lineage that make contact with multiple endothelial cells. The media is made up predominantly of smooth muscle cells and concentric elastic fibres making up the elastic laminae. The outermost part of the vessel is the adventitia, a less well-​defined layer composed mainly of fibroelastic tissue that provides structural integrity to the vessel, but also contains nerves, small feeding blood vessels (the vasa vasorum), and lymph vessels. However, the adventitia is also in continuity with perivascular adipose tissue (PVAT) that has paracrine relationships with the vascular wall. In simple terms, the intima may be con- sidered as the layer that transduces signals from the lumen of the vessel to the rest of the vessel wall and controls the interface with the blood; the media is the mechanical workhorse of the vessel, and the adventitia links the vessel wall to the local and wider environment. Not all vessels have each layer, and the layers vary in size and struc- ture between vessels. For example, capillaries are essentially endo- thelial cell tubes surrounded by pericytes, resistance vessels have a relatively thick media, and the large conduit arteries have a high pro- portion of elastic tissue and a rich vasa vasorum. In disease states, particularly atherosclerosis (see Chapter  16.13.1), the vessel wall may have a high content of inflammatory cells in the intima, media, and adventitia. All three layers coordinate to regulate the function of the blood vessel, and all three are involved in the pathogenesis of vascular disease. Large ‘conduit’ arteries perform the function of mass transport; smaller arteries and arterioles provide the predominate resistance to flow, and are therefore key determinants of blood pressure; capil- laries are thin-​walled and contribute most to passage of nutrients, gases, and cells through to tissues; venules provide postcapillary re- sistance and help determine capillary pressure; and larger venules and veins dynamically regulate the total capacitance of the circula- tory system. Cellular constituents of blood vessels Endothelium A monolayer of endothelial cells lines the intimal surface of the entire vascular tree (Fig. 16.1.1.2) to form the largest endocrine/​ paracrine organ in the body. Endothelial cells are metabolically very active and exert a profound influence on vascular reactivity, thrombogenesis and coagulation, and the behaviour of circulating cells. Abnormalities of endothelial function have been implicated in a wide variety of diseases ranging from atheroma and hypertension to acute inflammation and septic shock. During early development, the endothelium forms the first layer of the circulatory system and extends to produce a network of interconnecting tubes. This ability of endothelial cells to form tube-​like structures is retained even when they are grown in vitro. In vivo the endothelial tubes differentiate into arteries, arterioles, capillaries, veins, and lymph vessels, and regional differences in function and structure evolve such that the properties of endothe- lial cells vary between arterial and venous beds, between micro-​ and macrovasculature, between organs, and between different parts of individual organs—​perhaps the most striking example being the specialized layer of endothelial cells and pericytes that forms the blood–​brain barrier. Although heterogeneity of vascular Fig. 16.1.1.1  Image of a human coronary artery, imaged in vivo using optical coherence tomography during coronary angiography. The asterisk denotes the circular cross-​section of the imaging catheter, and the dotted lines show the optical shadow cast by the coronary guide wire, adjacent to the imaging catheter. The vessel lumen appears black, with the vessel wall highlighted in yellow pseudocolour. The layers of the vessel wall—​intima (I), media (M), and adventitia (A)—​are shown in the magnified inset box. 16.1.1  Blood vessels and the endothelium 3243 endothelium has long been recognized at the histological and im- munocytochemical level, recent studies using microarray analysis of global gene expression have begun to define these differences at the molecular level and promise to have important implications for understanding physiology, pathophysiology, and therapeutics. Heterogeneity of endothelial cell function undoubtedly has such im- plications. For example, endothelial cell heterogeneity may provide strategies to target therapeutic agents or imaging markers to specific organs by coupling them with antibodies or ligands to vascular bed-​ specific endothelial proteins. However, endothelial cells also have many features in common and several pathologies, including those causing premature vascular disease, are associated with widespread changes in the behaviour of endothelial cells. Anatomy of the endothelium Each endothelial cell is between 25 and 50 µm long, 10 to 15 µm wide, and up to 5 µm deep, and lies with its long axis aligned in the direction of the blood flow (Fig. 16.1.1.2). The underlying smooth muscle cells lie radially, are about 5 to 10 µm wide, and taper at either end so that a single endothelial cell can communicate with many smooth muscle cells, and vice versa. The endothelium also comes into intimate contact with circulating cells, and the total area of the luminal surface of the endothelium is in excess of 500 m2. This thin layer of cells is particularly susceptible to injury, and changes in endothelial cell morphology and turnover occur in experimental hypertension, diabetes, and atherosclerosis. Signal detection by endothelial cells The endothelial cell membrane expresses many receptors for circu- lating hormones, local mediators, and vasoactive factors released from blood cells. Endothelial cells sense pressure, stretch, and blood flow via a number of different sensors that vary in different vessels, reflecting the differences in pressure and blood flow across different vascular beds. For example, shear stress (viscous blood flow force) varies from c.10 dyn/​cm2 in large conduit arteries such as the aorta, to c.50 dyn/​cm2 in resistance arterioles, c.20 dyn/​cm2 in post-​capillary venules, and c.1 dyn/​cm2 in large veins such as the vena cava. Endothelial cell mechanosensors on the luminal surface include G-​ protein-​coupled receptors (such as the sphingosine 1-​phosphate re- ceptor 1 and the bradykinin B2 receptor), heterotrimeric G-​proteins, ion channels (such as TRPV4, TRPP2, TRPC1, Piezo1, and Piezo2), and the glycocalyx, a c.500 nm thick layer of glycosaminoglycans on the endothelial surface containing syndecan-​1 and −4. Shear stress responses are also localized in microtubule-​based primary cilia (con- taining with the ion channels PKD1 and PKD1) and protein-​coated membrane ‘pits’ called caveolae, containing the proteins Caveolin 1–​3 and Cavin 1–​3. In addition, endothelial mechanosensors are present at cellular junctions, including PECAM-​1, VE-​cadherin, and VEGFR2, forming mechanosensory complexes that respond to shear stress. On the basal (outer) part of the endothelial cell, other mechanosensors such as the integrins interact with the intimal extra- cellular matrix (ECM). Rapid endothelial cell responses to shear stress include K+ and Ca2+ influx, activation of MAP kinases, Akt and eNOS, leading to nitric oxide (NO) production that causes vasodilatation and S-​ nitrosylation of endothelial cell proteins such heat shock proteins, as well as cytoskeletal components such as tropomyosin and vimentin. Small GTPases such as RhoA and Rac are highly sensitive to shear stress. RhoA is transiently downregulated within 5 min of onset of shear stress, allowing rearrangement of the actin cytoskeleton. Endothelial cell integrins modulate the response to shear stress, for example, by sensing the nature of connections with ECM compo- nents, and ensure spatial organization of focal adhesion complexes, microtubules, and intracellular signalling pathways such as p38 MAP kinase, JNK, and p21-​activated kinase. Downstream consequences of shear stress transduction in- clude initial transcriptional activation of NF-​kB target genes, such as ICAM-​1, but in areas of sustained laminar flow there is downregulation of NF-​kB and increased ‘atheroprotective’ gene expression, mediated by the transcription factor KLF2. In areas of disturbed flow (i.e. loss of laminar shear stress), NF-​kB and other inflammatory signalling are sustained, leading to ICAM-​1 and VCAM-​1 expression and enabling monocyte recruitment. The endothelial cells in vascular damage and repair Vascular endothelial cells move in response to specific chemical sig- nals and can migrate to recover areas of endothelial damage or de- nudation (Fig. 16.1.1.3). The basic mechanisms of movement share similarities with those required to form vessels during development Fig. 16.1.1.2  Left panel: Immunostaining of an en face preparation of artery with CD31 (cell bodies red, nuclei blue), showing endothelial cells. Note that the endothelial cells are aligned in the direction of blood flow. Right panel shows a section of human internal mammary artery immunostained for endothelial nitric oxide synthase (red staining), demonstrating the endothelial cell layer on the luminal surface. Section 16   Cardiovascula r disorder 3244 (vasculogenesis) or during the process of formation of new vessels in adults (e.g. in tumour angiogenesis). Circulating endothelial progenitor cells (EPCs), derived from bone marrow, have been identified and are involved in the pro- cesses of vascular repair and the response to tissue injury. These progenitor cells are characterized by the expression of specific cell surface markers (CD34 and CD133) and can form colonies when cultured in vitro. There is also evidence that resident stem cells lo- cated in the vessel wall with properties of clonality, self-​renewal, and multipotentiality can replace local damaged or denuded endothelial cells. The relationship between the number of circulating endothelial cells and cardiovascular disease is complex. The number of circu- lating EPCs, typically estimated by colony growth in vitro from peripheral blood mononuclear cells, is thought to represent the restorative capacity of the vessel wall, with low numbers being in- dicative of disease progression and increased cardiovascular risk. Importantly, the number of circulating EPCs appears to decrease with age, and with known cardiovascular risk conditions such as dia- betes, hence it is likely that the ability to increase EPCs in response to vascular damage is a key feature of a healthy cardiovascular system able to repair itself. Acute adverse events such as myocardial infarc- tion are associated with a temporary increase in circulating EPC numbers. There is growing interest in the potential therapeutic delivery of EPCs—​or bone marrow-​derived cells capable of differentiating into EPCs and/​or endothelial cells—​for the treatment of cardiovascular disorders. For example, clinical studies have already been initiated in which autologous bone-​marrow-​derived cells have been admin- istered to patients for the treatment of acute myocardial infarction and peripheral vascular disease. In general, the results of these early clinical experiments have been mixed, and there remain important unanswered questions regarding the optimum cell type, the timing and route of delivery (e.g. intracoronary vs. intravenous), and the precise mechanism of potential beneficial effects. Other therapeutic strategies have been aimed at increasing endogenous EPC number and/​or EPC function, either (e.g. using statin drugs) or acutely (by administration of erythropoietin, cytokines, or growth factors) in ischaemic events such as myocardial infarction. Pericytes Pericytes are long cells (approximately 70 µm) with extending cyto- plasmic processes around endothelial cells that make multiple cel- lular contacts (Fig. 16.1.1.4). In small capillaries, it also seems that pericytes may extend connections to more than one vessel, possibly exerting some sort of coordinating influence. The overall coverage of the endothelium by pericytes varies between vascular beds, from 10% to 50%. The junctions between pericytes and endothelial cells appear to be rich in growth factors (particularly epidermal growth factor) that are important in regulating endothelial cell growth and may be vital for angiogenesis and inflammation. Pericytes can also differentiate in to other cells, such as fibroblasts. The nature of the junction between pericytes and endothelial cells may be important for regulating permeability at specialized sites such as the blood–​brain barrier, and in the response to ischaemic injury. In other areas, the contractile function of pericytes may pre- dominate. In the retina, where pericytes are particularly prevalent, their loss is associated with impaired hierarchical organization of vessels or even vessel regression, and this might contribute to dia- betic retinopathy. In inflammation, neutrophil transmigration from venules is regulated by adhesion to pericytes. The only genetic disease Fig. 16.1.1.3  An endothelial cell moving. The front end of the cell with leading lamella is on the right, stress fibres of contractile elements are seen in the centre and these end in focal adhesions. The retracting rear end of the cell is on the left. Courtesy of Dr B. Wojciak-​Stothard. Endothelial cell RBC Pericyte Fig. 16.1.1.4  Pericytes are observed outside small blood vessels in close association with endothelial cells. Reproduced with kind permission from the Department of Pathology and Laboratory Medicine, University of Pennsylvania. 16.1.1  Blood vessels and the endothelium 3245 to date in which pericyte loss has been implicated is Adams–​Oliver syndrome, a rare developmental disorder characterized by scalp and limb malformations, telangiectasia, and vascular problems. The potential roles of pericytes are listed in Box 16.1.1.1. These rather underinvestigated cells seem to retain a plasticity that enables them to differentiate into smooth muscle cells. Vascular smooth muscle cells Smooth muscle cells lie mainly circumferentially in the vessel media to provide contractile function, which is influenced by hormonal, endothelial, neuronal, and intrinsic influences (‘myogenic tone’), with contraction being triggered by a wave of calcium release. The regulation of vascular smooth muscle cell (VSMC) Ca2+ signalling is complex and heterogeneous. Extracellular Ca2+ entry is regulated by activation of the plasma membrane voltage-​dependent L-​type Ca2+ channels (LTCC) and TRP channels. Intracellular Ca2+ release from the sarcoplasmic reticulum (SR) is regulated by agonist activation of SR-​bound inositol trisphosphate (IP3) or ryanodine receptors (RyR). Calcium signalling is highly compartmentalized such that large changes in intracellular Ca2+ may lead to VSMC con- traction without activating other Ca2+-​dependent pathways, and vice-​versa. VSMC contraction is highly complex, but is effected by phos- phorylation of smooth muscle actin at Ser 19 by myosin light chain kinase (MLCK). MLCK is a Ca2+-​calmodulin dependent kinase that is activated by VSMC Ca2+ signalling. Other important aspects of VSMC contractility, via the cytoskeleton and focal adhesion com- plexes, are regulated by complex networks of Ca2+ -​dependent path- ways including the Ca/​CaM-​dependent kinase II (CaMKinase II) isoforms, protein kinase C (PKC), and MAP kinases. VSMC contraction is the key regulator of resistance to blood flow and hence blood pressure. There is a fourth-​power relationship be- tween resistance to flow and the radius of the vessel, which means that relatively small changes in the contractile state of smooth muscle can produce large changes in the resistance offered by the vessel. This is particularly important for small arteries and arterioles, which are the major determinants of systemic vascular resistance. The rela- tive thickness of the vessel wall compared to the size of the lumen is also an important determinant of resistance. As the wall:lumen ratio increases, there is a comparatively larger reduction in lumen size for every incremental shortening of the smooth muscle. In this way, smooth muscle hypertrophy or hyperplasia can lead to a func- tional hyperreactivity of the vessel wall, exemplifying the intimate connection between structure and function. Vascular smooth muscle cells are remarkably plastic and may adopt a range of phenotypes in response to local environmental changes. They may leave the quiescent contractile state and enter a replicative state, migrate into the intima, adopt a secretory phenotype that results in matrix deposition (including the develop- ment of bone-​like features and calcification), and may, under cer- tain conditions, contribute to inflammation within the vessel wall. Smooth muscle cells that replicate and secrete matrix contribute to the process of thickening of the vessel wall in vasculoproliferative syndromes including atherosclerosis, transplant vasculopathy, and the neointimal hyperplasia that characterizes vascular restenosis fol- lowing arterial stent implantation. Phenotypic modulation of vascular smooth muscle cells is under coordinated transcriptional regulation. In the normal vessel wall, the contractile smooth muscle phenotype is maintained by a tran- scriptional pathway involving signalling from the actin cytoskel- eton to SRF, a ubiquitous transcription factor that functions in a smooth muscle cell-​specific fashion by interacting with smooth muscle cell-​restricted cofactors of the myocardin family. This actin–​SRF–​myocardin pathway directly regulates genes encoding contractile proteins such as smooth muscle myosin and SM22. However, in response to inflammatory and other pathological stimuli, the contractile transcriptional pathway is repressed, and alternate transcriptional pathways are activated that promote pro- liferation, production of inflammatory mediators, and synthesis of matrix proteins. Key mediators of the synthetic smooth muscle cell phenotype include the platelet-​derived growth factor-​BB (PDGF-​BB) and Notch signalling pathways, and many of the Ca2+-​ dependent pathways that also regulate VSMC contractility, cyto- skeletal function, and interactions with the ECM. Recent evidence suggests that these transcriptional pathways are also regulated in an epigenetic fashion by smooth muscle cell-​specific programmes for modification of histones within the chromatin structure of smooth muscle-​restricted genes. As in the case of endothelial cells, there is clear heterogeneity in vascular smooth muscle cell phenotype in various vascular beds. Indeed, subsets of vascular smooth muscle cells are derived from distinct embryological precursors; vascular smooth muscle cells of the proximal aortic arch and great vessels are derived from neural crest (i.e. ectoderm), whereas vascular smooth muscle cells in the rest of the circulation are derived from somatic mesoderm. In the adult, another important example of functional heterogeneity is that the pulmonary and systemic vasculature differ markedly in their response to hypoxia. Hypoxia produces modest vasodilatation in the systemic vasculature, but marked vasoconstriction in the pul- monary circulation. This is likely an adaptive mechanism to prevent ventilation–​perfusion mismatch in the presence of alveolar disease (e.g. pneumonia). However, chronic hypoxia (e.g. in the presence of chronic respiratory disease) can result in pulmonary hyperten- sion and lead to right heart hypertrophy and failure. The precise molecular mechanisms regulating hypoxic pulmonary vasocon- striction are incompletely understood, but oxygen sensing mechan- isms in the mitochondria and voltage-​gated potassium channels on the plasma membrane of pulmonary vascular smooth muscle cells appear to play important roles. Control of vascular tone Endothelium extracts and inactivates circulating hormones, converts inactive precursors to active products, and synthesizes and releases a variety of vasoactive mediators (Fig. 16.1.1.5). Box 16.1.1.1  Roles of pericytes • Contractility • Barrier function and regulation of permeability • Neutrophil transmigration in inflammation • Signalling to control endothelial growth and angiogenesis • Vascular stabilization • Sensors of hypoxia and hypoglycaemia • Transdifferentiation into fibroblasts in wound healing, cancer metastasis Section 16   Cardiovascula r disorder 3246 Vasoconstrictor and vasodilator mediators allow the vessel to respond to changes in the local milieu, but the predominant background influence of the endothelium is dilator, with the re- moval of the endothelium leading to vasoconstriction. A  basal endothelium-​dependent dilator tone seems to provide a physio- logical counterbalance to the continuous constrictor tone of the sympathetic nervous system. Vasodilators The endothelium produces at least three key vasodilation mediators (Fig. 16.1.1.5): nitric oxide (NO), prostanoids, and hyperpolarizing factors. Nitric oxide Physiology The production of NO is responsible for endothelium-​dependent dilator tone that is generated by blood flow. NO is synthesized from the amino acid l-​arginine by the nitric oxide synthase (NOS) enzymes (Fig. 16.1.1.6; see also Fig 16.1.1.8). The vasodilator ac- tions of NO are mediated through the second messenger cGMP, generated when NO activates soluble guanylate cyclase (sGC) by binding to the haem group in the enzyme. A similar mechanism mediates NO signalling by inhibition of cytochrome c oxidase, ini- tially in a reversible manner, but irreversibly under certain condi- tions. Inhibition of this enzyme decreases oxygen utilization, and the release of NO by endothelial cells appears to be an important determinant of oxygen consumption in the vasculature. However, the signalling actions of NO are much broader than modification of enzyme function by haem binding. NO modifies protein functions through numerous chemical reactions involving nitrosylation of cysteine residues and nitration of tyrosines, including ion chan- nels, enzymes, and transcription factors, leading to change such as reduced adhesiveness of the endothelial cell for circulating white cells. A key role for endothelium-​derived NO is the nitrosylation of haemoglobin, leading to changes in oxygen affinity, which appear to play a fundamental role in oxygen delivery in the microvasculature. The arterial circulation of animals and humans is vasodilated continuously and actively by endothelium-​derived NO, and inhibition of the synthesis of NO with certain guanidino-​ substituted analogues of l-​arginine, including N-​G-​monomethyl-​ l-​arginine, leads to vasoconstriction, hypertension, and sodium retention. Shear stress—​the force caused by the viscous drag of flowing blood—​is an important physiological stimulus for the continuous production of NO. Shear stress increases NO produc- tion so the blood vessel relaxes and dilates, thereby reducing the shear stress and increasing flow and/​or reducing blood pressure. Noradrenaline ATP Neuropeptide Y Nitric oxide Blood cells Nerves Shear stress Hormones Autocoids Endothelial layer Fig. 16.1.1.5  Vascular endothelial cells lie at the interface between blood and the smooth muscle cells. They detect chemical and physical signals in the lumen of the blood vessel and adjust their output of biologically active mediators accordingly. This provides a mechanism of local regulation of vascular function. Rapid adjustment of vascular tone is probably achieved through a balance of endothelium-​derived nitric oxide and neuronally derived noradrenaline. Endothelin provides a slowly modulating constrictor tone and angiotensin II has the capacity to fine-​tune neuronal, endothelial, and smooth muscle function. ACE, angiotensin-​converting enzyme. Fig. 16.1.1.6  (a) Nitric oxide synthases (NOS) catalyse the conversion of l-​arginine and molecular oxygen to citrulline and NO. NOS enzymes are catalytically active as homodimers and require the binding of cofactors (flavin adenine dinucleotide, flavin mononucleotide (FMN), haem (Fe), and tetrahydrobiopterin (BH4)) and calmodulin (CaM) for optimal activity. Each NOS dimer coordinates a single atom of zinc. (b) Under conditions where NOS are ‘uncoupled’, the enzyme does not catalyse the conversion of l-​arginine to citrulline and NO, but instead generates superoxide or other reactive oxygen species (ROS) by reduction of molecular oxygen, driven by electron flow from NADPH via the flavin domain. Factors that cause NOS uncoupling include low levels of the cofactor tetrahydrobiopterin (BH4), inadequate levels of the substrate l-​arginine, or oxidative modification of the eNOS protein by glutathionylation (G) of specific cysteine residues. 16.1.1  Blood vessels and the endothelium 3247 This process of flow-​mediated dilatation appears is a homeostatic mechanism to regulate blood flow and coordinate tissue perfu- sion. The autoregulatory action of flow-​mediated dilatation op- poses classical myogenic autoregulation—​the process by which a blood vessel constricts in response to an increase in intraluminal pressure. Synthesis of NO is stimulated by acetylcholine, bradykinin, and substance P, and in many vessels the release of NO accounts for the vasodilator actions of these mediators, which are known as ‘endothelium-​dependent vasodilators’. Circulating hormones, including insulin and oestrogens, may also act on receptors on or within the endothelial cell to stimulate the release of NO acutely or to alter the expression of endothelial NO synthase chronically. Endothelial NO synthase (NOS) is activated either by increases in intracellular calcium, which causes binding of calmodulin, or by phosphorylation of specific serine or threonine residues in the protein, for example, by the kinases Akt or PKC (Fig. 16.1.1.8). Phosphorylation can either activate or inhibit the enzyme, for ex- ample at serine 1179 or threonine 495, respectively. Phosphorylation of eNOS mediates the physiological effects of shear stress, and hor- mones such as insulin, oestrogen, and vascular endothelial growth factor (VEGF). Veins differ from arteries and arterioles in that they do not seem to be actively dilated by the continuous release of NO, al- though the venous endothelium releases NO when it is stimulated by acetylcholine or bradykinin, and veins are highly sensitive to NO-​mediated vasodilatation. Furthermore, human veins do not release much NO in response to platelet-​derived mediators. Indeed, aggregating platelets constrict veins, due to the un- opposed action of vasoconstricting platelet-​derived mediators on the vascular smooth muscle. The reasons for the arteriovenous difference in NO production are not fully understood, but one consequence is that the guanylyl cyclase in venous smooth muscle is relatively upregulated and veins respond to smaller amounts of NO than do arteries or arterioles. This is of therapeutic rele- vance; NO is the active moiety of glyceryl trinitrate and other nitrovasodilators, and the low basal synthesis of endogenous NO by venous endothelium accounts, in part, for the venoselective action of these drugs. Pathophysiology Loss of NO leads to arterial vasoconstriction, has the potential to enhance platelet and white cell adhesion, and, in experimental models, may enhance atherogenesis. Several clinical conditions—​ including atherosclerosis, hypertension, hypercholesterolaemia, and diabetes—​are associated with a functional loss of NO-​ mediated effects. In the coronary vasculature, loss of NO predisposes to vasospasm and may contribute to the onset of anginal symptoms. Atherosclerotic coronary arteries constrict in response to the platelet-​derived me- diator serotonin (5-​hydroxytryptamine), whereas healthy vessels are stimulated to produce more NO and dilate. Flow-​dependent dilatation is also lost in such vessels, and the response to sympa- thetic stimulation is converted from dilatation to unopposed con- striction. Endothelial dysfunction precedes the development of overt atheroma, and there is a relationship between risk factors for ischaemic heart disease and impaired responsiveness of coronary arteries to endothelium-​dependent vasodilators. Furthermore, hypercholesterolaemia, even in the absence of angiographic evi- dence of atheroma in large vessels, is associated with abnormal endothelium-​dependent vasodilatation in coronary and peripheral arterioles. Modified low-​density lipoproteins appear to inhibit NO synthesis or accelerate its destruction, possibly by enhancing pro- duction of the superoxide anion. Basal endothelium-​dependent dilatation is also impaired in patients with essential hypertension and the degree of impair- ment increases with increasing blood pressure. It is not known whether the defect is a consequence or a cause of the raised pres- sure, but the fact that endothelial function appears to be restored by antihypertensive therapy argues in favour of such dysfunction being a response to raised pressure. Patients with diabetes show diminished endothelium-​dependent dilatation, and this defect does not reverse with treatment. Thus, patients with uncontrolled hypertension, diabetes, and hypercholesterolaemia all display defects of NO-​mediated vasodilatation and this could provide a common mechanism of vascular dysfunction in these diseases. Overproduction of NO may also contribute to disease. Bacterial endotoxin and some cytokines, including interleukin (IL)-​1 and interferon-​γ, induce expression of another NOS enzyme (inducible NOS, iNOS, or NOS2) in the endothelium, vascular smooth muscle, and inflammatory cells invading the vessel wall. Unlike the consti- tutive eNOS enzyme present in healthy endothelium, iNOS is not dependent upon agonist activation and produces large amounts of NO. In these quantities NO, either alone or in combination with superoxide, may contribute to tissue damage in addition to causing profound vasodilatation and hypotension such as that seen in septic shock. The NO pathway has been the basis for several important thera- peutic approaches. Administration of glyceryl trinitrate, a NO donor that directly activates soluble guanylate cyclase, has been a longstanding therapy (notably since the time of Alfred Nobel) for coronary ischaemia and heart failure because of its ability to produce systemic venous and coronary arterial vasodilatation, respectively. Inhibitors of phosphodiesterase-​5 (e.g. sildenafil, vardenafil, and tadalafil), the enzyme that inactivates cGMP in VSMC, which is the key downstream signalling molecule for NO, were initially developed for hypertension, but have been much more widely used for erectile dysfunction because of their effects on augmenting blood flow into the corpus cavernosum. PDE-​5 inhibitors are also used for the treatment of pulmonary hyper- tension, and ongoing studies are exploring their efficacy in pa- tients with heart failure related to primarily systolic or primarily diastolic dysfunction. Activators of soluble guanylate cyclase, the enzyme that produces cGMP, have also been developed as poten- tial therapies for systemic hypertension, pulmonary hyperten- sion, and peripheral vascular disease (see Box 16.1.1.2). Other commonly used drugs, such as statins, may also exert some of their beneficial effects through ‘pleiotropic’ mechanisms that are not primarily dependent upon cholesterol lowering but act to in- crease NO bioactivity. Prostanoids NO appears to be the dominant vasoactive factor released from endo- thelial cells under basal conditions, but it is by no means the only mediator produced. The endothelium is a rich source of prostanoids, including the vasodilators prostacyclin and prostaglandins E2 and Section 16   Cardiovascula r disorder 3248 D2 (PGE2 and PGD2). However, whereas inhibition of NO leads to profound and widespread changes in vascular tone, inhibition of prostanoid synthesis with aspirin (or other non​steroidal anti-​ inflammatory drugs, NSAIDs) does not, excepting in the renal vas- culature where dilator prostanoids do appear to be important in the regulation of basal renal blood flow: aspirin and other NSAIDs lead to vasoconstriction in the kidney, indicating tonic release of vasodilator prostanoids in this vascular bed. Furthermore, in the fetus and newborn, indometacin leads to the closure of the ductus arteriosus and a fall in cerebral blood flow suggesting a significant contribution of endothelium-​derived prostanoids to tonic vaso- dilatation in these beds, at least during development. The cerebral blood flow in adults also falls in response to indometacin, but not to aspirin and other cyclooxygenase (COX) inhibitors, and so the role of prostanoids is unclear. Vasodilator prostanoids are important in the vascular changes of inflammation, although whether these prostanoids derive exclusively from the endothelium is not known. The finding that the inhibition of COX-​II appears to be associated with increased cardiovascular risk is important and suggests that the balance of prostanoids in the vessel wall, and between endothelium and platelets, is a key determinant of the ‘stickiness’ of the endothe- lium to platelets and other circulating cells. Hyperpolarizing factors An endothelium-​derived hyperpolarizing factor has been identi- fied in some animal and human blood vessels. Hyperpolarization of vascular smooth muscle cells leads to a fall in calcium entry and vascular relaxation. Increasing evidence suggests that endothelium-​ dependent hyperpolarization may be particularly important in small arteries and arterioles. The chemical identity of endothelium-​ derived hyperpolarizing factor has not been clearly established, but products of activity of cytochrome P450, the cannabinoid anandamide, and the potassium ion have all been suggested as possible candidates. Recent data also suggests that the C-​type natri- uretic peptide accounts for this activity in some vessels. A picture is emerging that endothelium-​derived hyperpolarizing factor is not a single entity, but rather that hyperpolarization is a mechanism utilized by different mediators that vary between vessels. In add- ition, direct contact through gap junctions also provides a means for endothelial cells to hyperpolarize smooth muscle cells. Without specific inhibitors, it is not yet clear what role the variations in endo- thelial cell hyperpolarization of smooth muscle cells plays in human disease. Vasoconstrictors Although the predominant background influence of the endothe- lium is dilator, important vasoconstrictor factors are also synthesized and released. Endothelin The endothelins are a family of potent vasoconstrictor peptides of 21 amino acids, which are closely related to the snake-​venom toxin of the Israeli burrowing asp (Atractaspis engaddensis). Three types of endothelin have been described—​endothelin 1, 2, and 3—​and there are at least two endothelin receptors in human blood ves- sels, the endothelin A  and endothelin B receptors. Endothelins vasoconstrict and can promote the growth of vascular smooth muscle cells. Effects are mediated in part through the stimulation of increases in calcium and in part through calcium-​independent mechanisms, including activation of protein kinases. Endothelin 1 is synthesized from ‘big endothelin’ within human endothelial cells (Fig. 16.1.1.7). It is a potent and long-​ lasting constrictor of human blood vessels, and causes widespread vasoconstriction, hypertension, and sodium retention when in- fused into healthy volunteers. Antagonists of the endothelin A  receptor cause vasodilatation and can lower blood pressure, indicating that there is a tonic synthesis and release of endothelin A.  Several studies suggest that there may be important inter- actions between the sympathetic nervous system, the renin–​ angiotensin system, and the endothelin system, and that these may act in concert to control constrictor tone, with the endothelin system providing a slowly modulating background constrictor tone. Endothelins also exert an important influence on sodium reabsorption in the kidney. Although activation of endothelin B receptors on vascular smooth muscle causes constriction, activation of endothelial endothelin B receptors leads to the generation of vasodilator prostanoids and/​ or NO, hence endothelin can also produce transient vasodilatation in some circumstances. Binding of endothelin to endothelin B re- ceptors also seems to be important to clear the peptide from the circulation. Stimuli for endothelin production include thrombin, insulin, ciclosporin, adrenaline, angiotensin II, cortisol, various proinflammatory cytokines, hypoxia, and shear stress. The concentrations of endothelins circulating in plasma are low and may not reflect local concentrations achieved within the vessel wall, making it difficult to interpret the elevated values reported in many conditions. Nonetheless, activation of the endothelin system has been implicated in the pathogenesis of certain cardiovascular conditions. For example, a role for endothelin in the pathogenesis of vasospasm associated with subarachnoid haemorrhage and some types of renal ischaemia is suggested by experiments in animals. In addition, the increased production of endothelin has also been clearly implicated in the pathogenesis of a very rare form of secondary sys- temic hypertension caused by malignant haemangioendothelioma, a vascular tumour characterized by intravascular proliferation of Box 16.1.1.2  PDE5 inhibitors, cGC activators, and ADMA The pulmonary vasculature seems to be particularly sensitive to NO and the inhibition of NO synthesis causes pulmonary hypertension. These observations have been utilized therapeut- ically in the form of inhaled NO treatment, and amplification of NO signalling by inhibition of cGMP phosphodiesterase with sildenafil (see Chapter 16.15.2). Levels of VSMC cGMP are also increased by drugs that increasing the activity of soluble guanylate cyclase (sGC), either by activating the enzyme independently of the haem group (which can be oxidized or lost in pathophysio- logical states), or by stimulating the activity of the intact enzyme (e.g. riociguat). A naturally occurring amino acid, asymmetric dimethylarginine (ADMA), acts as an important endogenous inhibitor of NO synthesis, and the concentration of ADMA in blood is a predictor of cardiovascular risk. Accumulation of ADMA may be important in renal failure, providing a possible mechanism to link failing renal function with increased risk of atherothrombotic complications. 16.1.1  Blood vessels and the endothelium 3249 atypical endothelial cells. In this condition, the degree of hyperten- sion correlates with plasma levels of endothelin, and when the tu- mour is removed blood pressure and plasma endothelin levels fall. The role of endothelin in the pathogenesis of pulmonary hyper- tension and congestive heart failure has been studied most intensely. In pulmonary hypertension, selective ETA antagonists lower pul- monary vascular pressure in patients with advanced disease and have been approved for clinical use. However, the role of endothelin receptor antagonists in treating congestive heart failure is less clear. A substantial body of preclinical evidence indicates that selective ETA or non​selective ETA/​ETB antagonists prevent ventricular re- modelling and prolong survival in models of myocardial injury. However, although short-​term studies with endothelin antagonists produced beneficial hemodynamic effects in heart failure patients, long-​term studies failed to show significant effects on morbidity or mortality, and endothelin antagonists are not presently approved for heart failure. Angiotensin-​converting enzyme Angiotensin-​converting enzyme (ACE) is located primarily on the luminal surface of the endothelium (see Fig. 16.1.1.5). This en- zyme converts angiotensin I to angiotensin II and also metabolizes bradykinin to inactive products. The pulmonary vasculature pro- vides the largest area of endothelium and is important in the regulation of circulating levels of angiotensin II, but the activity of endothelial ACE in systemic vessels may be more important in determining the final concentrations of angiotensin II and brady- kinin that reach the blood vessel wall. Furthermore, endothelial cells also have the ability to synthesize renin and its substrate. It seems, therefore, as though the enzymatic machinery for a complete renin–​ angiotensin system is present within the vessel wall. The activity of the renin–​angiotensin system is clearly important in cardiovascular diseases including hypertension and heart failure, but the relative importance of local, compared with systemic, regu- lation of angiotensin II production is not yet clear. Furthermore, the full clinical significance of bradykinin metabolism by endothelial ACE has yet to be determined. It has been demonstrated that at least part of the vasodilator action of ACE inhibitors in certain isolated blood vessels is due to accumulation of bradykinin, which stimu- lates NO synthesis. Bradykinin and many other vasoactive pep- tides (e.g. substance P and natriuretic peptides) are broken down by the metalloendopeptidase, neprilysin (particularly in the lung and kidney). Neprilysin is the target of neprilysin inhibitor drugs such as sacubitril, which has been combined with valsartan (an angiotensin II receptor antagonist) for the treatment of heart failure. Prostanoids The endothelium synthesizes thromboxane and the unstable pros- taglandin endoperoxides PGG2 and PGH2. Overproduction of constrictor prostanoids by the endothelium has been implicated in animal models of diabetes and hypertension, but the significance of these findings for human disease remains uncertain. Reactive oxygen species Production of reactive oxygen species (ROS) influences blood vessel physiology by direct interactions with nitric oxide, and by modu- lating redox-​sensitive pathways such as gene expression and activity of key proteins by post-​translational oxidative modification. ROS such as the superoxide anion (O−2) are synthesized within the vas- cular wall by multiple enzyme systems within endothelial, vascular smooth muscle, and inflammatory cells (e.g. macrophages and neu- trophils). A major source are the NADPH oxidases that can be de- fined by at least five classes of a catalytic subunit termed Nox1–​5. The Nox2 enzyme typified by the neutrophil NADPH oxidase (but also expressed in endothelial cells and other inflammatory cells) is a major source of vascular superoxide. Vascular smooth muscle cells, where Nox1 and Nox4 predominate, also contribute. Stimulation by angiotensin II increases superoxide generation by Nox2 NADPH oxidases, and is a key feature of vascular pathophysiology. Other im- portant sources of ROS are mitochondria, xanthine oxidoreductase, and NOS. In addition to its important vasodilator properties, NO acts as a free radical scavenger. As is characteristic for such agents, NO itself is also a free radical (it has an unpaired electron in its outer orbit), and as such, reacts readily with other free radicals and ROS, re- sulting in the formation of the reactive nitrogen species peroxynitrite (ONOO−), and with other ROS to generate inorganic nitrite and nitrate (NO3−) in biological systems. Under certain physiological conditions (e.g. hypoxia), NO can be regenerated from nitrite by ni- trite reductases such as xanthine oxidoreductase, or haemoglobin. Lys-Arg Lys-Arg C N Trp-Val Big endothelin Endothelin-1 Activation of endothelin A and endothelin B receptors Dibasic-pair-specific endopeptidase Endothelin-converting enzyme Fig. 16.1.1.7  Endothelin-​1 (ET-​1), a cyclic (Cys1–​Cys15 and Cys3–​Cys11) 21-​amino acid peptide, is synthesized within the vascular endothelium as the product of an ‘inactive’ 39-​amino acid precursor known as ‘big ET-​1’, a conversion catalysed by a specific membrane-​bound zinc metalloproteinase endothelin converting enzyme (ECE). Big ET-​1, in turn, is the catalytic product of a larger (203 amino acids) precursor polypeptide termed ‘preproET-​1’ (a conversion that is believed to be mediated by a ‘furin-​like’ protease). The ECE-​mediated conversion of big ET-​1 to mature ET-​1 is an essential step in the expression of full biological activity. Upon release from the vascular endothelium, ET-​1 interacts with the underlying smooth muscle cells resulting in vasoconstriction. This action is mediated by two distinct G-​protein-​coupled receptors, ETA and ETB. Although the predominant action of ET-​1 is that of a vasoconstrictor, this effect is regulated by the concomitant release of vasodilatory factors (e.g. PGI2, NO) by the action of ET-​1 on endothelial ETB-​receptors. Although such an action tempers the contractile actions of ET-​1, it is postulated that endothelial dysfunction (e.g. diminished ability to synthesize and/​or release NO such as is seen in hypertension, atherosclerosis) results in aberrant ET-​mediated vasoconstrictor tone due to a loss in concomitant endothelial regulation. Section 16   Cardiovascula r disorder 3250 eNOS can also generate ROS (see Fig. 16.1.1.6b). This aspect of eNOS function, termed ‘eNOS uncoupling’, occurs when levels of the cofactor for NOS, tetrahydrobiopterin (BH4), are lowered due to oxidation or reduced biosynthesis. Uncoupling is also caused by conformational changes in eNOS due to oxidative modification of cysteine residues on the enzyme by glutathionylation. The posi- tive feedback loop created for generation of ROS is an important pathway resulting in endothelial dysfunction and other alterations in vascular redox signalling. Regulation of platelet function and haemostasis The endothelium synthesizes and releases prothrombotic and antithrombotic factors. However, healthy endothelium presents a thromboresistant surface, indicating that the antithrombotic factors predominate under basal conditions. Platelets Endothelial cells inhibit the aggregation and adhesion of plate- lets, and disaggregate aggregating platelets. Two mediators are of particular importance: NO and prostacyclin (or PGE2 in the microvascular endothelium). These act synergistically through different second messenger systems: cGMP for NO and cAMP for prostacyclin. Thiols and sulphydryl-​containing molecules react with NO to produce more stable adducts, including nitrosocysteine, nitrosoglutathione, nitrosoalbumin, and even nitrosohaemoglobin. Some of these compounds are formed in vivo and may enhance the antiplatelet effects of endothelium-​derived NO. Furthermore, interaction between NO and tissue plasminogen activator leads to the formation of nitroso-​tissue plasminogen activator, a molecule with fibrinolytic, antiplatelet, and vasorelaxant properties. It is not yet clear how important these NO adducts are in human physiology or pathophysiology. Deficient production of NO has been implicated in a wide variety of cardiovascular diseases (see ‘Nitric oxide’ section earlier), and ab- normalities of prostanoid synthesis occur in experimental models of atherosclerosis and diabetes. In the presence of a quiescent healthy endothelium, loss of basal NO alone does not lead to significant sys- temic platelet activation. However, loss of NO and prostacyclin at sites of endothelial damage, dysfunction, or activation promotes the formation of platelet aggregates and may contribute to thrombosis and vessel occlusion. In animals, stenosed endothelium-​denuded vessels lead to cyclical variations in flow as platelets stick to the vessel wall and release vasoactive and proaggregant mediators. If this also occurs in human vessels in vivo, it might be an important mech- anism of vasospasm and thrombosis. Under basal conditions the endothelium inhibits platelet activa- tion, but in response to certain stimuli, proaggregant, proadhesive mediators may be synthesized and released. Unstable prostaglandin endoperoxides activate platelets, platelet activating factor may be produced, and von Willebrand factor—​which is synthesized and stored within endothelial cells—​increases platelet adhesion. These changes occur in response to inflammatory mediators and may also result from endothelial ‘injury’, such as those occurring during cor- onary artery angioplasty or stent implantation. Coagulation Heparan sulphate is a glycosaminoglycan closely related to heparin, but less potent, which is found on the surface of endothelial cells. Antithrombin III is also expressed on the endothelial cell surface and, together with heparan sulphate, provides a mechanism for binding and inactivating thrombin. In addition, endothelial cells participate in the activation of the anticoagulant protein C, and se- cretion of protein S and thrombomodulin that is found on the cell surface. In the quiescent state, expression of anticoagulant factors pre- dominates, but when activated the endothelium may promote co- agulation. Receptors for clotting factors appear on the endothelial surface, von Willebrand factor is secreted, and tissue factor—​the principal cellular initiator of coagulation—​is expressed. Bacterial endotoxin, inflammatory cytokines, and glycosylated proteins acti- vate the endothelium and shift the balance in favour of coagulation. This may occur in response to infection, inflammation, or endothe- lial injury. Circulating levels of von Willebrand factor are increased in some patients with diabetes or hypertension. Fibrinolysis The endothelial cell surface has a fibrinolytic pathway. Urokinase and tissue plasminogen activator are secreted and there are spe- cific binding sites for plasminogen activators and plasminogen. Thrombin, adrenaline, vasopressin, and stasis of blood may be physiological stimuli for the release of tissue plasminogen activator from human endothelium. Plasminogen activator inhibitor 1 is also synthesized and bound by endothelium, providing a pathway for local inhibition of the fi- brinolytic system. Under basal conditions fibrinolysis is dominant, but the balance may be altered by a variety of local and circulating factors, including inflammatory cytokines and the atherogenic par- ticle lipoprotein(a), which inhibits plasminogen binding and hence plasmin generation. In the presence of atherosclerosis, the fibrino- lytic properties of the endothelium are diminished. Other important aspects of vascular and endothelial biology Cellular adhesion The resting endothelium prevents cells from adhering fully to the vessel wall, but allows leucocytes to ‘roll’ along its surface. The regulation of rolling, adhesion, and migration is governed largely by specialized glycoproteins known as cell adhesion molecules, which are expressed in varying amounts on the endothelial cell surface and interact with complementary adhesion molecules on circulating cells. Endothelial-​leucocyte adhesion molecule 1 (ELAM-​1, also known as E-​selectin), vascular adhesion molecule 1 (VCAM-​1), intercellular adhesion molecule 1 (ICAM-​1), and P-​selectin (also known as GMP-​140) are all expressed on cytokine-​ activated endothelium. The degree of expression and the type of adhesion molecules expressed determines the ‘stickiness’ of the endothelium for different cell types. Expression of adhesion molecules is an important mechanism of cellular adhesion during inflammation and is also important in 16.1.1  Blood vessels and the endothelium 3251 recruitment of T cells and monocytes in atherosclerosis. Increased expression of E-​selectin is seen in the coronary arteries of trans- planted hearts, and has been implicated in the rapid development of atherosclerosis in these vessels. NO and prostacyclin inhibit the adhesion of white cells to the endothelium and this effect may be mediated by changes in the expression or configuration of adhesion molecules. Certain endothelial cell adhesion molecules are shed into the plasma: changes in their concentration have been detected in a variety of cardiovascular diseases, but the significance of this is uncertain. Proinflammatory cytokines Cytokines are released from activated leucocytes in response to in- fection and immunological stimulation and are also produced by the vessel wall itself; IL-​1, IL-​6, and IL-​8, and colony stimulating factors are synthesized by endotoxin-​stimulated endothelial cells, and tumour necrosis factor (TNF) by human smooth muscle cells. A  large number of cytokines and chemokines alter endothelial functions, upsetting the balance of vasoactive mediators, altering thrombotic activity and the expression of adhesion molecules, or initiating apoptosis (programmed cell death). IL-​1 and some other proinflammatory cytokines alter the synthesis of NO (see ‘Nitric oxide’ section earlier) and a variety of prostaglandins; enhance the generation of thrombin, platelet activating factor, von Willebrand factor, and plasminogen activator inhibitor; alter endothelial per- meability; increase expression of ICAM-​1 and VCAM-​1; and may also cause endothelial cell damage and death. These findings are of direct relevance to the vascular changes occurring in inflammation and sepsis, and might also provide a link between acute or chronic immunological stimulation (e.g. infection) and the development of cardiovascular disease, including atherosclerosis or acute cardiovas- cular events. More recently it has been recognized that components of the innate immune pathway, such as Toll-​like receptors (TLRs), are expressed by cells in the vascular wall and play a role in the patho- genesis of cardiovascular disease. These receptors recognize spe- cific, highly conserved structural motifs in non​host pathogens, resulting in rapid activation of a coordinated innate immune re- sponse. However, TLRs may also be activated by damage-​associated molecular pattern molecules such as proteins released by injured or necrotic cells (e.g. heat shock proteins, HMBG1), and/​or modified by oxidation (e.g. oxidized LDL), by DNA released from the nucleus, or proteins that have been glycated in diabetes (advanced glycation end products, AGE), that are recognized by RAGE, the specific re- ceptor for AGE. These innate immune mechanisms are important in the vascular wall in atherosclerotic plaques or in the myocardium following ischaemic injury, by initiation and amplifying the patho- logic inflammatory response. Cell growth and angiogenesis The endothelium of healthy differentiated vessels inhibits prolif- eration of the underlying smooth muscle. Endothelium-​derived vasodilator, antiplatelet, and antithrombotic mediators (e.g. NO, prostacyclin) tend to inhibit the growth of vascular smooth muscle cells, whereas vasoconstrictor and prothrombotic mediators (e.g. endothelin, angiotensin) tend to promote it. Thus, the basal state of the endothelium, in which dilatation and thromboresistance pre- dominates, also prevents the growth of smooth muscle. The heparin-​ like molecules prevent cell growth and molecules similar or identical to platelet-​derived growth factor (PDGF) and fibroblast growth factor are endothelium-​derived growth promoters. Others such as transforming growth factor β (TGFβ), produced by endothelial cells, may either inhibit or promote cell growth, and the precise role of this molecule in vivo is unclear. The basal antiproliferative effects of the endothelium may retard the development of atherosclerosis and intimal proliferation. In addition to affecting the growth of underlying smooth muscle, endothelial cells are essential for the formation of new blood ves- sels. The ability of endothelial cells to initiate the formation of new vessels (angiogenesis and vasculogenesis; Fig. 16.1.1.8) is retained in adults, but the only place this occurs physiologically to any great extent is in the female reproductive tract. However, angiogenesis occurs in a wide range of disease states including atherosclerosis, rheumatoid arthritis, and tumour growth, and during wound Fig. 16.1.1.8  Formation of new blood vessels. Endothelial cells grown in a matrix (Matrigel) form tube-​like structures. The right-​hand panel shows the effect of inhibiting angiogenic signals such as vascular endothelial growth factor (VEGF). Reprinted from Biochemical and Biophysical Research Communications, Vol 308, Issue 4, Smith CL et al., Dimethylarginine dimethylaminohydrolase activity modulates ADMA levels, VEGF expression, and cell phenotype, pp. 984–​89. Copyright (2003), with permission from Elsevier. Section 16   Cardiovascula r disorder 3252 healing or in response to ischaemia. Positive and negative regu- lators of angiogenesis have been identified and a wide variety of cytokines, growth factors, and local autacoids can act alone or in concert to promote endothelial cell growth, migration, and tube formation. Of particular interest is VEGF, a growth factor produced by smooth muscle cells in response to hypoxia, inflammatory cyto- kines, and certain other growth factors. There is good evidence that VEGF can promote angiogenesis in a variety of animal models and in humans. Therapeutics that inhibit angiogenesis by targeting the VEGF pathway have shown clinical benefit in diabetic retinopathy and certain cancers. Intriguingly, it appears as though VEGF can increase the production of NO by endothelial cells, and this may be one of the effector molecules mediating some of the actions of this growth factor. In order to form endothelial tubes through tis- sues (i.e. angiogenesis), endothelial cells must degrade matrix and they are capable of synthesizing and releasing a variety of matrix metalloproteinases. Some of these matrix metalloproteinases may, in turn, affect endothelial function by regulating cell attachment, proliferation, and migration. Failure of endothelial cells to initiate appropriate angiogenesis in response to ischaemia may lead to tissue hypoxia, while excessive or inappropriate angiogenesis may contribute to a sustained inflammatory response in the vessel wall, disrupt vessel wall architecture, or lead to haemorrhage into athero- sclerotic plaques. Transport and metabolism The endothelium presents a permeability barrier for molecules in the bloodstream. Transfer of molecules from the bloodstream into the vessel wall across the endothelium can occur by transport through the endothelial cells or between them. The junctions between endo- thelial cells are maintained by specialized molecules, including cadherins, and are actively regulated. Transport between cells occurs when endothelial cells contract to leave intercellular gaps. This is an important mechanism for formation of localized oedema. Transport through cells occurs by transcytosis and is an important mech- anism for the passage of some macromolecules, including insulin. In addition, specialized channels for transport of water have been identified—​the aquaporins. The endothelium is intimately involved in lipid metabolism. Lipoprotein lipase is bound to proteoglycans on the endothelial cell surface, and receptors for low-​density lipoproteins are present in varying amounts. In quiescent endothelium, lipoprotein lipase is ac- tive, but there are few low-​density lipoprotein receptors, indicating that healthy endothelium provides a barrier for the entry of low-​ density lipoproteins into the vessel wall. However, under conditions in which a low-​density lipoprotein is taken into the endothelium, modification by oxidation occurs and this step may stimulate atherogenesis. Endothelial-​derived microvesicles Endothelial cell-​derived particles or cell fragments were first de- tected as presumed evidence of damaged or dead endothelial cell fragments (exosomes, microparticles, or apoptotic bodies). However, endothelium-​derived microvesicles have now been iden- tified as a potential biomarker of endothelial function and cardio- vascular disease, reflecting biological processes. Microvesicles are submicron-​sized particles shed from the plasma membrane of cells in response to cell activation, cell damage, or apoptosis. The number of circulating microparticles appears to be increased in patients with cardiovascular disease such that it is possible that they play a role in pathogenesis, and it has been proposed that they are a biomarker of endothelial function and vascular health. Microvesicles contain proteins, active lipids, and nucleic acids that may provide additional biological and pathophysiological in- formation, since these components are dependent on the nature and cause of microvesicle shedding. For example, microRNAs (e.g. miR-​ 126), which are endogenously expressed small non​coding RNAs that regulate gene expression at the post-​transcriptional level, have been implicated in regulating endothelial cell function and angio- genesis. Microvesicles are also a vehicle for cell-​to-​cell transfer of these signalling molecules, for example, between endothelial cells, platelets, and inflammatory cells such as monocytes. Specificity of cell-​to-​cell communication is mediated by cell surface proteins on microvesicles that are ligands for receptors on target cells. The adventitia and perivascular adipose tissue Nerves supplying the vessel wall enter through the adventitia into the media to provide a key influence on the contraction of vas- cular smooth muscle cells. The sympathetic nervous system is, of course, of prime importance in determining the contractile state of the vessel. In addition, cholinergic innervation influences some vas- cular beds, as do purinergic nerves. Pharmacological observation suggests that not all vessels are equally affected by denervation or interruption of specific neuronal influences. Resistance vessels and capacitance veins seem to be particularly regulated by sympathetic tone, and blockade of the sympathetic system causes not only a fall in arterial pressure but also major venous dilatation that leads to postural hypotension. In the brain, local neuronal projections have been implicated in providing a link between cerebral activation and the consequent increase in blood flow. Lymph vessels also permeate the adventitia of large vessels and are important to remove fluid. A network of small blood vessels, the vasa vasorum, is found in the adventitia of larger blood vessels. Vasa vasorum are found mainly in vessels that have relatively thick walls with many layers of vascular smooth muscle cells. An increase in vasa vasorum may be taken as an indication of vessel wall hyp- oxia. Stripping the vasa vasorum in large veins may contribute to both smooth muscle and endothelial dysfunction and damage, and, in the arterial system, can stimulate smooth muscle cell replication and promote an atherogenic type of lesion. The vasa vasorum re- sponds to vasoactive agents, but the pharmacology of these vessels is relatively poorly understood. Infiltration of the adventitia with in- flammatory cells may be an important feature of atherogenesis (see Chapter 16.13.1), and perivascular fat may interfere with vascular function through the generation of adipokines and inflammatory cytokines; this process has been implicated in the pathogenesis of cardiovascular disease in obese individuals. The adventitia surrounding the vascular wall also contains large numbers of adipocytes, forming the perivascular adipose tissue (PVAT). Although PVAT is typically in continuity with other sur- rounding adipose tissue, PVAT has particular cellular composition and pathophysiological roles that are distinct from other adipose tissue depots such as subcutaneous and visceral adipose tissue me- diated by adipocytokines. PVAT has anticontractile properties on small vessels due to a variety of vasoactive molecules produced in this tissue, such as 16.1.2 Cardiac physiology 3253 Rhys D. Evans, Kenn 16.1.2 Cardiac physiology 3253 Rhys D. Evans, Kenneth T. MacLeod, Steven B. Marston, Nicholas J. Severs, and Peter H. Sugden 16.1.2  Cardiac physiology 3253 H2S, H2O2, and adipocytokines. Other infiltrating inflammatory cell types including T cells and macrophages have an equally im- portant contribution. Most adipocytokines produced by the cells in PVAT have distinct paracrine effects on the vasculature. These can be proinflammatory/​pro-​atherogenic (e.g. resistin, IL-​6, TNFα, MCP-​1) or anti-​inflammatory/​antiatherogenic (e.g. adiponectin, omentin). The balance between pro-​and antiatherogenic adipokines is influenced by conditions such as obesity and diabetes. In human PVAT, PPAR​γ signalling is a major regulator of adipocytokine pro- duction, and its dysregulation in diabetes, obesity, and insulin resist- ance shifts the balance towards the production of proinflammatory mediators. Until recently, PVAT was considered to have mainly det- rimental effects on vascular homeostasis. However, recent evidence suggests that it ‘senses’ proatherogenic changes in the underlying vascular wall (e.g. changes in ROS production), and can modify its biosynthetic profile by activating PPAR​γ signalling, leading to in- creased production of ‘antioxidant’ adipokines such as adiponectin and reduced production of ‘pro-​oxidant’ adipokines such as IL-​6. Therefore, increasing evidence suggests that healthy PVAT may provide local defence mechanisms against vascular injury, and its biosynthetic profile is regulated by complex interactions between PVAT, the underlying vascular wall, and systemic factors. FURTHER READING Allt G, Lawrenson JG (2001). Pericytes: cell biology and pathology. Cells Tissues Organs, 69, 1–​11. Armulik A, et al. (2005). Endothelial/​pericyte interactions. Circ Res, 97, 512–​23. Asahara T, et al. (1997). Isolation of putative progenitor endothelial cells for angiogenesis. Science, 275, 964–​6. Atkins GB, Jain MK (2007). 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Cardiovascular biology of the asymmetric dimethylarginine:dimethylarginine dimethylaminohydrolase pathway. Arterioscler Thromb Vasc Biol, 24, 1023–​30. Vane JR, et al. (1998). Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol, 38, 97–​120. 16.1.2  Cardiac physiology Rhys D. Evans, Kenneth T. MacLeod, Steven B. Marston, Nicholas J. Severs, and Peter H. Sugden ESSENTIALS The function of the heart is to provide the tissues of the body with suf- ficient oxygenated blood, substrates and metabolites, and removal of waste products, to meet the moment-​to-​moment needs as dictated by metabolism, physical activity and postural and emotional changes. Functional anatomy of the cardiac myocyte Cardiac myocytes are the contractile cells of the heart and consti- tute the bulk of heart mass. There are structural and functional dif- ferences between the myocytes of the ventricles, the atria, and the conduction system: ventricular myocytes are elongated cells, packed with myofibrils (the contractile apparatus) and mitochondria (for ATP production). Myofibrils are repeating units (sarcomeres) made up of thin actin filaments anchored at the Z-​discs at either end of the sarcomere, and thick myosin filaments which interdigitate and interact with the thin filaments. Contraction results from sarcomere shortening produced by the ATP-​dependent movement of the thin and thick filaments relative to one another. Transverse (T-​) tubules facilitate extracellular Ca2+ entry into the cytoplasm (sarcoplasm) for contraction and signalling. Atrial myocytes differ from ventricular Section 16  Cardiovascular disorders 3254 myocytes, having few T-​tubules but more abundant caveolae. Myocytes of the conduction system are small and possess only a rudimentary myofibrillar structure. Myocytes are attached to adjoining cells and to the extracellular matrix to allow transmission of force. At some regions of contact (the intercalated discs), specialized structures (the gap junctions) contain channels which form contiguous electrical connections between a myocyte and its neighbours and allow passage of ions and small molecules. The sarcoplasmic reticulum surrounds the myofibrils and is a reservoir of the Ca2+ which participates in myofibrillar contraction. T-​tubules are deep, finger-​like indentations of the sarcolemma that abut the sarcoplasmic reticulum at junctional regions in register with the Z-​discs of the superficial sarcomeres. Cardiac action potential A potential difference (the membrane potential) is maintained across the plasma membrane (sarcolemma) such that the inside of the cell is negative compared to the outside by about 90 mV. This is caused largely by the efflux of K+ down its concentration gradient from the cell through K+ channels and until the electronegative force retaining K+ in the cell balances the tendency for efflux. When a myocyte is electrically excited, Na+ channels open and Na+ enters the cell down its own concentration gradient, producing a rapid inward current and depolarizing the cell towards its equilibrium poten- tial: the initial phase (phase 0) of the action potential. As the myocyte depolarizes, L-​type Ca2+ channels in the sarcolemma and T-​tubules open and Ca2+ enters the cell through its concentration gradient. A brief K+ efflux from the cardiomyocyte is associated with a small, transient repolarization (phase 1). The Na+ channels close rapidly, but the L-​type Ca2+ channels remain open for longer, maintaining depolar- ization: phases 1 and 2 of the action potential, where the tendency to depolarize is balanced by repolarizing outward current flow carried by a variety of K+ channels. The membrane potential in phase 2 is rela- tively stable and hence this phase is also known as the plateau phase. Ca2+ entry in close apposition to the junctional sarcoplasmic re- ticulum causes its Ca2+-​release channels (ryanodine receptors) to open, discharging about half of the sarcoplasmic reticulum Ca2+ res- ervoir into the cytoplasm (Ca2+-​induced Ca2+-​release). This increase in Ca2+ concentration (the Ca2+ transient) is sensed by a Ca2+-​binding protein (troponin C) that is a component of the thin filament regu- latory complex (the troponin–​tropomyosin complex). This initiates myofibrillar contraction, which starts about halfway through phase 2. As the L-​type Ca2+ channels close, the outward current flow through K+ channels predominates and the myocyte repolarizes towards the K+ equilibrium potential (phase 3). Ca2+ is removed from the cyto- plasm and returned to the sarcoplasmic reticulum by active transport mediated by the sarcoplasmic/​endoplasmic Ca2+-​ATPase (SERCA2). Ca2+ is also expelled from the cell by the plasma membrane Na+/​ Ca2+ exchanger (NCX), which is electrogenic (three Na+ exchanged for one Ca2+) and tends to prolong the plateau phase. The behaviour of the Na+/​Ca2+ exchanger is complex because—​depending on the Na+ and Ca2+ concentrations and the membrane potential—​it can reverse, thus mediating Ca2+ entry and repolarization. This occurs at depolarized potentials, and more so when intracellular Na+ is in- creased. In phase 4, repolarization is complete and the myocyte is electrically quiescent, with membrane potential maintained by the sodium-​potassium pump, until the next depolarization. Cardiac pacemaker and regulation of contractility The sinoatrial node (‘pacemaker’) in the right atrium contains modi- fied myocytes that exhibit a different form of action potential from ventricular myocytes because of differences in the expression of ion channels. The cell depolarizes spontaneously and gradually during phase 4 until an action potential is produced. This partly results from the presence of hyperpolarization-​activated cyclic nucleotide-​gated channels which are absent from ventricular myocytes and which open at negative voltages and carry an inward-​depolarizing Na+ current (‘funny’ current). Depolarization is then mediated by Ca2+ channel opening. The stimulus is transmitted in a controlled manner via the conduction system (AV node; His–​Purkinje system) to all re- gions of the heart. Whole organ physiology The strength of cardiac contraction is both an intrinsic function of the cardiomyocyte, dependent on the initial fibre length (precontraction loading), and on the intrinsic ‘contractility’ of the heart. Cardiac con- tractility is controlled largely by the sympathoadrenal system and the parasympathetic nervous system. β-​Adrenergic stimulation increases the tendency of the L-​type Ca2+ channel to open (positive inotropism). β-​Stimulation also increases relaxation (positive lusitropism) by stimulation of SERCA2 and an increased rate of release of Ca2+ from the troponin complex (relaxation being an energy-​dependent pro- cess). The positive chronotropic (rate) effects of β-​stimulation result from increased hyperpolarization-​activated cyclic nucleotide-​gated channel opening, causing an increased frequency of pacemaker de- polarization. These effects are all opposed by the (cholinergic) mus- carinic receptors of the parasympathetic nervous system. The energy requirements of the heart during rest and exertion are influenced by ventricular volume, outflow resistance (hence blood pressure), venous return, and the activity of the autonomic nervous system. An increase in ventricular volume increases wall tension during contraction, and an augmented myocardial oxygen supply is then required to maintain the same systemic blood pressure and stroke volume. The normal integration of the venous return, heart rate, stroke volume, and arterial blood pressure ensures that there is an adequate supply of oxygen and nutrients to the tissues. The activities of the sympathetic and parasympathetic nervous systems contribute to the adjustment of cardiac performance to immediate needs—​the former by increasing heart rate and myocardial contractility during exertion and emotion, the latter by maintaining a relatively slow heart rate at rest. Parasympathetic (vagal) fibres in the heart are distributed mainly to the sinoatrial node and the atria; sympathetic innervation is to both the atria and the ventricles. There is a normal diurnal variation in autonomic function, with an increased sympathetic outflow in the mornings, soon after wakening. Coronary blood flow occurs largely in diastole. It is autoregulated to meet myocardial metabolic requirements and may increase five-​ or sixfold during strenuous exercise. The inner layers of the ven- tricular muscle normally receive a slightly greater blood flow than the outer layers. Haemodynamic and ventilatory responses during exercise take 2–​3 min to equilibrate and adjust to an increased work- load and reach a new steady state. Regular exercise to at least 60% of maximal heart rate about three times a week improves effort toler- ance. Measurement of the cardiovascular response to exercise pro- vides an objective assessment of cardiac function. 16.1.2  Cardiac physiology 3255 Introduction The function of the heart is to pump sufficient oxygenated blood containing nutrients, metabolites, and hormones to meet moment-​ to-​moment metabolic needs and preserve a constant internal envir- onment. The heart has two essential characteristics—​contractility and rhythmicity. The nervous system and neurohumoral agents modulate relationships between the venous return to the heart, the outflow resistance against which it contracts, the frequency of con- traction, and its inotropic (contractile) state; there are also intrinsic cardiac autoregulatory mechanisms. An understanding of the mo- lecular mechanisms governing cardiac cell behaviour and the mech- anical, electrical, and hormonal control of the heart at a whole organ level is essential for the understanding of cardiac pathophysiology. Cardiac myocytes Cardiac myocytes (cardiomyocytes) are the contractile cells of the heart, and include ventricular and atrial myocytes, as well as cells specialized to provide the electrical impulse and conduction system. Myocytes constitute the bulk of the cellular volume, but because they are large cells they are fewer in number, being outnumbered by endothelial cells, smooth muscle cells of the vasculature, and fibro- blasts. Replication of ventricular myocytes is believed to decrease rapidly after birth in mammals, and occurs at an extremely low rate in adults, resulting in most cells being terminally differentiated; this is less clear for the atrial myocyte. Terminal differentiation has im- portant consequences for the heart in terms of its limited ability to survive haemodynamic insults or stresses, but also means that the myocardium is essentially resistant to malignant transformation. Morphology of the ventricular myocyte and its contractile machinery The ventricular myocyte is a large elongated cell (100–​150 µm long and 20–​35 µm wide) and is packed with striated myofibrils (the contractile elements) that alternate with rows of mitochon- dria (Fig. 16.1.2.1). Each myofibril is roughly cylindrical (2–​3 µm in diameter), stretches the length of the cell, and is anchored at each end in a fascia adherens junction. The myofibril comprises sarcomeres arranged in series. Sarcomeres consist of two arrays of filaments:  thin filaments, comprised predominantly of the protein actin, interdigitated with thick filaments of myosin. The characteristic striated appearance arises from the organization of these myofilaments within the myofibril (Fig. 16.1.2.1). The thick mito Sarcomere M line I band I band A band H zone Actin (thin filament) Z Z Myosin (thick filament) 1 μm Fig. 16.1.2.1  Upper panel: electron micrograph of ventricular myocyte showing the structure of the myofibrils. Portions of two myofibrils are shown in the field, with a row of mitochondria (mito) between. Lower panel: diagrammatic representation of the arrangement of the thick and thin filaments in relation to the striated pattern seen in microscopy. Section 16  Cardiovascular disorders 3256 filaments are confined to the A-​band at the centre of the sarcomere; the thin filaments extend out from either side of the Z-​disc (Z-​ line), crossing the I-​band, and penetrate partially into the A-​band, where they overlap and interact with the thick filaments. Each Z-​to Z-​disc repeat constitutes a sarcomere, and the distance between consecutive Z-​discs (the sarcomere length) is a measure of the con- tractile state of the myofibril. At the centre of the sarcomere lies the M-​line. Each myofibril contains 70–​80 sarcomeres. Myocytes have an irregular ‘branched’ morphology; through these branches, each ventricular myocyte typically connects to 10 or more of its neigh- bours to form the three-​dimensional branching, syncytium-​like structure of the myofibre. Structure of the contractile apparatus Thick filaments The myosin molecule comprises two heavy chains (molecular mass c.200 kDa) and two pairs of light chains (mass 18–​28 kDa). The my- osin heavy chains are arranged as dimers, with a tail and two heads (Fig. 16.1.2.2). The tails are packed together to form the shaft of the thick filament, while the heads protrude from the filament and lie close to the thin actin filaments. The myosin heads are the motor units of muscle: they bind and hydrolyse ATP to ADP and convert the free energy of ATP hydrolysis into mechanical work through their interaction with actin in the thin filaments (for details see ‘The mechanism of myofibrillar contraction’). Thin filaments Each thin filament comprises about 300 globular actin subunits (mo- lecular mass 42 kDa). The actin monomers have sites for interaction with the myosin heads and with a regulatory protein complex that confers Ca2+ sensitivity. The latter consists of the troponin complex (troponins I, C, and T) and the elongated protein α-​tropomyosin (Fig. 16.1.2.2). Troponin complexes are located at intervals along the actin filament. Tropomyosin forms two continuous strands along the thin filament and is responsible for cooperative propaga- tion of regulatory signals. Other structural components of the sarcomere The thin filaments are attached to the Z-​discs in a regular array with filaments on each side in opposite orientation (Fig. 16.1.2.1). The main structural component of the Z-​disc is the actin cross-​linking protein α-​actinin. Z-​discs are also associated with the T-​tubules and costameres (see next) and contain several additional proteins be- lieved to be associated with cell signalling. The M-​line (Fig. 16.1.2.1) contains the protein myomesin that cross-​links the thick filaments to maintain their orientation. In addition, the giant protein titin (connectin) extends from the M-​line to the Z-​disc. Titin contains multiple binding sites for several sarcomeric proteins, including myosin-​binding protein-​C (MyBP-​C; Fig. 16.1.2.2). It contributes to elasticity, passive tension, and thick filament positioning in the sarcomere. Intermediate filaments, costameres, and the plasma membrane skeleton The myofibrils are held in position by scaffold-​like webs of inter- mediate filaments made from a (non​contractile) protein, desmin, spanning the sarcolemma, mitochondria, and nucleus. Desmin filaments are anchored to costameres, which circumscribe the lat- eral plasma membrane. Apart from maintaining the spatial organ- ization of the contractile apparatus, the costameres mechanically Troponin T Troponin C Troponin I Myosin-binding protein C Actin Myosin head Myosin rod β-Myosin heavy chain Myosin light chain α-Tropomyosin Fig. 16.1.2.2  Structural arrangement of contractile proteins in the filament overlap zone of the sarcomere. Reproduced from Spirito et al. N Engl J Med 1997; 336: 775–​85. Copyright © 1997 Massachusetts Medical Society. All rights reserved. 16.1.2  Cardiac physiology 3257 couple the cells laterally to the extracellular matrix. Associated with the costameres, but closely applied to the entire cytoplasmic aspect of the lateral plasma membrane, is the membrane skeleton, a peri­ pheral membrane protein network of dystrophin and spectrin. The costameres, membrane skeleton, and intermediate filaments are linked to the glycocalyx and extracellular matrix by sets of integral plasma membrane proteins, notably the integrins and the compo- nents of the dystrophin–​glycoprotein complex. Coupling of the plasma membrane to the sarcoplasmic reticulum The plasma membrane (sarcolemma) contains openings of trans- verse (T)-​tubules and the caveolae, which are cholesterol-​enriched pits in which signal-​transducing and water-​channel proteins are concentrated (Fig. 16.1.2.3a). T-​tubules are long invaginations of the plasma membrane adjacent to the costameres and myofibril Z-​discs, and penetrate deeply into the cell. T-​tubules mediate extracellular Ca2+ (Ca2+ o) entry into the cell through the L-​type Ca2+ channels. Each myofibril is surrounded by a network of interconnecting membranous tubules and cisternae known as the sarcoplasmic re- ticulum (SR) (Fig. 16.1.2.3a). At multiple sites within this network, the membranes form flattened sacs, the junctional sarcoplasmic re- ticulum (JSR) cisternae, which press tightly against the peripheral plasma membrane and T-​tubules (Fig. 16.1.2.3b). The plasma mem- brane and T-​tubule domains facing the JSR membrane contain clus- ters of L-​type Ca2+ channels, while the nearby domains of the JSR are packed with Ca2+-​release channels (Fig. 16.1.2.3), also known as ‘ryanodine receptors’ because of their sensitivity to interference by the plant alkaloid ryanodine. The JSR is the major reservoir of intracellular Ca2+. This close spatial arrangement is important in control of the Ca2+ transient required for myofibrillar contraction. Following contraction, the sarcoplasmic/​endoplasmic reticulum Ca2+ATPase-​2 (SERCA2) pumps Ca2+ back into the SR lumen, causing myofibrillar relaxation. Connections between cardiac myocytes The myocyte can function as an autonomous contractile unit. To pro- duce a heartbeat, the contractile capabilities of the c.3 billion myocytes that constitute the human heart have to be electromechanically syn- chronized. This requires both an orderly spread of the wave of elec- trical activation and the effective transmission of contractile force from one cell to the next, throughout the heart. This is achieved by the intercalated discs, formed from specialized regions of the plasma membrane where adjacent cells interact. Intercalated discs are situated at the blunted ends of the main body of the myocyte and its side branches (Fig. 16.1.2.4). Three types of cell membrane junction—​the gap junction, the fascia adherens, and the desmosome—​connect the adjacent membranes at the disc. The fascia adherens and desmosome are forms of anchoring junc- tion which provide mechanical integrity between adjoining fibres; gap junctions contain clusters of connexons (Fig. 16.1.2.4). These gap junctions are clusters of intercellular channels which span two closely apposed plasma membranes and directly link adjacent cyto- plasmic compartments of neighbouring cells. They form the sites of electrical coupling between individual cardiac myocytes and permit direct cell-​to-​cell transmission of chemical signals (ions and small molecules of <1 kDa). The combination of connexin isoforms consti- tuting a gap junction channel is a major determinant of its functional properties and varies in different cardiomyocyte subsets. This ar- rangement renders the myocardium into a functional syncytium. Cardiac myocyte subtypes Atrial myocytes are significantly different to the ventricular myocytes just described; they are long and slender, with few or no T-​tubules but more abundant caveolae. By producing the peptide hormones atrial natriuretic peptide (ANP) and B-​type natriuretic peptide (BNP), they also function as secretory cells. The atria act as blood volume detectors: natriuretic peptides are released in re- sponse to increased central blood volume and participate in the con- trol of sodium and water balance and hence of blood pressure. A third, heterogeneous, group of modified and morphologically distinct myocytes makes up the pacemaker and conduction system. These cells show some resemblance to ventricular and atrial cells, but their primary function is impulse generation and its timed dis- tribution to the contractile myocytes at the appropriate point in the cardiac cycle. Myocytes of the sinoatrial and atrioventricular nodes are typically small (c.5 µm diameter), containing just a few rudimentary myo- fibrils, and small, sparse, gap junctions. These features contribute Ca L-type Ca channel T-tubule local Ca gradient SR lumen a cluster of Ca release channels (RyR) Ca release Ca Ca Na K Na/K ATPase Na/Ca X Ca release from clusters of SR release channels (a) (b) Ca Ca Na Na/Ca X T-tubule L-type Ca channels myofilaments phospholamban P SERCA 2 Ca Ca Ca SR lumen RyR JSR sarcoplasm sarcoplasm Na Fig. 16.1.2.3  Excitation-Contraction coupling in the heart. (a) L-​type Ca2+ channels allow Ca2+ influx across the plasma membrane, creating ICa. This influx increases the local Ca2+ concentration around a cluster of sarcoplasmic reticulum (SR) Ca2+-​release channels (ryanodine receptor) in sufficient amounts to open them (Ca2+-​induced Ca2+-​release). (b) The opening of clusters of SR Ca2+-​release channels allows SR Ca2+ reservoir to be discharged into the cytoplasm. Ca2+ fluxes combine to initiate contraction. The contraction process is terminated (1) by SERCA2 (regulated by phospholamban and dependent on phospholamban phosphorylation state), which pumps Ca2+ back into the SR, and (2) by the plasma membrane Na/​CaX which expels Ca2+ from the cell. JSR: junctional SR; RyR: ryanodine receptor. Intercalated disc Desmosome Fascia adherens Gap junction (f) Fascia adherens Desmosome 1 μm Gap junction 20μm 4μm ) b ( ) a ( (c) (e) (d) 100nm Channel (2 connexons) Connexin Connexon COOH Membrane } Gap Membrane NH2 Fig. 16.1.2.4  The intercalated disc and cardiac gap junction organization and structure. (a) Clusters of gap junctions at the intercalated discs revealed in a single ventricular cardiac myocyte by immunoconfocal microscopy. (b) One disc-​cluster of gap junctions viewed en face (reconstruction from a stack of serial optical sections). One of these immunolabelled spots corresponds to a single gap junction. (c) Electron micrograph illustrating the three types of cell junction of the intercalated disc. Gap junctions occur where the adjacent plasma membrane profiles run in close contact. The fascia adherens and the desmosome are characterized by a much wider intermembrane space (c.25 nm). (d) Viewing the membrane en face by freeze-​fracture reveals the gap junction as a cluster of particles (connexons). (e) The gap junction channel consists of a pair of connexons (hemichannels), one contributed by each of the adjacent plasma membranes. Each connexon is itself formed from six connexin molecules. The specific connexin type or types within the connexon is a major determinant of the functional properties of the gap junction channel. (f) The intercalated disc, permitting intercellular communication; the gap junction is rich in connexins. (a–​e) Reprinted from Severs NJ (2000). The cardiac muscle cell. BioEssays, 22, 188–​99 (Fig. 5). With permission from Wiley-​Blackwell. 16.1.2  Cardiac physiology 3259 to poor coupling, which in the atrioventricular node is essential to slowing of conduction to ensure time for atrial ejection. The cell population is morphologically heterogeneous: cells of the compact atrioventricular node, and those of the surrounding areas (the tran- sitional cells and posterior nodal extension), are distinctive, and myocytes of the His–​Purkinje system show a range of morpholo- gies according to their location, progressively increasing in size and myofibril content, and with more developed intercalated discs dis- tally, towards the ventricular myocardium. The cardiac action potential The membrane potential Electrical activity of the heart (membrane potential; action poten- tial) is based on differential distribution of ions across the cellular membranes. This distribution is achieved by the action of ion-​ transport proteins, including ion pumps and channels. Ion channels Electrical excitation of myocytes involves the movement of ions through specific channels. These are ‘excitable’ proteins embedded in membranes that contain pores capable of opening or closing in response to a stimulus, which could be a change in membrane po- tential, a neurotransmitter or hormone, an intracellular second mes- senger or ion, or mechanical stretch of the membrane. On opening, a channel becomes selectively permeable to a restricted series of ions. There are many different types of channel, often named after the most permeant ion they pass (e.g. Na+, Ca2+, and K+ channels). Ions move down their electrochemical gradients through the channel at high rates (>106 ions/​s), distinguishing them from other ion-​ transport proteins (e.g. the Na+/​K+-​ATPase or pump, and the Na+/​ Ca2+ exchanger (Na/​CaX); see ‘The Na+/​Ca2+ exchanger (Na/​CaX) and the Na+/​K+-​ATPase’, later on in this chapter) which move ions across plasma membranes several orders of magnitude more slowly. Hence cardiac excitation provides a means of coordinating the con- tractile activities of the four heart chambers and is the basis for the electrocardiograph (ECG; see Chapter 16.3.1). Origin of the membrane potential Cardiac membrane potential is determined by three factors: (1) ionic concentrations across the sarcolemma; (2) the permeability (conductance) of the sarcolemma to specific ions; and (3) the ac- tivity of electrogenic pumps that maintain the ionic concentration gradients. When a ventricular myocyte is at rest (diastole), there is a potential difference of about −90 mV across the plasma mem- brane, the inside of the cell being negative with respect to the out- side. This is principally caused by plasma membrane permeability to K+. The extracellular concentration of K+ (K+ o) is about 4 mmol/​ litre, and the intracellular (cytoplasmic) concentration (K+ i) is about 140 mmol/​litre, so K+ tends to diffuse out of the cell down its concentration gradient, resulting in the interior becoming nega- tively charged. An equilibrium is thus established where the elec- tronegative force retaining K+ inside the cell (mostly derived from negatively charged intracellular proteins) balances its tendency to diffuse out of the cell down its concentration gradient. This is termed the equilibrium potential (E) and can be calculated from the Nernst equation (see Table 16.1.2.1 for E values of relevant ions). At this potential, there will be no net flux of K+ ions through K+ channels and, if the membrane is only permeable to K+, then the membrane potential will be equal to EK. The membrane potential at any moment is dependent upon the equilibrium potentials for all permeant species and their rela- tive permeabilities. The actual transmembrane potential difference at rest and the calculated EK are rarely the same owing to a small leakage, mainly of Na+ into the cell down its concentration gradient (Na+ o = 140 mmol/​litre, Na+ i = 7–​10 mmol/​litre). To counteract this leak and to maintain the concentration gradients of Na+ and K+ upon which the generation of the membrane potential depends, the plasma membrane Na+/​K+-​ATPase uses free energy derived from the hydrolysis of ATP to pump these ions against their concentra- tion gradients. This process is electrogenic (three Na+ extruded for two K+ entering) and generates 3–​10 mV of the membrane potential. The action potential The action potential is divided into five phases (Fig. 16.1.2.5). The currents that flow are described in Table 16.1.2.1, Table 16.1.2.2, and Fig. 16.1.2.5. Depolarization from the resting potential is mediated by inward cation current flow. Phase 0 of the action potential When a myocyte is electrically stimulated, Na+ channels (Nav1.5) open and allow Na+ ions to enter the cell. The channels open by sensing potential difference more positive than about −65 mV across the cell membrane (‘voltage gated’; Fig. 16.1.2.5). Excitation depolarizes the cell membrane slightly and this increases the prob- ability of Na+ channel opening. A cardiac myocyte contains many thousands of Na+ channels, hence the current (I) generated by the movement of Na+ ions into the cell (INa) is the sum of the small cur- rents that flow through each individual channel. Positive charge is taken into the cell, the membrane potential increases (becomes less negative) towards the equilibrium potential for Na+ (ENa = +70 mV, Table 16.1.2.1), and the cell depolarizes (Fig. 16.1.2.5). The Na+ cur- rent causes the rapid upstroke (phase 0) of the action potential. The propagation velocity of the action potential across the whole heart is related to the rate of the rapid upstroke. Following activation and opening, the channels close very rapidly, even though the myocyte remains depolarized, a process termed ‘inactivation’. Inactivated channels cannot open again until the cell repolarizes, causing the refractory period during which a further stimulus cannot evoke an- other action potential (Fig. 16.1.2.5). Table 16.1.2.1  Ion concentrations in the quiescent myocyte, and their calculated equilibrium potentials (E). E is calculated from the Nernst equation, E = (RT/​zF) ln(ao/​ai), where potential E is in volts, T is the absolute temperature, R is the gas constant, F is the Faraday constant, z is the valency, and ao and ai are the extracellular and intracellular activities of the ion in question Ion Intracellular concentration (mmol/​litre) Plasma concentration (mmol/​litre) Calculated E (mV) Na+ 10 140 +70 K+ 140 4.5 –​91 Ca2+ 0.0001 2.3 +131 Cl–​ 20 110 +45 Section 16  Cardiovascular disorders 3260 The inactivation of each channel decreases the total number of Na+ channels that are conducting such that INa almost entirely in- activates within the first 5 ms of the action potential (the overall ac- tion potential in humans at rest lasts c.350 ms). Some Na+ channels do not inactivate so rapidly, allowing a small inward current to per- sist during the plateau phase of the action potential (phase 2, see next). In late phase 0 some L-​type Ca2+ channels (Cav1.2) also start to open, resulting in Ca2+ influx into the cardiomyocyte. Phase 1 of the action potential The characteristic notch observed in phase 1 of the action potential in ventricular myocytes (Fig. 16.1.2.5) is caused by a transient out- ward current (ITO), carried mainly by K+ ions flowing out of the cell (ITO1), but also by some Cl− current (ITO2), that partially repolarizes the membrane. The current inactivates within 30–​40 ms but is im- portant in determining action potential duration. A  component of ITO appears to be dependent upon intracellular Ca2+ concentra- tion (raised Ca2+ o increases ITO): this is the probable mechanism underlying action potential shortening during tachycardia. Phase 2 of the action potential Several currents flow during phase 2 (the action potential plateau), including ICa (Fig. 16.1.2.5). L-​type (‘long-​lasting’) Ca2+ channels, which take longer to activate and inactivate than Na+ channels, open within 3–​5 ms of the start of the upstroke and allow Ca2+ to flow into the cell (ICa). L-​type Ca2+ channels activate at more positive voltages than Na+ channels (around −35 mV). The influx of Ca2+ maintains depolarization (Fig. 16.1.2.5, Tables 16.1.2.1 and 16.1.2.2), and ini- tiates Ca2+-​induced Ca2+-​release (CICR) from the SR through the SR Ca2+-​release channels (ryanodine receptors), causing the myocyte to contract and hence crucial for excitation–​contraction coupling (see next). Hence, Ca2+ has a role in both membrane potential and signal transduction/​inotropy. In addition, a slow delayed rectifier K+ cur- rent (IKs) exports K+ in phase 2. The plateau phase (phase 2) of the action potential (Fig. 16.1.2.5) is prolonged in ventricular myocytes because of the properties of several types of K+ channel that give rise to several different K+ cur- rents. The main repolarizing current, IK, is composed of two distinct ‘rectifier’ currents, one activating more rapidly (IKr) than the other (IKs) (see Table 16.1.2.2). Both channels open at positive membrane potentials and close (deactivate) at negative potentials. Hence the plateau of the action potential is the result of a balance of inward (Ca2+) and outward (K+) current flow. Phase 3 of the action potential The final phase of repolarization begins with the termination of ICa and progressively increasing K+ current (IKr and IKs) (Fig. 16.1.2.5). As repolarization proceeds, the sodium-​calcium exchanger Na/​CaX responds to the increase in cytoplasmic Ca2+ concentration and pro- duces an inward current (INa,Ca) through the exchange of three Na+ entering the cell for one Ca2+ expelled; by producing an inward cur- rent, the Na/​CaX slows repolarization and prolongs the plateau. In ventricular myocytes, complete repolarization and a return to a nega- tive resting membrane potential is eventually achieved by (the large) IK1 (the ‘inward rectifier’; Fig. 16.1.2.5; Table 16.1.2.2). The channel through which this current flows possesses peculiar characteristics. Normally, because of the relative concentrations of K+ inside and outside the cell, there is outward movement of K+ ions that becomes ITo IKs ICa INaCa IKr IK1 K currents outward outward inward time Ca and Na/CaX current 1.0 0.1 Ca transient (µM) 1 2 0 +40 −40 −80 0 3 4 Relative refractory period Absolute refractory period Membrane potential (mV) Fig. 16.1.2.5  Ca2+ transient, membrane potential, K+ currents, and Ca2+-​related currents during a ventricular myocyte action potential. The inward Na+ current that produces the rapid upstroke of the action potential (depolarization) is not shown. Top panel: phases of the ventricular myocyte action potential. Upper middle panel: changes in cytoplasmic Ca2+ concentration during the action potential (Ca2+ transient). For a period between phase 0 and about midway through phase 3, cardiac muscle cannot be excited with another stimulus: the absolute refractory period. From about halfway through phase 3 until just before the end of phase 3, cardiac muscle is in its relative refractory period, when a stronger stimulus than normal is required to initiate an action potential. The states of refractoriness are related to the ability of ion channels to recover from a stimulus. This recovery is both voltage-​ and time-​dependent. Lower middle panel: K+ currents during one action potential. All K+ currents (ITO, IKs, IKr, and IK1) repolarize the myocyte because of outward K+ movement. Bottom panel: Ca2+-​related currents during one action potential. Because of the inward movement of Ca2+, Ca2+ current (ICa) is depolarizing. The Na/​CaX produces both outward and inward current (INa,Ca) depending on the phase of the action potential. The inward Na+ current is roughly 8–​10 times the size of the Ca2+ current and has largely inactivated by the time of the peak Ca2+ current. 16.1.2  Cardiac physiology 3261 larger the more positive the displacement from EK. However, the IK1 current flows through a channel that first increases its conductance but then decreases it as the cell depolarizes away from EK (anomalous rectification). Thus, there is outward flow of repolarizing current only over a narrow voltage range (around −30 to −80 mV)—​another reason for the prolonged cardiac action potential because a large, rapid, outward K+ current does not flow despite the membrane po- tential approaching 0 mV during the plateau phase. IK1 is responsible for the main (background) flow of K+ giving rise to the membrane potential. The channels through which IK1 flows are numerous in ventricular cells, fewer in atrial cells, and absent in pacemaker cells. The current is therefore large in ventricular cells and this is the reason that the resting membrane potential of ven- tricular myocytes lies near EK, whereas atrial cells have a more posi- tive (less negative) resting membrane potential, and SA nodal cells do not have a stable resting potential. Table 16.1.2.2  Plasma membrane currents in the cardiac myocyte Current Name/​Ion Activated by Blocked by Gene Protein Function Inward currents INa (Fast) Na+ current; Na+ Depolarization Tetrodotoxin, local anaesthetics SCN5A Nav1.5 Rapid upstroke of action potential (phase 0) ICa,L L-​type Ca2+ current (‘long-​lasting’); Ca2+ Depolarization Verapamil, Cd2+, dihydropyridines CACNA1C Cav1.2 Ca2+ influx that activates CICR, provides some Ca2+ for contraction (phase 0–​2) ICa,T T-​type Ca2+ current (‘transient’); Ca2+ Activates on depolarization but at more negative potentials than L-​type current Ni2+, mibefradil CACNA1G CACNA1H Cav3.1 Cav3.2 Channel density high in pacemaker and conducting tissue so may contribute to pacemaker activity (phase 4). Role in ventricular cells unclear (phase 2) If Hyperpolarization-​ activated, cyclic nucleotide-​gated cation channel; Na+, K+ Hyperpolarization, noradrenaline, cAMP, autonomic nervous system Cs+, ZD7288, ivabradine, zatebradine, cilobradine HCN2 HCN4 HCN2 HCN4 Exists in sinoatrial node and Purkinje fibres bringing membrane potential slowly to threshold (phase 4); also known as ‘funny’ current Inward and outward (reversible) current INa/​Ca Na/​CaX current; Na+, Ca2+ Ca2+ i (Na+) Ni2+, KB-​R7943 NCX1 SLC8A1 NCX 3Na+-​1Ca2+ exchange. Expels Ca2+ from the cell, maintains inward current flow near end of action potential, at positive potentials may reverse and mediate Ca2+ influx (phase 3, 4) Outward currents ITO Transient outward current; K+ (ITO1); Cl-​ (ITO2) Depolarization 4-​Aminopyridine KCNA4 KCND2 KCND3 Kv1.4 Kv4.2 Kv4.3 Early repolarization (phase 1; notch) ICl Chloride current; Cl-​ cAMP CFTR Early repolarization ICl,Ca Ca2+-​activated chloride current Ca2+ CLCA1 Early repolarization IKur Ultra-​rapid delayed rectifier; K+ Depolarization Tetraethylammonium, Cs+, Ba2+, 4-​ aminopyridine, flecainide, nifedipine, diltiazem, bupivacaine, propafenone, quinidine KCNA5 Kv1.5 Repolarization of cell (phase 1, 3) IKr Rapid delayed rectifier; K+ Depolarization Tetraethylammonium, Cs+, Ba2+, E-​4031, dofetilide, D-​sotolol, cisapride, BRL32872 KCNH2 hERG hERG, Kv11.1 Repolarization of cell (phase 2, 3) IKs Slow delayed rectifier; K+ Depolarization Chromanol 293B KCNQ1 KvLQT1 Kv7.1 Repolarization of cell (phase 2, 3) IK1 Inward (anomalous) rectifier; K+ Depolarization from EK Conductance of channel increases then decreases to zero at 0 mV Cs+, Rb+, Ba2+, intracellular Mg2+, spermidine, spermine KCNJ2 KCNJ12 Kir2.1 Kir2.2 Prolongs action potential duration, background K+ conductance. (phase 3, 4) Ip Na+/​K+ pump current (INaK); Na+, K+ Na+ i, K+ o Cardiac glycosides ATP1A1 3Na+-​2K+ ATPase exchanger. Maintains low [Na+]i IK,ACh Acetylcholine-​ activated K+ current (inward rectifier); K+ ACh, parasympathetic nerves Ba2+ KCNJ3 KCNJ5 Kir3.1 Kir3.4 Muscarinic receptor-​coupled. Activates additional K+ channels so slowing pacemaker potential (phase 3, 4) IKATP ATP-​activated K+ current; K+ ATP, nicorandil KCNJ11 Kir6.2 (SUR2A) Cardiac ATP homeostasis and metabolic matching (phase 1, 2); SUR subunits are sulphonylurea receptors Section 16  Cardiovascular disorders 3262 Phase 4 of the action potential This phase relates to the membrane potential during the electric- ally silent period between excitatory events in ventricular myocytes (Fig. 16.1.2.5); phase 4 is stable in these cells. Besides the underlying IK1 activity, it is accompanied by an electrogenic active sodium-​ potassium exchange giving rise to a Na+/​K+ pump current (IP). Differences in ion channel distribution alters the stability of phase 4 due to differing ionic currents and leading to spontaneous depolar- ization associated with pacemaker activity (‘pacemaker potential’). Regional variations in action potential The configuration of the cardiac action potential differs regionally within the heart (Fig. 16.1.2.6) because ion channel expression varies between cells. In the sinoatrial node, INa is very small and the main current responsible for the depolarizing upstroke is ICa, car- ried mainly by L-​type Ca2+ channels (ICa,L). The only repolarizing current is IK. IK1 is absent and, as mentioned earlier, this partially explains why sinoatrial node cells have a more depolarized ‘diastolic’ potential than ventricular myocytes. Sinoatrial node cells depolarize spontaneously during phase 4 (Fig. 16.1.2.6), owing to the absence of IK1 and the presence of a current activated on hyperpolarization called the ‘funny’ current (If), carried mainly by Na+ through hyperpolarization-​activated cyclic nucleotide-​gated (HCN) chan- nels, but also current (ICa,T) resulting from an influx of Ca2+ through voltage-​dependent T-​type (‘transient’) Ca2+ channels (abundant in these cells; see Table 16.1.2.2). Phase 4 is often termed the ‘pre-​ or pacemaker potential’ in nodal cells and is caused by the gradual de- crease in IK and increase in If and ICa,T (Fig. 16.1.2.6). Once the cell has depolarized to a voltage at which L-​type Ca2+ channels open (the threshold), a more rapid depolarization (caused by ICa,L) oc- curs, forming the upstroke (phase 0) of the sinoatrial node action potential. Acetylcholine (ACh) activates IK,ACh, which helps drive the membrane potential towards EK and slows the rate of depolarization, while β-​adrenergic stimulation increases the slope of the pacemaker potential and heart rate through an effect on If, affecting heart rate (Fig. 16.1.2.7). Atrial and ventricular myocytes do not have pacemaker poten- tials and spontaneously discharge only when injured or when there is abnormal ionic balance. The longest action potential is in Purkinje fibres (Fig. 16.1.2.6) and this acts as a ‘gate’ preventing retrograde activation by depolarization of adjacent ventricular myocytes. The mechanism of myocyte contraction Excitation–​contraction coupling The electrical events throughout the heart initiate and regulate con- traction (Fig. 16.1.2.5). Coupling of the electrical excitation of the heart to contraction (termed excitation–​contraction coupling or EC coupling) by Ca2+ ions involves the interaction of several proteins involved in Ca2+ homeostasis (Fig. 16.1.2.3). The T-​tubules carry depolarization deeply into the cell. During diastole (phase 4), when cytoplasmic Ca2+ concentrations are low (c.0.1 µmol/​litre), Ca2+ is sequestered by the Ca2+-​buffering protein calsequestrin within the JSR. Depolarization (phase 0)  then opens the L-​type Ca2+ chan- nels in the T-​tubule and plasma membrane allowing influx of Ca2+ (Figs. 16.1.2.3 and 16.1.2.5) and producing ICa (Fig. 16.1.2.5). Ca2+ influx increases the local cytoplasmic Ca2+ concentration around clusters of SR Ca2+-​release channels in the JSR sufficiently to open them (i.e. CICR), the number of channels activated in this way being mainly, though not exclusively, determined by the size of the Ca2+ Sinoatrial node Threshold potential 0 mV –50 mV –80 mV Atrial muscle Atrioventricular node Purkinje fibre Ventricular muscle 0 mV Fig. 16.1.2.6  Regional configurations of the action potential. In the sinoatrial (SA) and atrioventricular (AV) nodes, the cells spontaneously depolarize during diastole (phase 4 depolarization). When the membrane potential reaches a threshold, the complete action potential is initiated. Because the SA nodal cells have the fastest phase 4 depolarization, they act as the cardiac pacemaker. Adrenergic stimulation Threshold 0 – 50 Membrane potential (mV) Pacemaker potential Threshold 0 – 50 Membrane potential (mV) Cholinergic stimulation Normal rate Normal rate Fig. 16.1.2.7  Change in heart rate produced by altering the phase 4 slope of the pacemaker potential in the sinoatrial (SA) node. β-​Adrenergic stimulation increases (increased If), and cholinergic stimulation decreases (increased IK, ACh), the slope of the pacemaker potential, affecting the time taken to reach threshold. 16.1.2  Cardiac physiology 3263 current. CICR provides amplification, as the small ‘trigger’ Ca2+ in- flux through the L-​type Ca2+ channels evokes a much larger release of Ca2+ from the SR into the cytoplasm; also, the release of Ca2+ from the SR is under precise control as it is closely matched to the amount of Ca2+ influx. Cytoplasmic Ca2+ concentration rises to between 1 and 3 µmol/​litre (Fig. 16.1.2.5). The release of Ca2+ eventually ceases because the L-​type Ca channels inactivate, so the trigger influx de- clines, leading to closure of SR Ca2+ release channels. The mechanism of myofibrillar contraction Ca2+ release from the SR activates the contractile apparatus of the sarcomere (Figs. 16.1.2.2 and 16.1.2.8). The temporal relationship between the action potential, the Ca2+ transient, and the subse- quent development of tension is shown in Fig. 16.1.2.9. Sarcomere shortening is caused by the interaction of motor protein myosin in the thick filaments with actin in the thin filaments (Fig. 16.1.2.8). Myosin heads bind and hydrolyse ATP, retaining bound ADP and phosphate, and trapping the free energy of hydrolysis within the myosin molecule. The myosin–​ADP–​phosphate complex then binds to actin, leading to the release of the stored energy by a con- formational change that moves the actin filament by about 10 nm relative to the thick filament. This is known as the cross-​bridge cycle (Fig. 16.1.2.8) and results in the sliding of the thin filament past the thick filaments, and sarcomere shortening. If the muscle is under load, the cross-​bridge cycle generates force and work is done (the maximum efficiency is more than 60% in intact muscle). The mech- anical characteristics of contracting muscle can be described in terms of the relationship between shortening speed and force, and between sarcomere length and force (Fig. 16.1.2.10a). Maximum force is produced under isometric conditions, while maximum shortening speed is observed in unloaded muscle. Power output is the product of force and velocity and is optimal at about 30% of max- imum shortening speed (Fig. 16.1.2.10a). The isometric force produced by a muscle depends on the sarco- mere length, being optimal at 2.00–​2.25 µm where the overlap of thick and thin filaments is optimal and such that all the myosin cross-​bridges can interact with actin (Fig. 16.1.2.10b). In the heart, the sarcomere length is generally less than optimal, with ‘preload’ stretching the sarcomere to 2.1 µm at the end of diastole and the sarcomere shortening to 1.6 µm during systole. In this length range, stretching the cardiac muscle when it is relaxed leads to increased force in the subsequent contraction. This characteristic is respon- sible in part for the Frank–​Starling mechanism of the heart. Control of contraction by Ca2+ Muscle contraction is initiated by an increase in cytoplasmic Ca2+, which binds to the troponin complex of the thin filament. Troponin comprises three subunits. Troponin C is a Ca2+-​binding protein; in cardiac myocytes, the thin filament is activated when a single Ca2+ ion binds to troponin C. Troponin I is the inhibi- tory subunit. In relaxed muscle, the Ca2+ concentration is low and troponin I binds to a site on actin which blocks the binding of myosin cross-​bridges, thus preventing cross-​bridge cycling. In the presence of activating Ca2+ concentrations, Ca2+ binds to troponin C which then binds troponin I, preventing its interaction with actin, permitting actin–​myosin interaction. The third compo- nent, troponin T, binds to troponin C and troponin I and also to tropomyosin, independently of the Ca2+ concentration, thereby anchoring the regulatory complex on the thin filament (Fig. 16.1.2.2). There are cardiac-​specific isoforms of troponin I and troponin T, while troponin C is present in heart as the isoform found in skeletal muscle. The tropomyosin lies in a groove be- tween actin filaments, inhibiting interaction between actin and Action potential Force Ca transient Fig. 16.1.2.9  The relationship between the ventricular action potential, the Ca2+-​transient and the generation of force. The peak of force production is not achieved until near the end of the plateau phase of the action potential and lags behind the peak of the Ca2+-​transient, reflecting the time required for Ca2+-​induced Ca2+-​release and cross-​bridge cycling. (a) (e) (d) (b) (c) ADP ADP Pi Pi ATP actin filament myosin head myosin filament ATP Fig. 16.1.2.8  The cross-​bridge cycle. Exchange of ATP with ADP (a) on either a load-​bearing (b) or a resting-​length myosin head (c) results in a conformational change in the myosin head, causing a rapid dissociation of the myosin head from actin ((b) to (d) and (c) to (d), respectively). Following detachment from actin, the ATP is hydrolysed to ADP and Pi, both of which remain tightly bound to the myosin head (e). Hydrolysis is accompanied by a major conformational change which represents the reversal or a repriming of the power stroke. If an actin site is within reach of the myosin head, it will bind rapidly and reversibly to the actin site (a). When the myosin head binds actin, the interaction can promote a major change in conformation (the power stroke) which is accompanied by the dissociation of Pi ((a) to (b)). This step approximates to isometric contraction (no relative movement of actin and myosin), whereas the (a) to (c) steps approximate to an isotonic contraction (relative movement, with a release of the myosin ‘spring’). This power stroke consists of a reorientation of part of the myosin head that results in the displacement of the tip by up to 10 nm. Reproduced with permission from S. Weiss and M. A. Geeves. Section 16  Cardiovascular disorders 3264 myosin heads. Ca2+ binding to troponin C induces a conform- ational change, resulting in a shift of the tropomyosin in the actin groove and exposing the myosin head-​binding sites. The Ca2+-​sensitivity of cardiac myocytes is increased by stretch, promoting relaxation at the start of diastole (short sarcomere lengths) and activating contraction at the start of systole (long sarco- mere lengths). Moreover, this ‘stretch activation’ is delayed so that the enhanced contractility is synchronized with systole, thus con- tributing to the Starling effect. Termination of contraction Sarcoplasmic/​endoplasmic reticulum ATPase type 2 (SERCA 2) Contraction is terminated predominantly by Ca2+ reuptake into the SR by activation of SERCA2, an ATP-​requiring Ca2+ pump expressed in the network of non​junctional SR surrounding the myofibrils (Fig. 16.1.2.3a). SERCA2 activity is regulated by the extent of phosphor- ylation of the SERCA2-​associated protein phospholamban associ- ated with the activities of protein phosphatase-​1, inhibitor-​1 and PKCα, together with covalent modification by SUMOylation and acetylation. The Na+/​Ca2+ exchanger (Na/​CaX) and the Na+/​K+-​ATPase The sarcolemmal Na/​CaX antiporter contributes to lowering cyto- plasmic Ca2+ during the latter part of the action potential (phases 3 and 4) and during diastole (Fig. 16.1.2.5 and Table 16.1.2.2). Its activity is regulated by Ca2+ i through a large intracellular loop con- taining two Ca2+-​binding domains. The Na/​CaX utilizes the energy associated with the concentration and electrical gradients for Na+ to expel Ca2+ from the cell. It is electrogenic, promoting depolar- ization under these conditions. The exchange is sensitive to Na+ i concentration: when membrane potential is near its diastolic level and Na+ i is at normal physiological concentration, the Na/​CaX will eject Ca2+ from the cell; if Na+ i increases by a few mmol/​litre and the membrane potential becomes depolarized, the exchanger can re- verse and mediate Ca2+ entry. The sarcolemmal Na+/​K+-​ATPase is responsible for Na+ i extru- sion. Cardiac glycosides (e.g. digoxin) inhibit the Na+/​K+-​ATPase, preventing Na+ extrusion, which indirectly reverses the Na/​CaX into Ca2+ o uptake mode. Under these conditions, Ca2+ uptake by the SR may be increased, thereby augmenting the cardiac Ca2+ pool and facilitating CICR. The net effect of the cardiac glycosides is to increase the cytoplasmic concentration and availability of Ca2+ re- sulting in an increased force of contraction (positive inotropy). Ventricular myocytes possess other minor systems to decrease cytoplasmic Ca2+ concentrations, including the plasma membrane Ca2+ ATPase and mitochondrial Ca2+ uptake. SERCA2 and Na/​CaX contribute about 70% and 25%, respectively, towards relaxation, though these figures vary greatly between species. Whole organ physiology The cardiac cycle Electrical events initiate the cardiac cycle with depolarization of the sinoatrial (SA) node in the upper right atrium (Fig. 16.1.2.11). Cardiac muscle acts as a functional syncytium. Communication between neighbouring cells is mediated by gap junctions which form arrays of cell-​to-​cell channels. The generated action potential spreads from the sinoatrial node across the functional syncytium at a speed of 1.0–​1.2 m/​s. The first mechanical response is atrial systole. The atria comprise a single functional syncytium, and the vent- ricles also comprise a single, separate, syncytium. These two syncytia are not contiguous with each other and not capable of activating each other directly. The conduction of the electrical impulse from atrium to ventricle normally occurs only through the atrioven- tricular (AV) node (Fig. 16.1.2.11), a region of slow conductance at 0.02–​0.1 m/​s. This delays activation of the cells of the bundle of His (a) 1.0 0.5 0 0 0.5 1.0 Velocity Force Power 100% 0% 1.0 1.5 2.0 1 1 2 3 4 2 3 4 2.5 3.0 3.5µm Tension (b) Fig. 16.1.2.10  Force–​velocity–​power relationship in cardiac muscle. (a) Force–​velocity relationship (red symbols, black line). Maximum force is produced under isometric conditions (velocity V = 0), while maximum shortening speed is observed in unloaded muscle (force P = 0). The power-​velocity relationship (blue symbols, green line) is a parabola with maximum power being produced at an intermediate force and velocity. (b) Length–​tension relationship in cardiac muscle. At sarcomere length greater than 2.0 µm (­examples 2, 3), isometric tension depends on the amount of overlap between myosin cross-​bridges and actin filaments. At shorter sarcomere lengths (down to 1.6 µm; ­example 1), tension is reduced because of interference of thin filaments from opposite ends of the sarcomere. Below 1.6 µm sarcomere length, myosin filaments interfere with the Z-​line and tension falls rapidly. The range of sarcomere lengths during a normal cardiac cycle is shown in blue. Actin filaments: grey; myosin filaments: red. 16.1.2  Cardiac physiology 3265 arising from the AV node and allows time for completion of ven- tricular filling. The conduction velocity in the bundle of His is from 1.2 to 2.0 m/​s. The impulse passes via the right bundle branch and the two branches (anterior and posterior) of the left bundle, and spreads rapidly (2.0–​4.0 m/​s) through the Purkinje fibres and each muscle cell to produce an orderly sequence of ventricular contrac- tion (Fig. 16.1.2.11). Atrial and ventricular depolarization (P wave and QRS complex, respectively) and repolarization (T wave) can be recorded on the ECG (Fig. 16.1.2.12). While the recorded ECG is a summation of all the individual ac- tion potentials of the myocytes, the ECG voltage is much less than direct action potential recordings (about 1 mV compared to about 100 mV) because of the resistance of body tissues between the heart and the ECG electrodes. The specialized cells of pacemaker tissue have an inherent rhythmicity (unstable phase 4 membrane poten- tial) that is shared by the sinoatrial node, the atrioventricular node, and Purkinje tissue. Unlike other myocardial cells, these cells do not maintain a diastolic intracellular potential of about −90 mV but tend to depolarize spontaneously. Because the sinoatrial node has the fastest inherent discharge (depolarization) rate, and because there is a brief period after depolarization of the whole heart during which a further stimulus is ineffective—​the absolute refractory period—​the sinoatrial node is normally the pacesetter for the heart. However, if this does not occur, pacemaker tissue in the atrioventricular node, the bundle of His, or the Purkinje system will assume this role, in which case the heart rate is then considerably slower. Mechanical events The mechanical events following depolarization of the atrial and ventricular muscle and their timing in relation to the ECG, to pres- sure and flow changes, and to heart sounds are shown in five phases in Fig. 16.1.2.13. After the P wave, and coinciding with atrial sys- tole, ‘a’ waves appear in left atrial and right atrial pressure tracings due to atrial contraction, and an ‘a’ wave can be seen in the jugular venous pulse. Atrial contraction increases ventricular filling by about 10% (phase 1). The onset of ventricular contraction coincides with the peak of the R wave of the ECG; a rapid rise in intraventricular pressure closes the mitral and tricuspid valves, causing the first heart sound; mitral valve closure slightly precedes tricuspid valve closure and two components of the first heart sound may be heard (M1-T1). During this short isovolumetric period (phase 2 of Fig. 16.1.2.13), the pressure rises rapidly in the ventricles. When ventricular pres- sures exceed those in the pulmonary artery and aorta, the outflow valves open and ventricular ejection follows. The highest flow rate is in early systole, and pressures in the aorta and pulmonary artery rise. Normally, between 50 and 70% of the ventricular volume is ejected during systole (the ejection fraction), and this can be seen in the volume curve included in Fig. 16.1.2.13 (phase 3). The jugular venous pulse, during ventricular contraction, has a positive deflection in early systole, the ‘c’ wave, due to right ven- tricular contraction and bulging of the tricuspid valve into the right atrium. Descent of the tricuspid ring caused by ventricular contrac- tion then produces a negative ‘x’ descent, but as atrial inflow con- tinues the pressure rises in the atria and great veins, producing the ‘v’ wave. This reaches its peak just before the opening of the tricuspid valve, declining during early ventricular filling as the negative ‘y’ des- cent. The changes in the pulmonary veins and left atrium are similar. As the strength of ventricular contraction declines in late systole, coinciding with the end of the T wave, the aortic and pulmonary valves close, producing the dicrotic notch seen on both aortic and pulmonary artery pressure tracings in Fig. 16.1.2.13. Aortic closure slightly precedes pulmonary closure, and together these are respon- sible for the two components of the second heart sound (A2-​P2). A short period of further rapid decline in ventricular pressure ensues without change in the ventricular volume (the period of isovolumetric ventricular relaxation, phase 4), and at the end of this the mitral and tricuspid valves open. Valve opening is not normally audible. There is a pressure gradient from atrium to ventricle so that a period of Aorta Right bundle branch Anterior fasicle Purkinje system Posterior fasicle Left bundle branch Sinoatrial node Atrioventricular node Bundle of His Superior vena cava Fig. 16.1.2.11  Diagram of the heart showing the impulse-​generating and impulse-​conducting systems. From Junqueira LC, Carneiro J, (2005). Basic histology, 11th edn. McGraw-​Hill, New York. 10 mm 1 mm Voltage (in mV) Seconds S P R T U P VAT Isoelectric line 1.0 0.5 0 PR segment ST segment Q–T interval 0.04 0 0.2 0.4 0.6 0.8 1.0 QRS interval Q P–R interval Fig. 16.1.2.12  Diagram of electrocardiographic complexes, intervals, and segments. VAT, ventricular activation time. From Goldschlager N, Goldman MJ (1989). Principles of clinical electrocardiography, 13th edn. Appleton and Lange, East Norwalk, CT. Section 16  Cardiovascular disorders 3266 rapid ventricular filling follows, which coincides with the timing of the third heart sound. The rapid ventricular filling is reflected in the shape of the ventricular volume curve and is followed by a period of slower filling (phase 5), with a final sudden small increment from the next atrial contraction as ventricular diastole ends (phase 1). Third heart sounds are normally audible in children and young adults, but over the age of about 40 years this usually indicates ele- vation of ventricular end-​diastolic pressure (most frequently in the left ventricle). The myocardium and valvular structures become stiffer with ageing, and large increases in ventricular end-​diastolic pressure are then required to tense valvular structures and generate audible vibrations. A fourth heart sound usually indicates abnormal ventricular function, with increased end-​diastolic pressure. A fourth heart sound precedes the Q wave of the ECG, which must be distin- guished from a normal splitting of the two components of the first heart sound. The latter occurs after the Q wave (Figs. 16.1.2.12 and 16.1.2.13). Normal volumes, pressures, and flows The blood volume in normal adults is about 5 litres (haematocrit 45%), and, of this, about 1.5 litres are in the heart and lungs—​the central blood volume. The pulmonary arteries, capillaries, and veins contain about 0.9 litres, with only about 75 ml being in the pulmonary capillaries at any one instant. The volume of blood in the heart is about 0.6 litres. Left ventricular end-​diastolic volume is about 140 ml, stroke volume about 90 ml, and end-​systolic volume around 50 ml, reflecting an ejection fraction (stroke volume/​end-​ diastolic volume) of between 50 and 70%. The right ventricular ejec- tion fraction is similar. Of the 3.5 litres in the systemic circulation, most—​at least 60% of the total blood volume—​is in the veins. The systemic veins con- taining most of the blood volume are thin-​walled and easily disten- sible, and input of blood into the contracting heart is associated with only small changes in venous pressure: they act as a blood volume reservoir or ‘buffer’. By contrast, ejection of blood into the much less distensible arterial tree produces large pressure changes. The normal values for pressures generated in the heart and great vessels during the cardiac cycle are shown in Table 16.1.2.3. Pressures are measured with reference to a zero pressure empir- ically set at 5 cm below the sternal angle with the patient recum- bent. ‘Normal’ arterial blood pressure is considered later (see next, ‘Regulation of systemic arterial blood pressure’). Cardiac output is the product of stroke volume and heart rate (stroke volume = end-​diastolic volume –​ end-​systolic volume). It is related to body size and is best expressed as litre/​min per m2 of body surface area: the ‘cardiac index’. The mean cardiac index under resting and relaxed conditions is 3.5 litre/​min per m2, and values below 2 and above 5 are abnormal. The cardiac index de- clines with age. In persons of average size, resting whole body oxygen consumption is about 240 ml/​min, and the difference in oxygen content between arterial and mixed venous blood is about 40 ml/​litre (arteriovenous oxygen difference), giving a basal car- diac output of 6 litre/​min. In normal subjects, the arteriovenous difference in oxygen content at rest is maintained within narrow limits, from 35 to 45 ml/​litre; values of 55 ml/​litre and above are always abnormal. Pulmonary or systemic vascular resistance is estimated by dividing the difference between mean inflow pressure (pulmonary artery or aortic) and mean outflow pressure (left atrial or right atrial, usually in mm Hg) by the flow (usually in litre/​min) through the respective circulations. In normal subjects and patients without intracardiac shunts, this flow is the cardiac output. Normal pulmonary vascular resistance is less than 2 mm Hg/​litre per min (hybrid resistance units, Wood units; equivalent to 16 MPa.S.m−3, 160 dyn.S.cm–​5). Arterial blood pressure is the product of cardiac output and total peripheral (systemic) resistance. Stroke work is the integral of instantaneous ventricular pressure with respect to stroke volume, but is usually estimated as the product of stroke volume and mean ejection pressure. The orderly sequence of contraction in the normal cardiac cycle coordinates changes in Ventricular and aortic pressure (mm Hg) Ventricular volume (ml) Aortic blood flow (l/min) Pressure (mm Hg) Phases of cardiac cycle Carotid pressure (n = dicrotic notch) Radial pressure Left ventricular volume (at c′ , the mitral valve closes; at o′ , it opens) Right atrial pressure (left is similar) Jugular venous pressure, showing a, c, and v waves Pulmonary arterial pressure Right ventricular pressure 0 130 65 0 5 3 0 30 15 0 1 2 3 4 5 P R T U 1 2 3 4 o c a v n n c Diastole Atrial systole Ventricular systole Time (s) Electrocardiogram Heart sounds (phonocardiogram) Aortic pressure (at o, the aortic valve opens; at c, it closes) Left ventricular pressure 0 0.2 0.4 0.6 0.8 120 80 40 o′ c′ Fig. 16.1.2.13  Events of the cardiac cycle at a heart rate of 75 beats/​ min. The phases of the cardiac cycle, identified by the numbers at the bottom, are: (1) atrial systole; (2) isovolumetric ventricular contraction; (3) ventricular ejection; (4) isovolumetric ventricular relaxation; and (5) ventricular filling. Note that aortic pressure actually exceeds left ventricular pressure in late systole, but the momentum of the blood keeps it flowing out of the ventricle for a short time before the aortic valve is eventually forced shut, causing the second heart sound. The pressure relationships in the right ventricle and pulmonary artery are similar. The jugular venous pulse is similar in form to that seen in the right atrial pressure tracing. The ‘c’ wave interrupts the ‘x’ descent of the ‘a’ wave. The decline in pressure from the peak of the ‘v’ is the ‘y’ descent; the rate of decline reflects speed of ventricular filling. Modified with permission from Ganong WF (2005). Review of medical physiology, 22nd edn. McGraw-​Hill, New York. 16.1.2  Cardiac physiology 3267 instantaneous pressure and flow, so maximizing the transfer of en- ergy to the circulation. Normal left ventricular work output at rest is about 6 kg/​m2 per min. Myocardial mechanics When a muscle is activated to contract, it develops a potential for doing work. In isolated skeletal and heart muscle preparations, the stretching force applied to the muscle—​and therefore the length of the muscle—​can be varied before contraction; this is the preload. The activated muscle will begin to shorten when it has generated a force sufficient to overcome that exerted by the attached weight or load against which it contracts. When the force exerted by the load is so arranged that it is not applied to the relaxed muscle and is ap- plied only after the muscle has begun to develop tension, it is termed the afterload. If this load is so large that the activated muscle is un- able to overcome it, and so cannot shorten, the contraction produces tension only, and the contraction is isometric. When shortening does occur, external work is done. If the load is constant during the shortening, the contraction is said to be isotonic; if it changes, it is auxotonic. The tension produced by both skeletal and cardiac muscle during contraction depends on initial fibre length; during afterloaded iso- tonic contractions from a particular length, the amount and the speed of fibre shortening, and the tension developed, all depend upon the afterload. Over a range of loads the initial velocity of muscle shortening is most rapid and the most extensive shortening occurs when the load is smallest. The inverse relationship between initial velocity of fibre short- ening and load in an isotonic contraction is a fundamental one for both skeletal and cardiac muscle. There is, however, a major differ- ence between the two types of muscle in that the relationship at any one given length is constant in a skeletal muscle, whereas in cardiac muscle there are variations in inotropic state that are accompanied by considerable changes in the relationship between force and velocity. A positive inotropic effect produces a more extensive contraction from the same initial length and afterload, and a faster maximum velocity of shortening (Vmax). An increase in initial fibre length with no increase in inotropic state increases the force of contrac- tion but does not, however, change the maximum velocity of short- ening. This means that the force of contraction of cardiac muscle varies with fibre length ((pre-​)loading)—​for example, heterometric regulation, an aspect of the Frank–​Starling relationship—​but con- tractile force also independently varies with the ‘intrinsic’ contract- ility of the cardiac muscle fibre (inotropy)—​homeometric regulation. This is illustrated in Fig. 16.1.2.14. The contraction of the intact heart can be visualized as being similar mechanically to the afterloaded contraction of an isolated muscle strip. For the left ventricle, the preload is the distending force which stretches the muscle fibres in end-​diastole (i.e. a func- tion of ventricular filling), and the initial afterload is the force the ventricle must generate in order to open the aortic valve and eject blood against the systemic vascular (total peripheral) resistance. At the end of ejection, the ventricular muscle is isolated from the peripheral circulation, with the afterload then supported by the competent aortic valve, and the muscle relaxes against a compara- tively small force. Relaxation of the heart is an active process due to ATP-​dependent withdrawal of calcium ions from the cytoplasm surrounding the myofibrils. ‘Active’ relaxation is still proceeding in the ventricular wall when the atrioventricular valves open, and, if it is delayed—​as in the hypoxic heart—​the slower relaxation in- creases the stiffness of the ventricular wall and impedes filling. Wall thickness is also a determinant of compliance and relaxation rate. For this reason, filling pressures are higher for the thicker and stiffer left ventricle than for the thinner and more distensible right ventricle (Table 16.1.2.3). When the left ventricle is hypertrophied Table 16.1.2.3  Normal resting values for pressures in the heart and great vessels Site Systolic pressure (mm Hg) Diastolic pressure (mm Hg) Mean pressure (mm Hg) Right atrium ‘a’ up to 7, ‘v’ up to 5 ‘y’ up to 3, ‘x’ up to 3 Less than 5 Right ventricle Up to 25 End pressure before ‘a’ up to 3; end pressure on ‘a’ up to 7 Not applicable Pulmonary artery Up to 25 Up to 15 Up to 18 Left atrium (direct or indirect pulmonary artery/capillary wedge) ‘a’ up to 12, ‘v’ up to 10 ‘x’ up to 7, ‘y’ up to 7 Up to 10 Left ventricle 120 End pressure before ‘a’ up to 7; end pressure on ‘a’ up to 12 Not applicable Vmax Poa Pob Poc Force (afterload) Velocity of shortening a b c Fig. 16.1.2.14  Idealized relationships between velocity of fibre shortening and afterload or force developed during contraction of a strip of cardiac muscle under three different conditions. Curves a and b were obtained with the muscle in the same inotropic state but with a longer initial fibre length (greater preload) for curve b. Curves b and c were obtained with initial fibre length the same but with contractility increased in c by the addition of a drug producing a positive inotropic effect. The terms Vmax and P0 describe, respectively, a hypothetical maximum shortening velocity in the absence of any load (hence the broken lines), and the force developed in an isometric contraction. An increase in initial fibre length increases P0 but not Vmax; a positive inotropic change increases both P0 and Vmax. Section 16  Cardiovascular disorders 3268 due to chronic pressure overload, as in systemic hypertension or aortic stenosis, it becomes stiffer and filling pressures may then be abnormally high. Myocardial metabolism The heart depends on oxidative metabolism to synthesize sufficient ATP to supply its energetic needs, including the generation of ionic gradients and cross-​bridge cycling. In the normal myocardium about 70% of energy is derived from lipid oxidation and about 30% from glucose oxidation, with glycolysis contributing relatively minor amounts of ATP anaerobically. Of plasma lipids utilized for oxida- tion by the heart, non​esterified (‘free’) fatty acids (NEFA) are an im- portant energy source, especially in starvation and exercise when their plasma concentration is increased, but substantial fatty acid supply is also derived from circulating triacylglycerols (triglycer- ides; TAG) in plasma, including those contained in very low density lipoprotein and, in the post-prandial state, chylomicrons. Lipolysis of TAG in the lipoprotein particles is achieved by ac- tivity of the enzyme lipoprotein lipase (LPL), expressed in high copy number in the myocardium. LPL monomers are synthesized in the cardiomyocytes but are translocated in their active (dimer- ized, glycosylated) forms to their physiological site of action on the luminal surface of coronary endothelium, to which they are at- tached by a GPIHBP1 (glycosylphosphatidyl inositol-HDL binding protein 1)-heparan sulphate proteoglycan anchor (and from which they can be detached by heparin). Fatty acids liberated from TAG by LPL are assimilated into the underlying cardiomyocyte via fatty acid transporters (including fatty acid translocase; FAT/​CD36), possibly by the same route as NEFA, where they undergo mito- chondrial β-​oxidation for ATP production. Besides fatty acids and glucose, the heart can also readily oxidize lactate (in the presence of adequate oxygen provision) and ketone bodies (acetoacetate, 3-​hydroxybutyrate) as well as amino acids. The cardiomyocyte is rich in mitochondria (Fig. 16.1.2.1). Cardiac substrate selection is partly a function of plasma sub- strate concentration and plasma metabolic hormonal milieu, but it changes characteristically in cardiac and metabolic disease. In ventricular hypertrophy, myocardial metabolism reverts to a more fetal pattern of increased glucose utilization and diminished lipid oxidation. A similar pattern may also be seen in cardiac failure of diverse aetiologies. An explanation for this phenomenon is that since fatty acid molecules are more reduced and glucose mol- ecules more oxidized (and some ATP can be derived from glucose by anaerobic substrate-​level phosphorylation in glycolysis), greater amounts of oxygen are required to oxidize lipids than carbohydrates (glucose: 3.7 mol ATP/​mol O2; palmitate: 2.8 mol ATP/​mol O2), hence switching from fatty acid to glucose utilization may increase myocardial oxidative efficiency. By contrast, in diabetes mellitus lack of insulin or its signalling results in decreased glucose up- take (myocardium expresses insulin-​sensitive GLUT-​4 as well as GLUT-​1 glucose transporters) and oxidation by cardiomyocytes, with increased reliance on fatty acid utilization in keeping with the increased circulating lipids. This may lead to decreased efficiency of the diabetic myocardium and has been suggested as the mechanistic basis of diabetic (non​ischaemic) cardiomyopathy. By contrast to cardiomyocytes, the conducting system of SA and AV nodes and the His–​Purkinje cells relies more on anaerobic gly- colysis for its energy provision. Regulation of cardiac function Four essential factors determine the performance of the heart: (1) venous return, (2) outflow resistance (afterload), (3) inotropic state or contractility, and (4) heart rate. Changes in cardiac per- formance are accomplished by mechanisms that alter these four determinants. Venous return, preload, and the Frank–​Starling relationship The relationship described independently by Frank and Starling between end-​diastolic fibre length and force of contraction is shown in Fig. 16.1.2.15 and is the mechanism underlying the in- trinsic ability of the heart to eject whatever blood volume (within limits) it is presented with, and hence to match RV output precisely with LV output. When the ventricle ejects against a constant pres- sure, variations in venous return alter the degree of stretch of the muscle fibres in diastole, and this determines contraction strength and work output. The number of active force-​generating sites in each fibre increases as it lengthens so that, within limits, the force of contraction and stroke work are positively related to end-​diastolic fibre length (heterometric regulation). The relationship is curvi- linear when stroke work is plotted against end-​diastolic pressure as an index of preload, reflecting the exponential relationship between end-​diastolic pressure and end-​diastolic volume. When stroke work is plotted against end-​diastolic volume, the relationship between stroke work and preload is linear. The response of the heart at any particular time depends upon: (1) the intrinsic contractile state of the muscle (i.e. the biochemistry and contractile machinery); (2) the prevailing neurohumoral state (e.g. increased sympathetic outflow produces a more forceful con- traction (positive inotropic effect) at any given end-​diastolic fibre length); (3) extrinsic inotropic influences—​drugs which have either positive or negative inotropic effects. End-diastolic fibre length Stroke work (force of contraction) Positive inotropic effect Negative inotropic effect Fig. 16.1.2.15  The Frank–​Starling relationship: the relation between left ventricular end-​diastolic fibre length and left ventricular stroke work. Also shown, the displacement upward and to the left with an increase in contractility and downward and to the right with a reduction in contractility. Similar but not identical curves are obtained by plotting left ventricular stroke work as one measure of the force of contraction against ventricular end-​diastolic pressure or volume (see text). Similar function curves may be obtained from both ventricles and both atria. 16.1.2  Cardiac physiology 3269 End-​diastolic fibre length is determined by the force distending the ventricle at end-​diastole, and end-​diastolic pressure provides a reasonable indication of this force when the ventricle has normal distensibility or compliance; this is the preload. The systemic venous return and the elastic properties of the myocardium produce the end-​diastolic distending pressure for the right ventricle, and the pul- monary venous return and myocardial elasticity that for the left ven- tricle. For clinical purposes, it is convenient to equate venous return with preload because, as it changes from beat to beat, it adjusts the strength of the subsequent ventricular (and atrial) contraction by varying the force stretching the relaxed cardiac muscle and changing end-​diastolic fibre length. Outflow resistance or afterload Pulmonary and aortic valve opening pressures are determined largely by the pulmonary and systemic vascular resistances, as shown for the latter in Fig. 16.1.2.16. These resistances, together with an inertial component dependent upon the mass of blood within the vessels, the compliance (stiffness) of the vessels, and the physical characteristics of each vascular tree combined with the pul- satile nature of the flow, constitute the impedance to ventricular out- flow. This is the load against which the ventricle must contract and shorten. As this load is not applied in diastole to the relaxed muscle, it then being supported by competent aortic and pulmonary valves, it is described clinically as the afterload: it becomes applied to the muscle only after the ventricle has begun to develop tension. Regulation of systemic arterial blood pressure The regulation of the systemic circulation is well adapted to the vital function of maintaining constant, adequate tissue perfusion. There is a need to maintain a relatively constant arterial blood pressure when there are changes in posture and circulating blood volume. Systemic blood pressure is necessarily relatively high because selective tissue arteriolar tone is used to direct the available systemic blood flow to organs requiring augmented supply of substrate and oxygen as a re- sult of increased work and metabolism; this demands a high tonic arteriolar tone and hence high systemic vascular resistance. Systemic BP = CO × SVR, hence BP is regulated by those factors affecting CO (stroke volume, heart rate), as well as SVR (principally resistance vessel radius). The baroreceptors mediate rapid responses to alter- ations in aortic pressure, while a variety of hormonal and physical factors regulate the circulating blood volume. Baroreceptors The baroreceptor regulatory system comprises two groups of mechano-​ (stretch) receptors, which are widespread in the thoracic cardiovascular system, with high pressure cardiopulmonary baro- receptors located in the systemic arterial system, and low-​pressure volume receptors found in the large systemic veins of the thorax. Of the former, one group is clustered in the carotid sinuses near the bifurcations of the common carotid arteries in the neck, and a second group is located in the arch of the aorta. These respond to an increase in central arterial pressure by the firing of impulses, which pass by the glossopharyngeal (IX) and vagus (X) cranial nerves to the solitary tract nucleus in the medulla and inhibit sympathetic efferent outflow. Efferent impulses from these central connections pass via the right vagus nerve mainly to the sinoatrial node, and via the left vagus mainly to the atrioventricular node. The effect is to decrease the heart rate and the force of atrial contraction. There is also attenu- ation of sympathetic discharge to arteriolar smooth muscle in the limbs and visceral circulation, resulting in a release of peripheral ar- teriolar constriction and, therefore, peripheral vasodilatation. Thus, the immediate response to a rise in arterial pressure is slowing of the heart rate, reduced force of atrial contraction, and reduced vascular resistance. The net effect of this negative feedback system is to offset the elevation in blood pressure. Conversely, lowering blood pressure diminishes stimulation of the stretch receptors and reduces afferent traffic to the solitary tract nucleus, resulting in reduced inhibition of sympathetic outflow. There is, then, a quickening of the heart rate together with peripheral vasoconstriction so that the blood pressure increases. The changes in heart rate take place within 1 to 2 s and changes in vasomotor control within 5 to 6 s. Baroreceptor mechanisms effectively modulate the responses of blood pressure to postural change. Additionally, they adapt to main- tain the normal circadian variation in blood pressure (see ‘Diurnal variation in autonomic function’, later on in this chapter). They also maintain elevated arterial blood pressure in systemic hyperten- sion: the baroreflex acts around a ‘set point’ of blood pressure, and this is altered in systemic hypertension. Sensory input to the reflex is reduced in disorders of the autonomic nervous system (e.g. auto- nomic neuropathy), and in the prolonged weightlessness of space flight. Blood volume The circulating blood volume is relatively small, and a large propor- tion is contained in the veins (capacitance vessels; Fig. 16.1.2.16) so that any change in blood volume will affect venous return and, therefore, cardiac output and blood pressure. When blood volume is large and the veins full, there is little reduction in venous return on standing and cardiac output is maintained. However, when ef- fective blood volume is reduced and the veins are relatively empty, Pressure (mm Hg) 120 80 40 0 Systolic Diastolic TA Aorta Arteries Arterioles Capillaries Venules Veins Vena cava Fig. 16.1.2.16  Diagram of the changes in pressure as blood flows through the systemic circulation. The total cross-​sectional area of the vessels (TA) increases from 4.5 cm2 to 4500 cm2 in the capillaries. The major resistance to flow is at the arteriolar level, associated with the greatest decrease in blood pressure. Modified and reproduced with permission from Ganong WF (2005). Review of medical physiology, 22nd edn. McGraw-​Hill, New York. Section 16  Cardiovascular disorders 3270 on standing there is pooling of blood in the veins of the legs and a reduction in venous return and cardiac output, so that arterial blood pressure falls. Baroreceptor responses become evident within a few beats, the heart rate increases, and cardiac output and blood pressure are restored. Circulating blood volume is kept relatively constant by a combination of mechanisms which include systemic venous stretch (volume) receptors in the great veins and atria, together with the actions of natriuretic peptides, the renin–​angiotensin–​aldosterone system, vasopressin (ADH; AVP), and osmolality. Natriuretic peptides The discovery of secretory granules in the atria of the heart, and the demonstration in 1981 that they produce a natriuretic factor that in- hibits the reabsorption of sodium in the distal tubule of the kidney, enhanced understanding of the regulation of blood volume and car- diac performance. Three natriuretic peptides, all containing a similar 17 amino acid ring structure, have subsequently been identified. • Atrial natriuretic peptide (ANP) is a 28 amino acid peptide pre- sent in the circulation, and concentrations increase during volume expansion. ANP release is also stimulated by vasoconstrictors, atrial tachycardia, endothelin, and sympathetic stimulation of β-​receptors. The right atrium contains about 2–​4 times as much activity as the left, and release of the hormone is mediated largely by atrial wall distension. The effect is to produce a diuresis and to reduce cardiac and circulating blood volume and hence central venous pressure (i.e. the opposite effect to aldosterone). ANP also has a vasodilator action and opposes the vasoconstricting effects of noradrenaline and angiotensin II (inhibits renin and aldos- terone release). • The second natriuretic peptide was identified in brain tissue and is now referred to as B-​type natriuretic peptide (BNP). It is a 32 amino acid peptide, large amounts of which are found in the vent- ricles of the human heart, and circulating levels are increased in ventricular hypertrophy and cardiac failure. B-​type and ANP have similar actions. The half-​life of B-​type is about twice that of ANP, making it easier and more reliable to measure in blood, whence it may be used to diagnose and monitor heart failure. • The third natriuretic peptide to be identified was C-​type natriuretic peptide. This is distributed widely in tissues, but circulating con- centrations are low, hence while ANP and BNP have an essentially endocrine role, CNP is considered to be a paracrine effector. It is released by cardiac endothelium and exerts a local vasodilator ef- fect in complement with the NO and PGI2 systems, thereby consti- tuting at least part of the endothelium-​derived hyperpolarization relaxant activity. It also acts as a paracrine growth/​trophic factor and has anti-​inflammatory activity. In brief summary, natriuretic peptides contribute to the regula- tion of cardiac and circulating blood volume and of blood pressure. Both B-​type natriuretic peptide and N-​terminal pro-​brain natri- uretic peptide (NT-proBNP: an inactive 76 amino acid product of the BNP prohormone, released on BNP cleavage and release) are useful adjuncts to the clinical evaluation of dyspnoeic patients in that levels are elevated when breathlessness is due to cardiac failure. Renin–​angiotensin system The renin–​angiotensin–​aldosterone (RAA) system, which is both local and systemic, is of major importance in the regulation of circulating blood volume and the maintenance of normal blood pressure. Enhanced activity of systemic renin and angiotensin in- creases the production of aldosterone, which promotes reabsorp- tion of sodium by the kidney and expansion of circulating blood volume. All components of the renin–​angiotensin system are dis- tributed widely throughout tissues—​including the brain and the heart—​and increased activation of the system increases the risk of cardiovascular events. Angiotensin II is a potent vasoconstrictor that has a number of additional important actions on the vascu- lature (Fig. 16.1.2.17). The angiotensin-​converting enzyme (ACE) inhibitors in clinical use diminish angiotensin II production lo- cally and in the circulating blood, resulting in vasodilatation and decreased blood pressure. They may be used to offload the failing heart (decrease afterload). Both local and general effects appear important in mediating the benefits that accrue from the use of these drugs in the management of hypertension and congestive cardiac failure, and in the reduc- tion in rates of recurrence of coronary events in ischaemic heart disease by retarding the rate of atherosclerosis. The mechanisms mediating the latter include antioxidant effects, decreasing oxida- tive stress by a reduction in the production of potentially damaging free radicals (effects which are independent of blood pressure), anti-​inflammatory effects, and augmentation of the profibrinolytic effects of bradykinin. Angiotensin II receptor-​blocking drugs have also been shown to produce similar outcomes. Regulation of nitric oxide production A recently recognized contribution to endothelial function, which affects the afterload, is related to nitric oxide production, and its inhibition by asymmetric dimethylarginine (ADMA). Asymmetric dimethylarginine is produced by the physiological degradation of methylated proteins. ADMA inhibits the production of nitric oxide, which is derived directly from l-​arginine, present in all cells. ADMA levels are regulated by the balance between its production and its metabolism. The balance may be disrupted in clinical situ- ations, for example, in renal impairment. Reduced renal function increases the level of ADMA and this reduces endothelial dilatation. ADMA concentrations are also increased by low density lipopro- tein (both native and oxidized), hence ADMA-​induced blunting of NO-​mediated vasodilatation potentially aggravates dyslipidaemic coronary artery disease. Ventricular volume and afterload Ventricular volume also has a major effect on afterload, as pres- sure is equal to force per unit area. The force acting radially on the inner surface of the whole ventricle at any time during systole is the product of the intraventricular pressure and ventricular surface area at that time. If the left ventricle is assumed to be a sphere (surface area = πd2), the force opposing ejection at any time during con- traction is the product of the intracavity pressure and πd2 at that time. Thus, a doubling in left ventricular diameter from a normal value of 5–​10 cm would result in a fourfold increase in the force opposing ejection for the same intracavity systolic pressure; the ven- tricle would need to develop greatly increased wall tension to over- come that force. Because wall tension developed during systole is the major determinant of myocardial oxygen consumption, the contrac- tion will clearly be much less efficient in the larger heart for the same stroke volume and ejection pressure (stroke work). 16.1.2  Cardiac physiology 3271 During a normal heartbeat, the afterload is greatest at the be- ginning of ejection (rapid rise in pressure and maximum volume; Fig. 16.1.2.13), but decreases thereafter as the pressure reaches a plateau and then declines as the ventricle becomes smaller (i.e. its diameter increases). There is, therefore, a matching of the afterload to the declining intensity of the contraction as it proceeds to com- pletion (end-​systole), and fibres shorten at a relatively constant rate. This is less obvious in a large heart with low ejection fraction, where the volume change during ejection is a smaller proportion of the total ventricular volume. The end-​diastolic volume is influenced by preload, afterload, cir- culating blood volume, the inotropic state of the ventricle, heart rate, and neurohumoral influences. It is smaller in the erect than in the horizontal position because of reduced venous return, and it decreases with a moderate increase in heart rate because of an as- sociated positive inotropic effect. The proportion of end-​diastolic volume ejected during systole, the ejection fraction (normal 50–​70%), is a useful index of overall left ventricular function and is easily meas- ured non​invasively by nuclear gated blood-​pool scanning, two-​ dimensional echocardiography, and magnetic resonance imaging techniques. The ejection fraction is found to increase with exercise and with positive inotropic interventions. Values for normal right ventricular ejection fraction are of the same order as those for the left side of the heart. Role of the sympathoadrenal system in normal and failing hearts Catecholamines have positive inotropic, lusitropic, chronotropic, and dromotropic effects on the normal heart. The inotropic effect of catecholamines on the force of contraction is achieved by a pro- tein kinase-​A (PKA)-​mediated phosphorylation of the L-​type Ca2+ channel, which increases the probability of channels opening when the cell is depolarized, thus increasing ICa. Positive lusitropism (myocardial relaxation) occurs by a PKA catalytic subunit-​ mediated phosphorylation of phospholamban which inhibits SERCA2 in its hypophosphorylated state (Fig.  16.1.2.3a):  phos- phorylated phospholamban does not inhibit SERCA2. The effect of phospholamban phosphorylation is thus to activate SERCA2 and stimulate Ca2+ reuptake into the SR, and augment myofibril relax- ation. In addition, PKA phosphorylates cardiac troponin I, and this increases the rate of dissociation of Ca2+ from troponin C, increasing the rate of dissociation of myosin cross-​bridges from actin (i.e. stimulating relaxation). Positive chronotropism is achieved by increasing the frequency of depolarization in the sinoatrial node. Upon stimulation of the sympathoadrenal system, If (generated by HCN channels; Table 16.1.2.2) is activated to depolarize the mem- brane to the threshold level more rapidly and increase the rate of production of action potentials. The positive chronotropism of the sympathoadrenal system is in part mediated by the binding of PKA-​ derived cAMP to these HCN channels. This shifts their voltage de- pendence of activation to more depolarized potentials and increases both the rate of channel opening and the maximal current level. The net result is an increased frequency of depolarization and the heart rate increases. Sympathomimetic agents speed conduction in the AV node (positively dromotropic). In heart failure, the myocyte becomes relatively unresponsive to β-​adrenergic agonists, and consequently phosphorylation of the proteins responsible for the control of contractility is diminished. The β1-​adrenergic receptor abundance is downregulated and the ex- pression of proteins which antagonize β1-​receptor signalling is in- creased, thus the efficacy of β-​agonism is diminished. Many drugs that mitigate heart failure are targeted at the proteins that regulate the inotropic state. There is evidence also that SERCA2 expression is decreased, and this may contribute to the elevated cytoplasmic Ca2+ Renin Angiotensin I Angiotensin II Angiotensin III Aldosterone Vasoconstriction, increased blood pressure Vascular smooth muscle cell proliferation Endothelial dysfunction Inhibition of PAI-1 and PAI-2 Myocyte hypertrophy, ventricular remodelling Vasopressin secretion Extracellular matrix formation Renal tubular sodium reuptake Renal salt and water retention Reduced collagen turnover Increased blood volume Angiotensinogen Angiotensin converting enzyme Angiotensinases Chymase Hypotension Decreased sodium delivery Sympathetic stimulation Fig. 16.1.2.17  The renin–​angiotensin system. Section 16  Cardiovascular disorders 3272 concentrations sometimes seen in diastole during heart failure, with slowed cross-​bridge dissociation kinetics. This forms the mechan- istic basis for the poor relaxation and diastolic dysfunction character- istic of diastolic heart failure, associated with hypophosphorylation of PKA and PKG sites on cardiac titin (connectin, the giant c30,000 amino acid protein responsible for the passive elasticity of the muscle fibre), and the worsened mechanical function of the heart in this condition. Myocardial function is greatly altered by changes in inotropic state or contractility. Positive inotropic effects are thought to be medi- ated by activation of excitation–​contraction coupling mechanisms and are associated with an increased influx of calcium ions into cardiomyocytes and a more powerful contraction. Changes in the in- tensity of excitation–​contraction coupling (homeometric) are inde- pendent of the Frank–​Starling (heterometric) mechanism. Increases in the intensity shift the curve upwards and to the left, and decreases shift it downwards and to the right (Fig. 16.1.2.15). With a positive inotropic effect, the force of contraction, however measured, is in- creased for a given end-​diastolic fibre length and, if the afterload is the same, the initial velocity of fibre shortening is also increased (Fig. 16.1.2.14). In the intact heart there is more complete emptying during systole and hence a lower end-​systolic volume and higher stroke volume. Positive inotropy is achieved by increased PKA/​ cAMP activity, associated with phosphorylation of phospholamban (though with altered lusitropy), sensitization of troponin C to Ca2+, and phosphorylation of L-​type Ca2+ channels. Increased sympathetic stimulation, some drugs, calcium, and an increase in heart rate it- self (the staircase or Bowditch phenomenon; post-​ectopic potenti- ation, see ‘Heart rate’, next section) have positive inotropic effects. An increase in afterload can also cause a small increase in inotropy. Myocardial depressants, such as hypoxia and most anaesthetic drugs, have negative inotropic effects. Increased parasympathetic stimula- tion produces acetylcholine-​mediated negative inotropic effects that are confined almost entirely to the atria because of the anatomical distribution of vagal cholinergic endings in the myocardium. It is difficult to measure inotropic changes accurately in the human heart because changes in the intensity of excitation–​contraction coupling and changes in the Frank–​Starling relationship, though separate, are nevertheless closely interlinked. The peak rate of change of intraventricular pressure (peak dP/​dt) is a useful index of change in contractility (with changes in the maximum rate of pressure rise (+dP/​dtmax) relating to inotropy and changes in the maximum rate of pressure fall (–​dP/​dtmax) relating to lusitropy), provided that preload, afterload, and heart rate remain constant. Heart rate Frequency of contraction is the fourth essential determinant of cardiac performance. Normal heart rate is 60–​100 beats/​min, but varies with age. Tachycardia may be defined as HR more than 100 beats/​min and bradycardia as HR less than 60 beats/​min. Heart rate is regulated by intrinsic and extrinsic mechanisms. The former includes the increased heart rate observed with increased venous return and right atrial stretch (Bainbridge reflex). The latter may be considered as either neural (i.e. based on the autonomic supply to the heart through the two cardiac plexi at the base of the heart, with sympathetic stimulation being positively chronotropic and parasympathetic stimulation being negatively chronotropic) or humoral (e.g. catecholamines, thyroid hormones, and calcium acting as positive chronotropes and muscarinic alkaloids and po- tassium acting as negative chronotropes). Heart rate during rest and exertion may vary from 45 to 200 beats/​min in the healthy young adult. As changes can occur within seconds, an increase in heart rate is the usual and most effective way of producing a rapid increase in cardiac output. It plays the major role in the response to exercise, during which stroke volume does increase (more so in athletes and when in the erect, rather than the supine, position) but the changes are less marked than those of rate. In addition, an in- crease in contraction frequency itself produces a positive inotropic effect, whereby the force of contraction increases and reaches a new steady state within a few beats. This is termed the ‘positive staircase’, Treppe, or Bowditch effect. It may be a consequence of an augmented movement of calcium ions into myocardial cells with increased frequency of action potentials, combined with di- minished time for outward movement of calcium between beats. More forceful contractions also follow premature beats—​the phe- nomenon of post-​extrasystolic potentiation—​and the mechanism is probably the same. The extrasystole occurring prematurely is a weak contraction because of decreased filling time and an uncoor- dinated activation of the ventricle when the ectopic focus is within the ventricle. The next beat is delayed because of the refractory period of the extrasystolic beat, but is a more powerful contraction because of increased filling time and ventricular volume, and in- creased contractility. Calcium-​dependent changes similar to those of the Bowditch effect are probably responsible for the latter, and the increased contractility is independent of volume loading ef- fects. Recently it has become clear that intrinsic circadian clocks are involved in the control of heart rate, with time-​of-​day de- pendent oscillations in clock gene expression. The cardiomyocyte circadian clock influences many myocardial processes, including ion channels. Coronary blood flow Coronary blood flow accounts for about 4% of the cardiac output. The heart extracts most (70%) of the oxygen carried in the coronary circulation under resting conditions, the arteriovenous difference for oxygen across the heart being about 110 ml/​litre, while that for the whole body is only about 40 ml/​litre under resting conditions. Therefore, large increases in myocardial oxygen requirements must be met largely by increases in coronary blood flow, and this may in- crease five-​or sixfold during strenuous exercise. The greater part of this flow is to the left ventricle, of which at least two-​thirds occurs during diastole because of the throttling effect systole has on myo- cardial perfusion. The main coronary arteries are on the superficial (epicardial) surface of the heart, and because of this, and the hin- drance to coronary flow during systole, the subendocardial region of the left ventricle is more vulnerable to perfusion deficits in rela- tion to oxygen need than the outer two-​thirds of the muscle wall. Despite these mechanical problems, flow is normally evenly distrib- uted throughout the myocardium so that when regional coronary blood flow is measured experimentally using injected radioactive microspheres (in dogs), the ratio of endocardial to epicardial flow is approximately unity. In fact, the inner layers of the heart probably receive slightly more blood (up to 10%) than the outer layers. This is consistent with the subendocardium developing more tension than 16.1.2  Cardiac physiology 3273 the subepicardium, and is evidence for a greater rate of myocardial oxygen consumption in the inner layers. Myocardial oxygen requirements and coronary blood flow are finely adjusted and matched, with coronary vascular resistance subject to autoregulation. The nervous system and the heart The heart is richly supplied with sympathetic adrenergic nerves, whose terminals reach atrial and ventricular muscle fibres and im- pinge upon all pacemaker tissue, including the sinoatrial and atrio- ventricular nodes and Purkinje fibres. Sympathetic stimulation leads to an increase in myocardial contractility and heart rate, and in the rate of spread of the activation wave through the atrioven- tricular node and the Purkinje system. This is mediated by local noradrenaline release, which interacts with β-​adrenergic receptors. The key elements in these regulatory mechanisms are calcium ions and cAMP. The activated β-​receptor increases adenyl cyclase activity and the conversion of ATP to cAMP. Non​adrenergic non​cholinergic cotransmitters have recently been isolated and recognized as im- portant adjuncts to autonomic efferent transmission. These include non​peptides such as ATP, dopamine, and (at least in the enteric system) GABA and 5-hydroxytryptamine (5-​HT), but also peptides. Peptide cotransmitters released with noradrenaline and acetylcho- line have now been isolated and shown to influence autonomic function, and include neuropeptide Y (NPY), GnRH, and substance P. Neuropeptide Y is a peptide of 36 amino acids that is colocated with noradrenaline in most sympathetic nerves and is released with sympathetic stimulation. It is a powerful pressor agent with direct arteriolar vasoconstrictor action and also potentiates the pressor ac- tion of noradrenaline. The distribution of parasympathetic fibres is much more limited in the heart, being confined to the sinoatrial and atrioventricular nodes and the atria, with few, if any, fibres reaching the ventricles in humans, except perhaps in anatomical relation to coronary ar- teries and Purkinje tissue. The effects of parasympathetic nerve stimulation are mediated by local acetylcholine release, which slows the heart rate and speed of conduction through the atrioventricular node and Purkinje tissue, and depresses atrial contractility. The negative inotropic effects are associated with a lowering of the con- centration of intracellular cAMP. The effect of the nervous system on the heart at any one time is the sum of the activities of these two opposing control systems. They usually vary reciprocally. Under resting conditions, vagal inhibitory effects predominate, maintaining a slow heart rate, there being vir- tually no sympathetic outflow. With exercise, there is withdrawal of vagal activity and an increase in sympathetic outflow. Afferents from stretch receptors in the carotid sinus and aortic arch—​the baroreceptors—​also have a considerable effect on cardiac perform- ance, this effect being mediated via the adrenergic nervous system and vagal withdrawal. A fall in blood pressure reduces stretching in the carotid sinus and inhibitory afferent traffic so that the sympa- thetic outflow increases. As a consequence of this combined vagal and sympathetic effect, there is a quickening of the heart rate within one or two beats, a positive inotropic effect, and also a constriction of systemic veins and arterioles that increases preload and afterload. Elevation of pressure in the carotid sinus has the reverse effect. In cardiac failure, there is reduced variability in heart rate due to these autonomic mechanisms as there is then a predominance of adren- ergic activity. There are also mechanoreceptors in all four chambers of the heart (identified in dogs) and in the coronary vessels, which give rise to depressor reflexes. Their clinical relevance is uncertain, but they may contribute to the bradycardia and hypotension occurring in some patients with acute myocardial infarction—​in particular to the syn- cope that patients with critical aortic stenosis may experience with the onset of exercise when there is sudden left ventricular distension. Vagal afferents from reflexogenic areas in the infarcting left ventricle may be responsible for the bradycardia, gastric distension, nausea, and vomiting which frequently occur with the onset of inferior or posterior myocardial infarction, but not usually of anterior infarc- tion, which is generally associated with a marked increase in sym- pathetic activity. The cardiac receptors connected to afferent fibres running in cardiac sympathetic nerves, however, are very important because they are responsible for the perception of cardiac pain. Receptors have also been identified (in animals) at the junction of pulmonary veins with the atrial wall. These respond to mechanical distension with increased sympathetic outflow to the sinus node and inhibition of secretion of antidiuretic hormone from the posterior lobe of the pituitary gland. The result is a quickening of the heart rate and diuresis. Autonomic efferent activity The autonomic outflow to the heart is controlled by multiple inte- grative sites within the central nervous system, with complex inter- actions between afferent and central inputs. Autonomic responses are mediated through the suprapontine and bulbospinal pathways—​ both those arising ‘reflexively’ and those arising from various types of volitional or central ‘command’. Nevertheless, intrinsic mechan- isms are sufficient for adequate cardiac function in the absence of autonomic control, as prolonged survival after cardiac transplant- ation has shown. But in the denervated heart, dependent on intrinsic and humoral mechanisms, there is blunting of the normally rapid physiological adjustments mediated by the autonomic nervous system. Diurnal variation in autonomic function Variations in vascular tone and control of blood pressure and of hormone secretion and platelet function occur in a predictable way throughout the 24-​h cycle. In normal subjects, there is a cir- cadian rhythm of blood pressure changes that is not seen in pa- tients after cardiac transplantation, who have denervated hearts. There is a decline in both blood pressure and heart rate at night, and increases in both soon after wakening. This is due to a normal adrenergic surge in the early morning, which results in increased vascular tone and blood pressure. Increased forearm vascular re- sistance in the morning, with a reduction in the afternoon and evening, can be clearly identified in humans by assessing responses to α-​adrenergic blockade. It is likely that this occurs in coronary vessels as well. Measurable early morning increases in circulating catecholamines and in the propensity for platelets to aggregate can also be documented. The circadian rhythm of autonomic function is correlated with a significant tendency for myocardial infarction and sudden cardiac death to occur more frequently in the morning, soon after wakening. Section 16  Cardiovascular disorders 3274 There is also an increase in the occurrence of angina pectoris in the early morning, independent of the level of physical activity. Exercise and the heart: Cardiac reserve The heart responds to exercise with an increase in cardiac output, and values of 30 litres/​min may be achieved in a trained athlete. Exercising muscles extract more oxygen from the blood, but the re- sponse of the cardiac output is the principal determinant of delivery of oxygen to tissues and is the limiting factor for aerobic exercise. The cardiac response to exercise involves all the mechanisms al- ready discussed. Interaction within the central nervous system between higher and autonomic centres augments sympathetic dis- charge, and there is a withdrawal of vagal parasympathetic out- flow. The heart rate increases immediately, and redistribution of peripheral flow increases venous return and preload (increased end-​diastolic volume). There is venoconstriction, particularly in the large-​volume splanchnic circulation, and vasoconstriction and increased oxygen extraction in inactive parts. In active parts, there is vasodilation. This is most evident in the vascular beds of the ex- ercising skeletal muscles and of the heart itself. The overall effect is a marked lowering of total peripheral vascular resistance, which re- duces afterload and encourages greater systolic emptying of the left ventricle (decreased end-​systolic volume). Stroke volume increases during exercise in the upright position. During light to moderate exercise (running or cycling), for up to about 80% of maximum ex- ercise capacity there is an almost linear relationship between work intensity and heart rate response, cardiac output, and oxygen up- take. With further exercise, the heart rate and cardiac output re- sponses level off while additional increases in oxygen consumption occur by increased oxygen extraction and a greater widening of the arteriovenous difference for oxygen. The venous return increases in relation to the elevated cardiac output. Vasodilation in the working muscles that receive the bulk of the redirected blood permits high flow rates into the systemic venous capacitance vessels. Because of adrenergically mediated venoconstriction, the capacity of this system is reduced, so that blood moves rapidly into the right atrium. Venous return is also enhanced by the pumping action of the rhythmically contracting working muscles, by a decrease in intrathoracic pressure with forced inspiration, and by an increase in intra-​abdominal pressure. The augmented pulmonary blood flow results in only slight increases in pulmonary artery pressure because of the distensibility of the large pulmonary arteries, an increased area of the pulmonary ca- pillary bed due to the recruitment of more capillaries, and the low resistance offered by the normal pulmonary circulation (see Table 16.1.2.3), that is, the response of the pulmonary vasculature to in- creased RV output (CO) and increased PA pressure is to dilate pul- monary blood vessels and decrease pulmonary vascular resistance. Since the pulmonary circulation is in series with the right and left sides of the heart, this is a vital mechanism to permit the increased CO to traverse the lungs and explains why the RV does not need to maintain such high pressures as the LV, and hence is much thinner. The elevated cardiac output and larger stroke volume result in in- creased systolic blood pressure and pulse pressure, even though the afterload itself is reduced. Enhanced neurohumoral activity from ad- renergic stimulation of the heart and the adrenal glands (increased circulating adrenaline and noradrenaline) effect positive inotropic changes, to which tachycardia also contributes because of the Bowditch effect. There is a shift in the Frank–​Starling relationship to the left, increased speed and force of cardiac contraction, and ele- vated ejection fraction and stroke volume. Peak +dP/​dt is increased, and there is a rapid rise in coronary blood flow to meet myocar- dial oxygen requirements that increase linearly with the product of systolic blood pressure and heart rate. However, the increased heart rate is achieved by a shortened diastolic interval, leaving less time for coronary flow to occur. This may become limiting at very high heart rates. During moderate exercise, these changes together re- sult in a decreased or unaltered end-​diastolic volume and decreased end-​systolic volume. With severe exercise, end-​diastolic dimensions and end-​diastolic fibre length are slightly increased and the Frank–​ Starling mechanism then operates and further augments the force of contraction. The haemodynamic and ventilatory responses evoked by an in- crease to a new steady workload take about 2–​3 min to equilibrate and adjust oxygen supply to the greater demand. Protocols for ex- ercise testing are therefore usually based on work increments at 3-​ min intervals to allow time for a new ‘steady state’ to occur (e.g. in the standard Bruce exercise protocol). A steady state becomes pro- gressively more difficult to maintain as maximal exercise capacity is approached. Glycogen is used by the working skeletal muscles as a source of stored energy, and the anaerobic metabolism which ensues produces lactic acidosis and thereby further increases ven- tilation. As all cardiopulmonary transport mechanisms reach max- imum levels, shortness of breath, fatigue, and muscle pain become limiting symptoms; motivation then becomes a determinant of the duration of exercise. Ageing reduces the efficacy of cardiopul- monary transport mechanisms and, hence, exercise capacity. The heart rate response at peak exercise reflects this. In healthy individ- uals aged 20 years it is about 200 beats/​min, and at 65 years about 170 beats/​min. When exercise stops, the cardiopulmonary and metabolic changes return rapidly to resting levels, the rate following an exponential pat- tern in the first few minutes; the excretion and metabolism of lac- tate and other substances, and the dissipation of heat generated take longer (time constant of about 15 min or more). Reduced circulatory function slows the recovery rate. Training effects Regular exercise to about 60% of maximal heart rate for 20–​30 min three times a week is the minimum requirement for improved effort tolerance due to a training effect. The resting heart rate be- comes slower, while the cardiac output is maintained by an in- creased end-​diastolic volume and ejection fraction, and therefore stroke volume. In a ‘trained’ exercising individual, there is a reduced heart rate response to a standard submaximal workload, and sys- temic blood flow is more effectively distributed away from visceral and skin circulations to working muscles. Changes in muscle mito- chondria permit increased oxygen consumption. There is suggestive animal evidence that prolonged endurance training increases the calibre of coronary arteries and enlarges capillary surface area rela- tive to cardiac muscle mass. Myocardial protein synthesis increases. Adrenergic mechanisms appear to be involved in mediating this trophic response. Rhythmic exercise (e.g. running) and isometric exercise (e.g. weightlifting) have different physiological effects. The blood pressure rises disproportionately during the latter. The mech- anisms are partly reflex and partly mechanical from the contracting 16.1.2  Cardiac physiology 3275 muscles. Isometric exercise training is not recommended for cardiac patients because of the increased afterload it imposes. Regular exercise has other effects: it increases feelings of well-​ being and lowers blood pressure in normotensive and mildly hyper- tensive subjects. There are also diverse exercise-​related hormonal changes, including increased insulin sensitivity and the reduction of glucose-​stimulated insulin secretion—​of particular relevance to patients with type 2 diabetes. Regular exercise also improves the availability of nitric oxide, with its important vascular effects. These are considered elsewhere. To summarize, changes in the four essential determinants of cardiac function—​preload, afterload, heart rate, and contractility—​ combine to augment cardiac output and oxygen delivery during exercise. Measurement of the cardiovascular response to exercise is essential for the objective assessment of cardiac function. FURTHER READING Abdel-​Aleem S, Lowe JE (2012). Cardiac metabolism in health and di- sease. Kluwer Academic Publishers, New York, NY. Bers DM (2001). Excitation-​contraction coupling and cardiac contrac- tile force, 2nd edition. Kluwer, Dordrecht. Durgan DJ, Young ME (2010). The cardiomyocyte circadian clock: emerging roles in health and disease. Circ Res, 106, 647–​58. Ganong WF (2005). Review of medical physiology, 22nd edition. McGraw-​Hill, New York. Herring N, Paterson DJ (2018). Levick’s introduction to cardiovascular physiology, 6th edition. CRC Press, Boca Raton, FL. Houser SR, Margulies KB (2003). Is depressed myocyte contractility centrally involved in heart failure? Circ Res, 92, 350–​8. Ieda M, Zimmerman W-​H (2017). Cardiac regeneration (cardiac and vascular biology). Springer, New York, NY. Kaestner L (2012). Calcium signalling: approaches and findings in the heart and blood. Springer Science Media, Berlin. Kardami E, et al. (2010). Cardiac cell biology. Springer Science Media, Berlin. Katz AM (2006). Physiology of the heart, 4th edition. Lippincott Williams and Wilkins, Philadelphia, PA. Ko Y-​S, et al. (2004). Three-​dimensional reconstruction of the rabbit atrioventricular conduction axis by combining histological, desmin, and connexin mapping data. Circulation, 109, 1172–​9. Libby P, et al. (ed.) (2008). Braunwald’s heart disease: a textbook of cardi- ovascular medicine, 8th edition. Saunders Elsevier, Philadelphia, PA. Opie LH (2013). Stunning, hibernation and calcium in myocardial is- chemia and reperfusion. Kluwer Academic Publishers, Boston, MA. O’Rourke B (2010). Be still, my beating heart: never! Circ Res, 106, 238–​9. Pappano AJ, Wier WG (2019). Cardiovascular physiology, 11th edition. Mosby Physiology Series, Elsevier, Philadelphia, PA. Severs NJ (2000). The cardiac muscle cell. BioEssays, 22, 188–​99. Severs NJ, et al. (2004). Gap junction alterations in human cardiac dis- ease. Cardiovasc Res, 62, 368–​77. Solaro RJ, Tardiff JC (2013). Biophysics of the failing heart: physics and biology of heart muscle. Springer Science Media, Berlin. Willis MS, Homeister JW, Stone J (2014). Cellular and molecular pathobiology of cardiovascular disease. Academic Press–​Elsevier, Amsterdam. Young ME (2006). The circadian clock within the heart: potential in- fluence on myocardial gene expression, metabolism, and function. Am J Physiol Heart Circ Physiol, 290, 1–​16. Zipes DP, Jalife J (2013). Cardiac electrophysiology, 6th edition. Saunders Elsevier, Philadelphia, PA. 16.10 Tumours of the heart 3544 Thomas A. Traill 16.10 Tumours of the heart 3544 Thomas A. Traill ESSENTIALS Cardiac myxoma Cardiac myxomas are rare benign tumours that grow in the lumen of the atria, usually the left. Most are sporadic, but they can be asso- ciated with the Carney complex, where unusual freckling is typically the most obvious clinical clue. Symptoms and signs most commonly mimic those of mitral sten- osis. Systemic emboli occur in about 40% of cases. Constitutional effects predominate in a few patients who present with what seems to be an obscure multisystem disorder. In many patients, specific car- diovascular signs are inconspicuous or absent: an audible ‘tumour plop’ in early diastole, analogous to a mitral opening snap, is often reported only after the diagnosis is established. The diagnosis is almost always made by echocardiography. Treatment is by urgent surgical removal. Recurrence is uncommon, provided excision has been complete, except in Carney complex. Other tumours of the heart The most common tumour seen in adult patients is the benign papillary fibroelastoma, which should be surgically removed only if it has been discovered in the search for a source of otherwise unexplained embolism. Primary cardiac sarcomas are found more often in the right heart than in the left. Surgical resection is often attempted for obstructive symptoms, but recurrence and metastasis are common, and long-​ term outcome is very poor. Microscopic secondary deposits within the myocardium can often be found in patients who die of metastatic cancer, but these are rarely of clinical importance. Intraluminal spread of cancer to the heart by direct extension up the inferior vena cava is a particular fea- ture of renal cell carcinoma. Cardiac myxoma Cardiac myxomas are benign, typically golf ball-​sized, tumours that grow in the lumen of the atria, usually the left, attached by a stalk to the atrial septum. They are not common, but are important because they can present in several ways to general physicians, and because most can straightforwardly and permanently be removed by heart surgery. They are easily demonstrated by conventional transthoracic echocardiography, and it is usually the echocardiographer who makes the diagnosis; seldom has the patient been referred with this possibility in mind. Estimates of the prevalence of such a rare con- dition are necessarily approximate and range from 1 to 5 per 10 000 in autopsy series, or 2 per 100 000 in the general population, with a sex ratio of 2:1 in favour of women. As a cause of left atrial obstruc- tion, myxomas are 200–​400 times less common than mitral stenosis. Most patients are between 30 and 60 years of age, but there are re- ports of tumours occurring in infants and in older people. Most myxomas are sporadic, unassociated with other diseases, but there is at least one Mendelian syndrome involving myxoma, best named the Carney complex. This is caused by mutation in the protein kinase A regulatory subunit-​1-α gene (Carney complex type 1) or mutations in other genes and characterized by lentiginosis, multiple myxomas (most of them cardiac), skin fibromas, and various kinds of endocrine overactivity, which has included Cushing’s syndrome caused by pigmented adrenocortical hyperplasia, acromegaly, and Sertoli cell tumour. Unlike the usual kind of atrial myxoma, myx- omas in Carney’s syndrome may arise anywhere in the heart, are commonly multiple, and frequently recur. Inheritance of this rare disease is autosomal dominant, with centrofacial freckling as the most obvious outward marker of the phenotype. This freckling often involves unusual areas, for instance, the lips, conjunctiva, and vulva. Pathology Cardiac myxomas are benign. Local invasion is unknown and meta- static growth is exceptional, despite the lesions’ situation in the bloodstream. They take the form of polypoid masses arising from a stalk, ranging in size from 3 cm to as much as 10 cm or more, with a smooth or lobulated surface and gelatinous consistency. They are frequently covered with more or less adherent thrombus. More than 75% occur within the left atrium, with the base of the pedicle arising from the fossa ovalis or its rim. Occasionally, they arise from the base of the mitral valve leaflets, from the posterior part of the left atrium, or from within the right atrium. Sometimes they grow in both atria, in the form of a dumbbell. Ventricular myxomas are exceptional and seen almost exclusively as part of Carney’s syndrome. Left atrial 16.10 Tumours of the heart Thomas A. Traill 16.10  Tumours of the heart 3545 myxomas are not generally as large as those in the right atrium at the time they are first detected. The latter may almost fill the right atrium before they begin to obstruct systemic venous return. The histology is that of a loosely woven, sparsely cellular, con- nective tissue tumour with very infrequent mitotic figures. Several cell types are identifiable, including undifferentiated stellate and pol- ygonal cells, as well as smaller numbers of fibroblasts, smooth muscle cells, and endothelial cells. Among these are found macrophages and plasma cells, and rarely other mesodermal tissues, including bone. Cytogenetic studies fit with the general presumption that these in- dolent masses are indeed neoplastic, but immunohistochemical studies of differentiation markers do not clearly define the cell type of origin. It is suggested that the source is a primitive multipotential mesenchymal cell and that the predilection of these tumours for the atrial septum reflects the abundance of such cells in this region. Clinical features Left atrial obstruction The most common symptoms and signs mimic those of mitral stenosis, with left ventricular inflow obstruction as the chief patho- physiological change. The presenting symptoms are progressive breathlessness, orthopnoea, paroxysmal nocturnal dyspnoea, fluid retention, and atrial arrhythmias. Examination suggests rheumatic heart disease, and before the routine use of ultrasonography a few such patients were referred for mitral valve surgery and the lesion was first diagnosed at operation. Some patients may develop pul- monary hypertension before the diagnosis becomes apparent. Systemic embolism Systemic emboli occur in about 40% of patients and are frequently the first manifestation of disease. In contrast to mitral stenosis, such emboli often occur while patients are in sinus rhythm. Emboli may be sizeable, large enough even to occlude the aortic bifurca- tion, and, besides thrombus, they frequently contain tumour ma- terial, hence histological examination may be diagnostic. When systemic emboli are removed from patients, they should always be sent for histological analysis. Typically, patients with systemic em- bolism are referred for echocardiography, and the diagnosis is then easily made. Constitutional effects Constitutional effects of the neoplasm predominate in a few patients who present with what seems to be an obscure multisystem disorder. Symptoms and signs include fever, weight loss (which is more con- spicuous than in mitral stenosis and often occurs without severe left atrial obstruction), Raynaud’s phenomenon (rare), finger clubbing (rare), a raised erythrocyte sedimentation rate (present in about 60% of patients), and abnormal serum proteins with elevated immuno- globulin levels. These changes are usually attributed to abnormal proteins secreted by the tumour, although the nature of these has not been determined. Other haematological abnormalities include an- aemia, which may be due to mechanical haemolysis, polycythaemia, associated particularly with right atrial tumours, leucocytosis, and thrombocytopenia. Such constitutional changes may prompt an ini- tial diagnosis of infective endocarditis in patients who have heart murmurs, or lead to the suspicion of autoimmune rheumatic or vas- culitic disease, or of occult cancer. Physical signs In many patients, specific cardiovascular signs of myxoma are in- conspicuous or absent. In others, they vary from a prominent first heart sound to obvious changes similar to those of mitral valve disease. These include apical systolic murmurs, somewhat more common than diastolic rumbles, and—​in some patients—​signs of pulmonary hypertension, with accentuated pulmonary closure and tricuspid regurgitation. Some may have an audible ‘tumour plop’ in early diastole, analogous to a mitral opening snap, but this is often reported only after echocardiographic diagnosis. On combined echocardiographic and phonocardiographic recordings, the plop is seen to coincide with the end of the tumour’s downward movement into the ventricle, usually a short time after mitral valve opening. A rare but specific feature of the condition is variation of the aus- cultatory findings with change in posture; this may be particularly obvious in right atrial tumours. Investigations Chest radiography and electrocardiography do not help to distin- guish myxoma from mitral valve disease. Left atrial enlargement is common but seldom marked, and signs of pulmonary venous hypertension are infrequent. Calcification within the tumour is rarely demonstrable. Myxomas may be identified as filling defects on CT examinations of the chest. Echocardiography While the first account of left atrial myxoma diagnosed during life was not until 1951, it is now exceptional for the diagnosis to be made first at autopsy. This is chiefly attributable to the wide avail- ability of echocardiography, which has proved itself both reliable and specific for recognizing these tumours. It is no accident that the echocardiographic appearance of these lesions was among the first clinical reports by ultrasonographers in 1959. Fig. 16.10.1 illustrates a typical two-​dimensional transthoracic echocardio- gram from a patient with left atrial myxoma, and Fig. 16.10.2 images obtained from a transoesophageal approach in a different patient. A video recording would demonstrate the mobility of the mass as it flops to and fro within the atrium, restrained only by its peduncle. Transoesophageal echocardiography affords the opportunity to examine the tumour and its attachment with great precision; generally, this extra clarity is unnecessary, but on occasion the transoesophageal technique is helpful if there is difficulty in differentiating tumour from an atrial thrombus. The differential diagnosis of left atrial myxoma is seldom diffi- cult. Large masses may occasionally be difficult to distinguish from left atrial ball thrombus—​a lesion that is even rarer than myxoma. Smaller left atrial masses may be papillary fibroelastomas or in- fective vegetations caused by endocarditis. These can usually be dis- tinguished by their clinical context. Masses in the right atrium may also be due to thrombus, sometimes propagated from the inferior vena cava, or occasionally venous extension of abdominal cancers, particularly renal cell cancer. In a few patients, abundant strands of the Chiari network of right atrial trabeculation may give rise to similar echocardiographic appearances. Myxoma is the only neo- plasm of the heart to be found within its lumen: other cardiac neo- plasms grow within the walls. section 16  Cardiovascular disorders 3546 Other imaging Myxomas can also be identified by MR imaging (Fig. 16.10.3). Angiography has no role in diagnosis of myxoma, although it may be required as a prelude to surgery in the older patient in whom there is, or might be, coronary artery disease. Treatment and prognosis Atrial myxoma is treated by urgent surgical removal (Fig. 16.10.4). The risk is low, comparable to that of surgery for mitral valve disease. It is important to ensure complete re- moval of the base by excising a full-​thickness button of the (a) (b) (c) (d) (e) (f) Fig. 16.10.1  A large left atrial myxoma (T) recorded from the parasternal long-​axis (a, b) and from the apical four-​chamber views (c, d) in systole (a, c) and diastole (b, d). During diastole, the tumour prolapses into the left ventricle (LV), completely obstructing the mitral valve orifice (b, d). (e) M-​mode recording at the level of the mitral valve of a prolapsing left atrial myxoma. A dense array of wavy tumour echoes is seen behind the anterior leaflet of the mitral valve. (f) Continuous wave Doppler recording of tricuspid regurgitation velocity of the same patient. Peak velocity is 5 m/​s, corresponding to a 100 mm Hg transtricuspid gradient. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. From Lancellotti P, Zamorano J, Habib G, Badano L (eds) (2017). The EACVI textbook of echocardiography, 2nd edition, © European Society of Cardiology, by permission of Oxford University Press. 16.10  Tumours of the heart 3547 Fig. 16.10.2  A longitudinal transoesophageal view of a large left atrial myxoma (T). In systole (left) it remains inside the left atrium, while in diastole (right) it enters the mitral valve orifice, virtually occluding the orifice. Ao, aorta; LA, left atrium; LV, left ventricle. From Lancellotti P, Zamorano J, Habib G, Badano L (eds) (2017). The EACVI textbook of echocardiography, 2nd edition, © European Society of Cardiology, by permission of Oxford University Press. Fig. 16.10.3  A large left atrial myxoma is attached to the interatrial septum (*). (Top) Steady-​state free precession (SSFP) cine sequence in the HLA (left) and left ventricular outflow tract (LVOT; right) views. The myxoma prolapses through the mitral valve in diastole, causing significant obstruction to flow and mimicking mitral stenosis. (Bottom) T1-​weighted turbo spin echo (TSE) images with fat saturation, highlighting the tumour against the low signal of the moving blood. From Myerson SG, Francis J, Neubauer S (eds) (2013). Cardiovascular magnetic resonance (Oxford specialist handbooks in cardiology), by permission of Oxford University Press. section 16  Cardiovascular disorders 3548 atrial septum, the resulting defect being repaired with a small patch. Functional results of surgery are good. Some patients are left with mitral regurgitation, but this is seldom severe. Recurrence is un- common, provided excision has been complete, except in Carney’s syndrome. In these patients, regular echocardiographic follow-​up is required, at intervals of 6 months. The rare occurrence, after ex- cision, of the usual kind of myxoma generally occurs within the first 2 years; thereafter, follow-​up can safely be infrequent. Other tumours of the heart Although each individually is rare, taken together the other tu- mours of the heart have an incidence that roughly equals that of myxoma. They include benign lesions, seen especially in children; sarcomas; and secondary involvement by metastasis or direct tu- mour extension. They are generally first recognized or suspected during echocardiography. MRI, or occasionally echo-​directed transvenous biopsy, usually yields the diagnosis. Benign cardiac tumours Papillary fibroelastoma The most common tumour seen in adult patients is the papillary fibroelastoma, a small pedunculated mass that hangs off one of the left-​sided valve leaflets, usually the mitral valve. Its echocardiographic appearance is very characteristic. The size of the mass and presence of a peduncle distinguish this small tumour from the usual kind of Lambl’s excrescence, but histologically they are identical and, like Lambl’s excrescences, papillary fibroelastomas probably arise through organization of fibrinous material that collects at the trailing edges of the valve leaflets. Their importance lies in the fact that they have been labelled as a potential source of systemic embolism, and that some authors have recommended they should be removed as a matter of routine. The evidence to support this view is thin, and the author’s recommendation is to remove them only if they have been discovered in the search for a source of otherwise unexplained em- bolism. If they are an incidental echocardiographic finding, then it is safe to leave them alone; aspirin treatment is recommended. Fibroma, rhabdomyoma, hamartoma, and haemangioma These are tumours of childhood, rhabdomyoma being the character- istic cardiac tumour in patients with tuberous sclerosis. In contrast to myxomas and fibroelastomas, they grow within the myocardium, not into the lumen of the heart. Rhabdomyomas are usually asymp- tomatic, and when they are they should be left alone, since most re- gress spontaneously. Fibromas and hamartomas are both very rare, presenting with arrhythmias (particularly ventricular hamartomas or Purkinje cell tumours) or with haemodynamic abnormalities caused by their mass effect (Fig. 16.10.5). They require surgical excision, and when this is feasible the long-​term results of treatment are very good. Haemangiomas, also very rare, tend to grow and to develop multiple feeding vessels, so surgical excision is usually recommended. Cardiac sarcoma Primary cardiac sarcomas are found more often in the right heart than in the left (Fig. 16.10.6), and can have one of several cell types. Fig. 16.10.4  Left atrial myxomas that were removed surgically. Note the difference in appearance: the top myxoma has a smooth surface while the bottom one is villous, more friable, and prone to tissue fragmentation and embolism. Courtesy of Rute Couto MD, and Rui Rodrigues MD, from Lancellotti P, Zamorano J, Habib G, Badano L (eds) (2017). The EACVI textbook of echocardiography, 2nd edition, © European Society of Cardiology, by permission of Oxford University Press. Fig. 16.10.5  Apical four-​chamber view from a young child showing a voluminous fibroma (arrow) located in the interventricular septum, causing left ventricular outflow tract obstruction. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. Courtesy of Rui Anjos, MD, from Lancellotti P, Zamorano J, Habib G, Badano L (eds) (2017). The EACVI textbook of echocardiography, 2nd edition, © European Society of Cardiology, by permission of Oxford University Press. 16.10  Tumours of the heart 3549 Hemangiosarcoma is the most common, typically developing in the right atrium. Rhabdomyosarcoma may develop in the ventricular septum or in the right ventricular outflow tract, as may the still rarer osteosarcoma, or tumours that are undifferentiated. Since these tu- mours often present with mechanical effects, typically obstruction at the atrial or outflow tract level, surgical resection is often attempted. However, recurrence and metastasis are common, and long-​term outcome is very poor. Cardiac involvement by other malignancies Microscopic secondary deposits within the myocardium can often be found in patients who die of metastatic cancer, but intramyocardial secondaries of a size large enough to be of clinical importance are very rare (Fig. 16.10.7). By contrast, pericardial involvement by lymphoma, or by cancers of the lung, breast, pancreas, and other tumours is not un- common, and may sometimes be the first presentation of the tumour (see Chapter 16.8). Treatment is analogous to that of malignant pleural effusions, with drainage, creation of a window, or intrapericardial chemotherapy, depending on the rest of the clinical situation. Intraluminal spread of cancer, by direct extension up the inferior vena cava, is a particular feature of renal cell carcinoma. Diagnosis by echocardiography is generally obvious, as the tumour has a very characteristic appearance as it waves like seaweed in the right atrium and even dangles through the rest of the right heart. It may prove possible to resect the cava, along with the kidney and the tumour mass, under circulatory arrest. Fig. 16.10.6  Apical four-​chamber (left) and two-​chamber (right) views of a left atrial mass (arrows) that corresponded to a primary sarcoma removed completely with surgery. LV, left ventricle; RA, right atrium; RV, right ventricle. From Lancellotti P, Zamorano J, Habib G, Badano L (eds) (2017). The EACVI textbook of echocardiography, 2nd edition, © European Society of Cardiology, by permission of Oxford University Press. Fig. 16.10.7  A bulky right-​sided metastasis (T) causing right ventricular outflow obstruction in a patient with a primary germ cell tumour, which presented with syncope. A small pericardial effusion is also present. Ao, aorta; LA, left atrium; LV, left ventricle; RA, right atrium. From Lancellotti P, Zamorano J, Habib G, Badano L (eds) (2017). The EACVI textbook of echocardiography, 2nd edition, © European Society of Cardiology, by permission of Oxford University Press. section 16  Cardiovascular disorders 3550 FURTHER READING Cardiac myxoma Greenwood WF (1968). Profile of atrial myxoma. Am J Cardiol, 21, 367–​75. Lee KS, et  al. (2017). Surgical resection of cardiac myxoma—​a 30-​year single institutional experience. J Cardiothorac Surg, 12(1), 18. Pucci A, et al. (2000). Histopathologic and clinical characterization of cardiac myxoma: review of 53 cases from a single institution. Am Heart J, 140, 134–​8. Stratakis CA, KIrschner LS, Carney JA (2001). Clinical and mo- lecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation. J Clin Endocrinol Metab, 86, 4041–6. Wilkes D, McDermott DA, Basson CT (2005). Clinical phenotypes and molecular genetic mechanisms of Carney complex. Lancet Oncol, 6, 501–​8. Other tumours of the heart Burke A, Jeudy J Jr, Virmani R (2008). Cardiac tumours: an update. Heart, 94, 117–​23. Chen TW, et al. (2019). Primary cardiac sarcomas: a multi-national retrospective review. Cancer Med, 8, 104–10. Lee E, et al. (2018). Primary cardiac tumors associated with genetic syndromes: a comprehensive review. Pediatr Radiol, 48, 156–64. 16.12 Congenital heart disease in the adult 3559 S 16.12 Congenital heart disease in the adult 3559 S.A. Thorne ESSENTIALS Adults with congenital heart disease are a growing population, and now outnumber children with congenital heart disease in the United Kingdom. Many patients with repaired hearts can now, with spe- cialist care, expect to live a normal or near normal lifespan. Other survivors have complex, surgically altered hearts and circulations that reflect the surgical and interventional practices of the preceding two decades. Their long-​term outlook is unknown and they remain at lifelong risk of complications that may require further intervention. The organization of services to provide specialist care is key to their long-​term survival. The language of congenital heart disease The classification and description of complex congenital heart disease can appear intimidating, but should be easily understood by using a simple physiological approach that takes into account whether a condition is cyanotic or acyanotic, whether there is a shunt, and the implications of the morphology for pulmonary blood flow. The description of the congenitally malformed heart is aided by a sequential segmental analysis of the relationship of the three cardiac segments, which makes it possible to understand and describe how a complex heart is connected. The three segments to be considered are: (1) the atriums; (2) the ventricles; (3) the great vessels. The next step is to describe how each segment connects to the others. Cyanosis and pulmonary hypertension Cyanosis occurs as a result of a right-​to-​left shunt, with its natural history determined by the pulmonary blood flow. If pulmonary blood flow is limited (e.g. by pulmonary stenosis in the presence of a large ventricular septal defect), then pulmonary blood flow and ar- terial oxygen will be low, as will pulmonary artery pressure. Cyanotic patients with low or normal pulmonary artery pressure are usually amenable to surgical repair that abolishes the cyanosis. By con- trast, if the pulmonary circulation is unprotected (e.g. if the defect includes a large ventricular septal defect and no pulmonary stenosis), then pulmonary blood flow will be high and at high pressure, pul- monary vascular remodelling will occur, and—​without intervention—​ pulmonary vascular disease will eventually develop (pulmonary arterial hypertension; the Eisenmenger syndrome). Once pulmonary vascular disease is established, it is not possible to repair the defect and abolish the right-​to-​left shunt. The right ventricle Preservation of ventricular function is fundamental in allowing long-​ term survival with a good quality of life. The right ventricle is a key factor in the long-​term outcome of many congenital cardiac condi- tions. It may fail as a result of either long-​standing pressure or volume overload. (1) Pressure loading—​this occurs in patients in whom the right ventricle supports the systemic circulation, such as those with congenitally corrected transposition of the great arteries, and in those who underwent interatrial repair (Mustard or Senning operation) of simple transposition of the great arteries. The right ventricle is hyper- trophied, and ultimately fails, with tricuspid regurgitation secondary to annular dilatation hastening the decline. (2) Volume loading—​this commonly occurs as a result of pulmonary regurgitation secondary to pulmonary valvotomy or repair of tetralogy of Fallot in early life. There may be no audible murmur because there are often only remnants of pulmonary valve tissue, such that the regurgitant flow is laminar. Partly because of the lack of physical signs, and partly because pulmonary regurgitation is usually tolerated for many years before the right ven- tricle begins to fail, patients may present very late with a very dilated and impaired ventricle. Long-​standing large atrial septal defects pro- duce similar right ventricular volume loading effects. The right ven- tricle may be inherently abnormal, as in Ebstein anomaly where a combination of a functionally small ventricle and volume loading from tricuspid regurgitation may cause the right ventricle to fail. The Fontan circulation Hearts which have only one functional ventricle present a par- ticularly difficult challenge. Patients are cyanosed, and only a few will reach adulthood if left unoperated. The ultimate aim for pa- tients with only one functional ventricle is a Fontan circulation: a palliative approach that reduces ventricular volume loading and abolishes cyanosis. It is critically dependent on a low pulmonary vascular resistance, hence early control of pulmonary blood flow is paramount. If pulmonary blood flow is too high, it is controlled by placing a pulmonary artery band (i.e. by the creation of iatrogenic, protective pulmonary stenosis). If pulmonary blood flow is too low, the infant will not thrive, and pulmonary blood supply is augmented 16.12 Congenital heart disease in the adult S.A. Thorne section 16  Cardiovascular disorders 3560 by means of a systemic to pulmonary artery shunt. There are many variations of the Fontan operation, but all involve the separation of pulmonary and systemic circulations by using the single ventricle to support the systemic circulation and by connecting the systemic veins directly (or via the right atrium) to the pulmonary artery. There is thus no ‘pump’ in the pulmonary circulation, so although cyan- osis is abolished, the Fontan circulation is one of a chronic low output state. Thus, although the Fontan approach enables most pa- tients with a single ventricle to reach adulthood, they have a fragile circulation and will develop a range of complications. They are par- ticularly at risk if they have a tachyarrhythmia or acute non​cardiac illness, since they tolerate such insults poorly and are dependent on their medical teams’ understanding of their circulation to ensure good hydration, avoidance of vasodilatation, and rapid restoration of sinus rhythm. Tachyarrhythmia Tachyarrhythmias are a major cause of sudden death in patients with congenital heart disease, with scar-​related atrial tachyarrhythmias being common in those who have had previous cardiac surgery, and probably a commoner cause of death than ventricular arrhythmias. Atrial tachyarrthymias are the reason that patients who underwent interatrial repair (Mustard or Senning operations) of transposition of the great arteries are the congenital cardiac group with the highest incidence of sudden death. Their surgically created atrial ‘baffles’ mean that atrial function is abnormal, and ventricular filling is im- paired, particularly at high heart rates. Atrial flutter is common post Mustard or Senning, and patients are usually able to conduct 1:1 at a rate of 300 bpm, resulting in cardiovascular collapse. Correct management is rapid restoration of sinus rhythm, followed by flutter ablation. Patients with a Fontan circulation are similarly vulner- able to interatrial re-​entry tachyarrhythmias. Ventricular and atrial tachycardias may both occur in most survivors of complex con- genital heart disease, particularly after repair of tetralogy of Fallot. If ablation is not successful, consideration should be given to an internal cardioverter defibrillator. Pregnancy and contraception Many women with congenital heart disease wish to consider preg- nancy. For most this can be undertaken with only a small increased risk, but for some pregnancy carries a significant risk of compli- cation, long-​term morbidity, and death. Outcomes can be opti- mized by preconception counselling and specialist joint cardiac and obstetric care. Access to safe and effective contraception is important to allow patients to avoid potentially high-​risk pregnan- cies. Estrogen-​containing preparations are not suitable for those at risk of intracardiac thrombus or who have a right-​to-​left shunt; long-​acting progestogen-​only methods offer safe and effective alternatives Heart failure and end-​of-​life care As the population of adults with congenital heart disease ages, so the number developing heart failure increases. Conventional heart failure drugs have not been shown to have much benefit in this situ- ation, and there is a lack of clear guidance as to who will benefit from interventions such as cardiac resynchronization therapy. Cardiac transplantation is associated with a worse early mortality than acquired heart disease, but the long-​term outcome is as good. Transplantation is limited both by suitability of the recipient with a complex, surgically modified heart, and by donor availability. Services caring for patients need to develop a robust end-​of-​life pathway that focuses on symptoms and quality of life, and runs in parallel with other therapies. Introduction The growing number of adult survivors of congenital heart dis- ease will encounter medical staff from all areas of medicine and surgery. It is therefore important that all doctors have an under- standing of the principles of congenital heart disease and enough knowledge to know when to refer such patients to a specialist centre. As a result of advances in paediatric cardiac surgery and inter- vention, the outlook for the approximately 8 per 1000 babies born with congenital heart disease has changed dramatically in the last half-​century. Fifty years ago, 70% of children born with congenital heart disease died before their tenth birthday; now more than 80% survive to adulthood and in the United Kingdom there are more adults than children living with congenital heart disease. Despite such advances, only those with the simplest conditions (e.g. isolated secundum atrial septal defect or anomalous pul- monary venous drainage successfully repaired in childhood) may be considered cured of their heart disease. Most patients need con- tinued specialist follow-​up since they have residual lesions that may progress over many years and require timely intervention. Surgical techniques evolve continually, creating new populations with different surgically modified conditions and long-​term out- comes. Careful follow-​up is therefore crucial, not only to provide high standards of clinical care, but also to provide feedback about late results in order to inform initial management in infancy. As a result of such long-​term follow-​up information, the operation of choice for transposition of the great arteries became the arterial switch from the late 1980s, because of the late problems encountered in patients who had undergone interatrial repair with the Senning or Mustard operations. Surgical advances mean that patients with new surgically modi- fied conditions are reaching adulthood. Their outlook and the complications they may face are not known, so lifelong specialist surveillance is important. Left unoperated, hypoplastic left heart syndrome is lethal; survivors of the three-​stage surgical palliation are now reaching the adult clinics. They will form the largest new population over the next decade and face a more complex future than those with a ‘standard’ Fontan circulation. Classification and nomenclature The classification and description of complex congenital heart disease can appear intimidating. Nonetheless, a grasp of the basic principles is important to understand the anatomy and pathophysi- ology of congenital cardiac conditions. A  simple physiological 16.12  Congenital heart disease in the adult 3561 approach to classifying congenital heart disease takes into account whether a condition is cyanotic or acyanotic, whether there is a shunt, and the implications of the morphology for pulmonary blood flow (Table 16.12.1). Sequential segmental analysis The description of the congenitally malformed heart is aided by a segmental approach, which makes it possible to understand and de- scribe how a complex heart is connected. Any heart can be described by considering it as three segments (the atrial chambers, the ven- tricular mass, and the great arteries) and describing in a sequential manner how each segment is arranged and connected to the next segment (Figs. 16.12.1 and 16.12.2). Atrial arrangement Situs solitus is the usual arrangement of asymmetrical structures (i.e. morphological left atrium on the left, and right atrium on the right; morphological left main bronchus on the left, and right main Table 16.12.1  Classification of congenital heart disease Acyanotic Cyanotic: obligatory right-​to-​left shunt No shunt Left-​to-​right shunt Eisenmenger syndrome right to left shunt due to raised pulmonary vascular resistance Normal or low pulmonary blood flow Level of lesion Example of specific lesion Level of shunt Example of specific lesion Level of shunt Example of specific lesion (unoperated) Level of shunt Example of specific lesion Right inflow Ebstein anomaly Atrial PAPVD ASD AVSD Atrial Large ASD (uncommon cause) Atrial, with obstruction to pulmonary blood flow Severe pulmonary stenosis with ASD Left inflow Parachute mitral valve Cor triatriatum Ventricular VSD Ventricular Large VSD Ventricular, with obstruction to pulmonary blood flow Tetralogy of Fallot, Pulmonary atresia VSD, Univentricular heart with pulmonary stenosis Right outflow Infundibular stenosis Pulmonary stenosis Arterial PDA Aortopulmonary window Arterial Large PDA Aortopulmonary window Extra cardiac Pulmonary AVM, anomalous systemic venous connection e.g. left SVC to LA, veno-venous collaterals Left outflow Subaortic stenosis Bicuspid aortic valve Multiple AVSD Multiple Large AVSD Arterial Supravalvar stenosis Coarctation of the aorta ASD, atrial septal defect; AVSD, atrioventricular septal defect; LA, left atrium; PAPVD, partial anomalous pulmonary venous drainage; SVC, superior vena cava; VSD, ventricular septal defect. Fig. 16.12.1  The segments of the heart. section 16  Cardiovascular disorders 3562 bronchus on the right; stomach on the left, liver on the right). Situs inversus is the mirror-​image arrangement of these structures. Isomerism describes abnormal symmetry of paired structures that usually show laterality, as shown in Table 16.12.2. The pres- ence of isomerism of the atrial appendages should alert the phys- ician to the coexistence of complex associated lesions, including a variety of abnormalities of venous connections that may cause technical difficulties at cardiac catheterization and permanent pacemaker insertion. Right isomerism is commoner in males and left isomerism in females. Survival to adulthood with right isomerism is uncommon because of associated asplenia and se- vere cyanotic heart disease, including obstructed anomalous pul- monary venous drainage (the pulmonary venous confluence is a left atrial structure). The lesions associated with left isomerism tend to produce left-​to-​right shunts and little if any cyanosis. Atrioventricular connections In the normal heart, the atrioventricular connections are con- cordant (Fig. 16.12.2): • the right atrium connects to the right ventricle via the tricuspid valve • the left atrium connects to the left ventricle via a mitral valve If the atrioventricular connections are discordant: • the right atrium connects to the left ventricle via a mitral valve • the left atrium connects to the right ventricle via a tricuspid valve Ventriculo-​arterial connections In the normal heart, the ventriculo-​arterial connections are con- cordant (Fig. 16.12.2): • the left ventricle connects to the aorta via the aortic valve • the right ventricle connects to pulmonary artery via the pulmonary valve If the ventriculo-​arterial connections are discordant (transposition of the great arteries), then: Fig. 16.12.2  Sequential segmental analysis. 16.12  Congenital heart disease in the adult 3563 • the left ventricle connects to the pulmonary artery via the pul- monary valve • the right ventricle connects to the aorta via the aortic valve Cyanosis: A multisystem disorder Cyanosis occurs as a result of a right-​to-​left shunt. Cyanotic heart disease is a multisystem disorder; its manifestations are listed in Table 16.12.3. Secondary erythrocytosis Chronic hypoxia is the stimulus to the increased red blood cell mass and high haematocrit found in cyanotic heart disease. This physio- logical response increases the oxygen-​carrying capacity of the blood and improves tissue oxygenation sufficiently to reach a new equilib- rium at a higher haematocrit. The secondary erythrocytosis of cyan- otic heart disease is a physiological response, often associated with thrombocytopenia. It is fundamentally different from the patho- logical generalized increase in all haemopoietic stem cell lines found in the malignant disease polycythaemia rubra vera. Table 16.12.2  Diagnosis of atrial arrangement Situs solitus (normal arrangement) Situs inversus (mirror-​image arrangement) Right atrial isomerism Left atrial isomerism Atrial and appendagea morphology R-​sided morphological RA and appendage L-​sided morphological LA and appendage R-​sided morphological LA and appendage L-​sided morphological RA and appendage Bilateral morphological RA and appendages Bilateral morphological LA and appendages Pulmonary and bronchial morphologyb R lung trilobed L lung bilobed R-​sided main bronchus: short, L-​sided main bronchus: long R lung bilobed L lung trilobed R-​sided main bronchus: long, L-​sided main bronchus: short Bilateral trilobed lungs Bilateral short morphological R bronchi Bilateral bilobed lungs Bilateral long morphological L bronchi Abdominal arrangementc Aorta IVC Stomach Liver Spleen To L of spine To R of spine L-​sided R-​sided R-​sided Normal or mirror image Aorta and IVC on same side IVC anterior to aorta Usually L-​sided Midline Usually absent Aorta and azygos on same side Azygos posterior to aorta Usually R-​sided Midline Often polysplenia Ao, aorta, AV, azygos vein, IVC, inferior vena cava; L, left; LA, left atrium; R right; RA, right atrium; SVC, superior vena cava. a Readily identified on transoesophageal echocardiography. b Since bronchopulmonary situs nearly always follows atrial situs, atrial situs can be inferred from the chest radiograph. c Echocardiography shows the intra-​abdominal relations of the great vessels. In left isomerism, there is usually interruption of the IVC, and the abdominal venous return connects to the heart via a (right-​sided) azygos or (left-​sided) hemiazygos vein. The hepatic veins can be identified draining separately into the atriums. Table 16.12.3  Complications of cyanotic congenital heart disease Haematological Secondary erythrocytosis Iron deficiency (venesection, menorrhagia) Thrombocytopenia Haemorrhage Coagulopathy → Hyperviscosity symptoms? ↑ Risk of CVA Neurological CVA Cerebral abscess 2° to paradoxical embolism Hyperuricaemia Impaired renal clearance of uric acid Increased uric acid production? → Gout Renal abnormalities ↓ Uric acid clearance Glomerular proteinuria Mesangial matrix thickening Capillary and hilar arteriole dilatation → High risk of iatrogenic renal failure Bilirubin kinetics ↑ Haem breakdown → Pigment gallstones Digits and long bones Clubbing Hypertrophic osteoarthropathy Dental Gingival hypertrophy →↑ Risk of endocarditis Infection Endocarditis Cerebral abscess Skin Acne CVA, cardiovascular accident. section 16  Cardiovascular disorders 3564 Venesection was advocated historically to reduce the haematocrit to less than 65% in patients with cyanotic heart disease because of con- cerns about the effects of hyperviscosity. However, although a raised haematocrit is associated with increased blood viscosity, it also cor- relates with improved exercise tolerance, and does not correlate well with symptoms classically regarded as those of hyperviscosity (Box 16.12.1). Conversely, iron deficiency brought about by venesection is associated with increased symptoms akin to those of hyperviscosity (but does not cause an actual increase in viscosity) as well as an in- creased risk of stroke. Restoration of iron stores improves exercise tol- erance and symptoms. Cyanotic patients with iron deficiency should therefore have the cause of the deficiency treated and be given iron supplements sufficient to render them iron replete over a course of months. A prolonged course of low-​dose iron should allow iron stores to be replenished without causing a rapid rise in haematocrit. There is no evidence that venesection improves symptoms beyond a few days, nor that it carries any prognostic benefit. Thus, venesection to reduce elevated haemoglobin and haematocrit is rarely, if ever, indicated for the physiological erythrocytosis of cyanotic heart disease. Menorrhagia is common in women with cyanotic heart disease and may be sufficient to cause iron deficiency anaemia. It may be difficult to manage, the combined oral contraceptive pill being contraindicated because of the prothrombotic effects of the estro­ gen it contains, and tranexamic acid may similarly be associated with thrombosis. Norethisterone may provide short-​term relief. Progestogen-​only contraceptives have unpredictable effects on men- struation: the subdermal implant (e.g. Nexplanon®) is safe and causes oligomenorrhoea in some women. Mirena® IUS is a progestogen-​ eluting intrauterine device that causes oligomenorrhoea in most women, but great care is needed for those with cyanotic heart dis- ease or who have not undergone previous vaginal delivery because insertion may cause a vasovagal response and cardiovascular col- lapse. If menorrhagia is due to uterine fibroids, catheter emboliza- tion of the feeding uterine artery is safe and may be successful. Disorders of coagulation and blood vessels It is poorly understood why patients with cyanotic disease are at in- creased risk of haemorrhage and thrombosis. There is often a mild thrombocytopenia that may be due partly to shortened platelet survival time, and the large multimeric forms of von Willebrand factor and other clotting factors may be depleted. Coagulation testing may yield spurious results in patients with haematocrit over 55% unless the amount of citrate anticoagulant in the sample bottle is reduced. Bleeding may be minor and mucocutaneous, but major haemor- rhage may occur during surgery, or from the lungs. Pulmonary artery thrombosis is discussed next (see ‘Eisenmenger syndrome: defects with secondary pulmonary vascular disease’). Interestingly, sys- temic arterial atherosclerosis is rare in the cyanotic population, per- haps because of a combination of thrombocytopenia, upregulated nitric oxide, hyperbilirubinaemia, and hypocholesterolaemia. Other complications of cyanotic heart disease The risk of stroke is increased in cyanotic heart disease, with in- dependent risk factors being intravenous lines, arterial hyperten- sion, atrial fibrillation, iron deficiency, and prosthetic intravascular material such as endocardial pacing systems. The mechanism of stoke is often paradoxical embolism due to right-​to-​left shunting. Paradoxical air emboli are a cause of stroke in patients whose venous lines are not fitted with filters. Patients who require transvenous pacing should be anticoagulated to prevent paradoxical thrombo- embolism from pacing leads. Cerebral abscess is an uncommon but potentially devastating complication of cyanosis, with a mortality of around 13%. The right-​ to-​left shunt allows systemic venous blood to avoid passing through the lungs, where bacteria are removed by phagocytosis. The diagnosis should be considered in all cyanotic patients who present with fever, headache, and malaise, neurological signs, or altered consciousness. Similarly, patients who present with cerebral abscess of apparently unknown cause should have a right-​to-​left shunt excluded. The right-​to-​left shunt may be extracardiac:  for example, pulmonary arteriovenous malformation, or a persistent left superior vena cava (SVC) draining to the left atrium. A bubble contrast echocardiogram without Valsalva manoeuvre, via the left brachial vein, will detect such right-​to-​left shunting. Empirical treatment is usually a third-​ generation cephalosporin and metronidazole; blood cultures, and if possible stereotactic aspiration of pus with narrow antibiotic therapy and surgical drainage may be necessary for large abscesses. Despite the high incidence of hyperuricaemia, attacks of acute gout are uncommon and asymptomatic hyperuricaemia does not require treatment. Acute attacks should be treated with colchicine, avoiding non​steroidal anti-​inflammatory agents (NSAIDs) because of their detrimental effects on haemostasis and renal function. As in primary hyperuricaemia, allopurinol is useful in preventing recurrence. The renal abnormalities outlined in Table 16.12.3 are frequently not associated with abnormal baseline renal function. However, renal failure may be precipitated by hypotension and dehydra- tion, especially in combination with radiographic contrast media, NSAIDs, or aminoglycoside antibiotics. The mode of decline and eventual death is a combination of heart and renal failure in many patients with cyanotic heart disease, and care should be taken to titrate diuretic therapy cautiously to minimize worsening renal function. Renal dialysis or filtration is very poorly tolerated in this patient group and should be avoided: the failing cyanotic circulation does not cope with the haemodynamic demands of renal support, and deterioration and death are likely to occur rapidly. Acne is a common complaint in adolescents and adults with cyan- otic disease and may be widespread and psychologically debilitating. When severe it may also increase the risk of bacteraemia and endocarditis. Digital clubbing is almost universal in cyanotic heart disease, and some degree of hypertrophic osteoarthropathy of the long bones may occur in up to one-​third of patients. Symptoms include aching and tenderness of the long bones of the forearms and legs. Box 16.12.1  Symptoms of hyperviscosity • Headache • Faint, dizzy, light-​headed • Depressed mentation, sense of distance • Blurred vision, amaurosis fugax • Paraesthesiae • Tinnitus • Fatigue, lethargy • Myalgia, muscle weakness • Chest and abdominal pain • Restless legs 16.12  Congenital heart disease in the adult 3565 There is oedema and cellular infiltration, causing lifting of the peri- osteum that is visible radiographically, with new bone formation and resorption. Localized activation of endothelial cells by an ab- normal platelet population, with the ensuing release of fibroblast growth factors, may play a central role in the pathogenesis of both phenomena. Cyanotic patients become more hypoxic during air travel, as the partial pressure of oxygen in a pressurized aircraft is lower than that at sea level. However, such travel seems to be well tolerated at least for short and medium haul journeys and supplemental oxygen should not normally be necessary. Travellers should be warned to avoid dehydration and to plan their journeys to avoid having to carry baggage for long distances within large airports. Cyanotic patients are at risk of iatrogenic complications if they require surgery or intervention for non​cardiac conditions. See Box 16.12.2. Eisenmenger syndrome: Defects with secondary pulmonary vascular disease Eisenmenger syndrome is a cyanotic condition that occurs in pa- tients with a large (non​restrictive) communication between the systemic and pulmonary circulations that results in high pul- monary vascular resistance and pulmonary arterial hypertension, so that the shunt across the communication is reversed (right-​to-​ left) or bidirectional. The communication may be at atrial, ven- tricular, or arterial levels. In fetal life, pulmonary vascular resistance is high and there is muscularity of the pulmonary arterioles. In the normal circulation, pulmonary vascular resistance falls soon after birth and remodel- ling of the pulmonary arterioles occurs. However, if there is a large communication; for example, a ventricular septal defect, the effects of blood entering the pulmonary circulation at high volume and systemic pressure causes reverse remodelling, and instead of falling, the pulmonary vascular resistance rises. Endothelial dysfunction secondary to changes in shear stress and circumferential wall stress is thought to mediate these changes through altered expression of vasoactive mediators and growth factors such as endothelin-​1, nitric oxide, prostacyclin, and vascular endothelial and fibroblast growth factors. Corrective surgery in infancy usually prevents the development of this irreversible syndrome, so its incidence in the developed world is declining. However, when patients do present their management is dependent on a good understanding of their condition. For patients with established right-​to-​left shunting and pul- monary arterial hypertension, the diagnosis is clear. However, some have intermediate pathologies, and European guidelines attempt to clarify these: it is important to understand that despite the absence of a right-​to-​left shunt and cyanosis, potentially life-​threatening pulmonary artery hypertension is present (Table 16.12.4). Clinical findings Symptoms of breathlessness relate to the degree of hypoxia; many patients feel worse in hot weather or after a hot bath because the resulting systemic vasodilatation is not accompanied by a reduction in pulmonary vascular resistance, so the right-​to-​left shunt is en- hanced and they become more hypoxic. Exercise-​induced syncope may occur, and is exacerbated by hot weather and dehydration. Haemoptysis is common and may be fatal. Whatever the underlying defect, some examination findings are shared. Patients are cyanosed and clubbed and may be plethoric. There is a right ventricular heave and the pulmonary component of the second heart sound is palpable and loud. A pulmonary ejection click and pulmonary regurgitation may be audible. A soft systolic flow murmur may be heard from the dilated pulmonary artery. No systolic murmur can be heard from the lesion responsible for the pulmonary vascular disease since the chambers on both sides of the lesion are at equal pressure. It is frequently possible to distinguish between the common lesions associated with the Eisenmenger syndrome on clinical Box 16.12.2  Checklist for patients at high riska of iatrogenic complications during the perioperative period or during intercurrent illness • Seek advice from the patient’s congenital cardiology team • Maintain hydration—​intravenous fluids (via air filter if cyanotic to avoid the risk of paradoxical embolism) when nil by mouth • Maintain haemoglobin commensurate with degree of cyanosis to optimize oxygen-​carrying capacity • Avoid vasodilator agents—​especially at induction of anaesthesia • Protect the kidneys—​maintain hydration, avoid nephrotoxic agents (NSAIDs, aminoglycosides), use minimal volumes of contrast agents a Patients at high risk include those who are cyanotic and those with Eisenmenger syndrome or Fontan circulation. Table 16.12.4  Pulmonary arterial hypertension associated with congenital heart disease A Eisenmenger syndrome A large systemic to pulmonary artery shunt leads to a severe increase in pulmonary vascular resistance such that it exceeds systemic vascular resistance, and the shunt reverses (becomes right-​to-​left). The patient is cyanosed B Pulmonary artery hypertension associated with systemic to pulmonary shunt A moderate–​large defect causes a rise in pulmonary vascular resistance, but it remains less than systemic vascular resistance and the shunt remains left-​to-​right C Pulmonary artery hypertension and a small systemic to pulmonary shunt A small defect (e.g. VSD <1 cm or ASD>2 cm) coexists with pulmonary arterial hypertension. If pulmonary vascular resistance exceeds systemic vascular resistance, the shunt reverses and the patient is cyanosed. The clinical course is akin to idiopathic pulmonary arterial hypertension. It is likely that two different diagnoses are present, i.e. a patient with idiopathic pulmonary artery hypertension coincidentally has a small septal defect D Pulmonary artery hypertension after surgery to correct systemic to pulmonary artery shunt A large systemic to pulmonary shunt is surgically repaired but pulmonary artery hypertension is still present ASD, atrial septal defect; VSD, ventricular septal defect. section 16  Cardiovascular disorders 3566 grounds. The patient with an Eisenmenger patent arterial duct has differential cyanosis and clubbing, since fully saturated blood from the left ventricle supplies the aortic arch and its branches before mixing occurs with desaturated pulmonary arterial blood via the patent duct. The right hand may therefore be pink with no clubbing, the left may be slightly more cyanosed because of the origin of the left subclavian artery opposite the duct, and the toes are more deeply cyanosed and clubbed. The second heart sound may be closely or normally split. In contrast, cyanosis and clubbing is uniform when the right-​to-​left shunt occurs at atrial, ventricular, or ascending aortic (as in truncus arteriosus or aortopulmonary window) levels. The second sound is single in ventricular septal defect (VSD), atrio- ventricular septal defect (AVSD), and truncus, but may be split in an atrial septal defect (ASD). Investigations The chest radiograph shows a dilated pulmonary trunk because of high pulmonary blood flow in earlier life, but reduced blood flow as pulmonary vascular resistance rose means that the lung fields are oligaemic (Fig. 16.12.3). Unless cardiac failure intervenes, the heart size is usually normal, the effects of volume overload having regressed as pulmonary vascular resistance increased and the left-​ to-​right shunt diminished and disappeared. The electrocardiogram (ECG) shows P pulmonale and biventricular hypertrophy. The echocardiogram should establish the site of the shunt and allow an estimation of pulmonary arterial pres- sure and ventricular function. Cardiopulmonary exercise testing may be used with caution: pa- tients with Eisenmenger syndrome are among the most limited of those with congenital heart disease and maximal exercise testing may induce potentially fatal syncope. The less strenuous but still ob- jective 6-​min walk or shuttle tests are preferable measures of exercise capacity in these patients. High-​resolution CT scanning demonstrates the hypertensive pul- monary vasculature and any collateral vessels. It is also the investiga- tion of choice to show in situ pulmonary thrombus and pulmonary artery aneurysms, and to demonstrate the site of any pulmonary haemorrhage. Care should be taken to avoid contrast-​induced neph- ropathy by ensuring adequate hydration. Cardiac catheterization is unnecessary and potentially dangerous for patients with established pulmonary vascular disease. The only indication is for those patients in whom there is doubt about the presence and severity of pulmonary vascular disease and who would be considered for selective pulmonary vasodilator therapy or (rarely) surgical repair if reversibility can be confirmed. Histologically, pulmonary vascular disease progresses from medial hypertrophy through intimal proliferation with migration of smooth muscle cells, to progressive fibrosis and obliteration, dilata- tion, the development of angiomas, and finally fibrinoid necrosis. Those who have developed fibrotic and obliterative changes are likely to have irreversible pulmonary vascular disease. Routine lung biopsy is not recommended; it carries a high risk in the pulmonary hypertensive adult and is unlikely to show reversible pathology. In addition, thoracotomy scars from open lung biopsy are a relative contraindication to heart–​lung transplantation. Outcome and complications Survival into adulthood with Eisenmenger syndrome is common. Median life expectancy is around 40 years, which is better than for those with idiopathic pulmonary arterial hypertension. Markers of poorer prognosis include complex anatomy and physiology, coex- istent Down’s syndrome, decline in functional class, and the devel- opment of heart failure, renal dysfunction, and clinical arrhythmia. Serum uric acid increases with disease progression and may also be used as a long-​term predictor of mortality. The patient with Eisenmenger syndrome is prone to all the complications of cyanotic heart disease: nowadays the mode of death is most commonly due to heart failure or infection (including cerebral abscess). This con- trasts with Paul Wood’s description in the mid-​20th century, when pulmonary haemorrhage and periprocedural deaths predominated. Haemoptysis is usually due to rupture of small hypertensive intrapulmonary vessels, or more rarely to thrombosis in situ and pul- monary infarction. Massive haemoptysis is a well-​recognized cause of death. All patients should be admitted to hospital and the systemic pressure kept low by bed rest and β-​blockade; the pulmonary ar- tery pressure being the same as that measured in the brachial artery. NSAIDs should be stopped and vasodilators should not be given. If the haemoptysis is massive, diamorphine should be administered, fresh frozen plasma or cryoprecipitate may be given, and consider- ation should be given to selectively intubating the non​bleeding lung to allow an attempt to embolize a bleeding vessel. Bronchoscopy has no role and may worsen the haemorrhage. In situ thrombosis in the dilated pulmonary arteries of adults with Eisenmenger syndrome is common (prevalence of 20–​30%) and relates to the degree of cyanosis. It is best detected and quan- tified using high-​resolution CT scanning. Anticoagulation of any sort has not been shown to resolve such thrombus, and patients are at risk of pulmonary embolic episodes. Warfarin may increase the risk of bleeding while failing to reduce the thrombus, and aspirin should be avoided as it may exacerbate haemorrhage associated with thrombocytopenia. Fig. 16.12.3  Chest radiograph of a 35-​year-​old woman with Eisenmenger secundum atrial septal defect. The aortic knuckle is small and the central pulmonary arteries enlarged, indicating pulmonary arterial hypertension; the lung fields are clear. The cardiac silhouette is not enlarged. 16.12  Congenital heart disease in the adult 3567 Right ventricular failure may be precipitated by atrial arrhythmia and usually occurs after the age of 30 years. Decline may be her- alded by the onset of right ventricular failure, renal dysfunction, supraventricular arrhythmia, and haemoptysis. Death may be sudden and due to arrhythmia or massive haemoptysis. In some pa- tients death follows progressive hypoxia terminating in bradycardia and asystole from which they cannot be resuscitated. Intercurrent illness and non​cardiac surgery may pose major risks. The latter is particularly dangerous when carried out without the benefit of expert cardiology, anaesthetic, and periopera- tive care. A sound understanding of the pathophysiology is vital (Box 16.12.2). Management Until recently, treatment of patients with Eisenmenger syndrome has been palliative and symptom led, directed at avoiding iatrogenic and natural complications. Gentle exercise should be encouraged, but strenuous exertion avoided, since it may result in syncope. Long-​ term oxygen therapy may improve symptoms in some patients, but has not been shown to have prognostic benefit. Although this approach is still the mainstay of treatment, selective pulmonary vasodilators including phosphodiesterase inhibitors (e.g. sildenafil) and endothelin receptor antagonists (e.g. bosentan) may improve outcome and should be considered at least for patients with New  York Heart Association (NYHA) class  III symptoms. These drugs have been shown to improve outcome in other forms of pulmonary hypertension. Early data from small trials suggest that bosentan helps to maintain right ventricular function, quality of life, and exercise capacity. Sildenafil improves quality of life and exercise tolerance in many patients as they reach NYHA III. Pregnancy and contraception Pregnancy carries a particularly high risk (25–​40% maternal mor- tality). Pregnancy and contraception in congenital heart disease are discussed next. All women with pulmonary hypertension of any cause should be counselled about the risks and given access to safe, effective contraception. If a woman with Eisenmenger syndrome be- comes pregnant and chooses not to have a termination, she should be referred to a specialist pulmonary hypertension centre. Valve and outflow tract lesions Isolated pulmonary valve stenosis Isolated pulmonary stenosis is common, occurring in up to 10% of patients with congenital heart disease. There is usually fusion of the valve cusps leading to a doming appearance. Syndromic associ- ations are not unusual and include Noonan, Williams, and Alagille syndromes. Significant pulmonary stenosis results in right ventricular hyper- trophy and high right-​sided pressures; right-​to-​left shunting causing cyanosis may occur if there is a coexistent ASD or patent foramen ovale (PFO). Pulmonary stenosis is a better-​tolerated lesion than aortic sten- osis, with an excellent survival. Severe pulmonary stenosis usually presents in childhood, either as an asymptomatic murmur, or with failure to thrive, chest pain, dyspnoea, or cyanosis. Physical signs Patients are acyanotic unless there is an interatrial communication, in which case cyanosis can be severe. The venous pressure is raised only if the right ventricle has begun to fail and there is tricuspid re- gurgitation. There may be a right ventricular heave. The pulmonary component of the second heart sound is soft and there is a pul- monary ejection systolic murmur. An early diastolic murmur may also be present if there is coexistent pulmonary regurgitation. Investigations The ECG may demonstrate right ventricular hypertrophy. This re- gresses after relief of the stenosis. The chest radiograph reveals poststenotic dilation of the proximal pulmonary artery, and the lung fields may be oligaemic if the pulmonary stenosis is severe. Transthoracic echocardiography confirms the diagnosis and al- lows functional assessment of the severity of pulmonary stenosis and regurgitation as well as right ventricular hypertrophy, dilatation, and function. Management Adults with trivial (<20 mm Hg) pulmonary stenosis do not require regular follow-​up, since progression is unlikely. Approximately 20% of adults with mild stenosis (<50 mm Hg) may progress and ultim- ately require intervention, and most of those with a peak pulmonary valve gradient greater than 50 mm Hg require intervention. Balloon pulmonary valvotomy is the treatment of choice, unless the valve is thickened and dysplastic or regurgitant, or there are as- sociated anomalies requiring a surgical approach. Valvotomy is usu- ally successful and it is uncommon for stenosis to recur, however, the procedure invariably results in a degree of pulmonary regurgitation and so long-​term follow-​up is required. Lone infundibular stenosis and double-​chambered right ventricle Abnormally placed muscle bands cause either infundibular obstruc- tion or—​if placed more inferiorly—​subinfundibular obstruction and a double-​chambered right ventricle. The degree of obstruction may be mild in childhood, but progresses in adult life and causes symptoms as the right ventricle hypertrophies and outflow obstruc- tion becomes severe. A perimembranous VSD usually coexists and may close spontaneously. Treatment is by surgical resection of the obstructing muscle bands. Ebstein anomaly This rare, complex defect of the tricuspid valve occurs in 1 in 20 000 live births and affects both sexes equally. The risk may be increased by maternal exposure to lithium during the first trimester. In the normal heart, the tricuspid and mitral valves are formed from the endocardium of the right and left ventricles, respectively. The valve leaflets delaminate from the endocardium to form the atrioventricular valves. In Ebstein anomaly, there is failure of tri- cuspid valve leaflet delamination during fetal life, so that the leaflets adhere to the right ventricular myocardium, resulting in apical dis- placement of the functional tricuspid valve, tethering, redundancy, and fenestrations of the valve leaflets. There is a broad spectrum of severity of this condition, dependent upon the degree of failure of delamination. section 16  Cardiovascular disorders 3568 Ebstein anomaly is characterized by a spectrum of features: • Adherence of the tricuspid valve leaflets to the underlying myocardium due to failure of delamination in fetal life. • Apical displacement of the tricuspid valve hinge points and orifice: ■ As a result of the failure of delamination the septal and posterior (mural) leaflets insert further into the body of the right ventricle than in the normal heart (in which the mitral and tricuspid valves are offset so that the tricuspid valve is displaced up to 1.5 cm towards the right ventricular apex). ■ The ‘atrialized’ portion of the right ventricle is often thinner walled than the functional right ventricle due to congenital partial absence of the myocardium; as a result, the functional size of the right ventricle is reduced and that of the right atrium increased. • Dilation of the functional right atrium. • Dilatation of the true tricuspid valve annulus at the atrioven- tricular junction. This combination of features usually results in tricuspid regurgi- tation (or very rarely stenosis) and right heart dilation, providing a substrate for atrial and ventricular arrhythmias. Associated abnormalities A PFO or ASD is present in most cases, and allows cyanosis to de- velop as the disease progresses and right-​to-​left shunting occurs. Left-​heart abnormalities occur as a consequence of alterations in left ventricular geometry due to leftwards displacement of the interventricular septum (e.g. mitral valve prolapse may occur as re- sult of relatively long chordae in a left ventricle of reduced cavity size). Coexistent Wolfe–​Parkinson–​White syndrome, with single or multiple right-​sided pathways, occurs in 20% of patients. Ebstein anomaly may also form part of other complex congenital le- sions, including pulmonary stenosis and atresia and tetralogy of Fallot. When it coexists with congenitally corrected transposition of the great arteries, the tricuspid valve is the systemic atrioventricular valve. Clinical presentation and course There is a broad spectrum of severity, ranging from intrauterine or neonatal death to presentation in late adulthood. Mortality, both with and without surgery, is influenced by age at presentation, the condition of the tricuspid valve, the cardiac rhythm, and the func- tion and capacity of the right ventricle, including the severity of right ventricular outflow tract obstruction, and the size of the right atrium in relation to the other cardiac chambers. Arrhythmia is the commonest mode of initial presentation in adult life; presentation earlier in life is usually associated with severe disease and additional cardiac lesions. Cyanosis may develop in adulthood if there is an associated ASD or PFO; as the right ventricular filling pressure increases there is a parallel rise in right atrial pressure, and a right-​to-​left interatrial shunt is established. These patients are at risk of paradoxical em- bolism, but the risk of endocarditis is low because the tricuspid regurgitant jet is of low velocity. Heart failure may intervene as a result of the combination of se- vere tricuspid regurgitation and the onset of atrial fibrillation or flutter. These atrial arrhythmias may be particularly troublesome if a coexistent accessory pathway allows a rapid ventricular response rate. The onset of atrial fibrillation is a predictor of death within 5 years, and may account for the increased death rate in the fifth decade. Physical signs The patient may be acyanotic or cyanosed and clubbed. Even when tricuspid regurgitation is severe the jugular venous pressure may not be particularly high or the ‘v’ wave prominent because of the cap- acity of the right atrium and thin-​walled atrialized right ventricle to accommodate the low-​pressure regurgitant volume. Once right ventricular failure develops the jugular venous pressure rises further and the ‘a’ and ‘v’ waves become more prominent. In the uncommon situation of tricuspid stenosis, the ‘a’ wave is increased and may be giant. The first heart sound is widely split with a delayed tricuspid component, due to the extra distance that the large anterior leaflet has to travel to reach the limit of its systolic excursion. The second heart sound may be single because low pressure in the right ventricular outflow tract renders the pulmonary component inaudible, or it may be widely split, reflecting right bundle branch block. Third or fourth ventricular filling sounds may be present. The systolic murmur of tricuspid regurgitation varies from inaudible to loud enough to gen- erate a thrill, but is classically decrescendo and scratchy. Once the right ventricle begins to fail and the venous pressure rises, hepato- megaly, ascites, and peripheral oedema are common. Investigations The chest radiograph is characteristic (Fig. 16.12.4). The ECG typ- ically shows a superior axis and right atrial enlargement, with or Fig. 16.12.4  Chest radiograph of a 43-​year-​old woman with classic cardiac silhouette of Ebstein anomaly due to right atrial enlargement. The aortic knuckle and pulmonary arteries are inconspicuous and the lung fields oligaemic. 16.12  Congenital heart disease in the adult 3569 without right bundle branch block. The ‘p’ wave may be peaked and the PR interval prolonged, reflecting the prolonged conduction in the large right atrium, or there may be evidence of pre-​excitation. Right bundle branch block may occur due to abnormal activation and conduction in the atrialized right ventricle. Echocardiography establishes the diagnosis, severity, and asso- ciated abnormalities of Ebstein anomaly. The atrialized and func- tional portions of the right ventricle can be identified, as can the precise attachments and degree of tethering of the anterior leaflet of the tricuspid valve. Echocardiography is the investigation of choice in planning surgical intervention, tethering and restricted mo- tion of the anterior leaflet and a small right ventricle being strong predictors of the need for tricuspid valve replacement rather than repair. Cardiac catheterization is only necessary if specific haemo- dynamic questions remain after non​invasive assessment. Cardiopulmonary exercise testing is invaluable in assessing func- tional capacity when planning timing of surgery. Management Patients should be anticoagulated when atrial arrhythmias develop, particularly if there is an ASD. If re-​entry tachycardias cannot be controlled with antiarrhythmic drugs, radiofrequency ablation of accessory pathways may be performed. However, ablation may be made difficult by the size and abnormal shape of the right atrium and abnormal position of the accessory pathway or pathways. Symptomatic patients should be assessed for surgery. In addition, the asymptomatic patient with severe tricuspid regurgitation and normal cardiopulmonary exercise tolerance should be considered for repair if right ventricular function has begun to deteriorate. The timing of surgery may be difficult to decide in the adult patient, even in the few centres with reasonable experience. Once the patient has developed overt right heart failure with a raised venous pressure, hepatomegaly, ascites, and atrial fibrillation, ventricular function may have deteriorated such that repair of the valve is no longer possible and transplantation may need to be considered. Tricuspid valve repair or replacement in this rare condition should only be carried out in experienced congenital cardiac sur- gical centres. Successful repair of the Ebsteinoid valve is difficult, as evidenced by the many techniques described. The aim is to achieve a competent native valve with its insertion at the true annulus and a reduction in right atrial size. Where possible, valve replacement should be avoided, since long-​term outcomes are better with repair. If replacement is necessary, the inevitable need for later interven- tion if a bioprosthetic valve is placed should be weighed against the risk of mechanical valve thrombosis, which is much higher than for mechanical valves in other positions. A maze procedure should also be considered to reduce the long-​term risk of atrial flutter and fibrillation. For high-​risk patients in whom the right ventricle is thought to be unable to support the pulmonary circulation with a competent tri- cuspid valve, techniques to reduce its workload may be considered. The ‘1½’ ventricle repair combines tricuspid valve repair with a cavopulmonary anastomosis so that upper body systemic venous re- turn is directly to the pulmonary arteries, thus offloading the right ventricle. A single-​ventricle repair may also be used, resulting in a Fontan circulation (see ‘Fontan operation’). Other right ventricular anomalies Uhl’s anomaly and arrhythmogenic right ventricular cardiomyop- athy (see also Chapter 16.7.2) are rare sporadic or familial conditions affecting the right ventricle. Table 16.12.5 list the key distinguishing features. Early diagnosis and the screening of family members of affected individuals is challenging and requires experience. MRI and high-​ resolution CT are useful tools, but early abnormalities are subtle and may be overinterpreted. Cor triatriatum and congenital mitral valve anomalies Cor triatriatum This is a very rare defect in which one of the atriums (nearly always the left) is partitioned by a fibromuscular membrane into an upper chamber that receives the pulmonary veins, and a lower chamber connecting with the atrial appendage and mitral valve. This is thought to occur due to a failure of the common pulmonary venous chamber to incorporate into the body of the left atrium early in fetal life. As a result, a persistent membrane inserts into the atrial septum at the fossa ovalis and into the posterolateral wall just above the mouth of the left atrial appendage. An ASD coexists in about 50% of cases, allowing communication between the right and left atriums. The membrane may be intact, or pierced by one or more holes that are usually restrictive, causing supramitral stenosis. If the membrane obstructs pulmonary venous inflow, presen- tation is early in life, and adult survivors will have undergone sur- gical resection. First presentation in adulthood is unusual unless the membrane is non​restrictive or coexists with a large ASD. Patients may have signs of an ASD or mitral stenosis. New symptoms in adulthood may be due to fibrosis or calcification of the membrane so that it becomes restrictive, or from progressive mitral regurgitation. The diagnosis is made by echocardiography. The chest radio- graph may also be characteristic, showing signs of pulmonary venous congestion, but not the left atrial appendage enlargement that accompanies valvar mitral stenosis, since the appendage lies Table 16.12.5  Right ventricular cardiomyopathy and Uhl’s anomaly Arrhythmogenic right ventricular cardiomyopathy Uhl’s anomaly ‘Parchment heart’ Morphology Patchy, localized fibro-​fatty replacement of parietal myocardium mostly affecting outflow tract. Other parts of right and occasionally left ventricle may be involved Congenital absence of parietal ventricular myocardium with direct apposition of endocardium and epicardium. Normal interventricular septum and left ventricle Sex ratio 2:1 male:female Equal Typical presentation As young adult Exercise-​induced ventricular tachycardia: palpitation, syncope, sudden death In infancy Congestive cardiac failure section 16  Cardiovascular disorders 3570 in the low-​pressure atrial chamber. The lateral chest radiograph may show enlargement of the pulmonary venous compartment of the left atrium. Treatment is unnecessary if the membrane is unobstructive and there are no significant associated lesions. The results of surgical resection of obstructive membranes and the postoperative prog- nosis are good. Congenital mitral valve anomalies These are rare and frequently coexist with other lesions. A supramitral ring often coexists with congenital mitral stenosis. It differs from cor triatriatum in that the ring is sited inferiorly to the os of the ap- pendage and lies immediately above the mitral valve. Shone syndrome consists of four levels of left heart obstruc- tion: supramitral ring, parachute mitral valve, subaortic stenosis (often with bicuspid aortic valve), and coarctation of the aorta. Parachute mitral valve occurs when the two papillary muscles are fused or there is hypoplasia or absence of one papillary muscle; the valve and its ap- paratus are often additionally dysplastic. Obstruction occurs at the level of the abnormal papillary muscles. The parachute mitral valve may also be regurgitant if the chordae are elongated and not signifi- cantly fused. Shone syndrome forms part of a spectrum of left heart obstruction that has bicuspid aortic valve at one end and hypoplastic left heart syndrome at the other. The recurrence risk is greater than for many forms of congenital heart disease at around 10%. Isolated cleft mitral valve differs from the ‘cleft’ seen in an AVSD in being in the anterior (aortic) leaflet, directed towards the aortic outflow tract, rather than being in the space between the bridging leaflets and pointing towards the septum. The isolated cleft can be readily repaired to resemble a competent normal mitral valve. Left ventricular outflow tract obstruction Bicuspid aortic valve This is the commonest congenital cardiac anomaly, occurring in 1 to 2% of the population and four times more common in males than in females. Bicuspid aortic valve phenotypes are highly variable and may be associated with aortopathies (bicuspid aortopathy, Loeys–​ Dietz syndrome), genetic syndromes (e.g. Turner syndrome) and other structural cardiac anomalies such as aortic coarctation, Shone syndrome (serial left-​sided obstructive lesions) and hypoplastic left heart syndrome. The families of patients with bicuspid aortic valve associated with aortopathy or with other relatives with structural cardiac anomalies should be offered screening and genetic testing. Lifelong surveillance is necessary, even for patients with appar- ently isolated bicuspid aortic valve, since symptoms occur late in young people with aortic valve disease and aortic root dilatation may occur in later life. Exercise testing with echocardiography is useful in planning the timing of surgery in those with asymptomatic aortic stenosis and left ventricular hypertrophy: ST segment changes and a failure of blood pressure to rise or cardiac function to improve appropriately in response to stress indicate that intervention should be considered. Aortic stenosis and regurgitation are discussed in Chapter 16.6. Supravalvar aortic stenosis In this least common form of left ventricular outflow tract obstruc- tion there is a localized narrowing of the aorta immediately above the aortic sinuses. Fibromuscular thickening of the aortic wall at the site of obstruction may encroach into the coronary ostia or onto the aortic valve leaflets and adversely influence prognosis. Unlike other forms of left ventricular outflow obstruction, the coronary arteries lie proximal to the obstruction and so are exposed to high left ventricular pressures, resulting in premature atherosclerosis. The condition may be associated with Williams’ syndrome, when the prognosis may be worse since there is diffuse arterial involve- ment that may also involve the pulmonary and renal arteries (see Chapter 16.11). Subaortic stenosis Subaortic stenosis may be due to a discrete fibromuscular ridge or ring, or a long muscular tunnel. It may exist in isolation or as part of another lesion such as AVSD, where the ‘unwedged’ aorta; the elong- ated left ventricular outflow tract, and abnormal insertion of the left atrioventricular valve may all cause obstruction. Whether discrete or tunnel-​like, subaortic stenosis tends to progress and may recur following surgical resection. It may result in functional disruption of the aortic valve and secondary aortic regurgitation, which can pro- gress even after resection of subaortic stenosis. Atrial septal defects Interatrial communications are common both in congenital heart disease and in the general population. The different types of ASD are illustrated in Fig. 16.12.5. ASDs account for around 10% of con- genital heart disease. Types of atrial septal defect Patent foramen ovale PFO is a normal variant that occurs in 20–​30% of the population. There is no deficiency of atrial septal tissue, but after birth—​when left atrial pressure exceeds right atrial pressure and closes the PFO—​the valve of the foramen ovale fails to fuse with the septum. Interest has risen in PFO in recent years because of its potential to be a route for paradoxical embolism or for thrombosis in situ, especially if associated with an aneurysmal interatrial septum. PFO is associated with cryptogenic embolic stroke in young adults, with Right ventricle Right atrium SVC Anolmalous right pulmonary vein in sinus venosus ASD Sinus venosus Secundum Primum/ atroventricular Coronary sinus Sinus venosus IVC True atrial septum Fig. 16.12.5  Sites of atrial septal defects. The shaded area delineates the true atrial septum. Sinus venosus and coronary sinus defects are therefore not strictly atrial septal defects although they permit shunting at atrial level. 16.12  Congenital heart disease in the adult 3571 neurological decompression sickness in divers, and with migraine with aura. Device closure of a PFO appears to protect against re- current stroke due to paradoxical embolism and decompression sickness. Whether PFO closure should be considered for secondary provision following cryptogenic stroke is controversial. Careful consideration should be given to all risk factors in as- sessing a patient with an embolic stroke and a PFO for suitability for device closure of the PFO. If there are multiple risk factors for arterial disease, such as advanced age, smoking history, diabetes, hyperlip- idaemia, hypertension, or proven existing atherosclerotic disease, then device closure of a PFO is unlikely to reduce the risk of a fur- ther embolic event. The same is true for patients with risk factors for left-​sided intracardiac thrombosis, such as atrial fibrillation, mitral valve disease with a dilated left atrium, or left ventricular aneurysm. In contrast, patients with a PFO and previous embolic stroke who have risk factors for venous thrombosis, such as a thrombophilia or previous venous thromboembolism (i.e. whose stroke was likely to be due to paradoxical embolism) may be protected against further events by device closure. Ostium secundum atrial septal defect Secundum ASD accounts for 40% of left-​to-​right shunts in adults aged over 40 years. It is commoner in females, with a sex ratio of 2:1, and may be familial. It may occur as an isolated abnormality with autosomal dominant inheritance, be associated with Holt–​ Oram syndrome (autosomal dominant skeletal abnormalities and atrioventricular conduction defects due to TBX5 mutation), and is a common association with Down’s syndrome. ASD may be an incidental finding in an elderly patient at autopsy, and diagnosis in life may be delayed well into adulthood because of the absence of symptoms and subtlety of clinical signs. However, the natural history of this lesion is not benign: historically only 50% with unoperated non​restrictive (large) ASD survived to the age of 40 years, and 10% beyond 60 years of age. Presentation in adulthood may be with symptoms of exertional dyspnoea or palpitation, or as a result of incidental clinical or radiographic findings. However, 20% may have developed atrial fibrillation by 40 years, with the figure rising to around 60% by the age of 60 years. Similarly, the volume-​loaded right ventricle is well tolerated for many years, but may ultimately fail, usually after the fifth decade. Contributing factors to progression of symptoms with age may be increased left-​to-​right shunting due to an age-​related reduction in left ventricular compliance causing an increase in left ventricular end-​diastolic pressure and therefore left atrial pressure, and de- velopment of mitral regurgitation causing an increase in left atrial pressure. In addition, modest pulmonary arterial hypertension in- creases with age, so the right ventricle is exposed to pressure as well as volume overload, precipitating right ventricular failure. A left-​to-​right shunt at atrial level predisposes to paradoxical em- bolus since simple manoeuvres such as the Valsalva are sufficient to increase right atrial pressure and reverse the shunt. Patients with unoperated ASD are therefore at risk of embolic stroke, and should not dive because of the risk of paradoxical gas embolism. Interactions with coexisting heart disease Acquired disease may coexist and interact with congenital heart dis- ease, especially in the ageing patient. Left ventricular dysfunction due to coronary artery disease and systemic hypertension may in- crease the left-​to-​right interatrial shunt, resulting in a more rapid clinical deterioration. Similarly, mitral regurgitation increases the effective interatrial shunt and mitral valve abnormalities may be ac- quired secondary to the effects of a secundum ASD. There may be distortion of the anterior mitral valve leaflet with fibrotic shortened chordae due to the abnormal position of the interventricular septum as a result of chronic right ventricular overload. Lutembacher’s syn- drome is the association of mitral stenosis with secundum ASD. Mitral valve disease is underestimated in the presence of an ASD because the left atrium is able to decompress through the ASD. If significant mitral stenosis or regurgitation is overlooked at the time of ASD repair, left atrial pressure will rise and the patient may decompensate dramatically. It is therefore vital to ensure thorough assessment of the mitral valve in any patient in whom ASD closure is planned. Since left ventricular dysfunction may also be masked by an ASD, the defect serving to allow the left ventricle to offload, ventricular function must also be assessed carefully prior to ASD closure, particularly in elderly patients. Coexisting pulmonary stenosis may be overestimated in the pres- ence of an ASD, since Doppler velocities are increased in the pres- ence of a left-​to-​right shunt. Pulmonary vascular disease and atrial septal defect Mild pulmonary hypertension with ASD is a common finding with advancing age, but pulmonary vascular resistance is rarely in ex- cess of 6 Wood units and advanced pulmonary hypertension is rare. Few ASDs develop a right-​to-​left shunt secondary to pulmonary vascular disease, and a causal relationship between ASD and the Eisenmenger syndrome remains controversial. In ASD, unlike other lesions which may cause the Eisenmenger syndrome such as large VSD, the pulmonary vasculature is not exposed to increased flow at systemic pressure. ASD with a right-​to-​left shunt due to pulmonary vascular dis- ease and pulmonary hypertension occurs most commonly in young women, and in some cases may be due to idiopathic pulmonary arterial hypertension with an incidental ASD (see Table 16.12.4, pulmonary hypertension types A–​D). In this combination, the prog- nosis may be better than for idiopathic pulmonary arterial hyperten- sion with intact atrial septum, the septal defect protecting the right heart from pressure overload by allowing right-​to-​left shunting. Persistence of the fetal pulmonary vascular pattern may be impli- cated in the development of pulmonary hypertension in some young patients with ASD. Patients living or born at high altitude have a higher incidence of pulmonary vascular disease because of the ef- fects of relative hypoxia on the pulmonary vasculature. Clinical signs If the defect is non​restrictive the ‘a’ and ‘v’ waves of the jugular venous pulse tend to be equal. In older patients with reduced left ventricular compliance, the left and therefore right atrial pressure is raised, reflected by an elevated jugular venous pressure. A right ventricular heave may be felt at the left sternal border, and the di- lated pulmonary artery may be palpable in the left second inter- costal space. The first sound is loud because of increased diastolic flow across the tricuspid valve. If the left-​to-​right shunt is greater than approximately 2:1, the second heart sound is widely split and fixed, and there is loss of normal sinus arrhythmia. There may be a section 16  Cardiovascular disorders 3572 pulmonary flow murmur at the upper left sternal edge. Only if the ASD has a high gradient across it will it generate a murmur itself, usually a soft continuous murmur. This is the case if the defect is small and restrictive and the left atrial pressure high (e.g. if there is associated mitral stenosis). If the patient has pulmonary vascular disease, the signs will be the same as for pulmonary hypertension with right-​to-​left shunt. Investigations The ECG may show sinus node dysfunction, prolongation of the PR interval, right axis deviation, and QRS prolongation with rSr′ in lead V1—​which does not represent incomplete right bundle branch block, but occurs since the last part of the myocardium to depolarize is the right ventricular outflow tract that is enlarged and thickened due to volume overload. Postoperatively the ECG may show sinus node dysfunction due to damage when the SVC is cannulated, and the PR interval returning to normal as right atrial size decreases. Macro re-​entry circuits at the site of atrial surgery may result in postoperative ectopic atrial tachycardias. The typical chest radiograph shows dilated proximal pulmonary arteries with a small aortic knuckle, plethoric lung fields, and car- diomegaly secondary to dilatation of the right atrium and ventricle. Transthoracic echocardiography demonstrates the volume-​loaded right atrium and ventricle. The size of the shunt can be estimated and colour-​flow Doppler facilitates the detection of the site of the shunt. If transcatheter device closure is considered, a transoesophageal ap- proach is necessary to define the site and size of the ASD precisely and to identify the pulmonary veins. Cardiac catheterization is indicated only to calculate pulmonary vascular resistance if there is a suspicion of pulmonary hyperten- sion, or to exclude coexisting congenital or acquired cardiac path- ology such as coronary artery disease. Management Indications for closure of atrial septal defect Closure of an ASD is indicated if there is right heart volume over- load, left-​to-​right shunt is 1.5:1 or more, and the ASD is 10 mm or more in diameter. Prevention of recurrent paradoxical embolism is an additional indication for closure. Contraindications to closure are significant pulmonary hypertension (which may be suggested by a right-​to-​left shunt on exercise or at rest) and severe left ventricular dysfunction. In addition, merely closing the ASD in the presence of significant mitral valve disease is contraindicated. Irrespective of age, the benefits of device closure should be im- proved functional class, exercise capacity, and breathlessness. Repair of a large isolated secundum ASD by the third decade results in a normal life expectancy. Between the ages of 25 and 41 years it results in a good but shorter than normal life expectancy, but beyond the age of 41 years morbidity and mortality remain sig- nificantly higher than normal. Nonetheless, functional status and longevity are improved following repair over the age of 40 years, 5-​ and 10-​year survival being estimated as 98% and 95% respect- ively for patients who underwent repair, and 93% and 84% for those treated medically. Before undertaking repair, older patients (>60  years) should be thoroughly assessed for any subclinical left heart disease, in particular diastolic ventricular dysfunction, coronary artery or mitral valve disease, since these may be unmasked by isolated ASD closure. In balancing benefits and risks it must also be recognized that ASD repair in older patients does not reduce the risk of late atrial arrhythmia, particularly if there is right ventricular dysfunc- tion, elevated pulmonary artery pressure, or pre-​existing atrial ar- rhythmia. Whether the incorporation of a modified maze procedure or cryoablation into the surgical repair of ASD will reduce the long-​ term incidence of existing or de novo atrial arrhythmia remains to be determined. Secundum ASDs up to 4 cm stretched diameter may be closed by transcatheter devices so long as the surrounding rim of atrial septal tissue is sufficient. Criteria for device closure of secundum ASD are size less than 4 cm; a situation away from the atrioventricular valves and pulmonary and caval veins; and normal pulmonary venous drainage. The risk of major complication during device closure is 1 to 2%. Following closure, antiplatelet or anticoagulant therapy is recommended for 3 to 6 months. Surgical repair carries also carries a low mortality and morbidity, but perioperative atrial fibrillation is common and recovery time is longer. Other forms of atrial septal defect Sinus venosus atrial septal defect Sinus venosus defects account for 2–​3% of ASDs and have an equal sex incidence. They are not truly defects of the atrial septum, but since they allow shunting at atrial level, they are included in the classification of ASDs. The inferior border of the more common SVC type of sinus venosus defect is made by the superior limbus of the fossa ovalis, and the upper border comprises the junction of the SVC with the atrial mass. The superior caval vein overrides the atrial septum, connecting to both atriums, and the right upper pul- monary vein drains anomalously into the SVC. There may be an ec- topic atrial pacemaker because the defect is located in the area of the sinoatrial node. This may be reflected by a leftwards ‘p’ wave axis and an inverted ‘p’ wave in lead III. The sinus venosus defect may not be visualized with transthoracic echocardiography, and a transoesophageal approach is usually ne- cessary to define the defect and is associated anomalous pulmonary venous drainage. They are unsuitable for transcatheter device closure, both because there is no superior rim and because of anomalous drainage of one or more of the right pulmonary veins. The proximity of the sinus node to the SVC type of defect makes it vulnerable to damage during surgical repair; postoperative atrial pacing may be required. Coronary sinus defect The rarest form of ASD, this defect is at the site of entry of the cor- onary sinus to the right atrium. The unroofed coronary sinus is a variation of coronary sinus defect in which the partition between the coronary sinus and the left atrium is absent as the coronary sinus runs posteriorly along the floor of the left atrium. In this condition, a left SVC commonly connects directly to the left atrium, producing a right-​to-​left shunt and cyanosis. Ostium primum atrial septal defect This is a defect in the true atrial septum that exists as part of an AVSD and is discussed later in the chapter (see ‘Atrioventricular septal defects’). 16.12  Congenital heart disease in the adult 3573 Ventricular septal defects With the exceptions of bicuspid aortic valve and mitral valve prolapse, VSD is the commonest congenital cardiac malforma- tion, occurring in around 3 per 1000 live births. It occurs equally in both sexes. Defects may exist in isolation, in association with other lesions such as coarctation of the aorta, or as an integral part of lesions such as tetralogy of Fallot. This section deals with isolated VSDs. Morphology and classification An understanding of the basic anatomy of the ventricular septum is necessary to appreciate the various types of VSD. A VSD arises when there is failure of one of the components of the ventricular septum to develop correctly. The septum comprises four parts and is described as viewed from the right ventricle (Fig. 16.12.6): • Inlet septum—​separates the mitral and tricuspid valves • Muscular trabeculated septum—​extends from the tricuspid valve leaflet attachments to the muscle separating the tricuspid and pul- monary valves (the crista supraventricularis) • Outlet septum—​extends from the crista to the pulmonary valve • Perimembranous septum—​small fibrous area bordered by the aortic and tricuspid valves VSDs are classified by their location within the septum and by their borders, again viewed from the right ventricle. There are three types:  muscular, perimembranous and doubly committed subarterial (Figs. 16.12.6 and 16.12.7). The position of muscular and perimembranous VSDs may be inlet, trabecular, or outlet, depending on which part of the right ventricle they open into. Perimembranous VSD is the commonest type of defect. Only 5 to 7% of VSDs in Europe and North America are doubly committed subarterial defects, whereas they account for up to 30% of defects in Asian patients. Clinical presentation and complications of unoperated ventricular septal defect The presentation of an isolated VSD depends on its size and haemo- dynamic effects (Table 16.12.6). Perimembranous and doubly com- mitted subarterial VSDs may be associated with the development of aortic valve leaflet prolapse and aortic regurgitation, and the con- duction tissue in these types of defects is vulnerable to damage at operation. Adults with isolated unoperated restrictive VSDs are usually asymptomatic and acyanotic, with normal arterial and jugular venous pulses. There may be a thrill at the left sternal border, the left ventricular apex may be thrusting if the defect is large enough to cause volume overload, and a dilated pulmonary artery may be palpable. The second heart sound is usually normally split. There is a loud, harsh pansystolic murmur at the left sternal edge, which is softer and shorter (early systolic) in very small defects. Late complications of unoperated small VSDs include significant risk of endocarditis due to the high-​velocity jet from left-​to-​right ventricles, particularly if the jet is directed onto tricuspid valve tissue; aortic regurgitation if the aortic valve forms part of the border of the VSD; atrial arrhythmia if there is left heart volume overload; and small increased risk of sudden death and ventricular arrhythmia. A moderate-​sized restrictive VSD may cause left heart volume overload, and in the long term, atrial arrhythmias and left ventricular dysfunction. A VSD causes left, rather than right, ventricular dilata- tion because the left-​to-​right shunt reaches the right ventricle during ventricular systole: the right ventricle cannot dilate during contrac- tion, so the additional blood is directed straight into the pulmonary circulation and back into the left heart during diastole. Thus, the left heart is subject to volume overload. Membranous septum Inlet septum Outlet septum Muscular trabecular septum PV AV TV III IIa IIb I Fig. 16.12.6  Schematic representation to show the sites of different types of ventricular septal defects (VSDs). The heart is in cross-​section, viewed from the right ventricular aspect. I, muscular VSD; IIa, perimembranous outlet VSD; IIb perimembranous inlet VSD; III doubly committed subarterial VSD. AV, aortic valve, seen through VSD; PV, pulmonary valve; TV, tricuspid valve. section 16  Cardiovascular disorders 3574 Larger VSDs rarely present for repair in adulthood since the large left-​to-​right shunt is unlikely to allow unoperated survival unless pulmonary vascular disease has developed. Non​restrictive defects are not associated with the classical VSD murmur since left and right ventricular pressures are equal. Investigations Investigation should determine the type and number of VSDs, the size of the defect (restrictive or non​restrictive), an estimation of the size of the shunt (Qp:Qs), pulmonary artery pressure and resistance, and assessment of left and right ventricular function and volume and pressure overload. Associated lesions that may alter manage- ment should be identified, especially aortic regurgitation, subaortic stenosis, and right ventricular outflow tract obstruction. The chest radiograph is normal if the defect has been small from birth. If the VSD is (or has been) larger, the left ventricle, left atrium, and pulmonary trunk may be dilated and there may be increased pulmonary vascularity. The ECG shows a normal QRS axis unless there are multiple defects, when there may be left axis deviation. In the presence of a large left-​to-​right shunt the ‘p’ wave may be broad and there may be evidence of left ventricular hypertrophy. Two-​dimensional echocardiography identifies the number and site of defects as well as describing the morphology and associated de- fects. Doppler is used to estimate the size and direction of the shunt, and right ventricle to left ventricle pressure difference, but this may not be accurate if there is an obliquely lying muscular VSD. Cardiac catheterization is important to measure the size of shunt and pul- monary vascular resistance, with reversibility studies if baseline re- sistance is high. Management and prognosis Repair of a VSD is indicated in the presence of symptoms, if Qp:Qs is greater than 2:1, or if there is ventricular dysfunction with right ventricular pressure overload or left ventricular volume overload. Repair should also be undertaken if there are coexisting lesions such as significant right ventricular outflow tract obstruction, or more than mild aortic regurgitation or aortic valve prolapse in the pres- ence of an outlet VSD. An episode of endocarditis may also be con- sidered as an indication for VSD closure. If the pulmonary artery pressure is more than two-​thirds systemic pressure, repair should only be considered if Qp:Qs exceeds 1.5:1 or if there is evidence of reversibility in response to pulmonary vasodilators such as oxygen and nitric oxide. The surgical approach aims at avoiding damage to important structures such as the conducting tissues, which are especially vul- nerable in perimembranous defects. Transatrial repair reduces the risk of postoperative ventricular arrhythmias by avoiding a right ventriculotomy. Transient postoperative complete heart block is as- sociated with an increased risk of late high-​degree block, and per- manent pacemaker implantation is indicated in the 1–​2% of patients in whom complete heart block persists, even if they are asymptom- atic, because there is a significant risk of late sudden death. The prognosis after VSD repair in the early years of life is good, but if repair is delayed into late childhood left ventricular dilatation may persist and systolic function be impaired. Long-​term postoperative survival depends on the presence of pulmonary hypertension, left ventricular dysfunction, and complications such as aortic regurgita- tion and endocarditis. Transcatheter device closure of VSDs is possible providing that valvar apparatus can be avoided. Both muscular and selected perimembranous VSDs may be device closed, the latter requiring experienced hands to avoid damage to the aortic valve and heart block. This approach is particularly useful for defects that are diffi- cult to access or close surgically, and a hybrid surgical/​interventional technique may be used. Atrioventricular septal defects The key feature of an AVSD (previously termed endocardial cushion defect or atrioventricular canal) is a common atrioventricular Aortic valve RA RV PA TV PV * ** Fig. 16.12.7  Schematic representation of the transthoracic echocardiographic parasternal short-​axis view, to demonstrate sites of ventricular septal defects (VSDs).**, site of doubly committed subarterial VSD—​the aortic and pulmonary valves are in continuity and form the roof of the VSD.*, site of subaortic perimembranous VSD. PA, pulmonary artery; PV, pulmonary valve; RA, right atrium; RV, right ventricle; TV, tricuspid valve; VSD, ventricular septal defect. Table 16.12.6  Grading of ventricular septal defects by size Small Moderate Large Eisenmenger syndrome Pulmonary artery pressure: systemic pressure ratio <0.3 0.3–​0.6 RV = LV pressure RV ≥ LV pressure Qp:Qs <1.4: 1 1.4–​2.2: 1 2.2:1 <1.5: 1 Clinical grading Negligible haemodynamic changes, normal LV LA and LV enlargement and reversible pulmonary hypertension Pulmonary vascular disease (Eisenmenger syndrome) will develop unless there is RVOTO Restrictive (RV pressure < LV pressure in absence of RVOTO) Non​restrictive (equal RV and LV pressures in absence of RVOTO) Qp, pulmonary blood flow; Qs, systemic blood flow; RVOTO, right ventricular outflow tract obstruction. 16.12  Congenital heart disease in the adult 3575 junction and atrioventricular valve ring (Fig. 16.12.8). The atrio- ventricular septum is absent, and the atrioventricular valves share a common junction and fibrous ring, with a five-​leaflet atrioven- tricular valve. Since they share common leaflets, the valves are not correctly called mitral and tricuspid valves, but left and right atrio- ventricular valves. As a consequence, the normal offsetting of the right atrioventricular valve towards the right ventricular apex is absent. In addition, the aorta is ‘unwedged’ from its normal pos- ition between the left and right atrioventricular valves. The left ven- tricular outflow tract is therefore elongated (‘gooseneck’) and has the propensity to develop obstruction, often due to septal attach- ments of the left atrioventricular valve. ‘Cleft mitral valve’ refers to the commissure between the anterior and posterior bridging leaflets that renders the left atrioventricular valve potentially regurgitant. The left ventricular papillary muscles are abnormally placed an- teriorly and posteriorly instead of in the normal anterolateral and posteromedial positions. Ostium primum defect describes the atrial component of an AVSD. There are two types of AVSD, partial and complete. Both have a common atrioventricular junction, but in a partial AVSD the right and left atrioventricular valves have separate orifices and the VSD is usually small or absent, and in a complete AVSD there is a common atrioventricular valve and valve orifice, and the VSD is usually large. AVSD occurs with equal sex incidence. The complete form of the defect is most commonly associated with Down’s syndrome. A single gene defect may be responsible for AVSD in non​syndromic patients, when the recurrence risk is about 10% if the mother has an AVSD, less if the father is affected. The physiological consequences of an AVSD are the same as for other conditions with left-​to-​right shunting at atrial or ventricular level, but may be complicated by left atrioventricular valve regur- gitation or left ventricular outflow tract obstruction. Pulmonary vascular disease may develop if the VSD is large and non​restrictive. Patients with Down’s syndrome are at particular risk of this compli- cation, and coexisting upper airway obstruction and sleep apnoea, and abnormal pulmonary parenchyma, may be contributory factors. Investigations The ECG is distinctive, with a left and superior QRS axis and notching of ‘S’ waves in the inferior leads. The chest radiograph appearances depend on the degree of interatrial shunting and left atrioventricular valve regurgitation, the former producing cardiomegaly due to left heart dilatation and the latter left atrial enlargement. There may be increased pulmonary vascularity, particularly in young patients with complete AVSD and high pulmonary blood flow. Transthoracic echocardiography reveals the detailed anatomy of the defect and establishes the site and degree of shunting, the pres- ence and nature of left ventricular outflow tract obstruction, and the function and anatomy of the atrioventricular valves. The indications for cardiac catheterization are the same as for secundum ASD, namely to exclude inoperable pulmonary vascular disease. In addition, useful information may be obtained regarding the severity of left atrioventricular valve regurgitation and left ven- tricular outflow tract obstruction. Clinical presentation and course First presentation may occur in adulthood if the left-​to-​right shunt is small and the left atrioventricular valve is competent. Physical signs are the same as in other ASDs, and there may also be an apical pansystolic murmur. Paradoxical embolism is less common than in secundum ASD because the position of the primum defect low in the interatrial septum avoids the streaming of blood from the in- ferior vena cava that is most likely to carry emboli and is directed towards the midportion of the septum. Normal heart Partial AVSD Complete AVSD AV AV AV TV MV RAVV RAVV LAVV LAVV Superior bridging leaflet Inferior bridging leaflet Left mural leaflet Right inferior leaflet Right anterosuperior leaflet Fig. 16.12.8  Schematic representation of the atrioventricular junction in atrioventricular septal defect (AVSD). Short-​axis view, seen from the atrial aspect. In both forms of AVSD, there is a common atrioventricular valve ring guarded by five valve leaflets. In the partial defect, the superior and inferior bridging leaflets fuse to create two separate valve orifices. This fusion does not occur in complete AVSD, so there is a common valve orifice. AV, aortic valve; LAVV, left atrioventricular valve; RAVV, right atrioventricular valve. section 16  Cardiovascular disorders 3576 Most adult patients have undergone surgery to repair the defect and left atrioventricular valve: others have survived unoperated and may have developed pulmonary vascular disease. Late complications after repair of AVSD include recurrent atrioven- tricular valve regurgitation, the severity of which may increase with age in response to changes in the left ventricle due to ageing, ischaemia, or systemic hypertension; residual ASD or VSD; residual or recurrent left ventricular outflow tract obstruction, which may be difficult to relieve surgically if it involves left atrioventricular valve tissue; complete heart block, related to the abnormally positioned atrioventricular node that is particularly vulnerable to intraoperative damage; endocarditis, re- lating largely to the left atrioventricular valve; and atrial arrhythmia. It is vital to read the original operation note when planning ablation, since the mouth of the coronary sinus is often left opening into the left atrium, making it inaccessible to the electrophysiologist. Arterial disorders Coarctation of the aorta Aortic coarctation is a narrowing of the aorta, usually sited near the ligamentum arteriosum. It is one of the commonest congenital cardiac lesions, occurring in 1 in 12 000 live births, with a male to female ratio of 3:1. Coarctation is part of a generalized arteriopathy with consider- able variation in anatomy and severity, ranging from a mild obstruction to interruption of the aorta, and from a discrete fibromuscular shelf to hypoplasia of the arch. Coarctation is most strongly associated with bicuspid aortic valve, which coexists in up to 80% of cases. Ascending and descending aortopathy may be present, with medial changes and arterial wall stiffness; aneurysm formation, dissection, and the com- plications of hypertension require lifelong surveillance. Other associ- ations are VSD, patent arterial duct, subaortic ridge, and mitral valve abnormalities. It is a frequent finding in Turner’s syndrome and is also associated with congenital aneurysm of the circle of Willis. Clinical presentation and course Most patients present in infancy, but some survive into adulthood before being diagnosed at routine examination or during investi- gation for hypertension, leg claudication, angina, heart failure, or cerebral haemorrhage. Historically, more than 75% with unoperated coarctation died by age 50 years, from premature coronary disease, stroke, or aortic dissection. Clinical findings include upper body hypertension: the leg blood pressure is lower, as is that in the left arm if the subclavian artery is involved in the coarctation. If there is a good collateral supply, fem- oral arteries may be easily palpable, but they are usually reduced, with radiofemoral delay. Intercostal collaterals may be both visible and palpable over the patient’s back. There is an ejection systolic murmur from the site of coarctation, and systolic collateral murmurs may be heard. Fundoscopy shows a typical corkscrew appearance of the ret- inal vessels and there may be evidence of hypertensive retinopathy. Investigations There may be electrocardiographic evidence of left ventricular hypertrophy. The chest radiograph (Fig. 16.12.9) has a typical appearance. Transthoracic echocardiography may show left ventricular hyper- trophy, with the coarctation site visualized on two-​dimensional imaging and its severity assessed using Doppler mode from the suprasternal notch. A peak gradient of over 20 mm Hg is significant, especially if accompanied by a diastolic tail. MRI provides definitive non​invasive haemodynamic data and two-​ and three-​dimensional images of the coarctation site, collat- erals and related vessels (Fig. 16.12.10). It may obviate the need for angiography unless coronary disease is suspected. In the adult, diagnostic angiography is usually reserved for assessing coronary disease. Management Surgical repair Surgical repair is the conventional approach in neonates and chil- dren, with a risk of less than 1% for those with simple coarctation. Extensive collateral vessels and non​elastic diseased aortic tissue make surgical repair of adult coarctation challenging, and this is as- sociated with significant morbidity. The incidence of perioperative spinal cord ischaemia and paraplegia is up to 0.4%, those patients without an abundant collateral circulation probably being most at risk. Those with well-​developed collaterals are at risk of significant intraoperative haemorrhage. Early postoperative hypertension is common and may be difficult to control, and postoperative intes- tinal ileus may persist for several days. Transcatheter balloon dilatation and primary stenting of na- tive coarctation in adults are usually the preferred alternatives to Fig. 16.12.9  Chest radiograph of an 18-​year-​old man with unoperated coarctation of the aorta and bicuspid aortic valve. There is bilateral rib notching (arrows) and a prominent deformed aortic knuckle. The dilated ascending aorta (*) indicates the associated aortopathy. 16.12  Congenital heart disease in the adult 3577 surgery. The use of primary stents, particularly covered stents, is likely to support the aorta following dilatation and to reduce the risk of aortic dissection or late aneurysm formation. However, this interventional approach should only be done in specialist centres; careful follow-​up is required. Follow-​up after coarctation repair Follow-​up after repair of coarctation should be lifelong, since late complications are frequent: residual or recoarctation, aneurysm formation, persistent hypertension despite adequate repair, pre- mature atherosclerotic disease, and progression of associated le- sions such as bicuspid aortic valve and aortopathy. Older age at repair is the main risk factor influencing longevity. Late survival is 92% for patients repaired in infancy, 25-​year survival is 75% for those repaired between ages and 40 years, but 15-​year survival is only 50% for those repaired at age more than 40 years. Recoarctation may be diagnosed when the resting arm–​leg sys- tolic blood pressure gradient is 20 mm Hg at rest and 50 mm Hg after exercise. This occurs most commonly following neonatal repair by end-​to-​end anastomosis, and the diagnosis should be sought when there is new or persisting hypertension. Blood pressure should be recorded in both arms of all such patients; spuriously low readings may be obtained if one of the subclavian arteries (usually the left) is involved in the repair or recoarctation. MRI is the investigation of choice for both recoarctation and aneurysm formation after coarctation repair. High-​resolution CT is used following stent repair of coarctation (Fig. 16.12.11), since the artefact produced by the stent renders MRI unhelpful. Balloon angioplasty with or without stent insertion is used to relieve most recoarctations, but reoperation is required for some patients with complex anatomy. The 14-​year incidence of aneurysm formation at the site of repair is up to 27%; it occurs most commonly in adults and in those with Dacron patch repair. An aneurysm may rupture into the bronchial tree or oesophagus, hence any patient with a history of coarctation who presents with haemoptysis or haematemesis should undergo emergency non​invasive diagnostic imaging (MRI or CT) and surgical repair. Bronchoscopy and conventional angiography are contraindi- cated since they may cause further damage to the area. Hypertension is a major risk factor for atherosclerotic disease and may persist despite an apparently good result from surgical repair. Continuing hypertension relates in part to older age at time of sur- gery. Nonetheless, late repair of coarctation or re-​coarctation does render systolic hypertension easier to control. Patent arterial duct The pathophysiological consequences of a patent arterial duct in adulthood depend on the size of the shunt. Small ducts are of no haemodynamic significance and are associated with a low risk of infective endarteritis. Moderate-​sized ducts may cause left heart volume overload and late atrial fibrillation and ventricular dysfunc- tion. A large non​restrictive duct may cause pulmonary vascular dis- ease (see ‘Eisenmenger syndrome’, earlier). Duct closure is usually recommended if a duct is clinically detect- able (i.e. there is a systolic or continuous (machinery) murmur in the left subclavicular area, to avoid long-​term haemodynamic com- plications). Ducts up to 14 mm in diameter are usually suitable for transcatheter device closure. Pulmonary vascular disease should be excluded before repair of large ducts is undertaken. Fig. 16.12.10  MRI of a 20-​year-​old woman who presented with hypertension. There is a severe discrete coarctation (↓), multiple tortuous collaterals and a dilated ascending aorta (*) associated with a bicuspid aortic valve. Fig. 16.12.11  High-​resolution CT scan demonstrating stent deployed at native coarctation site. section 16  Cardiovascular disorders 3578 Aortopulmonary window In this rare condition there is a direct communication between adja- cent portions of the proximal ascending aorta and pulmonary artery. The communication is usually large and the physiological conse- quences are the same as for a large patent arterial duct. Rare patients surviving unoperated into adulthood will be cyanosed and have de- veloped the Eisenmenger syndrome. If pulmonary vascular resist- ance is low at the time of childhood repair, long-​term postoperative survival is good. Truncus arteriosus/​common arterial trunk This condition accounts for 1–​4% of all congenital heart disease. It may coexist with interrupted aortic arch, coarctation, coronary anomalies, and DiGeorge syndrome. A  single great artery arises from the heart and gives rise to the coronary arteries, aorta, and pul- monary arteries. There is a single semilunar ‘truncal’ valve that has three or more leaflets, and a subtruncal VSD. Most patients present in infancy with heart failure. If they are left unoperated, pulmonary vascular resistance rises, cyanosis becomes more marked, and the Eisenmenger syndrome becomes established. Repair before pulmonary vascular disease develops involves closure of the VSD, detachment of the pulmonary arteries from the common arterial trunk, and placement of a valved conduit from right ven- tricle to pulmonary artery. The truncal valve then functions as the aortic valve. Late complications following repair include truncal re- gurgitation, truncal (aortic root) dilation, ventricular dysfunction, and the need to replace stenotic conduits. Sinus of Valsalva aneurysm There is dilation of one of the aortic valve sinuses between the aortic valve annulus and sinotubular junction, and the aneurysm progres- sively dilates and may rupture. The right and non​coronary cusps are most often affected; rupture of a non​coronary sinus aneurysm is nearly always into the right atrium and of the right coronary sinus into the right ventricle or atrium. Involvement of the left coronary sinus is rare. Rupture usually occurs in early adulthood and may be precipitated by endocarditis. If sudden, it is accompanied by tearing chest pain, breathlessness, and sudden-​onset symptoms suggesting heart failure, with a loud continuous murmur and good systolic ventricular function. Small perforations may remain asymptomatic for many years. The diagnosis and site of the rupture is confirmed echocardiographically and/​or angiographically before surgical or transcatheter repair. Coronary artery anomalies The importance of congenital coronary anomalies lies in their poten- tial to impair myocardial blood flow and cause ischaemia and sudden death. Evidence of ischaemia is the main indication for repair. The major types of coronary anomaly are summarized in Box 16.12.3. Anomalous origin of the coronary arteries from an inappropriate aortic sinus Ischaemia is particularly associated with an anomalous proximal coronary course between the aorta and pulmonary trunk, an intra- mural proximal segment of the coronary artery inside the aortic wall, and acute angulation between the origin of an anomalous cor- onary artery and the aortic wall. Anomalous origin of the left coronary artery from the pulmonary artery This rare condition, known as ALCAPA, usually presents in infancy with myocardial ischaemia and left ventricular failure when pul- monary vascular resistance decreases. However, 10–​15% survive into adulthood because an adequate intercoronary collateral circulation is established. Adults may be asymptomatic or present with myocar- dial ischaemia or mitral regurgitation due to papillary muscle dys- function. Survival following surgical repair depends on the amount of ischaemic myocardial damage and degree of mitral regurgitation. Congenital coronary arteriovenous fistulas The coronary arteries arise normally from their aortic sinuses, but a fistulous branch communicates directly with the right ventricle in 40% of cases, the right atrium in 25%, pulmonary artery in 15%, or rarely the SVC or pulmonary vein. Survival to adulthood is usual, but lifespan may be reduced, depending on the size of the fistulous connection and the presence of myocardial ischaemia resulting from any coronary steal phenomenon. Symptoms increase with age and there is a risk of endocarditis, heart failure, arrhythmia, myocar- dial ischaemia and infarction, and sudden death. Surgical repair is recommended unless there is a trivial isolated shunt. Some smaller fistulae are suitable for transcatheter device occlusion. Systemic venous anomalies These anomalies frequently form part a more complex lesion, par- ticularly isomerism. Normal systemic venous drainage is illustrated in Fig. 16.12.12. Superior caval vein anomalies A persistent left-​sided SVC occurs in 0.3% of the general popu- lation, approximately 3% of patients with congenital heart dis- ease, and 15% of those with tetralogy of Fallot. The left SVC may be visible on the chest radiograph. It usually drains to the right atrium via the coronary sinus, which is seen to be dilated on two-​ dimensional echocardiography (Fig. 16.12.13). A right-​sided SVC is usually also present, but the two caval veins do not usually com- municate via the brachiocephalic vein. This common anomaly should be sought routinely at cardiac catheterization; although it Box 16.12.3  Major types of coronary anomaly • Anomalous origin from inappropriate aortic sinus or coronary vessel —​ LAD from right aortic sinus or right coronary artery (RCA) —​ Absent LMS (separate origins of LAD and Cx) —​ Cx from right aortic sinus or RCA or absent Cx —​ RCA from left aortic sinus, posterior sinus, or LAD —​ Single coronary artery from right or left aortic sinus • Anomalous origin from other systemic artery (rare) —​ Innominate, subclavian, internal mammary, carotid, bronchial arteries, or descending aorta • Anomalous origin from pulmonary artery • Coronary arteriovenous fistulae Cx, circumflex; LAD, left anterior descending; LMS, left main stem; RCA, right coronary artery. 16.12  Congenital heart disease in the adult 3579 does not have any haemodynamic significance, it may cause tech- nical difficulties during transvenous pacemaker insertion and car- diac surgery (Fig. 16.12.14). Other SVC anomalies are rare. An absent right SVC is associated with arrhythmias including atrioventricular block, sinus node dys- function, and atrial fibrillation. The left, or rarely the right, SVC may connect directly to the left atrium, causing an obligatory right-​to-​left shunt and cyanosis. This may be associated with isomerism of the atrial appendages. Inferior caval vein anomalies Azygos continuation of the inferior vena cava (IVC) occurs in 0.6% of patients with congenital heart disease. The infrahepatic portion of the IVC is absent and continues to the SVC via an azygos vein; the hepatic veins drain directly into the right atrium. This is often associated with complex lesions, particularly left isomerism. The chest radiograph reveals an absence of the IVC at the junction of the diaphragm with the right heart border and a dilated azygos vein (Fig. 16.12.15). Direct connection of the IVC Left internal jugular vein Left subclavian vein Left brachiocephalic vein Hemiazygos vein Ascending lumbar vein Lumbar azygos veins Azygos veins Right brachiocephalic vein Right subclavian vein Right internal jugular vein IVC SVC Fig. 16.12.12  Schematic diagram of normal systemic venous drainage. CS Ao LV LA RV Fig. 16.12.13  Persistent left superior vena cava. Transthoracic two-​ dimensional echocardiogram, parasternal long-​axis view. The coronary sinus, receiving the persistent left superior vena cava, is dilated. Ao, aorta; CS, coronary sinus; LA, left atrium; LV, left ventricle; RV, right ventricle. Fig. 16.12.14  Chest radiograph of a 56-​year-​old man with bicuspid aortic valve, aortic regurgitation, and coarctation. A left superior vena cava draining via the coronary sinus to the right atrium is marked by the path taken by the transvenous pacing leads, inserted for complete heart block. Fig. 16.12.15  Chest radiograph of a 50-​year-​old man with abdominal situs inversus (*) and laevocardia. Left atrial isomerism is inferred from the symmetrical long bronchi (bilateral morphological left lungs). The inferior vena cava is absent at the level of the diaphragm (small arrow), and the azygos vein receiving inferior caval venous blood is prominent (large arrow). section 16  Cardiovascular disorders 3580 to the left atrium is rare: the patient is cyanosed, as in the SVC–​left atrium connection. Pulmonary venous anomalies Total anomalous pulmonary venous drainage Total anomalous pulmonary venous drainage occurs in 1 in 17 000 live births. All four pulmonary veins drain into the right atrium, ei- ther directly or via a common vein into a systemic vein. The anom- alous veins may follow (1) a supracardiac course draining to the SVC, azygos, or brachiocephalic veins; (2) a cardiac course, draining to the right atrium directly or to the coronary sinus directly or via a persistent left SVC connection; or (3) an infradiaphragmatic course, draining to the portal vein or IVC. Since the pulmonary venous confluence is a left atrial struc- ture, total anomalous venous drainage is obligatory in right isom- erism: there are bilateral right atriums and no left atrium for the pulmonary veins to drain to. The presence of pulmonary venous obstruction is the most important predictor of a poor outcome. Associated anomalies include an obligatory right-​to-​left shunt, nearly always at atrial level. The condition presents in infancy, hence 98% of patients reaching the adolescent or adult clinic will have survived corrective surgery in early life. Unless there is residual pulmonary hypertension most such adults should be asymptomatic, having a normal cardiovas- cular examination and an excellent prognosis. Patients who are still growing may develop obstruction of the redirected pulmonary venous pathway and present with dyspnoea, signs of pulmonary oe- dema, evidence of pulmonary venous congestion on the chest radio- graph, and an obstructive echo Doppler flow signal at the site of the stenosis. The rare patient who reaches adulthood unoperated is likely to have survived because of a large ASD and unobstructed pulmonary venous drainage. They will be cyanosed, have developed pulmonary vascular disease, and be at risk of atrial tachyarrhythmias and right heart failure. The chest radiograph has the appearance of a large ASD with a small aortic knuckle, cardiomegaly, and a dilated main pul- monary artery. In addition, the anomalous veins may cause an ab- normal vascular shadow. Partial anomalous pulmonary venous drainage There is anomalous drainage of some of the pulmonary veins to the right atrium. In 90% of cases the anomalous pulmonary venous con- nection is between the right upper or middle pulmonary vein to the SVC or right atrium, usually in association with an ASD, 10 to 15% of all ASDs and nearly all SVC-​type sinus venosus ASDs being asso- ciated with partial anomalous pulmonary venous connection. Partial anomalous pulmonary venous drainage may present in adult life with signs of a left-​to-​right shunt at atrial level; the patho- physiological consequences are the same as for an ASD with an equivalent shunt. Transthoracic echocardiography may be indicative of a shunt at atrial level, but in adults it may not be possible to image the pul- monary veins and a transoesophageal approach is likely to be ne- cessary. The identification of all the pulmonary veins is crucial in assessing the suitability of a secundum ASD for transcatheter device closure, this technique being contraindicated in the presence of anomalous pulmonary veins (see ‘Atrial septal defects’, earlier). The indications for surgical repair are the same as those for re- pair of an ASD, but the surgical manoeuvres necessary to commit the anomalous pulmonary vein(s) to the left atrium should be taken into account when deciding whether surgery is appropriate. Surgical repair is straightforward when, for example, the right upper pul- monary vein drains to the superior vena cava in association with a sinus venosus ASD. However, a conduit or tunnelled repair may be required if the anomalous vein(s) drain to the inferior or superior vena cavae more distantly from the atrial mass. The low velocity, low-​pressure flow within such a repair is associated with a risk of subsequent obstruction and loss of perfusion to the affected lung tissue, with consequent loss of any benefit to the patient. Scimitar syndrome Partial anomalous pulmonary venous drainage also occurs as part of the rare familial ‘scimitar syndrome’ (OMIM 106700) in which part or all of the right pulmonary venous drainage is to the IVC below the diaphragm. The affected lung lobes are usually hypoplastic (Fig. 16.12.16) and are supplied with arterial blood from the descending aorta. Recurrent infection and bronchiectasis may de- velop in the hypoplastic lobes or lung. MRI demonstrates the ab- normal arterial supply and venous drainage of the affected lung segment, and may obviate the need for diagnostic cardiac cath- eterization. Surgical repair may be complicated by difficulty in maintaining perfusion to the affected lung, and lobectomy may be required. In view of this it should be remembered that patients pre- senting with scimitar syndrome for the first time in adult life have a good unoperated prognosis, similar to that of a small ASD. Fig. 16.12.16  Chest radiograph of a 25-​year-​old woman with scimitar syndrome. The heart is shifted into the right hemithorax because the right lung is small. The ‘scimitar’ shadow (arrow) is produced by the anomalous descending venous channel which drains into the dilated inferior vena cava (*). 16.12  Congenital heart disease in the adult 3581 Transposition complexes The nomenclature of the transposition complexes may cause confu- sion. There are two types: • Complete transposition of the great arteries (TGA)—​this condi- tion is described as concordant atrioventricular connection and discordant ventriculo-​arterial connection (Fig. 16.12.15), previ- ously known as D-​TGA (Fig 16.12.17). Without intervention it is not compatible with life, since once the arterial duct and foramen ovale have closed, there is complete separation of the systemic and pulmonary circulations such that deoxygenated blood from the systemic veins recirculates to the aorta, and oxygenated blood from the pulmonary veins recirculates to the pulmonary artery. • Congenitally corrected transposition of the great arteries (cTGA)—​this condition is described as discordant atrioven- tricular and ventriculo-​arterial connections. (Fig. 16.12.18), previously known as L-​TGA.  cTGA is congenitally physiolo- gically ‘corrected’: deoxygenated systemic venous blood reaches the pulmonary artery, albeit via the morphological left ven- tricle; oxygenated pulmonary venous blood reaches the aorta, but via the morphological right ventricle. Complete transposition of the great arteries (discordant atrioventricular connection, concordant ventriculo-​arterial connection) TGA accounts for about 5% of congenital cardiac malforma- tions and is four times more common in males than females. Associated anomalies such as VSD and pulmonary stenosis occur in approximately one-​third of patients. As described earlier, unoperated survival after closure of the foramen ovale and arterial duct have closed is dependent upon the presence of other associ- ated lesions, such as a VSD, which allow mixing of the two circula- tions. Without intervention, 30% die within the first week and only 10% survive their first year. If the atrial and ventricular septums are intact, immediate neo- natal management requires a prostaglandin infusion to maintain patency of the arterial duct until a balloon atrial septostomy is performed. Post-​septostomy, the neonate remains cyanosed, but there is usually adequate mixing to allow it to thrive until definitive surgery. There are survivors of four operative approaches in adult clinics:  interatrial repair (Mustard or Senning), arterial switch, Rastelli and ‘palliative’ Mustard/​Senning or arterial switch oper- ations. The indications and outcomes of each are described next. Interatrial repair: Mustard or Senning operations This approach was first described in 1957 and can be used for those with TGA or TGA with VSD. Interatrial repair involves excision of the atrial septum and placement of a saddle-​shaped patch (‘baffle’) to direct pulmonary venous blood into the right atrium and right ventricle and thence to the aorta (Fig. 16.12.19). Systemic venous blood is directed into the left atrium, left ventricle, and pulmonary artery. The right ventricle and tricuspid valve therefore support the systemic circulation. The Senning operation uses the patient’s own atrial septum to create the baffle, whereas the Mustard operation uses non​autologous material. The Mustard/​Senning operations have been superseded by the arterial switch operation, apart from ** * RA LA RV Ao LV PA TV MV Fig. 16.12.17  Schematic representation of complete transposition of the great arteries (discordant ventriculo-​arterial connections). The pulmonary and systemic circulations are completely separate once the arterial duct and foramen ovale close. Without intervention, the condition is not compatible with life. Ao, aorta; LA, left atrium; LV, left ventricle; MV, mitral valve; PA, pulmonary artery; RA right atrium; RV right ventricle; TV, tricuspid valve; **patent arterial duct; *patent foramen ovale. RA LA RV Ao LV PA TV MV Fig. 16.12.18  Schematic representation of congenitally corrected transposition of the great arteries (discordant atrioventricular and ventriculo-​arterial connections). The circulation is congenitally physiologically ‘corrected’ in that systemic venous blood reaches the pulmonary artery (via the left ventricle) and pulmonary venous blood reaches the aorta (via the right ventricle). Ao, aorta; LA, left atrium; LV, left ventricle; MV, mitral valve; PA, pulmonary artery; RA, right atrium; RV, right ventricle; TV, tricuspid valve. section 16  Cardiovascular disorders 3582 some uncommon situations in cTGA in which a Senning operation is part of a more complex procedure. However, there are still signifi- cant numbers of adult survivors of the interatrial repair. Clinical signs and complications after interatrial repair The systemic right ventricle causes a parasternal heave. The aortic component of the second heart sound may be palpable and loud, and the second sound single, due to the anterior-​lying aorta. The pres- ence of cyanosis suggests a baffle leak allowing right-​to-​left shunting between the systemic and pulmonary venous atriums. Systemic venous pathway obstruction may be associated with elevation of the jugular venous pressure and hepatomegaly. Complications after interatrial repair include: • Progressive bradycardias and sinus node disease, due to damage to the sinus node during repair. • Atrial flutter and interatrial re-​entry tachycardias, due to extensive atrial surgical scarring—​these are often poorly tolerated, are asso- ciated with sudden death, and should be treated with urgent DC cardioversion rather than antiarrhythmic drugs, since the latter can precipitate cardiovascular collapse if there is underlying im- paired ventricular function. After an episode of flutter, ablation should be performed. • Systemic venous pathway obstruction, which usually only causes symptoms if both the IVC and SVC pathways are narrowed—​if only one pathway is narrowed, the systemic venous blood flows along the azygos vein and drains to the heart via the unobstructed pathway; obstruction can usually be relieved by balloon dilation or stenting. • Pulmonary venous pathway obstruction such that flow into the atrium and systemic ventricle is obstructed—​the patient will be breathless, but clinical signs are few; it is demonstrated by echocardiography or MRI; surgical repair is usually necessary; transcatheter intervention is usually unsatisfactory. • Baffle leak—​holes along the baffle suture lines allow shunting which may be left-​to-​right, or right-​to-​left, causing cyanosis; a percutaneous approach sometimes allows successful closure of these interatrial communications. • Systemic atrioventricular valve regurgitation—​the tricuspid valve is poorly evolved to support systemic pressures and commonly be- comes regurgitant; if right ventricular function is adequate, valve replacement should be performed because valve repair is rarely successful. • Systemic ventricular failure—​the right ventricle may fail because it is inherently unsuitable to support the systemic circulation in the long term, because of long-​standing tricuspid regurgitation, and because of poor ventricular filling from the surgically con- structed atrial pathways. There has been much interest in whether placement of a pul- monary artery band to ‘retrain’ the left ventricle to enable it to sup- port the systemic circulation will allow takedown of the Mustard operation and performance of an arterial switch operation. This approach only appears to be possible in young children, or in older patients with a degree of left ventricular outflow tract obstruc- tion in whom the left ventricle has always retained near-​systemic pressures. Arterial switch operation As a result of the late complications of interatrial repair, a different surgical approach was developed that restored the left ventricle to the systemic circulation and avoided extensive atrial surgery: the arterial switch. Since the 1980s anatomical correction by the arterial switch op- eration has superseded interatrial repair as the operation of choice for most patients with TGA. Blood is redirected at arterial level by switching the aorta and pulmonary arteries so that the left ventricle becomes the subaortic ventricle supporting the systemic circulation. The coronary arteries are reimplanted into the neo-​aortic root. Late follow-​up appears good for these patients, but vigilance is required to detect late problems including neo-​aortic or pulmonary valve regurgitation, neo-​aortic root dilation, and pulmonary arterial stenosis. Late myocardial ischaemia due to coronary anastomotic stenoses is a theoretical complication, but has not yet become ap- parent as a major problem. Rastelli operation This operation is performed for patients with TGA, VSD, and pul- monary stenosis (Fig. 16.12.20). The VSD is closed so that the left ventricle carrying oxygenated blood empties into the aorta. The stenotic pulmonary artery is ligated and a conduit is placed be- tween the right ventricle and pulmonary artery. The main advan- tage of this operation is that the left ventricle supports the systemic circulation, but it commits the patient to several further conduit replacements—​some of which may now be carried out percutan- eously rather than surgically. ‘Palliative’ Mustard/​Senning or arterial switch operations These procedures are performed for patients with TGA, VSD, and pulmonary vascular disease to improve mixing of blood and oxy- genation. The VSD is left open. These patients should be treated in the same way as other patients with Eisenmenger syndrome. SVA PVA RV Ao LV PA MV TV Fig. 16.12.19  Schematic representation of intra-​atrial repair for complete transposition of the great arteries (Senning or Mustard operation). Ao, aorta; LV, left ventricle; MV, mitral valve; PA, pulmonary artery; PVA, pulmonary venous atrium; RV, right ventricle; SVA, systemic venous atrium; TV, tricuspid valve. 16.12  Congenital heart disease in the adult 3583 Congenitally corrected transposition of the great arteries (discordant atrioventricular and ventriculo-​arterial connections) cTGA is a rare condition, accounting for less than 1% of all con- genital heart disease. Both atrial and arterial connections to the vent- ricles are discordant, so pulmonary venous blood passes through the left atrium, through the right ventricle, and into an anteriorly lying aorta (Fig. 16.12.18). Similarly, systemic venous blood reaches the pulmonary trunk via the left ventricle. The circulation is therefore physiologically ‘corrected’, but the morphological right ventricle and tricuspid valve support the systemic circulation. More than 95% of cases have associated anomalies, most com- monly VSD and pulmonary stenosis, but also Ebstein anomaly of the systemic (tricuspid) atrioventricular valve, aortic stenosis, AVSD, abnormalities of situs, and coarctation. Congenital complete heart block occurs in around 5% of patients and may develop at any stage of life, particularly following surgery to the atrioventricular valve. Presentation depends on associated lesions. Patients with isolated cTGA may remain asymptomatic and undiagnosed into old age, but failure of the systemic ventricle, systemic atrioventricular valve re- gurgitation, or the onset of complete heart block and atrial arrhyth- mias usually results in presentation with symptoms from the fourth decade onwards. Those with VSD and pulmonary stenosis may be cyanosed, and those with VSD alone may present with pulmonary hypertension. A parasternal heave is usually palpable from the pressure-​loaded anteriorly lying systemic right ventricle; this may be especially prominent if it is also volume-​loaded by systemic (tricuspid) atrio- ventricular valve regurgitation. There may be a prominent aortic pulsation in the suprasternal notch and the aortic component of the second heart sound may be palpable and loud. The pulmonary component is soft or inaudible due to the posterior position of the pulmonary artery. The ECG may show varying degrees of atrioventricular block or evidence of pre-​excitation due to accessory pathways (associ- ated with Ebstein-​like anomalies of the systemic atrioventricular valve). There may be left axis deviation. The right and left bundles are inverted, so the initial septal activation is right-​to-​left, resulting in Q waves in V1–​2 and an absent Q in V5–​6; this pattern may be wrongly interpreted as a previous anterior myocardial infarction. The chest radiograph has a typical appearance (Fig. 16.12.21). Echocardiography confirms the discordant relations and assesses ventricular and systemic (tricuspid) atrioventricular valve function as well as other associated lesions. Ebstein anomaly may be diag- nosed if the tricuspid valve is apically displaced by more than 8 mm/​ m2. Cardiac catheterization is indicated to assess the haemodynamic importance of associated lesions. Angiotensin-​converting enzyme (ACE) inhibitors may be useful when there is systemic ventricular dysfunction or atrioventricular valve regurgitation, but there are no trial data to support their use. Transvenous atrioventricular sequential pacing is indicated for complete heart block; active fixation ventricular leads are required because of the absence of coarse apical trabeculations in the mor- phologically left subpulmonary ventricle. If there are associated intracardiac shunts, patients should be formally anticoagulated to reduce the risk of paradoxical embolism, or epicardial pacing should be considered. The conventional surgical approach to systemic atrioventricular valve regurgitation is tricuspid valve replacement (repair is rarely successful), but if systemic ventricular function is poor (ejection RA LA RV Ao LV PA VC Fig. 16.12.20  Schematic representation of Rastelli operation for transposition of the great arteries with ventricular septal defect and pulmonary stenosis. Ao, aorta; LA, left atrium; LV, left ventricle; PA; pulmonary artery; RA, right atrium, RV, right ventricle, VC, valved conduit. Fig. 16.12.21  Chest radiograph of a 23-​year-​old woman with congenitally corrected transposition of the great vessels. There is a narrow pedicle due to the abnormally related great arteries (small arrow) and the left heart border is straight (large arrow) due to the abnormal position of the left-​lying anterior ascending aorta. section 16  Cardiovascular disorders 3584 fraction <40%) transplantation may be the only option. Replacement of the tricuspid valve before the systemic right ventricle fails improves prognosis. Where there is coexistent VSD and pulmonary stenosis, classical repair involved closure of the VSD and insertion of a valved conduit between the left ventricle and pulmonary artery, with the right ventricle continuing to support the systemic circulation. Anatomical repair, so that the morphological left ventricle supports the systemic ventricle, has had success in children with systemic atrioventricular valve regurgitation and systemic ven- tricular dysfunction. For patients with an associated non​restrictive VSD the left ventricle is at systemic pressure and therefore ‘pretrained’ to support the systemic circulation. If there is no pul- monary stenosis, a ‘double switch’ may be performed, combining a Senning operation with an arterial switch operation. If there is also pulmonary stenosis, the Senning operation is combined with a Rastelli-​type repair. The regurgitant tricuspid valve and right ventricle are therefore placed in the pulmonary circulation. For children with corrected transposition whose left ventricle is at low pressure, a period of left ventricular ‘training’ is required before a double switch operation can be performed, which is achieved by placing a pulmonary artery band to increase left ventricular pres- sure and induce hypertrophy. Pulmonary artery banding per se may improve symptoms, since the increased left ventricular pres- sure causes the interventricular septum to move towards the sys- temic ventricle, reducing systemic atrioventricular regurgitation. The long-​term outcome of these anatomical approaches to cor- rected transposition is not yet known; complications relating to the dysfunction of the retrained left ventricle, conduit replacement, neo-​aortic valve regurgitation, and arrhythmia may become sig- nificant. There are reports of adults with VSD and pulmonary sten- osis having successfully undergone Senning–​Rastelli repair, but it is probably not possible to adequately ‘train’ an adult left ventricle that has been at low pressure for many years. Tetralogy of Fallot Tetralogy of Fallot is the commonest cyanotic defect, occurring in 1 in 3600 live births; it affects males and females equally. Most patients reaching the adult clinics have undergone radical repair, but some natural and palliated survivors may present. The fundamental abnormality in tetralogy of Fallot is anterocephalad deviation of the outlet septum which creates the four key features:  subvalvar pulmonary stenosis, VSD, an aortic valve that overrides the VSD, and right ventricular hypertrophy (Fig. 16.12.22). There is great anatomical variation, ranging from minimal aortic override to double-​outlet right ventricle (DORV), and from minimal pulmonary stenosis to pulmonary atresia. The VSD is perimembranous and there is usually add- itional pulmonary valvar stenosis. Associations Microdeletions of chromosome 22q11 may occur in associ- ation with tetralogy of Fallot, especially in its most severe form with pulmonary atresia. 22q11 deletions are associated with a broad spectrum of phenotypic abnormalities that form the velocardiofacial syndrome (which includes DiGeorge syndrome; OMIM 601362):  (1) other cardiac defects—​Fallot with right aortic arch, truncus arteriosus, pulmonary atresia with VSD, interrupted aortic arch; (2)  facial abnormalities—​cleft palate, hare lip, hypertelorism, narrow eye fissures, puffy eyelids, a small mouth, deformed earlobes; (3) psychiatric disorders and learning difficulties; and (4)  neonatal immune deficiency (thymic hypoplasia) and hypocalcaemia (parathyroid hypoplasia). Cardiac defects associated with tetralogy of Fallot include a right-​ sided aortic arch in 16%, a left SVC in around 15%, additional VSDs in 5%, and a secundum ASD (‘pentalogy’ of Fallot) in 8%. The most important associated coronary anomaly is the crossing of the right ventricular outflow tract by a left anterior descending coronary ar- tery arising anomalously from the right coronary sinus: this is vul- nerable to damage during surgical repair. Unoperated clinical course and management Without surgical intervention, only 2% of patients survive to their fortieth year. Those that do survive may be a selected group in whom subpulmonary stenosis was not severe in early life, but progressed with advancing age. Unoperated patients are at risk of the complications of cyanosis, endocarditis, atrial and ventricular arrhythmias, progressive ascending aortic dilatation (without the high risk of dissection found in Marfan syndrome), aortic regurgitation—​causing volume overload of both ventricles and subsequent biventricular failure, and systemic hypertension—​ adding additional pressure overload to the work of both ventricles and further contributing to the onset of biventricular failure. There is cyanosis and clubbing, a right ventricular heave, and sometimes a thrill over the right ventricular outflow tract. A right-​ sided aorta may be palpable to the right of the sternum. The second heart sound is usually single, and there is a loud pulmonary ejection murmur. There may be aortic regurgitation. * RA LA LV RV PA Ao Fig. 16.12.22  Schematic representation of tetralogy of Fallot. *Anterocephalad deviation of outlet septum creates ventricular septal defect, subpulmonary stenosis, aorta overriding crest of interventricular septum, and secondary right ventricular hypertrophy. Ao, aorta, LA, left atrium, LV, left ventricle, PA, pulmonary artery, RA, right atrium, RV, right ventricle. 16.12  Congenital heart disease in the adult 3585 The ECG shows right axis deviation and right ventricular hyper- trophy, and the QRS duration may be prolonged in older patients. The classical cardiac silhouette is a ‘coeur en sabot’ (i.e. a clog-​shaped heart), but this is more likely to be seen in tetralogy with pulmonary atresia (see ‘Pulmonary atresia with VSD’). The heart size is usually normal and pulmonary vascularity reduced. There may be a right-​ sided aortic arch indenting the right of the trachea, and there may be a prominent dilated ascending aorta. Two-​dimensional echocardiography reveals infundibular stenosis with or without pulmonary valve stenosis, right ventricular hyper- trophy, the typical VSD, and varying degrees of aortic override. There may be evidence of left ventricular volume overload, aortic root dilatation, and aortic regurgitation. Cardiac catheterization should be performed prior to surgical repair in adults. The anatomy of the right ventricular outflow tract obstruction and pulmonary arteries is defined, and pulmonary vascular resistance assessed. Selective coronary angiography dem- onstrates any anomalous origin and course as well as acquired cor- onary disease. Aortography shows aortic root dilatation and any aortopulmonary collaterals. MRI may be performed instead of con- ventional cardiac catheterization, except that it does not provide pulmonary vascular resistance data. Palliated history Helen Taussig first suggested palliative surgery in 1943, and the first Blalock–​Taussig shunt was performed in 1945 (Fig. 16.12.23 and Table 16.12.7). Nowadays, palliative shunts are usually performed as a staging procedure in small infants; however, occasional patients reach the adult clinic having had palliation without subsequent rad- ical repair. They are cyanosed and clubbed and have a continuous murmur under the clavicle and over the scapula on the side of the shunt. In a classical Blalock–​Taussig shunt the ipsilateral radial pulse is diminished or absent and the hand often small. Late complications of systemic to pulmonary artery shunts include infective endarteritis, acquired pulmonary atresia, aortic regurgitation, and biventricular failure, with increasing cyanosis and bronchopulmonary collateral development if the shunt blocks or is outgrown, and pulmonary vas- cular disease if the shunt is too big. Radical repair, late follow-​up, and reoperation Radical repair involves patch closure of the VSD with infun- dibular resection with or without pulmonary valvotomy or replace- ment: 86% of patients who underwent such surgery in the 1980s survive to 32 years of age, and survival for those operated in the current era is further improved. However, patients remain at risk of late complications including pulmonary regurgitation and sten- osis, aortic regurgitation, ventricular dysfunction, endocarditis, ar- rhythmia, and sudden death. Those repaired in early childhood and by a transannular approach have a better long-​term prognosis than those repaired later or by a transventricular approach. In many patients repair involves placing a patch across the an- nulus of the pulmonary valve in order to create an unobstructed right ventricular outflow. As a result, the pulmonary valve is incom- petent from the time of repair. The pulmonary regurgitant volume is relatively small early after repair, since the stiff hypertrophied right ventricle cannot accommodate much regurgitant blood, the fast heart rate of the small child reduces the time in which regurgitation can occur, and the capacitance of the child’s pulmonary vasculature is low. However, the right ventricle remodels and by the time young adulthood is reached, pulmonary regurgitation is often severe and the right ventricle dilates. Although pulmonary regurgitation is well tolerated for many years, it results in progressive right ventricular dilation and dys- function, impaired exercise tolerance, and increased risk of atrial and ventricular arrhythmias. A widening of the QRS complex be- yond 180 ms may be a marker for right ventricular dilation and dysfunction, these being risk factors for developing worsening functional class, sustained ventricular tachycardia, and sudden death. Pulmonary valve replacement is indicated if there is impaired Fig. 16.12.23  Chest radiograph of a 36-​year-​old man with tetralogy of Fallot palliated by a classic left Blalock–​Taussig shunt (small arrow). There is secondary dilatation of the left pulmonary artery (large arrow) and a right aortic arch (*). Table 16.12.7  Systemic to pulmonary arterial shunts Classical Blalock–​Taussig shunt Subclavian artery divided distally. Proximal subclavian artery anastomosed end-​to-​side to pulmonary artery Modified Blalock–​Taussig shunt Prosthetic graft between subclavian and pulmonary arteries Central shunts: Waterston shunta Side-​to-​side anastomosis between ascending aorta and (right) pulmonary artery Potts shunta Side-​to-​side anastomosis between descending aorta and (left) pulmonary artery Other Prosthetic graft between aorta and pulmonary artery a Now obsolete because not possible to adequately control the size of the shunt. section 16  Cardiovascular disorders 3586 exercise tolerance, sustained arrhythmia, progressive right ven- tricular dilation, or any evidence of right ventricular dysfunction. Replacing the pulmonary valve before irreversible right ventricular dysfunction occurs is likely to improve long-​term outcome. MRI is a valuable tool for assessing right ventricular size and function, and any deterioration. The timing of redo surgery for pulmonary regurgitation remains controversial, although some centres consider that pulmonary valve replacement should be performed before the indexed right ven- tricular end-​diastolic volume reaches 150 ml/​m2. Pulmonary regurgitation is worsened in the presence of pul- monary arterial stenosis that may occur at the site of a previous shunt. Right ventricular outflow tract obstruction may recur, espe- cially if a valved right ventricular to pulmonary artery conduit was placed, this being due to excessive formation of neointima (peel) in the conduit or to calcification of the valve. Most patients have right bundle branch block after repair (Fig. 16.12.24) due to surgical damage to the right bundle as it runs in the floor of the VSD. Bifascicular block and transient postoperative complete heart block carry a risk of developing late complete heart block. Atrial arrhythmias occur in 30% of long-​ term survivors and are a major cause of morbidity. Those with left-​sided volume overload and left atrial dilatation secondary to residual VSD or previous shunts are at particular risk of atrial flutter and fibrillation. Rapidly conducted atrial flutter is particu- larly poorly tolerated and is likely to be responsible for a proportion of sudden deaths, as are the ventricular arrhythmias that occur in up to 45% of patients. Syncope, poor NYHA functional class, and sustained monomorphic ventricular tachycardia are likely to be a significant risk factor for sudden death, as are atrial arrhythmias and heart block, and ECG parameters such as QRS duration >180 ms non​sustained VT. Adverse right ventricular risk factors include dilatation and dysfunction, outflow tract obstruction, hypertrophy, aneurysm, impaired myocardial blood flow, and pulmonary regurgitation. Surgical risk factors for late sudden death include transventricular versus transatrial repair, large ventriculotomy scar, residual VSD, previous palliative shunt, complex or multiple operations, im- paired left ventricular function, older age at operation, and length of follow-​up. (a) (b) Fig. 16.12.24  Electrocardiograms of a 35-​year-​old woman who underwent radical repair of tetralogy of Fallot. Preoperatively (a) there is right ventricular hypertrophy; postoperatively (b) there is right bundle branch block, due to damage to the right bundle as it runs in the floor of the ventricular septal defect. 16.12  Congenital heart disease in the adult 3587 Tetralogy of Fallot with absent pulmonary valve syndrome This variation accounts for approximately 3% of cases of tetralogy of Fallot. There is a ring-​like, usually stenotic malformation, with failure of development of the pulmonary valve cusps. The central pulmonary arteries are usually hugely dilated or aneurysmal. Double-​outlet right ventricle In DORV more than one-​half of the circumference of both great vessels arises from the morphological right ventricle. A complete or partial muscular infundibulum usually lies beneath each arterial valve. The anatomy and physiology are enormously varied, as are the surgical approaches to repair. The degree of pulmonary sten- osis and the relation of the VSD to the great vessels determine the haemodynamics. Most (80%) subaortic defects have pulmonary stenosis and Fallot-​ like physiology. The Taussig–​Bing anomaly accounts for less than 10% of DORV and describes a subpulmonary defect without pul- monary stenosis. There is transposition-​like physiology with cyan- osis and high pulmonary blood flow. As the pulmonary vascular resistance rises, pulmonary blood flow falls, and cyanosis increases. Unoperated survival to adulthood is uncommon, but occurs occa- sionally if the pulmonary vascular resistance establishes adequate but not excessive pulmonary blood flow. If such a survivor also has a patent arterial duct, there will be reversed differential cyanosis. Deoxygenated blood selectively enters the aorta to supply the arch vessels, whereas oxygenated blood enters the pulmonary artery and supplies the descending aorta via the duct; thus, the fingers are more cyanosed and clubbed than the toes. If the VSD is remote from the great vessels, a biventricular repair may not be possible and a single-​ventricle repair (Fontan) may be necessary. Pulmonary atresia with ventricular septal defect This is a complex and heterogeneous cyanotic condition. The intracardiac anatomy is the same as tetralogy of Fallot, but the right ventricular outflow tract is blind-​ended (atretic). The pulmonary blood supply is derived entirely from three different types of sys- temic vessels: (1) a large muscular duct that resembles a collateral; (2) a diffuse plexus of small ‘bronchial’ arteries arising from medias- tinal and intercostal arteries; and (3) large tortuous systemic arterial collaterals known as MAPCAs (major aortopulmonary collateral arteries), which arise directly from the descending aorta, from its major branches (usually the subclavian artery), or from bronchial arteries, and may connect with central pulmonary arteries or supply whole segments or lobes of lung independently. Prognosis and management depend largely on the pulmonary vasculature, in which there is considerable anatomical variation. Confluent pulmonary arteries with pulmonary vessels having a near normal arborization pattern to all segments of the lungs are associ- ated with the best prognosis. Here radical repair, with recruitment of MAPCAs to the native pulmonary arteries, a conduit from right ventricle to pulmonary artery, and closure of the VSD is likely to be possible, and the pulmonary vascular resistance is likely to be low. The 20-​year survival after radical repair is about 75%. The out- look is worse if there are no native pulmonary arteries and multiple tortuous MAPCAs with poor arborization. Radical repair may be extremely challenging or impossible, and pulmonary vascular resist- ance likely to be high. Such patients may be suitable for no or only palliative surgery and will remain cyanosed. Following surgical pal- liation, 20-​year survival is around 60%; unoperated survival is very poor, only about 8% reaching 10 years of age, and those that do reach adulthood have a mean age of death of 33 years. Clinical findings Examination findings in the unoperated or palliated patient are similar to those of the unoperated Fallot without pulmonary atresia, except that there are continuous collateral murmurs and often a collapsing pulse. The chest radiograph shows a right aortic arch in 25% of cases and has a typical appearance (Fig. 16.12.25). The pulmonary col- lateral vessels may follow a bizarre pattern. Colour-​flow Doppler may identify collateral vessels, but conventional angiography is re- quired to precisely delineate their origin, degree of ostial stenosis, and intrapulmonary course. High-​resolution CT and MRI are useful tools in imaging complex pulmonary vasculature. Outcome Late complications in unoperated or palliated survivors include increasing cyanosis due either to the development of pulmonary vascular disease in lung segments perfused at systemic pressure through non​stenosed collaterals, or to the progressive stenosis Fig. 16.12.25  Chest radiograph of a 21-​year-​old woman with tetralogy of Fallot and pulmonary atresia, no central pulmonary arteries, and multiple aortopulmonary collaterals which create an abnormal pulmonary vascular pattern. The typical ‘coeur en sabot’ silhouette is due to right ventricular hypertrophy and the pulmonary bay where the pulmonary artery should be (arrow). section 16  Cardiovascular disorders 3588 of collateral vessels. In the latter, good symptomatic relief may be obtained from stenting. The aortic root may become mark- edly dilated and aortic regurgitation may develop, resulting in biventricular volume overload and failure. Aortic valve endocar- ditis is a particular risk. Late complications after radical repair include those that follow repair of tetralogy of Fallot. In addition, patients face inevitable repeated conduit replacements, and right ventricular failure sec- ondary to high pulmonary vascular resistance. Hearts with univentricular atrioventricular connection Also known as univentricular or single-​ventricle hearts, these hearts are defined by the connection of both atriums to one ventricle, or by the absence of one of the atrioventricular connections. There is only one functional ventricle, although there is nearly always a second rudimentary and incomplete ventricle. When the rudimentary ven- tricle is of right morphology, it nearly always lies anteriorly. Less commonly, there is a posteriorly lying morphologically left rudi- mentary ventricle, and rarely, there is solitary ventricle of indeter- minate morphology. The two most common variants are double-​inlet left ventricle (DILV) and tricuspid atresia (Figs. 16.12.26 and 16.12.27) which together account for around 4–​5% of congenital heart disease. This section considers these two conditions, a discussion of more complex variants being beyond the scope of this text. Clinical course: Unoperated Presentation depends largely on pulmonary blood flow, which in turn is dependent on the degree of pulmonary stenosis. Those with severe obstruction to pulmonary blood flow present as neonates with severe cyanosis. Neonates without pulmonary stenosis have excessively high pulmonary blood flow and present in congestive cardiac failure with breathlessness and only mild cyanosis. The pres- ence of subaortic stenosis or other obstruction to systemic blood flow such as coarctation exacerbates heart failure and results in early decompensation. The outcome is most favourable for patients with left ventricular morphology, moderate pulmonary stenosis, and no subaortic sten- osis, and for those with ‘balanced’ pulmonary and systemic blood flow (i.e. moderately severe pulmonary stenosis and no obstruction to systemic blood flow). Unoperated survival into adulthood is un- common: 50% of patients with DILV die before 14 years, 50% with DORV die by 4 years of age. Nonetheless, rare patients with balanced circulation reach their sixth decade without surgical intervention. In the unoperated patient, there is cyanosis and clubbing. A giant ‘a’ wave may be present in the jugular venous pulse in tricuspid atresia. An absent right ventricular impulse and prominent left ven- tricular impulse are characteristic of DILV and tricuspid atresia. There may be a precordial thrill from pulmonary stenosis, particu- larly if the pulmonary artery lies anteriorly. If there are discordant ventriculo-​arterial connections, the aortic pulsation of the anteri- orly lying aorta may be prominent in the suprasternal notch. The second heart sound is usually single. If pulmonary vascular disease has developed there will be add- itional signs of pulmonary hypertension. Signs of congestive heart failure may be present in the ageing patient, particularly with the RA LA LV RV PA Ao Fig. 16.12.26  Schematic representation of double-​inlet left ventricle with discordant ventriculo-​arterial connections. Both atriums connect to the left ventricle via the tricuspid and mitral valves, so that systemic and pulmonary venous blood mix in the left ventricle and the patient is cyanosed. The left ventricle supports both the systemic and pulmonary circulations. The aorta arises from the rudimentary right ventricle via the ventricular septal defect (VSD). If the VSD is restrictive, it creates obstruction to systemic blood flow. Ao, aorta; LA, left atrium; LV, left ventricle; PA, pulmonary artery; RA, right atrium; RV, right ventricle; VA, ventriculo-​arterial; VSD, ventricular septal defect. RA LA LV RV PA Ao Fig. 16.12.27  Schematic representation of tricuspid atresia. Systemic venous blood leaves the right atrium via an atrial septal defect and mixes with pulmonary venous blood in the left atrium. The left ventricle thus supports both the systemic and pulmonary circulations and the patient is cyanosed. The rudimentary right ventricle does not play a functional role. Ao, aorta; LA, left atrium; LV, left ventricle; PA, pulmonary artery; RA, right atrium; RV, right ventricle. 16.12  Congenital heart disease in the adult 3589 onset of atrial arrhythmia, such that the venous pressure is raised, with hepatomegaly and peripheral oedema. The chest radiograph shows cardiomegaly due to chronic ven- tricular volume overload. If ventriculo-​arterial connections are dis- cordant, there is a narrow pedicle and the ascending aorta forms a straight edge along the left heart border. Pulmonary vascularity re- flects the pulmonary blood flow, the main pulmonary arteries being small where there is significant pulmonary stenosis, with large main pulmonary arteries indicating high pulmonary blood flow, either past or present. In tricuspid atresia the ECG usually shows right atrial hyper- trophy, normal PR interval, small or absent right ventricular forces, and left axis deviation. There are left axis deviation and large left ventricular forces in DILV. If the rudimentary chamber lies to the right the PR interval is usually normal, but if it lies to the left the PR interval may be prolonged or there may be complete heart block. Two-​dimensional echocardiography and colour-​flow Doppler allow detailed assessment of the anatomy and physiology, including ventricular morphology and pulmonary and subaortic stenosis. Cardiac catheterization is required to assess pulmonary artery anatomy and resistance. Surgical management of univentricular hearts: The Fontan operation Management requires a staged approach, the ultimate aim of which is to achieve a pink patient in whom the functionally single ventricle supports only the systemic circulation:  the Fontan operation. The first stage, in early life, is to obtain control of pulmonary blood flow. In those with excessive flow a pulmonary artery band is placed to create supravalvar pulmonary artery stenosis and limit pulmonary flow. In neonates with severe pulmonary stenosis a systemic artery to pulmonary artery shunt is placed to augment pulmonary blood flow. As the child ‘grows out of the shunt’ they become more cyanosed: the central shunt is replaced with a superior vena cava to pulmonary artery anastomosis (Glenn, or cavopulmonary anas- tomosis), as illustrated in Fig. 16.12.28. This reduces cyanosis, perfuses the pulmonary arteries at low pressure, and reduces the volume load on the single ventricle. However, as the child grows, the relative contribution of the SVC to the circulation diminishes, again resulting in progressive cyanosis. N A T N O F N N E L G L A N O IT C E RI D IB N N E L G L A C IS S A L C BILATERAL BIDIRECTIONAL GLENN in isomerism TOTAL CAVOPULMONARY CONNECTION SVC RA IVC RPA LPA SVC PA RA IVC PA RA PA RSVC LSVC HEPATIC VEINS SVC disconnected from RA. RPA disconnected from PA. SVC to RPA anastomosis created. SVC disconnected from RA. SVC anastomosed to confluent PAs. Proximal PA divided. Anastomosis created between RA and PA. RSVC disconnected from RA. LSVC disconnected, usually from coronary sinus. SVCs anastomosed to confluent PAs. Hepatic veins are the only remaining systemic venous return to RA since IVC drains via azygous continuation to SVC. SVC connected to PA. IVC connected via extra-cardiac conduit to PA, excluding RA from circuit RA PA SVC IVC RA EXTRA- CARDIAC CONDUIT Fig. 16.12.28  Evolution of the Fontan and total cavopulmonary connection operations. IVC, inferior vena cava; PA, pulmonary artery; RPA, right pulmonary artery; SVC, superior vena cava. section 16  Cardiovascular disorders 3590 The Fontan operation is usually completed by age 4 to 6 years. The principle of this approach is to separate the systemic and pul- monary circulations and abolish cyanosis. This is achieved by using the single functional ventricle to support the systemic cir- culation and leaving the pulmonary circulation without a ventricle (i.e. with phasic rather than pulsatile flow). Since its first descrip- tion in 1972 the atriopulmonary Fontan operation has evolved, so that now several variations exist. The favoured approach nowadays is the total cavopulmonary connection (TCPC), which avoids some of the late complications of the original approach. Nonetheless, all the variations result in the same basic physiology, the ‘Fontan circulation’. The Fontan circulation is one of a chronic low cardiac output state, critically dependent upon adequate systemic venous filling pres- sure to drive forward flow across the pulmonary vascular bed. It is a fragile circulation in which small changes in haemodynamics can result in a serious, sometimes catastrophic, fall in cardiac output. Problems that can cause trouble include dehydration, stenosis at the site of connection of the right atrium or systemic veins to the pulmonary artery, pulmonary embolism from in situ right atrial thrombus, a rise in pulmonary vascular resistance, atrial flutter, mi- tral regurgitation, a rise in left ventricular end-​diastolic pressure, aortic or subaortic stenosis, drug-​induced vasodilatation (e.g. an- aesthetic induction agents, nitrates), and positive pressure ventila- tion that reduces systemic venous return. Clinical features after the Fontan operation Most patients are acyanotic:  new or worsening cyanosis is cause for concern. The jugular venous pulse is usually slightly raised and the second heart sound single. No murmur arises from the Fontan connection. There may be a murmur of mitral regurgitation. In pa- tients with discordant ventriculoarterial connections, a loud sys- tolic murmur raises suspicion of subaortic stenosis (which may be at the level of the VSD). The liver edge is often palpable, but new or increasing hepatomegaly is a worrisome finding. Ascites often pre- cedes peripheral oedema in young patients with complications sub- sequent to a Fontan procedure. A combination of echocardiography and MRI provide anatomical and physiological data. Cardiac catheterization is needed to assess pulmonary vascular resistance. Cardiopulmonary exercise testing is a useful indicator of early signs of decompensation. Complications after the Fontan operation Patient selection is important in ensuring a good outcome of Fontan surgery. Survival ranges from 81% at 10 years for ‘perfect candidates’ to 60 to 70% for all patients. Preoperative risk factors for a poor outcome are pulmonary vascular resistance greater than 4 Wood units, mean pulmonary artery pressure more than 15 mm Hg, ven- tricular hypertrophy, impaired systolic ventricular function, severe atrioventricular valve regurgitation, aortic outflow obstruction, and small or distorted pulmonary arteries. However, even patients with none of these risk factors have limited exercise tolerance and are at risk of a great range of late complications. Complications include intra-​atrial re-​entry tachycardia (IART)/​ atrial flutter, sinus node dysfunction, progressive ventricular dys- function, atrioventricular valve regurgitation, development of subaortic stenosis, pathway obstruction, right lower pulmonary vein compression by dilated right atrium, thromboembolism (most centres anticoagulate adults with a Fontan circulation), recurrent ef- fusions, ascites, peripheral oedema, cyanosis (due to development of venous collaterals to the left atrium or pulmonary arteriovenous fistulas), protein-​losing enteropathy, and hepatic dysfunction including fibrosis, cirrhosis, and hepatocellular carcinoma. Careful surveillance is required to detect complications and offer interven- tion and counselling. A detailed discussion of these many complications is beyond the scope of this book, but atrial flutter/​IART merits further dis- cussion because it is an acutely life-​threatening complication (Fig. 16.12.29). Flutter is common after a Fontan procedure, and is poorly tolerated, causing a significant fall in cardiac output. Atrial transport is particularly important in the Fontan circulation to fa- cilitate left ventricular filling, so simply controlling the rate of atrial flutter is inadequate: rapid restoration of sinus rhythm is required. Time may be wasted once the patient seeks medical attention, be- cause the ECG appearances are often atypical and may be misin- terpreted as sinus tachycardia. If in doubt, intravenous adenosine will reveal flutter waves and confirm the diagnosis, but will not ter- minate the arrhythmia. Other intravenous antiarrhythmics should be avoided since they may precipitate cardiovascular collapse. The safest approach is DC cardioversion. Intravenous fluids should be given while the patient is nil by mouth to maintain systemic venous filling pressure. Care must be taken to avoid excessive sys- temic vasodilation at induction of anaesthesia, and allowance must be made for the fall in cardiac output that accompanies ventilation. Pregnancy in a woman with a Fontan circulation is possible, but carries a high maternal and fetal risk and requires care in a specialist centre. Women with good functional class and ventricular function who have not yet developed Fontan circulation complications have the best chance of success. Risks include an up to 70% chance of early miscarriage, as well as maternal haemorrhage, arrhythmia, and decompensation with a low output state. Prepregnancy counselling and secure contraception are key. Estrogen-​containing preparations are contraindicated; long-​acting progestogen-​only methods or the desogestrel containing progestogen-​only pill are the safest and most reliable options. Most adults with a Fontan circulation undergo functional decline by their fourth decade, with limited life expectancy. They face be- coming a ‘failing Fontan’ with a great range of complications and require a holistic, palliative approach to run in parallel with active interventions, including transplantation. Cardiac transplantation requires particularly careful assessment in an experienced specialist centre, but outcomes are good with prudent patient selection. Hypoplastic left heart syndrome Until recently hypoplastic left heart syndrome (HLHS) was not dis- cussed in adult texts, since there were no survivors to adulthood. With the introduction of the three-​stage Norwood operation, re- sulting in a complex Fontan-​type circulation, survivors are begin- ning to reach the adult clinic. HLHS is a heterogeneous syndrome in which the left side of the heart is unable to support the systemic circulation because of hypoplasia, stenosis, or atresia at different levels of the left side of the circulation. The three-​stage surgical approach to the condi- tion is as follows: 16.12  Congenital heart disease in the adult 3591 • Stage I (Norwood operation)—​performed in the first few days of life; the right ventricle and main pulmonary artery are used to re- construct the systemic outflow tract; pulmonary blood flow is pro- vided by a systemic–​pulmonary artery shunt or right ventricle to pulmonary artery conduit. • Stage II—​this operation is performed at around 2 years; the sys- temic shunt or conduit to the pulmonary artery is taken down, and the superior vena cava anastomosed to the pulmonary artery (cavopulmonary or Glenn shunt). • Stage III—​Fontan completion is performed at around 5 years, usu- ally with an extracardiac conduit. Fig. 16.12.30 shows a schematic representation of the Fontan cir- culation for HLHS. In early series only about 50% survived the three operations, but survival now approaches 70%. Those who reach the adult clinic will face the complications of any Fontan circulation, and in addition they are at risk of complications from ascending aorta and coarctation repair sites, coronary arteries arising from the hypoplastic remnant of ascending aorta, left pulmonary artery (a) (b) (c) Fig. 16.12.29  Electrocardiograms from a 24-​year-​old woman with tricuspid atresia and previous Fontan surgery: (a) sinus rhythm; (b, c) interatrial re-​entry tachycardias which were poorly tolerated and required urgent DC cardioversion. section 16  Cardiovascular disorders 3592 stenosis at site of arch repair, and failure of the right ventricle and tricuspid valve as they support the systemic circulation. Other important issues Transition to adult care and lifestyle issues in congenital heart disease The transition from paediatric to adult cardiology services requires a multidisciplinary approach, starting in an age-​appropriate way in early teenage years, transferring to an adult transition service between 16 and 18 years, and ending with a young adult who understands their condition and limitations and is ready to take responsibility for their own health. Young adults require education about their condition and an understanding about safe levels of exercise, appro- priate careers, recreational alcohol, and drugs. Young women need to understand what risks a pregnancy may carry, the need for safe and effective contraception, and prepregnancy counselling. Pregnancy and contraception in congenital heart disease Cardiac disease is the leading cause of pregnancy-​related death in the United Kingdom. All patients with congenital heart disease should be counselled from adolescence on their risk of pregnancy and their contraceptive options. The risk of pregnancy in congenital heart dis- ease ranges from being the same as that of the general population to a more than 25% risk of maternal death in pulmonary hyperten- sion. Each patient requires specialist individual assessment before embarking on pregnancy. An outline of the risks associated with different conditions is shown in Table 16.12.8: it should be remem- bered that risks are additive, so a repaired septal defect with poor ventricular function moves from a low-​risk to high-​risk category. Two principles should be remembered when considering contra- ceptive options:  the efficacy of the method, and cardiovascular safety of the method. The risk of estrogen-​containing preparations (which include the combined oral contraceptive pill) relates to their thrombogenicity. Patients at risk of intracardiac or pulmonary thrombosis and those with right-​to-​left shunts should not use these preparations. Progestogen-​only preparations are safe in cardiac dis- ease, but the mode of delivery may carry risk. For example, insertion of a progestogen-​eluting intrauterine device (Mirena® IUS) carries a risk of vasovagal syncope in nulliparous women, a reaction that can provoke cardiovascular collapse in cyanotic, pulmonary hyperten- sive, or post-​Fontan patients. In addition, although the progestogen-​ only ‘minipill’ is safe, its efficacy is poor. The desogestrel containing progestogen-​only pill combines cardiovascular safety with an ef- ficacy equal to that of the combined pill. Other safe and effective methods useful for most women with cardiac disease are the subdermal implant Nexplanon® and the injectable DepoProvera®. Heart failure and end-​of-​life care As with other cardiac conditions, heart failure is the mode of de- cline and death in many patients with congenital heart disease, but in contrast with many forms of acquired heart disease the decline often occurs earlier in life. Regular surveillance may allow the start of deterioration to be detected early, before the patient is aware of a change in symptoms. A fall in cardiopulmonary exercise capacity, a rise in biomarkers, and changes in echocardiographic parameters of ventricular function may all predate symptoms. Evidence for the use of ‘standard’ heart failure medication and resynchronization device therapy is lacking for many with con- genital heart disease, including those with systemic right ventricles, a single-​ventricle circulation, and those with subpulmonary right ventricular failure. Vigilance for life-​threatening arrhythmia should be maintained, with a low threshold to consider ablation and device therapy. Early holistic engagement with patients and their families is espe- cially important to allow planning for changes in lifestyle and job. Fig. 16.12.30  Hypoplastic left heart syndrome after the third stage Fontan completion. The right heart is used to support the systemic circulation and an ascending aorta is created from the pulmonary valve and pulmonary trunk. The aortic arch is enlarged with homograft tissue. An extracardiac conduit connects the IVC directly to the pulmonary arteries, and the SVC is also connected directly to the pulmonary arteries. Ao, aorta; IVC, inferior vena cava; LA, left atrium; LV, left ventricle; PA, pulmonary artery; RA, right atrium; RV, right ventricle; SVC, superior vena cava. 16.12  Congenital heart disease in the adult 3593 Table 16.12.8  Risk of maternal mortality in different congenital cardiac conditions mWHO 1 mWHO 2 if well and otherwise uncomplicated mWHO 2–​3 depending on individual mWHO 3 mWHO 4 Uncomplicated, small, or mild: • ​pulmonary stenosis • patent arterial duct • mitral valve prolapse Unoperated atrial or ventricular septal defect Mild systemic ventricular dysfunction Mechanical valve Pulmonary arterial hypertension (includes Eisenmenger syndrome) Successfully repaired simple lesions • atrial or ventricular septal defect • patent arterial duct • anomalous pulmonary venous drainage Repaired tetralogy of Fallot Repaired coarctation of the aorta Systemic right ventricle Severe systemic ventricular dysfunction Atrial or ventricular ectopic beats, isolated Most arrhythmias with structurally normal heart Native or bioprosthetic valve disease not considered class 1 or 4; includes most regurgitant valve lesions Fontan circulation Severe mitral stenosis, severe symptomatic aortic stenosis Aortopathies Aortopathies with significant aortic dilatation (Marfan 45 mm, bicuspid aortopathy 5 cm) Cyanotic heart disease with no pulmonary vascular disease Native severe coarctation Modified World Health Organization pregnancy risk, adapted from Thorne et al. (2006) and Regitz-​Zagrosek et al. (2011). mWHO 1 = no detectable risk of maternal mortality and no/​mild increase in morbidity. mWHO 2 = small increased risk of maternal mortality or moderate increase in morbidity. mWHO 3 = significantly increased risk of maternal mortality or severe morbidity. Expert counselling required and specialist cardiac and obstetric monitoring needed throughout pregnancy, childbirth, and the puerperium. mWHO 4 = extremely high risk of maternal mortality or severe morbidity; pregnancy contraindicated. If pregnancy occurs, termination should be discussed. If pregnancy continues, care as for class 3. Table 16.12.9  Risks of infective endocarditis or endarteritis in congenital heart disease Unoperated Operated Low risk: lesions with no or low velocity turbulence and no prosthetic material Anomalous pulmonary venous drainage Anomalous pulmonary venous drainage Secundum ASD Secundum ASD Ebstein anomaly Ebstein anomaly with repaired native valve Mild pulmonary stenosis VSD/​tetralogy of Fallot without residual lesions Isolated corrected transposition Patent arterial duct Eisenmenger syndrome without valvar regurgitation Fontan-​type procedures Arterial switch for transposition without residual lesions Moderate risk Systemic AV valve regurgitation Residual regurgitation of repaired native aortic or systemic AV valve Subaortic stenosis Non​valved conduits Moderate—​severe pulmonary stenosis Tetralogy of Fallot Double-​outlet right ventricle Univentricular heart with pulmonary stenosis Truncus arteriosus Coarctation Restrictive patent arterial duct High risk Bicuspid aortic valve Prosthetic valves Aortic regurgitation secondary to VSD or subaortic stenosis Aortopulmonary shunts, e.g. Gore-​Tex, modified Blalock–​Taussig Restrictive VSD Valved conduits ASD, atrial septal defect; AV, atrioventricular; VSD, ventricular septal defect. section 16  Cardiovascular disorders 3594 A particularly successful multidisciplinary model of care is to run a combined active and palliative care approach, which can include interventions such as heart transplantation in parallel with an em- phasis on quality of life and end-​of-​life planning. Bacterial endocarditis Endocarditis is discussed in Chapter 16.9.2; the risks for specific congenital lesions are outlined in Table 16.12.9. In the United Kingdom, National Institute for Clinical Excellence Guidelines 2016 do not recommend routine use of antibiotic prophylaxis for people with structural heart disease undergoing dental, upper and lower gastrointestinal, urogenital, or respiratory procedures. However, NHS Education for Scotland updated NICE Clinical Guideline 64 in 2018; antibiotic prophylaxis should be considered for high risk groups including those with prosthetic valves and conduits as well as cyanotic patients and those with previous endocarditis. Patients with other intracardiac prosthetic material should receive antibiotic prophylaxis for 6 months after surgery, or lifelong if there remains a residual shunt or regurgitant valve. Healthcare professionals are advised to discuss with patients the rationale behind not using rou- tine antibiotic prophylaxis, and to emphasize the importance of maintaining good oral hygiene. Advice on the risks of body piercing and tattooing should also be given, as should advice on the symp- toms that may indicate endocarditis and when to seek expert advice. It is likely that good oral hygiene and regular dental checks are more important in preventing endocarditis than whether or not antibiotic prophylaxis is given. FURTHER READING Anderson RH, Shirali G (2009). Sequential segmental analysis. Ann Pediatr Cardiol, 2, 24–​35. Ávila P, et al. (2017). Sudden cardiac death in adult congenital heart disease. Card Electrophysiol Clin, 9, 225–​34. Broberg CS, et al. (2006). Blood viscosity and its relationship to iron deficiency, symptoms and exercise capacity in adults with cyanotic congenital heart disease. J Am Coll Cardiol, 48, 256–​65. Cherian G, et al. (1983). Pulmonary hypertension in isolated atrial septal defect. Am Heart J, 105, 952–​7. Clapp S, et al. (1990). Down syndrome, complete AV canal and pul- monary vascular obstructive disease. J Thorac Cardiovasc Surg, 100, 115–​21. Del Sette M, et al. (1998). Migraine with aura and right-​to-​left shunt on transcranial Doppler: a case-​control study. Cerebrovasc Dis, 8, 327–​30. Diller GP, et al. (2006). Presentation, survival prospects and predictors of death in Eisenmenger syndrome: a combined retrospective and case-​control study. Eur Heart J, 27, 1737–​42. Driscoll DJ, et al. (1992). Five to fifteen year follow-​up after Fontan operation. Circulation, 85, 469–​96. Dupuis C, et al. (1992). The ‘adult’ form of the scimitar syndrome. Am J Cardiol, 70, 502–​7. Fyfe A, et al. (2005). Cyanotic congenital heart disease and coronary artery atherogenesis. Am J Cardiol, 96, 283–​90. Galiè N, et al. (2009). Guidelines for the diagnosis and treatment of pulmonary hypertension:  the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J, 30, 2493–​537. Geva T (2011). Repaired tetralogy of Fallot: the roles of cardiovascular magnetic resonance in evaluating pathophysiology and for pulmonary valve replacement decision support. J Cardiovasc Magn Reson, 13, 9. Hagen PT, Scholz DG, Edwards WD (1984). Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc, 59, 17–​20. Hjortshøj CMS, et al. (2017). Past and current cause-​specific mortality in Eisenmenger syndrome. Eur Heart J, 38(26), 2060–​7. Ho SY, et al. (1995). Colour atlas of congenital heart disease. Morphological and clinical correlations. Mosby-​Wolfe, London. Kirklin JW, Barratt-​Boyes BG (1993). Cardiac surgery, 2nd edition. Churchill Livingstone, New York. Knight M, et al. (eds) on behalf of MBRRACE-​UK (2014). Saving lives, improving mothers’ care –​ surveillance of maternal deaths in the UK 2012–​14 and lessons learned to inform maternity care from the UK and Ireland confidential enquiries into maternal deaths and mor- bidity 2009–​14. Perinatal Epidemiology Unit, University of Oxford, Oxford, 2016. Koller M, Rothlin M, Senning Å (1987). Coarctation of the aorta: re- view of 362 operated patients. Long term follow up and assessment of prognostic variables. Eur Heart J, 8, 670–​9. Konstanides S, et al. (1995). A comparison of surgical and medical therapy for atrial septal defects in adults. New Engl J Med, 333, 469–​73. Lumbiganon P, Chaitikpinyo A (2013). Antibiotics for brain abscesses in people with cyanotic congenital heart disease. Cochrane Collaboration/​ John Wiley & Sons, London. Mongeon FP, et al. (2008). Congenitally corrected transposition of the great arteries ventricular function at the time of systemic atrioven- tricular valve replacement predicts long-​term ventricular function. J Am Coll Cardiol, 57, 8–​17. Moodie DS, et  al. (1984). Long term follow up in the unoperated univentricular heart. Am J Cardiol, 53, 1124–​8. Moon RE, Camporesi EM, Kissolo JA (1989). Patent foramen ovale and decompression sickness in divers. Lancet, i, 513–​14. Murphy JG, et al. (1993). Long-​term outcome in patients undergoing surgical repair of tetralogy of Fallot. New Engl J Med, 329, 593–​9. Murtuza B, et al. (2011). Anatomic repair for congenitally corrected transposition of the great arteries: a single-​institution 19-​year ex- perience. J Thorac Cardiovasc Surg, 142, 1348–​57. Murtuza B, et al. (2017). Impact of mode of failure and end-​organ dys- function on the survival of adult Fontan patients undergoing cardiac transplantation. Eur J Cardiothorac Surg, 51(1), 135–​41. NICE (2008). Prophylaxis against infective endocarditis:  antimicro- bial prophylaxis against infective endocarditis in adults and children undergoing interventional procedures. Clinical guideline. http://​ guidance.nice.org.uk/​CG64/​Guidance/​pdf/​English Perloff JK, Child JS (1998). Congenital heart disease in adults. W. B. Saunders, Philadelphia, PA. Quinton E, et al. (2015). Prevalence of atrial tachyarrhythmia in adults after Fontan operation. Heart, 101, 1672–​7. Redington AN, et al. (1998). The right heart in congenital heart disease. Greenwich Medical Media, London. Regitz-​Zagrosek V, et al. (2011). ESC Guidelines on the manage- ment of cardiovascular diseases during pregnancy: the Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC). Eur Heart J, 32(24), 3147–​97. Regitz-Zagrosek V, et al. (2018). ESC Guidelines for the management of cardiovascular disease in pregnancy. Eur Heart J, 39, 3165–241. Roberts WC (1986). Major anomalies of coronary arterial origin seen in adulthood. Am Heart J, 111, 941–​62. 16.12  Congenital heart disease in the adult 3595 Sarris GE, et  al. (2006). European Congenital Heart Surgeons Association. Results of surgery for Ebstein anomaly: a multicentre study from the European Congenital Heart Surgeons Association. J Thorac Cardiovasc Surg, 32, 50–​7. Schamroth CL, et  al. (1987). Pulmonary arterial thrombosis in secundum atrial septal defect. Am J Cardiol, 60, 1152–​6. Stark J, de Leval MR (ed) (1994). Surgery for congenital heart defects. W. B. Saunders, London. Stout KK et al. (2018). AHA/ACC Guideline for the management of adults with congenital heart disease. Circulation, epub ahead of print. Tay EL, et  al. (2011). Replacement therapy for iron deficiency im- proves exercise capacity and quality of life in patients with cyanotic congenital heart disease and/​or the Eisenmenger syndrome. Int J Cardiol, 151, 307–​12. Thorne S, MacGregor A, Nelson-​Piercy C (2006). Risks of contracep- tion and pregnancy in heart disease. Heart, 92, 1520–​5. Van Hare GF, et al. (2015). AHA/​ACC scientific statement. Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: task force 4: congenital heart disease. JACC, 66(21), 735–​1097. Villafañe J, et al. (2013). Hot topics in tetralogy of Fallot. J Am Coll Cardiol, 62, 2155–​66. Warnes CA (2006). Transposition of the great arteries. Circulation, 114, 2699–​709. Warnes CA, et al. (2008). Guidelines for the management of adults with congenital heart disease: a report of the American College of Cardiology/​American Heart Association Task Force on Practice Guidelines. Circulation, 118, e714–​833. Wilson W, et al. (2007). Prevention of infective endocarditis: guidelines from the American Heart Association Rheumatic Fever, Endocarditis and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardio­ vascular Surgery and Anesthesia, and the Quality and Care Outcomes Research Interdisciplinary Working Group. Circulation, 116, 1736–​54. Wood P (1958). Eisenmenger syndrome: or pulmonary hypertension with reversed central shunt. Br Med J, ii, 701–​9, 755–​62. 16.13 Coronary heart disease 3596 16.13.1 Biology 16.13 Coronary heart disease 3596 16.13.1 Biology and pathology of atherosclerosis 3596 Robin P. Choudhury, Joshua T. Chai, and Edward A. Fisher 16.13 Coronary heart disease CONTENTS 16.13.1 Biology and pathology of atherosclerosis  3596 Robin P. Choudhury, Joshua T. Chai, and Edward A. Fisher 16.13.2 Coronary heart disease: Epidemiology and prevention  3603 Goodarz Danaei and Kazem Rahimi 16.13.3 Management of stable angina  3616 Adam D. Timmis 16.13.4 Management of acute coronary syndrome  3626 Rajesh K. Kharbanda and Keith A.A. Fox 16.13.5 Percutaneous interventional cardiac procedures  3655 Edward D. Folland 16.13.6 Coronary artery bypass and valve surgery  3666 Rana Sayeed and David Taggart 16.13.1  Biology and pathology of atherosclerosis Robin P. Choudhury, Joshua T. Chai, and Edward A. Fisher ESSENTIALS Formation of an atheromatous plaque—​this is an inflammatory pro- cess that involves the contribution of endothelial cells, lymphocytes, monocytes, and smooth muscle cells in conjunction with the de- position of atherogenic lipoproteins in the intimal layer of the vas- cular wall. The initial stage involves activation of the endothelium at regions of non​laminar flow in vessels resulting in increased perme- ability to Apo B-​containing lipoproteins. Inflammatory cells, in par- ticular monocytes, are recruited into the intimal layer of the vessel wall via the action of chemokines and adhesion molecules mobilized by activated endothelium. Progression of atheroma—​ingestion of low-​density lipoprotein by monocytes, predominantly via scavenger receptors, generates lipid-​rich foam cells. Atheroma progression is promoted by the failure to clear macrophages and foam cells that, on dying, re- lease cholesterol-​rich material promoting further inflammation. Leucocytes and endothelial cells also contribute through the release of growth factors that stimulate proliferation of vascular smooth muscle cells. These cells migrate from the medial layer to the intima where they undergo transformation to both a synthetic phenotype (contributing to extracellular matrix formation), and ‘macrophage-​ like’ vascular smooth muscle cells capable of phagocytosis of low-​ density lipoprotein. Further development of the atheromatous plaque—​extracellular matrix formation by vascular smooth muscle cells is stimulated by cytokines (e.g. TGFβ and platelet-​derived growth factor) released from T lymphocytes, platelets, and macrophages. The extracellular matrix confers structural integrity to the atheromatous plaque and the overlying collagen-​rich fibrous cap and promotes retention of lipoprotein molecules. Neovascularization of atheroma via the ac- tion of vascular endothelial growth factor results in susceptibility to plaque haemorrhage. Calcification is common although its patho- genic significance is uncertain. The progression of the atheromatous plaque is not always linear. Regression of atheroma—​previously observed in preclinical models, clinical regression of atheroma has also been demonstrated with increasing frequency as low-​density lipoprotein-​lowering has be- come more potent. In preclinical models, the mechanism appears to involve the resolution of the inflammatory state of plaque macro- phages, which remodels diseased artery towards a normal state in a process that is akin to wound healing. Clinical manifestations—​although atherosclerosis develops within the wall of the artery, eventual encroachment of the expanding plaque into the lumen may be sufficient to retard blood flow, causing stable angina. Progression may also occur in stepwise fashion due to minor plaque rupture or haemorrhage. Acute cor- onary syndromes arise from more profound, and usually abrupt, transformations of atheromatous plaques due to plaque haem- orrhage, erosion, and rupture that can precipitate the formation of occlusive luminal thrombus. Atheromatous lesions with a large lipid-​rich core and thin fibrous cap are predisposed to plaque rup- ture, releasing lipid-​containing prothrombotic material and giving rise to thrombosis. Thrombotic occlusion due to plaque erosion arises in areas denuded of endothelium and is more common in women smokers. 16.13.1  Biology and pathology of atherosclerosis 3597 Medical management—​therapies to promote atheroma regres- sion target plasma lipoproteins (especially low-​density lipoprotein cholesterol), plaque inflammation, and plaque remodelling. Dietary and pharmacological modification of plasma lipids are effective secondary prevention measures that have been shown to pro- mote plaque regression, but their impact on clinical events appears to relate to complex mechanisms that modify inflammation, plaque stability, and thrombosis and are more difficult to assess using cur- rent techniques. Specific therapies targeting the inflammatory component of the atheromatous plaque (in particular monocyte re- cruitment, macrophage function and apoptosis) are attractive, and the first evidence of possible clinical effectiveness of this approach is emerging. Initiation of atheroma Atherosclerotic plaques are not randomly distributed, but tend to form at the inner curvatures and branch points of arteries, where laminar flow is either disturbed or insufficient to sup- port the normal, quiescent state of the endothelium (the lining of endothelial cells that separates the circulating blood from the arterial wall). Mechanical transduction of laminar shear stress in- volves the activation of integrins with downstream inactivation of the Yes-​associated protein (YAP)/​transcriptional coactivator with a PDZ-​binding domain (TAZ), the prime mediators of the Hippo pathway. Loss of laminar stress leads to activation of YAP and TAZ, which promotes the activation of several in- flammatory pathways including the atherosclerosis-​promoting JNK-​protein. Activation of the endothelium is associated with increased permeability to lipoproteins and an accumulation of extracellular matrix proteins that cause diffuse intimal thickening and the retention of the atherogenic apolipoprotein B (apoB)-​ containing lipoproteins. Endothelial activation also promotes the recruitment of cir- culating monocytes that originate from either the bone marrow or spleen. Monocyte entry into the arterial intima depends on endothelial cell up-​regulation of molecules that mediate their arrest on the luminal surface of the endothelium. The recruited monocytes transmigrate across the endothelium, where they differentiate into macrophages, some of which encounter the retained apoB-​lipoproteins. The subsequent uptake of the re- tained apoB-​lipoproteins by these macrophages is one of the earliest pathogenic events in the nascent plaque and results in the development of macrophage foam cells. The mechanisms of foam cell formation have been intensely studied. Although macrophages can take up apoB-​containing lipoproteins through the low-​density lipoprotein (LDL) receptor, expression of this receptor is down-​regulated early during foam cell formation by the increased cellular cholesterol levels. These observations led to the hypothesis that lipoproteins must become modified in the artery wall and be taken up by other mechanisms, notably by scavenger receptors. Multiple means of LDL modification that facilitate cholesterol loading of macrophages in vitro have been identified, including oxidation. The physiologically rele- vant in vivo pathways of foam cell formation are still debated, though it is widely accepted that the appearance of foam cells in arterial sites represents the initiation of an atherosclerotic plaque. Leucocyte recruitment Though many cell types contribute to the formation of atheroscler- otic plaques, including endothelial cells, monocytes, dendritic cells (DCs), lymphocytes, eosinophils, mast cells, and smooth muscle cells, macrophage foam cells are so central in the initi- ation and progression of atherosclerosis that emphasis has long been placed on understanding the mechanisms of monocyte re- cruitment into plaques. Circulating monocytes in mice have been considered in two major subsets, Ly6Chi and Ly6Clow, with the corresponding subsets in humans being CD14+CD16− and CD14lowCD16+. In mice, and presumably in humans, the more in- flammatory monocyte subsets (Ly6Chi and CD14+CD16−) make up the majority of cells recruited to progressing atherosclerotic plaques and are thought to be the source of the M1 (classically ac- tivated) macrophages found in both murine and human plaques that are responsible for maintaining a chronic inflammatory state. While these classifications, based on the expression of molecules on the cell membrane, have provided insights into the potential for differential function within a given cell population, more so- phisticated appreciation of function is emerging from quantitative transcriptomic, metabolomic, and proteomic analyses. Monocyte recruitment, as noted earlier, begins at the luminal surface of the endothelium. The capture and rolling phases of the recruitment cascade depend on the immobilization of chemokines, particularly CC-​chemokine ligand 5 (CCL5) and CXC-​chemokine ligand 1 (CXCL1), to endothelial cell glycosa- minoglycans, and on P-​selectin, which is expressed on the lu- minal side of endothelial cells. Vascular cell adhesion molecule 1 (VCAM1) and intercellular adhesion molecule 1 (ICAM1), which bind to the integrins VLA4 and lymphocyte function-​associated antigen 1 (LFA1), respectively, are important for the firm adhe- sion of monocytes to the luminal surface of the endothelium. The next phase is the transmigration of monocytes across the endothelium into the intimal (subendothelial) space. This is mediated by chemokines secreted by endothelial cells, in- timal macrophages, and smooth muscle cells. Although several chemokines have been implicated in atherosclerosis, the three major chemokine receptor–​chemokine pairs involved in mono- cyte transmigration are CCR2–​CCL2, CX3CR1–​CX3CRL1, and CCR5-​CCL5. In addition to these chemokines, CD31 (also known von Willebrand factor; an endothelial cell surface immunoglobulin-​like adhesion molecule) and VCAM1 may also have a role in monocyte transmigration into atherosclerotic plaques. See Fig. 16.13.1.1. Although most studies of monocyte recruitment have been conducted in mice, the key players just described all have human homologues thought to function in similar ways. section 16  Cardiovascular disorders 3598 Progression of atheroma Beyond plaque initiation (see ‘Initiation of atheroma’ earlier), two factors conspire to promote the progression of atheroma. These are the ongoing entry and subsequent retention of the apoB-​containing lipoproteins, and the continued expansion of the plaque cellular component due to both recruitment of monocytes, and to the local proliferation of macrophages. Recruitment of monocytes to a site of inflammation is not ab- normal; rather, it is the failure to remove macrophages and re- solve the inflammation that leads to pathology. In part this is due to macrophage chemostasis (cellular paralysis) that is not typical in other settings (such as in pneumonia or wound healing) and which might reflect the expression of retention molecules that render the macrophages and foam cells relatively unresponsive to chemokines, as shown in mice. Macrophages are key cellular components of atherosclerotic plaque and produce interleukin-​1β (IL-​1β), which is also pro- moted by activation of NLRP3 inflammasomes by the formation of crystals as cellular cholesterol accumulates. Interleukin-​1β and interleukin-​1α exert pro-​inflammatory effects that are inhibited by the endogenous antagonist interleukin-​1 receptor antagonist (IL-​ 1RA). Atherosclerosis-​prone mice that are deficient for IL-​1β de- velop smaller lesions, and administration of IL-​1RA reduces early atherogenesis in mice, while IL-​1RA deficient mice have shown in- creased atherosclerosis and vascular inflammation, associated with destruction of elastic tissues. The key role of IL-​1β as a mediator of innate immunity and the effects of interleukin inhibition in ex- perimental atherosclerosis have led to interventions to reduce in- flammation through IL-​1β being in clinical trials for the treatment atherosclerosis and its complications. Atherosclerotic plaques contain cells with markers of senescence, with stress response marked by growth arrest along with secretion of a variety of biologically active molecules, collectively termed the senescence-​associated secretory phenotype. Senescent intimal foam cells increase the expression of pro-​inflammatory cytokines and chemokines in early atherosclerosis and promote degradation of connective tissue elements in advanced plaques. There is at least one other contributing factor; as in other tissues, a fraction of the macrophage population in plaques undergoes apop- tosis, and is normally phagocytosed by healthy macrophages in a pro- cess called ‘efferocytosis’. Even in an early plaque, in which the local environment is not fully toxic, clearance by efferocytosis cannot keep up with the influx of newly recruited monocytes, leading to plaque growth. As the disease advances, the plaque accumulates more in- flammatory and injurious factors that can signal macrophages and other immune cells through Toll-​like receptors (TLRs). Among other adverse effects, this reduces macrophage capacity to perform Vulnerable plaque • Fibrous cap weakens by proteolytic enzymes • Intraplaque haemorrhage may occur secondary to neovascularisation • Eventually may lead to rupture and thrombosis Intraplaque haemorrhage Neovascularisation ApoB-containing lipoproteins Circulating monocytes Adhesion molecules e.g. VCAM1, ICAM1 Monocyte recruitment and transmigration Foam cell formation Activation of endothelium • ↑ Permeability to lipoproteins • ↑ Expression of adhesion molecules • Activation of integrin-YAP/TAZ-JNK cascade Scavenger receptor Efferocytosis Intact/thick fibrous cap M1 M2 Pro-inflammatory Anti-inflammatory/ tissue repair VSMC phenotypic “switch” Macrophage-like Synthesize collagen Progression of atherosclerosis • ↑ Recruitment of leukocytes • ↑ Foam-cell formation and pro- inflammatory phenotype of recruited macrophage/foam cell • Activation of NLRP3 inflammasome Established atheroma • Large lipid-rich necrotic core with cholesterol crystals and foam cells • Efferocytosis of dead cells inhibited • VSMCs secrete collagen that forms fibrous cap but can also adopt a macrophage-like phenotype • ↑ Proliferation and chemostasis of inflammatory cells with ongoing inflammatory stimuli (e.g., continued entry of LDL) Thinning of fibrous cap eventually leads to plaque rupture / thrombosis Proteolytic enzymes e.g. MMPs Vasa vasorum Plaque rupture Macrophage Lipid-laden foam cell Macrophage/foam cell which has undergone necrosis or apoptosis Collagen Weakened collagen Vascular smooth muscle cells (VSMC) Lipid-rich necrotic core YAP/TAZ Loss of lamina flow Activation of inflammatory pathways NLRP3 inflammasome Crystal Local Proliferation Integrin Fig. 16.13.1.1  Stages of atherosclerosis progression from activated endothelium, to leukocyte recruitment, established atheroma, to eventual development of vulnerable plaque features. 16.13.1  Biology and pathology of atherosclerosis 3599 efferocytosis. This results in the disintegration of the dying macro- phages, with the release into the extracellular plaque environment of inflammatory material, thrombotic factors, and the cholesterol-​rich gruel found in the necrotic core. Efferocytosis of apoptotic cells (the process by which they are removed by phagocytic cells) has recently been recognized as an activator of a certain type of macrophage that resolves inflammation and favourably remodels tissues, hence its failure likely contributes to disease progression by sustaining the in- flammatory milieu. In parallel with the macrophage ‘itinerary’ just described, as the atheroma advances, other immune cells—​both innate (dendritic cells) and acquired (T and B lymphocytes)—​also enter the plaque and modulate its inflammatory state. For example, T lymphocytes, depending on their stimuli, can either exacerbate macrophage ac- tivation by the secretion of Th1 cytokines (e.g. IL-​1, IL-​6, TNFα) or ameliorate it by secreting Th2 cytokines (e.g. IL-​4, IL-​10). Furthermore, B cells can elaborate antibodies to substances gener- ated from the oxidation of LDL that resemble antigens derived from microorganisms, in an attempt to neutralize the harmful effects of these products, with levels of such antibodies considered by some as a marker of disease burden. Smooth muscle cells In normal arteries, vascular smooth muscle cells (VSMC) are con- fined to the medial layer, which is delimited from the intimal space, where plaques form and grow, and from the outer arterial wall by internal and external elastic laminae, respectively. The cells are in the ‘contractile’ state, meaning that they serve mainly to set the vas- cular tone in response to a variety of stimuli by either contracting or relaxing. Activated endothelial cells in coronary arteries not only upregulate their leukocyte recruitment factors, they also down-​ regulate their production of nitric oxide, increasing arterial tone and adversely affecting blood flow to the myocardium. The loss of vasorelaxation is not the only change in VSMC in the progressing plaque. Both activated leucocytes and endothelium secrete growth factors that stimulate the proliferation of VSMC, which then migrate out of the medial layer into the intima. The migration of synthetic VSMC to the subendothelium and their elaboration of collagen forms the fibrous cap. The historical view has been that the VSMC phenotype switches from ‘contractile’ to ‘synthetic’, in recognition of increased produc- tion of extracellular matrix (ECM) by these cells (see ‘Extracellular matrix’). However, it is now appreciated that the phenotypic spec- trum of VSMC in atheroma is more complex than originally real- ized. For example, VSMC can gain properties of inflammatory cells presumably because their TLRs become stimulated as they do in macrophages (see previous section). Another way in which the VSMC phenotype can be altered is by accumulating lipids. Relative to macrophages, whose transition to foam cells is enabled by their expression of scavenger receptors that take up large amounts of lipoprotein-​derived lipids well after their LDL receptors are down-​ regulated, VSMC appear to become engorged more through a phagocytic process. Once it occurs to a significant degree, however, the cells in vitro and in vivo assume a macrophage foam cell-​like state, both morphologically and phenotypically (in terms of cell-​ specific marker expression). In advanced plaques in patients, it has been estimated that as much as 40% of cells that would be tradition- ally classified as macrophage foam cells are actually of VSMC origin. Unlike the subendothelial VSMC that retain the synthetic pheno- type, it is likely that the ‘macrophage-​like’ VSMC have negative ef- fects on plaque inflammation and stability. Extracellular matrix The ECM is made up of a mixture of macromolecules including col- lagen, elastin, glycoproteins, and proteoglycans, that confer tensile strength and viscoelasticity to the arterial wall. However, the ECM components function beyond furnishing a scaffold for the arterial wall and developing atherosclerotic plaque. Some constituents (not- ably proteoglycans) bind apoB-​lipoproteins (described earlier), prolonging their residence in the intima. Retention of lipoprotein particles occurs due to steric hindrance and ionic interactions be- tween positively charged amino acids in apoB-​containing lipopro- teins and negatively charged residues in the glycosaminoglycan chains. As a result, extravasated LDL are liable to retention and sus- ceptible to the oxidative modification (and glycation) that drives atherogenesis. In addition to lipoprotein retention, as atherosclerotic plaques de- velop, the ECM participates in other processes that are important in the context of atherosclerosis and its complications, including cell migration and proliferation, and thrombosis. Furthermore, the distribution of fibrous elements relative to other components, such as the lipid-​rich necrotic core, can influence plaque behaviour. Elements of ECM can be found diffusely in a reticular distribution through the plaque but may also be found in a dense ‘fibrous cap’ overlying the lipid-​rich necrotic core. Indeed, when considering pathogenicity, the deposition of ECM, comprised of fibrous and cellular components, confers structure and stability. Disruption of the fibrous cap (discussed later) is a precipitant of acute vascular syndromes. The matrix also contains growth factors, and cleaving certain components such as laminin releases sequestered mediators that promote cellular migration. Cytokines such as TGFβ and platelet-​ derived growth factor from T cells, platelets, macrophages, and monocytes stimulate smooth muscle cells to produce ECM. Atherosclerotic plaques Cell death in atherosclerotic plaques As noted earlier, intimal macrophages can undergo apoptosis, a type of programmed death that usually prevents necrosis. This process occurs throughout atherosclerotic lesion development, and in ad- vanced atherosclerotic lesions, apoptotic macrophages necrose and coalesce to contribute to a lipid-​rich necrotic core that harbours the tissue factor that contributes to the formation of the intraluminal clot after plaque rupture. One mechanism underlying postapoptotic macrophage necrosis is the defective phagocytic clearance, or efferocytosis, of apoptotic cells. Studies in mouse models of ad- vanced atherosclerosis have provided evidence that several mol- ecules known to be involved in efferocytosis, including TG2, MFG-​E8, complement C1q, Mertk, lysoPC, and Fas, play important section 16  Cardiovascular disorders 3600 roles in the clearance of apoptotic cells in advanced plaques. Another mechanism related to postapoptotic macrophage necrosis that is emerging is a regulated process dubbed ‘necroptosis’, with several reports confirming its existence in preclinical models and beginning to identify the regulatory factors and their hierarchy. Neovascularization in atherosclerotic plaques Human arteries possess a microvasculature in their adventitial layers called the vasa vasorum. For the coronary arteries, normal vasa vasorum originate from branch points at regular intervals and run longitudinally along the vessel wall. A primary function of these ves- sels is to provide nutrients to the cells of the arterial wall. As plaques enlarge, angiogenic factors drive the formation of new blood vessels. For instance, oxidized phospholipids within the plaque can stimu- late the production of vascular endothelial growth factor isoforms in both monocytes and endothelial cells. New endothelial cell sprouts can form immature, leaky microvessels within the plaque. These ‘neo-​vessels’ also provide a site for entry of inflammatory mono- cytes that perpetuate the atherosclerotic process. Microvessels also present a potential site for intraplaque haemorrhage, which is asso- ciated with plaque progression. Plaque calcification Electron microscopy has shown that calcification can occur initially as microdeposits through mineralization of organelles in cells as- sociated with the lipid-​rich necrotic core. In some plaques, calcifi- cation progresses and can become diffuse and, particularly in older individuals, can become extensive. The presence of calcification has been targeted for quantification using CT techniques. Electron beam CT sensitively detects arterial calcification and its level can enhance prediction of risk of vascular complications over and above that associated with conventional risk factors. Furthermore, the process of calcification can be identified using positron emission tomography for 18F-​sodium fluoride. In cor- onary arteries, tracer uptake can be demonstrated in ‘culprit’ plaques after acute coronary syndrome (ACS; see later), and in symptom- atic carotid arteries uptake was associated with histological evidence of active calcification, macrophage infiltration, apoptosis, and ne- crosis. Yet to be determined, however, is the pathogenic significance of calcification. Although calcification may indicate the presence of atherosclerosis, it may at least in part reflect reparative processes. While the level of calcification has found some acceptance as a stratifying factor for risk of cardiovascular disease, it does not seem well suited as a parameter to reflect treatment efficacy. Indeed, treat- ment with statins, which reduces the risk of complications of athero- sclerosis, does not appear to alter plaque calcification. Positive remodelling of the arterial wall Atherosclerosis develops within the vessel wall and, as the lesion en- larges, its growth is often accommodated by positive remodelling of the artery. In other words, outward expansion of the artery can enable lesion growth without encroachment on the vessel lumen, at least initially. In the original description of this phenomenon in the left main stem coronary artery, the lumen area did not decrease in relation to the percentage of stenosis (i.e. the percentage of the vessel cross-​sectional area occupied by the plaque) for values up to 40%, but did diminish markedly and in close relation to the percentage of stenosis for values beyond that. So, human coronary arteries can enlarge in response to plaque growth to maintain their patency, but eventually this protective mechanism reaches a limit, and if the plaque continues to expand, stenosis ensues. Importantly, the com- pensatory outward expansion of the artery’s external elastic lamina can accommodate plaques with large lipid cores that do not appear on conventional X-​ray arteriography but which may nonetheless rupture suddenly, causing thrombus formation and ACS. Positive remodelling has important implications for identifica- tion of atheromatous lesions using arteriographic imaging tech- niques that, like angiography, focus on the lumen rather than the vessel wall. Intravascular ultrasound studies have shown that larger areas of plaque burden may exist in regions of the arteries with little or no luminal stenosis. Appreciation of this limitation has led to the emergence of imaging techniques (e.g. dual source computed tom- ography, magnetic resonance imaging [multicontrast and mapping techniques] and intravascular ultrasound) that focus on quantifica- tion and characterization of lesions directly. Patterns of disease progression The course of pathological events associated with atheroma that are described earlier may suggest an ordered and formulaic progression of atherosclerosis. While atheroma may advance through gradual progression of these physical and cellular processes, the develop- ment of individual lesions can also be punctuated by abrupt events, for example intraplaque haemorrhage, plaque erosion, and cap rup- ture. These events may occur relatively frequently, with a majority remaining subclinical. The healing phase that follows may involve smooth muscle cell proliferation and matrix deposition, which may stabilize but also enlarge the plaque and promote stenosis by con- strictive remodelling. Acute coronary syndromes An atherosclerotic plaque may develop over a period of several years and remain silent or subclinical throughout that time. Alternatively, encroachment of an enlarging but quiescent lesion may lead to symptoms of stable angina. Acute arterial syndromes typically occur due to the rupture or erosion of an atheromatous plaque. This ex- poses the contents of that plaque, including cellular debris, collagen, and tissue factor, to the elements of circulating blood that can ini- tiate blood coagulation, leading to partial or total thrombotic occlu- sion of the artery involved. Plaque rupture and erosion Post-​mortem studies of human coronary artery have identified features that are associated with atherosclerotic plaque rupture. Atheromatous lesions with a large lipid-​rich necrotic core and a thin fibrous cap with macrophage accumulation in the ‘shoulder’ regions seem to be susceptible to rupture. Propensity to rupture is further increased by the activity of proteolytic enzymes (matrix metalloproteinases) that digest and weaken elements of the fibrous cap. Plaque rupture exposes thrombogenic components of the plaque (including tissue factor and collagen) to the blood, leading to the generation of luminal thrombus, which may cause partial or total occlusion of the artery. As emphasized earlier, it is important to recognize that even lesions that do not cause a high degree of lu- minal stenosis can still behave in this way. 16.13.1  Biology and pathology of atherosclerosis 3601 Plaque erosion, in which a patch of endothelium becomes de- nuded, thereby exposing the intima to the circulating blood, also causes acute thrombosis. Endothelial loss may occur due to apop- tosis of endothelial cells or shedding of cells from the basement membrane due to the action of proteases such as gelatinases on type IV collagen, or other components of the basement membrane upon which endothelial cells rest. Sites of plaque erosion may not exhibit prominent macrophage or lymphocyte accumulation. The underlying plaque in erosions consists of a thickened intima or fi- brous cap atheroma, and lesions may be eccentric or calcified. Fatal thrombosis due to plaque erosion is associated with smoking, espe- cially in women. Compared with fibrous cap rupture, death due to plaque erosion occurs more often in younger individuals and may affect less severely narrowed arteries. Vulnerable plaque and the vulnerable patient While it is possible to identify individual lesions as the proximate cause of acute vascular events, these do not develop or behave in iso- lation. Numerous strands of evidence implicate systemic processes, especially in relation to inflammation, as drivers for atherosclerosis and or potential importance in affecting plaque behaviours acutely. Specifically, systemic inflammatory disease, such as rheumatoid arthritis, promotes atherosclerosis and its complications. In an ex- perimental model, acute myocardial infarction itself led to increased atherosclerotic plaque macrophage content and atherosclerosis pro- gression. However, remote drivers of inflammation may include fac- tors originating from the liver, adipose tissue, and gut microbiota. Appreciation of the role of systemic factors in the pathogenesis of atherosclerosis has implications for diagnosis, risk prediction, and treatments and is an emerging area of great clinical interest with sev- eral relevant patient intervention trials in progress and planned. Atherosclerosis regression While delayed progression of atherosclerosis is a worthy clinical goal, the disease process starts early in life and by the time most patients begin risk factor treatments, they have considerable plaque burden, making regression a more desirable goal. Indeed, in multiple studies a number of interventions, including dietary ap- proaches, genetic manipulations, infusion therapies, and pharma- cological treatments in multiple animal species (rabbits, pigs, mice), including non​human primates, have demonstrated favour- able effects on established atherosclerotic plaques. Most of these interventions have been ‘lipid/​lipoprotein centric’ and involved ei- ther lowering plasma levels of the apoB-​containing lipoproteins to reduce the formation and ongoing engorgement of the foam cells, or raising levels of cholesterol-​efflux agents (e.g. high-​density lipo- proteins, HDL) to unload cholesterol from these cells and return it to the liver for elimination through the bile as part of the process dubbed ‘reverse cholesterol transport’. See Fig. 16.13.1.2. A general finding has been that during atherosclerosis regres- sion, the plaque content of foam cells decreases. From recent studies in mouse models, evidence has accumulated to identify kinetic contributions to this decrease to include changes in mono- cyte recruitment, macrophage emigration, macrophage apoptosis and efferocytosis, and local macrophage proliferation. Knowledge of the critical role that the chronic inflammatory state of the plaque plays in the clinical disease process, especially the erosion and eventual rupture of a vulnerable plaque, has focused atten- tion on therapies that would dampen or even resolve the inflam- matory state in plaques. Preclinical findings have given cause for optimism that this approach will join the lipid-​centric approaches to realize plaque regression. For example, in mouse models it has been shown that the inflammatory state of the plaque foam cells is dynamic. Most are in the M1 activated state (which encour- ages inflammation) during disease progression, but under experi- mental regression conditions, there is enrichment of cells in the M2 state, which are sometimes referred to as anti-​inflammatory or tissue repair macrophages. It has been recently demonstrated that this change is instrumental in the resolution of the inflamma- tion and remodelling of the plaque to one with more stable features (i.e. fewer macrophages, thicker fibrous cap) in mouse models of atherosclerosis. This shift from M1 to M2 macrophages may be advantageous not only in atherosclerosis regression, as supported by recent preclin- ical studies in which the administration of agents that are strong polarizers of macrophages in vitro to the M2 state (such as IL-​13) has consistently led to delayed progression of atherosclerosis. One challenge for anti-​inflammatory therapies, of course, is targeting agents to the plaque for those having adverse systemic effects, but improvements in nanoparticle-​based therapies to achieve such spe- cificity are rapidly advancing. Clinical studies of plaque regression There are limited clinical studies that have also shown that sig- nificantly lowering plasma apoB-​containing lipoprotein levels or increasing the levels of functional HDL particles resulted in plaque regression, as judged by quantitative angiography or intravas- cular ultrasound. Patients in most of these trials had evidence of ACS, and the imaging techniques used were not only invasive (and therefore not appropriate in primary prevention studies), but also primarily sensitive to changes in plaque size, rather than compos- ition or inflammatory state. Such ‘qualitative’ changes are likely to be exceedingly important clinically as they are key components of plaque regression in preclinical models. Evidence of plaque regres- sion in the much larger primary prevention group is limited and largely restricted to non​invasive measurement of carotid intima-​ media thickness. Improved non​invasive techniques that assess plaque composition and activity are under development to assess the ability of current and future candidate therapies to favourably affect plaque characteristics. The first large clinical trial of an agent targeting the inflamma- tory component of the atheromatous plaque was reported in 2017. The CANTOS trial randomized 10 061 patients with previous myo- cardial infarction and elevated high sensitivity C-​reactive protein levels (suggesting presence of an inflammatory state) to receive canakinumab (an antibody against the potent inflammatory cyto- kine IL-​1β) or placebo. The middle (of three) dose of canakinumab was associated with a significantly lower rate of recurrent cardio- vascular events than placebo, although overall the agent was asso- ciated with no significant difference in cardiovascular or all-​cause mortality. Many other agents that might cause plaque regression (or less ideally stop their progression) are in clinical trials, or contem- plated for such testing. These include very aggressive LDL-​lowering section 16  Cardiovascular disorders 3602 using antibodies to PCSK9, infusions of HDL or artificial choles- terol acceptors (e.g. apoA1 Milano), and various anti-​inflammatory treatments. Finally, therapeutics can be envisioned that will manipu- late the content of plaque macrophages by regulating monocyte recruitment or macrophage emigration, macrophage apop- tosis and efferocytosis, and the proliferation of macrophages in plaques. Advances in genetic, immunological, and nanoparticle therapies will further enhance the likelihood of successful im- plementation of these and other, yet to be discovered, promising approaches. FURTHER READING Allahverdian S, et al. (2014). Contribution of intimal smooth muscle cells to cholesterol accumulation and macrophage-​like cells in human atherosclerosis. Circulation, 129, 1551–​9. Bosurgi L, et  al. (2017). Macrophage function in tissue repair and remodeling requires IL-​4 or IL-​13 with apoptotic cells. Science, 356, 1072–​6. Burke AP, et al. (1997). Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med, 336, 1276–​82. Cardilo-​Reis L, et al. (2012). Interleukin-​13 protects from atheroscler- osis and modulates plaque composition by skewing the macrophage phenotype. EMBO Mol Med, 4, 1072–​86. Childs BG, et al. (2016). Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science, 354, 472–​7. Detrano R, et al. (2008). Coronary calcium as a predictor of cor- onary events in four racial or ethnic groups. N Engl J Med, 358, 1336–​45. Duewell P, et  al. (2010). NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature, 464, 1357–​61. Dutta P, et al. (2012). Myocardial infarction accelerates atherosclerosis. Nature, 487, 325–​9. Galis ZS, et al. (1994). Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human ath- erosclerotic plaques. J Clin Invest, 94, 2493–​503. Glagov S, et al. (1987). Compensatory enlargement of human athero- sclerotic coronary arteries. N Engl J Med, 316, 1371–​5. Fig. 16.13.1.2  Mechanisms involved in atherosclerosis regression in experimental models. 16.13.2 Coronary heart disease Epidemiology and pr 16.13.2 Coronary heart disease: Epidemiology and prevention 3603 Goodarz Danaei and Kazem Rahimi 16.13.2  Coronary heart disease: Epidemiology and prevention 3603 Hansson GK, Hermansson A (2011). The immune system in athero- sclerosis. Nat Immunol, 12, 204–​12. Joshi NV, et al. (2014). 18F-​fluoride positron emission tomography for identification of ruptured and high-​risk coronary atherosclerotic plaques: a prospective clinical trial. Lancet, 383, 705–​13. Karunakaran D, et al. (2016). Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis. Science Advances, 2, e1600224. McGill HC Jr, et al. (2000). Effects of coronary heart disease risk factors on atherosclerosis of selected regions of the aorta and right coronary artery. PDAY Research Group. Pathobiological determinants of ath- erosclerosis in youth. Arterioscler Thromb Vasc Biol, 20, 836–​45. Moore KJ, Freeman MW (2006). Scavenger receptors in athero- sclerosis: beyond lipid uptake. Arterioscler Thromb Vasc Biol, 26, 1702–​11. Moore KJ, et al. (2013). Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol, 13, 709–​21. Moreno PR, et al. (1996). Macrophages, smooth muscle cells, and tissue factor in unstable angina. Implications for cell-​mediated thrombo- genicity in acute coronary syndromes. Circulation, 94, 3090–​7. Owen DR, et al. (2011). Imaging of atherosclerosis. Annu Rev Med, 62, 25–​40. Rahman K, et al. (2017). Inflammatory Ly6Chi monocytes and their conversion to M2 macrophages drive atherosclerosis regression. J Clin Invest, 127(8), 2904–​15. Ridker PM, et al. (2017). Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med, 377, 1119–​31. Robbins CS, et  al. (2013). Local proliferation dominates lesional macrophage accumulation in atherosclerosis. Nat Med, 19, 1166–​72. Rong JX, et al. (2003). Transdifferentiation of mouse aortic smooth muscle cells to a macrophage-​like state after cholesterol loading. Proc Natl Acad Sci USA, 100, 13531–​6. Rumberger JA, et al. (1995). Coronary artery calcium area by electron-​ beam computed tomography and coronary atherosclerotic plaque area. A histopathologic correlative study. Circulation, 92, 2157–​62. Ruparelia N, et al. (2017). Inflammatory processes in cardiovascular disease: a route to targeted therapies. Nat Rev Cardiol, 14, 133–​44. Schroeder BO, Backhed F (2016). Signals from the gut microbiota to distant organs in physiology and disease. Nat Med, 22, 1079–​89. Tabas I, Glass CK (2013). Anti-​inflammatory therapy in chronic dis- ease: challenges and opportunities. Science, 339, 166–​72. Tacke F, et al. (2007). Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J Clin Invest, 117, 185–​94. Thorp E, et al. (2008). Mertk receptor mutation reduces efferocytosis efficiency and promotes apoptotic cell accumulation and plaque ne- crosis in atherosclerotic lesions of apoe-​/​-​mice. Arterioscler Thromb Vasc Biol, 28, 1421–​8. Wang L, et  al. (2016). Integrin-​YAP/​TAZ-​JNK cascade mediates atheroprotective effect of unidirectional shear flow. Nature, 540, 579–​82. Weber C, Noels H (2011). Atherosclerosis: current pathogenesis and therapeutic options. Nat Med, 17, 1410–​22. Williams KJ, et  al. (2008). Rapid regression of atherosclerosis:  in- sights from the clinical and experimental literature. Nat Clin Pract Cardiovasc Med, 5, 91–​102. Williams KJ, Tabas I (1995). The response-​to-​retention hypothesis of early atherogenesis. Arterioscler Thromb Vasc Biol, 15, 551–​61. Wolfbauer G, et al. (1986). Development of the smooth muscle foam cell: uptake of macrophage lipid inclusions. Proc Natl Acad Sci U S A, 83, 7760–​4. 16.13.2  Coronary heart disease: Epidemiology and prevention Goodarz Danaei and Kazem Rahimi ESSENTIALS Coronary heart disease (CHD) is now the leading cause of death and disability globally. Despite recent declines in age-​adjusted death rates from CHD, the number of CHD deaths have been increasing due to a combination of growth in population numbers and their longevity. In addition, manifestation and outcome of CHD varies substantially between and within countries. Unlike many other common medical conditions that disable and kill and remain unpreventable, CHD is to a large extent preventable. There are strong, unconfounded relationships between several risk factors and CHD mortality and non​fatal myocardial infarction. The most important risk factors for CHD are smoking, high blood pres- sure, dyslipidaemia, diabetes, physical inactivity, unhealthy diet, and obesity. Controlling these risk factors, even in middle-​aged individ- uals, through lifestyle changes, medical treatment, or public health interventions, may reduce CHD incidence by almost one-​half. Despite the apparent triumph in risk prediction and control, the search for new biomarkers, both phenotypic and genotypic, remains a major focus of cardiovascular research. Several novel markers of risk (e.g. B-​type natriuretic peptide) have already been identified and many more are likely to emerge during the next few years. However, the causal significance of these biomarkers, or their contribution to risk prediction, awaits further clarification. Introduction Coronary heart disease (CHD) is a group of diseases character- ized by insufficient circulation in coronary arteries potentially leading to angina pectoris, myocardial infarction, heart failure and (sudden) coronary death. The underlying pathophysiology is most often coronary atherosclerosis, which is discussed in detail in Chapter 16.13.1. The process of atherosclerosis may begin in utero, but the manifestation of CHD is largely preventable by controlling the common risk factors of atherosclerosis. In this chapter, we pre- sent the current evidence on the global distribution of CHD and its determinants, focusing on risk factors for atherosclerosis. Other, less common and non​atherosclerotic variants of CHD include those caused by vasoconstriction such as Prinzmetal’s angina, paradoxical embolism, Kawasaki syndrome leading to coronary aneurysms and stenosis, chest trauma, irradiation, spontaneous coronary dissec- tion, and cardiac syndrome X. These collectively constitute a small proportion of the global CHD burden, hence here we use CHD and ischaemic heart disease (IHD) interchangeably. Global perspective Coronary disease was a rare condition at the beginning of the 20th century—​a time when deaths from CHD were greatly outnumbered section 16  Cardiovascular disorders 3604 by those due to infectious diseases. CHD is now the leading cause of death and disability in almost all regions of the world, causing an estimated 9 million deaths in 2015 (out of 56 million). Despite a 25% decline in the age-​standardized mortality rates from CHD since 1990, the number of deaths from CHD have increased by 50% due to growth in population numbers and their longevity (age-​standardized mortality rates are adjusted for differences in the age structure of the population and therefore take into account that populations have aged over time). Since 1980, age-​standardized CHD mortality rates have declined in most high-​income and many middle-​income coun- tries in the world, but rates of premature CHD (i.e. events occurring before the age of 70) may have increased in countries in central and eastern Europe; central, south, and southeast Asia, Oceania, and sub-​Saharan Africa. There are also substantial regional differ- ences. In 2015, countries in eastern Europe and Central Asia had the highest CHD mortality rates at more than 600 per 100 000, whereas those in eastern sub-​Saharan Africa had the lowest rates at less than 100 (see Fig. 16.13.2.1). There are vast disparities in age at death from CHD. Deaths occur at much younger ages in Central Asia, North Africa, the Middle East, and sub-​Saharan Africa. The differences in death rates and age at pres- entation across nations point to the largely preventable nature of CHD. In fact, half the decline in CHD mortality in high-​income countries in the recent decades is thought to be due to improvements in treatment, with the remainder due to modification of CHD risk factors. Substantial disparities in CHD within countries and across social and racial/​ethnic subgroups have also been identified. The increased risk in African Americans compared with the white population in the United States of America, and increased risk in the Asian popu- lation in the United Kingdom, are largely explained by higher levels of well-​known risk factors such as high blood pressure, smoking, and diabetes. The importance of modifiable risk factors is empha- sized by the fact that individuals who migrate from low-​risk popula- tions to high-​risk ones tend to adopt the cardiovascular risk of their adopted country. Individuals with lower education, social status, or in lower income groups in Europe and America also exhibit much higher rates of CHD due to a combination of worse risk factor pro- files and lower access to, and quality of, healthcare. A substantial body of epidemiological knowledge has been gen- erated in the past seven decades and the collective evidence from cross-​country comparison studies, prospective epidemiological studies, and randomized clinical trials has helped us understand the determinants of CHD and design clinical and public health inter- ventions to reduce CHD burden worldwide. Next, we summarize the key risk factors and the corresponding evidence that substanti- ates their effect on CHD. 100.00 52.73 150.00 200.00 250.00 300.00 350.00 Rate per 100 000 (a) 400.00 450.00 500.00 550.00 600.00 623.52 Fig. 16.13.2.1  Map of age-​standardized ischaemic heart disease mortality rate per 100 000 in 2015 in men (a) and women (b): the Global Burden of Disease 2015 Study. From Global Burden of Disease Study 2015 (GBD 2015) Results. Seattle, United States: Institute for Health Metrics and Evaluation (IHME), 2016. Available from http://​ghdx. healthdata.org/​gbd-​results-​tool 16.13.2  Coronary heart disease: Epidemiology and prevention 3605 Modifiable and non​modifiable risk factors Overview of risk factors The most important risk factors for CHD are smoking, high blood pressure, dyslipidaemia, diabetes, physical inactivity, un- healthy diet, and obesity. The Global Burden of Disease project estimated that in 2015, 55% of the CHD burden (as measured by disability-​adjusted life years) was attributable to non​optimal blood pressure, 48% to high serum total cholesterol, 28% to air pollution and about 20–​25% separately to each of the following risk factors:  smoking, high fasting plasma glucose, and high body mass index, diet low in nuts and seeds, whole grains, sea- food omega-​3 fatty acids, vegetables and diet high in sodium (Table 16.13.2.1). The sum of these proportions far exceeds 100% because one CHD case can be attributable to more than one risk factor (i.e. could have been prevented by controlling any of several risk factors). It is also worth noting that the ranking of the risk factors in the Table depends on both their relative risk for CHD and prevalence of each risk factor at the global level. A risk factor with a larger relative risk such as tobacco smoking may therefore appear below a risk factor with a smaller relative risk but higher prevalence, such as high blood pressure (here de- fined as systolic blood pressure of ≥110–​115 mm Hg). Lifelong exposure to these risk factors collectively explains about 70–​80% of the incidence of CHD, and over 75% of patients presenting with CHD will have at least one of these risk factors. Controlling these risk factors, even in middle-​aged individuals, may reduce CHD incidence by almost one-​half. Tobacco smoking, second-​hand smoke, and other forms of tobacco use Tobacco smoking is a major driver of CHD worldwide. Strong evi- dence from many prospective epidemiological studies and labora- tory experiments clearly indicate the harmful effects of tobacco on CHD through its impact on reducing oxygen-​carrying cap- acity, increasing blood pressure, damaging the endothelial cells, increasing inflammation, thrombosis, and oxidation of low-​density lipoprotein (LDL) particles. There is a strong dose–​response rela- tionship between the duration and intensity of smoking and risk of CHD, and heavy smokers may have up to five times higher risk of CHD than never smokers. The relative risks of tobacco smoking and CHD decline with age and are at least as large among women as among men. The 20th century has aptly been named the ‘to- bacco century’ to signify the substantial rise in tobacco consump- tion initially in the high-​income nations and subsequently its export into developing countries. After the publication of the first report of the Royal College of Physicians in the United Kingdom in 1962 and the Surgeon General’s report of 1964 in the United States of America, various public health interventions and policies including educational campaigns and raising taxes and banning advertising have led to lower tobacco smoking in many high-​ income countries which may have contributed substantially to reductions in CHD rates. For example, in the United States 12% of the decline in the CHD rates between 1980 and 2000 has been attributed to reductions in smoking prevalence. Smoking cessation is the most effective preventive measure for CHD. The harmful im- pact of smoking on CHD takes up to 10 years to revert to normal after quitting smoking, but the impact is large (Fig. 16.13.2.2). (b) Fig. 16.13.2.1  Continued section 16  Cardiovascular disorders 3606 Cessation programmes including nicotine patches and gums, behavioural counselling and group therapy programmes, and the use of antidepressants (in particular bupropion and nortriptyline) may increase quitting success rates, but preventing uptake of smoking remains the key challenge. Bans on sales of tobacco products to minors, bans on advertising, and increasing taxes are among the most cost-​effective ways to reduce CHD burden, and 179 countries have signed a global treaty, the Framework Convention on Tobacco Control, adopted in 2003, to implement these policies. Other forms of tobacco smoking (cigar, pipe, hookah) increase risk for CHD to a similar extent to cigarettes. Passive (second-​hand) smoking A significant component of the global impact of smoking on the incidence of CHD is related to passive smoking. Although the relative risk of CHD due to passive smoking is much lower than for active smoking, a substantially larger number of individuals are exposed to this harmful effect, raising the importance of banning smoking in public places. Table 16.13.2.1  Proportion of ischaemic heart disease burden (measured in disability-​adjusted life years in 2015) attributable to individual risk factors, worldwide along with the corresponding relative risks, Global Burden of Disease Study results 2015 Risk factors Proportion of IHD burden attributable (95% CI) Relative risk for IHD mortality At age 60–​64 Unit or comparison for relative risk Physiological and behavioural risk factors High blood pressure 55% (47, 62) 1.41 10 mm Hg High total cholesterol 48% (40, 56) 1.40 mmol/​litre Tobacco smoking, including second-​hand smoke 24% (21, 28) 2.4 Men 3.0 Women 1.25 Smoker versus non​smoker Second-​hand smoke High fasting plasma glucose 20% (14, 28) 1.18 mmol/​litre High body mass index 20% (14, 27) 1.41 Per 5 kg/​m2 above 25 kg/​m2 Physical inactivity and low physical activity 10% (7, 14) 1.41 1.25 1.13 Inactive Insufficiently active Sufficient but not highly active Dietary risk factors Diet low in nuts and seeds 25% (16, 35) 1.06 4 g/​day Diet low in whole grains 23% (13, 32) 1.1 50 g/​day Diet low in seafood omega-​3 fatty acids 19% (8, 30) 1.12 100 mg/​day Diet high in sodium 19% (10, 31) 1.09 g/​day Diet low in vegetables 18% (7, 30) 1.07 100 g/​day Diet low in fruits 14% (5, 24) 1.10 100 g/​day Diet high in trans fatty acids 7 (3, 12) 1.28 2% energy/​day Diet low in fibre 5% (2, 8) 1.30 20 g/​day Diet low in polyunsaturated fatty acids 5% (2, 8) 1.08 5% energy/​day Diet high in processed meat 5% (0, 10) 1.44 50 g/​day Environmental risk factors Air pollution 28% (24, 32) From 1.12 (for 10 microg/m3) to 1.71 (for 600 microg/m3) Household air pollution Lead exposure 3% (1, 4) 1.02 Per 10 µg/​g Global Burden of Disease Study results 2015 Results. Seattle, United States: Institute for Health Metrics and Evaluation (IHME), 2016. Available from http://​ghdx.healthdata.org/​ gbd-​results-​tool 2.5 0.0 0 10 20 Time since cessation (years) Cardiovascular mortality relative risk 30 40 50 0.5 1.0 1.5 2.0 Male Female Fig. 16.13.2.2  Relative risk of cardiovascular mortality by time since cessation of smoking. From Ezzati M, Lopez AD, Rodgers A, Murray CJL. Smoking and oral tobacco use. Comparative quantification of health risks: Global and regional burden of disease attributable to selected major risk factors. Geneva: World Health Organization; 2004. pp. 883–​957. 16.13.2  Coronary heart disease: Epidemiology and prevention 3607 E-​cigarettes Since 2004, electronic cigarettes (or e-​cigarettes) have been launched as a smoke-​free and implicitly harm-​free nicotine delivery device. A recent review of chemical and toxicological studies found that aero- sols are contaminated by toxic substances including nitrosamines, aldehydes, metals, and volatile organic compounds. The amount of nicotine delivered by e-​cigarettes easily surpasses the threshold limit values used in occupational health investigations for nicotine. Whether e-​cigarettes are good or bad for public health has been much debated. Concerns have been raised that uptake of e-​cigarettes among non​smokers may lead to habitual smoking. However, a re- cent Cochrane Review found that they can help people to quit smoking and reduce their cigarette consumption, and consequently regarded e-​cigarettes as a positive public health opportunity, while agreeing that continued vigilance and research was needed in this area. Public Health England has stated that e-​cigarettes are less harmful to health than normal cigarettes, and that when supported by a smoking-​cessation service help smokers to quit tobacco al- together. Recent (2017) US data has shown that e-​cigarette use is associated with higher smoking cessation rate at both individual and population levels. Blood pressure The invention of the sphygmomanometer in the last decade of the 19th century made the measurement of blood pressure at the bed- side possible, and the landmark description of the sounds and their relationship with pulse waves by Korotkoff in 1905 made the meas- urements more precise and standardized. As early as the first or second decade of the 20th century, the relationship between very high blood pressure and mortality was known and had led to the designation of ‘malignant hypertension’. However, the dominant view in the first half of the past century was that blood pressure lower than 210/​110 mm Hg was ‘benign’ and did not need to be treated. A vivid example of such views can be seen in the last years of the life of American president Franklin Delano Roosevelt, who died from a stroke in 1945 and had a systolic blood pressure of 300/​190 mm Hg on the day of his death. He had a recorded blood pressure of 186/​ 108 one year earlier, but his personal physicians had considered it ‘normal for a man of his age’. Despite a correct diagnosis of hyper- tension, hypertensive heart disease, and heart failure made by his cardiologist several months later, the understanding of high blood pressure as a risk factor and options for treatment were limited at that time. In 1948, three years after Roosevelt’s death, his successor Harry Truman signed the National Heart Act which stated that ‘the Nation’s health is seriously threatened by diseases of the heart and circulation, including high blood pressure’. Early evidence from analyses of life insurance records indicated that even presumably ‘normal’ levels of blood pressure are associ- ated with higher mortality. This view was further strengthened with large prospective studies conducted in the 1950s and onwards. It is now clear, based on evidence from more than 100 prospective co- hort studies and many randomized trials, that both systolic and dia- stolic blood pressure increase CHD risk in a continuum and that blood pressure levels even within the clinically ‘normal’ range may lead to higher risk of CHD (Fig. 16.13.2.3). These studies collect- ively indicate that in people without any known vascular disease the optimal level of systolic blood pressure may be as low as 110 mm Fig. 16.13.2.3  Relative risks of mortality from CHD in 61 cohort studies by age and separately for systolic and diastolic measurements. Reprinted from The Lancet, Vol. 360, Lewington S, et al., Prospective Studies Collaboration, Age-​specific relevance of usual blood pressure to vascular mortality: a meta-​analysis of individual data for one million adults in 61 prospective studies, 1903–​13, Copyright 2002, with permission from Elsevier. section 16  Cardiovascular disorders 3608 Hg. However, the debate on the optimal blood pressure level con- tinues because of insufficient evidence for the safety and efficacy of antihypertensive drugs at very low levels of blood pressure, and inconsistent evidence from observational studies in patients with known cardiovascular disease. Among various measures of blood pressure, systolic blood pres- sure measured via the brachial artery has been shown to be most strongly associated with CHD risk. Other measures such as dia- stolic blood pressure, pulse pressure, ankle–​brachial blood pres- sure index, and blood pressure measured at the wrist have also been used in epidemiological studies, but are weaker determinants of CHD risk. Mean systolic blood pressure levels have been declining since mid-​1970s in high-​income countries by as much as 3 mm Hg per decade, possibly due to better diagnosis and treatment of cases as well as reduced smoking prevalence and intensity. By contrast, during the past four decades blood pressure levels have remained stable in many developing countries and may have increased in south and southeast Asia, Oceania, and sub-​Saharan Africa. In 2015, global age-​standardized prevalence of hypertension (defined as sys- tolic blood pressure of 140 mm Hg or more, diastolic blood pressure of 90 or more or being on antihypertensive drugs) was 24% in men and 20% in women, leading to an estimated 1.1 billion hypertensive patients worldwide. Fig. 16.13.2.4 shows prevalence of hypertension by country and gender in 2015. Analyses of data from more than 100 prospective observational studies show similar relative risks from different cohorts in Western and Asian populations as well as similar relative risks by gender. However, it is clear that relative risks decline by age, possibly due to higher competing risks by other causes of death or higher baseline CHD risks. Nonetheless, because of high absolute risk of CHD in older people, lowering blood pressure levels in older age groups is expected to have preventive effects similar to those in younger indi- viduals. Pooled analysis of many large prospective studies indicates a 41% higher risk of CHD for each 10 mm Hg higher systolic blood pressure level among individuals 60 to 64 years old. Age-standardised adult prevalence of raised blood pressure Raised blood pressure, men 2015 55% (a) 45% 35% 25% 15% 5% Age-standardised adult prevalence of raised blood pressure Raised blood pressure, Women 2015 55% (b) 45% 35% 25% 15% 5% Fig. 16.13.2.4  Age-​standardized prevalence of hypertension by country and gender in 2015 in men (a) and women (b). Reprinted from The Lancet, Vol 389, NCD Risk Factor Collaboration (NCD-​RisC), Worldwide trends in blood pressure from 1975 to 2015: a pooled analysis of 1479 population-​based measurement studies with 19.1 million participants. 16.13.2  Coronary heart disease: Epidemiology and prevention 3609 Evidence from these observational prospective studies is corrob- orated by many randomized clinical trials of antihypertensive treat- ment, starting from trials of the Veteran’s Affairs healthcare system in the United States in the 1960s. Clinical trials of antihypertensive drugs have also shown that proportional effects are rather similar in different studied patient groups and using different classes of drug. See Chapter 16.17.2 for more details on diagnosis and management of hypertension. Serum lipids Dyslipidaemias are a major risk factor for CHD and are themselves affected by unhealthy diet, alcohol use, physical inactivity, and genetic factors. Early studies of familial hypercholesterolemia and studies by Ansel Keys and others in the 1950s on cross-​country com- parison of CHD rates pointed to the potential role of serum choles- terol in CHD. Subsequently, analysis of data from the Framingham Heart Study and other prospective epidemiological studies indi- cated that high serum cholesterol was indeed positively associated with CHD risk. Separation of subfractions of serum lipids based on their density led to the identification of LDL and high-​density lipo- protein (HDL) particles with opposite associations with CHD risk. In the past three decades, serum total and LDL cholesterol levels have declined in high-​income countries, which back in the 1980s had some of the highest levels observed worldwide. In contrast, serum cholesterol levels have increased in many developing coun- tries, especially in southeast Asia, creating a global convergence in serum total cholesterol levels. Unfortunately, information on trends on LDL is not available in many low-​ and middle-​income countries. As with high blood pressure, evidence from observational studies indicates a continuous increase in CHD risk with serum total chol- esterol levels with no threshold at the commonly used clinical cut-​off of 200 or 240 mg/​dl (5–​6 mmol/​litre). The risk of CHD con- tinues to decline with lower LDL cholesterol levels (about 80 mg/​ dl or 2 mmol/​litre). Pooled analysis of multinational studies shows similar relative risks for dyslipidaemia across different populations, and even in very low-​risk populations such as the Chinese. Although the relationship between cholesterol and risk is not strong in elderly people it remains a major contributor because of their higher abso- lute risk of CHD. Many randomized primary and secondary prevention clinical trials of cholesterol lowering, initially with fibrates and then with statins, support the important role of serum cholesterol in CHD. The results clearly demonstrate the beneficial effects of these drugs, with an estimated 25% reduction in relative risks of coronary events per 1 mmol/​litre reduction in LDL cholesterol, independent of the starting LDL cholesterol level. Initial fears of an increased risk of cancer with use of statins were not substantiated in later studies, but statins seem to increase the risk of diabetes mellitus slightly. Potential beneficial effects of having a higher HDL-​cholesterol are well documented in epidemiological studies. However, Mendelian randomization studies are now suggesting that HDL-​cholesterol may not be causally associated with CHD, and clinical trials that aimed at increasing HDL using niacin, fibrates, or cholesteryl ester transfer protein inhibitors have not been successful in reducing CHD risk. A few large-​scale studies are still underway. Observational studies have also found an association between apolipoproteins (i.e. apoAI and apoB) and lipoprotein-​associated phospholipase A2 with CHD risk. There is also some evidence that levels of non​fasting serum total cholesterol are as predictive as fasting levels for CHD risk. The current evidence on the role of serum triglycerides on CHD is mixed, with some large pooling pro- jects reporting no association between triglycerides and CHD after adjusting for other dyslipidaemias. Obesity Excess body fat (adiposity) has been linked to higher mortality since the first decades of the 20th century. Since then, various measures of adiposity have been used in clinical and epidemiological studies including relative body weight, body mass index (BMI), waist cir- cumference, waist-​to-​hip ratio, weight in water, and measurements of body fat using imaging modalities such as computed tomography (CT) scans. Among these measures, BMI, which ‘standardizes’ body weight to height (by dividing weight in kilograms by the square of height in metres) is most commonly used in epidemiological studies because of its ease of measurement and strong relationship with CHD and other health outcomes. However, it is well known that BMI does not measure fat mass and is a poor measure of adiposity in athletes and in elderly people. Furthermore, BMI does not reflect the distribution of fat in the body, which determines the biological impact of adiposity. For example, abdominal fat may be much more biologically active and therefore harmful than subcutaneous fat, and measures of abdominal obesity such as waist circumference and waist-​to-​hip ratio appear to be better predictors of cardiovascular diseases. The main determinants of adiposity are increased caloric intake and lower physical activity. Less important are changes in body me- tabolism and genetic factors. Almost half of the impact of obesity on CHD is mediated by hypertension, dyslipidaemia, and diabetes. Other factors including low-​grade chronic inflammation and in- creased coagulability are less important mediators. Globally, the number of obese adults has doubled in the past 30 years and obesity, defined as BMI greater than 30 kg/​m2, is on the rise in almost all regions of the world with a global prevalence of about 11% in men and 15% in women (see https://​www.ncdrisc. org). Childhood obesity is rising even faster than adult obesity: in 2015, prevalence of obesity was 5.6% in girls and 7.5% in boys aged 5 to 19 years. Observational epidemiological studies clearly indicate a con- tinuous relationship between BMI and CHD at levels above 25 kg/​ m2 and, in a similar manner to blood pressure and serum choles- terol, there seems to be no threshold value to define obesity. The op- timal levels of adiposity are the current focus of interest in many studies: some have shown risk reduction for CHD to levels as low as 21 kg/​m2; others have shown that the nadir may be higher, at around 23–​25 kg/​m2. Epidemiological evidence on the impact of weight change on CHD (especially weight loss) is mixed, partly due to analytical chal- lenges in separating any beneficial effect of weight loss from the harmful impact of undiagnosed diseases in which weight loss is a feature. Non​randomized studies of bariatric surgery in morbidly obese patients show rapid reversal of physiological changes after surgery, especially diabetes, but these observations may be due to hormonal changes rather than weight loss per se. There is little evidence from randomized clinical trials on the beneficial effect of weight loss in CHD. Clinical trials of diet have often managed to induce weight loss in the first year, but this has not section 16  Cardiovascular disorders 3610 been maintained for a sufficient period to detect a potential benefit. However, weight loss trials do show improvements in metabolic pro- files such as reduced blood pressure and serum cholesterol and im- proved glucose tolerance, which should in principle lead to future reductions in CHD risk. Such lack of evidence for benefits of weight loss increases the importance of preventing weight gain, starting in childhood or early adolescence. Diabetes mellitus Diabetes is a major risk factor for CHD. There has been a substantial increase in the number of patients with diabetes in almost all regions of the world, with a global prevalence of about 10% in adults in 2015. This rise has been partly fuelled by increases in obesity, and hence is expected to continue in the coming decades if current trends in un- healthy diet, urbanization, and physical inactivity continue. Early studies mostly focused on microvascular complications of diabetes and the threshold levels above which the risk of these com- plications sharply increased. These thresholds were then used to set clinical cut-​offs to diagnose diabetes. Recent studies indicate that—​similar to blood pressure, serum cholesterol, and adiposity—​the relative risks for different cardiovas- cular outcomes (when shown on a doubling scale) are linearly asso- ciated with various measures of blood glucose such as fasting plasma glucose, even down to levels below the conventional thresholds used to define diabetes (down to 4.9–​5.3 mmol/​litre) (Fig. 16.13.2.5). The landmark UKPDS study identified a quintet of modifiable risk factors for CHD in non-​insulin-​dependent diabetes mellitus, com- prising HDL and LDL cholesterol, haemoglobin A1C, systolic blood pressure, and smoking. Of these the relative risks were highest for LDL cholesterol and blood pressure. CHD risk in patients with dia- betes may be further refined by the detection of microalbuminuria as a reflection of early endothelial and microvascular damage. The optimal levels of blood glucose for CHD risk are still under debate, partly because several large randomized clinical trials of intensive glucose control among diabetic patients failed to show consistent reduction in risk. Early trials of intensive treatment were not powered to detect a small reduction in CHD risk, and more re- cent trials showed mixed results: some studies indicated increased risk, possibly due to higher age at enrolment or side effects of drugs, including hypoglycaemia, and others did not find an effect, possibly due to use of other preventive drugs in the control groups that re- duced the power to detect any change in the outcomes. Several large randomized trials have shown that modification of lifestyle (such as quitting smoking, weight loss, and a healthy diet) and medical intervention may substantially reduce the risk of dia- betes among high-​risk patients (i.e. obese individuals or those who have borderline high blood glucose). A particular focus of interest in diabetes prevention and control is improving the quality of dietary carbohydrates to include less processed carbohydrates and more whole grains. Another potential preventive intervention is reducing sugar-​sweetened beverage intake, which is associated with higher risk of obesity. Diet quality The evidence on diet quality and CHD has grown substantially in the last few decades and the focus of this line of research has changed from analysis of specific nutrients to foods and dietary patterns. Early epidemiological data identified the Mediterranean diet, which is high in olive oil, cereals, nuts, fruits, and vegetables, and low in animal fat, as protective against cardiovascular disease, and a recent large randomized trial has corroborated this finding. Next, we sum- marize the main evidence on CHD prevention by improving diet quality. Salt Our perception of salt (sodium chloride) has changed from being a common food preservative to becoming one of the main causes of high blood pressure, which is itself the leading risk factor for CHD. Many observational studies have reported a positive association between salt intake and risk of CHD, but some studies have also Fig. 16.13.2.5  Relative risk of stroke and CHD by fasting glucose levels. From Lawes CM, et al. (2004). Blood glucose and risk of cardiovascular disease in the Asia Pacific region. Diabetes Care, 27(12), 2836–​42. 16.13.2  Coronary heart disease: Epidemiology and prevention 3611 reported a lower intake of salt to be associated with higher risk of mortality. This observation may be due to the presence or severity of an underlying chronic disease (e.g. patients with advanced chronic kidney disease or congestive heart failure, which have high mor- tality, may have a low salt intake). Several dozen randomized clinical trials of salt reduction have shown reduction in blood pressure following short-​term feeding interventions that reduce salt intake. In meta-​analyses of these trials, each 2.3 g/​day lower salt intake has been associated with 4–​7 mm Hg reduction in systolic blood pressure, and the effects are larger in older or hypertensive individuals or individuals from particular racial/​ethnic groups (e.g. African Americans). Although a reduction in blood pressure is expected to reduce the risk of CHD and stroke, only the long-​term follow-​up of one of the larger salt reduction trials has shown some reduction in CHD risk. Future large-​scale trials are expected to provide a more definitive answer to the question of the effect of salt reduction on CHD in a range of populations and levels of baseline salt consumption. Salt intake has been stable in the past 20 years in many countries. However, the average global intake (c.10 g/​day) is almost double the level recommended by the World Health Organization (WHO), with some regions such as East and Central Asia, and eastern Europe, having much higher intake levels. The optimal level of salt intake is still highly debated and the most recent recommendations from national guidelines in the United States of America and the United Kingdom suggest 5.8 g/​day. There is some evidence that current ef- forts to reduce salt intake in the United Kingdom may have been re- sponsible for further reductions in CHD risk at the population level, and WHO recommends salt reduction programmes as one of the most cost-​effective ways to prevent CHD. Fat composition The relationship between dietary fat composition and CHD has been one of the major sources of controversy in the field of nu- tritional epidemiology. There is now a consensus that trans fats from hydrogenated oils increase the risk of CHD by increasing LDL cholesterol, and there is strong evidence that substituting sat- urated fats with polyunsaturated fats reduces CHD risk. The rec- ommendation for a low-​fat diet in the 1970s, which was used as a marketing technique by many food manufacturers, was based mostly on ecological studies in the 1960s that had shown a positive correlation between average saturated fat intake and CHD mor- tality across countries, and short-​term feeding studies and animal studies that had shown a rise in serum total cholesterol with higher saturated fat intake. However, more recent reanalyses of the feeding studies and results of prospective studies of diet and CHD showed no increased risk of CHD if saturated fat was substituted by carbohydrates, which could partly be explained by increases in both LDL-​ and HDL-​cholesterol. The importance of polyunsaturated fats (in particular those high in n-​3 and n-​6 fatty acids) was proposed following observa- tional studies in the 1970s that suggested a low incidence of CHD in Greenland and Alaskan Eskimos consuming a diet based on oily cold-​water fish. The beneficial effects could be mediated by the im- pact of polyunsaturated fats on coagulation, platelet and endothelial function, and serum LDL, and HDL composition and levels. The ef- fect of higher intake of polyunsaturated fatty acids in reducing CHD risk is consistent with recent evidence from a large randomized trial which showed lower CHD risk among individuals who received a serving (about 30 g) of nuts every day for 5 years compared with a usual Mediterranean diet. The impact of n-​3 polyunsaturated fatty acids on CHD preven- tion has also been widely studied. Meta-​analyses of observational studies show a protective effect of higher n-​3 intake, with benefi- cial effects for an intake of up to 250 mg/​day. However, the most recent meta-​analysis of randomized trials of n-​3 supplementa- tion did not find any reduction in mortality or risk of myocardial infarction. A recent global analysis of nutritional surveys indicated that be- tween 1990 and 2010 intakes of trans and saturated fatty acids re- mained stable, while those of n-​6 and n-​3 fatty acids increased. However, the current trends in developing countries toward higher intake of animal meat and processed foods which contain high sat- urated and trans fatty acids may well lead to a more harmful impact of fat composition on CHD. Other dietary risk factors Fruit and vegetables Low intake of fruits and vegetables has been linked to higher CHD risk in several prospective observational studies, leading to recom- mendations of at least five daily servings of fruits and vegetables. In the absence of randomized trials that directly evaluate this effect, there is still potential for such associations to be due to confounding by other lifestyle factors. The mechanisms and pathways for such potential effects are not clear, but could include the effects of fruits on increasing potassium intake and therefore lowering blood pres- sure and the potential benefits of fibre, antioxidants, micronutrients, and folate. Red and processed meat The controversy about the effect of fresh red meat intake on CHD continues, but there is ample evidence from observational studies on the harmful effects of processed meat on CHD (which could partly be due to the increased risk of diabetes): each 50 g per day higher intake of processed meat is associated with 44% higher risk of CHD. Folate, B12, and homocysteine There is strong evidence from observational studies that higher serum homocysteine levels are associated with CHD risk. However, randomized clinical trials of folate and vitamin B12 supplementa- tion that reduce serum homocysteine have found mixed results. A large study that used the methylene tetrahydrofolate reductase (MTHFR) gene to examine the effect of lower homocysteine on cardiovascular disease suggested that the observed association is unlikely to be causal. Dietary cholesterol The strong epidemiological data relating serum cholesterol to CHD summarized just now, along with early animal feeding studies, led to many researchers and clinicians recommending lowering dietary cholesterol in patients at risk of CHD. However, the correlation be- tween dietary cholesterol and serum cholesterol is quite weak and there is insufficient evidence on the impact of dietary cholesterol on serum cholesterol levels and risk of CHD. section 16  Cardiovascular disorders 3612 Dairy products There is no evidence that higher dairy intake is associated with CHD risk, possibly due to beneficial effects through blood pressure re- duction being balanced by harmful effects through increased risk of arterial calcification. Similarly, there is no evidence that intake of whole-​fat dairy would increase the risk of CHD. Exercise, fitness, and sedentary lifestyle Physical inactivity is associated with higher risk of CHD. Early studies in the 1960s on London bus conductors and longshoremen in San Francisco (California) found a clear gradient of CHD risk across levels of physical activity. Since then, several dozen obser- vational studies have found a dose–​response relationship with 30–​35% risk reduction for CHD in the most active individuals compared with the least active. This effect is believed to be partly mediated through weight loss as well as reductions in blood pres- sure and better metabolic and lipid profiles. The current preven- tion guidelines recommend at least half an hour of moderate or vigorous activity at least 5 days a week. Vigorous physical activity can also be a trigger for acute myocardial infarction and the overall risk should be balanced when encouraging patients to increase their physical activity. Cardiorespiratory fitness can be considered the consequence of physical activity and is often measured by exercise tolerance testing. A recent meta-​analysis of observational studies reported that each 1 km/​h higher speed of running or jogging is associated with a 15% reduction in risk of CHD. Finally, a new line of research has identified sedentary lifestyle as a risk factor for CHD above and beyond physical inactivity. Each add- itional 2 hours of screen time is linked to 5% higher risk of cardio- vascular events. The associations were weaker but still significant for overall sitting time. Reducing television watching time in children is one of the few interventions that have proved beneficial in control- ling childhood obesity. Alcohol More than 30 observational studies have found beneficial effects of regular and moderate alcohol drinking on CHD risk, and all types of alcohol beverages seem to confer this benefit similarly, the poten- tial mechanism perhaps being by reducing platelet adhesion. Heavy and binge drinking will offset these beneficial effects: higher alcohol intake increases blood pressure and risk of cardiac arrhythmias, and directly damages myocardial cells. In 2015, just over 40% of adults worldwide drank alcohol, with about one-​sixth of drinkers drinking large amounts and therefore not benefiting from potential CHD risk reduction. Massive and rapid changes in alcohol intake were responsible for the largest ob- served increase in CHD mortality in modern times, which hap- pened in Russia in the 1990s. Illicit drugs Among various illicit drugs, cocaine abuse has been clearly identi- fied as a trigger for acute myocardial events. Intake of marijuana also has the biological potential to increase the risk of atherosclerosis and act as a trigger of acute events. There is recent evidence from a large observational study in Iran that opium use may also increase CHD mortality. Sleep duration and quality Insufficient sleep is associated with higher risk of CHD, possibly through its effect on blood pressure as well as systemic inflamma- tion, oxidative stress, and endothelial dysfunction. An extreme example is obstructive sleep apnoea, which is linked to a potential doubling of CHD risk. Psychosocial factors Major depression has been associated with higher CHD risk in ob- servational studies, with the risk increasing by 80% in patients with a history of major depression episode. However, randomized trials of antidepressant treatment among CHD patients have provided mixed results. The role of stress in CHD was initially investigated by identifying ‘character types’ in the Framingham Heart Study in the 1950s. Chronic stress is a clear cause of high blood pressure and acute stress can trigger myocardial events. Evidence from studies con- ducted in the 1960s and 1970s also indicate that chronic stress can increase the risk of death following an acute myocardial infarction. More recently, ‘relaxation response’ has been shown to reduce blood pressure. Various types of psychosocial stress are associated with higher CHD risk. These include acute and chronic stressors and anxiety as well as a sense of deprivation and inequality, social isolation, and poor social support. The landmark Whitehall studies of British civil servants have provided strong evidence that socioeconomic position of an individual is a strong determinant of their CHD risk, possibly through changes in established cardiovascular risk factors such as smoking, hypertension, diabetes, and dyslipidaemia. See Chapter 2.14 for further discussion. Environmental factors The harmful effect of outdoor and indoor air pollution on CHD has been shown in observational studies. Higher concentrations of smaller particles (PM 2.5) is more strongly associated with risk of CHD than larger particles (PM 10). Globally in 2015, 28% of the burden of disease from CHD was attributed to air pollution. In rural areas and developing countries, similar harmful effects have been observed due to burning solid fuels indoors for cooking or heating. See Chapter 10.3.1 for further discussion. Recent evidence has also linked high road traffic noise levels to CHD, possibly through increasing blood pressure. Chronic lead exposure through inhalation (dust or fumes) and ingestion (water, food, cigarettes) has been associated with higher blood pressure, which could itself lead to higher CHD risk. Harmful effects have also been reported for cadmium exposure and high doses of arsenic. HIV and other infections With more successful and accessible HIV treatments, the inter- action between HIV and its treatment with CHD and other car- diovascular diseases has become a novel area of research. It is well known that some antiretroviral drugs increase serum cholesterol levels, the pathophysiology of HIV infection may itself lead to dyslipidaemia, and there is some evidence that effective HIV treat- ment may lead to weight gain. However, the overall impact of long-​ term HIV infection and antiretroviral treatment on CHD remains unknown. 16.13.2  Coronary heart disease: Epidemiology and prevention 3613 Other viral or bacterial infections such as Chlamydophila pneumo- niae, Helicobacter pylori, Cytomegalovirus (CMV) have also been associated with higher CHD risk, but there is currently no strong evidence that such associations are independent of other well-​ known risk factors. Chronic kidney disease There is strong evidence from observational studies that chronic kidney disease increases the risk of CHD, and cardiac disease is the leading cause of death among patients with end stage renal disease. Even minor impairment of renal function (chronic kidney disease stage 3, eGFR 30–​60 ml/​min) has been linked to slightly higher risk of CHD and points to the need for more aggressive management of classic risk factors in these patients. The potential mechanisms are through higher blood pressure levels, dyslipidaemia, anaemia, and increased systemic inflammation. Novel biomarkers Several inflammatory, haemostatic, and coagulation markers have been associated with higher CHD risk. Among these C-​reactive protein, fibrinogen, and interleukin-​6 are the most well-​known. However, there is still insufficient evidence on the exact role of these biomarkers, and hence it is not clear how they may be used to de- sign preventive interventions, but of particular interest is their use in improving risk prediction models and discovery of new therapeutic targets. Gender and genetic influences Gender Despite a lower incidence of myocardial infarction in women com- pared to men, CHD is the most common cause of death in women in most developed countries, and the rate of decline in death from coronary disease has been less for women than for men. The difference in incidence of coronary disease between men and women is not explained by conventional risk factors alone. Although there is no distinct inflection in the incidence of cor- onary disease in women around the menopause, the difference in incidence of CHD has been attributed to the impact of hormonal changes. This concept was supported by theoretical considerations on the impact of oestrogens and progesterone on the vasculature and thrombogenesis, and a meta-​analysis of observational studies suggesting that hormone replacement therapy (HRT) might be protective. The Women’s Health Initiative trial of HRT strongly refuted this hypothesis, finding an increased risk of events (odds ratio 1.29) among women randomized to HRT. Genetic influences Several studies have demonstrated the independent association of family history with the risk of cardiovascular disease, but the ob- served associations tend to add very little to risk discrimination when risk prediction models include other traditional risk fac- tors. Nonetheless, twin and family studies suggest that about half of the susceptibility to CHD is heritable; an effect that is most evi- dent among younger individuals. This observation has sparked nu- merous studies to unravel the genetic basis of CHD. Multiple genome-​wide association studies investigating tens of thousands of common single nucleotide polymorphisms (SNPs) have been reported. These studies have identified about 60 common SNPs that are associated with CHD risk, mainly among individuals from European and South Asian ancestry. This has led to a better understanding of the genetic architecture of CHD and has demon- strated that CHD largely derives from the effect of multiple common SNPs of small effect size, rather than rare variants with large effects. However, the identified SNPs together explain only about 10% of the genetic variance of CHD, partly because many of them contribute to risk through traditional risk factors, such as blood pressure and lipid metabolism. Despite this, the identified SNPs have revealed novel promising drug targets within established risk factor pathways and have identified a few novel pathways such as inflammation that may contribute to the pathogenesis of CHD. However, the relevance of many other genes to CHD remains unknown and subject to ongoing studies. The availability of large-​scale genotyping studies has also facilitated the development of Mendelian randomization studies as a method of assessing causality between a risk factor and an out- come, and these have (for instance) refuted the causal role of HDL-​ cholesterol, homocysteine, and CRP. Although genetic markers, in particular those that show poten- tial new causal pathways, are highly valuable for identification of new molecular targets for prevention and management of CHD, the anticipated clinical utility of genotyping for risk prediction has not (thus far) materialized. This is because conventional risk prediction scores are already relatively good at predicting CHD, questioning the incremental value of costly genotyping. It has been argued that more precise classification of subtypes of CHD is needed to better understand the impact of different mu- tations on the biology and pathophysiology of CHD. Supporting evidence for this line of thinking comes from a study that showed different SNPs to be associated with different manifestations of CHD, with some increasing the risk of coronary atherosclerosis while others are associated with the risk of plaque rupture and acute myocardial infarction. In addition to pathophysiological pathways, the impact of genetic variants may differ by presence or absence of comorbid conditions. In one large-​scale study, the same SNP was as- sociated with a significantly higher risk of CHD among patients with diabetes, but no significant difference in risk of CHD among patients without diabetes was observed. Clusters of risk factors: the metabolic syndrome The concept of metabolic syndrome (syndrome X or insulin re- sistance syndrome) was proposed in the late 1980s to designate a constellation of risk factors for CHD and other atherosclerotic car- diovascular diseases. The idea was that co-​occurrence of several risk factors may be due to common underlying pathophysiological pro- cesses and may confer a level of risk that is larger than the sum of the effect of each risk factor alone. The components of metabolic syndrome include hyperglycaemia, hypertriglyceridaemia, and low HDL levels, high blood pressure, and abdominal obesity. Some studies have found that the patients with metabolic syndrome have twice as high a CHD risk compared with individuals with no risk factor. However, others have argued based on similar analyses in different settings that the ‘syndrome’ may just be a co-​occurrence of a subset of cardiovascular risk factors and not an entity by itself. Irrespective of these debates, many clinicians continue to use this section 16  Cardiovascular disorders 3614 term to alert others of the presence of the cluster of risk factors in an individual. Combining risk factors to predict and manage risk in individuals Successful and cost-​effective prevention of CHD requires identifica- tion of high-​risk individuals who would benefit more from risk re- duction. One way of identifying high-​risk individuals is to measure their risk factor levels and use clinical thresholds for each risk factor separately to designate a high-​risk status (e.g. hypertensive or dia- betic). This approach has been used in the past 50 years and is still the method commonly proposed by clinical guidelines used by clin- icians. However, as just summarized, CHD is a multifactorial disease and most risk factors increase CHD even at levels well below the conventional thresholds used to define high-​risk status. Generally, single risk factors are rarely accurate enough in predicting future risk for individuals. For example, for a binary risk marker to provide good discrimination between those who will suffer an event from those who will not, the odds ratio of that marker with the outcome would need to be greater than about 9, which is not the case for any single risk factor described here. Therefore, to predict an individual’s risk one must combine the information on levels of the most im- portant risk factors. A common way of doing this is to use a risk pre- diction score. Most risk prediction scores combine CHD and stroke to provide a predicted risk for overall cardiovascular disease (CVD). The most well-​known risk score is the Framingham Risk Score, which is based on the analysis of the Framingham Heart Study co- hort in Massachusetts (United States). Each risk score is a com- bination of a ‘baseline’ or average risk and a set of coefficients for different risk factors that predict how each individual deviates from that average risk based on how much their risk factor levels deviate from mean risk factor levels in the target population. To apply a risk score to a new population, the average risk and mean risk factor levels must be recalibrated to correspond to the target population; otherwise the risk score will be biased. Most risk scores use information on the major CVD risk factors such as smoking, blood pressure, serum cholesterol, and diabetes. Others include socioeconomic factors and family history of heart disease as well. Although risk prediction scores, even when based on a few simple risk factors, are usually more accurate in estimating risk than indi- vidual risk factors or a qualitative summary of several risk factors by clinicians, their performance is still far from ideal. For those in- dividuals classified as having an intermediate level of risk, different risk scores may provide different results, hence many researchers are focusing on identifying new risk factors or risk markers that can help improve the performance of prevailing models that are based on traditional risk factors. Several potentially useful novel risk fac- tors are summarized earlier in the chapter, of which inflammatory markers have had the greatest potential in improving the predictive value of risk scores. In addition to the risk factors already men- tioned, several other biomarkers have been evaluated. For instance, blood B-​type natriuretic peptide levels or different types of vascular imaging (carotid intima-​media thickness and coronary calcium scoring) have shown some promising results. Further research is underway to establish the value of such markers to subgroups of pa- tients and healthcare systems. Most risk scores provide an approximate 10-​year risk of CHD or CVD risk and clinicians can then use this information, along with current clinical guidelines, to propose a prevention strategy for each patient. Primary intervention (i.e. for patients without pre-​existing diagnosis of vascular disease) is based on a threshold of risk. One example, the Globorisk chart (Fig. 16.13.2.6) uses age, gender, smoking, diabetes, systolic blood pressure, and serum total choles- terol to predict 10-​year risk of fatal and non​fatal CVD for 187 coun- tries worldwide. An office-​based version estimates the same risk using BMI instead of diabetes and serum cholesterol, allowing risk prediction in resource-​poor settings with limited access to a labora- tory. Most national and international guidelines recommend that individuals with a 10-​year risk of fatal or non​fatal CVD greater than 20% should be offered lifestyle advice and specific treatment for in- dividual risk factors. Use of these risk charts in conjunction with guidelines for treatment of hypertension (see Chapter 16.17.2) and other modifiable risk factors will guide priorities in drug therapy. Likely future developments Several risk factors have been shown to be significantly associated with future risk of CHD and a few of these, largely through random- ized trials, are known to cause CHD. Although new research into new CHD risk factors is likely to help identify new molecular targets for its prevention and manage- ment, the shorter-​term advantage that such new markers offer is an increasing accuracy in the estimation of CHD risk and treatment benefits. Large-​scale observational studies investigating the utility of new biomarkers, both phenotypic and genotypic, will help improve the accuracy of existing risk scores. This, combined with random- ized evidence (e.g. from large individual patient data meta-​analyses), will provide more granular information about the safety and efficacy of specific interventions in specific subgroups of patients. The com- bination of better risk prediction and better estimation of treatment effects in subgroups of patients is expected to lead to ‘personalized prevention’, where those with the greatest risk and greatest potential benefit of treatment will be offered an intervention. However, the challenge of maximizing benefits of preventive therapies for individ- uals as well as societies will not be solved by developing better risk scores and risk management algorithms alone. Previous research suggests that cardiovascular risk prediction models are not widely used, partly because many clinicians find risk calculation too time-​consuming and remain unconvinced of the pre- dicted risk. Automated data capture systems and better techniques for risk visualization may minimize clinician burden and facilitate communication of risks and uncertainties to patients and their fam- ilies. Similar tools could also make information directly accessible to patients and therefore increase their engagement, as well as that of their healthcare providers. Ultimately, a scenario could be envisaged in which there is seamless linkage between data capture, risk and benefit estimation, and clinical guidelines, resulting in the routine provision of personalized guidance for care that is both evidence-​ based and cost-​effective. However, given that the introduction of such innovative models in complex healthcare environments can have multiple intended and unintended effects, appropriately de- signed studies are needed to evaluate the actual effects of such system changes before more general recommendations are made. 16.13.2  Coronary heart disease: Epidemiology and prevention 3615 Fig. 16.13.2.6  Globorisk chart: 10-​year risk of fatal or nonfatal coronary heart disease or stroke in the United Kingdom, calculated using the following risk factors: age, gender, smoking, systolic blood pressure, and total cholesterol. Reprinted from The Lancet Diabetes and Endocrinology, Vol. 5, Ueda P, et al., Laboratory-​based and office-​based risk scores and charts to predict 10-​year risk of cardiovascular disease in 182 countries: a pooled analysis of prospective cohorts and health surveys, pp. 196–​213, Copyright 2017, with permission from Elsevier. 16.13.3 Management of stable angina 3616 Adam D. T 16.13.3 Management of stable angina 3616 Adam D. Timmis section 16  Cardiovascular disorders 3616 FURTHER READING Danaei G, et al. (2010). The promise of prevention: the effects of four pre- ventable risk factors on national life expectancy and life expectancy dis- parities by race and county in the United States. PLoS Med, 7, e1000248. Deloukas P, et  al. (2013). Large-​scale association analysis identifies new risk loci for coronary artery disease. Nat Genet, 45, 25–​33. Di Angelantonio E, et al. (2009). Major lipids, apolipoproteins, and risk of vascular disease. JAMA, 302(18), 1993–​2000. Di Cesare M, et al. (2013). The contributions of risk factor trends to cardiometabolic mortality decline in 26 industrialized countries. Int J Epidemiol, 42(3), 838–​48. Doll R, Peto R, Boreham J, Sutherland I (2004). Mortality in relation to smoking: 50 years’ observations on male British doctors. BMJ, 328(7455), 1519. Ezzati M, Riboli E (2013). Behavioral and dietary risk factors for noncommunicable diseases. NEJM, 369, 954–​64. Ford ES, Caspersen CJ (2012). Sedentary behaviour and cardiovascular disease: a review of prospective studies. Int J Epidemiol, 41, 1338–​53. Jousilahti P, et al. (2016). Primary prevention and risk factor reduction in coronary heart disease mortality among working aged men and women in eastern Finland over 40 years: population based observa- tional study. BMJ, 352, i721. Lopez AD, Adair T (2019). Is the long-term decline in cardiovascular- disease mortality in high-income countries over? Evidence from na- tional vital statistics. Int J Epidemiol, pii: dyz143, doi: 10.1093/ije/dyz143. Lu Y, et al. (2014). Metabolic mediators of the effects of body-​mass index, overweight, and obesity on coronary heart disease and stroke: a pooled analysis of 97 prospective cohorts with 1.8 million partici- pants. Lancet, 383(9921), 970–​83. Marmot MG, et al. (1991). Health inequalities among British civil ser- vants: the Whitehall II study. Lancet, 337(8754), 1387–​93. McPherson R, Tybjaerg-​Hansen A (2016). Genetics of coronary artery disease. Circ Res, 118(4), 564–​78. Moore SC, et al. (2012). Leisure time physical activity of moderate to vigorous intensity and mortality: a large pooled cohort analysis. PLoS Med, 9(11), e1001335. Mozaffarian D, et al. (2010). Effects on coronary heart disease of increasing polyunsaturated fat in place of saturated fat: a systematic review and meta-​analysis of randomized controlled trials. PLoS Med, 7, e1000252. Mozaffarian D, et al. (2014). Global sodium consumption and death from cardiovascular causes. N Engl J Med, 371(7), 624–​34. Rahimi K, Emdin CA, MacMahon S (2015). The epidemiology of blood pressure and its worldwide management. Circ Res, 116(6), 925–​36. Rose G (1985). Sick individuals and sick populations. Int J Epidemiol, 14(1), 32–​8. Roth GA, et al. (2015). Global and regional patterns in cardiovascular mortality from 1990 to 2013. Circulation, 132(17), 1667–​78. Zhao D, et al. (2019). Epidemiology of cardiovascular disease in China: current features and implications. Nat Rev Cardiol, 16, 203–12. 16.13.3  Management of stable angina Adam D. Timmis ESSENTIALS Angina—​the pain provoked by myocardial ischaemia—​is usually caused by obstructive coronary artery disease that is sufficiently severe to restrict oxygen delivery to the cardiac myocytes. Quality of life is impaired in direct proportion to the severity of symptoms. Clinical history remains the most useful basis for diagnosis and referral decisions to specialist services, the commonest indications being (1) new-​onset angina; (2) exclusion of angina in high-​risk indi- viduals with atypical symptoms; (3) worsening angina in a patient with previously stable symptoms; (4) new or recurrent angina in a patient with history of myocardial infarction or coronary revascularization; (5) assessment of occupational fitness (e.g. airline pilots). Investigation—​cardiac investigation is usually unnecessary in ­patients with non​anginal chest pain, but residual diagnostic uncer- tainty can be resolved in those with atypical or typical angina by CT coronary angiography, which is now the non​invasive test of choice. Medical treatment of angina involves (1) dealing with exacerbating comorbidities; (2)  secondary prevention by lifestyle modification (smoking cessation, exercise training, Mediterranean-​style diet, and so on) and drugs (aspirin, statins, and so on); (3) antianginal drugs (most com- monly β-​blockers, calcium channel blockers, and short-​acting nitrates). Patients with continuing moderate or severe stable angina des- pite optimal medical treatment should undergo invasive coronary angiography, particularly if they are identified as being at high risk on non​invasive testing. In symptomatic patients, revascularization is generally indicated if one or more of the major coronary arteries—​ or their large branches—​have flow-​limiting stenoses (>70% luminal narrowing) or occlusions. Percutaneous coronary intervention and coronary artery bypass grafting produce comparable symptomatic benefit. With regard to life expectancy, percutaneous coronary inter- vention does not produce survival benefit in patients with stable angina. By contrast, studies more than 40 years ago showed that cor- onary artery bypass grafting produced small gains in life expectancy in some patients. With current management strategies, patients with angina are living longer, but a few remain symptomatic with poor quality of life despite optimal medical treatment and having exhausted revascularization options. Psychological support is important to treat anxiety and depression and improve confidence, but other treatment options such as neuromodulatory techniques are not evidence-​ based and do not have guideline recommendations. Introduction Angina—​the pain provoked by myocardial ischaemia—​is usually caused by obstructive coronary artery disease that is sufficiently severe to restrict oxygen delivery to the cardiac myocytes (Box 16.13.3.1). It is one of the most common initial manifestations of coronary artery disease and occurs with almost equal frequency in women and men. Recent UK data indicate that, like other manifestations of coronary artery disease, the incidence of angina is declining. When angina occurs in patients without coronary artery disease it may be attributable to other ischaemic mechanisms such as se- vere anaemia resulting in inadequate oxygen delivery to the cardiac myocytes, or left ventricular hypertrophy secondary to hypertension or aortic stenosis resulting in increased oxygen demand. The appro- priately named syndrome X is a diagnosis of exclusion in patients with angina for which there is no clear cause despite full cardiac investigation: their coronary arteries are not obstructed; abnormal microvascular function is one proposed mechanism. Syndrome X 16.13.3  Management of stable angina 3617 is more common in women than in men, and symptoms are often resistant to treatment. Prognosis is usually good although some studies have shown a small increase in the risk of myocardial infarc- tion and death. In most patients with angina caused by coronary artery dis- ease, quality of life is impaired in direct proportion to the severity of symptoms (Fig. 16.13.3.1). Prognosis is often good, particularly in patients with chronic stable symptoms receiving contemporary secondary prevention therapy, but in those with recently diagnosed angina risk is greater, with a 2 to 3% incidence of death or non​fatal myocardial infarction in the first year. Recognition of the need for early investigation has led to the widespread implementation of chest pain clinics in the United Kingdom and elsewhere to provide patients with suspected angina prompt treatment to relieve symp- toms and reduce risk. Referral for specialist assessment Referral for specialist assessment (Box 16.13.3.2) is indicated in all patients with known coronary artery disease—​particularly those with previous myocardial infarction or coronary revascularization—​ who experience abrupt worsening of symptoms, often indicating plaque rupture and risk of impending infarction. However, referral decisions may be more difficult in patients presenting for the first time with chest pain. A  non​cardiac diagnosis accounts for most cases, but it is the task of the primary care or general physician to ensure that all those with suspected angina receive specialist as- sessment for confirmation of the diagnosis and risk stratification to identify those at greatest risk who need more intensive treatment. As in any screening process, false-​negative diagnoses in which patients receive inappropriate reassurance must be avoided. By contrast, a proportion of false-​positive diagnoses and referrals is acceptable, and among patients referred from primary care to chest pain clinics 75% have a non​cardiac diagnosis. In primary care, the diagnosis of angina is based largely on the character of the symptoms and the age and sex of the patient, other risk factors further helping to identify those with a high prob- ability of coronary artery disease (see next). Access to non​invasive diagnostic tests can be helpful in primary care or the non​specialist clinic, but there is often insufficient recognition of their limita- tions: the exercise ECG (for example) has a diagnostic sensitivity of only about 68%, which means that up to one-​third of all cases with coronary disease are missed. For this reason, the clinical history remains the most useful basis for diagnosis and referral decisions. Thresholds for referral should be lowered in high-​risk patients, including those with previous myocardial infarction and diabetes, and also in airline pilots and public service drivers whose occupa- tions might put others at risk in the event of myocardial infarction or sudden death. The recommendation that all patients with suspected angina be referred for specialist assessment leaves little room for prevarica- tion. Yet studies repeatedly show inequitable management of pa- tients with chest pain, those with the greatest need often being the very patients who receive the least intensive treatment. Thus, elderly patients with chest pain are at heightened risk, but are less likely than their younger counterparts to receive referral to chest pain clinics. Women are also disadvantaged and are less likely than men to be referred, even though it is increasingly recognized that angina in women is almost as common as in men and prognosis little better (Fig. 16.13.3.2). The reasons for this inequity are com- plex and poorly understood, but the consequences for healthcare are important. Box 16.13.3.1  Causes of angina Reduced myocardial oxygen supply • Coronary artery disease — Atherosclerosis — Spasm — Vasculitic disorders — Post radiation therapy • Severe anaemia Increased myocardial oxygen demand • Left ventricular hypertrophy — Hypertension — Aortic stenosis — Aortic regurgitation — Hypertrophic cardiomyopathy • Right ventricular hypertrophy — Pulmonary hypertension — Pulmonary stenosis • Rapid tachyarrhythmias Indeterminate mechanism • Syndrome X baseline 2 years expected % of life aspects affected Angina grade 0 0 10 20 30 40 50 60 1 2 3 4 3–4 Fig. 16.13.3.1  Effect of angina on quality of life. Data are at baseline and 2 years after randomization in the Randomized Intervention Treatment of Angina (RITA) trial, showing impact of angina on life aspects encoded in part 2 of the Nottingham Health Profile. Note how quality of life deteriorates rapidly with worsening angina. Reprinted from Pocock SJ, Henderson RA, Seed P, Treasure T, Hampton JR (1996). Quality of life, employment status, and anginal symptoms after coronary angioplasty or bypass surgery. 3-​year follow-​up in the Randomized Intervention Treatment of Angina (RITA) Trial. Circulation, 94(2), 135–​42. Box 16.13.3.2  Angina—​indications for specialist cardiological referral • New-​onset angina • Exclusion of angina in high-​risk individuals with atypical symptoms • Worsening angina in a patient with previously stable symptoms • New or recurrent angina in a patient with history of: — Myocardial infarction — Coronary revascularization • Assessment of occupational fitness (e.g. airline pilots) section 16  Cardiovascular disorders 3618 Clinical evaluation Angina varies considerably in its clinical presentation and its overlap with other entities can make the differential diagnosis of stable chest pain difficult. In most patients it is a manifestation of coronary ar- tery disease and the diagnostic challenge, therefore, is to determine whether the patient with chest pain has flow-​limiting coronary ob- structions. A detailed description of the symptom complex is the most important step in the diagnostic process and in the context of other factors, particularly age, sex, and coronary risk factors, allows the clinician to estimate the likelihood of coronary artery disease. The extent of work-​up required to exclude a non​cardiac cause needs to be individually determined. The diagnosis is informed by the clinician’s intuition, experience, and interviewing skills, supported by investiga- tions such as the resting ECG and other non​invasive tests. A careful history provides the most useful diagnostic informa- tion, with three key characteristics defining anginal chest discom- fort (Fig. 16.13.3.3). Character—​angina is experienced as a constricting discomfort across the front of the chest, often radiating to arms, throat, or jaw and lasting 5–​15 minutes. Provocation—​angina is nearly always provoked by exertion and sometimes by emotional stress. Relief—​angina is relieved promptly by rest or short-​acting nitrates. The presence of all three characteristics describes ‘typical angina’ while the presence of any two describes ‘atypical angina’. In patients with just one or none of these key characteristics, chest pain should be described as ‘non​anginal’. Angina is often worse in the morning, shortly after getting up, probably because catecholamine levels and blood pressure peak at this time of day. For similar reasons angina tends to be worse in cold weather and also after a heavy meal. In addition to typ- icality of symptoms and age and sex diagnosis is also influenced by a family history of premature coronary artery disease and by other risk factors—​particularly diabetes, smoking, hypertension, dyslipidaemia, and advanced chronic kidney disease. Despite the reliance on clinical history in making a diagnosis of angina, it can be misleading, with atypical features, such as exertional dyspnoea in the absence of chest pain. Atypical presentations are said to be more common in patients with diabetes but, contrary to popular belief, there is little evidence that this also applies in women and South Asian people. The physical examination is often normal in the patient with an- gina but may contribute to diagnosis if signs of major risk factors are identified, particularly hypertension, cutaneous manifestations of dyslipidaemia, and complications of diabetes such as retinopathy and neuropathy. Patients with signs of peripheral vascular disease (e.g. absent pulses, arterial bruits) have associated coronary involve- ment in most cases. Nitrate prescription angina (n>90 000) Test positive angina (n>27 000) Coronary mortality compared with sex-specific general population Lower 0.5 CI indicates confidence interval. 1.0 Coronary SMR 10 Higher Women Men Age group, y Sex 45–54 Women Men 55–64 Women Men 65–74 Women Men 75–84 Women Men 85–89 Women Men 45–54 Women Men 55–64 Women Men 65–74 Women Men 75–84 Women Men 85–89 Women Men Fig. 16.13.3.2  Prognosis of angina in women and men. Primary care electronic records for Finland linked with mortality data have permitted estimation of the prognosis of angina for men and women, presented here as standardized mortality ratios. Two mutually exclusive case definitions of angina were used based on nitrate prescription and test positivity, yielding over 90 000 and more than 27 000 cases, respectively. The data show that the contemporary prognosis of angina is not always good and at all ages is similar for men and for women. SMR, standardized mortality ratio. Reprinted from Hemingway H, McCallum A, Shipley M, Manderbacks K, Martikainen P, Keskimaki I (2006). Incidence and prognostic implications of stable angina pectoris among women and men. JAMA, 295, 1404–​11. 16.13.3  Management of stable angina 3619 Simple laboratory investigations may also contribute to diagnosis by identifying groups at heightened risk of coronary disease due to renal dysfunction, dyslipidaemia, or diabetes. Anaemia is also im- portant to document because it may cause or—​more commonly—​ exacerbate myocardial ischaemia. Non​invasive investigation Non​invasive testing is used primarily for diagnosis of coronary ar- tery disease, but also has a role in risk assessment (see next). By trad- ition, nearly all patients presenting with chest pain have an ECG, although it is of limited diagnostic value. Many patients with angina have a normal recording, although pathological Q waves reflecting previous myocardial infarction and regional ST-​segment or T-​wave changes show variable association with coronary disease. Other features of the ECG of potential relevance include tachycardia—​ particularly in patients with atrial fibrillation—​and evidence of left ventricular hypertrophy, either of which may cause or exacerbate myocardial ischaemia. Indications for non​invasive testing, based on Bayesian principles, are guided by the level of diagnostic uncertainty following the clin- ical assessment. A 25-​year-​old with transient stabbing pains in the left side of the chest unrelated to exertion, for example, has non-​ anginal symptoms and a positive non​invasive test would not modify that diagnostic judgement. All non​invasive tests may provide false-​ positive results with little incremental diagnostic value when the probability of coronary disease based on clinical assessment is very low. It is partly for this reason that contemporary NICE guidelines recommend no diagnostic testing in patients with non​anginal chest pain, unless the ECG shows changes suggestive of underlying cor- onary artery disease such as pathological Q waves or ischaemic ST-​ segment or T-​wave changes. By contrast, diagnostic uncertainty is greater in patients with typical or atypical chest pain, contemporary diagnostic models predicting an intermediate probability of coronary artery disease between 10% and 90%, regardless of age and gender. Guidelines therefore recommend non​invasive testing because the results, positive or negative, can help resolve diagnostic uncertainty and contribute to appropriate further management. The choice of non​invasive test has been the subject of much recent debate, with US guidelines favouring the exercise ECG and ‘func- tional’ imaging tests, while the UK’s 2016 NICE guideline update, based on cost-​effectiveness analysis, favours ‘anatomical’ imaging by computed tomography coronary angiography (CTCA) (Fig. 16.13.3.4). The European guideline also favours CTCA if the pretest probability of disease is low (<50%), but functional imaging tests are preferred if the probability is higher. The exercise ECG and functional imaging tests all seek to deter- mine if regional myocardial ischaemia can be induced by exertional or pharmacological (e.g. dobutamine) stress (Fig. 16.13.3.5). Induction of ischaemic changes is considered to be diagnostic of ob- structive coronary artery disease. Anatomical testing by CTCA, on the other hand, provides angiographic images of the coronary cir- culation and direct evidence of obstructive disease. The diagnostic value of CTCA tends to be higher than functional imaging tests, with sensitivity and specificity greater than 90% in most studies. Nevertheless, it should be recognized that none of non​invasive tests used in the diagnosis of angina is perfect, with all variably prone Take a history Physical examination (Routine investigation) • Identify risk factors for CVD • Identify signs of other CVD • Identify noncoronary causes of angina (eg severe aortic stenosis) • Exclude other causes of chest pain • Blood tests to rule-out conditions exacerbating anfina eg anaemia • Associated symptoms • Characteristics of chest pain • Age and sex • Cardiovascular history – – – • Cardiovascular risk factors • 12-lead ECG–changes consistent with coronary disease – Pathological Q waves – Left bundle branch block – Regional ST/T change Clinical diagnosis driven mainly by the characteristics of chest pain Central, lasting about 5–15 minutes Provoked by exertion or emotional stress Relieved promptly by rest or nitrtates NONANGINAL PAIN ≤1 characteristic ATYPICAL ANGINA 2 characteristics TYPICAL ANGINA all 3 characteristics Fig. 16.13.3.3  Clinical diagnosis of angina. Reproduced from Heart, Timmis A, Roobottom CA, vol. 103, pp. 982–​6, copyright 2017, with permission from BMJ Publishing Group Ltd. section 16  Cardiovascular disorders 3620 to delivery of false-​positive or false-​negative results. Partly for this reason, underdiagnosis of angina is quite common, and patients in chest pain clinics reassured with a diagnosis of non​cardiac chest pain account for up to one-​third of myocardial infarctions and coronary deaths during the next 5 years. Overdiagnosis is also common, as re- flected in the large and increasing proportion of patients with chest pain referred for cardiac catheterization and found to have unob- structed coronary arteries. Exercise ECG Once widely used for diagnosis of coronary artery disease, ex- ercise ECG testing is now giving way to the newer generation of noninvasive diagnostic tests described next. Details are described in Chapter 16.3.1. The sensitivity and specificity of the exercise ECG is 68% and 77%, respectively, with diagnostic value tending to be lower in women than in men. The regional development of planar or down-​sloping ST-​segment depression, with gradual recovery when exercise stops, is usually diagnostic when associated with typical chest pain. The exercise ECG may also provide prognostic information: low exercise tolerance, ST depression early during exercise, an exertional fall in blood pressure, or exercise-​induced ventricular arrhythmias all point to an increased risk of myocardial infarction or sudden death. The Duke treadmill score, which takes into account dur- ation of exercise, degree of ST-​segment deviation, and angina pro- vides a quantitative prognostic assessment and has proved useful for determining the urgency of coronary arteriography. Isotope perfusion imaging This is also widely used for diagnostic purposes and, although more costly and time-​consuming than the exercise ECG, has enhanced diagnostic accuracy (sensitivity 80–​90%, specificity about 80%). Details are described in Chapter 16.3.3. Fixed defects, present at rest and during stress, indicate areas of myocardial infarction, but re- versible defects are indicative of ischaemia in patients with angina. Isotope perfusion imaging also provides useful prognostic in- formation, the extent and severity of perfusion defects (fixed or re- versible), the degree of lung uptake of radioisotope (reflecting level of pulmonary capillary pressure), and the calculated ventricular volume and ejection fraction all predicting risk of future events. Cardiac magnetic resonance (CMR) perfusion imaging This has an important role in the investigation of patients with sus- pected angina. First-​pass perfusion imaging with gadolinium offers high levels of diagnostic accuracy (sensitivity c.90%, specificity Central chest discomfort lasting 5–15 minutes Provoked by exertion or emotional stress Relieved by rest or nitrates No diagnostic testing Diagnostic testing • ≥64-slice CTCA for all patients • Functional imaging if CTCA is non- diagnostic Typica anginal All 3 characteristics A typical angina 2 characteristics Pretest probability of obstructive coronary disease 10–90% refer directly for diagnostic testing Nonanginal pain ≤1 characteristics Clinical assessment Fig. 16.13.3.4  NICE guideline (2016 update) for investigation of chest pain. Angina Ischaemic ST depression Global LV dysfunction Regional systolic dysfunction Regional diastolic dysfunction Perfusion abnormality Normal LV function Perfusion imaging LV wall motion analysis Increasing myocardial oxygen demand Electrocardiography Clinical assessment Increasing exercise Fig. 16.13.3.5  Diagnosis of angina: functional testing for coronary artery disease. Functional tests are designed to identify evidence of regional ischaemia induced by exercise or drugs. Abnormalities of perfusion, left ventricular (LV) wall motion or electrical repolarization can all be detected by imaging or ECG monitoring. Ischaemia may also cause angina, emphasizing the importance of the clinical history in the diagnostic process. 16.13.3  Management of stable angina 3621 80%) for detection of myocardial ischaemia. Although unable to provide the same coronary anatomical definition as CT or conven- tional angiography, it also provides additional prognostic informa- tion about ventricular volumes, ejection fraction, and the extent of myocardial infarction, which combine to predict risk of future events. The identification of viable and hibernating myocardium with CMR may be used to guide revascularization strategies. Stress echocardiography This is used increasingly for diagnostic purposes in patients with suspected angina, but is more dependent than other non​invasive tests on the technical and interpretive skills of the operator. Details are described in Chapter 16.3.2. In expert hands the sensitivity and specificity are around 80% for diagnosing coronary artery disease in patients with suspected angina. Left ventricular imaging during dobutamine infusion permits assessment of regional wall motion in response to adrenergic stress, with decreasing systolic wall motion or wall thickening indicating ischaemia and the likelihood of cor- onary artery disease. CT coronary angiography (CTCA) This is emerging as the non​invasive imaging test of choice for many patients with suspected angina (Fig. 16.13.3.6). Modern scanners provide high quality angiographic images of the epicardial cor- onary arteries, with diagnostic sensitivity of around 95% reflecting the very low rate of false-​negative findings. This makes CTCA ideal for ruling out coronary artery disease, current European guidelines recommending its application in all patients with a probability of coronary artery disease between 10% and 50%. Specificity is also high compared with other imaging modalities, and based on a cost-​ effectiveness analysis the NICE guideline now recommends CTCA as the non​invasive imaging test of choice for patients with typical or atypical angina. All such patients have an intermediate probability of coronary artery disease between 10% and 90% according to con- temporary diagnostic models and stand to benefit from non​invasive testing to resolve diagnostic uncertainty. The effectiveness of CTCA for identifying patients with ob- structive coronary artery disease is confirmed by the enhanced diagnostic yield of invasive coronary arteriography in patients selected by prior CTCA instead of other non​invasive diagnostic tests. CT imaging also provides information about the arterial wall, particularly the severity and distribution of coronary cal- cification which relates to the severity of coronary atheroscler- osis. Nevertheless, some cautions about the clinical application of CTCA need to be acknowledged. Image quality and image in- terpretation may be adversely affected by obesity, high coronary calcium burden, cardiac arrhythmias, and tachycardia, although improvements in scanner technology have helped mitigate these factors (see Chapter 16.3.3) Risk assessment of angina Recent clinical trials of patients with chronic angina show that ag- gressive treatment under cardiological supervision reduces risk considerably such that long-​term prognosis is good, with all-​cause mortality rates of about 1.5% per year. However, prognosis is worse in cohorts attending chest pain clinics in the early weeks or months after symptom onset, with mortality rates in excess of 3% in the first year. Identification of high-​risk patients is therefore an important part of the initial assessment to inform decisions about the urgency and aggressiveness of treatment in individual cases. Clinical indicators of risk As with diagnosis, it is the clinical assessment that provides the most useful prognostic information in angina. Risk is greatest in patients who are old, those with typical symptoms and—​contrary to con- ventional wisdom—​those with more severe symptoms. Women and South Asians with angina do not appear to be at greater risk. Risk increases with the number of ‘reversible’ risk factors, particularly diabetes, smoking, hypertension, and dyslipidaemia, all of which are important targets for treatment. Risk is also increased in pa- tients with a history of myocardial infarction or stroke. Tachycardia is associated with increased risk, although treatment to slow the heart rate is directed primarily at preventing exertional ischaemia. Heart failure increases risk substantially. The most useful laboratory markers of risk are blood concentrations of lipids (particularly low-​ density lipoprotein (LDL) cholesterol and apolipoproteins), glycated haemoglobin, and creatinine. Cardiac troponin concentration, widely used for diagnosis of myocardial infarction, has more re- cently been identified as an independent predictor of risk in angina. Non​invasive testing for risk assessment Generally speaking, negative test results indicate a good prognosis and a low level of urgency for further invasive investigation. However, when test results suggest severe and extensive ischaemia, risk is often high with important implications for future management. Risk scores Many scores have been developed for determining cardiovascular risk in healthy populations and in patients with acute myocardial in- farction. Scores are also available for risk assessment in patients with suspected angina and in patients with an established diagnosis of chronic stable angina, based on many of the clinical and laboratory Fig. 16.13.3.6  Non​invasive coronary angiography by MDCT (multidetector CT). The right coronary artery (arrowed) is patent but has localized areas of dense calcification in its proximal and mid segments denoting atherosclerosis. section 16  Cardiovascular disorders 3622 variables described here, plus echocardiographic measurement of left ventricular function. As yet, angina risk scores have not found major application in clinical practice. Invasive testing for risk assessment In patients with angina, risk of myocardial infarction and cardio- vascular death is related to the extent and severity of angiographic coronary artery disease. Risk is particularly high when obstructive disease (luminal stenosis >50%) affects all three of the major cor- onary arteries. In patients with left main coronary artery disease, death is inevitable in the event of left main occlusion and urgent revascularization is usually recommended. Novel biomarkers A range of inflammatory markers, including C-​reactive protein, have been assessed in stable patients with coronary artery disease, but their incremental predictive value for future coronary events is very low once conventional risk factors have been taken into account. Brain natriuretic peptide may be more useful in this group of patients, although currently its main clinical application is in the diagnosis of heart failure. Circulating concentrations of troponin I or T measured with high sensitivity assays have also been shown to identify high-​risk subgroups in patients with stable angina. Treatment of angina The purpose of treatment is to correct symptoms and reduce risk, thereby improving both the quality of life and its duration (Fig. 16.13.3.7). General measures Comorbidities that exacerbate angina include anaemia, obesity, and thyrotoxicosis, all of which need treating. Most important, how- ever, is hypertension, which increases myocardial oxygen demand in proportion to its severity. Simple lowering of blood pressure will often correct angina without the need for additional symptomatic treatment. Atrial fibrillation is also important because it is common, particularly in elderly patients, and increases myocardial oxygen de- mand due to tachycardia. Symptom relief can often be achieved by heart rate control or cardioversion. Aortic stenosis is another cause of angina that can be corrected by valve replacement. Secondary prevention The risk of myocardial infarction, stroke, and cardiovascular death can be reduced by lifestyle modification and specific drug therapy. Logic also requires that major atherogenic risk factors—​particularly diabetes, smoking, hypertension, and dyslipidaemia—​are treated vig- orously in patients with angina, evidence for risk reduction being best for blood pressure control, smoking cessation, and LDL cholesterol reduction. Strict glycaemic control in type 2 diabetes, provides some protection against ischaemic end-points and the recently introduced sodium glucose co-transporter (SGLT-2) inhibitors and glucagon-like peptide (GLP-1) agonists seem particularly promising in this respect. Lifestyle modification Evidence-​based recommendations are for smoking cessation, ex- ercise training, and a Mediterranean-​style diet characterized by low intake of total and saturated fats and increased intake of fresh fruits and vegetables, and cereals rich in fibre, antioxidants, min- erals, vegetable proteins, and B-​group vitamins. Weight reduction in Fig. 16.13.3.7  Management of angina (NICE 2011). 16.13.3  Management of stable angina 3623 obese patients is also recommended, particularly those with hyper- tension, dyslipidaemia, or diabetes. Secondary prevention drugs All patients with angina should receive aspirin 75–​150 mg daily, its antiplatelet activity reducing the thrombotic response to plaque rupture and protecting against myocardial infarction and stroke. Patients intolerant of aspirin despite proton pump inhibition should be treated with a P2Y12 receptor antagonist (clopidogrel, prasugrel or ticagrelor) which offer equivalent protection. Patients with angina should also receive statin therapy to lower LDL cholesterol, thereby reducing lipid accumulation in the arterial wall and stabilizing the atherosclerotic plaque against rupture. The NICE guideline recommendation is for high intensity statin treat- ment with atorvastatin 80 mg daily with a view to reducing LDL cholesterol by at least 40%. European guidelines recommend treat- ment to an LDL target of 1.8 mmol/​litre. Failure to respond ad- equately to statins provides indication for the addition of ezetimibe to further lower LDL by reducing cholesterol absorption from the bowel. In those patients diagnosed with familial hypercholesterol- aemia, lipid PCSK9 inhibitors now have an indication for producing yet greater LDL reductions. The cardiovascular risk associated with low high-​density lipoprotein (HDL) is well established, but treat- ment to increase HDL with nicotinic acid derivatives does nothing to reduce risk in patients with coronary artery disease. The more potent cholesteryl ester transfer protein inhibitors have also proved ineffective and their development has been largely abandoned. Angiotensin-​converting enzyme (ACE) inhibition provides some additional protection against cardiovascular endpoints in patients with angina, but this probably relates to their blood pressure lowering effect and current recommendations are for their use only in patients with angina who have additional indications for ACE inhibition such as hypertension, heart failure, or diabetes. β-​Blockers, though widely used for symptomatic treatment, have no clear evidence-​based indication for secondary prevention in patients with angina unless there is associated left ventricular dys- function, when prognostic benefit is well established. Antioxidant vitamins C and E and omega-​3 fatty acids have failed the test of clinical trials for secondary prevention in coronary artery disease. Similarly, there appears to be no role for hormone replacement therapy for protecting against coronary events in postmenopausal women. Antianginal drugs Drugs used to treat angina reduce ischaemia by improving the balance between myocardial oxygen supply and demand (Fig. 16.13.3.8). Guideline recommendations are that medical therapy with antianginal drugs should be tried before angioplasty or surgery is considered, except in those patients with stable angina with left main stem or multivessel coronary disease in whom there is evidence that surgical revascularization might improve prognosis. The antianginal drugs recommended for initial treatment are a β-​blocker and a calcium channel blocker, together with a short-​ acting nitrate for prompt alleviation of angina attacks. If these drugs are not tolerated or are contraindicated, alternative antianginals listed next may be introduced, but if angina remains troublesome despite treatment with a β-​blocker and calcium channel blocker, revascularization requires consideration—​not the addition of fur- ther antianginal drugs. β-​blockers These drugs reduce myocardial oxygen demand, principally by slowing the heart rate, although reductions in left ventricular wall tension (blood pressure) and contractility also contribute. Resting heart rate should not be allowed to drop below 55 beats per minute. Choice of β-​blocker is largely determined by patient acceptability, with preference given to once-​daily cardioselective agents such as bisoprolol. Effective relief of exertional angina can often be obtained without recourse to other drugs if the heart rate response to exercise can be reduced sufficiently. There is a clear indication for β-​blockers when angina occurs in patients with heart failure or asymptomatic left ventricular dysfunction. They are usually well tolerated, but non​cardiac side effects, particularly fatigue and erectile dysfunction, may be troublesome even with cardioselective agents. β-​Blockers are contraindicated in patients with bronchial asthma. Calcium blockers Like nitrates, these are vasodilators and improve myocardial oxygen balance by their effect on coronary flow and peripheral resistance. Angina complicated by hypertension provides a clear indication for drugs of this class, and amlodipine is usually the pre- ferred agent. Diltiazem and verapamil are also useful because, in addition to vasodilator activity, they often produce minor reduc- tions in heart rate, although combination therapy with β-​blockers is best avoided. Nifedipine, which tends to increase heart rate, is not recommended for treatment of angina. Side effects of calcium blockers are related to vasodilatation and include facial flushing, postural dizziness, and ankle oedema. Nitrates These drugs improve myocardial oxygen delivery and reduce demand by direct coronary and peripheral vascular dilatation. Sublingual glyceryl trinitrate by tablet or spray should be given to all patients with angina, rapid absorption through the buccal mucosa providing symptomatic relief within 3 min. It can also be used prophylactically to prevent angina during exertion. Long-​ acting isosorbide mononitrate for regular oral administration is widely used, although variable tolerance to its therapeutic action Increased O2 delivery Coronary flow • Nitrates • Calcium blockers • Nicorandil • Revascularization (CABG, PCI) Reduced O2 demand Heart rate • β-blocker • Ivabradine LV wall tension • β-blocker • Nitrates • Nicorandil • Calcium blockers • Ranolazine Contractility • β-blocker • Calcium blockers Modify energy metabolism • Trimetazidine O2 delivery O2 demand Angina occurs if demand exceeds supply Fig. 16.13.3.8  Symptom relief with drugs. section 16  Cardiovascular disorders 3624 may occur. Side effects are rarely troublesome apart from headache during the first few days of treatment. Potassium channel openers Nicorandil is the only drug in this group licensed to treat angina. It is a vasodilator with effects comparable to those of long-​acting ni- trates. The principal side effect is headache. Less common but more serious are gastrointestinal ulcers that will not heal unless nicorandil is withdrawn. Trimetazidine This interesting compound is licensed for treatment of angina in a number of European countries (not the United Kingdom). Its pharmacological effects are metabolic, not haemodynamic, with coupling between glycolysis and carbohydrate oxygenation re- stored by shifting cardiac energy metabolism from oxygenation of fatty acids (the preferred myocardial substrate) to glucose, thus preserving intracellular ATP levels. Antianginal effects are compar- able to other agents. Side effects, including gastrointestinal disturb- ance, are rarely troublesome. Ivabradine Ivabradine inhibits the If channel in the sinus node, reducing the slope of diastolic depolarization and slowing the heart rate. The ef- fect of ivabradine on heart rate is comparable to that of β-​blockers, but it is only effective in patients with normal sinus rhythm (rate reduction does not occur in atrial fibrillation). Based on the results of a recent trial, however, the indication for ivabradine is restricted to patients with continuing symptoms in whom β-​blockers fail to reduce the heart rate below 70 beats per minute. In such patients the addition of ivabradine may be helpful but heart rate should not be allowed to fall excessively. There is an additional indication for ivabradine in patients who have a contraindication to or intoler- ance of β-​blockers and in whom calcium channel blockers such as amlodipine have failed to control symptoms. Ivabradine is gener- ally well tolerated and mild visual side effects tend to resolve during treatment. Ranolazine Ranolazine’s mechanism of action appears to involve inhibition of the late inward sodium channel which indirectly prevents calcium overload of ischaemic myocytes and reduces diastolic wall tension and oxygen demand. Heart rate or blood pressure are unaffected. Antianginal effects are additive to those of β-​blockers and calcium blockers. Side effects including constipation and dizziness are rarely troublesome. Revascularization In the patient with angina, revascularization provides a non-​ pharmacological means of improving myocardial oxygen delivery by restoring coronary flow to the ischaemic myocardium. More than 60% of all revascularization procedures in stable angina are now by percutaneous intervention using balloon angioplasty and stenting (Fig. 16.13.3.9). The remainder are by coronary artery by- pass surgery (CABG), the choice depending largely on the extent and severity of coronary artery disease. At present, this can only be determined by coronary angiography which is an essential pre- requisite of revascularization in the management of angina. See Chapters 16.3.4 and 16.13.5 for further discussion. Which patients with stable angina should undergo coronary angiography? Guideline recommendations are for angiography in patients with continuing moderate or severe angina despite optimal medical treat- ment comprising antianginal drugs (typically a β-​blocker and cal- cium channel blocker plus short-​acting nitrates), aspirin, and statins. Other groups for whom angiography is recommended include those who have been successfully resuscitated from sudden cardiac death (a) (b) Fig. 16.13.3.9  Coronary revascularization by PCI. Right coronary arteriogram (a) before stenting and (b) after deployment of a drug-​eluting stent across the diseased segment (arrowed) in the proximal part of the vessel. The patient had stable angina and experienced complete relief of symptoms after the procedure. 16.13.3  Management of stable angina 3625 or who have life-​threatening ventricular arrhythmias and those with suspected or known coronary artery disease whose jobs (e.g. piloting aircraft, driving public service vehicles) are dependent on a normal or fully revascularized coronary circulation. It may also be indicated in patients unwilling or unable to take antianginal drugs, or those in whom there is important diagnostic uncertainty despite non​invasive investigation. In patients whose angina has responded satisfactorily to medical treatment there is no absolute requirement for angiog- raphy but the potential for small gains in life expectancy with CABG for high-​risk coronary anatomy (left main or three-​vessel disease) should be discussed, and angiography offered to those who wish to have the coronary anatomy defined. Choice of revascularization procedure—​CABG vs. PCI In symptomatic patients who have undergone cardiac catheter- ization, revascularization is generally indicated if one or more of the major coronary arteries—​or their large branches—​have flow-​ limiting stenoses (>70% luminal narrowing) or occlusions. The choice of revascularization procedure is dependent on a range of factors and should be discussed in a multidisciplinary group that includes cardiologists and cardiac surgeons: • Coronary anatomy—​historically, PCI has been preferred for single-​vessel and two-​vessel coronary artery disease and CABG for more extensive disease. This preference, based largely on presumed prognostic benefit for CABG in patients with three-​ vessel or left main stem disease (see next), has now given way to procedure selection based on coronary scoring systems. Most widely used is the SYNTAX score designed to quantify the com- plexity of left main or three-​vessel disease according to simple lesion criteria readily accessible from the coronary arteriogram. If the SYNTAX score is less than 22, signifying low lesion com- plexity, 5-​year outcomes favour revascularization by PCI, re- gardless of the number of diseased vessels. If the SYNTAX score is higher CABG should also be considered, and for scores more than 33 (signifying severe lesion complexity) CABG produces unequivocally better 5-​year outcomes than PCI. In making revascularization decisions, however, other factors are also im- portant, and there is now clear evidence favouring CABG for patients with diabetes and multivessel disease. • Patient preference—​PCI is often preferred because it avoids sur- gery, requires no more than 48 h hospitalization (day-​case PCI is now feasible), and permits early return to normal activities within a few days of the procedure. In expressing a preference, however, it is important that the patient is properly informed of the relative risks and benefits of PCI and CABG in his or her particular case. • Procedural risk—​mortality is lower for PCI than CABG (0.9% vs. 2.2%). Stroke risk may also lower, but rates of non​fatal myocardial infarction are comparable. • Symptomatic benefit—​this is comparable for PCI and CABG, but recurrence of symptoms and need for repeat revascularization is higher for PCI because of coronary restenosis in the months following a successful procedure. Indeed, restenosis has been the Achilles heel of PCI, and until the introduction of coronary stents affected 30% or more of all patients. Since then stenting has become widespread, producing more effective coronary pa- tency although reductions in rates of restenosis to less than 10% had to await the introduction of drug-​eluting stents that deliver antiproliferative drugs (e.g. sirolimus, paclitaxel) locally within the coronary artery. The prospect of providing long-​term relief of symptoms without the need for repeat procedures has consider- ably enhanced the clinical value of PCI. • Prognostic benefit—​There have been no studies showing survival benefit for PCI in patients with stable angina. For CABG, the small gains in life expectancy that have been reported in patients with left main stem coronary disease and three-​vessel disease are from studies nearly 40 years ago and their contemporary relevance may have changed with advances both in surgical techniques and in medical therapy. Indeed, it is generally accepted that improvements in the prognosis of coronary artery disease in the last 25 years have little to do with revascularization, but much to do with lifestyle changes and advances in secondary prevention therapy. Refractory angina With current management strategies patients with angina are living longer, but some (perhaps 5 to 10%) remain symptomatic on optimal medical treatment, having exhausted revascularization options. These patients commonly have extensively collateralized coronary circulations and well-​preserved left ventricular function such that prognosis is not worse than other patients with angina, but quality of life is poor because of refractory symptoms. Psychological support is important to treat anxiety and depression and improve confidence. Other options for further antianginal therapy are not evidence-​ based and are not recommended in international guidelines. These include neuromodulatory techniques (stellate ganglion block, trans- cutaneous electrical nerve stimulation, spinal cord stimulation) and enhanced counterpulsation therapy using pressure cuffs applied to the lower limbs that are inflated sequentially during diastole. FURTHER READING Boden WE, et al. (2007). Optimal medical therapy with or without PCI in stable coronary disease. N Engl J Med, 35, 1503–​16. Doris MK, Newby DE (2016). How should CT coronary angiography be integrated into the management of patients with chest pain and how does this affect outcomes? Eur Heart J Qual Care Clin Outcomes, 2, 72–​80. Fihn SD, et  al. (2012). ACCF/​AHA/​ACP/​AATS/​PCNA/​SCAI/​STS Guideline for the diagnosis and management of patients with stable ischemic heart disease:  a report of the American College of Cardiology Foundation/​American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol, 60, e44–​e164. Head SJ, et al. (2014). The SYNTAX score and its clinical implications. Heart, 100, 169–​77. Jones DA, et al. (2013). Novel drugs for treating angina. BMJ, 347, f4726. Jordan KP, et al. (2017). Prognosis of undiagnosed chest pain: linked electronic health record cohort study. BMJ, 357, j1194. Montalescot G, et al. (2013). 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the manage- ment of stable coronary artery disease of the European Society of Cardiology. Eur Heart J, 34, 2949–​3003. 16.13.5 Percutaneous interventional cardiac proced 16.13.5 Percutaneous interventional cardiac procedures 3655 Edward D. Folland 16.13.5  Percutaneous interventional cardiac procedures 3655 Nunn CM, et al. (1999). Long-​term outcome after primary angioplasty. Report from the primary angioplasty in mycocardial infarction (PAMI-​I) trial. J Am Coll Cardiol, 33, 640–​6. Oler A, et al. (1996). Adding heparin to aspirin reduces the incidence of mycocardial infarction and death in patients with unstable an- gina. A meta-​analysis. JAMA, 276, 811–​15. Petersen JL, et al. (2004). Efficacy and bleeding complications among patients randomized to enoxaparin or unfractionated heparin for antithrombin therapy in non-​ST-​segment elevation acute coronary syndromes: a systematic overview. JAMA, 292, 89–​96. Pocock SJ, et al. (1995). Meta-​analysis of randomised trials comparing coronary angioplasty with bypass surgery. Lancet, 346, 1184–​9. PRISM. The Platelet Receptor Inhibition in Ischemic Syndrome Study Investigators (1998). A comparison of aspirin plus tirofiban with as- pirin plus heparin for unstable angina. N Engl J Med, 338, 1498–​505. PRISM-​PLUS. The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms Study Investigators (1998). Inhibition of the platelet glycoprotein IIb/​IIIa receptor with tirofiban in unstable angina and non-​Q-​wave mycocardial infarction. N Engl J Med, 338, 1488–​97. Rawles J, et al. (1994). Halving of mortality at 1 year by domiciliary thrombolysis in the Grampian Region Early Anistreplase Trial (GREAT). J Am Coll Cardiol, 23, 1–​5. Ryan TJ (1999). Early revascularisation in cardiogenic shock—​a posi- tive view of a negative trial. N Engl J Med, 341, 687–​8. Sabatine MS, et al. (2005). Addition of clopidogrel to aspirin and fi- brinolytic therapy for mycocardial infarction with ST-​segment ele- vation. N Engl J Med, 352, 1179–​89. Savonitto S, et al. (1997). Prognostic value of the admission electrocar- diogram in acute coronary syndromes. Results from the GUSTO-​IIb trial. Eur Heart J, 18 (Suppl), 335, 5–​82. Sharma A, et  al. (2017). Duration of dual antiplatelet therapy fol- lowing drug-​eluting stent implantation:  a systematic review and meta-​analysis of randomized controlled trials. Curr Probl Cardiol, 42, 404–​17. SIGN (2007). Risk estimation and the prevention of cardiovascular di- sease. SIGN Publication no. 97, Scottish Intercollegiate Guidelines Network, Edinburgh. http://​www.sign.ac.uk Sivers F (1999). Evidence-​based strategies for secondary prevention of coronary heart disease, 2nd edition. A&M Publishing, Guildford. Stone GW, et  al. for the ACUITY Investigators (2006). Bivalirudin for patients with acute coronary syndromes. N Engl J Med, 355, 2203–​16. Thygesen K, et al. (2019). Fourth universal definition of myocardial infarction (2018). European Heart J, 40, 237–69. Tunstall-​Pedoe H, et al. (1996). Sex differences in myocardial infarc- tion and coronary deaths in the Scottish MONICA population of Glasgow 1985–​1991. Circulation, 93, 1981–​92. Valgimigli M, et al. (2018). 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collab- oration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). European Heart J, 39, 213–60. Van de Werf F, et  al. (2005). Access to catheterization facilities in patients admitted with acute coronary syndrome:  multinational registry study. BMJ, 330, 441. Wallentin L, et al. (2009). Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med, 361, 1045–​57. Wiviott SD, et al. (2007). Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med, 357, 2001–​15. Yusuf S, et al. (1985). B-​blockade during and after mycocardial infarc- tion: an overview of the randomized trials. Progr Cardiovasc Dis, 27, 335–​71. Yusuf S, et al. (2001). 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N Engl J Med, 354, 1464–​76. 16.13.5  Percutaneous interventional cardiac procedures Edward D. Folland ESSENTIALS Percutaneous coronary intervention Percutaneous coronary intervention is the term applied to a var- iety of percutaneous, catheter-​based procedures that accomplish revascularization by angioplasty (enlargement of a vessel lumen by modification of plaque structure), stenting (deployment of an internal armature or stent), atherectomy (removal or ablation of plaque), or thrombectomy (removal of thrombus). The most common single indication for percutaneous coronary intervention is acute coronary syndrome. Randomized trials have shown that direct intervention for ST-​elevation myocardial infarction is superior to initial thrombolytic therapy when performed in appro- priate centres, and it can be used as a salvage procedure after failed thrombolytic therapy. Balloon angioplasty is the traditional, basic technique of cor- onary intervention, but this is now uncommonly employed as a stand-​alone treatment and finds its chief application in deployment of balloon-​expandable stents, which have become the intervention of choice in about 90% of cases undergoing percutaneous coronary intervention. A variety of percutaneous techniques can be used to remove atheroma or thrombus from coronary arteries as a prelude to angioplasty/​stenting. There are two main types of coronary stent—​‘bare metal’ and ‘drug eluting’. The latter contain a drug (e.g. sirolimus, paclitaxel, and others) that inhibits smooth muscle proliferation and thereby considerably re- duces the risk of restenosis, which is the most common complication section 16  Cardiovascular disorders 3656 of stenting. Restenosis typically presents as exertional angina at 1 to 6 months following intervention: if it is not present at 6 months, it is unlikely to occur. Stents with bioresorbable scaffolds are now available, but concern regarding late stent thrombosis has limited their use. Treatment of valvular and other diseases Percutaneous techniques can also be used to treat some forms of valvular disease and close cardiac defects in (highly) selected cases. Balloon valvuloplasty is the preferred treatment, when feasible, for patients with stenosis of mitral and pulmonic valves. Transcatheter aortic valve implantation has proven safe and effective as an alterna- tive to surgical valve replacement in patients for whom surgical risk is prohibitive, and recent trials have supported use in patients with inter- mediate surgical risk. Valve-​in-​valve transcatheter replacement is now an option for some patients with degenerated surgically implanted bioprosthetic valves. Percutaneous clipping of mitral valve leaflets has been accomplished in some patients with mitral regurgitation, with safety equivalent to that of surgical treatment but less benefit. Atrial septal defect and patent foramen ovale can be closed with a percutaneously delivered clamshell device, with randomized trials showing that patients having cryptogenic stroke and patent foramen ovale are less likely to sustain recurrent stroke when the defect is closed compared to long-​term anticoagulant or antiplatelet therapy. Occlusion of the left atrial appendage with a percutaneously delivered disc reduces the risk of embolic stroke in patients with atrial fibrillation and is an alternative to long-​term anticoagulation for some patients. Introduction The birth of interventional vascular medicine is generally cred- ited to Charles Dotter, a radiologist from Portland, Oregon, who in 1964 first dared to relieve atherosclerotic stenosis of a patient’s femoral artery by passage of a percutaneously introduced dilator. Although Dr Dotter had a few notable successes, which were widely publicized in the lay press, the scientific community scorned him. His radical concept lay dormant until a decade later when Andreas Gruentzig, a young German radiologist studying in Zurich, revived it. Dr Gruentzig was convinced that percutaneous dilatation of ath- erosclerotic stenosis was a sound concept and proposed that Dotter’s solid dilator be replaced by a catheter with an inflatable cylindrical balloon at its tip. Using catheters he created in his own kitchen, he proceeded carefully and logically in applying his technique first to animal models, then to human peripheral vessels, and finally in 1977 to his ultimate goal, the human coronary artery. News of Gruentzig’s percutaneous transluminal coronary angioplasty (PTCA) was quickly embraced by the medical community, and the era of percu- taneous coronary intervention (PCI) was born. This chapter deals with percutaneous approaches to treating coronary, valvular, and congenital heart disease. Percutaneous coronary intervention PCI is the current general term applied to a variety of percutaneous catheter-​based procedures that accomplish revascularization by either angioplasty (enlargement of a vessel lumen by modification of plaque structure), stenting (deployment of an internal armature or stent), atherectomy (removal or ablation of plaque), or thromb- ectomy (removal of thrombus). Several different devices have been developed to perform these procedures. The interventional cardi- ologist chooses among these approaches to best suit the particular requirements of each individual patient. Indications The indications for percutaneous revascularization have expanded dramatically during the past 40 years. In the early days of PTCA it was indicated for subtotal proximal occlusions of single vessels in patients with chronic stable angina pectoris who had failed medical therapy. As experience grew and equipment improved, patients with unstable angina, total occlusions, bypass grafts, multivessel disease, and acute myocardial infarction were added to the list. Currently, the most common single indication for PCI is acute coronary syn- drome (see Chapter 16.13.4). PCI has traditionally been performed only in hospitals having cardiac surgical backup. However, as the procedure has become safer and the need for emergency bypass surgery less frequent (cur- rently <1% of all cases), it has become more common, particularly in Europe, for these procedures to be performed in facilities where surgical backup is not on site. Likewise, all patients undergoing PCI were once required to be potential candidates for bypass surgery in case of failure of the percutaneous procedure. Now some patients who are poor surgical candidates may undergo salvage interven- tion as their best or only avenue for revascularization. The choice of initial treatment (pharmacological, interventional, or surgical) for patients with each of the aforementioned coronary syndromes has been guided by evidence from several randomized clinical trials and is treated in more detail in the later section headed ‘Outcomes’. Devices and techniques Balloon angioplasty Balloon angioplasty is the traditional, basic technique of coronary intervention, although it is now uncommonly employed as a stand-​ alone treatment. Nevertheless, it is fundamental to the deployment of coronary stents, which are currently the most widely utilized of the interventional devices. The equipment for angioplasty is shown in Fig. 16.13.5.1 and consists of a coaxial array of guiding catheter, balloon catheter, and steerable guide wire. The procedure is accom- plished by first engaging the left or right coronary orifice with the tip of the guiding catheter to access the vessel containing the target lesion and to provide backup support during advancement of the guide wire and balloon across the lesion (Fig. 16.13.5.2a). Next, the guide wire is advanced through the guide catheter into the ap- propriate vessel and across the lesion to be treated. Typical guide wires are 0.014 of an inch in diameter (c.0.36 mm) and have a flex- ible spiral coil tip that can be directed by rotating their proximal end outside the body. The balloon catheter is then advanced over the guide wire until the deflated balloon lies across the target lesion. Finally, the balloon is inflated with a solution of dilute contrast me- dium to a pressure sufficient to expand the cylindrical balloon to its nominal manufactured diameter (Fig. 16.13.5.2b). The balloon size is selected to match the estimated diameter of the nearest seg- ment of normal vessel and the length of the target lesion. Sometimes 16.13.5  Percutaneous interventional cardiac procedures 3657 intravascular ultrasound is used to assist in this choice. The balloon is then withdrawn and the result assessed by angiography and, occa- sionally, by ultrasound (Fig. 16.13.5.2c). Traditional angioplasty now finds its chief application in de- ployment of balloon-​expandable stents. However, angioplasty may serve as a stand-​alone interventional technique for the treatment of lesions of small vessels (<2.5 mm in diameter) and lesions lo- cated far distally or beyond tortuous segments where more rigid devices such as stents cannot reach. In experienced hands, with appropriate case selection, the initial success rate of balloon angio- plasty should exceed 95%. Abrupt closure of the vessel might be expected in about 3% of cases (usually due to dissection), but most of these can be corrected by deployment of a stent, resulting in a need for emergency bypass surgery in less than 1% of cases. The clinical consequence of vessel closure is often insufficient to justify surgery in vessels too small or distal for grafting. The technology of guide, balloon, and guide wire systems has ad- vanced to the point where few locations in the coronary anatomy are inaccessible. Totally occluded vessels can usually be success- fully crossed with appropriate manipulation of the right guide wire, enabling successful angioplasty. The success rate for angioplasty of totally occluded vessels depends upon the age, length, and com- position (thrombus vs. plaque) of the occlusion; it is well over 90% in cases of acute thrombotic occlusion, and over 50% in cases of chronic occlusion (>3 months). The chief disadvantage of balloon angioplasty is the phenomenon of restenosis, which is discussed in more detail later in this chapter, and which spurred the development of newer devices in the hope of preventing restenosis. Cutting balloon The cutting balloon has several tiny longitudinally mounted blades that become erect when the balloon is inflated and create linear cuts along the vessel wall. This was conceived as a method to dilate a vessel less traumatically and thereby reduce the likelihood of resten- osis. This goal was never realized for de novo lesions, but the device has been advantageous for treatment of recurrent stenosis within previously deployed stents (in-​stent restenosis) and for dilating le- sions located at the ostium of a vessel, which are otherwise often subject to elastic recoil when dilated. Stenting Bare metal stents Stenting has become the intervention of choice in about 90% of cases undergoing PCI. A modern-​day vascular stent is actually an arma- ture, or internal skeleton, for restoring and maintaining the cylin- drical structure of the diseased vessel. Most stents are made from a thin-​walled stainless steel or cobalt–​chromium steel tube in which slots have been carved. The slotted tube is then mounted securely on a deflated angioplasty balloon and deployed at the target lesion of the coronary artery by inflating the balloon at high pressure with dilute contrast medium. When the balloon is deflated the stent re- mains expanded against the vessel wall, its slots stretched into diamond-​shaped apertures (Fig. 16.13.5.3). Approximately 20% of the vessel wall is covered by metal, the remainder being an intrastrut aperture. This accounts for the surprisingly high patency of side Steerable guide wire Balloon Lesion Dilating catheter Guiding catheter Proximal pressure and injection Fig. 16.13.5.1  Balloon angioplasty. The guiding catheter gives access to the coronary artery and provides a platform against which the dilating apparatus can be advanced. The steerable guide wire is passed down the vessel being treated and provides a rail over which the balloon catheter can be advanced. Once centred on the atherosclerotic lesion, the balloon is inflated under pressure to dilate the narrowed segment of artery. Balloon catheter entering blockage (a) Inflated balloon stretching blockage (b) Re-opened artery after inflation (c) Fig. 16.13.5.2  A typical lesion (a) before, (b) during, and (c) after balloon angioplasty. section 16  Cardiovascular disorders 3658 branches following stent deployment, and the ability to access these side branches when necessary for further intervention. A variation of the slotted-​tube stent is a balloon-​deployed coiled wire (Wallstent and others). A coiled wire made from nitinol, or another alloy with shape-​retaining characteristics, is compressed into a tubular delivery sheath, which is advanced over a guide wire across the target lesion. Once in its proper position the sheath is drawn back, allowing the stent to expand to its original size and shape (Fig. 16.13.5.4). As with slotted-​tube stents, pre-​or post-​ deployment dilation with a balloon may be necessary, depending upon the nature of the lesion treated and the device used. Although one of the original stent designs, the self-​expanding stent is now used less commonly for coronary artery applications, but it still finds use in many peripheral vascular cases. Most current stent de- signs are hybrids, which incorporate desirable properties of both the slotted-​tube and coiled-​wire designs. Stents have gained remarkable popularity, mainly for three reasons. (1) Immediate complications are reduced because abrupt closure of the vessel due to dissection is less likely, emphasized by the fact that a stent is the best treatment for a balloon-​induced dis- section. (2) The immediate result is better in terms of the diameter and smoothness of the lumen, which turns out to be of more than cosmetic value because the early gain in lumen size relates directly to the late outcome. (3) Stents have been demonstrated in random- ized clinical trials to be effective in reducing the likelihood of late restenosis. However, stents do have some disadvantages, which include the fact that they cannot be deployed under some circumstances, their propensity to subacute thrombosis, and the persistence of some degree of restenosis (depending upon the size of the vessel and length of the lesion). Subacute thrombosis, a complication unique to stents, usually occurs within a few weeks after stent deployment. By contrast to restenosis, which is a gradual phenomenon, stent thrombosis is usually sudden, presenting as acute myocardial in- farction and requiring emergency revascularization, usually by bal- loon angioplasty. The likelihood of subacute thrombosis has been reduced to less than 1% by dual antiplatelet therapy with a com- bination of aspirin plus a thienopyridine (clopidogrel, prasugrel, ticagrelor, or ticlopidine). (a) (b) (c) Fig. 16.13.5.3  A balloon-​deployed coronary artery stent before (a), during (b), and after (c) deployment. With permission from Maisel WH, Laskey WK (2007). Drug eluting stents. Circulation, 115, e426–​7. Fig. 16.13.5.4  A self-​deploying coil stent. The stent unfurls as its delivery (containment) sheath is pulled back. Image provided courtesy of Boston Scientific. © 2018 Boston Scientific Corporation or its affiliates. All rights reserved. 16.13.5  Percutaneous interventional cardiac procedures 3659 Drug-​eluting stents The development of stents that gradually elute a drug into the sur- rounding vessel wall has reduced the need for repeat intervention due to restenosis from approximately 15% for bare metal stents to less than 5%. This technology is largely responsible for the rapid and sustained growth in popularity of stent procedures, such that most patients requiring coronary revascularization are now treated by percutaneous rather than surgical techniques. The design of the drug-​eluting stent incorporates a polymer matrix coating that con- tains a drug which inhibits the proliferation of smooth muscle cells in the surrounding vessel wall. The active drug slowly elutes from this coating into the underlying tissue while the vascular response to injury caused by vessel dilation is most active. Drug elution is usu- ally complete by 2 months after stent deployment, but by modulating the proliferation of smooth muscle cells the growth of neointima covering the stent struts is limited, reducing the likelihood of resten- osis of the treated vessel. The first two types of drug-​eluting stents to be commercially available use sirolimus and paclitaxel as the active drug. These drugs inhibit cell proliferation through different mechanisms, but have proven to be equally effective. Other drugs currently available in- clude everolimus and zotarolimus. Although excessive neointimal growth is undesirable, some is needed in order to cover the stent struts and prevent thrombosis. Dual antiplatelet drug therapy is necessary to minimize this risk as long as the struts are exposed. Bare metal stents are usually fully covered by 2 months, but drug-​ eluting stents may remain uncovered for 6 months or longer. For this reason, most cardiologists recommend that dual antiplatelet therapy be continued along with aspirin for at least 1 year following deploy- ment of drug-​eluting stents. Bioresorbable stents The concept of a stent which is gradually absorbed or degraded is attractive for several reasons. The metal stent scaffold is no longer needed after the vessel has healed from the trauma of dilation and implantation. The very presence of a metal scaffold and/​or its polymer matrix coating may promote inflammation, leading to lumen loss after the antiproliferative drug has been delivered, and thrombosis may occur if tissue coverage of metal struts is incom- plete. The metal scaffold also limits normal vascular motion as well as imaging by CT or MRI. In other words, the ideal coronary artery stent would disappear after it is no longer needed, which has driven the development bioresorbable stents. Two main types of bioresorbable stents are now available: one with a bioresorbable matrix applied to a conventional metal stent scaffold, and another in which the entire stent scaffold is non​metallic and absorbable. Two absorbable matrix stents studied in random- ized trials are the everolimus-​eluting Synergy (Boston Scientific) and biolumis eluting Nobori (Terumo), both of which are available for clinical use in Europe, and the Synergy stent has been available in the United States since 2015. They have comparable outcomes com- pared with conventional drug-​eluting stents in multiple studies, and a meta-​analysis of four different randomized trials suggests reduced incidence of very late (four years follow-​up) stent thrombosis. The Absorb (Abbott Vascular Corporation) and DESolve (Elixir Medical Corporation) stents deliver everolimus and novolimus re- spectively from a totally absorbable polymer scaffold. DESolve is available for clinical use in Europe, and Absorb has been FDA ap- proved in the United States since 2016. They are bulkier than equiva- lent metal devices and are prone to fracture, hence vessel sizing and proper stent deployment are critical. Although randomized trials show clinical outcomes that are non​inferior to those of conventional drug-​eluting stents, several randomized trials—​including the most recent ABSORB III trial—​indicate that the incidence of stent throm- bosis is twice that of conventional drug-​eluting stents. The AIDA trial comparing bioresorbable scaffolds with metallic stents in rou- tine percutaneous coronary intervention showed definite or prob- able device thrombosis at two years to be 3.5 versus 0.9% for the two groups respectively. Many cardiologists are therefore awaiting further evidence of benefit before embracing this enticing but ex- pensive technology. Atherectomy Rotational ablation Rotational ablation (Rotablator) is a method of pulverizing plaque into particles smaller than the size of a capillary, which wash away with the circulating blood. This process is accomplished by means of a diamond-​studded burr, which rotates at approximately 150 000 rev/​min (Fig. 16.13.5.5) and is advanced along a guide wire into the plaque. The diamond studs on the forward face of the olive-​shaped burr selectively cut into hard substances such as plaque and cal- cium, sparing the soft surface of normal tissue. During rotational atherectomy a vasodilating solution is infused into the artery prox- imal to the burr to prevent spasm and to maintain maximal coronary flow, which carries away particulate debris. Burrs are manufactured in sizes ranging from 1.5 mm to 2.5 mm in diameter. Atherectomy often requires the use of two or three burrs of progressively larger size until an adequate lumen size is achieved. Although occasion- ally used as a stand-​alone procedure, rotational ablation is usually employed to ‘debulk’ lesions prior to final dilatation with a balloon or stent. Rotational ablation was originally conceived as a potential solu- tion to the problem of postintervention restenosis. Unfortunately, it has failed to outperform balloon angioplasty in this regard and has assumed the role of a ‘niche’ device for special situations. It is most commonly used in the treatment of heavily calcified lesions that do not respond well to balloons and stents. It is also useful in treating diffuse, osteal, and bifurcating lesions. The frequency with which ro- tational ablation is employed varies by operator, but averages less than 5% of most centres’ cases. It has the disadvantages of being an expensive addition to other interventional modalities, is unable to adequately increase the lumen of large vessels, and is contraindi- cated in lesions containing thrombus. Due to its tendency to tran- siently decrease contractility during the ablation process, it is also Fig. 16.13.5.5  Rotational atherectomy. The rotating burr pulverizes plaque as it is advanced over the guide wire into the lesion. section 16  Cardiovascular disorders 3660 relatively contraindicated in patients whose left ventricular function is severely impaired. Directional coronary atherectomy Directional coronary atherectomy (DCA) is achieved with a device illustrated in Fig. 16.13.5.6 that utilizes a rotating cylindrical blade which is advanced across an open aperture near the tip of a cone-​ shaped catheter directed by a guide wire. Opposite the aperture is an eccentric balloon, which when inflated compresses plaque of the opposite vessel wall into the aperture, where it is cut away by the rotating blade and pushed into the nose cone. The direction of the aperture can be rotated so that slices of plaque are removed in a ra- dial fashion by multiple cuts taken at different locations around the circumference of the vessel. The catheter can then be withdrawn and the excised plaque removed from the nose cone. The catheter may be reintroduced, if necessary, for more atherectomy. Although DCA was originally devised with the hope of reducing the incidence of restenosis, it has failed to outperform balloon angio- plasty in most circumstances. It has therefore assumed the role of a ‘niche’ technology, which is useful in particular situations such as very eccentric proximal lesions, and lesions involving the ostia of major side branches. Removal of plaque at branch points seems to reduce the likelihood of plaque shifting from one branch to an- other as the respective lesions are dilated with balloons or stents. However, DCA has the disadvantage of requiring a rather large, stiff device, limiting its application to proximal lesions of large vessels. Furthermore, the removal of plaque seems to have surprisingly little effect on restenosis. DCA is currently employed in less than 5% of interventional cases. Other devices The transcutaneous excision catheter device was developed at about the same time as DCA. It employs a rotating conical blade that cuts away plaque and clot as it is advanced over a guide wire. The re- sulting debris is sucked back through the catheter into a reservoir outside the body. Although originally developed as an atherectomy device, it has found its chief application in treating clot-​laden le- sions, but it has not gained wide usage. Excimer laser coronary atherectomy (ELCA) employs a fibre-​ optic catheter directed by a guide wire to deliver bursts of excimer laser energy to the plaque. Disintegrated plaque washes away in the circulation. However, ELCA has also failed to solve the restenosis problem and is used uncommonly in most centres, but remains the sole surviving member of a number of laser applications that have been tried and failed over the past 40 years. It finds its most fre- quent application in treatment of osteal lesions, stent restenosis, and diffuse calcified disease. Because of the limitations of fibre size it is usually followed by balloon or stent treatment. Thrombectomy Thrombectomy is an adjunct to angioplasty and stent procedures in patients with acute myocardial infarction and thrombus-​laden le- sions. Its purpose is to prevent distal embolization by removing the thrombus prior to balloon dilation and stent deployment. The de- vices for achieving this have become simpler over time. The simplest and least expensive is called a Pronto, which is a catheter, delivered over a guide wire, that has a relatively large inner lumen attached to a suction syringe. As blood is withdrawn through the catheter, its tip is moved back and forth through the thrombus, picking it up and re- moving it. A more complex device called AngioJet uses the Venturi effect from a high-​velocity jet of water, which draws thrombus into a window near the tip of a catheter directed by a guide wire and pro- pels it into a reservoir. Another device called the Excisor employs a helical screw at the end of a catheter, which breaks up the clot so that it can be withdrawn through the catheter. Both these devices currently find their chief application in the treatment of degenerated and clot-​laden veingraft lesions. Although suction thrombectomy seems logical prior to crossing a thrombotic vessel occlusion in pa- tients with acute ST-​elevation myocardial infarction recent studies show no benefit from its routine use in this situation. Distal protection Distal protection devices are methods of capturing and collecting thrombus and other debris that may embolize distally from the target lesion during the use of many of the interventional tools just mentioned. They may be particularly beneficial during the treatment of old, degenerated vein grafts in which distal embolization is espe- cially common. Two general approaches are employed. The simplest is a guide wire with a filter on its end (Filterwire, Fig. 16.13.5.7). The filter looks like a windsock and catches debris released proximal to it. The other approach (PercuSurge) is to use a guide wire with a balloon near its tip which is progressively inflated until it occludes the distal portion of the vessel being treated. Intervention is then performed over the guide wire proximal to the occlusion balloon. Once the intervention is complete an export catheter is advanced over the guide wire and any debris removed by suction. Finally, the distal balloon is deflated, restoring flow, and the guide wire removed. Window Plaque (b) (d) Cutting element Atherocath (a) Balloon Nose cone (c) Fig. 16.13.5.6  Directional coronary atherectomy: (a) the catheter is inserted such that the blade housing is adjacent to the plaque to be removed. (b) The balloon on the opposite side of the blade housing is inflated, pushing the aperture over the plaque. (c) The rotating cylindrical blade is advanced across the window of the housing and cuts away plaque, packing it into the nose cone. (d) The catheter can be rotated to remove plaque elsewhere on the circumference of the vessel. 16.13.5  Percutaneous interventional cardiac procedures 3661 Brachytherapy The local, catheter-​based delivery of β-​or γ-​radiation has been demonstrated to reduce the incidence of recurrent stent resten- osis. Radiation is delivered with the assistance of a radiation ther- apist after initial treatment of stent restenosis with a cutting balloon, Rotablator, or conventional balloon. The benefit of brachytherapy appears to be limited to treatment of stent restenosis and it is not re- commended following initial deployment of a stent. Brachytherapy also prolongs the period of risk for subacute thrombosis, making it necessary to treat patients with both aspirin and clopidogrel for at least 6 months after treatment. However, the need for brachytherapy has been virtually eliminated by drug-​eluting stents. Not only is re- stenosis less likely after initial deployment of a drug-​eluting stent, but restenosis—​when it does occur—​is most effectively treated by concentric deployment of a second drug-​eluting stent. Selection and evaluation of treatment targets Fractional flow reserve In cases of acute myocardial infarction or single-​vessel disease the identification of the treatment target (so-​called ‘culprit lesion’) is usually straightforward. However, in patients having lesions of multiple vessels it is often unclear which vessels require treatment. Treating a lesion that is not responsible for causing ischaemia can create a problem where previously none existed. An unnecessary stent can still lead to restenosis and other complications, not to men- tion needless additional cost. On the other hand, failure to treat a vessel having borderline stenosis may overlook a source of ischaemia. Measurement of fractional flow reserve has proven to be a useful method of identifying the physiological significance of coronary ar- tery lesions, especially in vessels having lesions with borderline per- centage stenosis (50–​70%). It is performed using a pressure wire to cross an area of disease in a coronary artery; the pressure drop across a lesion is measured at rest and during maximal dilatation with an adenosine infusion. Fractional flow reserve (FFR) is the quotient of the mean pressure on either side of a coronary stenosis during max- imum vasodilation. An FFR quotient of less than 0.75 correlates with stress-​induced defects in myocardial perfusion imaging studies. Such a lesion is capable of causing ischaemia and merits treatment. The FFR therefore facilitates clinical decisions in the catheterization la- boratory. Well-​designed studies have shown that use of this method to guide treatment results in improved clinical outcomes. Intravascular ultrasound Intravascular ultrasound (IVUS) is a useful adjunct to interven- tional coronary procedures. It is performed by passing a small cath- eter having a rotating ultrasound crystal at its tip down a guide wire positioned in a coronary artery. Tomographic cross-​sectional im- ages of the artery are produced as the crystal is withdrawn. These images enable precise measurement of the dimensions of the arterial lumen plus visualization of the arterial wall and any plaque that might be present. Minimum cross-​sectional area of coronary artery stenosis measuring less than 4.0 mm2 indicates that the stenosis is severe enough to cause ischaemia and likely to need treatment. The most common application of IVUS is in measuring the diameter of normal artery adjacent to a lesion in order to choose a stent of ap- propriate size. IVUS is also very useful for assessing whether a stent has been adequately deployed. Optical coherence tomography Optical coherence tomography (OCT) is a method of creating cross-​ sectional images of the artery similar to those produced by IVUS. The difference is that reflected light, rather than ultrasound, is used to create the images. The advantage of OCT is that its spatial reso- lution is 10 times greater than that of IVUS. However, the use of light requires that the artery be flushed with saline in order to clear blood from the imaging field. Although this can be achieved safely, it is cumbersome enough that OCT has not yet gained widespread use in clinical practice. Complications PCI exposes the patient to all the potential complications of cardiac catheterization presented in Chapter 16.3.4. In addition, it carries the risk of other complications unique to interventional procedures. Most of these stem from four general processes that cause adverse outcomes in coronary artery intervention:  abrupt closure, distal embolization, stent thrombosis, and restenosis. Patient characteris- tics such as age, acute coronary syndrome, previous bypass surgery, and renal insufficiency are major determinants of risk. When con- sidering PCI for a patient, it is important to weigh the likelihood of these adverse outcomes against the expected chance of adverse events without intervention. The approximate frequencies of various specific complications from PCI are listed in Table 16.13.5.1. As in diagnostic catheterization, the likelihood of these complications also depends upon operator skill. Fig. 16.13.5.7  Distal protection device: FilterWire. Image provided courtesy of Boston Scientific. © 2018 Boston Scientific Corporation or its affiliates. All rights reserved. Table 16.13.5.1  Complications of percutaneous coronary intervention Complication Frequency (%)a Death 0.5–​2 Acute myocardial infarction 2–​5 Emergency bypass surgery 0.5–​2 Abrupt closure 1–​2 Subacute stent thrombosis <1 Peripheral arterial complications 5 Restenosis (clinical) 5–​30 a These rates are approximate and vary widely with the clinical setting and patient characteristics. These are in addition to the usual complications of cardiac catheterization presented in Chapter 16.3.4. section 16  Cardiovascular disorders 3662 Abrupt closure and distal embolization Abrupt closure and distal embolization account for most of the im- mediate complications of PCI, especially acute myocardial infarc- tion and emergency coronary artery bypass surgery. Dissection, spasm, and thrombosis are the leading causes of abrupt closure. The availability of stents has reduced the need for emergency by- pass surgery to less than 1% because these are an effective treatment for acute dissection in most cases. Nevertheless, dissection some- times extends with the addition of each stent, and occasionally the stent itself can be the cause of dissection at one of its edges. Acute thrombosis may occur in spite of routine prophylactic treatment with anticoagulants (heparin, low molecular weight heparin, or bivalirudin) and aspirin: glycoprotein IIb/​IIIa inhibitors may stop this process and are sometimes given prophylactically, especially in high-​risk cases. Incomplete stent deployment seems to be a leading cause of thrombotic occlusion. Distal embolization is surprisingly uncommon, except when patients have acute coronary syndromes or visible thrombus. It is especially troublesome for patients with de- generated or thrombus-​laden vein grafts. Embolization may result in discrete occlusion of branch vessels or the phenomenon called ‘no reflow’, which is manifest by reduced flow without identifiable occlusion and thought to be due to capillary plugging from showers of microemboli. Distal protection devices (Fig. 16.13.5.7) may help prevent these problems. Both abrupt closure and no reflow usually cause some degree of myocardial infarction, the likelihood of infarc- tion being a matter of how it is defined: non-​ST-​elevation infarction indicated only by a rise of troponin or creatine kinase enzymes is more common than ST-​elevation (Q wave) infarction. Stent thrombosis Thrombosis is a serious complication of particular concern for stents. It rarely occurs after the first 24 h following isolated balloon angio- plasty or atherectomy. However, when a stent is deployed it may occur at a later time and is manifest by acute myocardial infarction. It is a medical emergency that must be managed in a fashion similar to spontaneous acute infarction. Emergency reperfusion by balloon angioplasty is usually preferred, unless a catheterization laboratory is unavailable, in which case thrombolytic therapy is recommended. In the early days of stenting this complication occurred in over 3% of cases in spite of vigorous anticoagulation including intravenous heparin and warfarin, a treatment that required several days of hos- pital stay for the initiation of warfarin therapy and delayed the wide- spread acceptance of stenting. However, once the current treatment using oral antiplatelet agents was proven to be superior, the length of hospital stay and local bleeding complications were reduced, and the use of stents grew rapidly. Stent thrombosis now occurs in less than 1% of cases. Thrombosis is defined as subacute when it occurs between 1 day and 1 month following stent deployment. Subacute thrombosis is equally likely for bare metal and drug-​eluting stents. Thrombosis occurring more than one month after stent deployment is called late stent thrombosis and is particularly associated with drug-​eluting stents (both metallic and bioresorbable scaffolds). To minimize the risk of late stent thrombosis, dual antiplatelet therapy with aspirin and thienopyridine should be continued without inter- ruption for at least 6–​12 months following implantation of drug-​ eluting stents, and perhaps even longer for those with bioresorbable scaffolds. Restenosis Restenosis was once the Achilles heel of coronary intervention. In patients undergoing isolated balloon angioplasty the likelihood of restenosis at 6 months following intervention lies between 30 and 50% if defined by angiographic criteria, and approximately 25% if defined by the clinical recurrence of symptoms. The use of bare metal stents reduced the angiographic rate of restenosis to about 25% and the clinical rate to as little as 10%. Drug-​eluting stents have further reduced the rate to 5% or less, depending upon clinical and ana- tomic circumstances. The risk of restenosis varies according to indi- vidual factors such as vessel diameter and lesion length. Restenosis typically presents clinically as exertional angina at 1 to 6 months following intervention. Restenosis occurring more than six months after implantation is less likely, but still happens occasionally. As described earlier, it is caused by the proliferation and migration of smooth muscle cells into the lumen of the treated vessel, a process that can be significantly modulated by use of drug-​eluting stents. Outcomes Chronic stable angina Randomized clinical trials have shown that patients with single-​ and double-​vessel disease experience a more rapid and complete resolution of symptoms, and a greater improvement in treadmill exercise performance, when treated by balloon angioplasty rather than by pharmacological therapy for chronic stable angina pectoris. However, this comes at the price of a greater likelihood of repeat intervention or bypass surgery at 6 months, largely due to the need to treat restenosis. Nevertheless, the rate of bypass surgery becomes equal in both groups by 3  years. More recent studies employing drug-​eluting and bare metal stents continue to support these find- ings. Therefore, medical therapy is an acceptable initial strategy for low-​risk patients. Intervention is recommended for higher-​ risk patients and those not responding to medical therapy. When compared to coronary bypass surgery, PCI provides similar relief of symptoms and similar rates of mortality and myocardial infarc- tion at 5-​year follow-​up, with the exception of diabetic patients who have somewhat better 5-​year survival rates when treated surgically. Otherwise, the main difference between patient groups randomly assigned to surgery or percutaneous intervention is that repeat cath- eterization or revascularization is less frequent for those having sur- gery. Again, this difference is largely due to the effect of restenosis and less complete revascularization in the interventional group. See Chapter 16.13.4 for further discussion. Unstable angina The choice between initial aggressive treatment (catheterization and revascularization) and initial conservative treatment (medical therapy with catheterization and revascularization only for those who have continued evidence of ischaemia) for patients with un- stable angina has been controversial. However, recent studies favour an aggressive approach to these patients, especially those having high clinical risk or evidence of non-​STEMI. See Chapter 16.13.4 for further discussion. Acute myocardial infarction Percutaneous intervention has been shown to be an effective treat- ment for acute myocardial infarction with ST-​segment elevation 16.13.5  Percutaneous interventional cardiac procedures 3663 (STEMI), both as a salvage procedure after failed thrombolytic therapy and as a direct initial approach to reperfusion. Randomized trials have shown that direct intervention for STEMI is superior to initial thrombolytic therapy when performed in centres with ex- pert interventionists and catheterization facilities that are available around the clock. Direct PCI is also an option for patients presenting outside these centres provided that they can be transferred and ef- fectively treated in less than 90 min. In any case, direct PCI is the treatment of choice for patients in whom thrombolytic therapy is contraindicated and for patients who are haemodynamically un- stable. See Chapter 16.13.4 for further discussion. Economic considerations The cost of equipment and supplies for percutaneous coronary pro- cedures may become a limiting factor, particularly in developing countries and in healthcare systems with stringent budgets. Most catheters, guide wires, and other supplies are intended for onetime use. Expendable supplies alone cost approximately £750 ($US 1200) for a simple balloon angioplasty procedure. That cost may be multi- plied several-​fold when drug-​eluting stents are used—​these are two to three times more costly than bare metal stents, although the added cost is offset somewhat by the reduced likelihood of repeat procedures necessitated by restenosis. The coverage of this add- itional cost varies considerably throughout the world, depending on insurance and government policies. Nevertheless, the cost of a single percutaneous revascularization procedure usually remains less than that of a comparable coronary bypass operation. However, when the added cost of repeat percutaneous revascularizations necessitated by restenosis is considered, the price difference between the two therapeutic approaches narrows. Non​cardiac surgery in patients following coronary intervention An estimated 5–​10% of patients undergo non​cardiac surgery within 1 year following coronary stent implantation. When surgery is per- formed within 6 weeks of intervention there is a high risk of death or myocardial infarction usually secondary to stent thrombosis, this risk is highest in patients with drug-​eluting stents. The risk continues to be significant for at least 6 months. In individual cases the risk is higher, for example where a major coronary artery is stented (left main stem or proximal left anterior descending artery). For this reason it is rea- sonable try to defer elective surgery for at least 6 months following stent implantation. Where urgent surgery is required then a delay of 6 weeks is advisable. Where possible dual antiplatelet therapy should be continued in those operated on within 6 months except where the risks of perioperative bleeding are unacceptable. Percutaneous treatment of valvular and structural disease Allain Cribier in France developed the treatment of valvular stenosis by means of balloon catheters in the 1980s. The clinical utility of the procedure depends on the valve treated and the age of the patient. Percutaneous aortic valve replacement is now an effective alterna- tive to surgery in patients having very high surgical risk. Catheter-​ deployed clips can reduce the severity of mitral regurgitation. Mitral stenosis Balloon valvuloplasty of the mitral valve has become the treat- ment of choice for selected patients with rheumatic mitral stenosis. The most common approach to the mitral valve is via trans-​septal puncture of the left atrium from percutaneous access of the right femoral vein. After passing a stiff guide wire with a curved soft tip across the mitral valve, an appropriately sized balloon is centred on the valve and inflated with dilute contrast medium, tearing open the fused commissures and allowing the valve to open more nor- mally. A dumbbell-​shaped balloon, named after Dr Inoue, is often utilized, preventing the balloon from slipping off the valve during inflation (see Fig. 16.13.5.8). Clinical improvement, complications, and durability of the outcome from balloon mitral valvuloplasty have been shown to be comparable to surgical commissurotomy in appropriately selected patients. To be a candidate for balloon mitral valvuloplasty a patient must have no evidence of thrombus in the left atrium. Other features which auger poorly include im- mobility of the valve leaflets, severe calcification, thickening of the chordae tendineae, and more than mild regurgitation. Balloon mi- tral valvuloplasty is generally recommended as the procedure of first choice for patients with favourable anatomy. Mitral regurgitation Percutaneous treatment of mitral regurgitation is being approached by two different strategies. The first involves applying a clip to the mitral valve commissures, effectively creating a dual orifice valve. The second approach is to pass a ring into the coronary sinus which constricts the mitral valve annulus, enabling better coaptation of the valve leaflets. Experience is greatest with the clip device (MitraClip). The EVEREST II trial indicates that the severity of mitral regurgita- tion can be safely reduced in two-​thirds of cases. An attractive aspect of this procedure is that its performance does not preclude surgical repair if subsequently needed. Survival in this randomized trial is similar at 4 years follow-​up, but the likelihood of requiring surgery or repeat clipping is nearly 25% in the clip-​treated group. Surgical repair of the mitral valve remains the preferred treatment for most patients with mitral regurgitation requiring treatment. Percutaneous treat- ment is an acceptable option for patients with severe primary mitral regurgitation for whom the risk of surgery is high due to comorbidity. Aortic stenosis Experience with balloon valvuloplasty for patients with aortic stenosis has been disappointing, largely due to an almost universal tendency for the stenosis to recur within 1 year. Consequently, it is performed as a stand-​alone procedure only under unusual circumstances. It has a role for children with congenital aortic stenosis, where temporary treatment by valvuloplasty may allow the child to complete growth before requiring surgical valve replacement. It is now used to prepare the aortic valve in advance of transcatheter aortic valve implantation (TAVI). These valves are fashioned from bovine pericardium inside a cylindrical cage that is either balloon expandable (Edwards SAPIEN) or self-​expanding (Medtronic CoreValve) (see Fig. 16.13.5.9). TAVI has been studied in a randomized trial comparing the SAPIEN per- cutaneous valve with medical therapy in patients whose surgical risk for valve replacement is prohibitively high (PARTNER Study, cohort B). Patients randomized to TAVI showed improved outcome at one year compared to patients assigned to medical therapy (mortality section 16  Cardiovascular disorders 3664 (a) (b) (c) (d) Fig. 16.13.5.8  Percutaneous balloon mitral valvuloplasty. (a) The distal portion of the balloon is inflated after passing through the intra-​atrial septum and mitral valve. (b) The distal balloon is pulled back against the stenotic valve. (c) The proximal portion of the balloon is inflated, locking it across the valve. (d) The waist of the balloon is inflated, dilating the valve orifice. With permission from Nobuyoshi M, et al. (2009). Percutaneous balloon mitral valvuloplasty: A review. Circulation, 119, e211–​e219. (a) (b) (c) Fig. 16.13.5.9  Current widely available transcatheter valves. (a) The Edwards SAPIEN THV balloon-​ expandable valve (Edwards Lifesciences, Irving California, USA) incorporates a stainless-​steel frame, bovine pericardial leaflets, and a fabric sealing cuff. (b) The SAPIEN XT THV (Edwards Lifesciences) utilizes a cobalt chromium alloy frame and is compatible with lower profile delivery catheters. (c) The Medtronic CoreValve (Medtronic, Minneapolis, Minnesota, USA) incorporates a self-​expandable frame, porcine pericardial leaflets, and a pericardial seal. Reprinted from J Am Coll Cardiol, vol. 60, Webb JG, Wood DA, Current status of transcatheter aortic valve replacement, pp. 483–​92, Copyright 2012, with permission from the American College of Cardiology Foundation. 16.13.5  Percutaneous interventional cardiac procedures 3665 30.7% vs. 50.7%). Cohort A of this study randomized patients whose surgical risk was considered high, but not prohibitive. Mortality for patients receiving TAVI was less than surgically assigned patients at 1 month (3.45 vs. 6.5%), but similar at 1 year (24.3% vs. 26.8%) and 2 years (33.9 vs. 35.0). Symptom improvement was similar for both treatments. Risk of stroke was greater for TAVI at 1 month (5.5% vs. 2.4%), but not different by 1 and 2 years. As a result of this study TAVI became clinically available throughout the world in 2012. In 2016 the SAPIEN 3 and PARTNER 2 trials compared TAVI and surgical valve replacement in patients having intermediate surgical risk. Outcomes were statistically similar after two years’ follow-​up. The newest application of TAVI is treatment of failed bioprosthetic valves by valve-​in-​valve implantation. The Valve-​in-​Valve Inter­ national Data (VIVID) registry has demonstrated acceptable out- comes, including 83.2% one-​year survival. Pulmonary stenosis Balloon valvuloplasty is the treatment of choice for patients with pulmonary stenosis. Most are children whose valves respond well to this treatment, the advantage of avoiding surgery outweighing the moderate tendency for restenosis of these valves. Percutaneous closure of cardiac defects Atrial septal defects and patent ductus arteriosus can be closed percutaneously with catheter-​delivered devices. One such de- vice, called a clamshell (brand names include Amplatzer, Helex, and STARFlex), has been used for this purpose for some years (Fig. 16.13.5.10). It is now available throughout the world and is useful for closing smaller defects, although larger defects still require surgical closure. A concurrent non​randomized trial com- paring outcome for percutaneous versus surgical closure of atrial septal defect suggests shorter hospital stay and fewer complica- tions for the percutaneous approach, which is now often preferred for patients with smaller ostium secundum type defects. Closure of patent foramen ovale (PFO) can be accomplished by devices similar to the clamshell used for atrial septal defect (Amplatz PFO Occluder, STARFlex, Gore Helix/​Cardioform and others). Two randomized trials (CLOSE and Gore-​REDUCE) showed statistically significant reduction of recurrent stroke for patients treated by closure rather than medical therapy alone. PFO closure has also been advocated for migraine sufferers, but the Migraine Intervention with STARFlex Technology (MIST) trial did not show significant reduction of the primary study endpoint, although the overall burden of migraine was re- duced, hence closure of PFO for prevention of migraine remains controversial. Percutaneous left atrial appendage occlusion In patients with atrial fibrillation the most common cause of stroke is embolic thrombus originating from the left atrial ap- pendage, and long-​term anticoagulation is usually required. For patients who cannot tolerate anticoagulation a novel approach to stroke prevention is occlusion of the left atrial appendage with a device such as the Watchman pictured in Fig. 16.13.5.11. This de- vice seals off the source of most emboli and thereby reduces the risk of thrombotic stroke. Several devices are under development, but the Watchman has been most extensively studied and is the only such device approved for clinical use in the United States. The PROTECT AF trial published in 2013 compared patients ran- domized to Watchman implantation with those treated by conven- tional warfarin therapy. The primary endpoint (stroke, systemic embolism, and cardiovascular or unexplained death) occurred in 3 per 100 patient years for the Watchman group, compared to 4.9 for the warfarin group. However, procedural complications (includ­ ing 5% pericardial effusion) occurred in 8.7% of the Watchman group, leading to a subsequent study (PREVAIL) which dem- onstrated a more acceptable 4.2% procedural complication rate. Current guidelines recommend left atrial occlusion for patients with non​valvular atrial fibrillation who are not good candidates Fig. 16.13.5.10  Amplatzer septal occluder made of 0.005 inch (0.127 mm) Nitinol wire tightly woven into two round discs with a 4 mm connecting waist (arrowheads). Arrow indicates the negative microscrew adaptor mounted on the right atrial disc. Reprinted from J Am Coll Cardiol, vol. 31, Thanopoulos BD, Laskari CV, Tsaousis GS, Zarayelyan A, Vekiou A, Papadopoulos GS, Closure of atrial septal defects with the Amplatzer occlusion device: preliminary results, pp. 1110–​6, Copyright 1998, with permission from Elsevier. Fig. 16.13.5.11  Artist’s rendering of the Watchman device (Boston Scientific Corporation). The nitinol frame is covered with polyethylene and held in place by ten barbs. Image provided courtesy of Boston Scientific. © 2018 Boston Scientific Corporation or its affiliates. All rights reserved. 16.14 Diseases of the arteries 3674 16.14.1 Acute 16.14 Diseases of the arteries 3674 16.14.1 Acute aortic syndromes 3674 James D. Newton, Andrew R.J. Mitchell, and Adrian P. Banning 16.14 Diseases of the arteries CONTENTS 16.14.1 Acute aortic syndromes  3674 James D. Newton, Andrew R.J. Mitchell, and Adrian P. Banning 16.14.2 Peripheral arterial disease  3680 Janet Powell and Alun Davies 16.14.3 Cholesterol embolism  3688 Christopher Dudley 16.14.1  Acute aortic syndromes James D. Newton, Andrew R.J. Mitchell, and Adrian P. Banning ESSENTIALS The acute aortic syndromes are acute dissection, intramural haema- toma, and penetrating ulcer, and all involve disruption of the wall of the aorta with potentially devastating consequences. Although relatively uncommon, left unrecognized and untreated they can carry a mortality rate of up to 2% per hour and 50% within the first few weeks. Clinical presentation—​the pain of an acute aortic syndrome is typ- ically of instantaneous onset, cataclysmic in severity, pulsatile and tearing in quality, located either in the anterior thorax or back, and migrating if a dissection extends through the thorax. Patients usu- ally appear shocked, but blood pressure may be normal or raised and heart rate relatively slow. Physical signs typically reflect the re- gion of the aorta involved and effects of pressure on adjacent struc- tures: evidence of new aortic regurgitation or development of pulse deficits should be actively sought. Diagnosis—​abnormalities on the chest radiograph and ECG are common, but neither investigation is diagnostic and further imaging is always necessary by MRI, contrast-​enhanced CT, or transoesophageal echocardiography, depending on local availability and the clinical condition of the patient. Management—​every patient with a clinical suspicion of an acute aortic syndrome should receive effective pain relief and antihypertensive medication (intravenous labetalol or esmolol), aiming to maintain systolic blood pressure less than 120 mm Hg. For confirmed intramural haematoma or dissection of the as- cending aorta (type A), emergency surgery is indicated. Penetrating ulcers can be treated with endovascular stenting. When the as- cending aorta is spared (type B), aggressive control of blood pres- sure is the usual initial management, with surgery being considered if there is evidence of further progression of dissection or ischaemic complications. In the long term, strenuous efforts to control blood pressure are indicated for all patients who have survived aortic dis- section, with repeat imaging at least once a year. Introduction An acute aortic syndrome should be considered, even if only briefly, in the differential diagnosis of any patient complaining of acute chest pain and other symptoms (Box 16.14.1.1). A careful history and physical examination will often secure the diagnosis, which is then confirmed by appropriate non​invasive investigations. The consequences of missing an acute aortic syndrome can be disas- trous: when managing a patient with acute chest pain it is always prudent for clinicians to ask themselves ‘could this be an acute aortic syndrome?’ to ensure it features in the differential diagnosis before any antiplatelet or anticoagulant agents are administered. The three mechanisms of acute aortic syndromes are acute aortic dissection, acute intramural haematoma, and penetrating ulcer of the aortic wall (Fig. 16.14.1.1). Box 16.14.1.1  Symptoms that warrant consideration of an acute aortic syndrome • Chest pain • Syncope • Thoracic back pain • Neurological, mesenteric, or limb ischaemia • Abdominal pain • Symptoms of pericardial tamponade 16.14.1  Acute aortic syndromes 3675 Pathogenesis The aortic wall is composed of three layers: a thin intimal lining, a thicker medial layer (largely composed of elastin fibres that provide strength), and a thinner adventitial outer layer from which small blood vessels (the vasa vasorum) arise to nourish the outer layers of the media. Acute aortic dissection occurs when a breach in the integrity of the intima allows blood at high pressure to penetrate through and into the media. Through this tear, pulsatile blood flow can then propagate distally, parallel to the lumen, often spiralling and split- ting the arterial wall into an inner (intima–​medial) and outer layer (media–​adventitial). This process of tearing within the wall results in the formation of a false lumen, parallel to the original true lumen, and commonly of a similar or larger size (Fig. 16.14.1.2). Further communication between the lumens (or re-​entry tears) can occur and may reduce the pressure within the false lumen, thus limiting propagation of the dissection. However, the process often extends along the entire length of the aorta to the common iliac ar- teries, threatening the origins of branch vessels that may be avulsed or narrowed by the mass effect of the false lumen, and leading to ischaemia in the dependent vascular territories. When dissection extends retrogradely towards the heart it can cause occlusion of a coronary artery and distortion of the aortic valve, resulting in acute aortic regurgitation. Dissection may also rupture into the pericar- dial space, causing cardiac tamponade. The weakened aortic wall can rupture at any point along its length; this is usually fatal. Acute intramural haematoma was described by pathologists in 1920. It usually occurs when the small arterioles that run in the outer media of the aorta (the vasa vasorum) rupture and bleed, rarely it can occur following trauma. It is a medial/​adventitial event, with the intima remaining intact, and there is no false lumen (Fig. 16.14.1.3). The clinical presentation is very similar to that of acute aortic dissec- tion, with thoracic pain being the commonest presenting symptom. The diagnosis can only be made by exclusion of an intimal tear or a penetrating atherosclerotic ulcer. The intramural haematoma is not readily identifiable by aortography; but using non​invasive imaging, a circular or crescentic thickening of the aortic wall of more than 7 mm in depth associated with central displacement of any intimal calcification supports the diagnosis. There is increasing evidence that spontaneous intramural haematoma may be a precursor of aortic dissection. Clinical studies have supported this assertion: des- pite aggressive blood pressure control, up to 50% of patients with an intramural haematoma develop dissection or aortic rupture. Surgery is generally indicated when the ascending aorta is involved. Penetrating atherosclerotic ulcer presents with similar symptoms to aortic dissection, usually in elderly patients with disseminated atheroma. Intimal disruption caused by atheroma results in perfor- ation and secondary haemorrhage into the media. Imaging demon- strates an out-​pouching from the lumen into the aortic wall with localized haemorrhage and evidence of diffuse atheroma. Rarely, this can cause a localized dissection, but the main threat is the (b) (a) Penetrating aortic ulcer Spontaneous intramural haematoma Thrombus L Mural haemorrhage Intact intima Disrupted intima Medial haemorrhage Fig. 16.14.1.1  Mechanism of acute thoracic aortic syndromes: (a) spontaneous intramural haematoma; (b) penetrating atherosclerotic ulcer. Dissection flap true false Fig. 16.14.1.2  Transoesophageal echocardiography of the descending aorta showing a dissection flap separating the true and false lumens. Haematoma Aorta Fig. 16.14.1.3  Transthoracic echocardiography of the ascending aorta. The aorta is dilated and there is a posterior intramural haematoma. section 16  Cardiovascular disorders 3676 high incidence of rupture. Pseudoaneurysm formation can occur (Fig. 16.14.1.4). Treatment is usually with endovascular stenting to cover the ulcer, or with high-​risk surgery. Classification The commonest sites for thoracic aortic dissection to originate are in the ascending aorta, just above the sinuses of the aortic valve, and in the upper descending aorta just beyond the origin of the left sub- clavian artery. The Stanford group proposed a classification that is directly linked to patient management (Fig. 16.14.1.5). Aortic dis- section that involves the ascending thoracic aorta is classified as type A and demands consideration of immediate surgery, whereas dissection that spares the ascending aorta is classified as type B and initial management is usually medical. Aetiology The most common predisposing risk factor (70% of patients) for aortic dissection is hypertension. Although the processes involved in the initiation of dissection remain incompletely understood, medial haemorrhage from rupture of vasa vasorum appears to be important. When this process is self-​limiting and there is no ex- pansion of the resultant haematoma by recurrent bleeding, healing may occur with reabsorption of the haemorrhage. Alternatively, and particularly when the bleeding is extensive or recurrent, a large intramural haematoma may form around the circumference of the aorta. This alters the distribution of tensile stresses within the aorta, with much of the redistributed stress affecting the intima/​endothe- lium overlying the mass. An intimal tear may then result in split- ting and separation of the media, propagation of a false lumen, and dissection. Specific risk factors Patients with Marfan syndrome (see Chapter 16.11) may present with aortic dissection or aortic root dilatation and aortic regurgi- tation (Fig. 16.14.1.6). Abnormal fibrillin within the aortic media results in intimal instability, particularly when aortic dilation leads to increased wall stress. Although the absolute risk of dissection rises with increasing size of the ascending aorta, it is important to remember that all patients with Marfan syndrome are at risk, particularly when there is a family history of aortic dissection (Box 16.14.1.2). Loeys–​Dietz syndrome is an autosomal dom- inant connective tissue disorder caused by genetic mutations Pseudoaneurysm Fig. 16.14.1.4  Emergency aortography during endovascular closure of a pseudoaneurysm occurring due to a penetrating atherosclerotic ulcer. aortic regurgitation dilated aorta Fig. 16.14.1.6  Transthoracic echocardiography in a patient with Marfan syndrome. The aortic root is significantly dilated with a central jet of aortic regurgitation. Type A Type B Fig. 16.14.1.5  The Stanford classification of aortic dissection. Type A dissection involves the ascending aorta, irrespective of the distal extent of dissection. 16.14.1  Acute aortic syndromes 3677 in transforming growth factor-​β and leads to aortic dilation at a younger age than the Marfan syndrome. Patients with Ehlers–​ Danlos syndrome are also at risk of spontaneous dissection, not only of the aorta but of its principal branches, including the cor- onary arteries. Patients with coarctation of the aorta and those with bicuspid aortic valves also appear to be at increased risk of dissection, pos- sibly related to defects in aortic wall composition. Dissection may also occur in patients with Turner’s syndrome, Noonan’s syn- drome, and in the later stages of pregnancy, particularly in pa- tients with Marfan syndrome. In high-​risk patients with Marfan syndrome and a dilated aorta (or a family history of dissection) deferring pregnancy until after elective aortic root replacement may be advisable. Clinical features Most patients present with characteristic symptoms and clinical findings, in which case the diagnosis of dissection can be made with reasonable assurance. However, a few present atypically and it is worth considering the possibility of aortic dissection in any patient who is haemodynamically unstable without satisfactory explanation. The pain of acute dissection of the aorta can be described in terms of its (1) instantaneous onset, (2) cataclysmic severity, (3) pulsatile and tearing quality, (4) location either in the anterior thorax or back, and (5) migration as it follows the course of the dissection through the thorax. Careful interrogation about the presence of these five features will usually allow differentiation from other causes of chest pain. The instant onset, tearing/​pulsatile quality, and migratory pattern contrast with the pain of cardiac ischaemia, which is usu- ally gradual in onset (over minutes), tight or crushing, and more unchanging in its distribution in the anterior chest. Syncope shortly after the onset of typical pain is not common, but is another char- acteristic presentation of dissection, often caused by rupture of the false lumen into the pericardial cavity. Other uncommon modes of presentation include stroke and limb ischaemia, with or without pain, and very occasionally congestive heart failure resulting from severe aortic regurgitation. Although patients with dissection usually appear shocked, their blood pressure may be normal or raised and their heart rate rela- tively slow. The distribution of the abnormalities detected by phys- ical examination usually reflect the region of the aorta involved in the dissection and pressure on adjacent structures. Signs of aortic regurgitation or tamponade are likely to be found in a patient with dissection involving the ascending aorta, whereas absent upper limb pulses and cerebral abnormalities suggest involvement of the aortic arch. Expansion of the arch may compress venous return and cause engorgement of one or both jugular veins. Similarly, hoarseness and Horner’s syndrome can follow pressure on the left recurrent laryn- geal nerve and superior cervical ganglion, respectively. Tenderness over a carotid artery may be due to dissection extending up the ar- tery from the arch. Involvement of the descending aorta can result in visceral and lower limb ischaemia. Although traditional teaching emphasizes the relevance of blood pressure discrepancy between the arms, this is not a particularly sen- sitive sign, particularly when dissection spares the ascending aorta and arch. However, evidence of new aortic regurgitation or develop- ment of pulse deficits are specific signs of dissection and should be actively sought by the examining physician. Clinical investigation Abnormalities of the chest radiograph and electrocardiogram (ECG) are common in patients with dissection, but neither investi- gation is diagnostic and further imaging is always necessary. Chest radiograph Potential abnormalities on the chest radiograph include a widened aortic contour, aortic kinking, tracheal deviation, left pleural effu- sion, and a widened mediastinum (Fig. 16.14.1.7). The ‘calcium sign’ is medial displacement of the calcium in the aortic knuckle by more than 6 mm and occurs in 20% of cases. The chest radiograph is normal in 10% of patients with acute aortic dissection. Urgent portable anterior–​posterior chest radiographs are often of insuffi- cient quality to comment on the mediastinal contours and cannot be relied upon. Box 16.14.1.2  High-​risk conditions for acute aortic syndromes • Marfan syndrome • Loeys–​Dietz syndrome • Bicuspid aortic valve • Recent aortic manipulation • Prior aortic dissection • Known thoracic aortic aneurysm • Family history of aortic dissection or thoracic aneurysm • Hypertension Fig. 16.14.1.7  Chest radiograph in aortic dissection showing mediastinal enlargement. section 16  Cardiovascular disorders 3678 ECG Non​specific ST-​segment and T-​wave changes on the ECG are often found, as are changes of left ventricular hypertrophy related to pre- vious hypertension. The ECG is normal in one-​third of patients. Actual involvement of a coronary artery is relatively uncommon, presentation is usually with features of right coronary occlusion since involvement of the left main stem is usually rapidly fatal. An atypical distribution of ST-​elevation changes (i.e. generalized acute changes, affecting the anterior and inferior leads) is well recog- nized and should always alert the physician to the possibility of a diagnosis other than acute myocardial infarction and thereby re- duce the possibility of inadvertent administration of thrombolytic treatment. Blood tests The diagnosis of aortic dissection should not be delayed while the results of blood tests are awaited. Immunoassay of serum smooth muscle myosin heavy chains has a high sensitivity and specificity for the diagnosis of aortic dissection, but is not used in routine clin- ical practice. Cardiac enzymes are usually normal, but an elevated cardiac troponin on admission is a marker for a worse in-​hospital outcome. If there is haemolysis of blood in the false lumen, lactate dehydrogenase may be elevated. Haemoglobin may be reduced if there has been significant leakage of blood from the aorta. A mildly raised leucocyte count, and raised C-​reactive protein are common. D-​dimer is often elevated in dissection but is a non​specific finding. A normal D-​dimer test has been used in low risk patients to identify those unlikely to benefit from further aortic imaging. Key imaging studies The priorities when imaging a patient with suspected dissection are to confirm the diagnosis and to decide if the ascending aorta is involved (Stanford type A), as this will determine whether emer- gency surgery is required. The surgeon wants to know the entry site of the dissection, if the aortic valve is competent, if there is a pericardial effusion or tamponade, and if there is involvement of the coronary arteries. Several diagnostic techniques are available (Table 16.14.1.1). Historically, aortography was the investigation of choice, but it has several disadvantages. These include delay during the as- sembly of the catheter laboratory team, the risk of aortic rup- ture during catheter manipulation, and the nephrotoxicity of radiological contrast media when renal function may already be compromised by hypotension or renal artery involvement. CT, MRI, and echocardiography all have proven advantages over aortography. However, with the advent of primary percutaneous coronary intervention some patients do present to the cardiac catheter laboratory with a diagnosis of acute coronary syndrome. Aortic dissection should always be considered in those in whom coronary angiography is normal and further imaging performed if appropriate. Contrast-​enhanced CT is non​invasive, but requires the use of radiological contrast medium. In sensitivity and specificity, it is at least equivalent to aortography, but its accuracy is inferior to MRI, although this has been improved by the use of newer multislice CT scanners. MRI is non​invasive and provides excellent images of the whole aorta. Its sensitivity and specificity for dissection are up to 100% in some series, and the addition of cardiac gated and cine techniques can give information on luminal blood flow and valvular regurgitation (Fig. 16.14.1.8). MRI is therefore the investigation of choice for most diseases affecting the aorta, but it has several limita- tions in patients with suspected acute dissection of the aorta. These include the requirement for patient transfer to the scanner, with at- tendant delays, restricted access to the patient during scanning, and the high degree of patient cooperation required to obtain artefact-​ free images. The limited sensitivity and specificity of transthoracic echocardi- ography mean that it cannot be used to exclude aortic dissection. However, in some cases dissection of the ascending aorta can be confidently diagnosed using parasternal and suprasternal imaging, mandating urgent transfer to a surgical centre where additional in- formation can be obtained by transoesophageal echocardiography in the anaesthetic room. Transoesophageal echocardiography pro- vides detailed anatomical information about the morphology of a dissection and can also demonstrate the consequences of proximal extension, including the presence of aortic regurgitation, pericardial effusion, and involvement of the coronary artery ostia, thus making complementary investigations such as angiography unnecessary (Fig. 16.14.1.9). Table 16.14.1.1  Sensitivity and specificity of investigations for the diagnosis of aortic dissection Investigation Sensitivity (%) Specificity (%) MRI 99–​100 99–​100 CT 96–​100 96–​100 Transoesophageal echocardiography 98 95 Transthoracic echocardiography 59–​85 63–​96 Aortography 77–​88 94 Fig. 16.14.1.8  MRI of the chest. A dissection flap in the descending aorta and a left-​sided pleural effusion (large arrow) are visible. 16.14.1  Acute aortic syndromes 3679 Management Emergency management Lowering systolic blood pressure and limiting shear stress re- duces the likelihood of progression of dissection. Every patient with a clinical suspicion of dissection should therefore receive ef- fective pain relief (intravenous morphine is usually required) and antihypertensive medication pending a definitive diagnosis by imaging. Patients should be cared for in a high-​dependency area with continuous monitoring of the ECG and regular blood pres- sure and urine output measurement. Ideally, systolic blood pres- sure should be maintained below 110 mm Hg and heart rate to less than 60 bpm, using intravenous labetalol (initial dose 50 mg bolus followed by 1–​2 mg/​min) or intravenous esmolol. Both these agents produce a rapid and titratable reduction in blood pressure, with β-​blockade particularly appropriate in this context because it reduces the force of cardiac contraction and the rate of rise of the arterial pressure (dP/​dt). If blood pressure control remains suboptimal, an additional infusion of sodium nitroprusside may be used (0.5–​8 micrograms/​kg per min). Intravenous nitrates and oral calcium antagonist are alternatives in patients who are in- tolerant of β-​blockers. Patients presenting with or developing cardiogenic shock should undergo immediate echocardiography for investigation of pericardial tamponade. Emergency surgery is the treatment of choice, as peri- cardiocentesis can accelerate bleeding and is usually ineffective. The optimal management of patients with aortic dissection re- quires close liaison between those who admit patients as medical emergencies and cardiac surgical centres, using local guidelines for investigation that should reflect the available expertise and surgical opinion. Patients with a low clinical index of suspicion of dissection who are in a stable cardiovascular state should undergo prompt in- vestigation in their local hospital, using a nominated non​invasive technique—​usually CT scanning. Unless non​invasive imaging is available immediately, unstable patients with a high clinical index of suspicion should receive medical treatment and be transferred immediately to a surgical centre for both diagnostic imaging and management. This approach minimizes delay, a critical aspect of the management of acute aortic dissection. Surgery When the dissection involves the ascending aorta (type A), imme- diate surgery is required as there is a high risk of proximal exten- sion causing dissection of the coronary arteries, incompetence of the aortic valve, and rupture into the pericardium. Surgery usually involves excision of the intimal tear in the ascending aorta and interposition of a Dacron graft. This procedure protects the lower ascending aorta and valve from progressive dissection and prevents distal extension by reducing pressure within the false lumen. The false lumen may subsequently thrombose, or—​in cases with mul- tiple intimal tears—​may remain patent but decompressed. Replacement of the aortic valve is usually performed only when resuspension of the valve is not possible. However, in patients with Marfan syndrome the ascending aorta and valve are usually replaced with a composite graft to prevent subsequent annular dilatation. In cases where dissection extends into the aortic arch, some surgeons advocate that the arch and great vessels should be included in the initial repair as arch involvement is a strong predictor of a require- ment for repeat surgery. However, extended surgery can increase the duration of the operation and the risk of damage to the central ner- vous system, hence inclusion of the arch in dissection repair is gen- erally restricted to expert centres. Spinal cord damage and paraplegia is a common complication of aortic dissection repair, resulting from cross-​clamping of the aorta. Techniques to improve distal aortic perfusion can reduce the inci- dence of this complication to less than 5%. The overall operative mortality for surgical repair is between 10 and 20%. Further management of descending aortic dissection Proximal extension towards the heart is less likely when the dissec- tion begins distal to the left subclavian artery (type B). These patients (a) (b) Dissection flap Dissection flap aorta RCA Fig. 16.14.1.9  Transoesophageal echocardiography at the level of the aortic valve: (a) view along the aorta; (b) cross-​sectional view. There is a large dissection flap in the ascending aorta (type A) that nearly involves the ostium of the right coronary artery (RCA). 16.14.2 Peripheral arterial disease 3680 Janet Pow 16.14.2 Peripheral arterial disease 3680 Janet Powell and Alun Davies section 16  Cardiovascular disorders 3680 tend to be older than those with ascending aortic involvement and are more likely to have comorbidity. Diligent blood pressure man- agement is the usual initial treatment, as surgery on the descending thoracic aorta carries significant mortality and morbidity, including impaired blood supply to the spinal cord and paraplegia. However, some centres recommend elective surgery (after several weeks) in selected patients with Marfan syndrome, in younger patients with dissection associated with large aneurysms, and if thrombosis of the false lumen fails to occur. Surgery for type B dissection should be considered if there is evi- dence of proximal extension of the dissection, progressive aortic en- largement threatening external rupture, or ischaemic complications from involvement of major arteries. For example, the prognosis is extremely poor when ischaemia occurs in the territory of a major abdominal artery, in which case emergency surgical fenestration of the intimal flap can be life-​saving. Endovascular stenting to obliterate flow in the false lumen by deploying a covered stent across the site of intimal tear can relieve branch ischaemia and prevent further aneurysmal dilation in pa- tients with complicated dissection starting distal to the left sub- clavian artery. Follow-​up and prognosis Strenuous efforts to control blood pressure are indicated for all patients who have survived aortic dissection. β-​Blockers are the agents of choice for most, with other agents added as required. Most patients will require a combination of antihypertensive agents to achieve satisfactory blood pressure control (systolic <120–​130 mm Hg). Imaging at least once a year is recommended, using the modality with which there is most local expertise. Increased frequency of imaging is recommended following any acute event, for example severe chest pain, and for some patients with Marfan syndrome. The long-​term survival of patients with type A aortic dissection who have surgery and survive to discharge is encouraging: 90% are still alive at 3 years. Although patients who are treated med- ically have extremely high in-​hospital mortality (50%), two-​thirds of patients who survive to hospital discharge are alive 3 years later. The mortality is often not related to dissection but from other car- diovascular conditions. Patients with a history of atherosclerosis or prior cardiac surgery are at increased risk of death. In-​hospital mortality for patients treated medically with type B dissection is 10%, and 3-​year survival is approximately 70%. FURTHER READING Dake MD, et al. (1999). Endovascular stent graft placement for the treatment of acute aortic dissection. N Engl J Med, 340, 1546–​52. Estrera AL, et al. (2006). Outcomes of medical management of acute type B aortic dissection. Circulation, 114, 384–​9. Evangelista A, et al. (2005). Acute intramural hematoma of the aorta. A mystery in evolution. Circulation, 111, 1063–​70. Klompas M (2002). Does this patient have an acute thoracic aortic dis- section? JAMA, 287, 2262–​72. Kodolitsch Y, et al. (2004). Chest radiography for the diagnosis of acute aortic syndrome. Am J Med, 116, 73–​7. Macura KJ, et al. (2003). Pathogenesis in acute aortic syndromes: aortic dissection, intramural hematoma, and penetrating atherosclerotic aortic ulcer. Am J Roentgenol, 181, 309–​16. Nienaber CA, Eagle KA (2003). Aortic dissection: new frontiers in diagnosis and management. Part I: from etiology to diagnostic strat- egies. Circulation, 108, 628–​35; part II:  therapeutic management and followup. Circulation, 108, 772–​8. Nienaber CA, et al. (1993). The diagnosis of thoracic aortic dissection by noninvasive imaging procedures. N Engl J Med, 328, 1–​9. Silaschi M, et al. (2017). Aortic dissection: medical, interventional and surgical management. Heart, 103, 78–​87. Trimarchi S, et al. (2006). Role and results of surgery in acute type B aortic dissection: insights from the international registry of acute aortic dissection (IRAD). Circulation, 114, 357–​64. Tsai TT (2005). Acute aortic syndromes. Circulation, 112, 3802–​13. Tsai TT, et al. (2006). Long-​term survival in patients presenting with type A  acute aortic dissection:  insights from the international registry of acute aortic dissection (IRAD). Circulation, 114, 350–​6. Vilacosta I, et al. (1998). Penetrating atherosclerotic ulcer: documen- tation by transoesophageal echocardiography. J Am Coll Cardiol, 32, 83–​9. 16.14.2  Peripheral arterial disease Janet Powell and Alun Davies ESSENTIALS The most common presentations of peripheral arterial disease are intermittent claudication and abdominal aortic aneurysm. In patients under 50 years of age the cause of disease is most likely to be genetic, congenital, immunological, infectious, or traumatic; over 50 years of age the principal risk factor is smoking. Diagnosis—​the main diagnostic method used to confirm the diag- nosis of peripheral arterial disease is Doppler ultrasonography, in particular to estimate the ratio of systolic blood pressure at the ankle and in the arm, the ankle–​brachial pressure index (normal value 1.0–​ 1.4, <0.9 abnormal). Ultrasonography is the standard technique for demonstrating abdominal aortic aneurysms, usually defined as being when the maximum aortic diameter exceeds 3 cm. Critical leg ischaemia is defined as gangrenous change, ulceration, tissue loss, or rest pain lasting for 2 weeks, with an absolute ankle pressure of less than 50 mm Hg. Acute leg ischaemia Presents as a painful, pale, and pulseless limb, and is usually caused by thrombosis at the site of an atherosclerotic stenosis. Requires adminis- tration of analgesia and, if appropriate, rapid surgical intervention: (1) for irreversible ischaemia the options are amputation or palliative care; (2) for severe but potentially reversible ischaemia (white leg), sur- gery is usually the treatment of choice; and (3) for moderate limb is- chaemia (no paralysis and only mild sensory loss), arteriography with consideration of thrombolysis, endovascular angioplasty/​stenting, or surgical embolectomy/​endarterectomy/​bypass. 16.14.2  Peripheral arterial disease 3681 Chronic leg ischaemia Most commonly presents with claudication affecting the calf and thigh. This is associated with high cardiovascular risk, but only 5% will go on to lose a limb, and surgical or endovascular intervention is not usually required. Key elements in management are smoking cessa- tion, aspirin, and statins. Abdominal aortic aneurysm Ruptured abdominal aortic aneurysm typically causes collapse and severe back or abdominal pain: less than 20% reach hospital alive, and almost one-​half of those undergoing emergency surgical die within 30 days. By standard definition, 2–3% of men older than 55 years have an abdominal aortic aneurysm, but most of these are small (3–​5.5 cm). These should be managed by ultrasound surveillance, with attention to modification of cardiovascular risk factors. Repair is generally recommended for asymptomatic aneurysms larger than 5.5 cm in men ( >5 cm in women), or symptomatic aneurysms of any size. Minimally invasive endovascular aneurysm repair has an operative mortality of about 2%, which is only one-​ third of that associated with traditional open repair, but within 2 years the mortality advantage of endovascular repair has been lost and long-​term outlook is unknown. Introduction Peripheral arterial disease, defined for the purpose of this chapter as diseases of the abdominal aorta and its branches, has risk fac- tors and features that overlap with, but can be distinguished from, those of coronary artery disease. The two conditions often coexist, but patients with coronary disease are almost always referred dir- ectly to physicians, whereas those with peripheral arterial disease are referred directly to vascular surgeons, particularly in regions where angiology is a poorly developed specialty, since medical therapies are limited. Vascular surgeons also manage patients with arterial disease in the carotid vessels and upper limbs. These aspects re- ceive only passing mention in this chapter: for discussion regarding the clinical features and management of carotid artery disease, see Chapter 24.10.1. The most common presentations of peripheral arterial disease are intermittent claudication and abdominal aortic aneurysm. Most peripheral arterial disease remains asymptomatic. It is not a new disease that results from a modern Westernized lifestyle. Atherosclerotic disease, partially occluding the peripheral ar- teries, has been described in the mummies of ancient Egypt. Life as a cavalry officer was associated with an increased risk of popliteal aneurysm, a condition treated by ligation by John Hunter, the pi- oneering 18th-​century surgeon. Albert Einstein died of a ruptured abdominal aortic aneurysm. Techniques for repairing abdominal aortic aneurysms were not developed until the middle of the 20th century. This was the golden era for the development of vascular surgery as a specialty, with the increasing use of bypass surgery that reduced the need for amputa- tion. Today newer, less invasive approaches are being employed—​ angioplasty and endovascular stenting—​but few specific medical therapies are on the horizon. Aetiology and epidemiology Peripheral arterial disease may occur in young people, but the prevalence increases sharply with age. Both young and old may suffer from occlusive (stenosing) disease of the peripheral arteries or dilating (aneurysmal) disease, while vasospastic disease is un- common. However, the underlying causes of peripheral arterial disease in those below and above 50 years of age tend to be very different. Peripheral arterial disease in patients less than 50 years old In younger patients, the cause of disease is most likely to be genetic, congenital, immunological, infectious, or traumatic. Patients with familial hypercholesterolaemia and related inherited disorders of lipid metabolism may present with peripheral limb ischaemia. There are also congenital causes of early-​onset leg ischaemia. These in- clude aortic hypoplasia, which occurs during the embryonic fusion of the distal aortas, and popliteal entrapment, where the popliteal artery takes an unusual course through the head of the gastrocne- mius muscle, with exercise involving knee flexion causing intermit- tent occlusion of the artery and calf pain that resembles intermittent claudication. A  fierce immunological inflammatory response to smoking causes Buerger’s syndrome, which involves the artery, vein, and associated nerves in both the legs and the arms. This disease, seen principally in men, is particularly prevalent in the Indian sub- continent, and may resolve if the patient stops smoking. Sudden thrombotic occlusion of the iliac and distal arteries may occur in those below 50 years of age, suggesting the presence of an inherited thrombotic disorder. Embolic occlusion from a proximal source is also possible. Marfan syndrome may sometimes be confirmed only after a pa- tient has presented with a ruptured abdominal aortic aneurysm. In some variants of Ehlers–​Danlos syndrome, patients with mutations in type III collagen present with visceral artery aneurysms. In South Africa (and elsewhere), aneurysms of the abdominal, femoral, or popliteal arteries in those under 50 years have been attributed to infectious causes, from HIV to tuberculosis. Syphilitic aneurysms, which used to affect principally the thoracic aorta, are now rare. Peripheral arterial disease in patients over 50 years old For patients over 50 years of age, the principal risk factor for per- ipheral arterial disease—​stenosing, aneurysmal, or vasospastic—​is smoking. The pathology is atherosclerotic change with superim- posed thrombosis. Of patients who present with peripheral arterial disease, less than 5% have never smoked. For this reason, more men than women presented with peripheral arterial disease in the past, but recently more women are affected, perhaps a reflection of the increasing number who smoke. Nevertheless, unlike Buerger’s disease, cessation of smoking is not associated with an immediate dramatic improvement in symptoms and it may take several years without smoking to improve prognosis. Diabetes is another important risk factor for stenosing periph- eral arterial disease. Other risk factors include hypertension, raised levels of plasma fibrinogen, and hyperlipidaemia, with elevated plasma triglycerides being a common finding. The risk factors for dilating arterial disease are similar, with the exception of diabetes, which is rare. section 16  Cardiovascular disorders 3682 For aortic aneurysms, strong familial clustering has been ob- served, and genome wide association studies have identified as- sociations with several genes not associated with coronary artery disease, including those modifying the protease MMP-9. White and northern European populations appear to be at higher risk of aneurysmal disease than black populations. Stenosing and aneur- ysmal disease are associated with degenerative changes of the artery wall, the prevalence of both diseases increasing sharply with age (Table 16.14.2.1). Epidemiological studies also indicate a difference between stenosing and aneurysmal disease, with death from aneur- ysmal disease (aortic aneurysm) being more common among those of higher social classes and in affluent geographical areas. Leg ischaemia Clinical features The terms acute and chronic relate purely to the length of time that symptoms have been present and must not be confused with terms related to severity, such as critical limb ischaemia. Critical leg ischaemia Critical leg ischaemia is defined as gangrenous change, ulceration, tissue loss, or rest pain lasting for 2 weeks, with an absolute ankle pressure of less than 50 mm Hg, although patients with diabetes are difficult to include in this classification because ankle pressures in such patients may be unreliable due to arterial calcification. Acute leg ischaemia The incidence of acute leg ischaemia, which presents as a painful, pale, and pulseless limb, is 1 in 12 000 patients per year. It can be due either to an embolic event or to thrombosis of an atherosclerotic stenosis. The commonest cause of a peripheral embolus used to be rheumatic heart disease in a patient with atrial fibrillation, but this is now uncommon, and other sources of emboli, such as an aortic aneurysm, must be considered. The development of a thrombosis at the site of an atherosclerotic stenosis, in either the superficial femoral artery or the popliteal artery, is undoubtedly now the com- monest cause of acute leg ischaemia. However, it should be stressed that, whatever the cause, there is no difference on clinical examin- ation of the acutely ischaemic limb. Arterial trauma due to road traffic accidents and knife or gunshot wounds is becoming commoner, as is iatrogenic trauma following the insertion of intra-​arterial catheters for diagnosis or therapy. A  rare but dramatic cause of acute leg ischaemia is phlegmasia cerulea dolens, in which massive thrombosis of all the major veins of the limb occurs with gross swelling that obstructs the arterial supply. Patients with a thrombosis of a popliteal aneurysm may present with classic symptoms of pain, paralysis, loss of power, paraes- thesia, pallor, lack of pulse, and perishing cold. If the blood supply is not restored, fixed blue staining of the skin is a further sign of ir- reversible ischaemia, as is a tense calf with plantar flexion. However, most patients presenting with acute ischaemia have symptoms that are less severe. Chronic leg ischaemia Chronic leg ischaemia is much more common than acute ischaemia (Table 16.14.2.1), and its main cause is atherosclerosis. In the young patient, one should also consider cystic adventitial disease, entrap- ment of the popliteal artery, and occasionally fibromuscular hyper- plasia of the iliac arteries, particularly in women. Symptoms are pain on walking, claudication affecting the calf and thigh, rest pain, ulceration, and gangrenous change. Less com- monly, patients may present with buttock claudication and impo- tence (Leriche’s syndrome). Although the differential diagnoses of the acutely ischaemic limb are few, in the chronically ischaemic limb pain may be due to spinal stenosis or nerve-​root compression (spinal claudication) or arthritis of the hip or knee. Classically the patient with claudication will complain of cramp-​like pain in the calf, appearing after walking a particular distance, relieved by a few minute’s rest, and recurring again at the same distance if the pa- tient resumes walking. Failure of the pain to disappear on resting, or its reappearance after a shorter distance after each rest, suggests a possible musculoskeletal cause, particularly if distal pulses are pre- sent on examination. However, it should also be remembered that distal pulses may be felt at rest in the limbs of patients with claudi- cation due to peripheral vascular disease, but disappear on exercise to the point of pain. Investigations The main diagnostic method used to confirm the diagnosis of periph- eral arterial disease is Doppler ultrasonography (duplex scanning), Table 16.14.2.1  The increasing prevalence of peripheral arterial disease with age in the populations of northern Europe Age (years) Population Asymptomatic peripheral arterial disease (ABPI <0.9) (%) Intermittent claudication (%) Abdominal aortic aneurysm (>3 cm) (%) 55–​64 Men 8 1.2 1 55–​64 Women 7 0.8 0.2 65–​74 Men 16 2.5 2.5 65–​74 Women 11 1.2 0.4 75+ Men 30 4.0 6 75+ Women 30 1.5 1.5 ABPI, ankle–​brachial pressure index. Most peripheral arterial disease, both stenosing and dilating, is asymptomatic. The data have been derived from several studies and geographical variation may occur. 16.14.2  Peripheral arterial disease 3683 an example of which is shown in Fig. 16.14.2.1. The ratio of systolic blood pressure at the ankle and in the arm, the ankle–​brachial pres- sure index (ABPI), provides a physiological measure of blood flow at the level of the ankle. At rest, in a normal leg, the ABPI lies be- tween 1.0 and 1.4. As the blood flow in the leg is compromised, the ABPI falls sharply, and values below 0.9 are considered abnormal and likely to confirm the diagnosis of peripheral vascular disease. To emphasize the important overlap between this condition and cor- onary artery disease, a reduction in ABPI nearly always signals the presence of coronary artery disease, which is the cause of death in most patients with peripheral arterial disease. Exercise testing provides an objective method of assessing walking distance and helps with the identification of disease processes, such as angina, that may be limiting. It only needs to be used in those people who have a history of claudication but have normal resting ABPI, and can be used as a way of eliminating or suggesting other diagnoses. In addition to establishing the diagnosis of peripheral arterial disease, duplex ultrasonography is able to determine the site of dis- ease and indicate the degree of stenosis or length of an occlusion and hence aid in the planning of interventional treatment. Other imaging modalities such as CT scanning and magnetic resonance angiography can provide three-​dimensional reconstructions of the diseased vessels and may be used for planning surgical treatment. Angiography is only required as an adjuvant to endovascular treat- ment, for surgical planning in some circumstances, or in the man- agement of the acutely ischaemic limb. Attention to risk factors, in particular smoking, blood pressure, and exercise, are important issues. Management Critical and acute leg ischaemia Critical limb ischaemia requires administration of analgesia and rapid surgical intervention. The severity of ischaemia will determine the treatment options considered. However, all patients with a se- verely ischaemic limb should be given adequate analgesia and 5000 units of heparin intravenously. Many will be old and frail, with sig- nificant medical comorbidities. These issues must be considered in deciding whether or not surgical intervention is appropriate for any individual case, with action taken to improve those aspects of the patient’s medical condition that can be improved before surgery, or as part of continuing medical management. For a patient with irreversible ischaemia (fixed skin staining and tense muscles), the main decision is whether a primary amputation or palliative care should be offered. If severe but potentially reversible ischaemia is present (white leg), surgery is usually the treatment of choice. Delay while thrombolytic therapy is tried is not advisable in this group. For patients with moderate limb ischaemia, where there is no paralysis and only mild sensory loss, arteriography with con- sideration of the potential use of thrombolysis should be performed. However, it should be remembered that thrombolysis is associated with numerous potential complications, most notably gastrointes- tinal haemorrhage and stroke, and is contraindicated in the early postoperative period. If the limb is salvageable, it may be possible to offer the patient an endovascular procedure, such as an angio- plasty (with or without stenting). Surgical treatment can involve simple embolectomy, but may require a bypass procedure or end- arterectomy, and in the severely ischaemic limb fasciotomies may be needed to treat or prevent a compartment syndrome. For at least 10% of patients, it will not be possible to offer revascularization: a few of these may benefit from the use of a prostacyclin analogue (iloprost), which might diminish amputation rates and alleviate pain. Any benefits of gene therapy on avoidance of amputation, with vascular endothelial growth factor, fibroblast growth factor, or other molecular mediators, are far from established and the only large ran- domized trial was disappointing. Limb salvage rates for patients pre- senting with critical limb ischaemia are variable, probably 50–​60% at 2 years, dependent on the severity of disease. In a patient presenting with acute leg ischaemia the outlook is poor, with only about 60% leaving hospital with an intact limb. The 30-​day mortality for this group of patients can be as high as 30%, the main cause of death being cardiac disease. The strategy for manage- ment is described in Fig. 16.14.2.2. Controversial areas in the treat- ment of acute leg ischaemia include the role of arteriography, which technique of thrombolysis is the safest and most cost-​effective, and whether initial treatment with thrombolysis is beneficial or harmful as compared to surgery. A recently updated Cochrane review, which included five randomized trials comparing thrombolysis and sur- gery for the initial treatment of acute limb ischaemia, found no overall difference in outcomes (limb salvage or death) at 1  year. Initial thrombolysis was associated with higher risk of major haem- orrhage, stroke, and distal embolization, but also less severe degree of intervention overall. In the patient who has had an embolic event, long-​term anticoagulation should not be forgotten, and nor should a search for the source of embolus. If the patient is not in atrial fibrillation, and has normal cardiac enzymes and 12-​lead electrocardiogram (ECG), Fig. 16.14.2.1  Occlusion of the superficial femoral artery demonstrated by colour-​coded duplex ultrasonography. On the left, the common femoral artery (CFA) lies outside the colour box. In the colour box antegrade flow through the profunda femoris artery (PFA) is shown in blue. The red flash represents rebound flow against the occluded origin of the superficial femoral artery (SFA). section 16  Cardiovascular disorders 3684 then they should have an echocardiogram to exclude any valvular lesion, a 24-​h electrocardiogram (ECG) to look for arrhythmia, an ultrasound scan to exclude abdominal aortic aneurysm, and a screen for thrombophilia. In many centres a CT scan of the thoracic and abdominal aorta will be performed. Chronic leg ischaemia In chronic limb ischaemia, management depends upon the severity of the disease. Most patients present with claudication, which is rela- tively benign: symptoms of intermittent claudication will progress to critical limb ischaemia in less than one in five patients and only about 5% will go on to lose a limb. However, claudication identifies patients with a threefold increased risk of death from either heart disease or cerebrovascular disease compared with age-​ and sex-​ matched controls. It is important when planning treatment that all the potential risk factors are covered. In the past surgical interven- tion was usually considered unnecessary: at least one-​third will have improvement of symptoms with simple medical treatment and ex- ercise. However recent trials have suggested that either angioplasty with adjunct and stents or coated balloons or angioplasty combined with exercise therapy may offer early benefits (to 2 years) and longer-​ term results are awaited eagerly. The current treatment of patients with chronic lower leg pain is shown in Fig. 16.14.2.3. General management Careful attention must be paid to the cleanliness of ischaemic feet to avoid infection, and particular care should be given to the cutting of toenails. In many patients this is best done by a careful relative or chiropodist, since apparently minor lacerations can lead to ul- cers, infection, and gangrene. Patients are recommended to exercise. Walking to the point of claudication is not harmful and may improve collateral circulation with beneficial results. Supervised exercise therapy is more effective than merely providing advice to exercise more, but availability of such supervision is variable. Smoking is by far the most significant risk factor for occlusive ar- terial disease and every effort should be made to encourage smokers to stop. If patients undergo surgical treatment, then the long-​term patency rate following arterial reconstruction is four times greater in smokers who stop than in those who persist. Pharmacological treatment Since coronary artery disease is the main cause of death in those with peripheral arterial disease, patients with the latter condi- tion should receive similar cardiovascular risk reduction therapy to patients with coronary heart disease. Low-​dose aspirin therapy (75–​325 mg/​day) should be recommended for all. If aspirin cannot be tolerated, ADP receptor antagonists, such as clopidogrel, are equally effective in reducing the risk of cardiovascular events (stroke, myocardial infarction, and vascular deaths). Secondary prevention trials have demonstrated the benefits of statin therapy in reducing cardiovascular morbidity and mortality in those with stenosing atherosclerotic disease of the peripheral arteries. Statins also may improve operative cardiovascular mor- bidity and mortality, but neither fibrates nor chelation therapy offer benefits. The options for facilitating smoking cessation are increasing and nicotine replacement therapy or e-​cigarettes can be used with either bupropion or varenicline if necessary, although many will not stop smoking until surgery threatens. Vasodilators may be used where supervised exercise does not bring symptomatic improvement and further endovascular or sur- gical intervention is decided against, or as a bridge to future angio- plasty or surgery. There is evidence that praxilene (naftidrofuryl oxalate) and cilostazol (a selective cAMP phosphodiesterase in- hibitor) improves walking distance in those with intermittent clau- dication, although the mechanism of action is not clear, side effects are frequent, and the drug is contraindicated in patients with con- gestive heart failure. Surgical treatment In general, surgeons are conservative with respect to interventional treatment for patients with claudication, despite a possible early benefit for those having an endovascular procedure. However, in the patient who has severe claudication, with symptoms that signifi- cantly affect their quality of life, it is certainly possible and appro- priate to offer interventional treatment. Both endovascular techniques (angioplasty with or without stent) and bypass surgery are effective treatments, with little to choose between the two. For infrainguinal bypass, good-​quality autolo- gous vein is the conduit of choice. However, reasonable results can be obtained with synthetic grafts, particularly where the distal • Pain relief • Intravenous heparin (5000 IU) • Assessment of patient prognosis and limb salvage with vascular surgical consultation Irreversible Fixed skin staining Tense muscles Amputation or palliative care Severe White leg Surgery Moderate Dusky leg Mild sensory loss Duplex or arteriogram to evaluate treatment modaility Fig. 16.14.2.2  Management of the patient with an acutely ischaemic leg. ABPI ≥ 0.9 Nonvascular Orthopaedic opinion Possibly spinal claudication or arthropathy ABPI <0.9–0.6 Probably vascular Conservative therapy first Supervised exercise, risk factor modification e.g. aspirin, statins, smoking cessation, symptomatic relief consider angioplasty ABPI <0.5 Probably rest pain Intervention and secondary prevention Angioplasty, bypass or amputation if no other options available Fig. 16.14.2.3  Management of the patient with chronic lower leg pain, but no tissue loss, stratified by ankle–​brachial pressure index (ABPI). 16.14.2  Peripheral arterial disease 3685 anastomosis is above the knee. Below the knee, an adjuvant vein interposition in the form of either a Miller cuff or Taylor patch is used. Stenting is used widely, but its use is contentious, and, at least in the infrainguinal arteries, it may not be of value. The role of ex- ercise therapy compared with angioplasty in the treatment of mild to moderate claudication continues to be debated, but it might be prudent to consider the conjoint treatment of angioplasty with ex- ercise therapy. Ischaemia of the arm Ischaemia of the arm is usually a result of embolism from the heart. Occasionally the subclavian artery is diseased or has suffered trau- matic injury or radiation damage following radiotherapy. The basic principles of investigation and management are the same as for the leg. However, it should be noted that the upper limb has multiple interconnection of collateral vessels, hence occlusion of the major arterial supply may still leave a viable limb. The other disease process that needs to be considered in differential diagnosis is the thoracic outlet syndrome, which gives rise to symptoms in the arm as a result of arterial, venous, or neurological compression caused by an add- itional cervical rib or by scalene bands. Management may require surgical intervention, either cervical rib excision or thoracic outlet decompression with the removal of the first rib. Mesenteric ischaemia Mesenteric ischaemia is uncommon. Over one-​third of cases of acute mesenteric ischaemia are due to arterial embolism, with em- boli lodging at the ostium of the superior mesenteric artery in many cases. Patients with acute mesenteric artery thrombosis have often had symptoms of mesenteric ischaemia prior to the acute episode. Chronic mesenteric ischaemia typically presents with weight loss and abdominal pain on ingestion of food, the classic story being that the patient is constantly hungry, but frightened to eat. Other causes of acute mesenteric ischaemia include venous thrombosis and non-​ occlusive ischaemia secondary to hypoperfusion. Patients with acute mesenteric ischaemia will usually present with abdominal pain, but the abdominal physical signs may be much less dramatic than would be anticipated from the subsequent clinical course. Suspicion of the diagnosis should be heightened in the pres- ence of atrial fibrillation or widespread atheromatous vascular dis- ease. Patients may deteriorate suddenly and present in shock. The diagnosis of acute mesenteric ischaemia is difficult to make. In the acute situation, clues to look for include leucocytosis, hyperamylasaemia, and unexplained acidosis. Liver function tests are usually normal. Radiological imaging is rarely able to make a positive diagnosis, although it can be very useful in excluding other possibilities. Angiography is not always accurate. CT scanning can be helpful in the diagnosis of mesenteric venous thrombosis. Intensive resuscitation to replace fluids is essential. Surgery is usually necessary for the patient to survive, and the possibility of acute mesenteric ischaemia remains one of the dwindling number of reasons for requiring an emergency diagnostic laparotomy. Depending on the findings, resection of small bowel may suffice, but formal arterial surgery may be necessary, and in some unfortunate instances the extent of irreversible ischaemia can preclude any at- tempt at resection or revascularization. In cases where the sur- geon is unsure of the viability of bowel remaining after resection, a second laparotomy may be planned to assess the situation a few days later. Repeat laparotomy may also be required to examine, and if necessary resect, more bowel in the patient who is not ‘doing well’ postoperatively. The prognosis for patients who present with acute mesenteric ischaemia is poor. For patients who present with chronic mesenteric ischaemia, the aim of treatment is to improve blood flow and prevent the cata- strophic disaster of arterial occlusion. This is most commonly due to atherosclerosis, but in younger patients the median arcuate ligament syndrome needs to be considered (compression of the diaphrag- matic crura on the coeliac artery). The potential options, having identified the site of the disease process by duplex scanning and angiography, include angioplasty, endarterectomy, reimplantation, or a surgical bypass procedure. Abdominal aortic aneurysm Definition There is no fixed definition of an abdominal aortic aneurysm beyond agreement that it is a localized dilatation of the abdominal aorta, usually fusiform, with dilation starting distal to the renal arteries. Some would apply the term when the maximum aortic diameter is more than 1.5 times the diameter of the undilated proximal aorta. Manual palpation to detect abdominal aortic aneurysms is un- reliable, unless undertaken by a specialist on a non​obese patient. The most convenient method of screening for the presence of these aneurysms is ultrasonography, measuring the anterior–​posterior diameter. Since the reproducibility of ultrasound measurements of the suprarenal aorta is poor, a convenient working definition of an abdominal aortic aneurysm is when the maximum diameter ex- ceeds 3 cm, which in most people is more than 1.5 times the diam- eter of the undilated proximal aorta. Epidemiology Population screening studies in northern Europe have shown that the disease is usually without symptoms, much more common in men than in women (Table 16.14.2.1), and strongly associated with smoking. The decline in prevalence observed this century has been associated with a parallel decline in smoking prevalence. The asso- ciations with hypertension and hyperlipidaemia are inconsistent. The prevalence of large aneurysms (>5 cm in diameter) detected by screening is <1% in men and the large majority of screen-​detected aneurysms are 3 to 5 cm in diameter. The natural history of abdom- inal aortic aneurysms is progressive enlargement (with the diameter increasing by 2–​5 mm each year) without symptoms, until the aortic wall is so weakened that it ruptures, which is a catastrophic event. The infrarenal aorta is by far the most common site of aneur- ysmal dilatation, and usually the abdominal aorta is the only site of dilatation. When patients present with aneurysms of the iliac, femoral, or popliteal arteries, abdominal aortic aneurysm is often present and screening for this is mandatory. This emphasizes the tendency of some patients to have a more generalized form of dilating arterial disease. section 16  Cardiovascular disorders 3686 Most patients (60%) with abdominal aortic aneurysm die from cardiovascular causes, and up to 25% of other male family members may develop occult aneurysms. Ruptured aneurysms The symptoms of a ruptured abdominal aortic aneurysm are col- lapse (shock) and severe back or abdominal pain. Rarely a rup- tured aneurysm will present with gastrointestinal bleeding from an aortoduodenal fistula or high-​output cardiac failure from an aortocaval fistula. Less than half of patients with a ruptured abdominal aortic an- eurysm reach hospital alive, and even among those that undergo emergency surgical repair almost one-​third will die within 30 days. New evidence indicates that mortality may be reduced considerably if the rupture is repaired using endovascular repair under local an- aesthesia. With this bleak prognosis and the very significant costs associated with emergency repair following rupture, evidence has accumulated that screening of men over 65 years of age to detect those with the largest aneurysms, at highest risk of rupture, is cost-​ effective. Accordingly, national screening programmes for abdom- inal aortic aneurysm in men have been implemented in the United Kingdom, Sweden, and other countries. Management of ruptured aneurysms requires: • Access lines, cross-​matched blood, and resuscitation—​maintaining moderate hypotension at c.70 mm Hg may be beneficial. • Confirmation of diagnosis—​ultrasound (to show aneurysm); CT scan (to confirm diagnosis of rupture). • Rapid assessment, by an experienced vascular surgeon, of whether patient would benefit from emergency repair—​if yes, immediate endovascular or surgical repair, but remembering to respect any advance patient directives. Aneurysms detected before rupture Abdominal aortic aneurysms are commonly symptomless, but rupture—​as just explained—​is catastrophic. However, elective re- pair of an abdominal aortic aneurysm, a major surgical procedure, is not without risk. Traditionally, larger aneurysms have been repaired by cross-​clamping of the aorta and insertion of a Dacron inlay graft at open surgery. This is a durable procedure and effectively ‘cures’ the patient. However, although some specialized surgical centres report an operative mortality of less than 2% associated with this elective procedure, on a population basis the mortality is more likely to be 5–​6%, which is an important reason for avoiding surgery in those with small aneurysms. Minimally invasive endovascular aneurysm repair, via femoral access vessels, has developed rapidly. Only about two-thirds of pa- tients have an aneurysm that is anatomically suitable for this mode of repair with a standard commercial device but adjunct proced- ures widen the applicability to over three-quarters of patients. Randomized trials have shown that the operative mortality associ- ated with endovascular repair is less than 2%, which is only one-​third of the mortality associated with traditional open repair. However, within 2 years the mortality advantage of endovascular repair has been lost and a significant proportion of patients with endovascular repair require further interventions to ensure continued exclusion of the aneurysm. Hence many patients with endovascular repair are likely to require lifelong surveillance. The long-​term durability and cost-​effectiveness for this newer technique have been less well established. In the United Kingdom endovascular repair has been considered cost-​effective for elective procedures (http://​www.nice. org.uk/​TA167). However, new NICE guidelines are imminent and may be less favourable towards endovascular repair. However, most patients would prefer this approach, although some still prefer open repair principally because there is no requirement for long-​ term follow-​up. For endovascular repair, late secondary rupture is a greater problem than for open repair. Although the endovascular approach was initially developed for patients not considered fit for open surgery because of numerous comorbidities, the operative mortality rises to 9% in this cohort and there is no evidence that endovascular aneurysm repair prolongs patient survival. Two large randomized trials have shown that for aneurysms of 4.0 to 5.5 cm in diameter a policy of early elective open surgery confers no long-​term survival benefit, and hence early surgery should not be recommended. Later, two small trials comparing early endovascular repair versus surveillance also showed that early intervention con- ferred no survival benefit. The data of all four trials are summarized in a Cochrane review. For such patients’ surveillance, with measure- ment of ultrasound diameter every 6 months, is a safe policy that en- genders little patient anxiety, and the risk of aneurysm rupture is very low—​1% per year. By contrast, for patients with aneurysms greater than 6 cm in diameter the risk of rupture may be as high as 25% per year, and in most such cases elective repair is recommended. Over 90% of the patients enrolled in the trials were men, and in women recent guidelines recommend a diameter threshold of 5 cm. Repair is also recommended when symptoms are attributed to the aneurysm, whatever its size, the commonest being back or ab- dominal pain, or tenderness to palpation. It is assumed that such aneurysms are at high risk of rupture and need early repair. As the aneurysm dilates, onion-​skin layers of laminated thrombus deposit in the lumen, to leave a blood-​flow channel of approximately normal aortic diameter. These layers of thrombus are very stable and only in rare circumstances are the sources of emboli to the legs. The an- eurysms which most often provoke symptoms have very thick, inflamed, fibrotic walls, which entrap nerves and may become ad- herent to other tissues. These are known as inflammatory aneurysms and the thickened wall can often be detected by CT or MRI. They are technically demanding to repair. There is no convincing evidence that a course of preoperative corticosteroids is beneficial. In the Japanese population, inflammatory aneurysms have been associated with active cytomegalovirus infection. A strategy for the management of abdominal aortic aneurysms de- tected before rupture is shown in Fig. 16.14.2.4. Patients with small 3.0–3.9 cm Ultrasound surveillance at 1–2 yearly intervals Stop smoking Control hypertension Check lipids 4.0–5.5 cm Ultrasound surveillance at 6 monthly intervals Cardiovascular risk reduction With statin, smoking cessation, aspirin, etc. 5.6 + cm or symptomatic Consider intervention Cardiovascular risk reduction With statin, smoking cessation, aspirin, etc. Fig. 16.14.2.4  Management of men with asymptomatic, unruptured abdominal aortic aneurysm stratified by aneurysm diameter. 16.14.2  Peripheral arterial disease 3687 aneurysms should stop smoking and have their blood pressure con- trolled. Since screening detects mainly small aneurysms, it would clearly be beneficial if a treatment to limit aneurysm growth were available. Although β-​blockers or losartan have proved effective in limiting the dilation of the proximal aorta in patients with Marfan syndrome, there is no evidence that they are effective for abdom- inal aortic aneurysms. Furthermore, many patients with abdom- inal aortic aneurysm have impaired lung function, perhaps through smoking, and β-​blockers are often poorly tolerated. However, ef- fective control of blood pressure and cessation of smoking are both likely to minimize the rate of aneurysm growth and the risk of rup- ture, and statins may also be helpful. Intervention to exclude the an- eurysm remains the only available treatment for aneurysms larger than 5.5 cm in diameter. Medical management Just as for patients with limb ischaemia, patients with abdominal aortic aneurysm are at high risk of cardiovascular events. All patients with abdominal aortic aneurysm should be offered statin therapy to reduce the risk of morbidity and mortality from other forms of co- existent cardiovascular disease. Antiplatelet therapy should be con- sidered, and there is some evidence that, for hypertensive patients, angiotensin-​converting enzyme inhibitors minimize the chance of aneurysm rupture. Conventional surgical management Preoperative evaluation requires CT or MRI to define the anatomy and extent of the aneurysm. Cardiac, pulmonary, and renal func- tion should always be assessed, and optimal treatment instituted be- fore surgery: poor renal and lung function are associated with an increased risk of postoperative morbidity and mortality. The most common surgical approach to an abdominal aortic aneurysm is through a transperitoneal incision under general an- aesthesia. The retroperitoneal approach, which avoids bowel ma- nipulation and permits a more rapid return to oral diet, has similar cross-​clamp, operating, and recovery times. The transperitoneal approach offers the advantage of exploring the abdominal cavity for other pathology. In this approach, after the bowel has been removed from the operative field, the aorta is exposed anteriorly from the left renal vein to the bifurcation. The infrarenal neck of the aneurysm is exposed anteriorly and laterally so that an occluding clamp may be applied. Both common iliac arteries are exposed for the placement of the distal occluding clamps. The an- eurysm is opened longitudinally on the anterior surface and the remainder of the procedure performed from inside the aneurysm cavity. Usually following a small dose of intravenous heparin, ar- terial clamps are applied. Clot and debris are evacuated and any back-​bleeding lumbar or mesenteric arteries ligated. A  Dacron prosthesis is then sutured, end-​to-​end, to the normal-​diameter aorta above the aneurysm. This anastomosis is tested for leaks be- fore the graft is trimmed to appropriate length and sutured in place above the aortic bifurcation. The aneurysmal sac is closed over the prosthesis, before replacement of abdominal contents. Such tube grafts are the most common type, but when the iliac arteries are dilated or diseased a bifurcated prosthesis is used. The cross-​clamp time should be less than 1 h and the whole procedure completed within 2 to 4 h. The longest procedures involve inflammatory an- eurysms and cases where the proximal aneurysm neck lies above the renal arteries. The patient should be ready to leave hospital 6 to 9 days after the operation, with a durable repair. Endovascular aneurysm repair The technique of endovascular repair was introduced in the early 1990s and the technology has now stabilized. The procedure may be performed under general, regional, or even local anaesthesia. This flexibility allows endovascular repair in patients where general an- aesthesia is risky, and the avoidance of aortic cross-​clamping is an additional benefit for those with limited cardiac reserve. Preoperative investigation to evaluate the extent and size of the an- eurysm (spiral CT or MRI) is of critical importance. The length of the aneurysm neck below the renal arteries, angulation of the aorta, and tortuosity of the iliac arteries must be evaluated precisely so that the correct size of graft can be placed via the femoral artery, with modular component facilitating the placement of bifurcated endografts. The insertion of the graft is performed under fluoroscopic control. This requires the use of significant amounts of contrast material, which may underlie the unfavourable results reported in patients with pre-​ existing renal impairment. The proximal end of the graft is held in place by hooks and barbs, balloon, or self-​expandable stents. The length of the procedure is similar to, or less than, that for open repair, but the transfusion requirements are less and the patient re- covers more rapidly and is ready to leave hospital within 2 to 5 days and some recent reports indicate that day-case procedures are feasible for some patients. The long-​term success of the procedure depends on the successful exclusion of the aneurysmal sac and the security of the proximal attachment to prevent graft migration. Endoleaks may develop when the aneurysm is not completely excluded, the graft migrates or fatigues, or there is back-​bleeding from lumbar vessels or the inferior mesenteric artery into the aneurysm sac. These are associated with an important risk of continued aneurysm expansion and rupture. Data from 15-​year follow-​up of the earlier random- ized trials has led physicians to re-​evaluate the role of EVAR in the younger patient. These data have shown an early survival benefit of EVAR compared to open repair, but inferior late survival (beyond 8  years) mainly attributable to secondary aneurysm sac rupture. Lifelong annual surveillance with evaluation of the aneurysm with duplex or CT scanning is necessary, with reintervention if necessary. The endovascular revolution has affected the management of all categories of peripheral arterial disease, although in many instances the advantages and indications for the use of the (often more expen- sive) endovascular approach are not based on evidence from ran- domized trials. FURTHER READING ACC/​AHA (2006). 2005 guidelines for the management of peripheral arterial disease. J Am Coll Cardiol, 47, 123–​312. BASIL Trial Participants (2005). Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomized controlled trial. Lancet, 366, 1925–​34. Belch J, et al. (2011). Effect of fibroblast growth factor NV1FGF on am- putation and death: a randomised placebo-​controlled trial of gene therapy in critical limb ischaemia. Lancet, 377, 1929–​37. Berridge DC, Kessel DO, Robertson I (2013). Surgery versus thromb- olysis for initial management of acute limb ischaemia. Cochrane Database Syst Rev, 6(6), CD002784. 16.14.3 Cholesterol embolism 3688 Christopher Dudl 16.14.3 Cholesterol embolism 3688 Christopher Dudley section 16  Cardiovascular disorders 3688 Filardo G, et al. (2012). Surgery for small asymptomatic abdominal aortic aneurysms. Cochrane Database Syst Rev, 14(3), CD001835. NICE (2012). Peripheral arterial disease: diagnosis and management. Clinical guideline. https://​www.nice.org.uk/​guidance/​cg147 Patel R, Sweeting MJ, Powell JT, Greenhalgh RM; EVAR trial investi- gators (2016). Endovascular versus open repair of abdominal aortic aneurysm in 15-​years’ follow-​up of the UK endovascular aneurysm repair trial 1 (EVAR trial 1): a randomised controlled trial. Lancet, 388, 2366–​74. Setacci C, Ricco JB; European Society for Vascular Surgery (2011). Guidelines for critical limb ischaemia and diabetic foot—​introduction. Eur J Vasc Endovasc Surg, 42(Suppl 2), S1–​3. Thompson PD, et al. (2002). Meta-​analysis of results from eight ran- domized, placebo-​controlled trials on the effect of cilostazol on pa- tients with intermittent claudication. Am J Cardiol, 90, 1314–​19. Wanhainen A, et al. (2019). European Society for Vascular Surgery (ESVS) 2019 Clinical Practice Guidelines on the Management of Abdominal Aorto-iliac Aneurysms. Eur J Vasc Endovasc Surg, 57, 8–93. 16.14.3  Cholesterol embolism Christopher Dudley ESSENTIALS Cholesterol embolism occurring after vascular surgery or intraarterial angiographic procedures is not uncommon, but is often unrecog- nized. The clinical features mimic several conditions, including con- trast nephropathy and systemic vasculitis, and—​if misdiagnosed—​can result in the inappropriate use of powerful immunosuppressive drugs. A high index of suspicion is required when an elderly patient with widespread vascular disease develops a non​specific systemic illness with progressive renal impairment, particularly after vascular surgery or arteriography. Biopsy of affected tissue, especially skin or kidney, is diagnostic—​showing biconvex, needle-​shaped cholesterol clefts within the lumen of arteries or arterioles. Treatment is sup- portive and the prognosis is often poor. Introduction When atheromatous plaques ulcerate and become denuded of their endothelial covering, the underlying cholesterol-​rich extracellular matrix can become detached and embolize. If the dislodged plaque and superimposed thrombus is sufficiently large, occlusion of a major systemic artery results in infarction of the organ or ischaemia of the limb supplied. This has been termed ‘thromboembolism’. By con- trast, ‘atheroembolism’ or cholesterol-​crystal embolism occurs when much smaller and more numerous particles, composed principally of cholesterol crystals, lodge in a number of small arteries or arteri- oles simultaneously. The presence of a collateral circulation usually prevents infarction, and the event frequently passes unrecognized by the patient or their physician. However, tissue damage in certain organs can result from multiple showers of emboli. Because severe ulcerative atherosclerosis is most frequently present in the abdom- inal aorta, cholesterol embolism commonly affects the legs, gastro- intestinal tract, and kidneys. The condition usually presents as a complication of vascular surgery or angiographic procedures, when mechanical dislodgement of crystals from ulcerated plaques occurs. Anticoagulant and thrombolytic use has also been implicated as a predisposing factor. The clinical features are those of a systemic dis- order with renal failure that can mimic vasculitis, although more in- dolent cases with stable renal failure have been observed. Epidemiology The incidence of cholesterol-​crystal embolism found at post-​ mortem is high: 77% after aortic surgery, 30% after aortography, and 25.5% after cardiac catheterization. By contrast, the clinical syndrome of cholesterol-​crystal embolism is rare, complicating less than 2% of cardiac catheterizations. In two large renal biopsy series, an incidence of 1% was reported, and it has been suggested that cholesterol-​crystal embolism could account for 5–​10% of cases of acute kidney injury, although most nephrologists would regard this as an overestimate. Since the condition occurs in patients with severe atheromatous disease, it is most often seen in older male patients with obvious risk factors (e.g. hypertension, diabetes mellitus, smoking) and overt vascular disease (e.g. ischaemic heart disease, abdominal aortic an- eurysm, cerebrovascular disease). Although spontaneous cholesterol embolism can occur, it is much more common after vascular sur- gery or invasive radiology including aortography, angiography, and angioplasty. Under these circumstances, direct trauma to the vessel may result in detachment of atheromatous material from a ruptured plaque, or denude the endothelial lining of the vessel exposing the underlying atheroma for subsequent embolization. Angiography is the most common cause of cholesterol-​crystal embolization, ac- counting for approximately 80% of cases in some series. Anticoagulant use has been associated with cholesterol embolism, and it has been proposed that by preventing thrombosis of ulcerating atheromatous plaques, anticoagulants favour the dissemination of atheromatous material. However, a causal relationship is unproven and many patients with widespread atherosclerosis coincidentally receive anticoagulants for a variety of reasons. Cholesterol embolism following the use of thrombolytic agents and novel oral anticoagu- lants (NOACs) has been reported. Prevention Prevention is important, particularly with the increasing number of older patients submitted to invasive angiography. Non​invasive methods of arterial imaging such as CT or magnetic resonance angi- ography are to be preferred in patients with diffuse atherosclerosis. When invasive angiography is unavoidable, careful attention must be paid to the angiographic technique, including the arterial ap- proach (brachial, or radial instead of femoral, for cardiac catheter- ization), use of softer, more flexible catheters, and reduced catheter manipulation. 16.14.3  Cholesterol embolism 3689 Clinical features Symptoms are often non​specific with fever, weight loss, and my- algia. The clinical features are, otherwise, determined by the pattern of organ involvement and are usually referable to the gastrointes- tinal tract, kidneys, and legs. Bilateral skin changes over the lower extremities are the commonest physical finding and include livedo reticularis, a purpuric rash, ‘trash feet’, blue toes (acral cyanosis), and focal digital necrosis (Figs. 16.14.3.1 and 16.14.3.2). Ulceration, nodules, and petechiae have also been described. Despite these skin changes and the presence of calf claudication (or frank myositis), pedal pulses may be felt easily, emphasizing that small vessels are occluded in this disorder. Carotid and femoral bruits are frequently heard, reflecting widespread and generalized atherosclerosis. Abdominal pain, gastrointestinal bleeding, and pancreatitis may occur, and embolism to the stomach, small bowel, colon, gallbladder, and spleen have all been reported. The most frequently involved of these sites is the colon. Because of their large blood supply and proximity to the abdominal aorta, the kidneys are commonly affected. This usually manifests as a subacute stepwise deterioration in renal function over 2 to 6 weeks, invariably accompanied by a worsening of pre-​existing hypertension that can be labile and difficult to control. Cardiac failure with pul- monary oedema is a common accompaniment. Thus, a typical case is an elderly man presenting after angiography with progressive renal failure accompanied by a low-​grade fever, abdominal pain, livedo reticularis of the lower body, and purpura over the feet with focal digital ischaemia of the toes. Acute kidney injury with necrotizing glomerulonephritis and crescent formation on renal biopsy has been described, but is rare. A  further presentation is with slowly pro- gressive chronic kidney disease, which is underdiagnosed because extrarenal manifestations are absent and renal biopsy rarely under- taken. Cholesterol embolism has been reported in renal transplants. Transient ischaemic attacks, amaurosis fugax, and strokes can occur when embolism is from the carotid arteries or aortic arch. Retinal cholesterol-​crystal emboli may be observed on ophthalmoscopy as bright refractile plaques within the retinal arterioles, especially at their bifurcation. Spinal cord infarction has also been reported. Differential diagnosis The diagnosis is frequently missed during life, or confused with that of acute renal failure induced by radiocontrast media (contrast neph- ropathy) when renal failure occurs after arteriography. A high index of clinical suspicion is therefore required, particularly in elderly pa- tients with evidence of atherosclerotic disease who develop renal failure after arteriography or following aortic or cardiac surgery; cholesterol embolism should also be considered in the differential diagnosis of a multisystem disease in elderly patients. Spontaneous cholesterol-​crystal embolism associated with renal failure, fever, rash, and eosinophilia may, not surprisingly, be misdiagnosed as a vasculitic illness such as granulomatosis with polyangiitis (Wegener’s granulomatosis), microscopic polyangiitis, eosino- philic granulomatosis with polyangiitis (Churg–​Strauss syndrome), polyarteritis nodosa, or bacterial endocarditis (see Chapters 19.11.7, 19.11.9, and 16.9.2). A false-​positive antineutrophil cytoplasmic antibody (ANCA) test (not uncommonly by immunofluorescence, rarely to specific antigen) may further compound the diagnostic difficulty. Under these circumstances, renal biopsy is mandatory to make the correct diagnosis. Clinical investigation Laboratory findings are non​specific, but frequently include a raised erythrocyte sedimentation rate, plasma viscosity, and C-​reactive protein. Leucocytosis and a transient eosinophilia are common and may be pronounced. Depending on the tissue involvement, an elevation in creatine phosphokinase, amylase, lactate dehydro- genase (LDH), serum aspartate aminotransferase (AST), and al- kaline phosphatase may all be seen. Hypocomplementaemia is rare and usually mild. As stated earlier, ANCA have been re- ported, and their presence may further confuse the diagnosis with a multisystem vasculitic process. Mild proteinuria is generally pre- sent, and nephrotic-​range proteinuria has been reported. Urine microscopy may be bland or reveal red cells, white cells (particu- larly eosinophils), and hyaline and granular casts. Renal failure is frequently non​oliguric. Fig. 16.14.3.1  Livedo reticularis and vasculitic-​like erythematous nodules on the leg of a patient in whom cholesterol-​crystal embolization occurred after coronary angiography. Fig. 16.14.3.2  Purpuric spots and acral cyanosis of the toes from cholesterol embolism after aortic aneurysm repair. section 16  Cardiovascular disorders 3690 Histology The definitive histological diagnosis of cholesterol-​crystal embolism can usually be made from biopsies of kidney, skin, or muscle (including clinically uninvolved areas), although sampling error may miss the lesion due to its patchy distribution. Ante-​mortem histological diag- noses have also been made from other tissues, including a gastric biopsy, prostatic currettings, and a bone marrow biopsy. The diag- nostic feature is of biconvex, needle-​shaped cholesterol clefts within the lumen of arteries or arterioles that remain after the crystals have dissolved during routine histological preparation (Fig. 16.14.3.3). In fresh samples, the crystals can be identified by birefringence under po- larized light or by specific histochemical staining of cholesterol. In the kidneys, the typical finding is occlusion of small arteries and arterioles of between 150 and 200 µm in diameter, such as the arcuate and inter- lobular arteries, resulting in patchy areas of ischaemia and small areas of infarction. Crystals can also be seen within the glomeruli. In chronic cases, ischaemia produces a wedge-​shaped lesion involving all compo- nents of the renal cortex radiating towards the capsule. The glomeruli appear ischaemic and sclerosed and the tubules become atrophic and separated by interstitial fibrosis. Grossly, the kidneys may be reduced in size with a rough granular surface and wedge-​shaped scars. Based on animal studies involving the injection of atheromatous material, the presence of cholesterol crystals in the vascular lumen is thought to trigger a localized inflammatory and endothelial vascular reaction. Inflammatory cells (mainly macrophages and eosinophils) infiltrate, and multinucleated giant cells engulf the cholesterol crys- tals, but these are resistant to the scavenger effects of macrophages and may persist for many months. The inflammatory phase is fol- lowed by marked intimal thickening with concentric fibrosis and occlusion of the vessel. Depending on the extent of organ involve- ment, these pathological changes result in ischaemia, infarction, or—​rarely—​necrosis of the distal tissue. Management There is no effective therapy and no clinical trials of treatment in this condition have been performed. Steroids, aspirin, dipyridamole, and low molecular weight dextran have all been tried, but without any clear effect. There are anecdotal reports of a response to hydroxyl methyl glutaryl coenzyme A  (HMG CoA) reductase inhibitors (statins), theoretically inducing plaque stabilization, but recovery may have been spontaneous. Nevertheless, statin use is recom- mended, even when started after the condition has been diagnosed. Anticoagulants are of no proven benefit and should be avoided given their potential role in the pathogenesis of the disorder. Encouraging results with iloprost and low-​density lipoprotein apheresis have been reported, but these observations require replication. CT scanning of the aorta has been used to identify the precise source (e.g. aortic aneurysm, localized aortic plaque) of cholesterol emboli, and surgical replacement of the diseased vessel with a graft has been advocated. However, major surgery in elderly patients with widespread vascular disease and renal impairment carries signifi- cant risks and is generally avoided. Supportive therapy is directed at stopping anticoagulation unless essential, avoiding further angiographic or vascular surgical pro- cedures, controlling hypertension, and appropriate management of renal failure. Use of angiotensin-​converting enzyme inhibitors or angiotensin receptor blockers has been advocated, but careful moni- toring of renal function is required. Prognosis Mortality is high due to the coexistence of cardiac and vascular dis- ease with renal failure in elderly patients. Renal impairment may re- main stable, but frequently progresses such that dialysis is required, although partial recovery has been reported, even after several months of dialysis. The mechanism of this recovery is uncertain. FURTHER READING Elinav E, Chajek-​Shaul T, Stern M (2002). Improvement in cholesterol emboli syndrome after iloprost therapy. BMJ, 324, 268–​9. Fine MJ, Kapoor W, Falanga V (1987). Cholesterol crystal emboliza- tion: a review of 221 cases in the English literature. Angiology, 38, 769–​84. Hasegawa M, Sugiyama S (2003). Apheresis in the treatment of choles- terol embolic disease. Ther Apher Dial, 7, 435–​8. Lusco MA, et al. (2016). AJKD Atlas of renal pathology: cholesterol emboli. Am J Kidney Dis, 67(4), e23–​4. Meyrier A (2006). Cholesterol crystal embolism: diagnosis and treat- ment. Kidney Int, 69, 1308–​12. Mulay SR, Evan A, Anders HJ (2014). Molecular mechanisms of crystal-​related kidney inflammation and injury. Implications for cholesterol embolism, crystalline nephropathies and kidney stone disease. Nephrol Dial Transplant, 29, 507–​14. Oka H, et al. (2017). Cholesterol crystal embolism induced by direct Factor Xa inhibitor: a first case report. Intern Med, 57, 71–​4. Saric M, Kronzon I (2011). Cholesterol embolization syndrome. Current Opin Cardiol, 26, 472–​9. Scolari F, et al. (2003). Cholesterol crystal embolic disease in renal allo- grafts. J Nephrol, 16, 139–​43. Scolari F, et  al. (2007). The challenge of diagnosing atheroembolic renal disease: clinical features and prognostic factors. Circulation, 116, 298–​304. Scolari F, et  al. (2010). Atheroembolic renal disease. Lancet, 375, 1650–​60. Fig. 16.14.3.3  Renal biopsy demonstrating the characteristic needle-​ shaped cholesterol clefts occluding a medium-​sized renal arteriole with surrounding inflammatory cell infiltration, intimal proliferation, thickening, and concentric fibrosis. There is extensive autolysis (post-​mortem sample). 16.15 The pulmonary circulation 3691 16.15.1 Struc 16.15 The pulmonary circulation 3691 16.15.1 Structure and function of the pulmonary circulation 3691 Nicholas W. Morrell 16.15 The pulmonary circulation CONTENTS 16.15.1 Structure and function of the pulmonary circulation  3691 Nicholas W. Morrell 16.15.2 Pulmonary hypertension  3695 Nicholas W. Morrell 16.15.1  Structure and function of the pulmonary circulation Nicholas W. Morrell ESSENTIALS The normal pulmonary circulation distributes deoxygenated blood at low pressure and high flow to the pulmonary capillaries for the purposes of gas exchange. The structure of pulmonary blood ves- sels varies with their function—​from large elastic conductance ar- teries, to small muscular arteries, to thin-​walled vessels involved in gas exchange. Pulmonary vascular resistance is about one-​tenth of systemic vascular resistance, with the small muscular and partially muscular arteries of 50–​150 µm diameter being the site of the greatest con- tribution to resistance. The gas-​exchanging capillary surface area (c.125 m2) contains a blood volume of about 150 ml at any one time, with the blood–​gas barrier being only 0.2–​0.3 µm thick at its thin- nest part. In the normal pulmonary circulation, a large increase in cardiac output causes only a small rise in mean pulmonary arterial pressure because pulmonary vascular resistance falls on exercise: this is accomplished by a combination of vascular distensibility and re- cruitment. Pulmonary blood flow is heterogeneous: gravity causes increased blood flow in the more dependent parts of the lung; within a horizontal region—​or within an acinus—​blood-​flow heterogeneity is imposed by the branching pattern of the vessels. Many neural and humoral mediators can influence pulmonary vascular tone, including nitric oxide and prostacyclin. Alveolar hyp- oxia causes constriction of the small pulmonary arteries, whereas systemic arteries dilate when hypoxic: this hypoxic pulmonary vaso- constriction can reduce venous admixture and improve arterial oxy- genation in the presence of bronchial obstruction. Despite large regional differences in the matching of ventilation and perfusion within the normal lung, the overall lung ventilation–​perfusion ratio is maintained remarkably steady at around 0.85. Introduction The main function of the pulmonary circulation is respiratory gas exchange, a vital function that the lungs take over from the pla- centa at birth. The structure of the pulmonary circulation is highly adapted to fulfil this role. It receives the entire cardiac output from the right ventricle during each cardiac cycle, and this mixed venous blood is delivered at high flow but low pressure to the delicate al- veolar structures where gas exchange occurs. Blood flow is matched closely to the regional ventilation within the lung to optimize and maintain systemic arterial oxygenation. This chapter discusses the anatomy and physiology of the pulmonary circulation. Structure of the pulmonary circulation The pulmonary arteries and bronchi, together with lymphatics, run in a single connective tissue sheath in the centre of pulmonary segments and lobules, the so-​called bronchovascular bundle. The ‘conventional’ pulmonary arteries branch dichotomously and symmetrically, along with the airways, and they also give off extra branches between the conventional branching points, called ‘super- numerary’ or short branches. The intrapulmonary veins pursue a different course along the edges of lobules and segments, in the interlobular septa. The branching pattern of veins is similar to that of the pulmonary arteries. The branching pattern of the pulmonary arteries can be de- scribed by a ‘divergent’ approach, where the main pulmonary artery is called generation 1, with each division giving rise to generation 2, 3, and so on. An alternative is the ‘convergent’ ap- proach where the most peripheral branch is numbered ‘order 1’, and the orders increase until the main pulmonary artery (order 17) is reached. Fig. 16.15.1.1 shows this arrangement going from the precapillary arteriole of order 1, whose diameter is about 13 section 16  Cardiovascular disorders 3692 μm, to the main pulmonary artery (order 17) with a diameter of 30 000 μm. Note the ninefold expansion in cross-​sectional area of the pulmonary vascular bed from order 2 to order 1: it is these precapillary vessels that are often involved in disease processes that affect the pulmonary circulation. In the normal lung, the site of the greatest pulmonary vascular resistance (PVR) is in the small partially muscular and muscular pulmonary arteries (orders 4 to 6; 50–​150 μm diameter). The wall structure of the pulmonary arteries changes along their length depending on the function of the vessel (Fig. 16.15.1.2). All preacinar arteries have a complete muscular coat, but the muscle layer may be incomplete or absent in smaller intra-​acinar vessels. • Elastic arteries (orders 17–​13)—​these larger arteries have adven- titial, muscular, and intimal layers. The media, or muscular layer, is bounded by internal and external elastic laminae, with three or more elastic laminae within the muscle coat. Medial thickness is about 1 to 2% of external diameter. • Muscular arteries (orders 13–​3)—​these small arteries have a thicker muscle layer in relation to their external diameter (2–​5%), and they possess only internal and external elastic laminae; in the smallest arteries, the internal elastic lamina disappears. • Partially muscular arteries (orders 5–​3)—​the smooth muscle fibres investing the smallest pulmonary arteries taper off in a spiral, leading to an incomplete muscular coat (Fig. 16.15.1.2). Most ar- teries of 50–​100 μm external diameter are partially muscular. • Non​muscular arteries (orders 5–​1)—​these arteries have no elastic laminae. The smooth muscle cell is replaced by pericytes whose basement membrane fuses with that of the endothelial cell lining the vascular lumen. • Supernumerary arteries—​these are small, relatively thin-​walled arteries that branch sharply from the parent vessel between bifurcations of the conventional branching system, starting from orders 11 to 12. They provide a short cut for blood supplying the alveoli adjacent to the conduit arteries and bronchi, which would otherwise require a long and circuitous supply by the axial route. • Pulmonary veins—​the branching pattern and organization of the pulmonary veins is similar to that of the arteries, but with only 15 orders, because the four pulmonary veins converge on the left atrium without joining up to form an additional two orders. Veins do not have an internal elastic lamina. Their walls contain more elastic tissue and less muscle than arteries of the same size. There are supernumerary veins like the supernumerary arteries. • Capillary network—​the 300 million precapillary vessels lead into a network of alveolar septal capillaries with a blood volume (150 ml) equal to that in the pulmonary arterial or venous systems. The capillary surface area is about 125 m2 (c.86% of the alveolar sur- face area). Individual capillaries are not much wider than a single erythrocyte, hence the microvascular bed at normal vascular pres- sures is essentially a sheet of blood one red cell thick, exposed to alveolar gas on both sides. Alveolar capillaries have a thick side and a thin side. The thin side consists of the cytoplasmic exten- sions of the luminal endothelial cell and the alveolar epithelial cell with their fused basement membrane (0.2–​0.3 μm across). The thick side, up to 2 μm across, contains collagen, elastin, and fibro- blast processes to give structural support to the alveolus. Pulmonary vascular resistance The pulmonary circulation is a high-​flow, low-​pressure system whose vascular resistance is one-​tenth of systemic vascular resist- ance. PVR is the ratio of the mean pulmonary arterial–​venous pres- sure difference (Ppa − Ppv) to mean pulmonary blood flow (Qp): ( pa pv) p PVR(mmHg/litrepermin). P P Q − / Vascular volume (ml) Architecture of pulmonary arterial trees Main pulmonary artery 80 17 15 13 11 9 7 3 5 1 60 14.8 8.0 Diameter (mm) 5.8 3.65 2.1 1.3 0.8 0.5 Elastic Muscular Partially muscular Intra−acinar Terminal bronchioles Respiratory bronchioles Alveolar ducts Pre-capillary (300 × 106) Non muscular 0.2 0.14 0.08 0.05 0 Vascular cross-sectional area (cm2) 200 300 400 Arterial branch order Cross-sectional area 20 0 30 Vascular volume 0.35 40 100 Fig. 16.15.1.1  Map of the pulmonary arterial tree showing how vascular volumes, cross-​sectional areas, diameters, and wall structure vary with branch order number. Intermediate cell Pericyte Smooth muscle cell Arterial lumen Muscular Partially muscular Anatomy of peripheral pulmonary arteries Nonmuscular Fig. 16.15.1.2  The changing structure of pulmonary arteries. 16.15.1  Structure and function of the pulmonary circulation 3693 The normal PVR is less than 2 mm Hg/​litre per min at rest. The main determinants of PVR are captured in the equation for Poiseuille flow (steady flow of a Newtonian fluid through long, straight, unbranched tubes): PVR ~ / , 8 4 µ π l D where L is vascular path length, µ is the viscosity of blood, and D is vessel diameter. L/​D 4 is known as the geometric factor, the import- ance of which can be seen by considering that a 16% decrease in D leads to a twofold increase in PVR. In reality, the situation is more complicated because blood flow in the lungs is not of uniform vel- ocity, but is, of course, pulsatile. PVR normally falls on exercise despite the increase in cardiac output, hence Ppa rises only modestly, perhaps from 15 mm Hg at rest to 23 mm Hg. The fall in PVR during exercise is accomplished by a combination of vascular ‘distensibility’ (vascular compliance) and ‘recruitment’ (number of parallel pathways with flow). Vascular recruitment means that a vessel goes from a state of zero flow to one of finite flow. An increase in pulmonary arterial pressure during ex- ercise can distend pulmonary arteries. The total compliance of the pulmonary circulation is about 20 ml/​mm Hg, hence on heavy exer- cise, if all vascular pressures rose by 10 mm Hg, pulmonary vascular volume would increase by 200 ml, provided vessels had not reached their limiting size. The distribution of PVR can be partitioned into a three-​segment model, which can be described as having (1) arterial, (2) ‘middle’, and (3) venous segments. In isolated lungs, about 20% of the total PVR lies in the distensible ‘middle’ segment (capillaries and small arteries and veins), with 40% each in the arterial and venous seg- ments. This distribution can be altered by factors (e.g. hypoxia), that increase resistance predominantly in the ‘middle’ segment. Blood viscosity is a further factor that affects PVR (e.g. when polycy- thaemia increases PVR). Distribution of pulmonary blood flow Blood flow within the lung is heterogeneous in distribution. For example, between lung regions of secondary lobule size (c.10 cm3) there is a modest amount of gravity-​dependent heterogeneity, with flow increasing with vertical distance (more to the lower zones than the upper zones). Within these lung regions and within the respira- tory acinus there is a greater degree of heterogeneity, which is inde- pendent of gravity. Gravity-​dependent flow The effects of gravity are best illustrated by considering that, in the human erect posture at rest, mean pulmonary artery pressure (Ppa) at the level of the hilum is about 18 cmH2O, whereas the apex of the lung is 20 cmH2O above the hilum. Consequently, the apex of the lung will be perfused only during the systolic pressure peak. In the supine position, the apical blood flow increases, with the re- sult that the distribution from apex to base becomes more uniform. During exercise, with the increase in cardiac output, both upper and lower zone blood flow increases, but the upper increases more than the lower, so that flow becomes more even. The role of gravity in determining pulmonary blood flow was extended by West and encompassed in the three-​zone model of pulmonary circulation (Fig. 16.15.1.3). This model relies on the assumption that the site of major flow resistance is in the small vessels whose extravascular pressure is the alveolar pressure (Palv). There is no flow in zone I because Palv is greater than Ppa. Flow increases down zone II be- cause the driving pressure increases by 1 cm of H2O for each 1 cm distance down the lung. Flow increases with distance down zone III, although ΔP (Ppa − Ppv) remains constant, because local PVR decreases due to capillary distension and recruitment. The driving pressure for blood flow is determined by the relationship between Palv, Ppa, and pulmonary venous pressure (Ppv) down the up- right lung. A further zone (zone IV) is found at the lung base: in this zone, blood flow is observed to decrease with distance down the lung due to increased perivascular pressure in extra-​alveolar vessels. Gravity-​independent flow The branching pattern of pulmonary arteries imposes changes in perfusion that are independent of gravity. Within any given hori- zontal level of the upright lung, there is a decrease in blood flow in peripheral lung regions compared to central hilar regions. This is thought to be due to the reduction in Ppa in small acinar arteries with increasing distance from the hilum. This pattern is also seen at the level of the secondary lobule (the group of acini supplied by one terminal bronchiole), with a decreasing gradient of blood flow from the centre to the periphery. Regulation of pulmonary vasomotor tone The pulmonary circulation differs from the systemic in that it is under minimal resting tone and is almost fully dilated under normal conditions. Circulating and local production of vasodilators and vasoconstrictors contribute to the resting tone, with the balance tipped in favour of vasodilators. Nitric oxide, produced locally by endothelial cells, and the arachidonic acid metabolite prostacyclin are important vasodilators that contribute to this low pulmonary vascular tone. The autonomic nervous system interacts with humoral me- diators and haemodynamic forces in the control of pulmonary vascular tone, autonomic innervation of the lung being via parasympathetic (cholinergic:  predominantly vasodilator) and Ppa Ppv Palv Blood flow Zone I Palv>Ppa>Ppv Zone II Ppa>Palv>Ppv Zone III Ppa>Ppv>Palv Distance Fig. 16.15.1.3  The three-​zone model of pulmonary blood flow distribution. section 16  Cardiovascular disorders 3694 sympathetic (adrenergic: predominantly vasoconstrictor) nerves in the periarterial plexus. Hypoxic pulmonary vasoconstriction The pulmonary circulation responds to a reduction in the partial pressure of alveolar oxygen by vasoconstriction. This is opposite to the response to hypoxia in the systemic circulation, where tissue hypoxia leads to vasodilatation, hence improving tissue oxygen delivery. Hypoxic pulmonary vasoconstriction (HPV) probably plays little role in the normal distribution of pulmonary blood flow or regulation of ventilation–​perfusion relationships in hu- mans. However, in diseases characterized by airway obstruction, such as acute asthma or chronic obstructive lung disease, HPV can divert blood flow away from poorly ventilated lung regions, redu- cing venous admixture (shunt through poorly ventilated lung re- gions) and preserving arterial oxygenation. The magnitude of the response varies widely between individuals and is, at best, 50% effi- cient. It is noteworthy that populations indigenous to high-​altitude regions (e.g. Tibetans), lack HPV with no obviously detrimental effect. At high altitude, with low atmospheric partial pressures of oxygen, HPV would lead to generalized vasoconstriction and pul- monary hypertension, which is presumably more detrimental than the lack of HPV. Ventilation–​perfusion relationships In the normal lung, it is remarkable that pulmonary blood flow and ventilation are, in general, well matched given the heterogen- eity of blood flow described earlier. Of course, regional ventila- tion is also under similar constraints and forces as the blood flow. In terms of the structure and function of the airways and alveoli in brief, the airways run with the arteries in the bronchovascular bundle and the branching patterns are similar. Regional ventila- tion is under the influence of gravity: the lung sits in the thorax under its own weight, which leads to a gradient of intrapleural pressure, with more negative pressures at the top of the lung than at the bottom in the upright position. This means that the lung is more expanded at the apex than at the base at the end of a normal breath (functional residual capacity). Thus, the upper and lower parts of the lung are operating on different portions of their pressure–​volume curves. The result is that, during normal breathing, greater ventilation is delivered to the bottom than to the top of the lung. This gradient of regional ventilation down the lung is reminiscent of the gradient of blood flow just described. In fact, with increasing distance up the lung, the rate of change of ventilation per unit of alveolar volume is somewhat less than the rate of change of perfusion (about one-​third). This leads to large regional differences in the ventilation–​perfusion ratio up the lung (Fig. 16.15.1.4): alveoli at the bottom of the lung are rela- tively overperfused, leading to a low ventilation–​perfusion ratio (c.0.6); by contrast, alveoli at the apex of the lung are relatively underperfused, leading to ventilation–​perfusion ratios over 3.0. Nevertheless, the overall ventilation–​perfusion ratio for the whole lung is approximately 0.85. The regional ventilation–​perfusion ratio will determine the partial pressures of oxygen and CO2 found in the alveoli at a given level of the lung, and this will be reflected in the gas tensions found in pulmonary venous blood draining those alveoli. The result is that the Po2 is higher, and the Pco2 lower, in blood draining from the top of the lung, compared with the bottom. The matching of ventilation and perfusion in the normal lung ensures that the overall ventilation–​perfusion ratio remains fairly constant with changes in posture or exercise. Acknowledgement Much of the chapter written for the third edition of the Oxford Textbook of Medicine by the late J. S. Prichard has been retained here. Fig. 16.15.1.4  (a) O2–​CO2 diagram showing how the change in ventilation–​perfusion ratio up the lung determines the regional composition of alveolar gas. Dashed lines show the composition of mixed venous (pulmonary arterial) blood and inspired (tracheal) gas. (b) Effects of change in ventilation–​perfusion ratio up the lung on the regional composition of alveolar gas, with volumes of lung slices, ventilations, and blood flows also shown. 16.15.2 Pulmonary hypertension 3695 Nicholas W. Mo 16.15.2 Pulmonary hypertension 3695 Nicholas W. Morrell 16.15.2  Pulmonary hypertension 3695 FURTHER READING De Mello DE, Reid LM (1997). Arteries and veins. In: Crystal RG, et al. (eds) The lung: scientific foundations, 2nd edition, pp. 1117–​27. Lippincott-​Raven, Philadelphia, PA. Hughes JMB (1997). Distribution of pulmonary blood flow. In: Crystal RG, et  al. (eds) The lung:  scientific foundations, 2nd edition, pp. 1523–​36. Lippincott-​Raven, Philadelphia, PA. Hughes JMB, Morrell NW (2001). Pulmonary circulation: from basic mechanisms to clinical practice. Imperial College Press, London. Singhal S, et al. (1973). Morphometry of the human pulmonary ar- terial tree. Circ Res, 33, 190–​7. West JB, Dollery CT, Naimark A (1964). Distribution of blood flow in isolated lung: relation to vascular and alveolar pressures. J Appl Physiol, 19, 713–​24. West JB (1985). Ventilation/​blood flow and gas exchange, 4th edition. Blackwell Scientific Publications, Oxford. 16.15.2  Pulmonary hypertension Nicholas W. Morrell ESSENTIALS Symptoms of unexplained exertional breathlessness or symptoms out of proportion to coexistent heart or lung disease should alert the clinician to the possibility of pulmonary hypertension, and the con- dition should be actively sought in patients with known associated conditions, such as scleroderma, hypoxic lung disease, liver disease, or congenital heart disease. Heterozygous germ-​line mutations in the gene encoding the bone morphogenetic protein type II receptor (BMPR2) are found in over 70% of families with pulmonary arterial hypertension. Pulmonary hypertension is defined as a mean pulmonary arterial pressure greater than 25 mm Hg at rest, and may be due to increased pulmonary vascular resistance (e.g. pulmonary arterial hypertension), increased transpulmonary blood flow (e.g. congenital heart dis- ease), or increased pulmonary venous pressures (e.g. mitral stenosis). Exercise tolerance and survival in pulmonary hypertension is ultim- ately related to indices of right heart function, such as cardiac output. Investigation—​echocardiography is a good screening tool for the presence of pulmonary hypertension, but right heart catheteriza- tion is needed to confirm the diagnosis and guide treatment. CT pulmonary angiography and high-​resolution CT are important to exclude underlying chronic thomboembolic pulmonary hyperten- sion and parenchymal lung disease. In idiopathic pulmonary arterial hypertension a vasodilator study should be undertaken at the time of right heart catheterization to detect the few (5–​10%) patients who will have good long-​term survival on calcium channel blockers. Management—​treatments for pulmonary arterial hypertension include prostanoids, endothelin receptor antagonists, phospho- diesterase inhibitors, and direct activators of soluble guanylyl cyclase, which improve symptoms of breathlessness, exercise toler- ance, quality of life, and probably survival. Chronic thromboembolic pulmonary hypertension is an important diagnosis to make because selected patients with predominantly proximal disease can be cured by pulmonary endarterectomy. Introduction The normal pulmonary circulation, as described in Chapter 16.15.1, is a low-​pressure, high-​flow system that delivers the output of the right ventricle to the alveolar capillary network during each cardiac cycle for the purposes of gas exchange. Pulmonary hypertension is defined as a sustained elevation of mean pulmonary arterial pressure to more than 25 mm Hg at rest. Many diseases can lead to an elevation of pulmonary arterial pressure. Therefore, the term ‘pulmonary hypertension’ is not a final diagnosis, but a starting point for further investigation. In general terms, the main causes of pulmonary hypertension are (1) a nar- rowing or obstruction of the precapillary pulmonary arteries, (2) an increase in pulmonary venous pressure, (3) a persistent elevation of pulmonary blood flow, (4) chronic thromboembolic disease, or (5) miscellaneous causes. This simplified approach is worth keeping in mind during the assessment of patients found to have pulmonary hypertension, because it has major consequences for prognosis and management. Classification of pulmonary hypertension Table 16.15.2.1 shows the 5th World Symposium on Pulmonary Hypertension (2013) classification of pulmonary hypertension as determined by an international panel of experts. The grouping of causes in this classification takes into account similarities in aeti- ology, pathology, and haemodynamic assessment at right heart cath- eterization. The classification helps to understand the underlying cause of pulmonary hypertension in a given patient and to plan management, hence it is a useful framework to consider the various causes of pulmonary hypertension, described in more detail next. Pulmonary arterial hypertension The term pulmonary ‘arterial’ hypertension (PAH) refers to con- ditions characterized predominantly by a precapillary obstruction to blood flow through the pulmonary vascular bed, characterized hemodynamically by a mean pulmonary arterial pressure of greater than 25 mm Hg, an end-​expiratory pulmonary artery wedge pres- sure (PAWP) 15 mm Hg or less, and a pulmonary vascular resist- ance more than 3 Wood units. This elevation of pulmonary vascular resistance increases the driving pressure required to maintain blood flow through the lungs: pulmonary arterial pressure rises to main- tain adequate left ventricular filling. The normal mean pulmonary arterial pressure (c.17 mm Hg) is about one-​fifth of the systemic mean blood pressure. In PAH, mean pulmonary arterial pressure may approach systemic levels. The normally thin-​walled right ven- tricle struggles to cope with the increasing pressure. At first it under- goes a degree of hypertrophy, which increases its ability to generate higher pressures, but ultimately it begins to fail and cardiac output section 16  Cardiovascular disorders 3696 declines. It is the reduction in cardiac output that generates most of the clinical symptoms in patients, with dyspnoea and fatigue being the most common (Fig. 16.15.2.1). The function of the right heart is the main determinant of prognosis in patients with PAH. Epidemiology and aetiology PAH is broadly divided into idiopathic PAH (previously known as primary pulmonary hypertension), and PAH found with other known associated conditions or triggers. Idiopathic PAH is further divided into familial or sporadic disease, with about 10% of patients with idiopathic PAH having an affected relative. Idiopathic PAH is a rare disorder with an estimated incidence of 1 to 2 per million per year. It is more common in women (female:male sex ratio = 2.3:1), can occur at any age, but most commonly occurs between the ages of 40 and 50 years. PAH that is pathologically indistinguishable from the idiopathic form can occur in a range of associated conditions (Table 16.15.2.1). Of the autoimmune rheumatic diseases, the most common asso- ciation is with systemic sclerosis, where PAH can complicate the clinical course in 15–​20% of patients in the absence of interstitial lung disease. Other associated conditions include mixed connective tissue disease and systemic lupus erythematosus, and more rarely rheumatoid arthritis, dermatopolymyositis, and primary Sjögren’s syndrome. There is a well-​recognized association of PAH with congenital heart disease leading to left-​to-​right shunts. Overall, the preva- lence of PAH is 15–​30%, but varies depending on the nature of the underlying cardiac defect. Portal hypertension, usually associated with cirrhosis, is associated with PAH in less than 5% of patients. There is an unusually high prevalence of PAH (c.0.5%) in patients with HIV infection. Epidemiological studies have confirmed the association of PAH with amphetamine-​like diet pills: in the 1970s, increased numbers of patients with PAH were found to have been exposed to Aminorex, and in the 1990s further studies confirmed an association of PAH with appetite-​suppressant drugs of the fenfluramine and dexfenfluramine group. An epidemic of PAH also occurred in Spain in the 1980s, following the ingestion of contamin- ated rapeseed oil. Other more rarely associated conditions are listed in Table 16.15.2.1. Table 16.15.2.1  Clinical classification of pulmonary hypertension (NICE 2013) 1 Pulmonary arterial hypertension 1.1 Idiopathic PAH 1.2 Heritable PAH 1.2.1 BMPR2 1.2.2 ALK-​1, ENG, SMAD9, KCNK3 1.2.3 Unknown 1.3 Drug and toxin induced 1.4 Associated with: 1.4.1 Connective tissue disease 1.4.2 HIV infection 1.4.3 Portal hypertension 1.4.4 Congenital heart diseases 1.4.5 Schistosomiasis 1′ Pulmonary veno-​occlusive disease and/​or pulmonary capillary haemangiomatosis 1″ Persistent pulmonary hypertension of the newborn (PPHN) 2 Pulmonary hypertension due to left heart disease 2.1 Left ventricular systolic dysfunction 2.2 Left ventricular diastolic dysfunction 2.3 Valvular disease 2.4 Congenital/​acquired left heart inflow/​outflow tract obstruction and congenital cardiomyopathies 3 Pulmonary hypertension due to lung diseases and/​or hypoxia 3.1 Chronic obstructive pulmonary disease 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep-​disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental lung diseases 4 Chronic thromboembolic pulmonary hypertension (CTEPH) 5 Pulmonary hypertension with unclear multifactorial mechanisms 5.1 Haematologic disorders: chronic haemolytic anaemia, myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: tumoural obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH Main modifications to the previous Dana Point classification are in bold. BMPR2, bone morphogenic protein receptor type II; ENG, endoglin; PAH, pulmonary arterial hypertension. Reprinted from J Am Coll Cardiol, vol. 62 (25 Suppl), Simonneau G, et al., Updated Clinical Classification of Pulmonary Hypertension, pp. D34–​41, Copyright 2013, with permission from the American College of Cardiology Foundation. Increasing PVR Preclinical Symptomatic / stable Progressive / declining Cardiac output at rest Pulmonary pressure Cardiac output at peak exercise Fig. 16.15.2.1  Relationship between pulmonary hypertension, right ventricular function, and symptoms in pulmonary hypertension. Pulmonary arterial hypertension (PAH) is characterized by progressively increasing pulmonary vascular resistance. In the early stages, the disease is asymptomatic and only manifests during exercise or during unusually demanding activities, but over time there is a progressive reduction in cardiac output and increasing pulmonary vascular resistance (PVR), eventually progressing to cardiac failure and death. 16.15.2  Pulmonary hypertension 3697 The classification of PAH includes another rare pulmonary vas- cular disease, pulmonary veno-​occlusive disease (PVOD) and pul- monary capillary haemangiomatosis (PCH), which are the same entity. PVOD/​PCH is rarer than idiopathic PAH, but its true preva- lence is unknown. Persistent pulmonary hypertension of the new- born is a disorder characterized by a failure of vascular transition from fetal to a neonatal circulation and estimated to affect 0.2% of liveborn term infants. Genetics Familial or heritable PAH is a rare autosomal dominant condi- tion, with reduced penetrance. It is indistinguishable on clinical or pathological grounds from idiopathic PAH. Linkage studies local- ized the gene to the long arm of chromosome 2 (2q33). In 2000, heterozygous germ-​line mutations were identified in the BMPR2 gene encoding the bone morphogenetic protein type II receptor, which is a constitutively active serine-​threonine kinase that acts as a receptor for bone morphogenetic proteins (BMPs), these being members of the transforming growth factor β (TGFβ) superfamily. Mutations in BMPR-​II have now been identified in over 70% of cases of familial PAH, and similar mutations are also found in 15–​26% of patients thought to have sporadic or idiopathic disease. Many of these are unexpected examples of familial disease with low penetrance, although de novo mutations have also been reported. BMPR-​II mutations have been identified in most of the 13 exons of the BMPR2 gene, most (c.70%) being nonsense or frameshift mutations predicted to cause haploinsufficiency due to nonsense-​ mediated mRNA decay of the mutant transcript: only the wild-​type allele is expressed in these cases, reducing the amount of BMPR-​ II protein to about 50% of normal. About 30% of the mutations are mis-​sense mutations, which cause retention of mutant protein within the endoplasmic reticulum or affect important functional domains of the receptor, such as the ligand-​binding domain or the kinase domain. Mutations in BMPR-​II have also been found in a small proportion (c.10%) of patients with PAH associated with ap- petite suppressants, and in children with complicated PAH associ- ated with congenital heart disease. Mutations in another TGFβ receptor, ALK-​1, have also been re- ported in association with PAH. These are usually found in fam- ilies with hereditary haemorrhagic telangiectasia, but occasionally some family members develop severe PAH. These findings have highlighted the central role of the TGFβ signalling pathway in the pathogenesis of PAH. The BMPR-​II/​ALK-​1 receptor complex on endothelial cells has been found to be the major signalling com- plex for BMPs 9 and 10, providing major mechanistic insights into the pathobiology of PAH. Mutations in other TGFβ-​related genes have also been identified in rare cases of heritable PAH, including endoglin, Smad1, Smad9, and BMP9. In addition, mutations in the potassium channel KCNK3 have been reported in rare cases of her- itable PAH. Mutations in the eukaryotic translation initiation factor 2-α kinase 4 (EIF2AK4) were recently identified in families with autosomal recessive PVOD/​PCH, accounting for all familial cases and up to 25% of sporadic cases. Pathology Typical morphological appearances include increased musculari­ zation of small (<200 µm diameter) arteries and thickening or fibrosis of the intima, referred to as concentric intimal fibrosis (Fig. 16.15.2.2). In severe cases, dilatation of small pulmonary ar- terioles is seen and, sometimes, fibrinoid necrosis. In the larger elastic arteries, aneurysmal dilatation and atherosclerotic change may occur, the latter being otherwise extremely unusual in the normotensive pulmonary artery. The term plexogenic arteriopathy is used to describe the presence of plexiform lesions (200–​400 µm), which are tangles of capillary-​like channels adjacent to small pul- monary arteries. Plexiform changes are found in some 50% of cases of idiopathic PAH, but also in other causes of severe pulmonary hypertension, such as that due to congenital heart disease. In some cases of idiopathic PAH, there are pathological changes in the pulmonary venous circulation as well as in the arterial. If these dominate the pathology, the diagnosis is likely to be PVOD/​PCH, which has some distinct clinical features. The pathological hallmark of PVOD is the extensive and diffuse occlusion of pulmonary veins by intimal fibrous tissue, which may be loose and oedematous or dense and sclerotic. The intimal thickening is confined usually to the smaller veins. Accompanying arterial changes, particularly mus- cular hypertrophy, often coexist. Pulmonary and pleural lymphatics are dilated, and longstanding venous hypertension may lead to oe- dema and fibrosis. These changes often coexist with PCH, charac- terized by the presence of numerous foci of proliferating, congested, thin-​walled capillaries, which invade alveolar tissue, as well as the pleural, bronchial, and vascular tissue. Pathogenesis The process of pulmonary vascular remodelling described earlier in- volves proliferation of smooth muscle cells, fibroblasts, and endothe- lial cells in the vessel wall (Fig. 16.15.2.3). Endothelial dysfunction contributes to the pathogenesis of PAH, manifesting as an increase in the release of vasoconstrictors and a deficiency of endogenous vasodilators. Initially, there is an increased tendency towards endo- thelial cell apoptosis, though clonal survival of endothelial cells may lead to the plexiform lesions seen in severe PAH. The increase in medial and adventitial thickness and cell number may result from increased proliferation, but also from migration of precursor cells from within the vessel wall, the surrounding interstitium, and from circulating progenitor cells. At least in some forms of PAH, increased vasoreactivity may precede the structural changes in the vessels. Certain mediators and growth factors have been shown to be in- volved in driving the cellular changes (Fig. 16.15.2.4). Increased cir- culating and local pulmonary vascular expression of endothelin-​1 is observed in patients with PAH. As well as being a potent vaso- constrictor, endothelin stimulates smooth muscle and fibroblast proliferation via the endothelin A (ETA) and/​or endothelin B (ETB) receptors, the expression of which is increased in small hypertensive pulmonary arteries—​ETB receptors on the endothelium mediating endothelin-​1 clearance as well as release of nitric oxide and pros- tacyclin. Circulating levels of serotonin (5HT) are also elevated in PAH, and the known association of severe PAH with appetite-​ suppressant drugs of the fenfluramine/​dexfenfluramine group is thought to be partly due to increased serotonergic signalling by metabolites of these drugs. Serotonin stimulates mitogenesis of vas- cular cells via serotonin receptors, including the 5HT2A, 5HT2B, and 5HT1B receptors. In human pulmonary artery smooth muscle cells, a major proliferative pathway involves activation of mitogen-​activated section 16  Cardiovascular disorders 3698 protein kinases via the serotonin transporter, increased expression of which is found in hypertensive arteries. A relative deficiency of vasodilator pathways is observed in se- vere PAH, leading to an imbalance that enhances the activity of mitogenic and vasoconstrictor pathways. Patients with PAH pro- duce less endothelial-​derived prostacyclin. They also exhibit re- duced expression of nitric oxide synthase in their small pulmonary arteries, and consequently less nitric oxide release. Many of these CD31 α-SMA CD31 α-SMA Plexiform lesion Concentric intimal lesion Fig. 16.15.2.2  Representative images of vascular lesions in idiopathic PAH immunostained for the endothelial marker CD31, or the smooth muscle cell marker α-​smooth muscle specific actin (α-​SMA). In concentric intimal lesions, a single layer of cells adjacent to the vascular lumen stains for CD31 (upper left panel, open arrow), with concentric layers of cells comprising the vascular wall staining for α-​SMA (upper right panel). In plexiform lesions, CD31 stains a single layer of cells lining endothelial channels (lower left panel, arrows), with the supporting stroma staining for α-​SMA (lower right panel). From Atkinson C, et al. (2002). Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation, 105, 1672–​8. endothelium SMCs Endothelial damage elastic laminae disruption Normal Pulmonary hypertension SMC proliferation, ECM, and elastin proliferation SMC migration, neointima neointima adventitial fibroblasts collagen elastic laminae extracellular matrix narrowed lumen Fig. 16.15.2.3  Cellular mechanisms of pulmonary vascular remodelling. ECM, extracellular matrix; SMC, smooth muscle cell. Reproduced from Hughes, J. B. M. From Pulmonary circulation: Basic mechanisms to clinical practice (2001) with permission of Imperial College Press. 16.15.2  Pulmonary hypertension 3699 important vasodilator pathways also exert antiproliferative effects on smooth muscle cells and fibroblasts via production of the cyclic nucleotides cAMP and cGMP. Deficiency of these key vasodilator pathways has provided the rationale for many of the new therapies that have emerged over the past two decades (see ‘Newer agents’). Another important pathway involved in the process of pulmonary vascular remodelling includes loss of potassium channel (Kv1.5 and Kv2.1) expression and function, promoting smooth muscle cell con- traction and survival. Activation of vascular elastases within the vessel media and disruption of the elastic laminae is also a key step in disease pathogenesis. Inflammatory cells may also contribute, espe- cially in PAH associated with autoimmune conditions, accompanied by increased expression of inflammatory cytokines and chemokines in small pulmonary arteries. Pathological studies have identified the presence of throm- bosis in small pulmonary arteries of patients with PAH. It is not clear whether this represents in situ thrombosis as a consequence of the reduced blood flow, or embolic phenomena. Platelet dys- function has also been recognized in PAH, and an increased fre- quency of antiphospholipid antibodies associated with an increased thrombotic risk. The identification of mutations in the BMPR-​II receptor has high- lighted the important role of the TGFβ superfamily in the patho- genesis of familial PAH. Most mutations lead to a reduction in a critical signalling pathway, the Smad pathway, downstream of BMP receptors. This, in turn, leads to the failure of BMPs to activate tran- scription of important target genes. In smooth muscle cells, BMPR-​ II mutation leads to a failure of the normal growth suppressive and proapoptotic effects of bone morphogenetic proteins, favouring excessive pulmonary artery smooth muscle cell proliferation and survival (Fig. 16.15.2.5). In endothelial cells, by contrast, BMPR-​ II mutation promotes endothelial dysfunction and endothelial cell apoptosis. The combination of endothelial cell dysfunction and smooth muscle cell proliferation within the pulmonary circula- tion favours the development of vascular obliterative lesions and pulmonary hypertension. Clonal expansion of apoptosis-​resistant endothelial cells may contribute to the formation of plexiform le- sions. However, this simple model does not explain all of the features of heritable PAH. In particular, it does not explain why disease is confined to the lung circulation, although BMPR-​II is most highly expressed in the lung vasculature. In addition, it does not explain why the presence of the mutation is not sufficient on its own to cause disease, with gene penetrance as low as 20% in some families. These observations indicate that additional environmental and/​or genetic factors are necessary for disease manifestation. This puta- tive ‘second hit’ may further impact on BMP signalling pathways, leading to a critical reduction in bone morphogenetic signalling via Smad proteins and initiation of the process of pulmonary vascular remodelling. Although mutations in BMPR-​II are not generally found in most secondary forms of PAH, it is now becoming clear that dysfunction of the BMPR-​II pathway is involved in their pathogenesis. Further research is likely to reveal further clues to the involvement of this important pathway in vascular disease. Clinical features Symptoms The three main presenting symptoms are dyspnoea, chest pain, and syncope. The severity of symptoms is related to prognosis. A modified New York Heart Association (NYHA) score is a useful way to assess symptom severity and follow response to treatment (Box 16.15.2.1). Unexplained breathlessness on exertion should always raise the possibility of PAH, particularly in the setting of conditions known to be associated with pulmonary hypertension (Table 16.15.2.1). The condition may have an insidious onset: frequently, there is a delay of years between the onset of first symptoms and diagnosis. Syncope is an ominous sign, usually reflecting severe right ventricular dysfunc- tion. Other symptoms include lassitude, abdominal swelling from ascites, and ankle swelling. Small haemoptyses may occur at later stages. Clinical signs Tachypnoea may be present, even at rest. Peripheral cyanosis is common due to a low cardiac output. Central cyanosis occurs later as pulmonary gas exchange deteriorates or right-​to-​left shunting oc- curs through a patent foramen ovale. The jugular venous pulse may be elevated with a prominent ‘a’ wave, reflecting the increased force Endothelin-1 Angiotensin II serotonin NO PGI2 ANP Adrenomedullin Vasoconstrictors = vasodilators Normal Endothelin-1 Angiotensin II serotonin NO PGI2 Vasoconstrictors > vasodilators Pulmonary hypertension ANP Adrenomedullin Minimal resting tone Increased tone Vascular remodelling Fig. 16.15.2.4  An imbalance of pulmonary vascular vasodilators and vasoconstrictors contributes to the vascular constriction and remodelling in pulmonary hypertension. ANP, atrial natriuretic peptide; NO, nitric oxide; PGI2, prostacyclin. section 16  Cardiovascular disorders 3700 of atrial contraction, or—​if tricuspid regurgitation is present—​there may be a large ‘V’ wave. There may be a right ventricular heave and a pulsatile liver. On auscultation, forceful closure of the pulmonary valve leads to an accentuated pulmonary arterial component of the second heart sound. There are often a third and fourth right heart sound. The murmurs of tricuspid regurgitation (systolic) or pul- monary regurgitation (diastolic) may be heard. Jaundice, ascites, and peripheral oedema may be present at advanced stages of the disease. Differential diagnosis If the symptoms and clinical signs suggest pulmonary hypertension, the differential diagnosis should be considered with reference to the classification in Table 16.15.2.1. Most importantly, the presence of left heart disease, parenchymal lung disease, or congenital heart dis- ease should be excluded. Pulmonary hypertension due to chronic thromboembolic disease is important to detect because specific sur- gical treatment is available. Idiopathic PAH remains a diagnosis of exclusion. Clinical investigation The investigation of a patient with suspected pulmonary hyper- tension involves (1) the exclusion of other underlying causes and (2) an assessment of severity of pulmonary hypertension and right heart failure for prognosis and treatment. The investigations that are useful in identifying the aetiology of newly diagnosed, unexplained pulmonary hypertension are listed in Box 16.15.2.2. Blood tests A thrombophilia screen, including antithrombin III, proteins C and S, factor V Leiden, anticardiolipin antibodies, and lupus anticoagu- lant should be performed, and may reveal clotting abnormalities predisposing to chronic thromboembolic pulmonary hypertension (CTEPH). Thyroid function should be checked since both hypo-​ and especially hyperthyroidism are commonly reported associations. An autoantibody screen should be performed to exclude underlying autoimmune rheumatic or vasculitic disease: positive antinuclear antibodies (ANA) can be found in 30–​40% of patients with idio- pathic PAH, but a positive test for antineutrophil cytoplasmic anti- bodies (ANCA) would be uncommon. Since there is an increased incidence of unexplained pulmonary hypertension in HIV-​positive patients, this diagnosis should always be considered. MUTANT WILD TYPE cell membrane R - smad Normal pulmonary artery Primary pulmonary hypertension Co-smad P P P P R-smad BMP–2, –4, –7 GDF–5, –6 heterodimeric complex BMPR-II Type 1 receptor cell proliferation clonal expansion growth inhibition cell differentiation DNA binding partner gene transcription Fig. 16.15.2.5  The potential role of mutations in the bone morphogenetic protein type II receptor (BMPR-​II) in familial PAH. The wild-​type receptor signals in response to ligands by activating receptor-​regulated Smad proteins (R-​Smads), which dimerize with common partner Smads (Co-​Smads) to regulate gene expression in the vascular cell. Mutation in BMPR-​II disrupts Smad signalling and leads to abnormal vascular cell proliferation. BMP, bone morphogenetic protein; GDF, growth differentiation factors. By Hughes, J. B. M. From Pulmonary circulation: Basic mechanisms to clinical practice (2001). With permission of Imperial College Press. Box 16.15.2.1  Modified New York Heart Association functional classification of pulmonary hypertension • Class I—​pulmonary hypertension without resultant limitation of phys- ical activity. Ordinary physical activity does not cause undue dyspnoea or fatigue, chest pain, or near syncope • Class II—​pulmonary hypertension resulting in slight limitation of phys- ical activity. The patient is comfortable at rest. Ordinary physical ac- tivity causes undue dyspnoea or fatigue, chest pain, or near syncope • Class III—​pulmonary hypertension resulting in marked limitation of physical activity. The patient is comfortable at rest. Less than ordinary activity causes undue dyspnoea or fatigue, chest pain, or near syncope • Class  IV—​Pulmonary hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnoea and/​or fatigue may be present at rest. Discomfort is increased by any physical activity 16.15.2  Pulmonary hypertension 3701 Imaging The plain chest radiograph shows enlargement of the proximal pul- monary arteries, which may be dramatic, with peripheral pruning of the pulmonary vascular pattern, giving rise to increased peripheral radiolucency. If heart failure is present the heart may be enlarged, with particular enlargement of the right atrium (Fig. 16.15.2.6). The chest radiograph may also give clues to underlying diagnoses such as interstitial lung disease. Spiral contrast-​enhanced CT will detect proximal pulmonary arterial obstruction suggestive of acute or chronic thrombo- embolic disease (Fig. 16.15.2.7). A pattern of mosaic perfusion of the lung parenchyma is also a feature of CTEPH, and may be the only sign in predominantly distal disease (Fig. 16.15.2.8). A high-​ resolution CT scan will pick up unsuspected parenchymal abnor- malities, such as fibrosis. CT scanning is also useful to indicate more uncommon forms of PAH, such as PVOD, when there may be a degree of mediastinal lymphadenopathy and septal lines in the lung periphery, presumably indicating lymphatic and venous obstruction (Fig. 16.15.2.9). On ventilation–​perfusion lung scanning, the pattern of ventila- tion is usually normal in idiopathic PAH, and uneven ventilation Box 16.15.2.2  Investigation of the patient with suspected idiopathic pulmonary hypertension Blood tests • Full blood count/​film/​differential • Hb electrophoresis • Urea and electrolytes • Liver function including γ-GT • Thyroid function • Thrombophilia screen: − Antithrombin III − Protein C − Protein S − Factor V Leiden − Anticardiolipin antibody − Lupus anticoagulant • CMV DEAFF • Autoantibodies: − RhF − ANA − ENAs − Anti-​dsDNA − Anticardiolipin IgG and IgM − Anti-​sm/​anti-​SCL/​anti-​SS − Complement C3, C4, CH50 − ANCA • Serum angiotensin converting enzyme • Hepatitis screen • HIV test Imaging • Chest radiograph • Ventilation–​perfusion lung scan • High-​resolution and spiral CT • Pulmonary artery angiography Lung function • Pulmonary function tests • Exercise tests with saturation monitoring • Arterial blood gases on air Cardiac function • ECG • Echocardiogram • Diagnostic cardiac catheterization Miscellaneous • Urine microscopy • Abdominal ultrasound—​cirrhosis Fig. 16.15.2.6  Chest radiograph demonstrating cardiomegaly with dilated right heart chambers and dilatation of the proximal pulmonary arteries in a patient with PAH secondary to an atrial septal defect. Courtesy of Dr Nick Screaton, Addenbrooke’s Hospital. Fig. 16.15.2.7  Image from a CT pulmonary angiogram at the level of the right main pulmonary artery demonstrating dilatation of the main pulmonary artery (PA) with laminated thrombus in the distal right pulmonary artery (arrow) in keeping with proximal CTEPH. Courtesy of Dr Nick Screaton, Addenbrooke’s Hospital. section 16  Cardiovascular disorders 3702 should suggest underlying lung disease. The pattern of perfusion is also virtually normal, although small patchy perfusion defects may be present. This is in contrast to the appearance in CTEPH when segmental or larger perfusion defects persist, often indistinguishable from the pattern of acute pulmonary embolism (Fig. 16.15.2.10). Pulmonary artery angiography is really only required if the diagnosis is likely to be CTEPH, in which situation angiography will provide precise anatomical information regarding the location of vascular obstruction, indicated by abrupt cut-​off of vessels or intravascular webs, that may be of great use if surgical endarterec- tomy is being contemplated. However, CT pulmonary angiography or MR angiography may be employed in place of conventional angiography. The main contribution of MRI is in the assessment of patients with suspected intracardiac shunts or with anomalous vascular anatomy (e.g. if a shunt is suspected on the basis of right heart catheterization but cannot be demonstrated by echocardiography). MRI can also provide further pulmonary angiographic images. Pulmonary function tests The typical pattern for standard pulmonary function test for dis- ease confined to the pulmonary circulation is to find normal lung volumes; normal forced expiratory volume in 1 s (FEV1)/​vital cap- acity (VC) ratio (>0.75), indicating no airflow obstruction; and low transfer factor (diffusing capacity, TLco), and low transfer coefficient (Kco). The low diffusing capacity probably results from a combination of a reduced cardiac output and disease affecting the small arteri- oles, thereby reducing local perfusion. If the Kco is less than 50% predicted with normal spirometry, a diagnosis of PVOD/​PCH should be suspected. Additional findings in the pulmonary func- tion tests—​such as marked airflow obstruction (e.g. severe chronic obstructive pulmonary disease) or a restrictive defect (e.g. pul- monary fibrosis)—​would indicate the presence of an underlying cause for the pulmonary hypertension. However, subtle changes in lung volumes and mild airflow obstruction have been reported in a few patients with PAH. In some groups of patients at high risk of developing PAH (e.g. in scleroderma), the low transfer coefficient can be monitored at intervals, with breathlessness accompanied by a fall in the low transfer coefficient sometimes being the first sign of this complication. Exercise testing Significant PAH is always associated with a reduced exercise cap- acity, one of the most useful tests of this being the 6 min walk test, with monitoring of heart rate and oxygen saturation. This can readily be repeated to assess patients over time and as a measure of response to treatment. A normal distance is more than 500 m, with a low 6 min walk predictive of a poor survival. Full cardiopulmonary exercise testing is technically more demanding to perform and is only recommended if the diagnosis is in doubt (e.g. if there was a need to document cardiovascular limitation on exercise). Peak oxygen uptake on exercise is low and the anaerobic threshold is reduced to about 40% of normal. There is excessive ventilation for a given degree of oxygen consumption or CO2 output, even at rest. There is no ventilatory impairment when underlying lung disease is absent. There is often a pronounced tachycardia at submaximal exercise, and usually arterial oxygen desaturation. ECG In symptomatic PAH, the ECG is abnormal in 80 to 90% of cases, but it has inadequate sensitivity (55%) and specificity (70%) as a Fig. 16.15.2.8  Coronal multiplanar reconstruction demonstrating extensive mosaic perfusion in both lungs in a patient with CTEPH. Courtesy of Dr Nick Screaton, Addenbrooke’s Hospital. Fig. 16.15.2.9  Transverse CT image through the lower zones demonstrating heterogeneous attenuation of the lung parenchyma, centrilobular ground-​glass opacities, and smooth thickening of the interlobular septa in a patient with pathologically proven veno-​ occlusive disease. Courtesy of Dr Nick Screaton, Addenbrooke’s Hospital. 16.15.2  Pulmonary hypertension 3703 screening tool for detecting pulmonary hypertension. The typical appearances are right-​axis deviation (more than + 120°) in the limb leads, and a dominant R wave and T wave inversion in the right pre- cordial leads, accompanied by a dominant S wave in the left precor- dial leads, suggesting right ventricular hypertrophy (Fig. 16.15.2.11). Tall, peaked P waves in the right precordial and inferior leads denote right atrial enlargement. Right bundle branch block is common. Echocardiography Echocardiography remains the best screening test for significant pulmonary hypertension. It detects the presence, and direction, of intracardiac shunts. Usually this is possible using conventional transthoracic techniques, but if visualization is poor or a small shunt is still suspected, then transoesophageal echocardiography may be necessary. In addition, the left ventricle can be assessed to determine whether there is a contribution from left ventricular systolic or diastolic dysfunction to elevated pulmonary arterial pressure. The function of the right side of the heart can also be as- sessed qualitatively and quantitatively. Atrial and ventricular dimen- sions and wall thickness can be measured, and paradoxical bowing of the intraventricular septum into the left ventricular cavity may be seen during systole as a consequence of greatly elevated right-​ sided pressures. Continuous-​wave Doppler echocardiography is used to measure high-​flow velocities across cardiac valves, one of the most commonly derived indices in the right heart being the pul- monary artery systolic pressure estimated by Doppler echocardiog- raphy from measurement of the velocity of the tricuspid regurgitant jet (c.80% of patients with PAH and 60% of normal subjects, have measurable tricuspid regurgitation). The maximum flow velocity (v) of the regurgitant jet is measured and inserted into the modi- fied Bernoulli equation for convective acceleration pressure change, giving an estimate of right ventricular systolic pressure (RVSP): RVSP v RAP, 2 4 where RAP is right atrial pressure, which can be estimated clinically from the height of the jugular venous pressure. In the absence of pul- monary valve stenosis, the right ventricular systolic pressure is equal to the pulmonary artery systolic pressure (PASP). There is a reason- able correlation between Doppler estimates of PASP and catheter measurements. Newer echocardiographic techniques such as three-​ dimensional echo and tissue Doppler are being evaluated. Right heart catheterization Right heart catheterization remains the best technique for con- firming the diagnosis of pulmonary hypertension and for providing important prognostic information. An elevated mean pulmonary arterial pressure of greater than 25 mm Hg at rest is the accepted definition. In patients with idiopathic PAH the mean pulmonary arterial pressure may exceed 60 mm Hg. The pulmonary capillary wedge pressure (PCWP) can also be determined at catheterization, which is an approximation of left atrial pressure. An elevated PCWP (>15 mm Hg) generally indicates left heart disease. Measurement of PCWP is often unreliable in the presence of CTEPH. Sampling of venous blood oxygen saturation as the catheter passes down from the right atrium to right ventricle may detect a sudden ‘step-​up’ in oxygenation, which would indicate the presence of a left-​to-​right shunt. Cardiac output can be determined by thermodilution or the Fick method. Indicators of right heart failure, and hence poorer prognosis, in- clude (1) an elevated right atrial pressure (>10 mm Hg); (2) an ele- vated right ventricular end-​diastolic pressure (>10 mm Hg); (3) a reduced mixed venous oxygen saturation (Svo2 <63%); and (4) re- duced cardiac output (<2.5 litre/​min). Vasoreactivity studies A subgroup (5–​10%) of patients with idiopathic and anorexigen-​ associated PAH demonstrate a marked reduction in pulmonary vascular resistance following the administration of a vasodilator. Perfusion Ventilation Fig. 16.15.2.10  Perfusion scintigram demonstrates multiple perfusion defects in a patient with CTEPH. Courtesy of Dr Nick Screaton, Addenbrooke’s Hospital. section 16  Cardiovascular disorders 3704 These patients are the only group that respond favourably to long-​ term treatment with vasodilator therapy in the form of calcium channel blockers (see ‘Disease-​targeted therapies’), and are thus an important group to identify. Vasodilator studies are undertaken at the time of right heart catheterization, the preferred agent being in- haled nitric oxide, or an intravenous infusion of prostacyclin or ad- enosine. A positive response is defined as a fall in mean pulmonary arterial pressure of at least 10 mm Hg to below 40 mm Hg, accom- panied by an increase or no change in cardiac output. Conventional treatments All patients with suspected severe PAH are best referred to a spe- cialist centre for initial assessment and treatment. A multidiscip- linary team approach to planning treatment is preferred, with input from respiratory physicians and cardiologists, transplant physicians, and cardiothoracic surgeons, radiologists, specialist nurses, and pal- liative care specialists. Assisting patients to adapt to the uncertainty associated with chronic, life-​shortening disease is essential if they are to successfully adjust to the demands of their illness and its treat- ment. The overall aims are to improve symptoms and quality of life, increase exercise capacity, and improve prognosis. Supportive medical therapy Patients with right heart failure and fluid retention may require di- uretics. Decreasing cardiac preload with diuretics is often enough to alleviate episodes of right heart failure. However, caution should be exercised because faced with a reduction in vascular filling pres- sures, patients with severe PAH will not be able to increase cardiac output effectively, which may result in systemic hypotension and syncope. Antiarrhythmics may be required for sustained or paroxysmal atrial fibrillation. Patients with severe PAH are prone to this com- plication because of stretching of the overloaded right atrium, and atrial fibrillation can significantly compromise the already reduced cardiac output in patients with PAH, hence it should be treated ag- gressively. Rate control with digoxin is possible, but if not contra- indicated, pharmacological cardioversion with amiodarone is preferable. Electrophysiological mapping of arrhythmias and ab- lation of arrhythmogenic pathways may be indicated in selected patients. Anticoagulation Warfarin therapy to maintain the international normalized ratio (INR) between 2 and 3 is recommended in all patients with idio- pathic and familial PAH. Two retrospective studies and one small prospective study have demonstrated a survival benefit of anticoagulation, almost doubling survival rate in idiopathic PAH over a 3-​year period. The consensus is that patients with PAH as- sociated with autoimmune rheumatic tissue disease should also receive warfarin, unless contraindicated. The risk–​benefit ratio of anticoagulation in other forms of PAH is undetermined. Oxygen therapy Oxygen therapy is indicated for symptomatic relief of breath- lessness. There are no published trials of the benefit of long-​term oxygen therapy in hypoxaemic patients with PAH. Nocturnal Fig. 16.15.2.11  Twelve-​lead ECG from a patient with idiopathic PAH showing a rightward axis, p pulmonale, poor R wave progression, and ST segment changes indicative of right ventricular strain in the anterior chest leads. 16.15.2  Pulmonary hypertension 3705 oxygen has been shown to be of no benefit in Eisenmenger’s syn- drome. Ambulatory oxygen may be beneficial if there is evidence of correctable desaturation of 4% and to less than 90% during a 6 min walk test. Consideration should be given to in-​flight supplemental oxygen for air travel. Disease-​targeted therapies Calcium channel blockers Patients with idiopathic PAH and a documented acute vasodilator response at cardiac catheterization, as defined just now, should be offered long-​term treatment with a calcium channel blocker. This is associated with very significant improvement in symptoms and prognosis in this subset of patients, although only 50% of those who respond in the cardiac catheterization laboratory will maintain a long-​term response. Long-​term responders account for less than 5% of idiopathic PAH patients. Calcium channel blockers should be avoided in any patient with significant signs of right ventricular failure, or until this is controlled, because of their negative inotropic effects. For this reason, and the risk of systemic hypotension, calcium channel blockers should not be prescribed without confirmation of a vasodilator response at cardiac catheterization:  indiscriminate prescribing will lead to increased mortality in the PAH population. Treatment should be started in hospital, using diltiazem, amlodipine, or nifedipine, and carefully titrated against systemic blood pressure. The aim is to in- crease the dose to the maximum tolerated. Targeted PAH therapy In recent years, remarkable advances have been made in the avail- ability of therapeutic agents for PAH. In the early 1980s, carefully timed heart–​lung transplantation was the only option known to im- prove prognosis. We now have a range of pharmacological agents available and licensed for treatment in this condition, based on data from clinical trials that have almost exclusively recruited patients with idiopathic and anorexigen-​associated PAH, although often including a subset of patients with PAH associated with systemic sclerosis. The drugs are used to reduce pulmonary vascular resist- ance and improve cardiac output: they all improve exercise perform- ance, and some prolong life. Fig. 16.15.2.12 presents an algorithm summarizing the pharmacological approach to treating PAH, based on current recommendations. Prostanoids Epoprostenol was the first treatment to be developed for the treat- ment of PAH during the 1980s. This has minimal oral bioavailability, has a half-​life in the circulation of less than 2 min, and thus must be given by continuous intravenous infusion. It produces acute haemodynamic effects in some patients; most experience a fall in pulmonary vascular resistance with long-​term use even in the ab- sence of acute improvements. These observations support the view that long-​term administration of these agents may reverse some of the vascular remodelling, as well as having a vasodilator effect. Epoprostenol has been shown to improve haemodynamics, exercise PDES inhibitors Continue calcium- channel blockers Atrial septostomy or lung transplantation Intravenous epoprostenol or endothelin-receptor antagonist or prostacyclin analogues Endothelin-receptor antagonist or prostacyclin analogues or intravenous epoprostenol Class IV Class III Pulmonary arterial hypertension (NYHA functional class III or IV) Conventional therapy (oral anticoagulant ± diuretics ± oxygen) Acute vasodilator response Oral calcium-channel blockers Sustained response No improvement or deterioration YES NO NO YES Fig. 16.15.2.12  Algorithm showing the evidence-​based approach to treatment in patients with PAH. Reproduced from Humbert M, Sitbon O, Simonneau G (2004). Treatment of pulmonary arterial hypertension. N Engl J Med, 351, 1425–​36. Copyright © 2004, Massachusetts Medical Society. All rights reserved. section 16  Cardiovascular disorders 3706 tolerance, quality of life, and survival in patients in NYHA class III and IV. The dose may have to be increased on a regular basis because of tachyphylaxis, and side effects are usually experienced when starting epoprostenol or when escalating the dose, including jaw pain, cutaneous flushing, nausea, and diarrhoea, as well as myalgias. Acute withdrawal of epoprostenol (e.g. if the infusion pump fails, can causes severe rebound pulmonary hypertension that can be fatal). Recurrent sepsis due to line infection can also be problematic. Although epoprostenol remains a proven therapy in PAH, the complexity of its administration and the availability of newer oral agents mean that its use tends to be reserved for patients with se- vere haemodynamic compromise. Stable analogues of prostacyclin have been developed with longer half-​lives and improved bioavail- ability: iloprost can be given by the intravenous or inhalation route; treprostinil can be given subcutaneously, intravenously, or by inhal- ation, and is approved for use in patients in NYHA class II, III, and IV. Beraprost is an orally available prostacyclin analogue, although the dose may be limited by gastrointestinal side effects. Selexipag is an oral selective prostacyclin receptor agonist that is structurally distinct from prostacyclin. Endothelin receptor antagonists Bosentan, an orally active dual-​selective ETA/​ETB receptor antag- onist, has been shown to improve exercise capacity, functional class, haemodynamics, echocardiographic, and Doppler variables, and time to clinical worsening in idiopathic PAH. Its most significant side effect is elevation of the hepatic transaminases, which is usu- ally reversible on stopping the drug. Sitaxentan and ambrisentan are newer ETA selective agents with similar efficacy to bosentan, though sitaxsentan was recently withdrawn due to reports of irre- versible hepatotoxicity. All patients on these agents require monthly monitoring of liver function tests. The United States Food and Drug Authority (FDA) recently approved a new dual-​selective ET receptor antagonist, macitentan, for PAH. Phosphodiesterase inhibitors Sildenafil is an orally active selective inhibitor of cGMP-​ phosphodiesterase type 5. It acts by inhibiting the breakdown of cGMP, with vasorelaxant and antiproliferative effects in pulmonary vascular smooth muscle. Sildenafil improves exercise tolerance and pulmonary haemodynamics in short-​term studies in PAH. Tadalafil is a once daily PDE5 antagonist licensed for use in PAH. Stimulators of soluble guanylate cyclase Riociguat, a novel stimulator of soluble guanylate cyclase, was re- cently approved by the FDA for use in patients with PAH and in patients with chronic thromboembolic pulmonary hypertension. Hypotension may limit dosing and the drug should be avoided in combination with a PDE5 inhibitor. Combination therapy There is considerable theoretical and experimental evidence to sup- port the use of combinations of the aforementioned disease-​targeted therapies in PAH, which is a progressive disease. Most patients even- tually deteriorate on monotherapy, and the addition of further agents has been shown to provide clinical benefit. Indeed, early introduc- tion of initial combination therapy (ambrisentan and tadalafil) has been shown to improve outcomes in a clinical trial. Other strategies Atrial septostomy Atrial septostomy involves creating a right-​to-​left shunt between the atria, the preferred technique being percutaneous graded balloon dilatation. The rationale for this procedure is that patients with PAH and a patent foramen ovale have improved survival. Creating the shunt reduces right ventricular preload, which relieves the failing right ventricle and can increase cardiac output and improve exercise capacity. The increase in cardiac output is at the expense of a re- duction in systemic arterial oxygen saturation, but systemic oxygen delivery is usually improved. The procedure is usually reserved for patients who are failing on maximal medical therapy or as a bridge to transplantation for PAH patients in NYHA class IV. Patient se- lection is vital. A high right atrial pressure (>20 mm Hg) and low arterial oxygen saturation (<80% on air) prior to septostomy are as- sociated with a high mortality related to the procedure, although impact on survival has not been formally assessed. Transplantation Transplantation of the lungs or heart and lungs developed as a treat- ment for end-​stage PAH during the 1980s. The advent of modern, targeted therapies has reduced the number of patients referred for transplantation, but the long-​term outcome of patients who remain in NYHA functional class III or IV remains poor. Lung or heart–​ lung transplantation therefore remains an important mode of treat- ment for patients failing medical therapy. Patients with PVOD/​PCH have a particularly poor outlook; they respond poorly to available medical therapies and should be referred early for transplantation assessment. In general, patients presenting with NHYA class IV symptoms should be referred for transplantation assessment at the time of presentation, because their prognosis is poor. Additional indica- tors of poor prognosis include (1) a 6 min walking distance less than 332 m; (2) peak oxygen consumption less than 10.4 ml/​min per kg; (3) cardiac index less than 2 litre/​min per m2; (4) right atrial pres- sure greater than 20 mm Hg; (5) mean pulmonary arterial pressure greater than 55 mm Hg; (6) mixed venous oxygen saturation of less than 63%. Those with significant improvement after 3 months of medical therapy can be removed or suspended from listing for trans- plant. The choice of procedure varies between centres, but single lung, bilateral lung, and heart–​lung transplantation are used in pa- tients with PAH. International registry figures show that the 1-​year mortality post-​transplantation is highest in patients with idiopathic PAH, compared with any other indications, with median survival post-​transplantation between 4 and 5 years. Prognosis The prognosis of PAH varies depending on the underlying associ- ation or cause. Prognosis is most closely linked to indices of car- diac function, especially cardiac index. Historical data in the period prior to the availability of modern, targeted therapies suggest an expected median survival for idiopathic pulmonary arterial hyper- tension between 2.5 and 4 years, and a 3-​year survival of about 60%. The prognosis is worse for patients with underlying systemic scler- osis, autoimmune rheumatic disease, HIV disease, and anorexigen-​ associated PAH, and that for patients surviving to adulthood with PAH associated with a congenital intracardiac defect is substantially 16.15.2  Pulmonary hypertension 3707 better than patients with idiopathic disease. At least in patients with idiopathic PAH, targeted therapies seem to improve survival to some extent, though definitive studies are awaited. Women with se- vere PAH should be advised that pregnancy carries a very high mor- tality because of the associated increased burden on the right heart. Other conditions associated with pulmonary hypertension One of the commonest causes of pulmonary hypertension is that occurring as a complication of chronic lung disease including interstitial lung disease and chronic obstructive pulmonary dis- ease (COPD). In COPD, pulmonary hypertension is due to a combination of hypoxic pulmonary vasoconstriction, hypoxia-​ driven pulmonary vascular remodelling, and a reduction in capil- lary cross-​sectional area in emphysema. Lung hyperinflation and polycythaemia may also contribute. The prevalence of pulmonary hypertension in patients with severe COPD may be as high as 50%, but the average mean pulmonary arterial pressure is of the order of 25 mm Hg and progresses slowly (<1 mm Hg/​year). It is likely that ventilatory impairment due to obstructed airways contributes most to the exercise limitation in these patients. Nevertheless, there are relatively unusual cases of COPD in which the pulmonary hyper- tension dominates. Patients with combined pulmonary fibrosis and emphysema are particularly prone to develop severe pulmonary hypertension. These patients are often profoundly hypoxic, have emphysema with variable degrees of fibrosis on CT scanning, and demonstrate a low DLCO. Severe pulmonary hypertension in the setting of chronic lung disease is defined as a mean pulmonary ar- terial pressure of 35 mm Hg or more, or 25 mm Hg or more with low cardiac index (<2.0 litres min−1 m−2). In these patients targeted therapy for PAH may be indicated in addition to optimization of their lung disease medication. Pulmonary hypertension is detectable in some 5% of patients with sarcoidosis. This may develop in the context of end-​stage pulmonary fibrosis, but may also present as an isolated sarcoid vasculopathy in patients with relatively little parenchymal lung involvement. A falling DLCO in the face of preserved lung volumes may be the first clue to this in a sarcoid patient with worsening dyspnoea. In patients with vasculopathy, there may be a marked response to immunosup- pression with prednisolone, which is worth trying before embarking on targeted PAH therapy. It is often stated that the commonest worldwide cause of pul- monary hypertension is schistosomiasis. When one considers how many patients are infected with schistosomiasis, this may be true, but true prevalence figures are hard to come by. The clinical pic- ture in schistosomiasis is usually dominated by the effect on the urinary tract (Schistosoma haematobium) or liver (S. mansoni and S. japonica). Pulmonary hypertension is thought to be due to granu- lomata in or adjacent to pulmonary arterioles caused by the reaction to the presence of schistosome eggs. Likely future developments The next few years will see further important advances in our under- standing of the pathobiology of PAH. The application of whole genome and whole exome sequencing at scale will allow greater understanding of the genetic contribution to PAH. Intensive research into the TGFβ/​BMP signalling pathway in pulmonary vascular cells and tissues are elucidating the mechanisms by which mutation in the BMPR2 gene leads to PAH. This knowledge is allowing the de- velopment of experimental therapies aimed at prevention, arrest, or reversal of the process of pulmonary vascular remodelling in PAH. Trials are already exploring the impact of growth factor inhibition and anti-​inflammatory strategies in PAH, and the next few years is likely to see more of these experimental studies using drugs initially developed for use in oncology and autoimmune diseases. Cell-​based therapy using circulating progenitor cells is also being evaluated. New pathways are being targeted which impact on ion channels, cell survival, cell metabolism and endothelial function, including activators of the peroxisome proliferator activated receptors. Novel biomarkers of disease activity and progression are being identified. Imaging modalities using the latest advances in echocardiography, CT scanning, and MRI are being developed to maximize the infor- mation derived from these techniques, which may then replace in- vasive right heart catheterization. Chronic thromboembolic pulmonary hypertension (CTEPH) Pathogenesis CTEPH occurs when a clot fails to resolve completely after an acute pulmonary embolic event. The rate of resolution of clots after acute pulmonary embolism varies and is longer in patients with pre-​ existing cardiopulmonary disease, but normal perfusion should be restored by 4 to 6 weeks after an acute event. To some extent, the rate of resolution depends on the initial clot burden or the size of the acute pulmonary embolism. If the clot fails to resolve, it be- comes organized before it can be completely fibrinolysed, and this organized thrombus is incorporated into the wall of the pulmonary artery, becomes covered by endothelial cells, and forms a false in- tima. The organized material occludes the vascular lumen, which increases pulmonary vascular resistance and leads to pulmonary hypertension. The true prevalence of CTEPH is hard to ascertain, because it is not usually sought in patients who are recovering from acute pul- monary embolism, but it is almost certainly underdiagnosed. One well-​designed study found that 4% of patients with a history of acute pulmonary embolism had a persistent elevation of pulmonary ar- terial pressure after 2 years. Those with a higher initial clot burden (massive pulmonary embolism) are more likely to develop CTEPH than those with minor pulmonary embolism. The more widespread use of thrombolysis for acute pulmonary embolism is often assumed to reduce the prevalence of CTEPH, but no data at present support this view. It is of note that some of the classic risk factors for acute deep vein thrombosis (DVT)/​pulmonary embolism are not found with increased frequency in the population that develops CTEPH. For example, the factor V Leiden polymorphism, which leads to ac- tivated protein C resistance and is found with high prevalence in the population of patients with acute DVT, is not overrepresented in patients with CTEPH. By contrast, the prevalence of protein C and S deficiency is increased in patients with CTEPH, but these con- ditions account for only a few patients. The strongest genetic risk factor is a non-​O blood group, which is driven by the A1 allele. In addition, some 10% of patients with CTEPH may have circulating section 16  Cardiovascular disorders 3708 antiphospholipid antibodies. Recent research points to a deficiency in the ability to fibrinolyse established clots as a predisposing factor. Other important predisposing factors include previous splenectomy and inflammatory bowel disease. Clinical presentation Patients often present with persistent symptoms of dyspnoea after an acute embolic event despite the recommended period of anticoagulation, up to 60% having a prior documented episode of previous venous thromboembolism, although some patients may present with gradually worsening dyspnoea in the absence of acute events. On physical examination, there may be pulmonary flow murmurs resulting from turbulent flow across partially obstructed large pulmonary arteries: these are audible on chest auscultation in up to 30% of patients with CTEPH. Otherwise, the clinical presenta- tion is similar to that described earlier for PAH. Investigation The work-​up of patients referred with a suspected diagnosis of CTEPH requires a multidisciplinary approach involving surgeons, physicians, and radiologists. Imaging plays a key role in determining whether a patient is suitable for the surgical procedure of choice, pul- monary endarterectomy. CT pulmonary angiography with modern multislice scanners is a rapid and non​invasive technique that can provide several important pieces of information in the assessment of patients with suspected CTEPH, both assessing the presence of any associated lung disease or tumours, and most importantly giving an accurate assessment of the extent of proximal organized clots (Fig. 16.15.2.7). Although occlusion of very small arteries cannot be visualized directly in the case of predominantly distal disease, the characteristic appearance of ‘mosaic perfusion’ suggests the presence of peripheral disease (Fig. 16.15.2.8), and ventilation–​ perfusion lung scans also usually show multiple segmental perfusion defects not matched by defects in ventilation in this circumstance (Fig. 16.15.2.10). CT can also reveal the extent of right ventricular hypertrophy and dilatation, although this is probably best seen by MRI. Three-​dimensional reconstruction of the two-​dimensional CT and MR images can help decide whether the distribution of dis- ease is suitable for pulmonary endarterectomy. The use of a combin- ation of these techniques means that the more invasive traditional pulmonary angiogram can be avoided in most patients. Treatment About 60% of cases of CTEPH is potentially suitable for surgery. Of the patients who are not suitable for surgical management, many may be suitable for targeted therapy with the new pharmacological agents described previously for PAH. Pulmonary endarterectomy involves removal of organized thrombi from the proximal pulmonary arteries. The procedure is a major operation that usually requires the patient to undergo re- peated cycles of cardiopulmonary bypass with cerebral cooling, which ensures a bloodless field of view for the surgeon, who can then enter the left and right main pulmonary arteries via an arteri- otomy. The aim is to identify a dissection plane along the base of the false intima and to dissect distally as far as possible, when it is often possible to remove organized material down to the level of seg- mental pulmonary arteries (Fig. 16.15.2.13). With successful clear- ance of proximal clots, the pulmonary vascular resistance can fall dramatically postoperatively, and near normalization of resistance can be achieved in the long term. There are two main aspects to patient selection for this pro- cedure. Comorbidities are important predictors of perioperative mortality and require careful assessment. A  further important consideration is the distribution of the disease, as organized clots need to be anatomically accessible to the surgeon. If the organ- ized material is predominantly of a distal distribution within the pulmonary arteries (i.e. involves subsegmental vessels), there is a high risk that pulmonary vascular resistance will not decrease after the procedure and that the patient will be left with significant pul- monary hypertension. (a) (b) Fig. 16.15.2.13  The surgical technique of pulmonary endarterectomy (a) and the surgical specimen obtained from a patient undergoing surgery for CTEPH (b). Reproduced from Huikuri HV, Castellanos A, Myerburg RJ (2001). Sudden death due to cardiac arrhythmias. N Engl J Med, 345, 1473–​82. Copyright © 2001, Massachusetts Medical Society. All rights reserved. 16.15.2  Pulmonary hypertension 3709 Despite careful patient selection, the operation is high risk, with perioperative mortality varying between 3% and 20% depending on the experience of the centre. However, in those who survive surgery, the long-​term outlook is often excellent after a successful procedure, with marked improvements in exercise cap- acity, NYHA functional status, and quality of life. To prevent further thromboembolism, patients have an inferior vena cava filter sited prior to the operation and are maintained on lifelong warfarin. Likely future developments Much remains unknown about the natural history of CTEPH and the risk factors for failure of resolution of an acute embolic event. Large studies designed to prospectively follow up patients with acute embolism over many years will be necessary to get a clearer picture of the underlying causes. Whether chronic thromboembolic pulmonary embolism always results from embolic phenomena or whether in situ thrombosis also contributes remains uncertain. The distinction between CTEPH leading to occlusion of small periph- eral pulmonary arteries and idiopathic PAH can be difficult in some cases, and indeed they may be part of the same spectrum of disease. Selection of patients likely to respond favourably to surgery can be difficult, and improved imaging or physiological assess- ments are needed. These, along with advances in anaesthetic technology and surgery, are likely to improve further the already impressive results of surgery. The use of balloon angioplasty for the dilatation of proximal partially occlusive chronic thrombo- embolic disease is currently being evaluated. The response of in- operable CTEPH to targeted pharmacological therapy has been evaluated recently and has led to the recent approval of riociguat, a stimulator of soluble guanylate cyclase, in CTEPH. We are also likely to see further medical interventions aimed at reducing the incidence of CTEPH after acute pulmonary embolism. FURTHER READING Abenhaim L, et al. (1996). Appetite-​suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med, 335, 609–​16. Archibald CJ, et  al. (1999). Long-​term outcome after pulmonary thromboendarterectomy. Am J Respir Crit Care Med, 160, 523–​8. Barst RJ, et al. (1994). Survival in primary pulmonary hypertension with long-​term continuous intravenous prostacyclin. Ann Intern Med, 121, 409–​15. Barst RJ, et  al. (1996). A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med, 334, 296–​301. Bonderman D, et al. (2007). Predictors of outcome in chronic thrombo- embolic pulmonary hypertension. Circulation, 115, 2153–​8. Deng Z, et al. (2000). Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-​II gene. Am J Hum Genet, 67, 737–​44. Fedullo PF, et al. (2011). Chronic thromboembolic pulmonary hyper- tension. Am J Respir Crit Care Med, 183, 1605–​13. Fuster V, et al. (1984). Primary pulmonary hypertension: natural his- tory and the importance of thrombosis. Circulation, 70, 580–​7. Galie N, et al. (2005). Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med, 353, 2148–​57. Galie N, et al. (2013). Updated treatment algorithm of pulmonary ar- terial hypertension. J Am Coll Cardiol, 62, Suppl, D60–​72. Heath D, Segel N, Bishop J (1966). Pulmonary veno-​occlusive disease. Circulation, 34, 242–​8. Heath D (1996). Pulmonary vascular disease. In:  Hasleton PS (ed) Spencer’s pathology of the lung, pp. 649–​93. McGraw-​Hill, London. Higenbottam T, et al. (1984). Long-​term treatment of primary pul- monary hypertension with continuous intravenous epoprostenol (prostacyclin). Lancet, i, 1046–​7. Hoeper MM, et  al. (2002). New treatments for pulmonary arterial hypertension. Am J Respir Crit Care Med, 165, 1209–​16. Hoeper MM, et al. (2013). Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol, 62, Suppl, D42–​50. Humbert M, et al. (2004). Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol, 43, Suppl 1, S13–​24. Humbert M, Sitbon O, Simonneau G (2004). Treatment of pulmonary arterial hypertension. N Engl J Med, 351, 1425–​36. International PPH Consortium, et al. (2000). Heterozygous germ-​line mutations in BMPR2, encoding a TGF-​β receptor, cause familial pri- mary pulmonary hypertension. Nat Genet, 26, 81–​4. Kay JM, Smith P, Heath D (1971). Aminorex and the pulmonary circu- lation. Thorax, 26, 262–​70. Kim NH, et al. (2013). Chronic thromboembolic pulmonary hyper- tension. J Am Coll Cardiol, 62, Suppl, D92–​9. Loyd JE, Primm RK, Newman JH (1984). Familial primary pulmonary hypertension: clinical patterns. Am Rev Respir Dis, 129, 194–​7. McGoon MD, et  al. (2013). Pulmonary arterial hypertension: epidemiology and registries. J Am Coll Cardiol, 62, Suppl, D51–​9. McMahon TJ, Bryan NS (2017). Biomarkers in pulmonary vas- cular disease:  gauging response to therapy. Am J Cardiol, 120, S89–​95. Moser KM, et al. (1983). Chronic thrombotic obstruction of major pulmonary arteries. Results of thromboendarterectomy in 15 pa- tients. Ann Intern Med, 99, 299–​304. Newman JH, et al. (2004). Genetic basis of pulmonary arterial hyper- tension:  current understanding and future directions. J Am Coll Cardiol, 43, Suppl 1, S33–​9. Olschewski H, et  al. (2002). Inhaled iloprost for severe pulmonary hypertension. N Engl J Med, 347, 322–​9. Palevsky HI, et al. (1989). Primary pulmonary hypertension: vascular structure, morphometry, and responsiveness to vasodilator agents. Circulation, 80, 1207–​21. Pengo V, et  al. (2004). Incidence of chronic thromboembolic pul- monary hypertension after pulmonary embolism. N Engl J Med, 350, 2257–​64. Pepke-​Zaba J, et al. (1991). Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension. Lancet, 338, 1173–​4. Piazza G, Goldhaber SZ (2011). Chronic thromboembolic pulmonary hypertension. N Engl J Med, 364, 351–​60. Rich S, et al. (1987). Primary pulmonary hypertension. A national pro- spective study. Ann Intern Med, 107, 216–​23. Rich S, Kaufmann E, Levy PS (1992). The effect of high doses of blockers on survival in primary pulmonary hypertension. N Engl J Med, 327, 76–​81. Rubin LJ, et al. (2002). Bosentan therapy for pulmonary arterial hyper- tension. N Engl J Med, 346, 896–​903. Rudarakanchana N, et al. (2002). Functional analysis of bone mor- phogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Hum Mol Genet, 11, 1517–​25. section 16  Cardiovascular disorders 3710 Seeger W, et al. (2013). Pulmonary hypertension in chronic lung dis- eases. J Am Coll Cardiol, 62, Suppl, D109–​16. Simonneau G, et al. (2013). Updated clinical classification of pul- monary hypertension. J Am Coll Cardiol, 62, Suppl, D34–​41. Soubrier F, et al. (2013). Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol, 62, Suppl, D13–​21. Southgate L, et al. (2019). Molecular genetic framework underlying pulmonary arterial hypertension. Nat Rev Cardiol, doi: 10.1038/ s41569-019-0242-x. Tuder RM, et  al. (2013). Relevant issues in the pathology and pathobiology of pulmonary hypertension J Am Coll Cardiol, 62, Suppl, D4–​12. Wagenvoort C, Wagenvoort N (1970). Primary pulmonary hyperten- sion: a pathological study of vessels in 156 clinically diagnosed cases. Circulation, 42, 1163–​84. Xiong PY, et al. (2017). Models and molecular mechanisms of World Health Organization Group  2 to 4 pulmonary hypertension. Hypertension, 71, 34–​55. 16.16 Venous thromboembolism 3711 16.16.1 Deep ven 16.16 Venous thromboembolism 3711 16.16.1 Deep venous thrombosis and pulmonary embolism 3711 Paul D. Stein, Fadi Matta, and John D. Firth 16.16 Venous thromboembolism CONTENTS 16.16.1 Deep venous thrombosis and pulmonary embolism  3711 Paul D. Stein, Fadi Matta, and John D. Firth 16.16.2 Therapeutic anticoagulation  3729 David Keeling 16.16.1  Deep venous thrombosis and pulmonary embolism Paul D. Stein, Fadi Matta, and John D. Firth ESSENTIALS Deep venous thrombosis Deep venous thrombosis (DVT) is diagnosed in 1–​2% of hospital- ized patients, but is often silent and is found much more frequently at autopsy. Patients typically complain of pain and/​or swelling of the leg, but often the diagnosis will be considered only when the physician detects unilateral leg swelling. Investigation—​given the sinister nature of untreated DVT, it is im- portant to confirm or refute the diagnosis with appropriate inves- tigations whenever clinical suspicion is aroused, unless the general condition of the patient makes this inappropriate. Management al- gorithms have been developed to guide strategy for investigation. These typically use scoring systems to stratify the clinical probability that the particular patient has a DVT (or pulmonary embolism). Those with a low clinical probability proceed to D-​dimer testing, with fur- ther investigation not pursued if this is negative. Patients with either a high clinical probability, or a low clinical probability but elevated D-​dimer, proceed to tests for the presence of thrombus in the leg veins, typically by ultrasonography. Management—​a first episode of proximal DVT, diagnosed by non-​ invasive testing, should be treated with anticoagulation for 3 months. Longer duration of treatment may be recommended for those whose thrombosis occurred in the absence of a reversible risk factor or in those with a thrombophilic condition or cancer. For patients who do not have cancer, dabigatran, rivaroxaban, apixaban, or edoxaban are recommended over a vitamin K antagonist or low-​molecular-​weight heparin. Initial parenteral anticoagulation is given before dabigatran and edoxaban. If treatment is initiated with heparin (low molecular weight or unfractionated) or fondaparinux, it should be administered for ≥5 days before dabigatran and edoxaban. If a vitamin K antagonist is to be used, stop heparin or fondaparinux when the international normalized ratio is greater than 2.0 for 24 h or more. In patients with cancer, low-​molecular-​weight heparin is suggested over a vitamin K antagonist or novel oral anticoagulant. In patients with DVT, home treatment is recommended if home circumstances are adequate. DVT carries extensive morbidity irrespective of pulmonary embolism: severe post-​phlebitic syndrome occurs in 9% of patients by 5 years. Pulmonary embolism Acute pulmonary embolism is the third most common cardiovas- cular problem after coronary heart disease and stroke. It is a compli- cation of DVT, with emboli originating in the legs in 80% or more of cases. Immobilization, irrespective of the cause, is the most frequent predisposing factor. Common symptoms are dyspnoea (c.75%), pleuritic chest pain (c.50%), cough (c.35%), and calf or thigh pain or swelling (c.40%). Circulatory collapse (systolic blood pressure <80 mm Hg or loss of consciousness) is an uncommon (8–​15%) mode of presentation in patients entered into clinical trials, but likely to be more frequent in routine clinical practice. Tachypnoea (respiratory rate 20 cycles/​min or greater) is the most common physical sign (50–​70%), and abnor- malities may be found on respiratory (30–​50%) or cardiac (20–​30%) examination. Investigation—​algorithms similar to those used to guide manage- ment of patients with suspected DVT are used when pulmonary em- bolism is suspected or needs to be excluded. Patients with a low, ‘unlikely’, or moderate clinical probability and negative D-​dimer are not investigated further. Patients with a high clinical probability, and those with an elevated D-​dimer, proceed to tests for the presence of pulmonary emboli, typically by contrast-​enhanced spiral CT, perhaps in combination with CT venous-​phase imaging. Management—​treatment with anticoagulants while awaiting the outcome of diagnostic tests may be appropriate, particularly if the tests cannot be obtained immediately. All patients who are hyp- oxic should be given supplementary oxygen at high concentration. Anticoagulation is as described for DVT. Thrombolytic therapy is section 16  Cardiovascular disorders 3712 not indicated as routine treatment, but is advised for those with PE who are hypotensive or require ventilatory support, and those who deteriorate after starting anticoagulant therapy. Inferior vena cava filter—​this is recommended for patients with proximal DVT or pulmonary embolism if anticoagulants are contraindicated or pulmonary embolism has recurred while on adequate anticoagulant therapy. Administrative data show a lower in-​hospital all-​cause mortality with vena cava filters in patients with pulmonary embolism if they are haemodynamically un- stable (in shock or on ventilatory support) or require thrombolytic therapy or pulmonary embolectomy, and in some other patient groups, but these apparent reductions in mortality have not been investigated by randomized controlled trials. A very few survivors of acute pulmonary embolism develop chronic pulmonary thromboembolic hypertension. Treatment is pulmonary thromboendarterectomy, but only at experienced centres. Introduction Deep venous thrombosis (DVT) and pulmonary embolism (PE) are sometimes described together using the term ‘thromboembolism’. PE is a complication of DVT, with thrombi in 80% or more of cases originating in the legs. Management strategies of PE have been de- veloped that are based on the diagnosis of either PE or DVT, pro- vided the patient has good respiratory reserve. Treatment with anticoagulants is the same for both. Some physicians believe that patients can be managed better if it is known whether acute PE is present, even if a diagnosis of DVT is already established. Prognosis of untreated disease The frequency of fatal PE in patients with untreated DVT has di- minished as diagnostic tests have made it possible to diagnose DVT before it becomes extensive. In 1955, prior to the use of sensitive non​invasive tests for the early detection of DVT, the risk of fatal PE in untreated patients with clinically apparent DVT was 37%. Based on a diagnosis by radioactive fibrinogen scintiscans, the risk of fatal PE in patients with untreated DVT, most of which were subclinical, was about 5%. Early diagnosis has also reduced the risk of death from PE. In the early 1960s the mortality in untreated patients with acute PE, diagnosed on the basis of clinical features, was 26–​37%, and an add- itional 36% died of recurrent PE. In 2008, the estimated case fatality rate from acute PE was 6.2%. Among patients in the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) with mild PE who inadvertently escaped treatment, the mortality was 4–​5%. Deep venous thrombosis Incidence and pathology In 2008, DVT was diagnosed in 1.7% of hospitalized patients aged 18 years or more in the United States of America. This represented 250 patients per 100 000 adult population. The condition is often silent: among patients with DVT detected by screening with 125I-​ fibrinogen scans, clinical evidence was present in 49%. Proximal DVT was found at autopsy in 22% of patients who died of various causes in a tertiary care hospital. Thrombosis of the leg veins usually occurs without inflammation. Inflammation of the walls of the veins, when it occurs, is usually secondary to the thrombosis. No clear evidence indicates that in- flammation of the veins prevents embolization, or that embolization is more frequent in those patients with thrombi not associated with venous inflammation. The valve pockets are a frequent site of origin of thrombi. Clinical features Patients may complain of pain or swelling of the leg, but physical examination remains the means by which attention is usually drawn to the potential diagnosis of DVT. DVT sometimes, but not always, leads to swelling of the leg. If restricted to the popliteal and calf veins, swelling is confined to below the knee, but if thrombosis involves the femoral and pelvic veins (or inferior vena cava), then swelling of the thigh is also expected. A difference of circumference of the calves of 1.0 cm or more, measured 10 cm below the tibial tuberosity, is ab- normal. It is important to repeat the measurement of circumference of the calves and thighs at frequent intervals: proximal extension of a thrombus is likely to cause increased swelling. Repeated meas- urements should be made from a fixed point. It is good practice for the position of the first measurement to be marked indelibly on the patient’s skin. Homans’ sign is positive when active and/​or passive dorsiflexion of the foot associated with any of the following: (1) pain, (2) incom- plete dorsiflexion (with equal pressure applied) to prevent pain, or (3) flexion of the knee to release tension in the posterior muscles with dorsiflexion. This sign was present in 44% of patients with DVT of the lower leg, and in 60% of patients with femoral venous thrombosis. The elicitation of pain with inflation of a blood pressure cuff around the calf to 60 to 150  mm Hg has been recommended as a test for DVT. However, this test has not been shown to be more helpful than the assessment of direct tenderness or leg circumference. In one study, the sensitivity of oedema, erythema, calf tenderness, palpable cord, or Homans’ sign alone, or 1 cm or more calf asym- metry alone was 55 to 80%, but the specificity was only 49%. The combination of one of these signs plus 1 cm or more ipsilateral calf asymmetry increased the specificity to 87%, but decreased the sensi- tivity to 15–​33%. The specificity increased to 91% with one of these signs in combination with 2 cm or more calf asymmetry. Only 3–​ 10% of patients had one or more qualitative signs plus 3 cm or more ipsilateral calf asymmetry: in these the specificity for DVT was 96%. Other clinical features of DVT, whose sensitivity and specificity have not been tested, include increased temperature on the affected side, cyanotic discoloration of the limb, and persistent engorgement of superficial veins. Superficial varicose veins almost always empty when the patient lies down: if they remain engorged, this suggests problems with drainage through the deep veins. In very rare cases, tense venous oedema can cause arterial compression and venous gangrene. Differential diagnosis The clinical diagnosis of DVT is not always straightforward. Many of the findings described earlier can also be found in those 16.16.1  Deep venous thrombosis and pulmonary embolism 3713 with muscular strains and bruising, ruptured Baker’s cyst, or plantaris tendon, superficial thrombophlebitis, cellulitis, and other traumatic conditions. The presence of bruising near either malleolus suggests ruptured Baker’s cyst or other cause of calf haematoma. Given the sinister nature of untreated DVT it is important to con- firm or refute (so far as is possible) the diagnosis with appropriate investigations whenever clinical suspicion is aroused, unless the general condition of the patient makes this inappropriate. Investigation Detection of evidence of thrombus within the circulation: D-​dimer D-​dimer is a specific degradation product released into the cir- culation by endogenous fibrinolysis of a cross-​linked fibrin clot. A  D-​dimer measured by enzyme-​linked immunosorbent assay (ELISA) below a cut-​off of 300–​540 ng/​ml (the values differ slightly from one study to another) make the diagnosis of DVT (or PE) un- likely. However, a concentration of D-​dimer above the cut-​off level is not useful for making a positive diagnosis because of the large number of false-​positive tests. Conventional ELISA assays are cumbersome and not suited for emergency use, which limited the practical utility of D-​dimer meas- urements until the development of rapid ELISA assays. These pro- vide the best balance of sensitivity and specificity among the various assays for the safe diagnostic handling of patients with suspected DVT and PE. Detection of the physical presence of thrombus in leg veins The ‘gold standard’ is contrast venography, but this can be unpleasant for patients, is time consuming for radiology departments, and ex- pensive, hence it is now rarely performed except as part of research protocols. It has been replaced by B-​mode ultrasonography as the preferred first-​line diagnostic technique. Among patients with DVT proven by contrast venography, B-​mode ultrasonography using compression showed a 95% sensitivity in symptomatic patients. In asymptomatic patients who were evaluated because of a high risk of DVT, venous compression ultrasound showed a sensitivity of only Table 16.16.1.1  Pretest clinical probability scoring system and care pathway for the patient with suspected deep venous thrombosis (a) Pretest probability score Criteria Score Active cancer +1 Paralysis, plaster cast +1 Bed rest >3 days, surgery within 4 weeks +1 Tenderness along veins +1 Entire leg swollen +1 Calf swollen >3 cm +1 Pitting oedema +1 Collateral veins +1 Alternative diagnosis likely –​2 (b) Pretest probability Low 0 Moderate 1 or 2 High 3 or more (c) Management algorithm Pretest probability score Action Result Further action 0 or 1 Perform D-​dimer Negative No further investigation Positive Perform ultrasonography 2 or more Do not perform D-​dimer Perform ultrasonography Negative Withhold treatment and repeat ultrasonography in 10–​14 days. If serial ultrasonography is negative, PE rarely occurs Positive Diagnosis of venous thrombosis established Notes Pretest probability score from Wells et al. (1997). This management algorithm is typical of many used, but further prospective evaluation is warranted. If the physician’s judgement is that DVT is very likely in a particular case, then they should proceed to investigations directed at detecting thrombus in leg veins whatever the scoring algorithm would suggest. If the result of ultrasonography is negative, and repeat ultrasonography in 10–​14 days is also negative, PE rarely occurs. All patients who are discharged with ‘DVT excluded’ should be given written information describing how they can be reassessed if symptoms worsen or fail to settle over the next few days. Thromboembolic events have been linked to oestrogen-​containing oral contraceptives, but the absolute risk is low and their frequency has been reduced with the use of preparations that contain less than 50 μg of oestrogen. Oral contraceptives may increase the risk of venous thromboembolism after surgery even if their oestrogen content is low. section 16  Cardiovascular disorders 3714 67%. Regarding veins of the calves, venous compression ultrasound was 93% sensitive in symptomatic patients, but only 26% sensitive in asymptomatic high-​risk patients subsequently found to have DVT. In all instances, specificity was 97–​99%. Venous-​phase contrast-​enhanced spiral CT is useful for imaging the veins of the pelvis and thighs, particularly in combination with spiral CT pulmonary angiograms. This offers a comprehensive study for thromboembolism, but increases exposure to ionizing radiation, hence CT pulmonary angiography is not typically accompanied by CT venography. Gadolinium-​enhanced magnetic resonance (MR) venography fol- lowing an intravenous injection was sensitive for DVT in the veins of the thighs and pelvis but often technically inadequate. Specificity was 95 to 100%. Usage is restricted by cost, availability, and risk of nephrogenic systemic fibrosis/​nephrogenic fibrosing dermopathy in patients with poor renal function. Fibrinogen-​uptake radionuclide scanning was used extensively in the 1960s. It is more sensitive for DVT in the calves than in the thighs, meaning that its value is limited because of the greater risk of PE with DVT in the thighs than in the calves. Strategy for diagnosis Management algorithms have been developed to identify patients at low risk of DVT who can be spared extensive testing. These algo- rithms typically use scoring systems to stratify the clinical probability that the particular patient has a DVT and then proceed to D-​dimer testing of those with low probability. Patients with a low clinical prob- ability and a negative D-​dimer test should not be investigated further for thromboembolic disease. Patients with a high or moderately high clinical probability, or a low clinical probability but elevated D-​dimer, proceed to tests for the presence of thrombus in the leg veins, typic- ally by ultrasonography. An example of a pretest scoring system and management algorithm is shown in Table 16.16.1.1. Prevention The prevention of DVT is critical in the prevention of PE. Risk fac- tors for DVT are almost certainly the same as those for PE (see later section in this chapter). Recommendations for the prevention of DVT are shown in Tables 16.16.1.2–​16.16.1.7. Despite recommendations for the prevention of DVT in hospitalized patients, an increase in sec- ondary DVT in patients hospitalized in the United States of America from 1991 through 2006 suggests that efforts to prevent DVT in high-​ risk patients are inadequate (Fig. 16.16.1.1). In the United Kingdom, recognition of such inadequacy has led commissioners of healthcare to mandate use of a risk scoring tool for venous thromboembolism in all patients admitted to hospital, with the possibility of financial penalties for those that do not achieve a very high rate of compliance. Treatment Proximal DVT leads to PE more frequently than DVT confined to the calf. Patients with acute isolated calf vein DVT without severe symp- toms or risk for extension can be followed with serial non​invasive testing for 2 weeks without treatment with anticoagulants unless there is extension. If such imaging reveals extension to the proximal veins, or extension within the distal veins, then anticoagulation is recommended. Table 16.16.1.2  Recommendations for prevention of venous thromboembolism in patients undergoing general, abdominal–​pelvic, cardiac, and thoracic surgery Indication Recommendation General and abdominal–​pelvic surgery Very low risk for VTE Early ambulation Low risk for VTE Mechanical prophylaxis, preferably intermittent pneumatic compression Moderate risk for VTE, not high risk for major bleeding LMWH or low-​dose unfractionated heparin or mechanical prophylaxis, preferably with intermittent pneumatic compression Moderate risk for VTE, high risk for major bleeding Mechanical prophylaxis, preferably with intermittent pneumatic compression High risk for VTE, not high risk for major bleeding LMWH or low-​dose unfractionated heparin and elastic stockings or intermittent pneumatic compression High risk for VTE, cancer surgery, not high risk for major bleeding LMWH, 4 weeks High-​risk for VTE, high risk for major bleeding Mechanical prophylaxis, preferably with intermittent pneumatic compression. Start LMWH or low-​dose unfractionated heparin when risk of bleeding diminishes Cardiac surgery Uncomplicated Mechanical prophylaxis, preferably with intermittent pneumatic compression Complicated LMWH or low-​dose unfractionated heparin and mechanical prophylaxis, preferably with intermittent pneumatic compression Thoracic surgery Moderate risk for VTE, not high risk for bleeding Low-​dose unfractionated heparin or LMWH or intermittent pneumatic compression High risk for VTE, not high risk for bleeding LMWH or low-​dose unfractionated heparin and intermittent pneumatic compression or elastic stockings High risk for VTE, high risk for bleeding Mechanical prophylaxis, preferably with intermittent pneumatic compression. Start LMWH or low-​dose unfractionated heparin when risk of bleeding diminishes LMWH, low-​molecular-​weight heparin; VTE, venous thromboembolism. Adapted from Guyatt GH, et al. (2012). Antithrombotic therapy and prevention of thrombosis, 9th ed. American College of Chest Physicians Evidence-​Based Clinical Practice Guidelines. Chest, 141(suppl), 7S–​47S. 16.16.1  Deep venous thrombosis and pulmonary embolism 3715 Table 16.16.1.3  Recommendations for prevention of venous thromboembolism in patients undergoing orthopaedic surgery Surgical procedure Recommendation Total hip arthroplasty or total knee arthroplasty LMWH, fondaparinux, apixaban, dabigatran, rivaroxaban, low-​dose unfractionated heparin, adjusted-​dose vitamin K antagonist, aspirin, or intermittent pneumatic compression for minimum of 10–​14 days, preferably up to 35 days. LMWH is the preferred antithrombotic agent. Antithrombotic agent and intermittent pneumatic compression recommended in hospital. Intermittent pneumatic compression only if high risk of bleeding. Suggest against inferior vena cava filter even if contraindication to both pharmacological and mechanical thromboprophylaxis. Hip fracture surgery LMWH, fondaparinux, low-​dose unfractionated heparin, adjusted-​dose vitamin K antagonist, aspirin, or intermittent pneumatic compression for minimum of 10–​14 days and preferably up to 35 days. LMWH is the preferred antithrombotic agent. Knee arthroscopy, no history of prior venous thromboembolism No thromboprophylaxis INR, international normalized ratio; LMWH, low-​molecular-​weight heparin; VTE, venous thromboembolism. Adapted from Guyatt GH, et al. (2012). Antithrombotic therapy and prevention of thrombosis, 9th ed. American College of Chest Physicians Evidence-​Based Clinical Practice Guidelines. Chest, 141(suppl), 7S–​47S. Table 16.16.1.4  Recommendations for prevention of venous thromboembolism in patients undergoing neurosurgery Surgical procedure Recommendation Spinal surgery or craniotomy Not high risk for VTE Mechanical prophylaxis, preferably with intermittent pneumatic compression High risk for VTE Mechanical prophylaxis, preferably with intermittent pneumatic compression and pharmacological prophylaxis after risk of bleeding decreases LMWH, low-​molecular-​weight heparin; VTE, venous thromboembolism. Adapted from Guyatt GH, et al. (2012). Antithrombotic therapy and prevention of thrombosis, 9th ed. American College of Chest Physicians Evidence-​Based Clinical Practice Guidelines. Chest, 141(suppl), 7S–​47S. Table 16.16.1.5  Recommendations for prevention of venous thromboembolism in patients following major trauma, traumatic brain injury, acute spinal cord injury Indication Recommendation Major trauma LMWH or low-​dose unfractionated heparin or mechanical prophylaxis, preferably with intermittent pneumatic compression. Inferior vena cava filter should not be used for primary prevention of VTE Major trauma, high risk for VTE LMWH or low-​dose unfractionated heparin and mechanical prophylaxis. Mechanical prophylaxis only, preferably with intermittent pneumatic compression, if high risk of bleeding. Add LMWH or unfractionated heparin when risk of bleeding diminishes INR, international normalized ratio; LMWH, low-​molecular-​weight heparin. VTE, venous thromboembolism Adapted from Guyatt GH, et al. (2012). Antithrombotic therapy and prevention of thrombosis, 9th ed. American College of Chest Physicians Evidence-​Based Clinical Practice Guidelines. Chest, 141(suppl), 7S–​47S. Table 16.16.1.6  Recommendations for prevention of venous thromboembolism in patients with medical conditions Medical conditions in hospital Recommendation Acutely ill hospitalized medical patients, low risk of VTE No prophylaxis Acutely ill hospitalized medical patients, increased risk of VTE Low-​dose unfractionated heparin, LMWH, or fondaparinux. Compression stockings or intermittent pneumatic compression if high risk of bleeding Critically ill, critical care unit Low-​dose unfractionated heparin or LMWH Critically ill, critical care unit, high-​risk bleeding Compression stockings and/​or intermittent pneumatic compression. Pharmacological prophylaxis when risk of bleeding decreases Chronically immobilized, nursing home, or at home No thromboprophylaxis Outpatients, solid tumours, and additional risk factors for VTE LMWH or low-​dose unfractionated heparin Outpatients, thrombophilia, no prior VTE No thromboprophylaxis LMWH, low-​molecular-​weight heparin; VTE, venous thromboembolism. Adapted from Guyatt GH, et al. (2012). Antithrombotic therapy and prevention of thrombosis, 9th ed. American College of Chest Physicians Evidence-​Based Clinical Practice Guidelines. Chest, 141(suppl), 7S–​47S. section 16  Cardiovascular disorders 3716 Recommendations for treatment are shown in Table 16.16.1.8, with further details discussed in Chapter 16.16.2. With generally increasing pressure to avoid hospital admission, or to keep admis- sions as short as possible, some patients with a primary diagnosis of PE or DVT who are being treated with vitamin K antagonists, dabigatran or edoxaban are being discharged from hospital before adequate heparin can be administered, and before vitamin K antag- onists can become antithrombotic. An increased mortality has been observed among patients with PE discharged in 4 days or fewer if inadequately treated, hence if patients are to be discharged before adequate heparin can be admin- istered, outpatient treatment with low-​molecular-​weight heparin (LMWH) for at least 5 days should be administered if dabigatran or edoxaban are to be used and until the international normalized ratio (INR) is ≥2.0 for 24 hours if a vitamin K antagonist is em- ployed. Extended outpatient treatment with LMWH may be con- sidered as well as treatment with novel oral anticoagulants. Clinical trials of dabigatran and edoxaban required a lead in with paren- teral anticoagulants for at least 5 days, hence there is no evidence to support the immediate use of these drugs without prior paren- teral anticoagulation. By contrast, rivaroxaban and apixaban do not require prior treatment with parenteral anticoagulants, although in clinical trials these had been given to most patients for 1 or 2 days before randomization. Complications DVT itself carries extensive morbidity irrespective of PE. Severe post-​phlebitic syndrome (venous ulcer or combinations of pain, cramps, heaviness, pruritus, paraesthesia, pretibial oedema, in- duration, hyperpigmentation, venous ectasia, redness, or pain with calf compression) occurs in 9% of patients by 5 years after a 3-​month course of treatment with anticoagulants. A multicentre placebo-​controlled trial found that routine use of graduated compression stockings did not reduce the incidence of post-​ thrombotic syndrome, hence these are no longer recommended. Compression stockings might, however, have reduced symptoms of acute DVT or symptoms of post-​thrombotic syndrome in those who developed it. Acute pulmonary embolism Incidence Acute PE is the third most common cardiovascular problem after coronary heart disease and stroke. In 2008, 0.9% of patients aged 18 years or more hospitalized in short-​stay hospitals in the United States of America had PE. This represented 135 patients per 100 000 adult population. Age-​adjusted rates were similar in men and women. Silent PE, on average, was diagnosed in 36% of patients with proximal DVT and 13% with distal DVT. The incidence of acute PE increases exponentially with age and is much more frequent in adults than in children, but it is not rare in children. In autopsy studies encompassing university as well as non-​ university hospitals, when the pathologist judged that PE con- tributed to death or caused death, the diagnosis was unsuspected ante-​mortem in over one-​half of cases. Some of these were in patients who died of malignancy, in whom a diagnosis of PE may (appropri- ately) not have been actively pursued. However, the time-​honoured point remains as valid today as ever: a high index of suspicion is necessary to reduce the number of patients with unsuspected PE. Predisposing factors Immobilization, irrespective of the cause, is the most frequent predisposing factor (Table 16.16.1.9). Immobilization of even 1 or 2 days may predispose to PE and most patients with PE are immo- bilized less than 2 weeks. Obesity is also a risk factor. Pregnancy-​associated DVT has increased in recent years, the rate being over twice that in non​pregnant women. The rate of DVT following caesarean section is twice the rate following vaginal de- livery. By contrast, higher rates of PE have not been shown in preg- nancy, but this may be because of reluctance to perform imaging studies in pregnant women. There has been much interest in the subject of genetic pre­ disposition to thromboembolism. Heterozygosity for the factor V Leiden mutation increases susceptibility three-​to eight- fold in a variety of circumstances. Other genetic and acquired thrombophilic factors include protein C deficiency, protein S deficiency, antithrombin deficiency, prothrombin 20 201A, high concentration of factor VIII, hyperhomocystinaemia, hep- arin cofactor II deficiency, dysfibrinogenaemia, decreased levels of plasminogen, decreased levels of plasminogen activators, antiphospholipid antibodies, heparin-​induced thrombocyto- penia, and myeloproliferative disorders. For full discussion of these and related issues, see Chapter 22.7.4. Table 16.16.1.7  Recommendations for prevention of venous thromboembolism during long-​distance air travel Long-​distance travel Frequent ambulation, calf muscle exercise Additional risk factors for VTE Frequent ambulation, calf muscle exercise, and below-​knee graduated compression stockings providing 15–​30 mm Hg of pressure at ankle. Recommend against aspirin or anticoagulants LMWH, low-​molecular-​weight heparin; VTE, venous thromboembolism. Adapted from Guyatt GH, et al. (2012). Antithrombotic therapy and prevention of thrombosis, 9th ed. American College of Chest Physicians Evidence-​Based Clinical Practice Guidelines. Chest, 141(suppl), 7S–​47S. 175 25 1986 1996 2006 75 125 DVT/100 000 population Principal Dx DVT Secondary Dx DVT All DVT Dx Fig. 16.16.1.1  Population-​based prevalence of deep venous thrombosis (DVT) in the United States of America according to year. Incidence of principal diagnosis of DVT (admitting diagnosis) did not change from 1986 to 2006. Secondary diagnoses of DVT (occurring during hospitalization) increased. Total incidence of DVT increased in parallel. Grey bars, principal diagnosis DVT; white bars, secondary diagnosis DVT; black bars, all DVT diagnoses. Data from Stein PD, Matta F, Dalen JE (2011). Is the campaign to prevent venous thromboembolism in hospitalized patients working? Chest, 139, 1317–​21. 16.16.1  Deep venous thrombosis and pulmonary embolism 3717 Clinical features The clinical characteristics of acute PE have been derived from pro- spectively acquired data of patients recruited in trials of diagnostic investigations or therapies such as the PIOPED studies. Such trials clearly only include those in whom there was sufficient clinical sus- picion to lead physicians to obtain diagnostic tests: whether subtle PE was overlooked is undetermined. The specificity of signs, symp- toms, and ordinary clinical tests was low among patients with sus- pected PE in whom the diagnosis was eventually excluded. Symptoms In patients in whom the diagnosis is not confused by pre-​existing cardiac or pulmonary disease, dyspnoea is the most common symptom, occurring in 73% of cases both in PIOPED and PIOPED II (Table 16.16.1.10), with dyspnoea only on exertion in 16%. Dyspnoea (at rest or during exertion) and orthopnoea were more frequent in patients with PE in main or lobar pulmonary arteries than in patients in whom the largest vessel with PE was a segmental pulmonary artery. The onset of dyspnoea occurred within seconds Table 16.16.1.8  Recommendations for treatment of venous thromboembolism and/​or pulmonary thromboembolism Condition Treatment High clinical suspicion of DVT or PE or intermediate clinical suspicion if results of diagnostic tests delayed >4 h Give anticoagulants while awaiting outcome of diagnostic tests. Confirmed proximal DVT or PE and no cancer Suggest dabigatran, rivaroxaban, apixaban, or edoxaban over vitamin K antagonist. Initial treatment with parenteral anticoagulation is required for dabigatran, and edoxaban. Confirmed proximal DVT or PE and cancer Suggest LMWH over vitamin K antagonist, dabigatran, rivaroxaban, apixaban, or edoxaban. Suggest LMWH once daily rather than twice daily. Start vitamin K antagonists with LMWH, unfractionated heparin or fondaparinux on first treatment day. Treat PE or DVT with anticoagulants for 3 months if provoked by surgery or a transient risk factor. Treat a first unprovoked PE or DVT for longer than 3 months if a low or moderate risk of bleeding, and for 3 months if a high-​risk of bleeding. Treat DVT or PE associated with active cancer for longer than 3 months. In patients with an unprovoked DVT or PE who are stopping anticoagulant therapy, aspirin may help prevent recurrent PE or DVT, but it is less effective than anticoagulants. Compression stockings are not recommended for routine use to prevent post-​thrombotic syndrome. Recommend against inferior vena cava filter in patients with DVT unless contraindication to anticoagulants. Acute proximal DVT Suggest anticoagulants alone over catheter directed or systemic thrombolysis or operative thrombectomy. Acute proximal DVT Home treatment if circumstances adequate. Recurrent PE or DVT The generally accepted consensus recommendation is to insert an inferior vena cava filter if patient has recurrent PE. Some, to avoid a filter, suggest LMWH if recurrent PE or DVT occurs while on a non-​LMWH anticoagulant. If recurrent PE or DVT occurs while on LMWH, increase the dose of LMWH. Isolated distal DVT Serial imaging for 2 weeks rather than anticoagulation unless severe symptoms or risk factors for proximal extension. Treat with anticoagulants if proximal extension or extension but remaining confined to the distal veins. Distal superficial vein thrombosis, >5 cm Prophylactic doses of fondaparinux of LMWH for 45 days. DVT and low-​risk PE In patients with DVT, or low-​risk PE, home treatment is recommended if home circumstances are adequate. Massive PE, hypotension (systolic blood pressure <90 mm Hg) or high risk of developing hypotension, no high bleeding risk Systemic thrombolytic therapy, short infusion time preferred (2 h). Infuse through peripheral vein rather than pulmonary artery. Massive PE, highly compromised patients unable to receive thrombolytic therapy or whose critical status does not allow sufficient time to infuse thrombolytic therapy Catheter extraction or fragmentation or pulmonary embolectomy. Pulmonary embolectomy if failed catheter-​assisted embolectomy. Inferior vena cava filter and PE Inferior vena cava filters are recommended for patients with PE if anticoagulants are contraindicated. In most patients with PE, vena cava filters are not recommended. However, the American College of Chest Physicians 2016 guidelines indicated that recommendations against the use of IVC filters in anticoagulated patients with hypotension from severe PE may not apply to this select subgroup. Other subgroups not assessed by randomized controlled are discussed in the section on inferior vena cava filters. LMWH, low-​molecular-​weight heparin. Modified from Kearon C, et al. (2012). Antithrombotic therapy for VTE disease. Antithrombotic therapy and prevention of thrombosis, 9th ed. American College of Chest Physicians Evidence-​Based Clinical Practice Guidelines. Chest, 141(suppl), e419S–​e494S and from Kearon C, et al. (2016). Antithrombotic therapy for VTE disease: Chest guideline and expert panel report. Chest, 149, 315–​52. section 16  Cardiovascular disorders 3718 or minutes in 72% of cases, and within seconds, minutes, or hours in 83%. In some, however, the onset of dyspnoea occurred over days. Pleuritic chest pain (66% of patients with PE and no pre-​existing cardiopulmonary disease in PIOPED and 44% in PIOPED II) oc- curred much more often than haemoptysis (13% in PIOPED and 5% in PIOPED II). Cough was common (37% and 34% in PIOPED and PIOPED II) among patients with PE and no pre-​existing cardiopulmonary disease. This was non​productive or productive of bloody (typically blood-​streaked, but it can be pure blood or blood-​tinged) or puru- lent (5% of cases) sputum. Signs Tachypnoea (respiratory rate ≥20/​min) was the most common sign of acute PE among patients with no prior cardiac or pul- monary disease (70% of patients in PIOPED and 54% in PIOPED II) (Table 16.16.1.11). Tachycardia (heart rate >100/​min) occurred in 30% and 24% of patients with PE in PIOPED and PIOPED II, and the pulmonary component of the second sound was accentuated in 23% and 15% of cases. DVT was clinically apparent in 11% of pa- tients with PE in PIOPED, but more frequently in PIOPED II (47%). A right ventricular lift, third heart sound, or pleural friction rub were uncommon, each occurring in 4% or less of patients with PE. Most patients with PE who had rales (crepitations) had pul- monary parenchymal abnormalities, atelectasis, or a pleural effusion on the chest radiograph. Among patients with PE and no other source of fever, temperature 39.9°C or lower was present in 99.7% and fever of 40.0°C or higher occurred in 0.3%. Temperature 37.7°C or less was present in 86%. Fever in patients with pulmonary haemorrhage/​infarction was not more frequent than among those with no pulmonary haemorrhage/​ infarction. Clinical evidence of DVT was often present in patients with PE and otherwise unexplained fever. Circulatory collapse (systolic blood pressure <80 mm Hg or loss of consciousness) was an uncommon mode of presentation: 15% in PIOPED and in 8% in PIOPED II. However, patients with circula- tory collapse may not be candidates for recruitment into trials of diagnostic investigations or therapies, and patients with circulatory collapse often die within the first few hours, hence it may be that the incidence of circulatory collapse as determined from published series is falsely low. Patients with pulmonary infarction have less se- vere PE than patients with isolated dyspnoea, and those with circu- latory collapse probably have the most severe of all. Combinations of symptoms and signs Dyspnoea or tachypnoea (respiratory rate ≥20/​min) was present in 90% and 84% of patients with acute PE and no pre-​existing cardiac or pulmonary disease in PIOPED and PIOPED II. Dyspnoea or tach- ypnoea or pleuritic pain was present in 97% and 92%, respectively. Dyspnoea or tachypnoea or pleuritic pain or radiographic evidence Table 16.16.1.9  Predisposing factors for pulmonary embolism in all patients irrespective of previous cardiac or pulmonary disease (n = 383) Predisposing factor Cases (%) Immobilization 54 Surgery 42 Lung disease 27 Malignancy 18 Coronary heart disease 20 Thrombophlebitis—​ever 19 Myocardial infarction 13 Trauma—​lower extremities 12 Heart failure 12 Chronic obstructive pulmonary disease 10 Stroke 10 Asthma 7 Pneumonia—​acute 7 Prior PE 6 Oestrogen 6 Collagen vascular disease 4 Postpartum—​3 months or less 2 Interstitial lung disease 2 Unpublished data from PIOPED in Stein PD (2016). Pulmonary embolism, 3rd edn. Wiley Blackwell, Oxford. Table 16.16.1.10  Symptoms of pulmonary embolism in patients without pre-​existing cardiac or pulmonary disease Symptoms PE (%) PIOPED I  (n = 117) PIOPED II (n = 127–​133) Dyspnoea Dyspnoea (rest or exertion) 73 73 Dyspnoea (at rest) 55 Dyspnoea (exertion only) 16 Orthopnoea (≥2 pillow) 28 Pleuritic pain 66 44 Chest pain (not pleuritic) 4 19 Cough 37 34 Haemoptysis 13 5a Purulent 5 Clear 5 Non​productive 20 Wheezing 9 21 Palpitations 10 Calf or thigh swelling 41 Calf swelling only 28 33 Calf and thigh swelling 7 Thigh swelling only 1 Calf or thigh pain 44 Calf pain only 26b 23 Calf and thigh pain 17 Thigh pain only 3 a Haemoptysis, patients with PE: 2, slightly pinkish; 4, blood-​streaked; 1, all blood (<1 teaspoonful). b ‘Leg pain’. Data from Stein PD, et al. (1991). Clinical, laboratory, roentgenographic and electrocardiographic findings in patients with acute pulmonary embolism and no pre-​existing cardiac or pulmonary disease. Chest, 100, 598–​603 and Stein PD, et al. (2007). Clinical characteristics of patient with acute pulmonary embolism: data from PIOPED II. Am J Med, 120, 871–​9. 16.16.1  Deep venous thrombosis and pulmonary embolism 3719 of atelectasis or a parenchymal abnormality was present in 98%. The remaining patients usually had either DVT or an unexplained low Pao2. PE was rarely diagnosed in the absence of dyspnoea or tachyp- noea or pleuritic pain. Dyspnoea or tachypnoea occurred in 92% of all patients with PE (irrespective of pre-​existing cardiopulmonary disease) in whom the pulmonary emboli were in main or lobar pulmonary arteries, but in only 65% of patients in whom the largest PE was in segmental pul- monary arteries. Dyspnoea or tachypnoea or pleuritic pain occurred in 97% of patients with proximal PE and 77% of patients with pul- monary emboli in only segmental pulmonary arteries. Accuracy of clinical assessment To emphasize the point that the diagnosis of PE is difficult to make, senior staff physicians and postgraduate fellows taking part in the PIOPED study were uncertain of the diagnosis in most patients. Using individual judgement without any specific predetermined criteria, senior staff were correct in the diagnosis in 88% of cases when their clinical assessment indicated a high probability of PE. When their clinical assessment indicated a low probability of PE, senior staff correctly excluded PE in 86%. Postgraduate fellows, on the basis of clinical assessment, were more accurate in excluding PE than they were in making the diagnosis. Objective scoring systems for the probability of acute PE give probability assessments similar to those of experienced physicians and do not require experience or clinical judgement. An example of a scoring system that is mostly objective is shown in Table 16.16.1.12. Differential diagnosis The commonest presentation of acute PE is with dyspnoea and/​or pleuritic chest pain. There are several other possible causes of these symptoms, the commonest being musculoskeletal pain and pneu- monia. Musculoskeletal chest pain can be very similar to that caused by pleurisy, and splinting of the chest can lead to a perception of breathlessness that may be exacerbated by anxiety. If there is an obvious history of local trauma to the chest, then the patient will rarely present to the physician, but it is worthwhile to ask specifically whether there has been any trauma or unaccustomed physical ac- tivity, whether the pain can be brought on by particular movements, and to examine carefully for local tenderness of the ribs, muscles, or costal margins. However, tenderness can sometimes be found in cases of pleurisy, and chest pain was reproduced by palpation in 20% of patients with PE. Appropriate history often supports a diagnosis of musculoskeletal pain. Pneumonia complicated by pleurisy can cause dyspnoea and chest pain. Important features to look for in the history include pre- ceding systemic upset (flu-​like symptoms), high fever, and rigors, and on examination, high fever, ‘toxic appearance’, and chest signs of pneumonic consolidation. If a positive diagnosis of another cause of dyspnoea and/​or pleuritic chest pain cannot be made, then the default position should be to assume that the patient has PE until proven otherwise. Table 16.16.1.11  Signs of pulmonary embolism in patients without pre-​existing cardiac or pulmonary disease Signs PE (%) PIOPED I (n = 117) PIOPED II (n = 127–​133) General Tachypnoea (≥20/​min) 70 54 Tachycardia (>100/​min) 30 24 Diaphoresis 11 2 Cyanosis 1 0 Temperature >38.5°C (>101.3°F) 7 1 Cardiac examination (any abnormality) 21 Increased P2 23 15 Third heart sound 3 Fourth heart sound 24 Right ventricular lift 4 4 Jugular venous distension 14 Lung examination (any abnormality) 29 Rales (crackles) 51 18 Wheezes 5 2 Rhonchi 2 Decreased breath sounds 17 Pleural friction rub 3 0 DVT Calf or thigh 11 47a Calf only 32 Calf and thigh 14 Thigh only 2 Homans’ sign 4 P2, pulmonary component of second sound. a Number of patients with PE who had one or more signs of DVT: oedema, 55; erythema, 5; tenderness, 32; palpable cord, 2. Data from Stein PD, et al. (1991). Clinical, laboratory, roentgenographic and electrocardiographic findings in patients with acute pulmonary embolism and no pre-​existing cardiac or pulmonary disease. Chest, 100, 598–​603 and Stein PD, et al. (2007). Clinical characteristics of patient with acute pulmonary embolism: data from PIOPED II. Am J Med, 120, 871–​9. Table 16.16.1.12  A model to determine the clinical probability of pulmonary embolism according to Wells and associates Clinical feature Score (points) Clinical signs and symptoms of DVT (objectively measured leg swelling and pain with palpation in the deep vein system) 3.0 Heart rate>100/​min 1.5 Immobilization ≥3 consecutive days (bed rest except to access bathroom) or surgery in previous 4 weeks 1.5 Previous objectively diagnosed PE or DVT 1.5 Haemoptysis 1.0 Malignancy (cancer patients receiving treatment within 6 months or receiving palliative treatment) 1.0 PE as likely or more likely than alternative diagnosis (based on history, physical examination, chest radiograph, ECG, and blood tests) 3.0 Score: <2.0, low probability; ≤4, unlikely probability; >4, likely probability; >6.0, high probability. Data from Wells PS, et al. (2000). Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-​dimer. Thromb Haemost, 83, 416–​20 and from Wells PS, et al. (2001). Excluding PE at the bedside without diagnostic imaging: management of patients with suspected PE presenting to the emergency department by using a simple clinical model and D-​dimer. Ann Intern Med, 135, 98–​107. section 16  Cardiovascular disorders 3720 Investigation Detection of evidence of thrombus within the circulation: D-​dimer As when considering the diagnosis of DVT, a ‘negative’ D-​dimer test is useful for excluding PE in patients who are clinically thought to be at low risk, but a ‘positive’ result does not establish the diagnosis. Hence, when used in the appropriate clinical context, D-​dimer testing is useful in defining a group of patients with suspected PE who do not require further investigation. In ranking the D-​dimer assays according to their sensitivity values and likelihood of increasing certainty for ruling out PE, the ELISA and quantitative rapid ELISA assays are significantly su- perior to the semiquantitative latex and whole-​blood agglutination assays. The quantitative rapid ELISA assay is more convenient than the conventional ELISA and provides a high level of certainty for a negative diagnosis of PE as well as DVT. A  particle-​enhanced immunoturbidometric assay (quantitative latex agglutination) gives results comparable to the rapid ELISA. The 3-​month risk of PE in untreated patients with a negative rapid ELISA D-​dimer measurement and low or intermediate clin- ical probability Geneva score was 0% (0 of 220). With a negative D-​dimer by rapid ELISA or quantitative latex agglutination assay and an unlikely (≤4) Wells score, PE occurred in 0.4% (4 of 1028), and with an unlikely (≤10) revised Geneva score in 1 of 320 (0.3%). Detection of the physical presence of thrombus in the pulmonary circulation Ventilation–​perfusion lung scans By 2001 in the United States of America the use of CT pulmonary angi- ography surpassed the use of ventilation–​perfusion lung scans for the diagnosis of acute PE, the use of ventilation–​perfusion lung scans having fallen into disfavour after the PIOPED trial because in most patients they led to an indeterminate result. Now, two decades since PIOPED was published, advances have been made in imaging equipment, improved methods of interpretation, and new radiopharmaceuticals. With such advances, and recognizing the risk of radiation with CT angiography, radionuclear imaging is receiving renewed interest. Based on the results of PIOPED, a high-​probability lung ventilation–​perfusion scan (Fig. 16.16.1.2) indicates PE in 87% of patients (Table 16.16.1.13) and a normal scan excludes PE. In the absence of any other information an intermediate probability scan indicates a 30% chance of PE and a low-​probability scan of 14%. A low-​probability ventilation–​perfusion scan by the criteria used in PIOPED does not therefore exclude PE. Intermediate and low-​probability interpretations may be grouped as ‘non​diagnostic’, which was frequently the case in PIOPED. Prior clinical assessment in combination with interpretation of the ventilation–​perfusion scan improves diagnostic validity (Table 16.16.1.13). If the ventilation–​perfusion scan is interpreted as high probability for PE, and if the clinical impression is concord- antly high, then the positive predictive value for PE is 96%. If the ventilation–​perfusion scan is low probability and the clinical sus- picion is concordantly low, then PE is excluded in 96% of patients. The probability of PE can be determined based on the number of mismatched defects. Since PIOPED, criteria for the interpretation of very low probability lung scans (positive predictive value <10%) have been developed and tested. Fewer mismatched perfusion defects are required to diagnose PE among patients with no prior cardiopul- monary disease. Adding clinical assessment to the stratification re- sults in a more accurate evaluation. Outcome studies, as opposed to studies of accuracy as was PIOPED, showed that in patients with low probability, very low probability, or normal ventilation–​perfusion lung scans there was no fatal PE and non​fatal PE in only 0.17% after 3–​12 months without anticoagulants. Using revised PIOPED criteria, some have shown that in patients with suspected acute PE and a normal chest radiograph the perfu- sion lung scan was diagnostic (high probability, normal, or very low probability) in 89% of patients (Table 16.16.1.14). There were no non​diagnostic perfusion scans when interpreted by the PISAPED criteria (Table 16.16.1.15). After elimination of non​diagnostic scans, sensitivity with modified PIOPED criteria was 86% and specificity was 93%. With PISAPED criteria, sensitivity was 72% and specificity was 97%. It may be, therefore, that with updated techniques, perfu- sion scintigraphy in a patient with a normal chest radiograph can provide diagnostic accuracy similar to CT angiography at a lower cost and with a lower radiation dose. Although not routine practice in most centres, it can be useful to obtain a post-​therapy baseline ventilation–​perfusion lung scan for use in the event of suspected recurrent PE. This will Fig. 16.16.1.2  Ventilation lung scan (left panel) and perfusion lung scan (right panel): posterior views with left (L) and right (R) indicated. The ventilation scan, equilibrium phase, shows nearly normal ventilation. The perfusion scan shows absent perfusion in the left lower lobe and mismatched perfusion defects in the left upper lobe. Perfusion defects (grey areas) are also shown in the right lung. This ventilation–​perfusion lung scan was interpreted as showing high probability for PE. 16.16.1  Deep venous thrombosis and pulmonary embolism 3721 assist in determining if abnormalities subsequently discovered on a ventilation–​perfusion scan are new or residual. A residual abnor- mality of perfusion 1 year after PE is more frequent among patients with prior cardiopulmonary disease than among patients with none. SPECT ventilation–​perfusion lung scan imaging Single-​photon emission computed tomography (SPECT) ventilation–​perfusion lung scan imaging may further improve the accuracy of pulmonary scintigraphy. SPECT offers the advan- tages of tomographic sections over traditional planar ventilation–​ perfusion imaging. The ability to obtain SPECT lung scans was still in its relatively early stages when the PIOPED investigation of planar lung scans was published. Dual-​ and triple-​headed gamma cameras with ultrahigh-​resolution collimators have been devel- oped, as have new radiopharmaceuticals for ventilatory studies, prominent among which is 99mTc-​Technegas (Cyclomedica, Lucas Heights, Australia), which consists of ultrafine carbon particles that behave physiologically like a gas. Many investigators have found SPECT ventilation–​perfusion lung scan imaging to be better than planar imaging. Among its ad- vantages are the avoidance of overlapping of small perfusion de- fects by normal tissue and a higher contrast resolution than planar scans. It can, therefore, detect abnormalities—​particularly at the subsegmental level and in the lung bases—​where the segments are tightly packed. Review showed that the sensitivity of SPECT was higher than planar lung scans in 4 of 5 investigations, and specifi- city was generally higher, equal, or only somewhat lower than planar ventilation–​perfusion lung scans. Non​diagnostic SPECT lung scans were reported in ≤3% by most investigators. Pulmonary angiography Pulmonary angiography is no longer the diagnostic gold standard for PE (Fig. 16.16.1.3). It is associated with serious complications in about 1% of patients and has been replaced by contrast-​enhanced CT. Contrast-​enhanced spiral CT The sensitivity of multidetector (mostly 4-​detector) CT angiography alone and in combination with CT venous-​phase venography was in- vestigated in PIOPED II. The CT angiogram among 824 patients was of insufficient quality for a conclusive interpretation in 6.2%. Among 773 patients with an adequate CT angiogram, the sensitivity of CT angiography was 83% and specificity was 96% (Fig. 16.16.1.4): posi- tive predictive value was 86% and negative predictive value was 95%. Positive predictive values were 97% for PE in a main or lobar artery, 68% in those in whom the largest vessel with PE was a segmental pulmonary artery, and 25% among only a few patients in whom the largest PE was in a subsegmental branch. Table 16.16.1.13  The probability of pulmonary embolism using clinical assessment in combination with ventilation–​perfusion lung scans Clinical science probability (%) 80–​100 20–​79 0–​19 All probabilities Scan category PE+/​No of patientsa % PE+/​No of patients % PE+/​No of patients % PE+/​No of patients % High probability 28/​29 96 70/​80 88 5/​9 56 103/​118 87 Intermediate probability 27/​41 66 66/​236 28 11/​68 16 104/​345 30 Low probability 6/​15 40 30/​191 16 4/​90 4 40/​296 14 Near normal/​normal 0/​5 0 4/​62 6 1/​61 2 5/​128 4 Total 61/​90 68 170/​569 30 21/​228 9 252/​887 28 a PE+ indicates angiogram reading that shows PE or determination of PE by the outcome classification committee on review. PE status is based on angiogram interpretation for 713 patients, on angiogram interpretation and outcome classification committee reassignment for 4 patients, and on clinical information alone (without definitive angiography) for 170 patients. Source data from A National Investigation by the PIOPED Investigators (1990). Value of the ventilation/​perfusion scan in acute pulmonary embolism—​results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). American Medical Association. Table 16.16.1.14  Modified PIOPED II scintigraphic criteria Diagnosis Criteria PE present High probability (≥2 segmental equivalents of perfusion scan-​chest radiograph mismatcha) PE absent Normal perfusion Very low probability Non​segmental lesion, e.g. prominent hilum, cardiomegaly, elevated diaphragm, linear atelectasis, costophrenic angle effusion with no other perfusion defect in either lung Perfusion defect smaller than radiographic lesion 1–​3 small segmental defects A solitary chest radiographic–​perfusion scan matched defect in the mid or upper lung zone confined to a single segment Stripe sign around perfusion defect (best tangential view) Pleural effusion ≥ 1/​3 of the pleural cavity with no other perfusion defect in either lung Not diagnostic All other findings a May be ≥2 large segmental mismatches, or 1 large and 2 moderate mismatches or 4 moderate segmental mismatches. This research was originally published in JNM. Sostman H et al. Sensitivity and specificity of perfusion scintigraphy combined with chest radiography for acute pulmonary embolism in PIOPED II. J Nucl Med. 2008;49(11):1741–​8. Table 1. © by the Society of Nuclear Medicine and Molecular Imaging, Inc. Table 16.16.1.15  PISAPED scintigraphic criteria Diagnosis Criteria PE present One or more wedge-​shaped perfusion defects PE absent Normal or near normal perfusion Contour defect caused by enlarged heart, mediastinum, or diaphragm Perfusion defect, not wedge-​shaped Not diagnostic Cannot classify as PE-​positive or PE-​negative Modified from Sostman HD, et al. (2008). Sensitivity and specificity of perfusion scintigraphy combined with chest radiography for acute pulmonary embolism in PIOPED II. J Nucl Med, 49, 1741–​8. section 16  Cardiovascular disorders 3722 The combination CT angiogram with venous-​phase imaging of the pelvic and thigh veins (CT venogram) among 824 patients was of insufficient quality for a conclusive interpretation in 11%. Among the 737 patients with an adequate CT angiogram/​CT venogram combination, the sensitivity was 90% and specificity was 95%, with positive predictive value 85% and negative predictive value 97%. Among patients with suspected PE who were evaluated by 64-​ detector CT, 10.8% were shown to have PE by CT angiography and an additional 1.3% had venous thromboembolism based on a positive CT venogram with a negative CT angiogram. A 1.3% yield would seem poorly cost effective, but among the patients shown to have venous thromboembolism, 11% were diagnosed only by CT venography, which is a proportion that some would consider sufficiently high to merit consideration of its use. Most, however, believe that CT venography is unnecessary with CT pulmonary angiography, because the risk from radiation outweighs the bene- fits of additional diagnoses. In patients with a high risk of lower-​ extremity DVT, or elderly patients with low risk of radiation effects and limited cardiopulmonary reserve, CT venography is recom- mended by some. As with ventilation–​perfusion scans, better prediction can be made if imaging results are interpreted in the light of clinical information (Table 16.16.1.16). Among patients with a high or intermediate probability prior clinical assessment based on the Wells score, a posi- tive CT angiogram had a positive predictive value for PE of 96% and 92% respectively. In patients with a low or intermediate probability prior clinical assessment and a negative CT angiogram, the negative predictive values for exclusion of PE were 96% and 89% respectively. Positive and negative predictive values were considerably reduced when scan results were discordant with clinical probabilities. MRI Potential advantages of gadolinium-​enhanced MR angiography are that it does not involve the use of iodinated contrast agents, it is min- imally invasive, and patients are not exposed to ionizing radiation. In small studies it shows a sensitivity for PE in proximal or segmental branches that ranges from 77% to 100% and specificity that ranges from 95% to 98%, but sensitivity for subsegmental branches was not evaluated prior to PIOPED III. Gadolinium-​enhanced venous-​ phase imaging of the veins of the pelvis and thighs in combination with imaging of the pulmonary arteries would permit a comprehen- sive study for thromboembolism comparable to the combination of contrast-​enhanced spiral CT of the pulmonary arteries in combin- ation with venous-​phase CT of the veins of the lower extremities. The PIOPED III trial of the accuracy of gadolinium-​enhanced MR pulmonary angiography showed that most centres had diffi- culty in obtaining adequate quality MR pulmonary angiograms (MRA). The investigators defined an adequate quality MRA as ad- equate opacification through subsegmental vessels. Among 371 patients, adequate quality images were obtained in the main or lobar pulmonary arteries in 91%, of the segmental pulmonary ar- teries in 87%, and of the subsegmental branches in 73%. Averaged across participating centres, MRAs were technically inadequate in 25%, but the figure at one centre was only 11%. Including patients with technically inadequate images, MRA identified 57% with PE. Technically adequate MRA had a sensitivity of 78% and specificity of 99%, and the sensitivity of MRA for detecting PE in a main or lobar pulmonary artery was 79%. Pulmonary embolism was rarely identi- fied by MRA when the largest PE was in a segmental or subsegmental branch. Specificity was 98% to 100%, irrespective of the order of the vessel. The combination of a technically adequate MRA with MR venography (MRA/​MRV) had a higher sensitivity than MRA alone, Fig. 16.16.1.3  Selective digital subtraction pulmonary angiogram of the left pulmonary artery showing multiple intraluminal filling defects indicative of pulmonary thromboemboli. One of these has been identified with an arrow. Fig. 16.16.1.4  Contrast-​enhanced spiral CT showing a large intraluminal filling defect (arrow). 16.16.1  Deep venous thrombosis and pulmonary embolism 3723 92%, while maintaining a high specificity of 96%. However, either MRA or MRV was technically inadequate in 52% of patients. This led the investigators to conclude that MRA should only be con- sidered at centres that routinely perform it well, and for patients who have contraindications to standard tests. Nephrogenic systemic fibrosis (also known as nephrogenic fibrosing dermopathy) has been reported in patients with moderate or severe renal failure and in pa- tients on dialysis following MRA with gadolinium-​containing con- trast agents. Other diagnostic approaches are recommended in such patients. Other tests Electrocardiography Electrocardiographic (ECG) abnormalities are common in acute PE (Table 16.16.1.17), with a normal ECG found in only 30% of patients. Acute ventricular dilatation is speculated to be the most likely cause of the ECG changes. Abnormalities of the ST segment and T wave are by far the most frequent observation, with non​specific ST seg- ment or T-​wave changes seen in about 50% of patients in whom the severity of PE ranged from mild to severe. Atrial flutter or atrial fib- rillation in patients with acute PE is nearly always limited to individ- uals with prior heart disease. Electrocardiographic manifestations of acute cor pulmonale (S1Q3T3, complete right bundle branch block, P pulmonale, or right axis deviation) are less common than ST-​segment or T-​wave changes and are not sensitive for right ventricular dilata- tion. One or more of these abnormalities occurred in 26% of patients with submassive or massive acute PE not associated with cardiac or pulmonary disease (32% of patients with massive PE). Left axis devi- ation occurs more frequently than right axis deviation. The ECG may simulate an inferior infarction with Q waves and T-​wave inversion in leads II, III, and aVF, or anteroseptal infarction characterized by QS or QR waves in V1 and T-​wave inversion in the right precordial leads. The development of Q waves and extensive T-​wave inversion in the anterior and lateral leads has also been observed. However, a pseudoinfarction pattern is seen in only 3% of patients. Inversion of the T waves is the most persistent ECG abnormality, disappearing in only 22% of patients 5 or 6 days after the PE was diag- nosed, although resolving in 49% by 2 weeks. Depression of the ST segment tends to resolve somewhat faster, and abnormalities of depolar- ization resolve more quickly than abnormalities of repolarization. Well over half of the ECGs that showed pseudoinfarction, S1S2S3, S1Q3T3, right ventricular hypertrophy, or right bundle branch block no longer show these abnormalities 5 or 6 days after the diagnosis is made. Patients with ST-​segment abnormalities, T-​wave inversion, pseudoinfarction patterns, S1Q3T3 patterns, incomplete right bundle branch block, right axis deviation, right ventricular hyper- trophy, or ventricular premature beats have larger perfusion defects on the lung scan or larger defects on the pulmonary arteriogram than those with normal ECGs. Such patients have higher pul- monary arterial pressures and in general have a low partial pressure of oxygen in arterial blood. The electrocardiographic abnormalities in patients with PE are not specific, although they may suggest the presence of PE. For ex- ample, patients with pneumonia often show QRS abnormalities or non​specific ST-​segment or T-​wave changes comparable to those seen in PE. Chest radiography The findings on the plain chest radiograph—​when used together with the history, physical examination, electrocardiogram, and simple Table 16.16.1.16  Positive and negative predictive values of CT pulmonary angiography in relation to prior clinical assessment High clinical probability (Wells score >6) n/​N (%) Intermediate clinical probability (Wells score 2–​6) n/​N (%) Low clinical probabilitya (Wells score <2) n/​N (%) CTA positive (positive predictive value) 22/​23 (96) 93/​101 (92) 22/​38 (58) CTA or CTV positive (positive predictive value) 27/​28 (96) 100/​111 (90) 24/​42 (57) CTA negative (negative predictive value) 9/​15 (60) 121/​136 (89) 158/​164 (96)a CTA and CTV negative (negative predictive value) 9/​11 (82) 114/​124 (92) 146/​151 (97)a CTA, CT pulmonary angiography; CTV, CT venous-​phase imaging. a To avoid bias for calculation of the negative predictive value in patients with a low-​probability prior clinical assessment, only patients with a reference test diagnosis by V/​Q scan or conventional pulmonary digital subtraction angiography were included. Modified from Stein PD, et al. (2006). PK for the PIOPED II Investigators. Multidetector computed tomography for acute pulmonary embolism. N Engl J Med, 354, 2317–27. Copyright © 2006 Massachusetts Medical Society. Reprinted with permission. Table 16.16.1.17  Electrocardiographic manifestations of pulmonary embolisms in patients without prior cardiac or pulmonary disease (n = 89) Patients with electrocardiographic findingsa (%) Rhythm disturbances Atrial flutter 1 Atrial fibrillation 4 Atrial premature contractions 4 Ventricular premature contractions 4 P wave P pulmonale 2 QRS abnormalities Right axis deviation 2 Left axis deviation 13 Incomplete right bundle branch block 4 Complete right bundle branch block 6 Right ventricular hypertrophy 2 Pseudoinfarction 3 Low voltage (frontal plane) 3 ST segment and T wave Non​specific ST-​segment or T-​wave abnormalities 49 a Some patients had more than one abnormality. Data from Stein PD, et al. (1991). Clinical, laboratory, roentgenographic and electrocardiographic findings in patients with acute pulmonary embolism and no pre-​existing cardiac or pulmonary disease. Chest, 100, 598–​603. section 16  Cardiovascular disorders 3724 laboratory tests—​assist in identifying PE. The chest radiograph, when normal in a patient who is dyspnoeic, hints that PE is a diagnostic possibility. Among patients with PE and no prior cardiopulmonary disease a normal chest radiograph is found in 16% (Table 16.16.1.18). Atelectasis or a pulmonary parenchymal abnormality are the most frequent abnormalities present (68%). Pleural effusions are found in about one-​half of cases and are usually small, with most limited to blunting of the costophrenic angle. In some studies, an elevated hemidiaphragm is the most frequent abnormality. Westermark’s sign (a prominent central pulmonary artery and decreased pulmonary vascularity) is identified by radiologists in only 7% of patients with PE. In cases of PE, those with a normal plain chest radiograph have the lowest pulmonary artery mean pressures. The highest pulmonary artery mean pressures are in patients with a prominent central pul- monary artery or cardiomegaly. Echocardiography Echocardiography may show right ventricular dilatation and evi- dence of pulmonary hypertension, which—​in the proper clinical setting—​may strengthen the clinical impression that PE has oc- curred. Transoesophageal echocardiography sometimes may show proximal pulmonary emboli, but it has limited value in this regard. Arterial blood gases and alveolar–​arterial oxygen difference A low partial pressure of oxygen in arterial blood (Pao2) is typical of acute PE and supports the diagnosis, but patients with acute PE can have a normal Pao2. Among patients with acute PE and no prior cardiopulmonary disease who have measurements of the Pao2 while breathing room air, 24% have a Pao2 of 80 mm Hg (10.5 kPa) or higher, and even among patients with submassive or massive acute PE, 12% have a Pao2 of this level or higher. A  normal alveolar–​ arterial oxygen difference (alveolar–​arterial oxygen gradient) does not exclude acute PE. No value of the alveolar–​arterial oxygen dif- ference is diagnostic of PE, and no value can exclude the diagnosis. Other routine blood tests Among patients in whom a possible or definite cause for leuco- cytosis is eliminated, 80% of patients with PE have a normal white blood cell count, 6% a count of 10.1–​11.9 × 109/​litre, and 13% a count of higher than this. A white blood cell count of 20 × 109/​litre or greater is rarely if ever seen. Leucocytosis is not more frequent in patients with the pulmonary haemorrhage/​infarction syndrome than in other patients with acute PE. Biomarkers Cardiac troponin I (cTnI) and creatine kinase isoenzyme MB (CK-​ MB) are useful for assessment of prognosis in stable patients with acute PE who have right ventricular dilatation. Patients with a di- lated right ventricle have a mortality from PE of 13–​29% if cardiac biomarkers are elevated, compared with 4% if they are not. Elevated biomarkers are not prognostically significant if right ventricular size is normal. Only a few patients with PE had an abnormal CK-​MB, which limits its value if used as the only indicator of prognosis. Strategy for diagnosis With increasing severity of PE, from pulmonary infarction to iso- lated dyspnoea to circulatory collapse, trends suggest that the preva- lence of signs and symptoms increases, but generally recognized symptoms may be absent, even in patients with large pulmonary emboli. Clues that can assist the physician in assessing the possi- bility of PE, and avoiding inadvertent exclusion of the diagnosis are as follows: • Dyspnoea—​onset is usually, but not always, within minutes or hours, and may be present only on exertion. Frequent in patients with large pulmonary emboli, but often absent in those with small pulmonary emboli • Orthopnoea—​often present in dyspnoeic patients with PE • Circulatory collapse—​may occur with PE in patients who do not have dyspnoea or tachypnoea or pleuritic pain • Tachypnoea—​frequent in patients with large pulmonary emboli, but often absent in those with small pulmonary emboli • Crepitations (rales)—​common among patients with pulmonary infarction, but less so in those with isolated dyspnoea or circula- tory collapse; they occur in those with radiographic evidence of a parenchymal abnormality • ECG—​a normal ECG is frequent in patients with the pulmonary infarction syndrome, but uncommon in those with isolated dyspnoea; non​specific ST-​segment and T-​wave changes are the most frequent abnormality • Chest radiograph—​abnormalities are more common among pa- tients with pulmonary infarction but are often observed in those with isolated dyspnoea; patients with circulatory collapse may have a normal chest radiograph • Ventilation–​perfusion scan—​a high-​probability interpretation occurs in a minority of patients with the pulmonary infarction syndrome but in the majority of those with the isolated dyspnoea syndrome; a low-​probability scan may occur in patients with PE and circulatory collapse • Oxygenation—​a Pao2 higher than 80 mm Hg (10.5 kPa) is not uncommon in patients with the pulmonary infarction syndrome, but such levels are uncommon in those with the isolated dyspnoea syndrome. Subjecting all patients who might have a PE to complex, expensive, and/​or invasive tests is best avoided. Management algorithms have been developed to identify those at very low risk, who can then be Table 16.16.1.18  Chest radiograph findings in pulmonary embolism in patients with no previous cardiac or pulmonary disease (n =117) Patients with radiographic finding (%) Atelectasis or pulmonary parenchymal abnormality 68 Pleural effusion 48 Pleural based opacity 3 Elevated diaphragm hemidiaphragm 24 Decreased pulmonary vascularity 21 Prominent central pulmonary artery 15 Cardiomegaly 12 Westermark’s signa 7 a Prominent central pulmonary artery and decreased pulmonary vascularity. Data modified from Stein PD, et al. (1991). Clinical, laboratory, roentgenographic and electrocardiographic findings in patients with acute pulmonary embolism and no pre-​ existing cardiac or pulmonary disease. Chest, 100, 598–​603, with permission. 16.16.1  Deep venous thrombosis and pulmonary embolism 3725 spared imaging tests. These algorithms typically use scoring systems to stratify the clinical probability that the particular patient has a PE, proceeding to D-​dimer testing of those a clinical probability that is not high. Untreated patients with a low or intermediate clinical probability by Geneva score or ‘unlikely’ clinical probability by Wells score and negative D-​dimer by rapid ELISA or quantitative latex ag- glutination test had a 3-​month incidence of PE of 0–​0.4%. There was no fatal PE on follow-​up. Patients with such a clinical probability and D-​dimer need not to be investigated further. Patients with a high clinical probability and patients with an elevated D-​dimer proceed to tests for the presence of pulmonary emboli, typically by contrast-​enhanced spiral CT. Recommendations for the approach to the diagnosis of acute PE based on use of a pretest scoring system (Table 16.16.1.12) and D-​dimer followed by imaging are discussed next. Recommendations for the diagnostic approach to patients in whom PE is not excluded by clinical assessment in combination D-​ dimer test depend on clinical probability, age, gender, pregnancy, the complexity of associated lung disease as determined from the plain chest radiograph, and the severity of illness. For patients with an elevated D-​dimer and patients with a high-​ probability clinical assessment irrespective of the D-​dimer, CT pul- monary angiography is recommended for most patients. If CT angiography is negative and clinical probability is low or intermediate, treatment is unnecessary, but a venous ultrasound is recommended if clinical assessment is intermediate or high prob- ability. In those with a high-​probability clinical assessment and negative CT angiogram, additional options include serial venous ultrasound examinations, pulmonary scintigraphy, and pulmonary digital subtraction angiography. If CT angiography shows main or lobar pulmonary emboli, treat- ment is indicated irrespective of the clinical probability. With seg- mental or subsegmental pulmonary emboli the certainty of the CT diagnosis should be reassessed if clinical probability is low or inter- mediate, but treatment is indicated if the clinical probability is high. In those with segmental or subsegmental PE and a low or inter- mediate probability clinical assessment, pulmonary scintigraphy, a single venous ultrasound examination, or serial venous ultrasound examinations are optional. CT angiography should be repeated if image quality is poor. It appears safe to withhold treatment of isolated subsegmental PE provided that (1) pulmonary-​respiratory reserve is good, (2) there is no evidence of DVT, (3) the major risk factor for PE was transient and no longer present, (4) there is no history of central venous cath- eterization or atrial fibrillation, and (5) the patient is willing and able to return for serial venous ultrasound examinations. Other considerations A venous ultrasound examination prior to imaging with CT angiog- raphy or prior to imaging with a ventilation–​perfusion lung scan is optional and may guide treatment if positive. However, about 50% of patients with PE have negative non​invasive leg tests for DVT, even though DVT is the source of the PE. Scintigraphy as the first imaging test It may be that, with updated techniques, perfusion scintigraphy in a patient with a normal chest radiograph can provide diagnostic ac- curacy similar to CT angiography at a lower cost and with a lower radi- ation dose. Opinion is divided on whether perfusion lung scans or CT angiograms should be obtained as a first imaging test in patients with a nearly normal chest radiograph. Some opt for perfusion imaging only if the patient is pregnant or young or has a contraindication to CT angiography, as with chronic kidney disease. Patients with emphy- sema, chronic obstructive pulmonary disease, or poorly controlled asthma may require a ventilation scan in addition to a perfusion scan even if the chest radiograph appears nearly normal. Some suggest use of the PISAPED criteria for interpretation. Some now favour the use of SPECT scintigraphy over planar ventilation–​perfusion lung scans. Recommendations For women of reproductive age In women of reproductive age with a normal chest radiograph, if D-​dimer is positive, most recommend either a perfusion lung scan as the first diagnostic test, or venous ultrasound to be followed by a perfusion lung scan. If the chest radiograph is abnormal, most rec- ommend a CT pulmonary angiogram. For patients who are pregnant Most investigators recommend venous ultrasound before imaging tests with ionizing radiation in patients who are pregnant. The European Association for Nuclear Medicine recommends a per- fusion scan without a ventilation scan, and a lower dose of radio- isotope. Others believe that rapid diagnosis is crucial and radiation is a secondary issue. If a CT pulmonary angiogram is performed, imaging should be strictly limited to the thoracic cavity, and low kVp, if applicable, should be utilized. For haemodynamically stable young men The effect of radiation on male reproduction is uncertain. In young men with a normal chest radiograph, opinions differ on which imaging test should be performed. In young men with an abnormal chest radiograph, most recommend CT pulmonary angiography as the first imaging test. For haemodynamically stable older men and women The risk of radiation-​induced cancer is small with older men and women. Most recommend CT pulmonary angiography as the first imaging test in such patients, irrespective of whether the chest radio- graph is normal. Opinion differs, however, and scintigraphy is re- commended by many, particularly if the chest radiograph is normal. For patients with allergy to iodinated contrast material D-​dimer with clinical assessment is recommended to exclude PE. Patients with mild iodine allergies may be treated with steroids prior to CT imaging. Venous ultrasound and pulmonary scintig- raphy are recommended as alternative diagnostic tests in patients with severe iodine allergy. Serial venous ultrasound is an option, as is gadolinium-​enhanced CT angiography. For patients with impaired renal function D-​dimer with clinical assessment is recommended to exclude PE. If further investigation is warranted, venous ultrasound is recom- mended, followed by treatment if positive, and pulmonary scintigraphy if venous ultrasound is negative. Serial venous ultrasound is an option if scintigraphy is non​diagnostic. However, as always it is a matter of balancing benefits and risks, and if the index of suspicion is high, then many physicians will proceed with CT pulmonary angiography. section 16  Cardiovascular disorders 3726 For patients in extremis Bedside echocardiography in combination with bedside leg ultra- sonography are generally recommended as rapidly obtainable bed- side tests. In an appropriate clinical setting, either right ventricular enlargement or poor right ventricular function, or a positive venous ultrasound, can be interpreted as resulting from PE. Others recom- mend a portable perfusion scan or immediate transfer to an inter- ventional catheterization laboratory, but in many instances neither of these will be available. A combination of a negative bedside echo- cardiogram and venous ultrasound suggests that the patient may be in extremis for some other reason than PE, but the diagnosis of PE can be pursued with CT angiography, if this is feasible, and such imaging may be appropriate if and when the patient stabilizes. Serial non​invasive leg tests Instead of imaging the lungs, an alternative strategy for the diag- nosis of PE is to detect and treat DVT. Such a strategy can only be applied to patients with adequate cardiorespiratory reserve, because even a small recurrent PE might be dangerous if reserve is poor. In practice this means obtaining serial ultrasonography of the legs over a period of 2 weeks, and treating if DVT is shown. Among patients with suspected PE who had a non​diagnostic ventilation–​perfusion lung scan, and negative non​invasive leg tests (one study required low or intermediate probability clinical assessment and another normal cardiorespiratory reserve), PE at 3 months follow-​up occurred in only 0.4% to 0.6%. However, most now believe that with many safe and accurate imaging options available, management on the basis of serial non​invasive leg tests is rarely (if ever) indicated. Treatment—​general measures All patients who are hypoxic should be given supplementary oxygen at high concentration (enough to restore normal Pao2). In the early stages continuous monitoring of arterial oxygen tension by pulse oximetry is advised, with particularly careful clinical and arterial blood gas monitoring of those with coincident chronic chest disease in case CO2 retention is problematic. Resuscitation Patients with massive PE and circulatory collapse may look as though they are about to die, with cool peripheries, cyanosis, profound hypo- tension, and marked elevation of the jugular venous pulse. Features typical of long-​standing pulmonary hypertension (palpable right ven- tricular heave, right ventricular gallop, loud P2, hepatomegaly, ascites, peripheral oedema) are unlikely to be present. This dramatic haemo- dynamic picture may not be simply due to the direct anatomical effects of occlusion of main pulmonary vessels (the same picture is not seen after pneumonectomy, when one pulmonary artery is tied off com- pletely), but also secondary to pulmonary neurogenic reflexes and local release of vasoactive substances, including 5-​hydroxytryptamine and thromboxane from activated platelets. Every effort should be made to support the circulation until meas- ures designed to deal with the embolus (usually thrombolysis—​see next) can be applied and take effect. Treatment—​antithrombotic It is common and sensible practice to begin anticoagulant treat- ment as soon as the diagnosis of PE is suspected, unless there are serious concerns about the potential side effects of anticoagulation or imaging is immediately available. The antithrombotic regimen is the same as for DVT: see Table 16.16.1.8 and Chapter 16.16.2. Three direct oral factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) and one oral direct thrombin inhibitor (dabigatran)—​ were approved by the United States Food and Drug Administration (FDA) for treatment of venous thromboembolism (VTE). Some such drugs have also been approved for extended treatment (rivaroxaban, apixaban and dabigatran) or for prophylaxis (rivaroxaban and apixaban) following knee or hip replacement. Betrixaban, a direct factor Xa inhibitor, was approved for the prophylaxis of VTE in pa- tients hospitalized with an acute medical illness. None of these drugs requires monitoring of anticoagulant levels. They are as effective as conventional therapy with enoxaparin followed by a vitamin K an- tagonist in the treatment of DVT and PE. All of the novel oral anticoagulants have comparable rates of bleeding or less bleeding than treatment with a low-​molecular-​weight heparin/​vitamin K antagonist. If bleeding occurs, the anticoagulant effect of the factor Xa inhibitors apixaban and rivaroxaban (but only these drugs) can be reversed with andexanet alfa. The anticoagulant effect of the direct thrombin inhibitor dabigatran can be reversed with idarucizumab. Resolution rate with anticoagulants Most patients (81%) treated with anticoagulants show complete CT angiographic resolution after 28 days, with emboli resolving at a faster rate in main or lobar pulmonary arteries than in segmental branches (Fig. 16.16.1.5). Among patients with no prior cardio- pulmonary disease who are treated with anticoagulants, resolution of 90% or more on perfusion lung scans is shown at 1 year in 91% of cases, compared with only 72% of those with prior cardiopul- monary disease. Thrombolytic therapy Thrombolytic therapy is not indicated for the routine treatment of PE. Hypotension, continuing hypoxemia while receiving high frac- tions of inspired oxygen (Fio2), and requirement for ventilatory Day 1 0 100 75 50 Resolution (%) 25 Days 2–7 Days 8–28 28 Days Main or lobar Segmental Fig. 16.16.1.5  Resolution of pulmonary emboli in main or lobar (▲) pulmonary arteries (PA) or segmental branches (●) according to number of days after initial CT angiogram. Bars = 95% confidence interval. Rate of resolution was slower in segmental branches. Data from Stein PD, et al. (2010). Resolution of pulmonary embolism on CT pulmonary angiography. AJR Am J Roentgenol, 194, 1263–​8. 16.16.1  Deep venous thrombosis and pulmonary embolism 3727 support are indications for intervention. Analysis of data from 72 230 unstable (in shock or requiring ventilatory support) patients with PE throughout the United States of America from 1999 to 2008 showed that in-​hospital mortality with thrombolytic therapy was 15% compared with 47% in those who did not receive thrombolytic therapy. Mortality was further reduced to 7.6% if a vena cava filter was used in addition to thrombolytic therapy compared with 33% mortality in those who received a vena cava filter, but no thrombo- lytic therapy. All-​cause mortality in unstable patients was lower with thrombolytic therapy in every age group, including older people, irrespective of comorbid conditions. Right ventricular dysfunction on the echocardiogram of normo- tensive patients with PE may indicate impending haemodynamic instability. For this group meta-​analysis showed mortality was 1.4% with thrombolytics versus 2.9% with anticoagulants, but this benefit was offset by major bleeding in 7.7% with thrombolytics, versus 2.3% with anticoagulants. A more rapid lysis of pulmonary thromboemboli occurs with thrombolytic agents than occurs spontaneously in patients treated only with anticoagulants, but pulmonary reperfusion as demonstrated on perfusion lung scans is similar after 2 weeks in patients treated with thrombolytic agents and patients treated with anticoagulants. In 1973 the Urokinase Pulmonary Embolism Trial showed no improvement of mortality and no difference of the rate of re- currence of PE among stable patients treated with thrombolytic therapy and patients treated with anticoagulants. There have been no subsequent prospective randomized trials to contradict these results, although a trend suggesting a lower rate of recurrent PE has been shown among patients with right ventricular dysfunction who were treated with tissue plasminogen activator. Thrombolysis has risks. Based on pooled data the frequency of major bleeding from tissue plasminogen activator among patients with PE in randomized trials was 14.7%. This occurred despite the fact that all studies excluded patients at a high risk of bleeding, such those with recent surgery, recent biopsy, peptic ulcer disease, blood dyscrasia, or severe hepatic or renal disease. The risk of intracranial haemorrhage with tissue plasminogen activator (2%) was higher among patients with PE than among patients who received tissue plasminogen activator for myocardial infarction. Even though there are risks of thrombolysis, mortality is lower in unstable patients (in shock or requiring ventilatory support) who receive thrombolysis than those who do not receive it. Regimens of thrombolytic therapy When thrombolytic therapy is appropriate, current evidence sup- ports a short (2-hour) infusion through a peripheral vein. The most widely used regimen In the United States is recombinant tissue plasminogen activator (rt-PA)(altelplase) 100 mg IV over 2 hours. In the United States, it is recommended that IV unfractionated hep- arin should be discontinued during the infusion of rt-PA. • In Europe, rt-​PA is administrated using a 10-​mg bolus, followed by a 90-​mg continuous IV infusion with concomitant unfractionated heparin. Inferior vena cava filters Recommendations for use of inferior vena cava filters are shown in Table 16.16.1.8. The Prévention du Risque d’Embolie Pulmonaire par Interruption Cave (PREPIC) study, a randomized controlled trial of permanent filters plus anticoagulants (n = 200) compared with anticoagulants alone (n = 200) was performed in patients with proximal DVT, with or without symptomatic PE. Fewer patients in the filter group showed symptomatic PE at 1 year (1.1% versus 5.0%) and at 8 years 6.2% versus 15.1%) after recruitment. Recurrent DVT, however, was more frequent in the filter group and there was no difference in mortality. The Prévention du Risque d’Embolie Pulmonaire par Interrup­tion Cave 2 (PREPIC2) trial was a randomized controlled trial of retriev- able filters in stable patients with acute pulmonary embolism. This trial showed no reduction of mortality in 200 stable patients with fil- ters compared with 199 who did not receive a filter. Subgroups that might benefit from filters could not be assessed. Such subgroups are haemodynamically unstable patients (in shock or on ventilatory support) 2) require thrombolytic therapy and are stable, 3) undergo pulmonary embolectomy, 4) have solid malignant tumors (except liver gall bladder, bile ducts and ovary) and are >60 years old, 5) have chronic obstructive pulmonary disease and are >50 years old, 6) very elderly (>80 years) even though stable, and 7) patients who suffer re- current PE during the first 3 months (while on anticoagulants). These subgroups were shown to reduce in–hospital mortality based on ad- ministrative data from retrospective cohort studies of huge United States government or commercial databases. These results have not been assessed by randomized controlled trials and are not endorsed by authoritative guidelines. Routine insertion of an inferior vena cava filter is not indicated solely on the basis of a continuing predisposition for DVT, although in special circumstances this may be the best approach (e.g. in high-​ risk patients with DVT, severe pulmonary hypertension, and min- imal cardiopulmonary reserve). Several vena cava filters have been designed for percutaneous in- sertion and many are retrievable. They differ in outer diameter of the delivery system, maximal caval diameter into which they can be in- serted, hook design, retrievability, biocompatibility, and filtering effi- ciency. They may be effective alone in preventing PE, but anticoagulant therapy after insertion of a filter is recommended for the duration of treatment that would be required without a filter. Thereafter, anticoagu- lant therapy can be discontinued even though the filter remains in place. Complications of permanent vena cava filters include improper anatomical placement, filter deformation, filter fracture, insufficient opening of the filter, and filter migration; also perforation, thrombosis, and stenosis of the cava wall. Symptomatic occlusion of the inferior vena cava is the most frequent complication, occurring in about 9% of pa- tients. Complications at the site of insertion of the catheter do not differ from complications observed locally with other catheter techniques. DVT at the puncture site generally has been reported in 8% to 25%. Retrievable vena cava filters typically are successfully removed after 1 to 3 months, but some have been successfully removed after 1 year. PE after insertion of an inferior vena cava filter is uncommon (1%), and fatal embolism is rare. Possible mechanisms that can ex- plain PE after filter insertion are: (1) ineffective filtration, especially with tilting of the filter; (2) growth of trapped thrombi through the filter; (3) thrombosis on the proximal side of the filter; (4) filter mi- gration; (5) filter retraction from the caval wall; (6) embolization through collaterals; (7) embolization from sites other than the in- ferior vena cava; and (8) incorrect position of the filter. Over the last two decades, the use of inferior vena cava filters in the United States section 16  Cardiovascular disorders 3728 of America has increased markedly in patients with PE, patients with DVT alone, and patients at risk who had neither PE nor DVT. The use for primary prevention in patients who do not have DVT or PE has accelerated. Extensive use of permanent and retrievable vena cava filters indicates a liberalization of indications, but despite the benefits of retrievability, retrieval has been attempted in only a mi- nority of patients. For patients with retrievable IVC filters in whom the transient risk of PE has passed, the benefit/risk profile begins to favor filter removal between 29 and 54 days after insertion. Catheter interventions Catheter-​tip devices for the extraction or the fragmentation of PE have the potential of producing immediate relief from massive PE. Such interventions may be particularly useful in patients in whom there is a contraindication to thrombolytic therapy. A suction-​tip device for extraction of PE has been used in some patients, and thrombus fragmentation with a guide wire, angiographic catheter, balloon catheter, or specially designed devices has been reported in small case series or case reports. The release of fragmented thromboemboli into the distal pulmonary arterial branches is not a problem. A registry of management strategies used by hospitals throughout Germany showed use of catheter fragmentation in 1.3–​ 6.8% of patients with PE, depending on severity. Although originally it was thought that catheter embolectomy or fragmentation could substitute for thrombolytic therapy, it now appears to be an adjunct to thrombolysis, allowing a larger surface area of the fragmented emboli to be exposed to thrombolytic agent. Among patients who undergo fragmentation with standard angio- graphic catheters, the rate of successful clinical outcome with a local infusion of thrombolytic agents in combination with fragmentation is higher than with a systemic infusion. Pulmonary embolectomy Thrombolytic therapy is likely to give better results than embol- ectomy, although the latter may have life-​saving potential in some instances. The average operative mortality in the United States of America among 620 unstable patients operated from 2004 to 2008 was 40%, and among 1550 stable patients, mortality was 23%. These data reflect average results. Advanced centres with expertise might show a lower mortality. A candidate for pulmonary embolectomy should meet the following criteria: (1) massive PE, angiographic- ally documented if possible; (2) haemodynamic instability (shock) despite heparin therapy and resuscitative efforts; and (3) failure of thrombolytic therapy or a contraindication to its use. Chronic pulmonary thromboembolic hypertension The vast majority of PE resolve because of natural thrombolytic pro- cesses. Residual emboli, if any, undergo fibrovascular organization causing chronic obstruction to pulmonary arterial blood flow. It is estimated that 2.8% of patients with PE develop chronic thrombo- embolic pulmonary hypertension, usually within 3 years after the acute PE. The predominant symptom of chronic thromboembolic pulmonary hypertension is unexplained dyspnoea on exertion, often following an asymptomatic period of several months or years after the acute PE. The reference standard for the diagnosis is com- bined right heart catheterization to quantify the haemodynamic im- pairment, and conventional pulmonary angiography to determine the extent and proximal location of the chronic thromboembolic obstruction. CT pulmonary angiography is essential to exclude rare conditions that may present with similar signs and symptoms such as fibrous mediastinitis, mediastinal carcinoma, and pulmonary artery sarcoma. Pulmonary thromboendarterectomy in an experienced centre is the treatment of choice in symptomatic patients with surgically ac- cessible thromboemboli. Early diagnosis is important because the surgical mortality in patients who have progressed to dyspnoea at rest is substantially greater than among those with less severe symp- toms. Neither anticoagulants nor vasodilators are effective, with the haemodynamic and symptomatic benefits of medical therapy being modest in comparison to those resulting from successful pulmonary thromboendarterectomy. See Chapter 16.15.2 for further discussion. FURTHER READING Agnelli G, Becattini C (2010). Acute pulmonary embolism. N Engl J Med, 363, 266–​74. Agnelli G, et al. (2013). AMPLIFY Investigators: oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med, 369, 799–​808. Chatterjee S, et al. (2014). Thrombolysis for pulmonary embolism and risk of all-​cause mortality, major bleeding, and intracranial hemorrhage: a meta-​analysis. JAMA, 311, 2414–​21. Collaborative Study by the PIOPED Investigators (1990). Value of the ventilation/​perfusion scan in acute pulmonary embolism—​results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). JAMA, 263, 2753–​59. Fedullo P, et al. (2011). Chronic thromboembolic pulmonary hyper- tension. Am J Resp Crit Care Med, 183, 1605–​13. Goldhaber SZ (2016). Requiem for liberalizing indications for vena caval filters? Circulation, 133, 1992–​4. Guyatt GH, et al. (2012). Antithrombotic therapy and prevention of thrombosis, 9th ed. American College of Chest Physicians Evidence-​ Based Clinical Practice Guidelines. Chest, 141(suppl), 7S–​47S. Kearon C, et  al. (2012). Antithrombotic therapy for VTE disease. Antithrombotic therapy and prevention of thrombosis, 9th ed. American College of Chest Physicians Evidence-​Based Clinical Practice Guidelines. Chest, 141(suppl), e419S–​94S. Kearon C, et al. (2016). Antithrombotic therapy for VTE disease: chest guideline and expert panel report. Chest, 149, 315–​52. Mismetti P, et al. (2015). PREPIC2 Study Group. Effect of a retriev- able inferior vena cava filter plus anticoagulation vs anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clin- ical trial. JAMA, 313, 1627–​35. Morales JP, et al. (2013). Decision analysis of retrievable inferior vena cava filters in patients without pulmonary embolism. J Vasc Surg Venous Lymphat Disord, 1, 376–84. PREPIC Study Group (2005). Eight-​year follow-​up of patients with permanent vena cava filters in the prevention of pulmonary em- bolism: the PREPIC (Prevention du Risque d’Embolie Pulmonaire par Interruption Cave) randomized study. Circulation, 112, 416–​22. Schulman S, et al.; RE-​COVER II Trial Investigators (2014). Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation, 18, 129, 764–​72. Sostman, HD et al. (2008). Sensitivity and specificity of perfusion scin- tigraphy combined with chest radiography for acute pulmonary em- bolism in PIOPED II. J Nucl Med, 49, 1741–​8. Stein PD, et  al. (1991). Clinical, laboratory, roentgenographic and electrocardiographic findings in patients with acute pulmonary embolism and no pre-​existing cardiac or pulmonary disease. Chest, 100, 598–​603. 16.16.2 Therapeutic anticoagulation 3729 David Kee 16.16.2 Therapeutic anticoagulation 3729 David Keeling 16.16.2  Therapeutic anticoagulation 3729 Stein PD, et  al. (2004). D-​dimer for the exclusion of deep venous thrombosis and acute pulmonary embolism: a systematic review. Ann Intern Med, 140, 589–​602. Stein PD, et al. (2006). Diagnostic pathways in acute pulmonary em- bolism:  recommendations of the PIOPED II investigators. Am J Med, 119, 1048–​55. Stein PD, et al. (2006). Multidetector computed tomography for acute pulmonary embolism. N Engl J Med, 354, 2317–​27. Stein PD, et al. (2007). Clinical characteristics of patients with acute pulmonary embolism: data from PIOPED II. Am J Med, 120, 871–​9. Stein PD, et al. (2010). Early discharge of patients with venous thrombo- embolism: implications regarding therapy. Clin Appl Thromb Hemost, 16, 141–​5. Stein PD, et  al. (2010). Outcome in stable patients with acute pul- monary embolism who had right ventricular enlargement and/​or elevated levels of troponin I. Am J Cardiol, 106, 558–​63. Stein PD, et al. (2010). Silent pulmonary embolism in patients with deep venous thrombosis: a systematic review. Am J Med, 123, 426–​31. Stein PD, et al. (2011). Elevated cardiac biomarkers with normal right ventricular size indicate an unlikely diagnosis of acute pulmonary embolism in stable patients. Clin Appl Thromb Hemost, 17, E153–​7. Stein PD, et al. (2011). Prognosis based on cardiac biomarkers and right ventricular size in stable patients with acute pulmonary em- bolism. Am J Cardiol, 107, 774–​7. Stein PD, et  al. (2012). Diagnosis and management of isolated subsegmental pulmonary embolism: review and assessment of the options. Clin Appl Thromb Hemost, 18, 20–​6. Stein PD, et al. (2012). Impact of vena cava filters on in-​hospital case fatality rates from pulmonary embolism. Am J Med, 125, 478–​84. Stein PD, et al. (2012). Trends in case fatality rates in patients with pul- monary embolism according to stability and treatment. Thrombosis Research, 130, 841–​46. Stein PD, Matta F (2012). Pulmonary embolectomy for acute pul- monary embolism. Am J Med, 125, 471–​7. Stein PD, Matta F (2012). Thrombolytic therapy in unstable patients with acute pulmonary embolism: save lives but underused. Am J Med, 125, 465–​70. Stein PD, Matta F (2013). Treatment of unstable pulmonary embolism in elderly and those with comorbid conditions. Am J Med, 126, 304–​10. Stein PD, et al. (2014). A critical review of SPECT imaging in pul- monary embolism. Clin Transl Imaging, 2, 379–​90. Stein PD (2016). Pulmonary embolism, 3rd edition. Wiley Blackwell, Oxford. Stein PD, et al. (2019). Optimal therapy for unstable pulmonary em- bolism. Am J Med, 132, 168–71. Stein PD, et al. (2019). Usefulness of inferior vena cava filters in stable patients with acute pulmonary embolism. Am J Cardiol, 123, 1874–77. Tapson VF (2008). Acute pulmonary embolism. N Engl J Med, 358, 1037–​52. van Belle A, et  al. (2006). Effectiveness of managing suspected pul- monary embolism using an algorithm combining clinical probability, D-​dimer testing, and computed tomography. JAMA, 295, 172–​9. Wells PS, et al. (1997). Value of assessment of pretest probability of deep-​vein thrombosis in clinical management. Lancet, 350, 1795–​8. Wells PS, et al. (2000). Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-​dimer. Thromb Haemost, 83, 416–​20. Wells PS, et al. (2001). Excluding PE at the bedside without diagnostic imaging: management of patients with suspected PE presenting to the emergency department by using a simple clinical model and D-​dimer. Ann Intern Med, 135, 98–​107. 16.16.2  Therapeutic anticoagulation David Keeling ESSENTIALS Low-​molecular-​weight heparins have largely replaced unfractionated heparin. Their much more predictable anticoagulant response com- bined with high bioavailability after subcutaneous injection means that the dose can be calculated by body weight and given subcuta- neously without any monitoring or dose adjustment. Their wide- spread use resulted in most patients with deep vein thrombosis being managed as outpatients, and this is also increasingly the case for un- complicated pulmonary embolism. Oral vitamin K antagonists (most commonly warfarin) have his- torically been the mainstay of long-term anticoagulant therapy, but direct acting oral anticoagulants (DOACs) that specifically target thrombin or factor Xa are increasingly used to treat acute venous thromboembolism and for stroke prevention in atrial fibrillation. Particular issues—​(1) in patients with cancer and venous thrombo- embolism, giving low-​molecular-​weight heparins for the first 6 months of long-​term anticoagulant therapy has been shown to be superior to vitamin K antagonist; (2) high-​dose loading regimens of warfarin are un- necessary and may increase the risk of over-​anticoagulation and bleeding; (3) warfarin for venous thromboembolism and atrial fibrillation should be given with a target INR of 2.5 (range 2.0–​3.0); for patients with prosthetic heart valves the target INR is usually greater; (4) indefinite anticoagulation is required for patients with atrial fibrillation or a mechanical heart valve; for venous thromboembolism a careful clinical decision is required re- garding duration of treatment; (5)  for patients with atrial fibrillation anticoagulation is much more effective than aspirin in preventing stroke; (6) if warfarin needs to be stopped for surgery, full-​dose heparin does not have to be given perioperatively unless the risk of thromboembolism is high, and warfarin can be continued in patients having dental extractions. Introduction The main indications for therapeutic anticoagulation are venous thromboembolism (VTE), deep vein thrombosis (DVT), and pul- monary embolism (PE) (see Chapter 16.16.1), and the prevention of stroke in patients with atrial fibrillation or mechanical heart valves. Oral vitamin K antagonists (in the United Kingdom, mostly war- farin) have been the mainstay of treatment, but oral direct inhibitors of thrombin or factor Xa (direct acting oral anticoagulants, DOACs) are being increasingly used to treat VTE and to prevent stroke in atrial fibrillation. When warfarin is used in acute venous thrombo- embolism, initial anticoagulation with heparin is required because warfarin takes time to become effective. Therapeutic anticoagulation for venous thromboembolism DVT and PE are aspects of the same disease—​VTE. Forty per cent (40%) of patients with DVT without clinical evidence of PE have section 16  Cardiovascular disorders 3730 evidence of emboli on lung scanning. The principles of therapeutic anticoagulation are the same for both. In proximal DVT and PE this has historically involved immediate anticoagulation with heparin, followed by a period of anticoagulation with warfarin (or other oral vitamin K antagonists). Distal DVT can be managed in the same way, but an alternative strategy is to use serial non​invasive testing (e.g. ultrasonography), which only reliably detects proximal throm- bosis, to ensure that suspected distal thrombosis does not extend above the knee, withholding treatment if it does not. There is clear evidence that an immediately acting anticoagu- lant is needed in the initial phase and that anticoagulation with oral vitamin K antagonists alone is inadequate. Warfarin can be commenced on the first day and heparin is continued for 5 days or until the international normalized ratio (INR) is greater than 2.0 for two consecutive days, whichever is the longer. Extending the period of heparinization from 5 to 10 days is not more effective and increases the risk of heparin-​induced thrombocytopenia. The DOACs act immediately and rivaroxaban and apixaban have been used to treat acute VTE without initial heparin. Dabigatran and edoxaban have also been used for acute VTE, but with initial heparin. Heparin Heparin, a glycosaminoglycan, is composed of alternating uronic acid and glucosamine saccharides that are sulphated to a varying degree. Its mode of action is to potentiate the activity of the serine protease inhibitor (serpin) antithrombin, whose main mode of ac- tion is to inhibit thrombin, but which also inhibits several other coagulant proteases such as factor Xa. A specific pentasaccharide sequence (see ‘Fondaparinux’) determined by the sulphation pat- tern along the heparin chain binds to antithrombin and causes a conformational change, giving it full activation against factor Xa but only partial activation against thrombin. Heparins of 18 sac- charides (molecular weight (MW) 5400)  or more can extend across the intermolecular gap and also bind to thrombin giving full antithrombin activity, which is lost if the chains are shorter. Unfractionated or standard heparins are a mixture of chains of dif- ferent lengths (MW 5000–​35 000, mean 13 000) and low-​molecular-​ weight heparins (LMWH, MW 2000–​8000, mean 5000) are derived from them by enzymatic or physicochemical cleavage. LMWH have, with good reason, largely replaced unfractionated heparin for the treatment of venous thromboembolism, but the use of the latter is discussed first. Anticoagulation with unfractionated heparin Unfractionated heparin has most often been given by continuous intravenous infusion, the rate of which has to be adjusted, usually by measuring the activated partial thromboplastin time (APTT). An inadequate APTT response in the first 24 h may increase the risk of recurrence of thromboembolism, although this does not seem to be critical if the starting infusion rate is at least 1250 IU/​h. A validated regimen is to give a bolus dose of 80 IU/​kg and to start the infusion at 18 IU/​kg/​h, performing the first APTT estimate after 6 h. The dose is then usually adjusted to maintain the APTT between 1.5 to 2.5 times the average laboratory control value. With older APTT reagents, this corresponded to a therapeutic heparin level of 0.3–​0.7 IU/​ml by anti-​Xa assay. However, many current APTT reagents show an increased sensitivity to unfractionated heparin and, with these, higher ratios should be aimed for. The local laboratory should advise on the appropriate therapeutic range with its reagent. When the dose is therapeutic, the APTT should be checked daily. An alternative is to give unfractionated heparin subcutaneously once every 12 h, and a meta-​analysis suggested that this might be more effective and at least as safe as continuous intravenous infu- sion. A reasonable starting dose is 250 IU/​kg, adjusting the dose ac- cording to the mid-​interval APTT. Anticoagulation with LMWH The key clinical property of LMWHs is that they produce a much more predictable anticoagulant response than unfractionated hep- arin. This, combined with the fact that they have very high bio- availability after subcutaneous injection, means that the dose can be calculated by body weight and be given subcutaneously without any monitoring or dose adjustment. The actual dosage used dif- fers slightly with the different LMWH and the manufacturers’ re- commendations should be followed, but a typical dose is 200 IU/​ kg once a day. They are at least as effective and at least as safe as unfractionated heparin. Their widespread use resulted in most pa- tients with DVT being managed as outpatients, and this is increas- ingly the case for low-​risk PE. LMWH is renally excreted and so the dose needs to be reduced in patients with renal failure, with monitoring and (if necessary) adjustment of the dose based on anti-​Xa levels. In patients with cancer, giving LMWH for the first 6 months of long-​term anticoagulant therapy has been shown to be superior to switching to a vitamin K antagonist. Complications of heparin treatment If a patient on intravenous unfractionated heparin is excessively anticoagulated, it is usually sufficient simply to stop the infusion, the half-​life being 1 to 2 h. If bleeding is severe, the heparin can be neutralized with protamine sulphate, giving 1 mg for every 100 IU that has been infused over the previous hour. The reversal of LMWH is more problematic. Although protamine sulphate may not neutralize the smaller chains, it is often clinically effective, though estimating an appropriate dose is more difficult (the max- imum dose is 50 mg, so this is often given if the subcutaneous in- jection was recent). Heparin-​induced thrombocytopenia is a feared complication, but much less common now that short courses of LMWH are used. It is due to the development of an antibody to the heparin–​platelet factor 4 complex and can be associated with serious venous and arterial thrombosis. Heparin must be stopped if heparin-​induced thrombo- cytopenia is likely and an alternative immediately acting non​heparin anticoagulant substituted. Fondaparinux The specific pentasaccharide sequence of heparin which binds to antithrombin has been chemically synthesized and is marketed as the drug fondaparinux. Like LMWH it is given by subcutaneous injection with no monitoring. It is equivalent to heparin in the treatment of venous thromboembolism, and is superior to heparin in the treatment of unstable angina and non-​ST elevation myo- cardial infarction. It carries virtually no risk of heparin-​induced thrombocytopenia. 16.16.2  Therapeutic anticoagulation 3731 Warfarin The oral vitamin K antagonists have historically been the mainstay of long-​term anticoagulant therapy. Warfarin is the commonest vitamin K antagonist given; acenocoumarol (which has a shorter half-​life) and phenindione (which has a higher incidence of skin rashes) are seldom used in the United Kingdom. The procoagulant factors II, VII, IX, and X (and the anticoagulants protein C and pro- tein S) need vitamin K for the γ-​carboxylation of the glutamic acid residues that form their gla domains. Without this post-​translational modification they cannot bind calcium, and as a consequence cannot bind to anionic phospholipid surfaces such that assembly of the key coagulation complexes is disrupted. Warfarin takes several days to become effective, so heparin is given initially if immediate anticoagulation is needed. When war- farin is started, the vitamin K-​dependent factors fall according to their half-​lives. Factor VII and protein C have the shortest half-​lives, so that despite a prolongation of the INR due to factor VII deficiency, warfarin may initially be procoagulant. This is the mechanism for the rare problem of warfarin-​induced skin necrosis, most often de- scribed in those with protein C deficiency. Initiation and monitoring of anticoagulation with warfarin Monitoring of warfarin treatment is by the INR. This is a manipu- lation of the prothrombin time (PT) to allow for the different sen- sitivities of various laboratory reagents to the warfarin-​induced coagulopathy. The INR equals (PT/​MNPT)ISI where MNPT is the (mean normal) control PT and ISI is the international sensitivity index of the thromboplastin used in the assay. For the treatment of DVT and PE, the target INR should be 2.5 (target range 2.0–​3.0). If the initial coagulation tests are not prolonged, it has been cus- tomary to give 10 mg of warfarin on the first evening and check the INR the following morning, adjusting the dose according to the daily INR results until the patient is stable. With such regimens, most patients received 10 mg of warfarin on the first 2 days. There is, however, no evidence to suggest a 10 mg loading dose is superior to 5 mg, and regi- mens that start with 5 mg doses, or a single 10 mg dose followed by 5 mg doses, may be preferable to regimens that start with repeated 10 mg doses. This is the case in patients with an increased risk of bleeding (e.g. people >60 years old, and those with liver disease or cardiac failure). The dosing algorithm used in Oxford is shown in Table 16.16.2.1. When patients are stable, they may go for up to 8 weeks between INR checks. If the INR is unstable, patients are seen more frequently, but it should be noted that with warfarin it takes approximately 1 week (5 times the half-​life of 36 h) to reach a new steady state after dose ad- justment, hence more frequent dosage alteration is inadvisable. Complications of warfarin treatment The only major complication of warfarin treatment is bleeding. Risk factors for bleeding are increasing age, a history of stroke, a history of gastrointestinal bleeding, anaemia, renal impairment, diabetes, and recent myocardial infarction. A significant problem in control is the starting and stopping of other medication. Many drugs interact with warfarin (see Table 16.16.2.2 for those with the most evidence) such that patient (and doctor) education and constant vigilance are essential. Close monitoring of the INR is advised when concomitant medication is altered. The approach taken to reverse over-​anticoagulation with warfarin depends on the circumstances (see Box 16.16.2.1). Prothrombin complex concentrates, unlike fresh frozen plasma, reliably and rap- idly correct the defect and should be used in life-​threatening situ- ations such as intracranial bleeding. Small doses of phytomenadione (vitamin K1) can lower a high INR without making subsequent anticoagulation difficult, as is the case if high doses are given. Direct acting oral anticoagulants (DOACs) The ideal anticoagulant would be orally active and have a wide thera- peutic index, predictable pharmacokinetics and dynamics (negating the need for monitoring), minimal interactions with other drugs and food, a rapid onset of action, an antidote, and minimal non-​ anticoagulant side effects. Heparin needs to be given parenterally. Warfarin has a slow onset of action, a narrow therapeutic index, unpredictable pharmacokinetics and dynamics, and significant Table 16.16.2.1  A warfarin induction regimen Days 1 and 2 Day 3 Day 4 INR Dose (mg) INR Dose (mg) Give 5 mg each evening if baseline INR <1.4 <1.5 10 <1.6 10 1.5–​2.0 5 1.6–​1.7 7 2.1–​2.5 3 1.8–​1.9 6 2.6–​3.0 1 2.0–​2.3 5 3.0a 0 2.4–​2.7 4 2.8–​3.0 3 3.1–​3.5 2 3.6–​4.0 1 4.0a 0 a and seek advice on further management Table 16.16.2.2  Many drugs interact with warfarin; the evidence is strongest for those listed Potentiation Inhibition Amiodarone Barbiturates Cimetidine Carbamazepine Clofibrate Chlordiazepoxide Cotrimoxazole Cholestyramine Erythromycin Griseofulvin Fluconazole Rifampicin Isoniazid Sucralfate Metronidazole Miconazole Omeprazole Paracetamol Phenylbutazone Piroxicam Propafenone Propranolol Statins Sulfinpyrazone section 16  Cardiovascular disorders 3732 drug and dietary interactions that make regular monitoring essen- tial. New anticoagulants were therefore much sought, and the most promising targets were Xa and thrombin (Fig. 16.16.2.1). An oral direct thrombin inhibitor (dabigatran) and three oral direct Xa in- hibitors (rivaroxaban, apixaban, and edoxaban) have now emerged into clinical practice. These DOACs directly inhibit their target co- agulation factors and so do not require antithrombin for their action. Oral direct thrombin (IIa) inhibitors Dabigatran etexilate is orally absorbed and rapidly converted to dabigatran, which inhibits both free and clot-​bound thrombin. Peak levels occur 2 h after a dose and the half-​life is 12–​17 h, the drug being 80% renally excreted. A fixed dose of 150 mg twice a day has been shown to be as effective as warfarin in the treatment of acute venous thromboembolism, though heparin was still given for the first 5 days. It has also been compared with warfarin for the prevention of stroke and systemic embolization in atrial fibrillation, with 110 mg twice a day showing similar efficacy with reduced major bleeding, and 150 mg twice a day showing improved efficacy with similar major bleeding. A specific antidote for dabigatran, the monoclonal antibody idarucizumab, is available, which rapidly and completely reverses anticoagulation in patients taking dabigatran. Oral direct Xa inhibitors Three oral direct Xa inhibitors are currently available (rivaroxaban, apixaban, and edoxaban). All have a rapid onset of action and inhibit free Xa and Xa bound in the prothrombinase complex. • Rivaroxaban has a half-​life of 7–​13 h and renal clearance is 33%. 15 mg twice a day for 3 weeks followed by 20 mg once a day is as ef- fective as warfarin in the treatment of venous thromboembolism, with reduced major bleeding; 20 mg once a day is equivalent to warfarin for the prevention of stoke and systemic embolization in atrial fibrillation, • Apixaban has a half-​life of 10–​14 h and renal clearance is 25%. 10 mg twice a day for 1 week followed by 5 mg twice a day is as ef- fective as warfarin in the treatment of venous thromboembolism with reduced major bleeding; 5 mg twice a day is more effective than warfarin for the prevention of stoke and systemic emboliza- tion in atrial fibrillation with less major bleeding. • Edoxaban has a half-​life of 8–​10 h and renal clearance is 50%; 60 mg once a day is as effective as warfarin in the treatment of venous thromboembolism, but heparin was still used for the first 5 days. 60 mg once a day is as effective as warfarin for the prevention of stoke and systemic embolization in atrial fibrillation with less major bleeding; 30 mg once a day is used in those with renal im- pairment or low body weight. At present there are no factor Xa inhibitor antidotes that are widely available. Andexanet alfa is a decoy receptor for apixaban and rivaroxaban that as of 2019 had been approved or conditionally approved by some regulatory authorities, but is available only in few locations at considerable expense. Low (<20 units/kg) or moderate (20–30 units/kg) doses of FEIBA (factor eight inhibitor bypassing activity) may be effective in DOAC-related major bleeding. Clinical decision making in venous thromboembolism Selecting an anticoagulant The DOACs offer an alternative to vitamin K antagonists for the treatment and secondary prevention of VTE and for stroke preven- tion in atrial fibrillation. They cannot be used in patients with mech- anical heart valves. Logistically they are much simpler to use as they do not require dose adjustment or monitoring. They result in less major bleeding and carry half the risk of intracranial haemorrhage. The lack of a specific antidote to reverse the effects of oral direct Xa inhibitors is a disadvantage compared to vitamin K antagonists and dabigatran, but all the current Xa inhibitors have short half-​lives, hence this has not been a major problem in clinical practice and a specific antidote should become more widely available. The DOACs are not a good choice for the poorly compliant, and renal function should be assessed before they are prescribed. Duration of anticoagulation After an acute VTE event, 6  months of anticoagulation has been shown to be more effective than 6 weeks of anticoagulation, and 3 months has been shown to be equivalent to 6 months. After three months of anticoagulation the important clinical decision is to de- cide who can stop anticoagulation and who should take some form of Box 16.16.2.1  Management of over-​anticoagulation with warfarin Major bleeding • Stop warfarin • Give prothrombin complex concentrate (PCC) 25–​50 IU/​kg (only use fresh frozen plasma (FFP) 15 ml/​kg if PCC is not available) • Give phytomenadione 5 mg intravenously Minor bleeding • Stop warfarin • Give phytomenadione 1–​3 mg intravenously High INR without bleeding • Stop warfarin until INR <5 • If INR >8 give phytomenadione 1–​5 mg orally TF/VIIa IX IXa VIIIa X II IIa Va AT Fondaparinux Fibrinogen Fibrin Bivalirudin Argatroban Dabigatran Rivaroxaban Apixaban Edoxaban Xa Fig. 16.16.2.1  Anticoagulants targeting Xa and thrombin. Roman numerals represent the coagulation factors (a—​indicates the activated forms), TF, tissue factor; AT, antithrombin. 16.16.2  Therapeutic anticoagulation 3733 long-​term anticoagulation for secondary prevention. This is a matter of balancing the risk of recurrence against the risk of bleeding on anticoagulation: 2–​3% of people on warfarin have a major bleed each year and the case fatality is 10%, giving a fatality rate of 0.25% per year (mostly from intracranial haemorrhage). However, warfarin is highly (approximately 90%) effective at preventing recurrence. The risk of a recurrent venous thromboembolism (VTE) after a first VTE is approximately 5% per year, which with a case fatality rate of 5% also gives a fatality rate of 0.25% per year. Factors that may either increase the risk of bleeding or increase the risk of recurrence need to be taken into account. The risk of recurrence is higher for proximal DVT and PE than for distal DVT, and it is lower if a transient risk factor was present (e.g. recent surgery, use of the contraceptive pill). For patients with a first episode of distal DVT (whether provoked or unprovoked), or a first episode of proximal DVT or PE secondary to a transient (reversible) risk factor, treatment is recommended for 3 months. For patients with a first episode of unprovoked proximal DVT or PE, treatment is recommended for at least 3 months and con- sideration should be given to long-​term treatment where there are no risk factors for bleeding and where anticoagulant control is good. An important consideration is that recurrences are more common in men than women. It has also been shown that a raised D-​dimer level after discontinuing anticoagulation predicts an increased risk of re- currence. Factor V Leiden and the prothrombin mutation do not in- crease the risk of recurrence of a clinically significant event. Whether deficiencies of antithrombin, protein C, or protein S increase the risk of recurrence is less clear, but testing for these is less helpful than paying attention to the history (unprovoked versus provoked, male versus female) and considering, in selected cases, a D-​dimer test. Antiphospholipid antibodies are thought to increase the risk of re- currence, but the evidence is from poor quality studies. If the first event was a symptomatic PE, subsequent events are more likely to be PE, as compared to if the first event was a DVT. For patients with two or more episodes of objectively documented venous thrombo- embolism, or those with a first event and an ongoing risk factor (such as cancer), indefinite treatment should be considered. Taking all this into account, a reasonable approach is indicated in Table 16.16.2.3. Fibrinolysis Thrombolytic agents dissolve thrombi by directly or indirectly activating the zymogen plasminogen to plasmin. Plasmin then de- grades fibrin to soluble peptides, but cannot distinguish fibrin in pathological thrombi from fibrin in haemostatic plugs. The use of thrombolytic agents for venous thromboembolism re- quires careful individual assessment. It is not often given in DVT, though its use should be considered in iliofemoral thrombosis. Thrombolysis in massive PE may be life-​saving but for submassive PE, although thrombolysis achieves more rapid resolution than heparin alone, there is no clear evidence of lasting benefit (see Chapter 16.16.1). Streptokinase (which forms a complex with plasminogen that then activates free plasminogen), urokinase, and tissue plasminogen activator (tPA) have all been used. For PE, streptokinase is recom- mended as a 250 000-​IU loading dose followed by an infusion for 24 h at 100 000 IU/​h. Urokinase is given as a 4400 IU/​kg loading dose followed by 2200 IU/​kg for 12 h.  Following the success of rapid fibrinolytic regimens in myocardial infarction, tPA given as 100 mg over 2 h has been used for PE, and the use of more rapid regimens with the other two agents has also been suggested (see Chapter 16.16.1 for further discussion). Treatment in pregnancy Heparin and LMWH do not cross the placenta and can be used in pregnancy. LMWH is more convenient, and the osteopenia some- times seen with prolonged use of unfractionated heparin seems not to be a problem with LMWH. Warfarin, which crosses the placenta, can cause an embryopathy if given between 6 and 12 weeks of gesta- tion. At any time, it can cause fetal bleeding and has been associated with central nervous system abnormalities. The DOACs cannot be used in pregnancy. The usual treatment recommended for venous thromboembolism in pregnancy is to continue with full-​dose subcutaneous LMWH until term. Warfarin can be used for the 6 weeks of the puer- perium: women taking warfarin can breastfeed. See Chapter 14.7 for further discussion. Treatment for atrial fibrillation Atrial fibrillation affects 2–​5% of people over the age of 60 and is associated with a stroke rate of 5% a year. In patients with atrial fib- rillation, warfarin given to a target INR of 2.5 (target range 2.0–​3.0) prevents two-​thirds of fatal or disabling strokes, though it becomes less effective when the INR is less than 2.0. Aspirin reduces stroke in atrial fibrillation by only approximately 20% and should not be used for this purpose. Compared to warfarin the DOACs are as or more effective, with the same or reduced major bleeding. In patients with atrial fibrillation, the following increase the risk of stroke: congestive heart failure, hypertension, increasing age, dia- betes, previous ischaemic stroke or transient ischaemic attack, vas- cular disease, and female sex. One scheme used to assess patients (CHA2DS2-​VASc) gives points for these risk factors. Patient with a score of zero do not usually receive anticoagulation, whereas those with a score of 2 or more are usually anticoagulated. Women with a score of 1 are not anticoagulated, but for men there has been a trend to recommend anticoagulation. If warfarin is used rapid anticoagulation is not usually required and a slow-​loading regimen (such as starting patients on 3 mg of war- farin daily for 1 week and determining subsequent doses by weekly INR measurement) is safe and achieves therapeutic anticoagulation in most patients within 3 to 4 weeks. Treatment for mechanical heart valves Vitamin K antagonists are recommended for all patients with mech- anical prosthetic heart valves, the overall risk of embolic stroke if not anticoagulated being 8% per year. Emboli are more common from mi- tral mechanical valves than from aortic mechanical valves, and caged-​ ball valves are more thrombogenic than bileaflet or tilting-​disc valves. Table 16.16.2.3  Duration of warfarin treatment Event Duration of treatment 1st distal DVT 1st proximal DVT or PE with TRFa 3 months 1st unprovoked proximal DVT or PE 3 months or long term 1st proximal DVT or PE with ongoing risk factor Recurrent VTE Long term a TRF, transient risk factor (e.g. surgery, combined pill, pregnancy, plaster cast). section 16  Cardiovascular disorders 3734 Various national and international recommendations are made regarding the target INR in patients with mechanical heart valves, with 3.5 traditionally being advised. This is reasonable for caged-​ball valves, but for tilting-​discs and bileaflet valves the target INR can pos- sibly be lower, for example, 2.5 (range 2.0–​3.0) for aortic valves and 3.0 (range 2.5–​3.5) for mitral valves. When a new valve is inserted, it is recommended that unfractionated heparin or LMWH be given until the INR is stable and at a therapeutic level for two consecutive days. Perioperative management of therapeutic anticoagulation Warfarin does not need to be stopped for dentistry, nor for some minor surgery. For many operations, however, warfarin will need to be temporarily discontinued. It can generally be stopped 5 days be- fore surgery and the INR be checked on the day of surgery (checking the day before obviates the risk of cancellation as a small dose of oral vitamin K can be given if necessary). The main clinical deci- sion is whether to give bridging therapy with treatment-​dose hep- arin perioperatively when the INR is less than 2.0. This depends on balancing the risk of bleeding with the risk of thromboembolism. Treatment-​dose heparin is usually given for those at high risk of thromboembolism, such as patients with a mechanical mitral valve, but must not be (re-​)started for at least 48 h after high bleeding risk surgery (Table 16.16.2.4). The DOACs have short half-​lives and so bridging is not required. They can normally be stopped 1 or 2 days preoperatively, although renal function needs to be taken into consideration, particularly for dabigatran. They must not be given for at least 48 h after surgery with a high bleeding risk. FURTHER READING Burnett AE, et al. (2016). Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment. J Thromb Thrombolysis, 41, 206–​32. Connolly SJ, et al. (2009). Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med, 361, 1139–​51. Dager WE, Roberts AJ, Nishijima DK (2019). Effect of low and mod- erate dose FEIBA to reverse major bleeding in patients on direct oral anticoagulants. Thromb Res, 173, 71–6. Giugliano RP, et al. (2013). Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med, 369, 2093–​104. Granger CB, et al. (2011). Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med, 365, 981–​92. Kearon C, et  al. (2016). Antithrombotic therapy for VTE dis- ease: CHEST guideline and expert panel report. Chest, 149, 315–​52. Keeling D, et  al. (2011). Guidelines on oral anticoagulation with warfarin—​fourth edition. Br J Haematol, 154, 311–​24. Keeling D, et al. (2016). Peri-​operative management of anticoagulation and antiplatelet therapy. Br J Haematol, 175, 602–​13. Patel MR, et al. (2011). Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med, 365, 883–​91. Table 16.16.2.4  Management of warfarin anticoagulation perioperatively, recommendations for bridging when warfarin is stopped 5 days before surgery Risk Preoperatively Postoperatively until INR> 2 High risk e.g. VTE within 1 month; mechanical mitral valve; AF and history of stroke in last three months Treatment-​dose heparina (either IV UFH or SC LMWH) Treatment-​dose heparinb (either IV UFH or SC LMWH) Low risk e.g. VTE >3 months ago, bi-​leaflet aortic valve with no other risk factors, AF without recent stroke Nil or prophylactic LMWH Prophylactic LMWH AF, atrial fibrillation; IV, intravenous; LMWH, low-​molecular-​weight heparin; SC, subcutaneous; UFH, unfractionated heparin; VTE, venous thromboembolism. a Stop full-​dose IV UFH 6 h before surgery and check APTT before operation begins, omit full-​dose SC LMWH on day of surgery. b Therapeutic dose heparin must not be given for at least 48 h after high bleeding risk surgery. 16.17 Hypertension 3735 16.17.1 Essential hyperten 16.17 Hypertension 3735 16.17.1 Essential hypertension: Definition, epidemiology, and pathophysiology 3735 Bryan Williams and John D. Firth 16.17 Hypertension CONTENTS 16.17.1 Essential hypertension: Definition, epidemiology, and pathophysiology  3735 Bryan Williams and John D. Firth 16.17.2 Essential hypertension: Diagnosis, assessment, and treatment  3753 Bryan Williams and John D. Firth 16.17.3 Secondary hypertension  3778 Morris J. Brown and Fraz A. Mir 16.17.4 Mendelian disorders causing hypertension  3796 Nilesh J. Samani and Maciej Tomaszewski 16.17.5 Hypertensive urgencies and emergencies  3800 Gregory Y.H. Lip and Alena Shantsila 16.17.1  Essential hypertension: Definition, epidemiology, and pathophysiology Bryan Williams and John D. Firth ESSENTIALS ‘Essential hypertension’ is high blood pressure for which there is no clearly defined aetiology. From a practical perspective, it is best defined as that level of blood pressure at which treatment to lower blood pressure results in significant clinical benefit—​a level which will vary from patient to patient depending on their absolute cardiovascular risk. Historically, most guidelines define ‘hypertension’ as an of- fice blood pressure greater than or equal to 140/​90  mm Hg, but some recent recommendations prefer home or ambulatory blood pressure (blood pressure) averages. When using 24 h am- bulatory blood pressure or home blood pressure averages to define hypertension, the diagnostic thresholds are lower than those used with office measurement, with a value of 135/​85 mm Hg typically used for both daytime ambulatory blood pressure and home measurements. Isolated diastolic hypertension (systolic blood pressure (SBP) <140 mm Hg, and diastolic blood pressure (DBP) >90 mm Hg) is more common in younger people, and isolated systolic hyperten- sion (SBP >140 mm Hg, DBP <90 mm Hg) is the most common form of hypertension in older people. American guidelines include a category of ‘prehypertension’ (SBP 120–​139 mm Hg and/​or DBP 80–​89 mm Hg), the reason for this being that blood pressure in this range is associated with both adverse cardiovascular outcome and a high rate of progression to hypertension. Epidemiology In 2000, it was estimated 25% of the world’s adult population were hypertensive, and predicted that this would rise to 29% by 2025. By the age of 60, more than one-​half of adults in most regions of the world will be hypertensive. There is a continuous relationship between blood pressure and cardiovascular risk from blood pressure values as low as 115/​75  mm Hg. The relationship is steeper for stroke than it is for coronary heart disease, and is magnified by age. There is a doubling in risk of stroke and ischaemic heart disease mortality for every 20/​10 mm Hg increase in blood pressure. Most people with hypertension are over the age of 50 years, and in these SBP is by far the most important contributor to the burden of cardiovascular disease attributable to hypertension. Pathogenesis and pathophysiology The pathogenesis of essential hypertension is a complex inter- play between (1) genetic predisposition, (2) lifestyle and environ- mental influences, and (3)  disturbances in vascular structure and neurohumoral control mechanisms. Genetic predisposition—​blood pressure runs in families, with a remarkably consistent level of correlation of around 0.2 between first-​degree relatives found in many studies. This means that if the blood pressure of one member of the family deviates from the norm by +10 mm Hg, the first-​degree relative will deviate by +2 mm Hg on average. Variants in a large number of genes, involving virtually all of the main physiological systems affecting blood pressure, have shown association with blood pressure in one or more studies, but the effect of any individual variant is likely to be modest. section 16  Cardiovascular disorders 3736 Lifestyle and environmental influences—​the exploding prevalence of hypertension in economically developing regions reflects lifestyle changes, so-​called ‘Westernization’, more than anything else, with the most important influences on blood pressure being sodium in- take, obesity, and alcohol intake. Pathophysiology—​a characteristic finding in essential hypertension is an inappropriate increase in peripheral vascular resistance relative to the cardiac output. This is due to remodelling of small arteries (ar- terioles), which is characterized by an increase in their media/​lumen ratio, but it is not clear whether these changes are a consequence or a cause of raised blood pressure. The functional integrity of large conduit arteries (i.e. the aorta), which becomes stiffer, also influences the development of hypertension—​especially systolic hypertension. The specific role of the renin–​angiotensin–​aldosterone system in the development of essential hypertension remains unclear, but thera- peutic agents that inhibit this system have proved to be very effective treatments. The sympathetic nervous system is involved in the acute and chronic regulation of blood pressure, but whether disturbances in it play a major role in the initiation and maintenance of chronic essential hypertension remains unknown. The hypertensive phenotype and target organ damage Although blood pressure measurement is used to define hyperten- sion, hypertension is more than just blood pressure. Essential hyper- tension is commonly associated with metabolic disturbances (the ‘insulin resistance phenotype’) and multisystem structural damage that conspire to enhance cardiovascular risk beyond that which can be attributed to blood pressure alone. Left ventricular hypertrophy is a classic feature of untreated or in- adequately treated long-​standing hypertension, and is a very potent predictor of premature cardiovascular disease and death. Inhibition of the renin–​angiotensin–​aldosterone system is particularly effective at regressing left ventricular hypertrophy, which is associated with dramatically improved prognosis for people with hypertension. Hypertension is the single most important risk factor for stroke, and is increasingly recognized as a major factor contributing to the rate of cognitive decline in later life. Patients with renal disease often have hypertension, people with hypertension can develop renal dis- ease, and the age-​related decline in GFR is more rapid in people with essential hypertension, but renal function is usually well pre- served throughout life in patients with mild to moderate essential hypertension. Retinal changes caused by hypertension are discussed in Chapter 16.17.2. Implications of the evolution of hypertensive injury The process of hypertensive injury to target organs evolves silently over many years. Current treatment guidelines have been devel- oped from an evidence base relating to changes in hard clinical end-​points derived from studies in elderly patients at the end of the hypertensive disease process. Future treatment strategies must surely focus on preventing the evolution of the silent disease pro- cess, rather than simply battling with its consequences. Definitions of hypertension The commonest form of hypertension has been termed ‘essential hypertension’, i.e. hypertension for which there is no clearly defined aetiology. Blood pressure is normally distributed within populations and thus the definition of ‘hypertension’ is a moving target. From a practical perspective it is best defined as that level of blood pressure at which treatment to lower blood pressure results in significant clin- ical benefit, which will change as new evidence from clinical trials emerges. This statement also highlights the conundrum in definition of ‘hypertension’ because the risk associated with blood pressure is a continuum and the level of pressure at which treatment results in ‘significant clinical benefit’ for any individual will depend on their absolute cardiovascular risk. There is substantial evidence that treating systolic pressure (SBP) above 160 mm Hg and/​or a diastolic pressure (DBP) above 100 mm Hg is beneficial; there is also evidence that treating pressures above 140/​90  mm Hg is worthwhile, especially in higher-​risk patients. Historically, most guidelines have therefore defined ‘hypertension’ as an office blood pressure of 140/​90 mm Hg or more, with various grades of hypertension also specified (Table 16.17.1.1). The hyper- tension guidelines in the United States of America include a category of ‘prehypertension’ (SBP 120–​139 mm Hg and/​or DBP 80–​89 mm Hg), which is discussed later in this chapter. NICE guidance in the United Kingdom has rather confusingly created additional termin- ology, with stage 1 hypertension being clinic BP more than 140/​ 90 mm Hg with ambulatory blood pressure monitoring (ABPM) or home blood pressure monitoring (HBPM) more than 135/​85 mm Hg, stage 2 hypertension being clinic BP more than 160/​100 mm Hg with ABPM or HBPM more than 150/​95 mm Hg, and severe hyper- tension being clinic SBP more than 180 mm Hg or clinic DBP more than 110 mm Hg. It is important to note that the diagnostic thresholds for hyperten- sion vary according to the method of measurement. The aforemen- tioned blood pressure thresholds for diagnosis have been defined according to seated blood pressure measurements, so-​called ‘office blood pressures’. However, the increasing use of automated blood pressure monitoring, either at home or with ambulatory devices, has shown that there can be marked discrepancies between clinic blood pressure measurements and those obtained at home or when ambulatory. This has led to much discussion as to whether conven- tional clinic blood pressure measurements are still the best way of establishing the diagnosis of hypertension. When using 24 h am- bulatory blood pressure or home blood pressure averages to define Table 16.17.1.1  Classification of hypertension. Grades 1–​3 replace the old terminology of ‘mild’, ‘moderate’, and ‘severe’. The ‘high normal’ blood pressure range corresponds to ‘prehypertension’ in the United States guideline Category Systolic Diastolic Optimal <120 and <80 Normal 120–​129 and/​or 80–​84 High normal 130–​139 and/​or 85–​89 Grade 1 hypertension 140–​159 and/​or 90–​99 Grade 2 hypertension 160–​179 and/​or 100–​109 Grade 3 hypertension 180 and/​or 110 Isolated systolic hypertension 140 and <90 Reproduced from Mancia G, et al. (2007). 2007 ESH-​ESC Practice Guidelines for the Management of Arterial Hypertension: ESH-​ESC Task Force on the Management of Arterial Hypertension. J Hypertens, 25, 1751–​62. 16.17.1  Essential hypertension 3737 hypertension, the diagnostic thresholds are lower than these office blood pressures, typically quoted values being 135/​85 mm Hg for both daytime ambulatory blood pressure monitoring and home blood pressure measurements. Subtypes of hypertension Various categories of blood pressure can be identified in popula- tions, with isolated diastolic hypertension (IDH) (SBP <140 mm Hg, DBP >90 mm Hg) being more common in younger people and isolated systolic hypertension (SBP >140 mm Hg, DBP <90 mm Hg) being the most common form of hypertension in older people, with systolic/​diastolic hypertension (SDH) (SBP>140 mm Hg and DBP 90 mm Hg) bridging the two extremes of age (Fig. 16.17.1.1). Although traditionally DBP was considered to carry the greatest prognostic significance, it is now clear that this is not the case. Most people with hypertension are over the age of 50 years, and in them SBP is by far the most important contributor to the burden of cardiovascular disease attributable to hypertension. The different patterns of blood pressure and the relative import- ance of DBP and SBP with regard to prognosis reflect progression of the underlying pathology. The pathogenesis of hypertension in younger people is characterized by an increased peripheral vas- cular resistance. This results in an increased diastolic pressure, with any associated rise in systolic pressure ‘cushioned’ by a com- pliant aorta, hence the commonly observed IDH. With ageing there is progressive stiffening of the aorta, a consequent reduction in large-​artery compliance, and a reduced capacity to sustain dia- stolic pressure and to cushion systolic pressure. The result is an age-​related widening of pulse pressure as diastolic pressure falls alongside a progressive rise in SBP, hence the emergence of ISH (Fig. 16.17.1.2). Epidemiology Global prevalence The global prevalence of hypertension when defined either as a blood pressure of 140/​90  mm Hg or over, or the use of antihypertensive medication, was estimated to be 972 million in the year 2000, representing about 25% of the world’s adult popula- tion. The global prevalence of hypertension is expected to rise dra- matically by about 60% by 2025, representing 29% of the world’s 17% 100% 80% 60% 40% 20% 0% <40 Age (y) Frequency of hypertension subtypes in all untreated subjects (%) 60–69 16% 80+ 70–79 50–59 40–49 11% 20% 20% 16% Fig. 16.17.1.1  Blood pressure subtypes in the United States of America according to age. The percentage values at the top of each column indicate the prevalence of hypertension in that age band. Blue shaded bar, isolated systolic hypertension; brown shaded bar, systolic/​diastolic hypertension; purple shaded bar, isolated diastolic hypertension. Reproduced from Franklin SS, et al. (2001). Predominance of isolated systolic hypertension among middle-​aged and elderly US hypertensives, Hypertension, 37, 869–​74. 0 70 80 110 mm Hg 130 150 (a) (b) Diastolic blood pressure Systolic blood pressure Men Diastolic blood pressure Systolic blood pressure Women Age, y 0 70 80 110 mm Hg 130 150 30–39 30–39 50–59 50–59 Age, y 60–69 60–69 70–79 70–79 ≥80 ≥80 40–49 40–49 18–29 18–29 Non-Hispanic black Mexican American Non-Hispanic white Fig. 16.17.1.2  Data from the United States of America NHANES III population survey (1988–​91) showing the progressive rise in SBP with age and the rise in DBP up until age c.50 years, after which DBP falls and pulse pressure widens. This pattern is typical of Westernized countries and explains the high prevalence of isolated systolic hypertension in older people in these countries. Reproduced from Burt VL, et al. (1995). Prevalence of hypertension in the US adult population. Hypertension, 23, 305–​13. section 16  Cardiovascular disorders 3738 adult population and affecting 1.6 billion people (Fig. 16.17.1.3). Most of this increase in the worldwide burden of hypertension is expected to result from an increase in the number of people with hypertension in economically developing regions, hence almost 75% of the world’s hypertensive populations will be in economic- ally developing regions by 2025. The prevalence of hypertension in almost all regions of the world increases with age and more steeply in women. By the age of 60, more than one-​half of adults in most regions of the world will be hypertensive. India and Asia have and will most likely continue to have the lowest rates of hypertension, whereas the highest rates are likely to remain in Latin America, the Caribbean, former Soviet re- publics, and sub-​Saharan Africa. Consequently, hypertension is set to remain the single most important preventable cause of premature death worldwide over the next two decades, with the World Health Organization (WHO) estimating that about 7.1 million deaths per year may be attributable to hypertension, and that suboptimal blood pressure (SBP ≥115 mm Hg by their definition) is responsible for 50 2000 37.4 39.1 20.6 40.7 34.8 22.0 23.7 Men Women 22.6 19.7 17.0 14.5 26.9 28.3 40 30 20 10 0 50 2025 Rate of hypertension (%) 41.6 42.5 Established market economies Middle eastem crescent China Other Asia and islands Sub-Saharan Africa Latin America and the Caribbean India Former socialist economies 39.1 45.9 22.9 23.6 44.5 40.2 24.0 27.0 27.7 18.8 17.1 27.0 28.2 40 30 20 10 0 27.0 20.9 35.3 37.2 Fig. 16.17.1.3  Frequency of hypertension in people aged 20 years and older by world region and gender in 2000 (upper panel) and projected to 2025 (lower panel). Reprinted from The Lancet, Vol. 365, Kearney PM, et al., Global burden of hypertension: analysis of world-​wide data, pp. 217–​23. Copyright (2005), with permission from Elsevier. Women aged 65 years 100 (a) 80 60 40 20 0 Years of follow-up Risk of hypertension, % 1976–1998 1952–1975 100 80 60 40 20 0 0 2 4 6 8 10 12 14 16 18 Years of follow-up 20 0 2 4 6 8 10 12 14 16 18 20 Men aged 65 years (b) Fig. 16.17.1.4  Lifetime risk of hypertension in women and men aged 65 years. Reprinted from Vasan RS, et al. (2002). Residual lifetime risk for developing hypertension in middle-​aged women and men, the Framingham Heart Study. JAMA, 287, 1003–​10. Copyright © 2002, American Medical Association. 16.17.1  Essential hypertension 3739 62% of cerebrovascular disease and 49% of ischaemic heart disease worldwide, with little variation by sex. Lifetime risk The prevalence of hypertension increases with age, affecting over one-​half of those aged 60–​69 years and over three-​quarters of those aged over 70 years in the United States of America and most devel- oped countries. As indicated earlier, almost all of the age-​related rise in the prevalence of hypertension is due to a progressive rise in SBP. The lifetime probability of developing hypertension is about 90% for men and women who were not hypertensive at 55 or 65 years old and survived to age 80 to 85 (Fig. 16.17.1.4). Cardiovascular morbidity and mortality associated with hypertension Elevated blood pressure increases the risk of cardiovascular mor- bidity and mortality. Data from observational studies of over 1 mil- lion people has indicated a continuous relationship between blood pressure and cardiovascular risk from blood pressure values as low as 115/​75 mm Hg (Fig. 16.17.1.5). The relationship is steeper 120 140 160 180 120 140 160 180 1 2 4 8 16 32 64 128 256 Age at risk: 80–89 years 70–79 years 60–69 years 50–59 years 40–49 years Usual systolic blood pressure (mm Hg) Systolic blood pressure (a) (b) (a) (b) IHD mortality (floating absolute risk and 95% CI) 80 70 1 2 4 8 16 32 64 128 256 Age at risk: 80–89 years 70–79 years 60–69 years 50–59 years 40–49 years 90 Usual diastolic blood pressure (mm Hg) Diastolic blood pressure IHD mortality (floating absolute risk and 95% CI) 1 2 4 8 16 32 64 128 256 Age at risk: 80–89 years 70–79 years 60–69 years 50–59 years Usual systolic blood pressure (mm Hg) Systolic blood pressure Stroke mortality (floating absolute risk and 95% CI) 1 2 4 8 16 32 64 128 256 Age at risk: 80–89 years 70–79 years 60–69 years 50–59 years Usual diastolic blood pressure (mm Hg) Diastolic blood pressure Stroke mortality (floating absolute risk and 95% CI) 110 100 80 70 90 110 100 Fig. 16.17.1.5  Relationship between usual blood pressure at the start of a decade and the risk of ischaemic heart disease (IHD, top panel) and stroke (bottom panel) mortality rates in that decade, for each decade for each decade of life. Reprinted from The Lancet, Vol. 360, Lewington S, et al., Age-​specific relevance of usual blood pressure to vascular mortality: a meta-​analysis of individual data for one million adults in 61 prospective studies, pp. 1903–​13. Copyright (2002), with permission from Elsevier. section 16  Cardiovascular disorders 3740 for stroke than it is for coronary heart disease and is magnified by age. For every 20/​10 mm Hg increase in blood pressure, there is a doubling in risk of stroke and ischaemic heart disease mortality. Hypertension also increases the risk of congestive cardiac failure, end-​stage renal disease, and dementia. Moreover, data from the Framingham Heart Study also indicates that there is a doubling of risk of cardiovascular complications in patients with blood pressure levels above normal but not yet classified as having overt hyperten- sion (Fig. 16.17.1.6). This was the basis for the American guide- lines introducing the term ‘prehypertension’ (SBP 120–​139 mm Hg and/​or DBP 80–​89 mm Hg) to emphasize that this level of blood pressure (1) is not benign, (2) is associated with an elevated car- diovascular disease risk, and (3)  predicts with a high degree of certainty that blood pressure is on an upward trajectory and that affected people are almost certain to develop more severe hyper- tension, unless there is intervention with effective lifestyle changes and/​or drug therapy. Systolic blood pressure as the main risk factor For many years DBP was considered the main denominator for defining the threshold and treatment targets for hypertension. This is no longer the case. As indicated earlier, there is a pro- gressive rise in DBP up to about the age of 50 years and there- after it usually falls. By contrast, SBP begins to rise relentlessly from the age of around 40 years (Figs. 16.17.1.1 and 16.17.1.2). Thus, at the age of peak prevalence of hypertension (i.e. older than 60 years), SBP is the major contributor to the diagnosis of the condition and its associated risk. Below the age of 50 years, DBP is also important. Fig. 16.17.1.7 illustrates the shift in the major risk burden attributable to hypertension, from DBP to SBP, at about the age of 50 years. However, because most hypertension (>75%) occurs over the age of 50 years, SBP rather than DBP is by far the most important contributor to the huge global cardio- vascular risk burden attributable to hypertension. SBP is also the most difficult to treat, which has led some to argue that for pa- tients over the age of 50 years the attention of doctors should be focused solely on the SBP. What method of blood pressure measurement best predicts cardiovascular outcome? It has been known for many years that ambulatory blood pressure measurement (ABPM) provides better prediction of mortality than clinic measurements (Fig. 16.17.1.8). The US Preventive Services Task Force (2015) conducted a thorough review of the literature looking at studies comparing ABPM vs. office blood pressure measurement (OBPM), and home blood pressure measurement (HBPM) vs. OBPM. Eleven studies reported that daytime, night-​time, and 24-​hour ABPM predicted stroke and other fatal and non​fatal CV events independently of OBPM (Fig. 16.17.1.9). Five studies suggested similar results for HBPM, but there was insufficient data to allow firm conclusions. Only a single study compared HBPM with ABPM, which was insufficient to allow conclusions to be drawn. OBPM added no significant predictive capacity independently of ABPM (Fig. 16.17.1.10). In healthcare sys- tems where they are readily available, ABPM or HBPM should be used as the basis for diagnosing (and therefore treating) hypertension. Time (yr) Optimal Normal High normal Optimal Normal High normal Women (a) No. at risk Optimal 1875 1867 1851 1839 1821 1734 887 1126 1115 1097 1084 1061 974 649 891 874 859 840 812 722 520 Normal High normal Optimal 1005 995 973 962 934 892 454 1059 1039 1012 982 952 892 520 903 879 857 795 795 726 441 Normal High normal 0 0 2 4 6 8 10 Cumulative incidence (%) 2 4 6 8 10 12 Time (yr) Men (b) No. at risk 0 4 2 6 8 10 12 14 Cumulative incidence (%) 14 0 2 4 6 8 10 12 14 Fig. 16.17.1.6  High normal blood pressure and the risk of cardiovascular disease. Cumulative incidence of cardiovascular events in women (a) and men (b) without hypertension, according to blood pressure category at the baseline examination. For this analysis, optimal blood pressure was defined as SBP less than 120 mm Hg and DBP less than 80 mm Hg, normal blood pressure as SBP 120–​129 mm Hg and/​or DBP 80–​84 mm Hg, and high normal blood pressure as SBP 130–​139 mm Hg and/​or DBP 85–​89 mm Hg (95% confidence intervals are shown). Reprinted from Vasan RS, et al. (2001). Impact of high-​normal blood pressure on the risk of cardiovascular disease. N Engl J Med, 345, 1291–​7. Copyright © 2001, Massachusetts Medical Society. P = 0.008 25 −1.5 −1.0 −0.5 0.0 0.5 1.0 35 Age (years) β(SBP) - β(DBP) 65 75 55 45 Fig. 16.17.1.7  The impact of DBP and SBP on the risk of coronary heart disease as a function of age. A β-​coefficient level less than 0.0 indicates a stronger effect of DBP on coronary heart disease (CHD) risk, a β-​coefficient level greater than 0.0 indicates a greater importance of SBP. The ‘switch’ from DBP to SBP occurs at around age 50 years. Reprinted from Franklin SS, et al. (2001). Does the relation of blood pressure to coronary heart disease risk change with aging? Circulation, 103, 1245. (http://​circ. ahajournals.org/​cgi/​content/​abstract/​103/​9/​1245). 16.17.1  Essential hypertension 3741 3.5 2.2 1.9 1.6 1.3 1.0 0.7 Nighttime Nighttime 24-hour 24-hour Daytime Daytime Clinic Clinic 3.0 2.5 2.0 1.5 5-Year risk of cardiovascular death (%) 1.0 0.5 90 110 130 150 Systolic BP (mm Hg) 170 190 210 230 50 60 70 80 Diastolic BP (mm Hg) 90 100 110 120 130 Fig. 16.17.1.8  Adjusted five-​year risk of cardiovascular death in 5292 patients. Curves are for average night-​time, 24-​hour, and daytime ambulatory readings, and for clinic readings. Reprinted from Dolan E, et al. (2005). Superiority of ambulatory over clinic blood pressure measurement in predicting mortality: the Dublin outcome study. Hypertension, 46, 156–​61. Study Cardiac events or mortality Staessen, 1999 Systolic: Cardiac end points, fatal and nonfatal 1.11 (0.91, 1.35) 1.06 (1.01, 1.10) 1.06 (1.02, 1.10) 1.10 (0.94, 1.29) 1.25 (1.10, 1.42) 1.32 (1.03, 1.68) 1.10 (0.98, 1.25) 1.30 (1.19, 1.42) 1.07 (1.00, 1.15) 1.21 (1.04, 1.42) 1.29 (0.98, 1.71) 1.17 (1.05, 1.32) 1.02 (0.99, 1.05) 1.05 (0.96, 1.14) 1.24 (1.03, 1.49) .5 1 2 Systolic: CV mortality Systolic: CV mortality Systolic: CV mortality Systolic: CV mortality Systolic: MI or stroke, fatal and monfatal Systolic: Stroke, fatal Systolic: Stroke, fatal or nonfatal Systolic: Stroke, fatal or nonfatal Systolic: All-cause mortality Systolic: All-cause mortality Systolic: All-cause mortality Systolic: All-cause mortality Systolic: Major CV events (CV death, MI or stroke) Systolic: Cardiac mortality (fatal HF, MI, sudden death) Dolan, 2005 CV events or mortality Dolan, 2005 Gasowski, 2008 Hansen, 2005 Staessen, 1999 Clement, 2003 Hemida, 2011 Stroke Dolan, 2005 Clement, 2003 Staessen, 1999 All cuase mortality Clement, 2003 Dolan, 2005 Hansen, 2005 Staessen, 1999 Note: Weights are from random effects analysis Abbreviations: CI = confidence interval; CV = cardiovascular; HF = heart failure; HR = hazard ratio; MI = myocardial infarction. Outcome HR (95% Cl) Fig. 16.17.1.9  Risk for cardiovascular and mortality outcomes: systolic 24 hr ABPM, adjusted for OBPM. Each 10 mm Hg increase in systolic 24 hr ABPM, adjusted for OBPM, was consistently associated with an increased risk for fatal or non​fatal stroke or cardiovascular events. From Piper MA, et al. (2014). Screening for high blood pressure in adults: A systematic evidence review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 121. AHRQ Publication No. 13-​05194-​EF-​1. Rockville, MD: Agency for Healthcare Research and Quality. section 16  Cardiovascular disorders 3742 Pathogenesis and pathophysiology of hypertension The pathogenesis of essential hypertension has remained some- thing of an enigma, in part reflecting the fact that the basis for the diagnosis (i.e. an elevated blood pressure), has so many potential causes. From a physiological perspective, the pressure in the circu- lation is the product of the cardiac output (CO) and impedance to flow, that is, peripheral resistance (PR): blood pressure CO PR. × Both cardiac output and peripheral resistance can be influenced by several control mechanisms, including activity of the renin–​ angiotensin–​aldosterone system, activity of the sympathetic nervous system, and other factors influencing salt and water homeostasis. In addition, vascular structural changes associated with hypertension play a role in accentuating its severity and con- ferring resistance to treatment. These structural changes include small-​artery remodelling that results in a reduced media/​lumen ratio (which increases peripheral resistance) and large-​artery stiffening (which changes pulse wave characteristics and reduces the compliance of the circulation). Recent reports suggest that a reduced diameter of the proximal aorta may also be a factor con- tributing to the development of hypertension. Whether structural changes precede and predispose to the onset of hypertension, or follow it, or both, remains a subject of considerable debate. In some cases (probably <10%) a discrete cause for hyper- tension will be identified (see Chapter  16.17.3). In most other circumstances the pathogenesis of essential hypertension (i.e. hypertension that is not due to a recognized secondary cause), is a complex interplay between (1) genetic predisposition, (2) lifestyle and environmental influences, and (3) disturbances in structure and the aforementioned control mechanisms. These are in turn compounded by the effects of ageing on the cardiovascular and renal systems. Genetic factors (this section written by Professor Nilesh J. Samani) Historical perspective The history of the genetics of hypertension is marked by a celebrated debate in the 1950s and 1960s between Platt and Pickering, two doyens of British medicine. On the basis of a finding of a bimodal distribution of blood pressures in some families of patients with hypertension, and evidence of hypertension transmitted over three generations in a few pedigrees, Platt argued that hypertension was a distinct genetic disorder with a likely autosomal dominant mode of inheritance. By contrast, Pickering and colleagues showed that in the general population there was no obvious discontinuity of blood pressure distribution and that the familial resemblance of blood pressure spanned the whole range of blood pressures, and was not different for those with hypertension. Thus, Pickering argued that blood pressure, like height and weight, was a quantitative trait; and that although there was a significant genetic contribution, this was polygenic and that hypertension represented one extreme of the trait but was not a distinct disorder, except perhaps for rare monogenetic forms embedded in the blood pressure distribution curve. Today, the overwhelming mass of evidence supports the Pickering concept, although several mendelian disorders that predispose to hyperten- sion have been described (see Chapter 16.17.4). Genetic epidemiology of blood pressure and hypertension The extent of familial aggregation of blood pressure has been studied in diverse ethnic groups living in distinct places, ranging from Polynesians to Middle Americans. A remarkably consistent level of correlation of around 0.2 between first-​degree relatives has been found, meaning that if the blood pressure of one member of the family deviates from the norm by + 10 mm Hg, the first-​degree rela- tive will deviate by + 2 mm Hg on average. Studies in children and infants suggest that the familial resemblance in blood pressure starts very early and is maintained throughout life. Attempts to partition the familial resemblance of blood pressure between shared genes and shared environment have been made through studies of adoptees and twins. In the Montreal Adoption Study, correlations between natural siblings compared with adoptive siblings, and between parents and natural children compared with parents and adopted children, were at least twice as great. Similarly, several studies have documented much higher correlations in blood pressure between monozygotic twins (0.55–​0.85) compared with dizygotic twins (0.25–​0.50), although the results from twin studies have to be viewed with caution as there is substantial evidence of ex- cess sharing of sociocultural environments by twin pairs, especially monozygotic. However, taken altogether the epidemiological data suggest that genetic factors account for about 40 to 45% of the population vari- ability of blood pressure, common household environment for about 10–​15%, and non​familial factors for the remaining 40 to 45%. Although determination of familial correlations of blood pressure provides an overall view of the impact of heredity in determining blood pressure, a more relevant measure of the importance of genetic factors in determining susceptibility to Study Any stroke Ohkubo, 2005 CV mortality Gasowski, 2008 Ohkubo, 2005 Note: Weights are from random effects analysis .5 1 2 Systolic: CV mortality Systolic: CV mortality Systolic: Stroke, fatal or nonfatal 1.04 (0.94, 1.15) 0.96 (0.79, 1.16) 1.04 (0.91, 1.19) Outcome HR (95% Cl) Abbreviations: CI = confidence interval; CV = cardiovascular; HF = heart failure; HR = hazard ratio; MI = myocardial infarction. Fig. 16.17.1.10  Risk for cardiovascular and mortality outcomes: systolic OBPM, adjusted for systolic 24 hr ABPM. Systolic OBPM adds no significant predictive capacity for cardiovascular and mortality outcomes when systolic 24 hr ABPM data is available. From Piper MA, et al. (2014). Screening for high blood pressure in adults: A systematic evidence review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 121. AHRQ Publication No. 13-​05194-​EF-​1. Rockville, MD: Agency for Healthcare Research and Quality. 16.17.1  Essential hypertension 3743 hypertension is relative risk. This is the ratio of the risk of an indi- vidual developing the condition given its presence in a first-​degree relative compared with the overall population risk. For relatively rare monogenetic conditions such as cystic fibrosis, relative risk is as high as 500. For common and complex polygenic disorders, relative risk tends to be much lower. For hypertension, relative risk estimates vary between 2 and 5 depending on the criteria used to define family history. Values are highest when both parents have hypertension before the age of 55 years. Genes involved in ‘essential hypertension’ Given the importance of hypertension as a risk factor for several cardiovascular diseases, a huge effort has been made in the last 20 years to identify genes where variants affect blood pressure and increase risk of hypertension or hypertension-​related end-​organ damage. Most of the studies have involved association analyses of so-​called candidate genes whose products are known or suspected to be involved in regulation of blood pressure. A smaller number have used linkage analyses in collections of affected sib pairs to iden- tify genetic loci in a systematic manner. Variants in a large number of genes, involving virtually all the main physiological systems af- fecting blood pressure, such as the renin–​angiotensin–​aldosterone system (Table 16.17.1.2) and the sympathetic system, have shown association with blood pressure in one or more studies. The findings to date suggest that the effect of any individual variant is likely to be modest. For example, a meta-​analysis of 32 case–​control studies (corresponding to 13 760 patients) of the methionine to threo- nine (M235T) polymorphism in the angiotensinogen gene, one of the most studied variants, found that the TT genotype conferred a 31% increased risk of hypertension compared with the MM geno- type. There is evidence that variants may act in an additive or epi- static fashion. For example, one prospective study of 678 initially normotensive subjects found that combined carriage of the angio- tensin converting enzyme DD genotype (at the insertion (I)/​deletion (D) polymorphism in the gene), the tryptophan (Trp) allele at codon 460 in the α-​adducin gene, and the CC genotype at the –​344C/​T promoter polymorphism in aldosterone synthase CC genotype, in- creased the risk of developing hypertension by 252% over a median follow-​up of 9.1 years compared with other genotypes. The Trp allele of α-​adducin, part of a ubiquitous α/​β heterodimeric cytoskeletal protein which affects sodium absorption in the kidney, has also been associated with greater blood-​pressure-​lowering response to thiazide diuretics. Also, in one study of hypertensive subjects diuretic therapy was associated with a lower risk of com- bined myocardial infarction or stroke than other antihypertensive therapies in carriers of this adducin variant. Such findings raise the prospect of better prediction and individually tailored treatment for hypertension. However, inconsistent findings between studies re- flecting, at least in part, poorly understood gene–​gene and gene–​ environment interactions, have hampered progress and significant clinical application so far. While genetic dissection of essential hypertension has proved challenging, the genetic basis of several monogenic forms of hyper- tension has been elucidated during the same period. The findings have provided novel and illuminating insights into the molecular regulation of blood pressure and particularly the role of the kidney and sodium homeostasis. See Chapter 16.17.4 for further discussion. Environmental and lifestyle influences on the development of hypertension The prevalence of hypertension can be powerfully influenced by local lifestyles and customs. There are several lines of evidence that support this conclusion, including studies of migrant populations, comparisons between different communities, prospective popula- tion studies, and randomized trials of lifestyle interventions. There is little doubt that the exploding prevalence of hypertension in eco- nomically developing regions reflects lifestyle changes, so-​called Westernization, more than anything else. Migrant studies Migration studies have provided powerful evidence to illustrate the importance of the local environment and lifestyle on the level of blood pressure and the prevalence of hypertension. Studies of mi- gration from rural to urban areas of Africa and Australia typically report marked increases in migrant blood pressure, body weight, and sodium intake, coincident with the adoption of more sedentary lifestyles, usually within months of migration. This latter point is important because it helps discriminate between powerful lifestyle factors and genetics—​that is, the changes in blood pressure are more nurture than nature. Population studies Studies of specific populations are often very informative. Populations in specific regions of the world (e.g. primitive rural populations such as the Yanomamo Indians of Brazil), do not show much evidence of an age-​related rise in blood pressure, suggesting that the progressive rise in SBP seen in urban populations is not inevitable. This could reflect genetic differences in vascular structure in discrete popula- tions, but most likely reflects influence of the local environment, and customs. Evidence in support of this conclusion comes from a classic study which compared Italian nuns with a control group of women from the same town. In the control group, blood pres- sure typically rose with age, whereas the nuns, from a similar genetic background, showed no such rise in blood pressure over 20 years of follow-​up. Thus, essential hypertension is undoubtedly a ‘disease of urbanization’, reflecting the impact of lifestyle factors. Specific lifestyle influences on blood pressure The most important lifestyle/​environmental influences on blood pressure are sodium intake, obesity, and alcohol intake. Early Table 16.17.1.2  Some genes with evidence for common variants influencing blood pressure or risk of hypertension Gene Role Angiotensinogen Substrate for renin Angiotensin converting enzyme Converts angiotensin I to angiotensin II Angiotensin receptor (type 1) Main vascular receptor for angiotensin II Aldosterone synthase Promotes synthesis of aldosterone α-​Adducin Cytoskeletal protein involved in sodium homeostasis G-​protein β3 subunit Involved in G-​protein signalling Reprinted from The Lancet, Vol. 349, Cusi D, et al. Polymorphisms of α-​adducin and salt sensitivity in patients with essential hypertension, pp. 1353–​7, Copyright 1997, with permission from Elsevier. section 16  Cardiovascular disorders 3744 nutritional deficiency may be important, and recent evidence sug- gests that psychosocial factors are likely to play some role in the development of essential hypertension. A  small socioeconomic gradient of blood pressure has also been observed. Interestingly, this gradient is negative for developed countries and positive for developing countries, which probably reflects the higher preva- lence of obesity and higher intakes of alcohol and salt among those of higher socioeconomic status in developing countries, com- pared to the reverse in more economically developed regions of the world. With regard to dietary influences on blood pressure, recent evidence (discussed later) suggests that diets rich in fruit and vegetables with low total and saturated fats may protect against hypertension. Low calcium intake, although associated with hypertension in population studies, is now considered to play no part in pathogenesis. Dietary salt intake There has been vigorous debate about the role of dietary salt in the genesis of hypertension. It is clear that sodium balance is a key factor determining the blood pressure of an individual. Moreover, it is intriguing that the various monogenic forms of hypertension that have been characterized by genetic studies all involve disturbances to renal sodium handling (see Chapter 16.17.4). Review of the evi- dence from population-​based studies and studies of dietary inter- vention support the hypothesis that dietary sodium intake has an important impact on blood pressure, and recent studies have also highlighted the importance of salt intake in the genesis of hyper- tension in children and the effectiveness of sodium restriction at reducing blood pressure. That said, there will clearly be some pa- tients whose blood pressure will be more sensitive to dietary so- dium intake than others. As indicated in Chapter 16.17.2, dietary sodium restriction forms part of the lifestyle interventions recom- mended by all guidelines as part of the treatment strategy for hyper- tension, and to delay the development of hypertension in people with prehypertension. A related but different question is whether dietary sodium restric- tion could influence not only blood pressure, but also cardiovascular disease outcomes. Recent studies suggest that this is likely to be the case. People allocated to a sodium-​restricted diet experienced a 30% lower incidence of cardiovascular events in the next 10–​15 years, irrespective of sex, ethnic origin, age, body mass, and blood pres- sure. As the people randomized into these studies were not hyper- tensive (blood pressure c.125/​85 mm Hg) it is conceivable that the benefits, impressive as they are, might have been even greater in a hypertensive population. These findings support current guideline recommendations and underline the importance of education and national health policies to reduce dietary sodium intake. Obesity and blood pressure Fat people generally have higher blood pressures than lean people. Fat arms can lead to overestimation of blood pressure when small cuffs are used, but the relation between body weight and blood pressure persists after correcting for arm circumference. Although body mass index (BMI) is often used to define obesity, visceral adi- posity seems to be more important in defining the relationship be- tween blood pressure and obesity. Visceral obesity also increases the likelihood of coexisting ‘metabolic syndrome’ (see ‘Hypertension and the metabolic syndrome’ later in the chapter) in people with hypertension. In untreated hypertensive people, fat tends to pref- erentially accumulate intra-​abdominally and intrathoracically, and the magnitude of the visceral adiposity is quantitatively related to the blood pressure. Importantly, the adiposity–​blood pressure link is observable from early childhood and a key predictor of the likeli- hood of developing overt hypertension. Recent analysis of longitudinal data from the Bogalusa Heart Study (Louisiana, USA) tracked the association between obesity in childhood and the risk of developing hypertension. Excess adi- posity was present in one-​fifth of those with normal blood pressure, one-​third of those with prehypertension, and more than one-​half of those with hypertension. Moreover, these associations were evident in children as young as 4 to 11 years, suggesting that the avoidance of obesity could markedly reduce the prevalence of hypertension in middle-​aged adults. In support of the strength of the association be- tween BMI and the risk of developing hypertension, in a study of 36 424 Israel Defense Forces employees (mean age c.35 years), BMI was the strongest predictor of prehypertension, with a 10–​15% increase in risk for every 1 kg/​m2 increase in BMI. The strong cause–​effect relationship between obesity and hypertension has been confirmed by intervention studies showing that weight reduction results in a fall in blood pressure. Alcohol intake and blood pressure Epidemiological data have consistently shown an association be- tween alcohol intake and blood pressure, and intervention trials confirm that blood pressure falls when alcohol is withdrawn from heavy drinkers. Analysis of data from the National Health and Nutrition Examination Survey (NHANES, 1999–​2000) showed that an alcohol intake of up to two drinks per day had no effect on blood pressure, which is consistent with previous reports that moderate drinking (2–​3 units daily) does not appear to exert a pressor effect. Heavier alcohol intakes, patterns of alcohol con- sumption, and the types of alcohol consumed can also influence blood pressure. Binge drinking can exert a pressor effect, but the mechanism accounting for the pressor effects of alcohol remain undefined. However, whatever the mechanism, data from the WHO Global Burden of Disease survey in 2000 attributed 16% of all hypertensive disease to alcohol. There has been controversy about whether moderate alcohol con- sumption might actually reduce cardiovascular disease risk. For example, in a prospective study of almost half a million men and women in the United States of America, the relative risk of death from cardiovascular disease in moderate drinkers compared with non​drinkers was 0.7 for men and 0.6 for women. However, it is im- portant to emphasize that these kinds of analyses run the risk of con- founding by an unmeasured disease effect modifier that tracks with different patterns of alcohol consumption. Sleep and blood pressure Blood pressure characteristically falls during sleep. A recent longitu- dinal analysis of the first NHANES (n = 4810) examined the impact of sleep duration on the risk of developing hypertension. This risk was increased by about twofold in adults in middle age who sleep for less than 5 h each night. Even after adjusting for obesity and dia- betes (the risk of which also increase with sleep deprivation), the risk remained around 1.6-​fold. There are some mechanisms that might account for this relationship: it may simply reflect a longer duration 16.17.1  Essential hypertension 3745 of sympathetic nervous system activation as a consequence of less time asleep and hence a higher 24 h average blood pressure load, giving rise to a higher risk of longer-​term cardiovascular structural damage and hence to sustained hypertension. There is also a clear association between obstructive sleep apnoea and hypertension. An apnoea–​hypopnoea index of 15 or more (i.e. breathing decreases or stops ≥15 times per hour of sleep) is associ- ated with a threefold increase in the risk of developing hyperten- sion. Moreover, in such patients continuous positive airway pressure can be effective in lowering both night-​time and, to a lesser extent, daytime blood pressure. Doctors should therefore consider sleep de- privation and obstructive sleep apnoea in their assessment of people developing hypertension. Psychosocial stress and blood pressure Blood pressure elevation is a well-​recognized acute stress response, and the act of taking the blood pressure can increase the SBP by up to 75 mm Hg in some patients. However, the role of chronic stress in the pathogenesis of hypertension has been difficult to assess, (1) be- cause of individual variability in the response to stress, (2) because it is difficult to objectively measure chronic stress, and (3) because stress can induce behavioural and lifestyle choices that could influ- ence blood pressure independently of stress per se. One measure of stress that appears to be robust in predicting blood pressure is an individual’s perception of control in their em- ployment. Using ABPM it has been shown that in men—​but not in women—​job strain is associated with an elevated blood pressure, both at work and also while at home and during sleep. Job strain in this context was defined as having a highly demanding job, but with the individual having little control over it. By contrast, people em- ployed in equally demanding jobs, but where they have an element of control over their work, have less stress, and less elevation of blood pressure. This effect of job strain on blood pressure is independent of other environmental and lifestyle influences, and is as strong as the impact of obesity. Early origins of hypertension—​impact of fetal and infant growth An association between low birth weight and risk of developing hypertension and premature cardiovascular disease has been recog- nized in many epidemiological studies. A large family-​based study explored the mechanisms underlying the associations of birth weight and gestational age with SBP measured at 17 to 19 years of age. This suggested that the inverse associations of birth weight and gesta- tional age with SBP are not explained by confounding resulting from a family’s socioeconomic status, or other factors that are shared by siblings. Variations in maternal metabolic or vascular health during pregnancy, or placental implantation and function, may explain these associations. Other studies have suggested that this relationship may relate to fetal programming of increased risk for hypertension via a reduction in nephron number, thereby increasing salt sensitivity. Another hypothesis has suggested that increased nutritional support to promote ‘catch-​up growth’ in the immediate postnatal period for babies who are small for gestational age could ameli- orate the risk for developing hypertension. This hypothesis was tested in a cohort of small for gestational age babies who had been fed with either a standard or nutrient-​enriched (28% more protein than standard) formula after birth. The enriched feed promoted faster postnatal weight gain and was associated with higher (not lower) blood pressure in later childhood, which does not sup- port the promotion of faster weight gain in infants born small for gestational age. Prehypertension predicts hypertension The presence of mild elevation in blood pressure for age pre- dicts the likelihood of developing hypertension. In a study of pa- tients with prehypertension (SBP 120–​139 mm Hg and/​or DBP 80–​89 mm Hg) the annual rate of progression to hypertension (≥140/​90  mm Hg) was greater than 15% per year despite life- style advice. In addition to an elevated blood pressure, people with prehypertension often also have the characteristic meta- bolic phenotype associated with hypertension (see later section in this chapter) and evidence of endothelial dysfunction and cardiovascular structural damage. This may explain why an ana- lysis of data from the Women’s Health Study in the United States of America, involving over 60 000 women followed for 7 years, showed that the presence of prehypertension was associated with an almost doubling in risk of any cardiovascular event—​including death, myocardial infarction, stroke, or hospitalization for heart failure—​when compared to those with normal blood pressure. Prehypertension was also more common in people with diabetes, when it was associated with an almost fourfold increase in risk of cardiovascular disease when compared to people without diabetes and normal blood pressure. Kidney, vascular structure, and neurohumoral control systems and the development of hypertension The maintenance of an adequate mean arterial pressure is funda- mental to life, hence there are many homeostatic mechanisms de- signed to achieve this despite fluctuations in posture, volume status, exercise, and other metabolic demands. There is considerable re- dundancy within these control systems, such that inhibition of one system is compensated for by increased activity of another, which is important when considering the design of effective strategies to lower blood pressure. Kidney The kidney is important for blood pressure regulation via two key mechanisms: (1) the regulation of sodium and volume homeostasis, and (2)  the regulation of the activity of the renin–​angiotensin–​ aldosterone system. The transplantation of a kidney from a genet- ically hypertensive rat into a normotensive control rat results in the development of hypertension in the recipient, and the converse is also true. In humans, significant renal impairment is almost invari- ably associated with hypertension, which in large part relates to dis- turbances in sodium handling, and as stated previously almost all of the single-​gene defects resulting in the development of hypertension involve disturbances in the renal tubular handling of sodium (see Chapter 16.17.4). The kidney is also intimately involved with sensing and setting of blood pressure via the activity of the renin–​angiotensin–​aldosterone system. Reduced renal perfusion pressure (e.g. in renal artery sten- osis) results in activation of the renin–​angiotensin–​aldosterone system, which in turn elevates blood pressure to try and restore renal perfusion pressure via several mechanisms (see later in this section of this chapter). section 16  Cardiovascular disorders 3746 Structure of small arteries A characteristic finding in essential hypertension is an inappropriate increase in peripheral vascular resistance relative to the cardiac output. The main site of this resistance is small arteries (arterioles), which undergo inward eutrophic remodelling that is characterized by an increase in their media/​lumen ratio. These changes result from vascular remodelling (i.e. rearrangement of existing material in the vascular media around a smaller lumen), and there is often also evidence of some hypertrophy and/​or hyperplasia of the resi- dent myocytes. There has been much debate about whether these changes in small-​artery structure antedate and thus contribute to the develop- ment of hypertension, and/​or whether they are the consequence of an elevated blood pressure and the trophic effects of neurohumoral activation (i.e. sympathetic nervous system and the renin–​ angiotensin–​aldosterone system) in people with hypertension. Whatever the mechanism, studies of small arteries isolated from bi- opsies in humans, or retinal vascular structural changes (especially narrowing), suggest that the magnitude of structural changes of the small arteries is strongly predictive of future cardiovascular events. It is also predictive of the likelihood and magnitude of structural changes elsewhere (i.e. left ventricular hypertrophy). Structure of large arteries The functional integrity of large conduit arteries such as the aorta also influences the development of hypertension, especially sys- tolic hypertension. The pulsatile nature of blood flow exerts chronic cyclical stress on the walls of these arteries, and over time this re- sults in deterioration in their elastic properties as a consequence of thinning, splitting, and fragmentation of the elastin fibres within the media. This process is accelerated in people with hypertension, resulting in progressive dilatation in aortic root diameter and ar- terial stiffening. In turn, this reduction in arterial compliance in- creases pulse wave velocity, increases systolic pressure and central aortic pulse pressure, and reduces diastolic pressure. This explains the very high prevalence of systolic hypertension with advancing age (see Fig. 16.17.1.2) and the progressive age-​related disappearance of diastolic hypertension. The process of age-​related stiffening of the aorta is accelerated by post-​translational modification of vascular wall proteins such as col- lagen by the formation of advanced glycation end products (AGEs). AGE formation is accelerated in people with diabetes, thereby ex- plaining the earlier onset of isolated systolic hypertension in patients with this condition. It is conceivable that if aortic function and es- pecially its elasticity were genetically determined, then accelerated degeneration of aortic elastic function could also be a factor in the development of systolic hypertension in younger people. Aside from aortic function, there is current debate about whether the diameter of the aortic root is causally related to the likelihood of developing hypertension. This has been prompted by recent observations that central aortic pulse pressure appears to be inversely related to aortic root diameter, prompting speculation that a smaller effective root diameter might also contribute to the development of hypertension. Endothelium The endothelium plays a key role in the regulation of vascular tone. Endothelial cells form nitric oxide (NO) from L-​arginine via the activity of nitric oxide synthase (eNOS), which is tonically activated by shear stress and relaxes vascular tone. NO also inhibits platelet aggregation and inhibits vascular smooth muscle cell proliferation. Hypertension, even in its earliest stages, has been associated with ‘endothelial dysfunction’, usually by demonstrating a reduction in forearm blood flow in response to agents that promote NO release such as acetyl choline or its mimetics. NO production has also been shown to be decreased in people with hypertension. It is not clear whether endothelial dysfunction and decreased NO production are a cause or consequence of an elevated blood pres- sure, but the latter seems most likely. Whatever the mechanism, a reduction in NO production would be expected to increase vascular tone and may also contribute to vascular proliferation and remod- elling (see earlier). NO donors such as glyceryl trinitrate (GTN) are very effective at lowering blood pressure in the acute setting, and are especially effective at reducing central aortic pressure. However, the use of NO donors to lower blood pressure outside of the acute setting has been bedevilled by their short duration of action and the fact that tolerance to them develops rapidly. The actions of some commonly used antihypertensive drugs, angiotensin converting en- zyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), have in part been attributed to their local potentiation of NO. The endothelium also produces a powerful vasoconstrictor, endothelin. This seems less important in the chronic regulation of blood pressure, even though inhibitors of endothelin have been shown to lower it. The biology and actions of NO and endothelin are discussed in greater detail elsewhere (Chapter 16.1.1). Oxidative stress Numerous studies in experimental animals and humans have in- dicated that hypertension is associated with markers of increased systemic oxidative stress (i.e. the increased production of oxygen free radicals such as superoxide and hydrogen peroxide). These are short-​lived reactive species that have the potential to cause cellular damage via oxidation of proteins, lipids, and DNA. They also react with and inactivate NO, thereby providing a mechanism for reduced NO levels and increased vascular tone. The mechanism for increased oxidative stress in hypertension is not known, but studies have sug- gested that this may in part relate to activation of NADH/​NADPH oxidase within vascular cells. Of interest, this vascular oxidase is ac- tivated by angiotensin II, which provides a link between the renin–​ angiotensin–​aldosterone system and endothelial dysfunction and may contribute to the pressor effect of angiotensin II. Renin–​angiotensin–​aldosterone system The renin–​angiotensin–​aldosterone system, whose main ef- fector molecules are angiotensin II and aldosterone, plays an important role in the regulation of blood pressure. Angiotensin II is produced by an enzymatic cascade (Fig. 16.17.1.11). Renin synthesis—​the rate-​limiting step for the production of angio- tensin II—​may take place in several tissues apart from the kidney, including the adrenal, heart, the blood vessel wall, and brain. In the kidney renin is produced by the juxtaglomerular apparatus in response to falls in renal perfusion pressure, sodium depletion, and increased sympathetic nerve activity. However, the renin–​ angiotensin–​aldosterone system is active both in the circulation and locally within tissues. 16.17.1  Essential hypertension 3747 The two principle angiotensin receptors are AT1 and AT2. The major actions of angiotensin II are via the AT1 receptor, which is the target for the ARB class of blood-​pressure-​lowering agents. The AT2 receptor is less ubiquitously expressed than the AT1 receptor, is markedly up-​regulated during tissue repair, and its activation produces effects that appear to oppose those of AT1 activation, sug- gesting that the two receptors may operate a yin–​yang relationship. Angiotensin II elevates blood pressure by several different mech- anisms: (1) it is a direct pressor agent promoting vasoconstriction, and it also increases superoxide production by the endothelium, which reduces NO availability (see earlier); (2) it increases sodium reabsorption by the kidney via direct tubular effects and via simu- lation of aldosterone release from the adrenal cortex; (3) it can have trophic effects on vascular cell growth and has been implicated in the small-​artery remodelling process that results in increased per- ipheral vascular resistance; (4) it acts centrally on AT1 receptors in the nucleus tractus solitarius (NTS) to desensitize the afferent com- ponent of the baroreceptor reflex. In addition to these pressor actions, angiotensin II has also been implicated in the development of end-​organ damage through (1) trophic effects on the myocardium, resulting in left ventricular hypertrophy; (2) the development of glomerular hypertension, al- buminuria, and interstitial fibrosis, leading to chronic renal disease; (3) pro-​oxidant effects, contributing to the development of athero- sclerosis. Consequently, the renin–​angiotensin–​aldosterone system has become a popular target for drug therapy to lower blood pres- sure and limit its cardiovascular consequences. Aldosterone is the other effector molecule of the renin–​ angiotensin–​aldosterone system. It is produced by the adrenal cortex in response to many stimuli, including sodium and volume depletion, angiotensin II, excess potassium intake, trauma, and stress. It acts on the distal tubule of the kidney to promote sodium absorption in exchange for potassium. An inappropriate increase in production of aldosterone can lead to the development of hyperten- sion (e.g. Conn’s syndrome and adrenal hyperplasia), as discussed in Chapter 16.17.3. The specific role of the renin–​angiotensin–​aldosterone system in the development of essential hypertension remains unclear, al- though therapeutic agents that inhibit this system have proved to be very effective treatments. Plasma renin levels vary widely in es- sential hypertension, from low (30%), to normal (50%), to high (20%): they are inversely related to sodium loading and tend to de- cline with ageing. Thus, patients with low renin levels are gener- ally older and have volume-​dependent hypertension. Hypertensive patients with higher renin levels are generally younger, and their increased renin may reflect increased levels of sympathetic nervous system activity (see next section). Black people at any age have a high prevalence of low-​renin hypertension, suggesting a primary role for sodium retention in the pathogenesis of their hyperten- sion. Although the baseline renin level is rarely measured in rou- tine clinical practice, age has been used as a surrogate in the recent hypertension guidelines in the United Kingdom for predicting the most effective initial therapy in people with essential hypertension. If plasma renin levels are measured, it is important to recognize that they can be affected by concomitant blood-​pressure-​lowering therapy, with almost all commonly used classes of antihypertensive drugs increasing plasma renin, the main exception being β-​blockers which suppress it. Sympathetic nervous system The sympathetic nervous system is involved in the acute and chronic regulation of blood pressure. It is known to be involved in the regu- lation of arteriolar resistance, cardiac output, and volume regulation, renin release by the kidney, and catecholamine and mineralocorticoid release by the adrenal gland. It is by necessity a complex system that in- volves (1) vasomotor control centres within the brain; (2) the periph- eral nervous system providing efferent and afferent signals; and (3) the adrenal medulla. Several nuclei within the central nervous system are involved in the regulation of blood pressure, with control integrated in the rostral ventrolateral nucleus of the medulla oblongata—​the vaso- motor centre—​that is particularly influenced by the nucleus tractus solitarius (NTS) which receives its input from peripheral afferents such as baroreceptor activation in the aortic arch, carotid sinus, and cardiac ventricles and atria. The NTS also receives excitatory and in- hibitory inputs from other regions of the brain (e.g. the brain stem and cortex), and its outputs to the vasomotor centre tend to inhibit sym- pathetic outflow and thus buffer acute rises in blood pressure—​the baroreceptor reflex arc. Another important influence on the rostral ventrolateral nucleus–​NTS complex is the action of angiotensin II. The area postrema in the floor of the fourth ventricle does not have a blood–​brain barrier, which allows circulating angiotensin II to blunt the inhibitory effect of the NTS on the rostral ventrolateral nucleus, thereby increasing central sympathetic outflow. The various inputs and outputs are summarized in Fig. 16.17.1.12. Environmental and behavioural impacts on blood pressure are pri- marily coordinated via the hypothalamus. The posterolateral hypo- thalamus is responsible for the classical ‘fight or flight’ response, and lesions in this area reduce blood pressure. By contrast, lesions in the anterior hypothalamus can substantially increase blood pressure. The peripheral vascular α-​adrenergic system (α1 receptors) is also important in maintaining enhanced vascular resistance in Angiotensinogen Renin ACE Angiotensin II Angiotensin I AT-1 receptor AT-n receptor Chymase Cathepsin-G tonin t-PA Fig. 16.17.1.11  The renin–​angiotensin system. The enzyme renin cleaves its substrate angiotensinogen to generate the decapeptide angiotensin I, which is then cleaved by angiotensin converting enzyme (ACE) to generate angiotensin II, which binds to a family of specific angiotensin receptors. Its main effect on blood pressure regulation is via the AT-​1 receptor, the functions of other angiotensin receptors (AT-​ n) being poorly defined. Angiotensin II can also be generated by other proteolytic enzyme systems such as chymases and tissue plasminogen activators (t-​PA). These pathways may be important for local angiotensin II generation in disease. section 16  Cardiovascular disorders 3748 hypertension, with some studies suggesting that peripheral α-​adrenergic responsiveness might be especially enhanced in black people with hypertension. The importance of the sympathetic nervous system in the regu- lation of blood pressure is beyond question, but a key unanswered question is whether disturbances to the regulation of the sympa- thetic nervous system play a major role in the initiation and main- tenance of chronic essential hypertension. Most surveys of younger people with prehypertension or grade 1 hypertension indicate the presence of an elevated heart rate, indicative of sympathetic nervous system activation. Other studies have reported elevated circulating catecholamine levels in young patients with prehypertension, and that such elevations predict the risk of developing hypertension. Further studies have used radiolabelled nor-​epinephrine (noradren- aline) to demonstrate enhanced ‘spillover’ indicative of enhanced sympathetic nervous system activity, or microneurography to dem- onstrate increased sympathetic nervous system activity in young hypertensives. It must be emphasized, however, that simple demon- stration of enhanced activity of a particular system at a single snap- shot in time cannot be taken as evidence of a direct causal role: the critical question is whether the level of activity is appropriate or inappropriate in the context of the overall integrated physiological regulation of blood pressure. In this regard, a full understanding of the role of the sympathetic nervous system in the genesis of essential hypertension in humans has been hindered by the complexity of the system and the rather crude instruments used to evaluate the system in vivo. Some remain to be convinced of the importance of the sym- pathetic nervous system in the genesis of essential hypertension, while others argue that given the importance of the sympathetic nervous system in regulating blood pressure, then—​even if essen- tial hypertension has an unrelated aetiology—​abnormal activity of the sympathetic nervous system must be permissive in maintaining blood pressure elevation. Sympathetic nervous system, obesity, and the metabolic syndrome Obesity is associated with increased muscle sympathetic nerve ac- tivity, and increased sympathetic nervous system activity has been implicated in the pathogenesis of obesity-​related hypertension. Hypertension is often associated with features of a metabolic syn- drome (see ‘Hypertension and the metabolic syndrome’ in the next section) characterized by insulin resistance, dyslipidaemia, and im- paired glucose tolerance. Increased sympathetic nervous system ac- tivity has also been implicated in the development of this syndrome, and drugs therapies that reduce central sympathetic outflow or block α1 adrenergic receptors improve insulin sensitivity and fea- tures of the metabolic syndrome. Natriuretic peptides The natriuretic peptide system—​including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-​type natriuretic pep- tide (CNP)—​is an endocrine system that is involved in the regulation of salt and water homeostasis. ANP is secreted primarily by the right atrium in response to atrial wall stretch. BNP was initially identified in the brain, hence the name, but is predominantly produced in the ventricles in response to stretch. CNP is produced by vascular endo- thelial cells and in the kidney. These natriuretic peptides bind to spe- cific cell membrane receptors on target tissues and induce natriuresis and diuresis; they also decrease renin secretion and aldosterone, and induce vasodilatation and a modest fall in blood pressure. These physiological actions suggested a potential role for reduced natriuretic peptide levels or action in the pathogenesis of hypertension, hence these have been measured in patients with essential hypertension. The results have been conflicting, with no clear pattern emerging. This in part reflects the fact that levels of natriuretic peptides, especially BNP, will be elevated in people with early or established left ventricular dys- function and other hypertension-​related complications, but it does not preclude a future role for drugs that augment the activity of natri- uretic peptides in the clinical management of hypertension. The hypertensive phenotype and target organ damage in hypertension Although blood pressure measurement is used to define hyper- tension, hypertension is more than just blood pressure. Essential hypertension is commonly associated with metabolic disturbances and multisystem structural damage that conspire to enhance car- diovascular risk beyond that which can be attributed to blood pressure alone. Hypertension and the metabolic syndrome Few people with essential hypertension simply have an elevated blood pressure: many also have associated disturbances in metab- olism which are typical of the ‘insulin resistance phenotype’, notably predisposition to impaired glucose tolerance, elevated triglyceride levels, reduced HDL-​cholesterol values, and hyperuricaemia. These metabolic disturbances appear to precede and may even predict the likelihood of developing hypertension: in large prospective popu- lation studies in the United States of America and Europe the de- velopment of hypertension could be predicted by a person’s initial Inhibitory Excitatory Arterial baroreceptors Vagal afferents NTS Vagal efferents Ach NE Vagal/Sympathetic neurons Emotion central command Hypothalamus supraoptic N. paraventricular N. Cardiopulmonary receptors Ergoreceptors Renal afferents Fig. 16.17.1.12  Organization of the nervous system control of blood pressure. Peripheral inhibitory and excitatory inputs are integrated in the nucleus tractus solitarius (NTS), whose central inputs are integrated via the hypothalamus. The NTS regulates sympathetic outflow via the rostral centrolateral nuclei of the medulla oblongata. The balance of sympathetic and vagal outflow influences cardiac output, heart rate, vasoconstrictor tone, renin release, and renal blood flow, also catecholamine and mineralocorticoid release. Adapted from Abboud FM (1982). The sympathetic system in hypertension. State-​of-​ the-​art review. Hypertension, 4(Suppl II), 208–​25. 16.17.1  Essential hypertension 3749 metabolic profile. Even in those with optimal initial blood pressure levels (<120/​80 mm Hg), increasing obesity and the aforementioned abnormal lipid profile were major predictors of the development of hypertension. With regard to obesity, the accumulation of visceral fat (i.e. ab- dominal obesity) is most strongly associated with hypertension and attendant metabolic disturbances. Indeed, the link between visceral fat content and indices of insulin resistance and metabolic syndrome is demonstrable even in lean patients when MRI is used to quantify visceral fat. Moreover, the link between visceral adiposity and blood pressure is present from early childhood and explains the approxi- mately twofold increase in risk of developing type 2 diabetes in pa- tients with essential hypertension. The frequent coexistence of obesity with other features of meta- bolic syndrome in patients with hypertension underscores the need to view hypertension as more than just blood pressure in the context of cardiovascular disease risk management, and it points to the im- portance of early lifestyle interventions as the foundation for pre- vention and treatment. Vascular structural changes and atherosclerosis Aorta and large arteries The arterial system is designed to convert the pulsatile flow gen- erated by cardiac contraction into steady flow in the capillary bed. Thus, the aorta is both a conduit and an elastic reservoir designed to buffer pulsatile blood flow. Over time, recurrent pulsatile stress pro- duces uncoiling, disruption, and calcification of elastic fibres within the aortic wall. At the same time, relatively inelastic collagen is in- creased and made more rigid by post-​translational modification by the accumulation of AGEs. Such age-​related processes cause loss of the normal elastic reservoir function of the aorta and other large ar- teries. These changes are accelerated by the presence of high blood pressure and hence occur at an earlier age in hypertensive patients. In addition to these structural changes, elevation in pressure it- self contributes to a loss of large-​artery compliance and buffering be- cause, as pressure increases, the elastic fibres become fully stretched, thereby transferring load-​bearing function to the relatively inelastic collagen fibres. As a result of these changes, the pressure wave gener- ated by left ventricular contraction is no longer buffered by the aorta and proximal large arteries, but instead is transmitted into the arterial tree with greater amplitude. This is manifested clinically as increased brachial pulse pressure, with higher systolic and lower diastolic pres- sures. More importantly, the resulting increase in pulse wave velocity and changes in arterial haemodynamics contribute to an elevation in central aortic systolic and pulse pressures and an increase in ven- tricular loading conditions—​changes that cannot always be appreci- ated by measurement of the brachial blood pressure alone. Increased large-​artery stiffening and reduced compliance also re- duces the sensitivity of the carotid and aortic baroceptors to stretch, which blunts the normal rapid buffering of changes in blood pres- sure. As a result, blood pressure becomes more labile and the circu- latory adaptation to acute postural changes may become impaired, producing symptoms of postural dizziness in older people. Resistance vessels The characteristic structural change in the smaller arteries and ar- terioles of hypertensive patients is an increase in wall/​lumen ratio, the characteristics and pathogenesis of which have been discussed earlier. These changes have important functional consequences. The vessels can still dilate in response to stimuli such as warmth or drugs, but maximal vasodilatation is reduced. The converse is also true; responsiveness to pressor agents or stimuli becomes enhanced. These structural changes in resistance vessels also contribute to the characteristic increase in vascular resistance in hypertension, and they render vital organs more susceptible to ischaemic damage at the small-​vessel level (e.g. small-​vessel ischaemic brain damage). Atheroma in hypertension Hypertension is associated with an increased risk of generalized ath- erosclerotic disease. This is likely to result from an interplay of many factors, including pressure and haemodynamic stress, metabolic dis- turbances, inflammatory and oxidative stresses, endothelial disturb- ances, and neurohumoral activation. The overwhelming importance of haemodynamic factors and pressure is illustrated by (1) the predilection for atheroma to develop at sites of increased haemodynamic stress within the circulation (e.g. arterial bifurcations); and (2) the fact that atheroma is rarely observed in a low-​pressure circulation (e.g. the pulmonary circu- lation or venous system, unless pulmonary hypertension develops, or veins are grafted into the arterial circulation). Two recent studies have been important in establishing a direct link between pressure and the development and/​or regression of atherosclerosis. Using a mouse genetically prone to develop atheroma, the placement of a suprarenal clip was used to generate aortic constriction (a high renin state) and hypertension. The atheromatous plaque area was greatly increased by the presence of hypertension and was not obviously ameliorated by administration of an ARB. This study therefore sug- gested that pressure and not activation of the renin–​angiotensin–​ aldosterone system was the main cause of accelerated atheroma in this model. Further data from a human study that used intravascular ultrasonography to quantify changes in coronary atheroma sug- gested that the patients’ in-​trial blood pressure determined whether there was progression, stabilization, or regression of atheromatous plaque over a 2-​year period. Thus, a large body of evidence supports the hypothesis that blood pressure plays a key role in the initiation and progression of atheroma in humans. It is also likely that haemo- dynamic stress plays an important role in the process of plaque rup- ture, as well as the plaque burden. The heart in hypertension Left ventricular hypertrophy is a classic feature of untreated, or in- adequately treated, long-​standing hypertension. In this regard it can be considered the hypertensive equivalent of the glycated HbA1c for patients with diabetes: it is an index of the prevailing blood pres- sure load. Left ventricular hypertrophy is demonstrable in about 50% of untreated hypertensive patients using echocardiography, but only 5 to 10% when using conventional ECG criteria (Sokolov–​ Lyon ­criteria or Cornell voltage duration product). Pressure load on the left ventricle is unquestionably the most important patho- genic factor, with ambulatory monitoring blood pressure meas- urements much better correlated with left ventricular hypertrophy than clinic measurements of pressure. Pressure load is compounded by stiffening of the aorta with ageing, but neurohumoral factors, including the activity of the sympathetic nervous system and renin–​ angiotensin–​aldosterone system, also appear to be important. section 16  Cardiovascular disorders 3750 Left ventricular hypertrophy is a very potent predictor of pre- mature cardiovascular disease and death. Its presence on the ECG, especially when associated with a characteristic ‘strain pattern’ (see Chapter 16.3.1), is associated with a two-​to threefold increase in risk of cardiovascular disease morbidity and mortality, including a marked increased risk of stroke and heart failure. Using echocardi- ography to characterize left ventricular hypertrophy, recent studies suggest that concentric hypertrophy carries a worse prognosis that eccentric hypertrophy (Fig. 16.17.1.13). Pathological features There are two pathological features of the cardiac changes in hyper- tension that culminate in the development of left ventricular hyper- trophy: an increase in size of cardiomyocytes, which increases the muscular mass of the left ventricle, and an increase in extracellular matrix deposition within the ventricle, which contributes to an in- crease in wall stiffness. The increase in left ventricular mass and stiff- ness manifests initially as impaired relaxation during diastole, which is often detectable on echocardiography in hypertensive patients at diagnosis, even before the left ventricular mass is sufficiently in- creased to be classified as indicating hypertrophy. Over time, in un- treated or poorly treated patients, cardiac changes will progress to impaired systolic function and ultimately overt heart failure. Myocardial ischaemia In addition to impaired cardiac diastolic and systolic function, the hypertensive heart is also predisposed to myocardial ischaemia be- cause of (1) increased myocardial oxygen consumption due to in- creased cardiac afterload; (2) impaired endocardial blood flow due to the structural and functional changes in small arteries just de- scribed; (3) an increase in the systolic time interval and reduced diastolic filling time and pressures due to large-​artery stiffening and impaired ventricular–​vascular coupling, and (4) increased risk of coronary atheroma in people with hypertension. Cardiac arrhythmias The aforementioned structural and ischaemic changes also predispose to an increased prevalence of simple and complex ventricular arrhyth- mias in people with hypertensive left ventricular hypertrophy. In add- ition, it has recently been recognized that atrial fibrillation is much commoner in older people with hypertension. Moreover, in hyperten- sive patients with left ventricular hypertrophy the risk of developing atrial fibrillation is at least twofold greater, and increases further as a function of advancing age, increased systolic pressure, increased left ventricular mass, and increased left atrial diameter. The combination of these latter two cardiac features is a particularly potent predictor of the risk of developing atrial fibrillation in hypertensive patients. Regression of left ventricular hypertrophy Recent clinical studies suggest that inhibition of the renin–​angiotensin–​ aldosterone system is particularly effective at regressing left ven- tricular hypertrophy. This is important, because there is now clear evidence that regression of the ECG manifestations of left ventricular hypertrophy is associated with dramatically improved prognosis for people with hypertension (50% reduction in risk of cardiovascular death over 5 years). Moreover, blockade of the renin–​angiotensin–​ aldosterone system may be particularly effective at reducing the risk of developing atrial fibrillation in people with hypertensive left ven- tricular hypertrophy. Consensus in guidelines is that lowering blood pressure is of paramount importance for patients with left ventricular hypertrophy, but that effective renin–​angiotensin–​aldosterone system blockade should also be part of the treatment strategy. The brain in hypertension Hypertension is the single most important risk factor for stroke and is increasingly recognized as a major factor contributing to the rate of cognitive decline in later life. All categories of stroke—​ischaemic (large and small vessel), haemorrhagic, and embolic—​are increased in hypertensive patients. Cerebral (atherothrombotic) infarction Infarction accounts for about 80% of the strokes suffered by patients with hypertension. It is usually attributable to atheroma of one of the larger cerebral arteries (usually the middle cerebral artery), or to small-​vessel (lacunar) infarction. Although poorly characterized, it is likely that embolic stroke is also more common in people with hypertension, especially those with left ventricular hypertrophy, be- cause of the increased likelihood of paroxysmal or sustained atrial fibrillation on a background of increased left atrial size. Intracerebral haemorrhage This accounts for 10–​15% of strokes in patients with hypertension and is usually the result of rupture of a small intracerebral degenera- tive microaneurysm (Charcot–​Bouchard aneurysm). These lesions develop in the small (<200 µm diameter) perforating arteries in the region of the basal ganglia, thalamus, and internal capsule. Hyaline degeneration (lipohyalinosis) occurs in the aneurysmal wall, with a defect in the media at the neck of the aneurysm. The incidence of Charcot–​Bouchard aneurysms is closely correlated with age and blood pressure, the two factors acting additively so that lesions are rarely if ever seen in younger normotensive people. The relation- ship between blood pressure and haemorrhagic stroke appears to be steeper in people of Chinese/​East Asian origin. Mean LVMI (g/m2) 149±32 79±9 75±11 141±21 104±8 104±7 RWT <0.44 CV events (%) 1 tertile (LVMI < 91 g/m2) 2 tertile (LVMI 91–117 g/m2) 3 tertile (LVMI >117 g/m2) 40 30 20 10 0 RWT ≥0.44 Fig. 16.17.1.13  Concentric vs. eccentric left ventricular hypertrophy and cardiovascular risk in hypertensive patients. All patients had echocardiographic evidence of left ventricular hypertrophy (LVH). Concentric LVH was defined as a relative wall thickness (RWT) greater than or equal to 0.44. Cardiovascular events increased progressively per LVH tertile at follow-​up, and were greater in each tertile of LVH in those with concentric LVH (shaded bars). CV, cardiovascular; LVMI, left ventricular mass index. Data from Muiesan ML, et al. (2004). Hypertension, 43, 731–​8. 16.17.1  Essential hypertension 3751 The remaining strokes in hypertensive patients are due to sub- arachnoid haemorrhage. Transient ischaemic attacks due to dis- ease of extracranial vessels are also more frequent in hypertensive subjects. Hypertension and cognitive function Hypertension is increasingly recognized as an important cause of de- mentia, with increased blood pressure in mid-​life associated with an increased risk of dementia in later life. Cognitive decline is related to diffuse small-​vessel cerebrovascular disease in untreated hyperten- sion and in older patients. Functional imaging studies have shown relative reductions in blood flow in parietal and fore-​brain areas in hypertensive patients during memory tasks and areas of cortical and subcortical hypometabolism. More advanced vascular disease gives rise to multiple, punctate, hyperintense white matter lesions on MRI scanning. These are due to focal ischaemia, either as a re- sult of lipohyalinosis or microatheromatous disease, tortuosity, and narrowing of the perforating arteries. All degrees of impairment of cognitive performance may occur as a result of these lesions, ranging from effects only detectable with sensitive psychometric testing, to lacunar strokes and Binswanger’s disease. Hypertensive encephalopathy The brain is protected from wide fluctuations in blood pressure by blood flow autoregulation (i.e. the intrinsic capacity of the cerebral vessels to constrict in the face of increased pressure and dilate in the face of decreased pressure to maintain a constant flow). Resistance vessel remodelling and hypertrophy may enhance protection against higher perfusion pressures, thereby extending the upper limits of the autoregulatory range in long-​standing hypertension. However, such remodelling may also impair the autoregulation of blood flow when faced with decreased pressure because of impaired capacity of hyper- trophied resistance vessels to dilate, thereby predisposing to small-​ vessel ischaemia. In severe hypertension focal areas of vasodilatation can develop if blood pressure rises above the autoregulatory range, resulting in localized perivascular oedema and fibrinoid necrosis. Focal haemorrhages, ischaemia, and infarction may result, giving rise to the clinical picture of encephalopathy (see Chapter 16.17.5). The kidney in hypertension Patients with renal disease often have hypertension, and people with hypertension can develop renal disease. The age-​related decline in GFR is more rapid in people with essential hypertension. However, GFR is usually well preserved throughout life in patients with mild to moderate essential hypertension, hence the development of end-​ stage renal disease in such patients is unusual in the absence of any other renal lesions. The decline in GFR, when it does occur, is due to progressive glomerulosclerosis, most likely driven by raised intraglomerular capillary pressures, which also explain the increased urinary albumin excretion rates in these patients. Increased urinary albumin excretion rate has in turn been linked to increased likeli- hood of more widespread endothelial/​vascular dysfunction and an increased risk of premature cardiovascular disease and death, hence the kidney—​and urinary albumin excretion rate in particular—​has been proposed as the earliest clinical indicator of significant pres- sure mediated vascular injury. Significant hypertension-​induced glomerulosclerosis is much more likely in two settings (1) severe and accelerated hypertension, resulting in so-​called hypertensive nephropathy; and (2) in the pres- ence of intrinsic renal disease (i.e. due to diabetes or glomeruloneph- ritis). Effective control of blood pressure is of substantial importance in retarding the progression of renal impairment in these settings. Another important association between hypertension and renal disease is atheromatous renal vascular disease. In these patients, hypertension is usually moderate to severe, and the condition is characteristically associated with a progressive ischaemic nephrop- athy due either to proximal renal artery (often ostial) disease and/​or smaller branch artery disease. It may be associated with small-​vessel cholesterol embolization, the affected patients usually being older, with evidence of widespread atheromatous disease. The eye in hypertension The findings in the retina of patients with hypertension range from mild generalized retinal–​arteriolar narrowing, through to the devel- opment of more significant changes of flame-​shaped or blot-​shaped haemorrhages, cottonwool spots, hard exudates, microaneurysms, or a combination of all of these factors. Swelling of the optic disc can also be seen. The classification of these changes and their patho- physiology and significance are discussed in Chapter 16.17.2. The evolution of hypertensive injury—​from physiology to philosophy The process of hypertensive injury to target organs evolves silently over many years, the magnitude and rate of progression determined largely by the level of blood pressure, but also by individual sus- ceptibility (Fig. 16.17.1.14). In the prehypertensive phase, patients may already have disturbances in blood pressure regulation (i.e. re- sponses to pressor stimuli, visceral obesity, and subtle features of the metabolic syndrome). The injurious process and metabolic disturb- ances then progress though a silent phase, often lasting many years, during which there is subtle damage to many target organs as just mentioned (i.e. vascular wall, myocardium, brain, kidney, and eye). This subtle early damage is potentially preventable and/​or revers- ible, but progresses if untreated to more sinister markers of more advanced damage—​the so-​called intermediate or surrogate disease markers that can be detected in many cases by simple tests such as the ECG, or urinalysis for albumin or protein. Untreated or poorly treated, this progressive hypertension-​mediated damage culmin- ates in overt cardiovascular, renal, and cerebrovascular disease and clinical events—​the so-​called ‘hard clinical end-​points’ that form the evidence base for treatment guidelines. Alongside, the meta- bolic syndrome is evolving, increasing the risk of developing dia- betes and magnifying the cardiovascular risk burden associated with the blood pressure elevation. Along the way, the conduit arteries are stiffening with damage and age, and the systolic pressure is rising and becoming more difficult to treat. Current treatment guidelines have been developed from an evi- dence base relating to changes in hard clinical end-​points derived from studies in elderly patients at the end of the hypertensive dis- ease process. Somehow, we have to try to translate that evidence into strategies for treating younger patients at the start of the disease process when their risk of clinical events is low. Future treatment strategies must surely focus on preventing the evolution of the silent disease process, rather than simply battling with its consequences. section 16  Cardiovascular disorders 3752 To meet that challenge, we need more and better studies of younger patients with hypertension to better characterize the impact of treat- ments on the evolution of hypertensive disease, and to determine the robustness of the associated intermediate or surrogate disease markers at predicting treatment benefit. FURTHER READING Epidemiology Asia Pacific Cohort Studies Collaboration (APCSC) (2005). Joint effects of systolic blood pressure and serum cholesterol on car- diovascular disease in the Asia Pacific region. Circulation, 112, 3384–​90. Chobanian AV (2007). Isolated systolic hypertension in the elderly. N Engl J Med, 357, 789–​96. Dolan E, et  al. (2005). Superiority of ambulatory over clinic blood pressure measurement in predicting mortality: the Dublin outcome study. Hypertension, 46, 156–​61. Ezzati M, et al. (2002). Selected major risk factors and global and re- gional burden of disease. Lancet, 360, 1347–​60. Franklin SS, et  al. (1997). Hemodynamic patterns of age-​related changes in blood pressure: the Framingham Heart Study. Circulation, 96, 308–​15. Lawes CMM, et al. (2006). Blood pressure and the global burden of disease 2000. Part I: estimates of blood pressure levels. J Hypertens, 24, 413–​22. Lawes CMM, et al. (2008). Global burden of blood pressure related disease, 2001. Lancet, 371, 1513–​18. Lewington S, et  al. (2002). Age-​specific relevance of usual blood pressure to vascular mortality: a meta-​analysis of individual data for one million adults in 61 prospective studies. Lancet, 360, 1903–​13. MacMahon S, Meal B, Rodgers A (2005). Hypertension—​time to move on. Lancet, 365, 1108–​9. National Clinical Guideline Centre (2011). Hypertension—​the clinical management of primary hypertension in adults. Clinical guideline. http://​www.nice.org.uk/​guidance/​cg127 Piper MA, et al. (2014). Screening for high blood pressure in adults: a systematic evidence review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 121. AHRQ Publication No. 13-​05194-​EF-​1. Agency for Healthcare Research and Quality, Rockville, MD. Vasan RS, et al. (2001). Impact of high-​normal blood pressure on the risk of cardiovascular disease. New Engl J Med, 345, 1291–​7. Wang Y, Wang QJ (2004). The prevalence of prehypertension and hypertension among US adults according to the new joint national committee guidelines:  new challenges of the old problem. Arch Intern Med, 164, 2126–​34. William B, et al. (2008). Systolic pressure is all that matters. Lancet, 371, 2219–​21. Xie W, et al. (2018). Blood pressure-lowering drugs and secondary prevention of cardiovascular disease: systematic review and meta- analysis. J Hypertens, 36, 1256–65. Yusuf S, et al. (2004). Effect of potentially modifiable risk factors associ- ated with myocardial infarction in 52 countries (the INTERHEART study): case-​control study. Lancet, 364, 937–​52. Pathophysiology Aksnesa TA, et al. (2007). Prevention of new-​onset atrial fibrillation and its predictors with angiotensin II-​receptor blockers in the treat- ment of hypertension and heart failure. J Hypertens, 25, 15–​23. Target organ damage: • LVH • Vascular structural damage • Systolic hypertension • LV dysfunction • Small vessel brain disease • Albuminuria/Declining GFR Metabolic syndrome to diabetes Metabolic syndrome to diabetes Treatment guidelines Treatment guidelines Number of Drugs Clinical Trials Clinical Trials CVD risk Evolution of disease; 10–50 yrs Cardiovascular disease: • CHD / CHF • Stroke / TIA • Dementia • Renal disease • Macular degeneration • Death Older Hypertension: • Lipid disorder • Glucose disorder • BP dysregulation • No TOD • No CVD Younger +/– +/– +/– Drug treatment Hypertensive Damage Hypertension Clinical disease Pre-hypertensive Hard end-points Surrogate end-points Fig. 16.17.1.14  The clinical progression of hypertension. blood pressure, blood pressure; CHD, coronary heart disease; CHF, congestive heart failure; CVD, cardiovascular disease; GFR, glomerular filtration rate; LV, left ventricular; TIA, transient ischaemic attack; TOD, target organ damage. 16.17.2 Essential hypertension Diagnosis, assessme 16.17.2 Essential hypertension: Diagnosis, assessment, and treatment 3753 Bryan Williams and John D. Firth 16.17.2  Essential hypertension: Diagnosis, assessment, and treatment 3753 Devereux RB, et al. (2004). Prognostic significance of left ventricular mass change during treatment of hypertension. JAMA, 292, 2386–​8. Drukteinis J, et  al. (2007). Cardiac and systemic hemodynamic characteristics of hypertension and prehypertension in ado- lescents and young adults: the Strong Heart Study. Circulation, 115, 221–​7. Elliott WJ, Meyer PM (2007). Incident diabetes in clinical trials of antihypertensive drugs:  a network meta-​analysis. Lancet, 369, 201–​7. Jin H, Huang Y, Yang G (2019). Association between α-adducin rs4961 polymorphism and hypertension: a meta-analysis based on 40432 subjects. J Cell Biochem, 120, 4613–19. Lip GYH, Blann AD (2000). Does hypertension confer a prothrombotic state? Virchow’s triad revisited. Circulation, 101, 218–​20. Mancia G, et al. (2007). The sympathetic nervous system and the metabolic syndrome. J Hypertens, 25, 909–​20. Mancini JGB, et al. (2004). Surrogate markers for cardiovascular dis- ease. Circulation, 109 Suppl, IV 22–​30. Mason JM, et al. (2005). The diabetogenic potential of thiazide-​type diuretic and beta-​blocker combinations in patients with hyperten- sion. J Hypertens, 23, 1777–​81. Okin PM, et  al. (2004). Electrocardiographic strain pattern and prediction of cardiovascular morbidity and mortality in hyper- tensive patients. Hypertension, 44, 48–​54. Okin PM, et al. (2006). Electrocardiographic strain pattern and pre- diction of new-​onset congestive heart failure in hypertensive patients:  the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study. Circulation, 113, 67–​73. Ong KL, Barter PJ, Waters DD (2014). Cardiovascular drugs that increase the risk of new-onset diabetes. Am Heart J, 167, 421–​8. Psaty BM, et  al. (2002). Diuretic therapy, the alpha-​adducin gene variant, and the risk of myocardial infarction or stroke in persons with treated hypertension. JAMA, 287, 1680–​9. Sironi AM, et al. (2004). Visceral fat in hypertension. Hypertension, 44, 127–​33. Srinivasan SR, Myers L, Berenson GS (2006). Changes in meta- bolic syndrome variables since childhood in prehypertensive and hypertensive subjects:  the Bogalusa Heart Study. Hypertension, 48, 33–​9. Staessen JA, et al. (2001). Effects of three candidate genes on preva- lence and incidence of hypertension in a Caucasian population. J Hypertens, 19, 1349–​58. Swales JD (1985). Platt versus Pickering: an episode in recent medical history. Keynes Press, London. Taddei S, et  al. (2000). Endothelial dysfunction in hypertension. J Nephrol, 13, 205–​10. Wang JG, et  al. (2006). Carotid intima-​media thickness and antihypertensive treatment:  a meta-​analysis of randomized con- trolled trials. Stroke, 37, 1933–​40. Wang F, Han L, Hu D (2017). Fasting insulin, insulin resistance and risk of hypertension in the general population: a meta-analysis. Clin Chim Acta, 464, 57–63. Ward R (1990). Familial aggregation and genetic epidemiology of blood pressure. In: Laragh JH, Brenner BM (eds) Hypertension: path- ophysiology, diagnosis and management, pp. 81–​100. Raven Press, New York. 16.17.2  Essential hypertension: Diagnosis, assessment, and treatment Bryan Williams and John D. Firth ESSENTIALS Essential hypertension is almost invariably symptomless, and usually detected by routine screening or opportunistic measurement of blood pressure. Key questions to answer in the assessment of a person pre- senting with an elevated blood pressure are: (1) Do they have hyper- tension, that is, is the blood pressure persistently elevated? (2) Are there any associated clinical features that might warrant further evaluation to exclude secondary causes of hypertension? (3) Are there factors that might be contributing to an elevated blood pressure, including lifestyle or dietary factors, or concomitant medication? (4) Is there any associ- ated target organ damage or comorbidity that influences the overall cardiovascular disease risk and subsequent treatment of the patient? Diagnosis It is normal to find large variations in blood pressure measured in a single individual, hence it should be measured as accurately as possible using the British Hypertension Society protocol. All adults should have their blood pressure measured routinely at least every 5 years. Automated home blood pressure measurements (HBPM) and ambulatory blood pressure measurement (ABPM) recordings provide much more infor- mation than standard office blood pressure measurements with regard to diagnosis and efficacy of treatment of hypertension, and some recent guidelines recommend that they should be used routinely for diagnosis. The appropriate thresholds for diagnosis of hypertension depending on the method of blood pressure measurement are (1) office or clinic—​ systolic blood pressure (SBP) 140 mm Hg, diastolic blood pressure (DBP) 90 mm Hg; (2) ABPM 24 h—​SBP 130 mm Hg, DBP 80 mm Hg; daytime—​SBP 135 mm Hg, DBP 85 mm Hg; night-​time—​SBP 120 mm Hg, DBP 70 mm Hg; and (3) home measurements—​SBP 135 mm Hg, DBP 85 mm Hg. The European Society of Hypertension classification of hypertension is described in Chapter 16.17.1. Isolated office hypertension (‘white coat’ hypertension) should be diagnosed whenever office blood pressure is greater than or equal to 140/​90 mm Hg on at least three occasions, while 24 h mean and daytime blood pressures are within their normal range. Clinical examination and investigation Fundoscopy is the most convenient method of directly visualizing vascular pathology and provides important prognostic information. Three grades are recognized: (1) mild—​generalized and focal arteriolar narrowing, arteriolar wall opacification, and arteriovenous nipping; (2) moderate—​as (1) plus flame-​shaped blot haemorrhages and/​or cotton wool spots and/​or hard exudates and/​or microaneurysms; and (3) severe—​as (2) plus swelling of the optic disc. Aside from measurement of blood pressure and fundal examin- ation as just detailed, particular features to look for on examination section 16  Cardiovascular disorders 3754 are evidence of secondary effects of sustained hypertension on the heart, and features that might suggest the presence of a secondary cause of hypertension (coarctation—​absent/​delayed femoral pulses, cardiac murmur; and renovascular disease—​renal bruit). Patients with essential hypertension need only a limited number of routine investigations, namely (1) urine strip test for blood and urinary albumin:creatinine ratio (ACR) for proteinuria; (2)  serum creatinine and electrolytes; (3)  blood glucose—​ideally fasted; (4) cholesterol and HDL-​cholesterol—​ideally fasted; and (5) 12-​lead electrocardiogram (ECG). Management The treatment of hypertension is directed towards reducing risk rather than treating symptoms, and best advice and treatment is informed by formal estimation of a patient’s overall cardiovascular risk. Most international guidelines recommend that, for office blood pressure, an optimal treatment target should be less than 140/​90 mm Hg in patients under the age of 60 years. The 2018 European guide- lines differ, stating that—provided treatment is well tolerated—treated BP should be targeted to less than 130/80 mm Hg in most patients. Recommendations differ for older patients: current American guide- lines suggest treating to a goal of less than 150/​90 mm Hg for patients aged over 60 years; the British Hypertension Society/​NICE guideline recommends the same higher target for those over 80 years; and the 2018 European guideline recommends a target of SBP 130–139 mm Hg ‘if tolerated’. Most international guidelines no longer recommend lower blood pressure targets for populations at higher cardiovascular risk. Although early studies focused primarily on DBP as the treatment target, SBP is the more important prognostic factor, is invariably more difficult to control, and should be the main focus of treatment. The most effective lifestyle interventions for reducing blood pressure are (1) modifications to diet to induce weight loss, (2) regular aerobic ex- ercise, and (3) reduction of excessive alcohol and/​or sodium intake; all smokers should be offered advice and help to quit to reduce cardiovas- cular (and other) risks. Many patients will require more than one drug to control blood pressure: monotherapy is rarely sufficient. The blood pressure response to an individual class of blood pressure lowering medication is heterogeneous, hence there is no ‘perfect drug’ for every patient, but some trials have indicated that certain comorbidities or target organ damage provide compelling indications for inclusion of specific classes of drug therapy in the treatment regimen. There is wide variation in the international guidelines with re- gard to the preferred initial therapy for essential hypertension: (1) the (American) Joint National Committee (JNC) 8 guideline recom- mends initial drug treatment with an angiotensin converting enzyme inhibitor (ACE inhibitor), angiotensin receptor blocker (ARB), calcium channel blocker (CCB), or thiazide-​type diuretic (TTD) in non​black hypertensive patients, with a CCB or TTD preferred in black patients; (2) the 2018 European guideline suggests that initial therapy should be with two drugs—an ACEi or ARB combined with a CCB or TTD in a single pill combination; (3) the British Hypertension Society/​NICE guideline suggests that the most appropriate initial blood pressure lowering agent for (a) people aged 55 years or over (without type 2 diabetes), and for black people of African or Caribbean family origin of any age (without type 2 diabetes), is a CCB, with a TTD preferred if a CCB is not suitable, and (b) for people under 55 years of age, or any patient with type 2 diabetes, an ACE inhibitor or a low-​cost ARB is preferred initial therapy. All guidelines recognize that combinations of blood pressure lowering drugs are often required to achieve recommended blood pressure goals. The British guideline provides explicit guidance on preferred combinations of treatment if one agent fails to achieve ad- equate control: step 2—​a CCB combined with either an ACE inhibitor or ARB; step 3—​add a TTD; step 4—​add higher-​dose TTD, spironolac- tone, an α-​blocker or a β-​blocker. European and American recom- mendations are similar. Patients with hypertension and deemed to be at high cardiovas- cular risk (>10% over 10 years) should receive advice to adjust their lifestyles and be considered for treatment with statin therapy and low-​dose aspirin to optimize their risk reduction. Indications for specialist referral include uncertainty about the decision to treat, investigations to exclude secondary hypertension, severe and complicated hypertension, and resistant hypertension. Introduction There are several important issues that must be considered in the as- sessment of people presenting with an elevated blood pressure: • Does the patient have hypertension (i.e. is the blood pressure per- sistently elevated?) • Are there any associated clinical features that might warrant fur- ther evaluation to exclude secondary causes of hypertension? (see next and Chapter 16.17.3) • Are there factors that might be contributing to an elevated blood pressure, including lifestyle or dietary factors, or concomitant medication? • Is there any associated target organ damage or comorbidity that influences the overall cardiovascular disease risk and subsequent treatment of the patient? These factors, along with the age and ethnicity of the patient, will inform the decision to treat, the urgency of the need to treat, the need for further investigation, and the choice of treatment. Symptoms Essential hypertension is invariably symptomless and usually de- tected by routine screening or opportunistic measurement of blood pressure. However, once a patient has been labelled as ‘hypertensive’ it is not uncommon for them to associate preceding symptoms with their elevated blood pressure. Some patients will claim that they can recognize when their blood pressure is elevated, usually on the basis of symptoms such as plethoric features, palpitations, dizziness, or a feeling of tension. Screening surveys have demonstrated that these symptoms occur no more commonly in untreated hypertensive pa- tients than they do in the normotensive population. However, there are two important caveats to the symptomless nature of essential hypertension: (1) symptoms may develop as a consequence of target organ damage, (2) headache may be a feature of severe hypertension. Headache Most headaches in hypertensive patients are tension headaches, not related to blood pressure at all, although they become more common 16.17.2  Essential hypertension: Diagnosis, assessment, and treatment 3755 when patients become aware of the diagnosis. The classic hyperten- sive headache is present on waking in the morning, situated in the occipital region, radiating to the frontal area, throbbing in quality, and wears off during the course of the day. It is generally associated with more severe hypertension. Effective treatment of hypertension reduces the incidence of such headaches. Morning headaches in obese hypertensive patients may be related to sleep apnoea. Epistaxis Epistaxis is not associated with mild hypertension but is more common in moderate to severe hypertension. However, the associ- ated anxiety can elevate blood pressure when patients present with bleeding, hence it is particularly important that patients are not automatically labelled as hypertensive, with care taken to dissociate hypertension as a cause of epistaxis from a pressor response to the epistaxis itself. Male impotence Patients rarely volunteer information about impotence, but there is an increased prevalence of erectile dysfunction in untreated hyper- tensive men. This is related to two factors: remodelling of small ar- teries and increased risk of atheroma, both of which vascular changes can reduce penile blood flow despite the elevation in blood pressure. Furthermore, erectile dysfunction can develop or worsen as a con- sequence of treatment, for the most part related to the reduction in blood pressure before any concomitant change in vascular structure. Nocturia This is common in people with untreated hypertension as a conse- quence of a reduction in urine-​concentrating capacity. The symp- toms usually improve with treatment. Symptoms associated with target organ damage If patients develop cardiac, vascular, cerebrovascular, and/​or renal complications as a consequence of long-​standing untreated or poorly treated hypertension, then symptoms related to these complications may be present. Target organ damage and associated symptoms are discussed in Chapter 16.17.1. Physical examination Blood pressure measurement Large variations in blood pressure measured in a single individual are normal, hence it should be measured as accurately as possible using the British Hypertension Society (BHS) protocol (Box 16.17.2.1). Blood pressure should initially be measured in both arms because there can be large interarm difference in blood pressure. The finding of a difference of greater than 20 mm Hg may indicate the presence of underlying vascular disease, especially subclavian stenosis. When there is a significant interarm difference in blood pressure reading, the arm with the higher pressure should be used for all subsequent measurements. All adults should have their blood pressure measured routinely at least every 5 years. Those with high-​normal blood pressure (sys- tolic blood pressure (SBP) 130–​139 mm Hg or diastolic blood pres- sure (DBP) 85–​89 mm Hg) and those who have had high blood pressure readings at any time previously should have their blood pressure remeasured annually. These measurements can be made in the clinic, in the home setting, or using ambulatory blood pressure monitoring (ABPM), as described later in the chapter. Seated blood pressure recordings have been the standard method for diagnosing hypertension for more than 100  years, are the method used most often in epidemiological studies and clinical out- come trials, and are unequivocally linked to clinical outcomes and mortality in a graded way. However, recordings are often performed badly and can underestimate or overestimate BP in comparison with ABPM, even when performed well. The patient should be seated and rested for a few minutes beforehand. At least two measurements should be taken, and if the first measurement is more than 10 mm Hg higher than the subsequent one, then it should be discarded and a further reading taken. Standing blood pressure (after at least 2 min standing) should be measured in elderly or diabetic patients to ex- clude significant orthostatic hypotension. The timing of blood pressure measurement should take account of the timing of medication. Treatment decisions should not be based on single blood pressure readings: the average of two read- ings at each of at least three visits (depending on severity) should be used to guide the decision to treat. The time between visits will vary according to the severity of the hypertension, ranging from days or weeks to months. In patients with severe hypertension, especially when there is unequivocal evidence of target organ damage, the de- cision to treat may be made at the time of first presentation. When measuring blood pressure, the upper arm should be sup- ported at heart level during recordings, and it is important that an appropriate cuff size is used, with the bladder encircling at least 80% of the upper arm. Using too large a cuff results in an underestimation of blood pressure and too small a cuff will lead to overestimation. If the auscultatory method is used to measure blood pressure, then Korotkoff phase I (first appearance of sound) and phase V sounds (disappearance of sound) should be taken for SBP and DBP, respect- ively. If phase V goes to zero, then phase IV (muffling of sound) should be recorded. The beat-​to-​beat variability associated with atrial fibrillation can make blood pressure measurement difficult and semiautomatic or Box 16.17.2.1  British Hypertension Society protocol for blood pressure measurement • Use a properly maintained, calibrated, and validated device • Measure sitting blood pressure routinely:  standing blood pressure should be recorded at the initial estimation in elderly and diabetic patients • Remove light clothing, support arm at heart level, ensure hand is re- laxed, and avoid talking during the measurement procedure • Use cuff of appropriate size, and rapidly inflate the cuff to 20 mm Hg above the point where the brachial pulse disappears • Lower cuff pressure slowly (2 mm/​s) • Read blood pressure to the nearest 2 mm Hg • Measure diastolic as disappearance of sounds (phase V) • Take the mean of at least two readings: more recordings are needed if marked differences between initial measurements are found • Do not treat on the basis of an isolated reading Reprinted by permission from Williams B, et  al. (2004). Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society, 2004—​BHS IV. Journal of Human Hypertension, 18, 139–​85. section 16  Cardiovascular disorders 3756 automated devices can be very inaccurate in such circumstances, in which case multiple readings of auscultatory measurements are recommended. Blood pressure monitors The sphygmomanometer has been the mainstay of blood pressure measurement for over 100 years, but its use is likely to decline as a consequence of the decommissioning of mercury-​based devices and the emergence of automated and semiautomated devices for routine blood pressure measurement in the office and home and for ABPM. It is important to note that there are different diagnostic thresh- olds for the diagnosis of hypertension dependent on the method of measurement; that is, when using multiple home or ambula- tory blood pressure values to measure an average blood pressure, then the average value used to define hypertension is lower than the equivalent office blood pressure threshold of 140/​90 mm Hg (Table 16.17.2.1) and it should be noted—​as stated earlier—​that automated devices are inaccurate in patients with atrial fibrillation, in whom blood pressure should be measured manually. Detailed guidance on blood pressure measurement and a wide range of val- idated monitors is available from http://​www.bhsoc.org. Ambulatory blood pressure measurements (ABPM) ABPM recordings improve the sensitivity and specificity of the diag- nosis of hypertension compared to clinic and home blood pressure monitoring, although they cannot be used for people with signifi- cant pulse irregularity (e.g. atrial fibrillation), who require manual auscultation. They also provide much more information regarding the efficacy of treatment of hypertension. When compared to office blood pressure, there is a much steeper relationship between ABPM averages and target organ damage indices and cardiovascular events, no doubt reflecting that fact that more measurements are obtained and the ‘white coat’ or ‘office’ effect (see ‘White coat’ or isolated of- fice hypertension) is eliminated. Generally, ABPM devices are pro- grammed to record blood pressure at 20 min intervals during the day and 30 min intervals at night. A diary is provided to record activity and sleep patterns. In addition to the 24 h blood pressure average, ABPM also provides information on blood pressure profiles (e.g. daytime and night-​time averages), the ‘dipper status’ (i.e. the re- lationship between night-​time and daytime blood pressure averages, blood pressure variability throughout the day, the morning surge in blood pressure, and—​more recently—​indices of aortic function via the ambulatory stiffness index). Each of these parameters adds value over and above the assessment of office blood pressure, hence such techniques are increasingly used for the assessment of people with hypertension. Clinical indications for the use of ABPM are shown in Box 16.17.2.2. Home blood pressure measurements (HBPM) It is increasingly common for patients to measure their own blood pressure at home using monitors that measure blood pressure on the upper arm, wrist, or finger. The average of frequent measurements may be more reproducible and reliable than clinic measures, and HBPM has been shown to be a better predictor of clinical outcomes. Validated devices should be used, with an average of duplicate morning and evening HBPM recorded daily for at least 4 days and ideally for 7 days. The measurements should be recorded seated after 5 min rest, with those taken on the first day discarded. Advocates of HBPM argue that it may reduce unnecessary treatment (by revealing the diagnosis of ‘white coat’ hypertension) and increase treatment compliance, against which must be balanced the fact that in some patients it can lead to inappropriate concern and anxiety. Other features Fundal examination Fundoscopy is the most convenient method of directly visualizing vascular pathology and provides important prognostic informa- tion. Signs of hypertensive retinopathy are frequently seen in adults 40 years and older, and are predictive of incident stroke, congestive heart failure, and cardiovascular mortality—​independently of trad- itional risk factors. The Keith Wagener classification of fundal appearances has been used for many years, but has serious shortcomings. This classifica- tion identified four grades of hypertensive retinopathy. Grade I and II changes, which result from arteriolar thickening, are often diffi- cult to differentiate from each other, and the prognostic significance of the grade I and II subclassification is unclear. A more practical three-​grade classification (i.e. mild, moderate, and severe) has been proposed (Table 16.17.2.2). The mild changes of generalized retinal–​ arteriolar narrowing and arteriovenous nipping are related to both the blood pressure at diagnosis and chronic exposure to an elevated blood pressure, hence they appear to be an index of the chronicity of blood pressure elevation (Fig. 16.17.2.1a). The changes of mod- erate hypertensive retinopathy are the changes of mild retinopathy plus flame-​shaped or blot-​shaped haemorrhages, cotton wool spots, hard exudates, microaneurysms, or a combination of all of these fac- tors. Severe retinopathy (malignant or accelerated hypertension) is characterized by all of the aforementioned changes plus swelling of the optic disc (Fig. 16.17.2.1b). These moderate and severe fundal changes are more closely related to more recent elevation of blood Table 16.17.2.1  Diagnostic thresholds for hypertension according to different methods of measurement SBP (mm Hg) DBP (mm Hg) Office or clinic 140 90 24 hour 125 80 Day 135 85 Night 120 70 Home 135 85 DBP, diastolic blood pressure; SBP, systolic blood pressure. Box 16.17.2.2  Possible indications for ambulatory blood pressure monitoring • Unusual blood pressure variability • Possible ‘white coat’ hypertension • Informing equivocal treatment decisions • Evaluation of nocturnal hypertension • Evaluation of drug-​resistant hypertension • Determining the efficacy of drug treatment over 24 h • Diagnosis and treatment of hypertension in pregnancy • Evaluation of symptomatic hypotension 16.17.2  Essential hypertension: Diagnosis, assessment, and treatment 3757 pressure, suggesting they are the consequence of more transient and severe blood pressure elevation. The flame-​shaped haemorrhages are superficial and shaped due to constraints imposed by nerve fibres. Dot and blot haemorrhages are deeper than the nerve fibres and thus are not so constrained. Haemorrhages usually disappear after a few weeks of effective blood pressure control. There are two types of exudates: hard or waxy exudates represent the end result of fluid leakage into the fibre layers of the retina from damaged vessels, with fluid re- absorption leaving a protein–​lipid residue that is slowly removed by macrophages; soft exudates or cotton wool patches are usu- ally larger than hard exudates and have a woolly, ill-​defined edge, but they are not true exudates, rather nerve fibre infarcts caused by hypertensive vascular occlusion. Unlike hard exudates, these lesions disappear within a few weeks of establishing adequate antihypertensive therapy. Severe fundal changes are characterized by disc swelling (i.e. papilloedema) resulting from raised pressure in the disc head sec- ondary to severe vascular damage and increased permeability. Venous distension is followed by increased vascularity of the optic disc, which has a pink appearance with blurring of the disc mar- gins and loss of the optic cup. Raising of the optic disc with anterior displacement of the vessels occurs later. The surrounding retina often shows oedema, small radial haemorrhages, and cotton wool exudates. Moderate or severe fundal changes represent malignant or accelerated hypertension and carry the same adverse prognosis and should be treated as a medical urgency (see Chapter 16.17.5). Other fundal changes associated with hypertension Hypertension also predisposes to the development of several sight-​ threatening complications that can be detected by fundoscopy. Retinal vein occlusion  This is characterized by dilated and tor- tuous retinal veins and the presence of retinal haemorrhages, cotton wool spots, and oedema of the macula and optic disc. In the case of central retinal vein occlusion, all four fundal quadrants are involved (Fig.  16.17.2.2a); only one fundal quadrant is involved if there is a branch vein occlusion (Fig. 16.17.2.2b). Central retinal vein occlusion can either be ischaemic or non​ischaemic, patients with an ischaemic central retinal vein occlusion typically having poor visual acuity and a relative afferent pupillary defect. Ophthalmic follow-​up is needed to diagnose and prevent the two main com- plications of retinal vein occlusion, namely neovascularization and macular oedema. Retinal arteriolar embolization  Due to cholesterol crystals, platelet/​fibrin clot, or calcium, this is twice as common in people with hypertension compared to those who are normotensive, with the risk further accentuated in cigarette smokers and those with diabetes. Retinal artery occlusion  Also more common in people with hypertension, central retinal artery occlusion typically presents with a sudden, painless, unilateral loss of vision, associated with a cherry red spot (Fig. 16.17.2.3a). Branch retinal artery occlusion (Fig. 16.17.2.3b) will present with a sudden, painless, visual field defect: there may be only minimal impairment of central vision. Retinal arterial macroaneurysms  These can be either fusiform or saccular. They are uncommon, but are rarely seen in patients without hypertension. When they occur, about 20% are bilateral and 10% are multiple. They are usually discovered by routine fundoscopy in Table 16.17.2.2  Modern classification of hypertensive retinopathy Mild hypertensive retinopathy Retinal arteriolar signs, such as generalized and focal arteriolar narrowing, arteriolar wall opacification, and arteriovenous nipping Moderate hypertensive retinopathy The signs above plus flame-​shaped or blot-​ shaped haemorrhages, cotton wool spots, hard exudates, microaneurysms, or a combination of all of these factors Severe hypertensive retinopathy The signs above plus swelling of the optic disc ) b ( )a ( AVN AVN CWS FH DS Fig. 16.17.2.1  (a) Signs of mild hypertensive retinopathy. (b) Signs of severe hypertensive retinopathy. AVN, arteriovenous nipping; CWS, cotton wool spots; DS, swelling of the optic disc; FH, flame-​shaped retinal haemorrhage. Reprinted from The Lancet, Vol. 369, Wong T, Mitchell P, The eye in hypertension, pp. 425–​35. Copyright (2007), with permission from Elsevier. section 16  Cardiovascular disorders 3758 asymptomatic hypertensive patients, but can present acutely, with visual loss secondary to haemorrhage or exudation. Non​arteritic ischaemic optic neuropathy  This is also more common in people with hypertension, occurring (in one series) with a yearly incidence of 1 in 10 000. It presents with sudden unilateral visual loss and optic disc oedema. There is no effective treatment and prospects for visual recovery are poor. General physical examination All patients with hypertension should have a thorough phys- ical examination. Aside from measurement of blood pressure and fundal examination as just detailed, particular features to look for are evidence of secondary effects of sustained hypertension on the heart, features that might suggest the presence of a secondary cause of hypertension, and evidence of other vascular pathology (absent pulses, arterial bruits) (Box 16.17.2.3). Cardiac examination may reveal a sustained apex beat, or fea- tures of cardiac failure that might be secondary to hypertension. It is sometimes said that the second component of the aortic sound is loud in moderate or severe hypertension, but this is not a reliable finding. In coarctation of the aorta the femoral pulses will be absent or di- minished and delayed, and there may be various murmurs (usually a systolic murmur at the sternal border and a continuous murmur at the back of the chest), also visible or palpable collateral arteries on the back of the chest or in the axillae. Blood pressure measured in the legs will be lower than that in the arms. An abdominal bruit is reported in 4–​20% of normal people, most commonly in those aged over 40  years, when it is typic- ally systolic and audible only between the xiphisternum and the umbilicus. In patients with severe hypertension that is difficult to control, the finding of an abdominal bruit in both systole and AVN BRVO (a) (b) Fig. 16.17.2.2  (a) Central retinal vein occlusion involving all four fundal quadrants. (b) Branch retinal vein occlusion (BRVO) involving a single fundal quadrant, also showing a good example of arteriovenous nipping (AVN). Reprinted from The Lancet, Vol. 369, Wong T, Mitchell P, The eye in hypertension, pp. 425–​35. Copyright (2007), with permission from Elsevier. ) b BRAO RE ( )a ( Fig. 16.17.2.3  (a) Central retinal artery occlusion with a characteristic cherry red spot. (b) Retinal–​arteriolar emboli (RE) and retina branch artery occlusion (BRAO). Reprinted from The Lancet, Vol. 369, Wong T, Mitchell P, The eye in hypertension, pp. 425–​35. Copyright (2007), with permission from Elsevier. 16.17.2  Essential hypertension: Diagnosis, assessment, and treatment 3759 diastole strongly supports the diagnosis of renovascular hyper- tension, but a bruit confined to systole is much less likely to be of significance. Diagnosis and categories of hypertension Different categories of hypertension can be recognized on the basis of the results of clinic and ambulatory blood pressure meas- urements (Fig. 16.17.2.4). ‘White coat’ or isolated office hypertension In some patients office blood pressure is persistently elevated al- though their 24 h blood pressure or home blood pressure aver- ages are within the normal range. This has been termed white coat hypertension or isolated office hypertension, and is diagnosed when clinic BP is more than 140/​90 mm Hg on at least three oc- casions and more than 20/​10 mm Hg more than ABPM or home average readings. It is important to note that blood pressure will generally fall with repeated readings in all patients, hence it is the chronicity of the office blood pressure elevation that is important to establish the diagnosis. Surveys suggest that white coat or isolated office hypertension may be present in as many as 15% of the general population and about 25% of all hypertensives (usually grade 1). There is consid- erable debate about its prognostic significance: some studies report association with evidence of hypertensive target organ damage, but others do not. However, overall it appears that white coat hyper- tension is not benign, with the associated risk probably sitting be- tween those with hypertension confirmed by office readings and ABPM, and those with definitively normal pressures by all methods of measurement. When white coat hypertension is diagnosed, the best advice is to monitor blood pressure and target organ damage via ABPM or home blood pressure averages and not treat unless these pressures are persistently elevated. Masked hypertension Less attention has been paid to masked hypertension (i.e. patients with a normal office blood pressure but elevated ABPM or home blood pressure averages) than to those with white coat hyperten- sion. Estimates of prevalence range from 10% to 30% of the popula- tion, and as HBPM becomes more popular the detection of masked hypertension will increase. Most of these will be prehypertensive, with clinic BP 130–​139/​85–​89 mm Hg, but these patients are likely to have target organ damage and are at increased cardiovascular risk, probably more so than those with white coat hypertension (Fig. 16.17.2.5). Masked uncontrolled hypertension is common in people with treated hypertension and should be considered particularly in pa- tients who have clinical evidence of hypertensive target organ damage, but in whom office blood pressure appears normal. ABPM should be used to confirm BP control (including nocturnal read- ings), particularly in higher-​risk groups and/​or those with border- line control of clinic BP, and treatment should be offered to control ABPM average. Cost-​effectiveness of different methods of diagnosing hypertension A more expensive method of confirming a diagnosis of hyperten- sion may be more cost-​effective if, by increasing the accuracy of diagnosis, it avoids treatment costs in some patients. There are no Box 16.17.2.3  Initial assessment of the patient with hypertension • Identifiable causes of hypertension: − Drugs (NSAIDs, oral contraceptive, steroids, liquorice, sympatho- mimetics, i.e. some cold cures) − Renal disease (present, past or family history, proteinuria and/​or haematuria: palpable kidney(s)—​polycystic) − Renovascular disease (abdominal or loin bruit) − Obstructive sleep apnoea (snoring, daytime somnolence) − Coarctation (radiofemoral delay or weak femoral pulses) − Phaeochromocytoma (paroxysmal symptoms) − Conn’s syndrome (tetany, muscle weakness, polyuria, hypokalaemia) − Cushing’s (classical clinical characteristics) − Hypothyroidism or hyperthyroidism (classical clinical characteristics) − Acromegaly (classical clinical characteristics) • Contributory factors − Overweight − Excess alcohol (>3 units/​day) − Excess salt intake − Lack of exercise − Environmental stress • Complications of hypertension/​target organ damage − Stroke, TIA, dementia, carotid bruits − LVH and/​or LV strain on ECG, heart failure − Myocardial infarction, angina, CABG, or angioplasty − Peripheral vascular disease − Fundal haemorrhages or exudates, papilloedema − Proteinuria − Renal impairment (raised serum creatinine) • Cardiovascular disease risk factors − Smoking − Diabetes − Total cholesterol:high-​density lipoprotein-​cholesterol ratio − Family history − Age − Sex • Drug contraindications CABG, coronary artery bypass graft; LVH, left ventricular hypertrophy; NSAIDs, non​steroidal anti-​inflammatory drugs; TIA, transient ischaemic attack. White coat hypertension Elevated Elevated Normal Normal Ambulatory blood pressure Clinic blood pressure Sustained normotension Sustained hypertension Masked hypertension Fig. 16.17.2.4  Categories of hypertension dependent on clinic and ambulatory blood pressure measurements. section 16  Cardiovascular disorders 3760 studies that have compared clinic blood pressure monitoring with both ABPM and HBPM from a cost-​effectiveness perspective, but the NICE analysis of 2011 concluded that ABPM was the most cost-​ effective option. It is appropriate to note, however, that arguments about cost-​effectiveness depend on a wide range of assumptions, including the costs of ABPM and HBPM, the frequency and cost of subsequent measurements of blood pressure in those deemed not to be hypertensive, and the costs of treatment of those declared to have hypertension. Establishing the diagnosis of hypertension In most healthcare systems hypertension will and should continue to be diagnosed on the basis of office blood pressure measurements. Within the United Kingdom, the NICE recommendations are that, unless severe hypertension (>180/​110 mm Hg) is found, a clinic measurement above 140/​90 mm Hg should be followed by ABPM, with at least two measurements taken per hour during the person’s normal waking hours and an average value of at least 14 readings used to confirm the diagnosis (>135/​85 mm Hg). HBPM can be used if the patient cannot tolerate ABPM. The most recent American guidelines (JNC8) do not make new comment on diagnosis of hypertension, although the US Preventive Services Task Force (2015) recommends ABPM. European guide- lines (2018) use conventional office blood pressure measurements or ABPM/HBPM as an alternative strategy. Routine investigation Patients with essential hypertension need only a limited number of routine investigations, which must include: • urine strip test for haematuria • urinary albumin:creatinine ratio (ACR) for proteinuria • serum creatinine (estimated GFR) and electrolytes • glycated haemoglobin (HbA1c) • cholesterol and HDL-​cholesterol—​ideally fasted • ECG These routine investigations help inform the assessment of target organ damage and cardiovascular disease risk. With regard to renal function, it is now almost universal laboratory practice to report an ‘estimated’ GFR (eGFR) calculated using an algorithm based on the serum creatinine measurement and the patient’s age. Testing for proteinuria should be by quantification on a spot urine sample of the urinary albumin/​creatinine ratio (ACR). More sophisticated assessment tools are available, but the aforementioned list is suffi- cient for routine clinical practice. Note that only two of these rou- tine investigations contribute to the detection of underlying causes of hypertension, namely urinalysis (renal causes) and serum cre- atinine and electrolytes (renal causes and mineralocorticoid ex- cess), although the ECG may very rarely show U waves as a clue to one of the hypokalaemic syndromes. Indications for further investigation for causes of secondary hypertension are given in Chapter 16.17.3. A chest radiograph and urine microscopy are not routinely re- quired. Echocardiography is more sensitive at detecting left ven- tricular hypertrophy than an ECG, but is not required routinely, although it is valuable to confirm or refute the presence of left ven- tricular hypertrophy when the ECG shows voltage criteria sug- gestive of this. Assessment of cardiovascular disease risk The cardiovascular risk associated with hypertension is not elim- inated by the treatment of blood pressure alone. This is because many patients have established cardiovascular damage which may not necessarily reverse with treatment of blood pressure, also life- style habits such as smoking and dietary factors that may not have changed since therapy was initiated. Other factors are also im- portant:  patients with high blood pressure often have associated disturbances in their metabolic profile (especially lipids and glucose 40 Cardiovascular events, untreated Total mortality, untreated P<0.0001 P<0.0001 35 30 25 Event (%) 20 15 10 5 0 40 35 30 25 20 15 10 5 0 0 3 6 9 12 0 3 6 9 12 Sustained hypertensives Masked hypertensives White-coat hypertensives Normotensives Fig. 16.17.2.5  Prognosis of white coat and masked hypertension. Data includes 6458 participants with 714 events. Adapted from Stergiou GS, et al. (2014). Prognosis of white-​coat and masked hypertension: International database of home blood pressure in relation to cardiovascular outcome. Hypertension, 63, 675–​82. 16.17.2  Essential hypertension: Diagnosis, assessment, and treatment 3761 tolerance) that contribute to their risk, which has led many inter- national guidelines to recommend that cardiovascular risk should be formally assessed in all patients with hypertension to determine whether they are at low, medium, or high risk. Risk calculations based on the Framingham cohort have been used in the United States of America and the United Kingdom, and European guidelines have used a risk score based on mortality data from European countries. Pragmatism in risk assessment is im- portant, with the risk factors cited in the guidelines being conventional markers that can easily be documented in a basic clinical setting (i.e. SBP, age, gender, low-​density lipoprotein (LDL) cholesterol, presence of diabetes, smoking history, and the presence or absence of structural damage, e.g. ECG evidence of left ventricular hypertrophy). Recent surveys suggest that more than 90% of population-​attributable risk for cardiovascular disease can be explained by these risk factors. The use of more sophisticated risk assessment by adding any of the recently advocated biomarkers, such as C-​reactive protein, adds little to the conventional methods of cardiovascular risk estimation. Cardiovascular disease risk thresholds for intervention currently define ‘high-​risk’ patients as having a 10-​year Framingham-​derived cardiovascular disease risk of 10% or more, and such patients should be offered antihypertensive drug treatment if their blood pressure is elevated. The typical hypertensive male aged 55 years or more has this level of cardiovascular disease risk. Formal cardiovascular dis- ease risk estimation is not necessary for patients with hypertension and established cardiovascular disease, diabetes, or overt end organ damage: they are already at sufficient cardiovascular disease risk to benefit from multifactorial risk factor intervention. Patients with hypertension and deemed to be at high risk should receive strong advice to adjust their lifestyles and be considered for treatment with statin therapy and low-​dose aspirin to optimize their risk reduction (see next section). Clinical management Initial considerations Blood pressure is elevated sporadically in everybody. Key objectives in the assessment of essential hypertension are to establish whether blood pressure is persistently elevated; the level to which blood pres- sure is elevated (i.e. the severity of hypertension); and the presence or absence of hypertension-​mediated target organ damage. The initial assessment is usually followed by a period of observation, the dur- ation of which will be dependent on the severity of the hypertension and the associated cardiovascular disease risk and damage. Lifestyle advice should be provided during this observation period, with drug therapy initiated depending on the level of blood pressure and overall cardiovascular disease risk at the end of the observation period. Establishing the diagnosis Patients with essential hypertension usually present in one of three ways: • as an asymptomatic individual whose blood pressure has been meas- ured at routine examination for employment, insurance, or as a re- sult of screening or preoperatively—​the most common presentation; • as a patient whose blood pressure has been measured opportunis- tically when presenting with an unrelated disorder; or • as a result of symptoms produced by hypertension, or by the acute or chronic complications of hypertension—​the least common presentation. Repeated blood pressure measurements over a period of obser- vation are usually necessary to establish the diagnosis. Exceptions to this are patients presenting with severe hypertension in whom fundal examination or other assessment of target organ damage (e.g. left ventricular hypertrophy or renal impairment) clearly reveals the presence of hypertension-​mediated damage, indicative of the fact that the blood pressure needs treatment. The period of observation required before initiating drug therapy is dependent on the severity of the hypertension and the presence or absence of cardiovascular disease, diabetes, and/​or target organ damage. Those with more severe hypertension and disease require emergency or urgent intervention with drug therapy to lower their blood pressure, whereas those with less severe hypertension and/​ or the absence of damage or disease can be monitored over a longer period—​up to many months—​before initiating drug therapy. This period of observation is important because it is used to repeat blood pressure measurements, confirm the presence of sustained hyperten- sion, and get a more accurate appreciation of the associated risk, also to implement lifestyle interventions that may reduce blood pressure. Diagnostic thresholds for therapeutic intervention, the observation period, and treatment targets The diagnostic thresholds and appropriate interventions for the levels of hypertension severity are shown in Fig. 16.17.2.6, and the recommended period of observation for different grades of hyper- tension are shown in Table 16.17.2.3. Although there is general consensus about the management of grade II (i.e. ≥160/​100 mm Hg) or more severe hypertension, the British guidelines have trad- itionally been more cautious than other guidelines with regard to drug therapy for uncomplicated grade I hypertension (140–​159/​ 90–​99 mm Hg; see Fig. 16.17.2.6 and Table 16.17.2.3). Most other guidelines recommend treating all patients under the age of 60 years with a blood pressure sustained above 140/​90 mm Hg, and the 2018 European guidelines state that treatment can be considered for pa- tients with high normal BP (130–139/85–89 mm Hg) when cardio- vascular risk is very high due to established cardiovascular disease, whereas the 2019 British (NICE) guidelines have recommended drug therapy for those with grade I hypertension only when there is associated cardiovascular disease or target organ damage, or a calculated risk of cardiovascular disease at least 10% over 10 years. There is genuine uncertainty about the cost-​effectiveness of treating otherwise low-​risk people with grade I  hypertension, but this must be balanced by recognition that the greatest burden of blood pressure-​attributable disease in populations is in those with grade I hypertension because it is so common. Moreover, blood pressure will invariably continue to rise in patients with grade I hyperten- sion, and there is concern that the subtle vascular damage that is occurring while these patients remain untreated may not be revers- ible when treatment is eventually initiated at higher levels of pres- sure. Thus, while a prolonged period of observation and lifestyle intervention for uncomplicated, low-​risk, grade I hypertension is considered acceptable, it is inevitable that most of these patients will eventually (if not immediately) require drug treatment. Further differences between guidelines relate to older patients:  current section 16  Cardiovascular disorders 3762 American guidelines suggest treating to a goal of less than 150/​ 90 mm Hg for patients over 60 years of age; the British guideline recommends the same higher target for those over 80 years of age; and the 2018 European guideline suggests a systolic target of 130–​139 mm Hg in patients over 80 years of age ‘if tolerated’. The reason that the 2018 European guidelines recommend a lower treatment threshold than most other guidelines is worthy of some comment. The SPRINT trial, published in 2015, found that patients at high risk of cardiovascular events but without diabetes (excluded because of the findings of the ACCORD trial) had lower rates of fatal Clinic blood pressure < 140/90 mm Hg Normotensive Clinic blood pressure ≥ 140/90 mm Hg Clinic blood pressure ≥ 180/110 mm Hg Refer same day for specialist care Consider starting antihypertensive drug treatment immediately Offer ABPM3 (or HBPM4 if ABPM is declined or not tolerated) Offer to assess cardiovascular risk and target organ damage ABPM/HBPM < 135/85 mm Hg Normotensive ABPM/HBPM ≥ 135/85 mm Hg Stage 1 hypertension ABPM/HBPM ≥ 150/95 mm Hg Stage 2 hypertension Offer antihypertensive drug treatment Consider specialist referral Offer lifestyle interventions Offer patient education and interventions to support adherence to treatment Offer to check blood pressure at least every 5 years, more often if blood pressure is close to 140/90 mm Hg 1 Signs of papilloedema or retinal haemorrhage 2 Labile or postural hypotension, headache, palpitations, pallor and diaphoresis 3 Ambulatory blood pressure monitoring 4 Home blood pressure monitoring Offer annual review of care to monitor blood pressure, provide support and discuss lifestyle, symptoms and medication Consider alternative causes for target organ damage If evidence of target organ damage If target organ damage present, established cardiovascular disease, renal disease, diabetes or 10-year cardiovascular risk > 10% If younger than 40 years If accelerated hypertension1 or suspected phaeochromocytoma2 Fig. 16.17.2.6  Thresholds and appropriate inventions depending on blood pressure. Note: if ABPM or HBPM are not available, then proceed as advised in Table 16.17.2.3. From National Clinical Guideline Centre (2011). Hypertension—​the clinical management of primary hypertension in adults. Clinical Guideline 127, with modification from National Clinical Guideline Centre (2019) Hypertension in adults: diagnosis and management. Clinical Guideline 136. 16.17.2  Essential hypertension: Diagnosis, assessment, and treatment 3763 and non​fatal major cardiovascular events and deaths from any cause (composite main end-​point 1.65%/​year versus 2.19%/​year) if treated to a target of systolic BP less than 120 mm Hg (121.4 mm Hg achieved) compared to less than 140 mm Hg (136.2 mm Hg achieved), albeit at the expense of a higher burden of some adverse events. Some com- mentators argue that these findings are not representative for trials with baseline normotension and low levels of previous cardiovas- cular disease, in which antihypertensive treatment does not protect against death or major cardiovascular events, and they also note that the way in which blood pressure was measured gives lower readings than those obtained in other clinical trials and in routine clinical practice. However, the SPRINT findings—along with some recent meta-analyses—led the 2018 European guideline authors to state that, provided treatment is well tolerated, treated BP should be targeted to less than 130/80 mm Hg in most patients, whilst noting that in some groups of patients the evidence for this is ‘less compelling’. Explanation to the patient The treatment of hypertension is directed towards reducing risk rather than treating symptoms. It is imperative, therefore, to ex- plain the significance of high blood pressure at the earliest op- portunity. Many patients find difficulty in grasping the concept of blood pressure variability and are often alarmed by the inevitable occasional high reading. Discussion of the rationale for evalu- ation and treatment, together with an explanation of the nature of high blood pressure and its very high prevalence, reassures patients and may improve adherence to treatment. Further com- prehensive advice for patients may be obtained from http://​www. bpassoc.org.uk. Lifestyle advice Blood pressure is strongly influenced by lifestyle factors such as diet and exercise and their consequences such as on body weight. Effective lifestyle modification for patients with grade I hyperten- sion may lower blood pressure as much as a single blood pressure lowering drug, and combinations of two or more lifestyle modifi- cations may be even more effective. Lifestyle interventions may re- duce the need for drug therapy for people with mild hypertension, can enhance the antihypertensive effects of blood pressure lowering medication, and can favourably influence overall cardiovascular disease risk. The most effective lifestyle interventions for reducing blood pres- sure in clinical trials are modifications to diet to induce weight loss, regular aerobic exercise, and restrictions in alcohol and sodium intake. The expected reductions in blood pressure with these life- style manoeuvres are shown in Table 16.17.2.4, and recommended Table 16.17.2.3  Typical observation periods for different grades of hypertension and associated cardiovascular disease, diabetes, and/​or target organ damage Grade of hypertension Typical observation period Accelerated (malignant) hypertension (papilloedema and/​or fundal haemorrhages and exudates, or with acute cardiovascular complications e.g. aortic dissection) Immediate treatment—​usually requiring acute hospital admission (see Chapter 16.17.5) BP ≥220/​120 mm Hg Treat immediately—​hospital admission not usually required Grade III hypertension BP >180–​219/​110–​119 mm Hg Confirm by repeated measurements over 1–​2 weeks, then treat Grade II hypertension BP 160–​179/​100–​109 mm Hg In the presence of cardiovascular disease, diabetes, or target organ damage: confirm over 3–​4 weeks, then treat No cardiovascular disease, diabetes, or target organ damage: lifestyle measures, re-​measure weekly initially, and treat if BP persists at these levels over 4–​12 weeks Grade I hypertension: BP 140–​159/​90–​99 mm Hg Cardiovascular disease, diabetes, or target organ damage: either confirm or refute diagnosis by (a) ABPM) or HBPM, or (b) repeat clinic measurement within weeks, then treat if diagnosis confirmed No clinical cardiovascular disease, diabetes or target organ damage: lifestyle advice and either confirm or refute diagnosis by (a) ABPM or HBPM, or (b) re-​measure clinic BP at monthly intervals for 3–​6 months. If mild hypertension persists, estimate 10-​year cardiovascular diseases risk and treat if this is ≥20% (if <20%, keep under annual review) ABPM, ambulatory blood pressure measurement; BP, blood pressure; HBPM, home blood pressure measurement. Modified and updated from Williams B, et al. (2004). BMJ, 328, 364–​40. Table 16.17.2.4  Blood pressure reductions associated with lifestyle interventions for patients with hypertension Intervention Recommendation Expected SBP reduction (range) Weight reduction Maintain ideal BMI (20–​25 kg/​m2) 5–​10 mm Hg per 10 kg weight loss DASH eating plan Consume diet rich in fruit, vegetables, low-​fat dairy products with reduced content of saturated and total fat 8–​14 mm Hg Dietary sodium restriction Reduce dietary sodium intake to <100 mmol/​day (<2.4 g sodium or <6 g sodium chloride) 2–​8 mm Hg Physical activity Engage in regular aerobic physical activity, e.g. brisk walking for at least 30 min most days 4–​9 mm Hg Alcohol moderation Men ≤21 units/​week 2–​4 mm Hg Women ≤14 units/​week BMI, body mass index; DASH, Dietary Approaches to Stop Hypertension; SBP, systolic blood pressure. section 16  Cardiovascular disorders 3764 lifestyle interventions to reduce blood pressure and/​or cardiovas- cular disease risk are shown in Box 16.17.2.4. Patients are often enthusiastic to try lifestyle changes rather than take drug therapy. This is a reasonable initial option in pa- tients with grade I hypertension who do not have associated target organ damage or high cardiovascular disease risk. In patients with more severe hypertension or those at high risk, lifestyle measures should be recommended alongside drug therapy. This is important because these measures may improve the effectiveness of drug therapy and also contribute to a reduction in overall cardiovas- cular risk. Note, however, that effective implementation of lifestyle measures requires enthusiasm, knowledge, patience, and consid- erable time spent with patients and other family members. It is best undertaken by well-​trained health professionals (e.g. prac- tice or clinic nurses), and should be supported by clear written information. Weight reduction Many patients with hypertension are overweight, and weight re- duction by calorie restriction is an appropriate recommendation. The blood pressure lowering effect of weight reduction may be en- hanced by increased regular aerobic physical exercise, by alcohol moderation in heavy drinkers, and by a reduction in sodium intake. On average, blood pressure may fall by as much as 1 mm Hg per kg weight loss, although results vary in studies and the maximum overall effect of combined lifestyle interventions is an average of 10 mm Hg fall in SBP. Body mass index (BMI) is frequently used as a measure of overweight, but other measures of obesity—​particularly central obesity—​are better markers of adverse cardiovascular out- comes in people with hypertension. In this regard, weight reduction also has beneficial effects on associated risk factors such as insulin resistance, risk of developing diabetes, and dyslipidaemia. Dietary salt reduction Sodium intake influences blood pressure and all international guidelines recommend dietary sodium restriction. Dietary salt re- duction from an average of 10 to 5 g/​day (5 g = 1 teaspoon) lowers blood pressure by about 5/​2 mm Hg, with larger blood pressure falls in elderly people, blacks, and those with higher initial blood pres- sure levels. About one-​third of people will achieve a reduction of 5/​ 5 mm Hg or more. These effects are additive to the blood pressure lowering effect of a healthy diet (e.g. the Dietary Approaches to Stop Hypertension (DASH) diet; http://​www.nhlbi.nih.gov/​health/​ public/​heart/​hbp/​dash/​). Many patients will already be aware of the relationship between salt and blood pressure and will have discontinued adding salt at the table and even when cooking, but few are aware of the large amount of salt in processed foods, such as bread (one slice contains 0.5 g salt), some breakfast cereals, ready-​prepared meals, and flavour en- hancers such as stock cubes or manufactured sauces. Patients, and those who cook for patients, should be provided with specific written advice, such as that from http://​www.bpassoc.org.uk. Increased fruit and vegetable consumption Using the DASH diet, which increased vegetable consumption from two to seven portions per day, blood pressure was lowered by around 7/​3 mm Hg in hypertensive patients. Hypertensive pa- tients should therefore be given clear advice to increase fruit and vegetable intake to at least five portions per day. When this is com- bined with an increased use of low-​fat dairy products and reduc- tion of total and saturated fat, then blood pressure falls averaging 11/​6 mm Hg are seen. The mechanism whereby fruit and vegetable consumption lowers blood pressure is uncertain, but it may be due to an associated increase in potassium intake, as suggested by some supplementation studies. Physical activity Regular physical activity, especially when combined with dietary measures, can be particularly effective at reducing blood pressure (Table 16.17.2.4). The activity should be regular, aerobic (e.g. brisk walking), and tailored to the individual. For example, three vigorous training sessions per week may be appropriate for fit younger pa- tients, or brisk walking for 20 min/​day in older patients. This activity will be expected to reduce SBP and DBP by about 2–​3 mm Hg, with the combination of exercise and diet reducing both by 5–​6 mm Hg. Heavy physical exercise should be discouraged in people with severe hypertension or those in whom hypertension is poorly controlled. Exercise can be recommenced once drug therapy has been started and blood pressure is better controlled. In addition to its effects on blood pressure, physical exercise ap- pears to exert a strong protective effect against cardiovascular mor- tality and is associated with a lower risk of coronary heart disease in men and women. Protection is lost when exercise is discontinued. Any activity appears to be of benefit, but people who are more active appear to gain more protection. A reasonable strategy is regular aer- obic exercise (e.g. brisk walking) for at least 30 min, ideally on most days, but at least 3 days per week. Alcohol intake An alcohol intake of above 21 units per week is associated with blood pressure elevation, and binge drinking is associated with an increased risk of stroke. Hypertensive patients should be ad- vised to limit their alcohol intake to 21 units per week (men) and 14 units per week (women). On average, structured interventions to reduce alcohol consumption have a small effect on blood pres- sure, reducing SBP (and possibly DBP) by about 2–​3  mm Hg. Consumption of smaller amounts of alcohol, up to the recom- mended limit, may protect against cardiovascular disease and should not be discouraged. Box 16.17.2.4  Lifestyle measures that lower blood pressure and reduce cardiovascular disease risk Measures to lower blood pressure • Weight reduction • Reduced salt intake • Limitation of alcohol consumption • Increased physical activity • Increased fruit and vegetable consumption • Reduced total fat and saturated fat intake Measures to reduce cardiovascular disease risk • Cessation of smoking • Reduced total fat and saturated fat intake • Replacement of saturated fats with monounsaturated fats • Increased consumption of oily fish 16.17.2  Essential hypertension: Diagnosis, assessment, and treatment 3765 Caffeine consumption Following caffeine consumption there is a dose-​related increase in SBP of 5–​15 mm Hg and of DBP of 5–​10 mm Hg that persists for several hours. A systematic review of studies of median duration 8 weeks showed that people drinking an average of five cups of caf- feinated coffee a day had blood pressure 2.4 mm Hg (systolic) and 1.2 mm Hg (diastolic) higher than controls (no coffee, or decaffein- ated coffee). There is no good data on the effect of withdrawing or limiting caffeine intake in patients with hypertension. Sleep and blood pressure Blood pressure characteristically falls during sleep, and sleep duration impacts on the risk of developing hypertension. The risk of developing hypertension in one survey was increased by about twofold in adults in middle age who sleep 5 h or less each night. This may simply re- flect a higher 24 h average blood pressure load and longer duration of sympathetic nervous system activation as a consequence of less time asleep, which in turn would give rise to a higher risk of longer-​term cardiovascular structural damage, leading to sustained hypertension. Whatever the mechanism, sleep deprivation should be considered in the assessment of people developing hypertension. Consistent with the association between sleep deprivation and hypertension, high blood pressure is more common in patients with obstructive sleep apnoea. Although this could be explained by the fact that both conditions are commoner in males and in obese individuals, a few studies indicate that continuous positive airways pressure can reduce blood pressure, particularly nocturnal pressures, implying a causal relationship. Lifestyle strategies to reduce cardiovascular risk in hypertensive patients Cigarette smoking Patients with hypertension should be encouraged and given support to stop smoking. Nicotine replacement therapy and other strategies are safe and effective in people with hypertension and double the chance of quitting smoking. Those who fail on their first attempt to quit should be encouraged to continue trying: the chance of success increases with the number of quit attempts. Although smoking is not a major contributor to an elevated blood pressure, it does signifi- cantly amplify the cardiovascular risk associated with hypertension. Smoking is a major factor related to the persistent increase in cor- onary and stroke mortality in men with treated hypertension. Those who stop smoking experience a rapid decline in risk, by as much as 50% after 1 year, but up to 10 years may be needed to reach the risk level of those who have never smoked. Smoking an e-cigarette causes an acute rise in blood pressure of about 10/7 mm Hg that lasts for about 30 minutes, which is comparable to the effect of smoking a conventional (tobacco) cigarette, but overall vaping poses only a small fraction of the risks of smoking and switching com- pletely from smoking to vaping conveys substantial health benefits. Reduced dietary saturated fat intake Reducing dietary fat intake can reduce serum cholesterol values, which can reduce the risk of cardiovascular disease. All patients should be advised to keep total dietary intake of fat to less than one-​ third of their total energy intake, to keep the intake of saturated fats to less than one-​third of their total fat intake, and to replace saturated fats by an increased intake of monounsaturated fats. These dietary changes can be very effective, but reduce serum cholesterol by only about 6% on average, in part because of difficulty in sustaining such dietary discipline. A regular intake of fish and other sources of n-​3 fatty acids (at least two servings of fish per week) will further improve lipid profiles and has been shown to reduce blood pressure. Lifestyle modifications that are ineffective at lowering blood pressure Dietary supplements The best available evidence does not support the use of calcium, magnesium, or potassium supplementation (i.e. tablets), individu- ally or in combination, to achieve a worthwhile reduction in blood pressure. Inadequate information is available from randomized con- trolled trials to support any recommendation for garlic, herbal, or other complementary medicines. Psychological stress reduction Structured interventions to reduce stress (e.g. stress management programmes, meditation, yoga, cognitive therapies, breathing exer- cises, biofeedback, and acupuncture) have been shown to modestly reduce blood pressure in some but not all studies. However, many of these interventions are time consuming and have been short term, and it is difficult to know whether they would be an effective inter- vention for adequate blood pressure control over the longer term. Pharmacological treatments The treatment of hypertension has been subjected to many large randomized controlled trials that have compared active treatments with placebo, and different treatment strategies with each other. Hypertension has the most impressive evidence base in medicine to guide treatment decisions, and analysis of this has provided im- portant guiding principles with regard to treatment strategies: • Effective blood pressure lowering is overwhelmingly important in reducing the risk of major cardiovascular events in people with hypertension, thus the first priority in treatment is to control blood pressure. • Many patients will require more than one drug to control blood pressure; monotherapy is rarely sufficient. • Although early studies focused primarily on DBP as the treatment target, SBP is invariably more difficult to control and should now be the main focus of treatment. • The blood pressure response to an individual class of blood pres- sure lowering medication is heterogeneous, hence there is no ‘per- fect drug’ for every patient. • Some trials have indicated that certain comorbidities or target organ damage provide compelling indications for inclusion of specific classes of drug therapy in the treatment regimen. • There is inadequate clinical outcome data for treatment studies of younger patients as most of the studies, especially the more recent ones, have been conducted in patients over the age of 55 years, and typically with a mean age over 65 years. Blood pressure lowering therapy is effective at reducing the risk of stroke, myocardial infarction, heart failure, chronic kidney dis- ease, peripheral vascular disease, and death. It may also be effective at reducing the risk of vascular dementia. On average, lowering blood pressure by 20/​10 mm Hg will reduce the risk of major cardiovascular section 16  Cardiovascular disorders 3766 events by one-​half, with the reduction in stroke risk appearing to follow the predicted reduction in risk based on the epidemiological association between stroke and blood pressure. There appears to be a shortfall in the reduction in risk of ischaemic heart disease with blood pressure lowering when compared to epidemiological predic- tions, which is best addressed by attention to concomitant risk fac- tors. Importantly, the risk reduction associated with blood pressure lowering appears to be continuous across a wide range of blood pres- sures, thus the absolute benefit from treatment is greatest in those with the highest absolute cardiovascular disease risk. This provides the rationale for advocating the use of complementary strategies to re- duce cardiovascular disease risk (e.g. statins and antiplatelet therapy) in those with established vascular disease, target organ damage, or at high calculated cardiovascular disease risk (i.e. a calculated cardio- vascular disease risk of 20% or more over 10 years). The main classes of blood pressure lowering therapies are sum- marized in this section. Those that have been used in clinical trials are shown in Table 16.17.2.5. The overriding treatment priority is to control blood pressure, but there is general consensus among international guidelines about indications and contraindications for the use of specific classes of blood pressure lowering therapy in specific clinical situations, and these are detailed in Tables 16.17.2.6 and 16.17.2.7. It is important to note that these lists are not compre- hensive and are subject to change as new evidence emerges, and the reader is directed towards the information sheets for each specific drug for more detailed prescribing information. Diuretics Thiazides Thiazide-​type diuretics (TTDs) were the first major class of drug used to treat hypertension on a large scale and they remain one of the main therapeutic options for the treatment of essential hypertension. Commonly used examples include chlortalidone, hydrochlorothiazide, and bendroflumethiazide. TTDs lower blood pressure by a complex series of mechanisms. Urinary loss of sodium resulting from a blockade of renal tubular reabsorption of sodium is integral to the antihypertensive effect. The early changes in salt and water balance are often accompanied by counteractivation of sev- eral vasoconstrictor mechanisms, including the renin–​angiotensin–​ aldosterone system, which may transiently raise peripheral vascular resistance and attenuate blood pressure lowering. There is subse- quently a gradual reduction in peripheral vascular resistance and a new steady state of reduced total body sodium and blood pressure. The sustained actions of thiazide/​thiazide-​like diuretics on the kidney make them preferable to loop diuretics for the control of blood pressure. This is because loop diuretics are shorter acting, and the short-​term sodium and water loss is usually compen- sated for by sodium retention during the latter part of the dosing interval and reduced blood pressure lowering efficacy. There is really no place for loop diuretics in the routine management of essential hypertension, but TTDs become ineffective in patients with a glomerular filtration rate below 30 ml/​min and in such Table 16.17.2.5  Drugs used in clinical trials of treatment of hypertension Class of drug Drug Target dose (mg) ACE inhibitors Captopril 150–​200 Enalapril 20 Lisinopril 40 Angiotensin receptor blockers Eprosartan 600–​800 Candesartan 12–​32 Losartan 100 Valsartan 160–​320 Irbesartan 300 β-​blockers Atenolol 100 Metoprolol 100–​200 Calcium channel blockers Amlodipine 10 Diltiazem extended release 360 Nitrendipine 20 Thiazide-​type diuretics Bendroflumethiazide 10 Chlortalidone 12.5–​25 Hydrochlorothiazide 25–​100 Indapamide 1.25–​2.5 Table 16.17.2.6  Indications favouring the use of specific classes of blood pressure lowering drugs Thiazide diuretics Isolated systolic hypertension (elderly) Heart failure Hypertension in blacks ACE inhibitors Heart failure LV dysfunction Postmyocardial infarction Diabetic nephropathy Non​diabetic nephropathy LV hypertrophy Carotid atherosclerosis Proteinuria/​microalbuminuria Atrial fibrillation Metabolic syndrome Angiotensin receptor blockers Heart failure Post-​myocardial infarction Diabetic nephropathy Proteinuria/​microalbuminuria LV hypertrophy Atrial fibrillation Metabolic syndrome ACEi-​induced cough β-​Blockers Angina pectoris Post-​myocardial infarction Heart failure Tachyarrhythmias Glaucoma Pregnancy Calcium antagonists (dihydropyridines) Isolated systolic hypertension (elderly) Angina pectoris LV hypertrophy Carotid/​coronary atherosclerosis Pregnancy Hypertension in blacks Diuretics (antialdosterone) Heart failure Post-​myocardial infarction Calcium antagonist (verapamil/​diltiazem) Angina pectoris Carotid atherosclerosis Supraventricular tachycardia Loop diuretics Stage 4 and 5 chronic kidney renal disease Heart failure 16.17.2  Essential hypertension: Diagnosis, assessment, and treatment 3767 patients loop diuretics are often required for effective blood pres- sure lowering, especially when there is clinical evidence of sodium and water retention. The main adverse effects of TTDs are hypokalaemia, hyponatraemia (less commonly), impaired glucose tolerance, and small increments in blood levels of LDL cholesterol and triglycerides. TTDs elevate serum uric acid levels and should be avoided in patients predisposed to gout. They should also be avoided in those receiving lithium because of a high risk of lithium toxicity. An incidental advantage of thiazides may be re- duction in osteoporosis as a result of calcium retention. To minimize the adverse effects of TTDs, low doses of these drugs have been recommended by guidelines for the treatment of essen- tial hypertension, and these are well tolerated. On the basis of some small studies it has been assumed that the dose response to TTDs is generally flat (unlike the adverse effect profile), and this has been used to further justify the low-​dose strategy for TTDs, but it should be emphasized that some patients do respond to and tolerate higher doses. Moreover, when thiazides are combined with drugs that block the renin–​angiotensin system (e.g. ACE inhibition), then the dose response is steeper and higher doses may be used in patients with more resistant hypertension. Potassium-​retaining diuretics Potassium-​retaining diuretics (e.g. spironolactone or amiloride), are effective blood pressure lowering agents that are much less commonly used for the routine treatment of hypertension. They can be very effective in combination with TTDs, and are increas- ingly used as part of a multidrug strategy for the treatment of re- sistant hypertension. They are used and effective in large doses in the treatment of primary aldosteronism. They have the advan- tage over TTDs in not causing hypokalaemia or hyperuricaemia and do not impair glucose tolerance, but spironolactone causes nipple tenderness and gynaecomastia in some patients, which is dose-​dependent and can limit its use. Eplerenone, which was de- veloped to bind selectively to mineralocorticoid receptors with minimized binding to progesterone and androgen receptors, does not have such sexual adverse effects. As would be antici- pated from their mode of action, if potassium-​sparing diuretics are used in combination with drugs that block the activity of the renin–​angiotensin system or in patients with renal impairment, then monitoring of serum potassium is required because of the increased risk of hyperkalaemia. β-​Adrenoceptor blocking drugs (β-​blockers) β-​Blockers reduce blood pressure and cardiovascular events in ­patients with hypertension. Most β-​blockers, with the exception of those with strong intrinsic sympathomimetic activity, reduce cardiac output due to their negative chronotropic and inotropic effects. As with diuretics, short-​term haemodynamic responses can be off-​set by counteractivation of vasoconstrictor mechanisms, which may limit initial blood pressure lowering. Longer-​term reduction in arterial pressure, which occurs over days, is due to restoration of vascular re- sistance to pretreatment levels. Partial blockade of renin release from the kidney may contribute to the later haemodynamic response. β-​Blockers differ in their duration of action, their selectivity for β1-​receptors, lipophilicity, and partial agonist activity. Side effects include lethargy, aches in the limbs on exercise, impaired concen- tration and memory, erectile dysfunction, vivid dreams, and exacer- bation of symptoms of peripheral vascular disease and Raynaud’s syndrome. They are contraindicated in asthma and can cause adverse metabolic effects, including impaired glucose tolerance and worsening of dyslipidaemia—​notably reduced HDL-​cholesterol and raised triglycerides. There is accumulating evidence that β-​blockers increase the likelihood of new-​onset diabetes, particularly when combined with TTDs. Moreover, meta-​analyses suggest that there is a shortfall in cardiovascular protection with β-​blocker-​based treat- ment for hypertension (especially in stroke reduction) when com- pared to treatment with other main drug classes. As a consequence, British and American guidelines do not recommend β-​blockers as an initial therapy for uncomplicated hypertension, and they should only be used when there is a compelling indication other than blood pressure control (e.g. in patients with hypertension and angina or chronic heart failure). One exception is in younger women of child- bearing potential, in whom β-​blockers are often very effective at lowering blood pressure, perhaps due to higher-​renin levels of younger people, and safer than ACE inhibition or angiotensin re- ceptor blockers (ARBs) in those anticipating pregnancy. Calcium channel blockers This class of drug has been extensively used in treating hypertension since the 1970s: they are very effective at reducing blood pressure and have an extensive evidence base supporting their use. In add- ition to their blood pressure lowering properties, they are also ef- fective antianginal agents. Table 16.17.2.7  Compelling and possible contraindications to specific classes of blood pressure lowering therapies Compelling Possible Thiazide diuretics Gout Metabolic syndrome Glucose intolerance Pregnancy β-​Blockers Asthma AV block (grade 2 or 3) Peripheral artery disease Metabolic syndrome Glucose intolerance Athletes and physically active patients Chronic obstructive pulmonary disease Calcium antagonists (dihydropyridines) Tachyarrhythmias Heart failure Calcium antagonists (verapamil, diltiazem) AV block (grade 2 or 3) Heart failure ACE inhibitors Pregnancy Angioneurotic oedema Hyperkalaemia Bilateral renal artery stenosis Angiotensin receptor antagonists Pregnancy Hyperkalaemia Bilateral renal artery stenosis Diuretics (antialdosterone) Renal failure Hyperkalaemia ACE, angiotensin converting enzyme; AV, atrioventricular. Data from Williams, et al. BHS Guidelines 2004. Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society, 2004—​BHS IV. section 16  Cardiovascular disorders 3768 There are two main groups of calcium channel blocker (CCB), the dihydropyridines (e.g. amlodipine, nifedipine) and the non​dihydropyridines (e.g. diltiazem, verapamil). The dihydropyrid­ ine CCBs act mainly by inducing relaxation of arterial smooth muscle by blocking L-​type calcium channels, thereby inducing peripheral vascular relaxation with a fall in vascular resistance and arterial pressure. Non​dihydropyridine CCBs also block calcium channels in cardiac muscle and reduce cardiac output. Verapamil has an additional antiarrhythmic action through its effects on the atrioventricular node. The earlier formulations of some dihydropyridines, such as cap- sular nifedipine, had a rapid onset of action, unpredictable effects on blood pressure, and were accompanied by reflex sympathetic stimulation and tachycardia. With the availability of longer-​acting formulations of dihydropyridine CCBs, these shorter-​acting CCBs have no place in the management of hypertension, even (and espe- cially) in the emergency setting (see Chapter 16.17.5). Side effects of dihydropyridine CCBs include dose-​dependent peripheral oedema, which is not due to fluid retention but results from transudation of fluid from the vascular compartments into the dependent tissues due to precapillary arteriolar dilatation. This oedema does not respond to diuretic therapy but is alleviated by limb elevation, and there is some evidence that it may be reduced by coadministration of an ACE inhibitor or ARB because of their effects on venous capacitance. Gum hypertrophy can occur with dihydropyridine CCBs, but is rarely seen with non​dihydropyridine CCBs. Non​dihydropyridine CCBs cause less peripheral oedema but are negatively inotropic and negatively chronotropic and should therefore be avoided in patients with compromised left ventricular function, and used with caution in combination with β-​blockers. Verapamil use is commonly accompanied by constipation. Blockade of the renin–​angiotensin system The renin–​angiotensin system has been a very popular target for drug development to treat hypertension. Inhibition of the renin–​angiotensin system is predictably effective at lowering blood pressure by inhibiting the various central and peripheral pressor effects of angiotensin II, and blockade may also lower blood pressure by other mechanisms involving improvements in endothelial function, vagal tone, and baro- receptor function, and via inhibition of the renal tubular reabsorption of sodium. In addition, inhibition of the renin–​angiotensin system has been promoted by clinical trial evidence showing reduced morbidity and mortality with these treatments in patients with heart failure, delay in the progression of renal disease, and reduction in cardiovascular events in patients at high cardiovascular risk. ACE inhibitors The ACE inhibitors, which block the conversion of angiotensin I to angiotensin II, were the first effective drugs to inhibit the renin–​ angiotensin system and have been used to treat hypertension since the late 1970s. The resulting reduction in levels of angiotensin II leads to vasodilatation and a fall in blood pressure. Angiotensin II has many additional actions that are potentially harmful to the cardiovascular system and have been implicated in the pathogenesis of structural changes in the heart, blood vessels, and kidneys in hypertension. Sharp falls in blood pressure following the introduction of ACE inhibitors may occur when the renin–​angiotensin system is acti- vated (e.g. in patients who are dehydrated, in heart failure, or have accelerated hypertension). This is rarely a problem when therapy is initiated in uncomplicated hypertensive patients. Side effects of ACE inhibitors include the development of a persistent dry cough in about 20% of users. This is more common in women and in people from Asia, and only disappears after discontinuation of the drug. Another rare but important complication is angio-​oedema, which occurs in around 1% but is much more common in the black popu- lation (c.4%). ACE inhibitors should be avoided in women of child- bearing potential because of the danger of fetal renal malformation. They should not be used in patients with known bilateral renal artery disease because they may precipitate deterioration in renal function and renal failure. It should be routine practice to check the serum creatinine 10–​14 days after initiation of ACE inhibition, and to stop the drug if this has risen by more than 30%: lesser elevations can be tolerated. Particularly careful monitoring of renal function and serum potassium is required in patients with more advanced renal impairment of any cause because of the risk of hyperkalaemia. Angiotensin receptor blockers (ARBs) In the 1990s, the ARBs, which are highly selective inhibitors of the angiotensin II type 1 receptor (AT-​1), emerged as an alternative to ACE inhibition. In general, they are as effective as ACE inhibitors at reducing blood pressure, but appear to have a longer duration of action, and in common with ACE inhibitors they inhibit the actions of angiotensin II on the cardiovascular system and kidney. They are very well tolerated by patients, with a placebo-​like adverse effect profile. Cough and angio-​oedema are much less likely to occur than with ACE inhibitors and most guidelines recommend switching pa- tients to an ARB when an ACE-​induced cough occurs. Cautions and contraindications are similar to those outlined for ACE inhibitors. Direct renin inhibition A third strategy to inhibit the renin–​angiotensin system for the treat- ment of hypertension is direct renin inhibition, the first non​peptide, orally active, direct renin inhibitor being aliskiren. This has high specifi- city for renin and is a potent renin inhibitor with a long half-​life (c.24 h). It inhibits the rate-​limiting step in angiotensin production, notably the renin-​dependent conversion of angiotensinogen to angiotensin I, and in initial studies appeared to have similar blood pressure lowering effi- cacy to other means of inhibiting the renin system (i.e. ACE inhibition or ARBs), but with less side effects than ACE inhibition. However, the combination of aliskiren with ACE inhibitor or ARBs was found to have serious adverse cardiovascular and renal outcomes in a large clinical trial (ALTITUDE) that was stopped following interim data analysis, as a result of which some regulatory authorities have stated that the com- bination of these drugs is contraindicated (in patients with diabetes) or not recommended (in other patients), and recommended that aliskiren should not be used in those with eGFR less than 30 ml/​min (CKD4). α-​Adrenergic blocking drugs The original members of this class (e.g. prazosin) were short acting drugs that blocked the activation of α1 adrenoceptors in the vas- culature, leading to vasodilatation. The dosages that were initially recommended were too high, and postural hypotension and syn- cope proved serious problems that retarded the acceptance of this class of drugs, although the use of lower doses and the development of longer-​acting agents (e.g. doxazosin) has largely overcome this problem. Blockade of sphincteric receptors improves symptoms in 16.17.2  Essential hypertension: Diagnosis, assessment, and treatment 3769 patients with benign prostatic hypertrophy, and occasionally these same sphincteric effects can worsen symptoms of stress incontin- ence in women. Uniquely among antihypertensive drugs, the α1-​ antagonists produce modest favourable changes in plasma lipids, with a reduction in total and LDL cholesterol and triglycerides, and an increase in high-​density lipoprotein (HDL) cholesterol. Centrally acting sympatholytic drugs Some of the earliest drugs developed to treat hypertension targeted the activation of the sympathetic nervous system at various levels, including the cardiovascular regulatory nuclei in the brainstem, the peripheral autonomic ganglia, and the post-​ganglionic sympathetic neuron. With one or two exceptions, few of these agents have any re- sidual role to play in the modern treatment of hypertension because side effects are common, often unpleasant, and potentially harmful. Methyldopa Methyldopa reduces sympathetic outflow from the brainstem. It was originally developed in the late 1950s and for many years it was one of the mainstays of antihypertensive therapy. However, it frequently causes sedation, impaired psychomotor performance, dry mouth, and erectile dysfunction. This unfavourable impact upon quality of life led to it being replaced by more effective drugs, although it is still used extensively in the management of hypertension of pregnancy, which is now its main indication. Clonidine Clonidine is now rarely used because of its short duration of action and risk of a withdrawal syndrome after discontinuing the drug: sudden dis- continuation results in a rebound rise in catecholamines with features that may resemble phaeochromocytoma, such as severe hypertension, tachycardia, and sweating. This is exacerbated when patients are also receiving non​selective β-​blockers such as propranolol. The syndrome is treated by readministering the drug and then gradually discontinuing it, or the intravenous infusion of labetalol in an emergency. Moxonidine Moxonidine is a newer centrally acting agent that is an imidazoline receptor agonist, acting to reduce sympathetic outflow and blood pressure. It has a lower incidence of side effects and is better toler- ated than other centrally acting agents. Direct vasodilators Hydralazine Hydralazine was previously extensively used as part of a stepped care regimen. However, its main disadvantages were sympathetic activation and the development of a lupus-​like syndrome, particularly in patients with the slow acetylator genotype, which together with the need for multiple daily dosage have resulted in its replacement by other agents, except for occasional use in severe hypertension and hypertension as- sociated with pregnancy. No end-​point trials have been carried out. Minoxidil Minoxidil is a very potent vasodilator. Its use is confined to specialist practise for the treatment of severe and resistant hypertension because of its side effects, which include stimulation of body hair growth, tachycardia, and severe fluid retention. For this reason, combination with a potent loop diuretic and a β-​blocker is almost always necessary. Other therapies Hypertension is common, as are the side effects of its treatment, which continue to drive the search for new drugs that might be safer, more effective, better tolerated and/​or have additional benefits (e.g. on endothelial function). Drugs under investigation include endothelin receptor antagonists and phosphodiesterase type 5 inhibitors. Pharmacological treatment strategies Initial drug therapy After a suitable period of observation and after assessment of con- comitant risk factors, comorbid disease, and overall cardiovascular disease risk, a decision may be reached to treat the patient with drug therapy. However, even when this is contemplated it is important to continue to emphasize the importance of lifestyle changes to re- duce cardiovascular risk and enhance the efficiency of blood pres- sure lowering medications, and it is also important to view the patient’s blood pressure in the context of their overall cardiovascular risk burden and decide whether other therapies such as statins and antiplatelet therapy might also be appropriate. Once a decision has been made to initiate drug therapy, it is usual to commence treatment with a single drug. Monotherapy will on average reduce systolic pressure by 7 to 13 mm Hg and diastolic pressure by 4–​ 8 mm Hg. This will give some indication as to whether monotherapy is likely to be effective at achieving the recommended blood pressure goal, but there is marked heterogeneity in response among individ- uals to particular drugs. Treatment should normally commence with a low dose of the drug selected. If an adequate response is not obtained, the dose of the initial drug can be increased. However, if there has not been much response to the starting dose and the patient’s blood pressure remains well short of the target blood pressure, then a more appropriate action would be to add a second drug, either separately or as a combination tablet, mindful of the fact that most people with hypertension require two or more drugs to adequately control their blood pressure. Alternatively, if the initial drug produced a weak re- sponse, or none at all, and the patient could conceivably get to their blood pressure goal on monotherapy, then the first drug could be dis- continued and replaced with another class of antihypertensive agent. Initial therapy with a two-​drug combination The heterogeneity of blood pressure responses to different classes of blood pressure lowering drugs and the likelihood that most people will be uncontrolled by monotherapy, and that up-titration in people at high risk may be too slow and leave them at risk for too long, has led to the suggestion that more people should be initiated on treatment with low-​dose combination therapy. Low-​dose two-​drug combination therapy has long been recommended in European and American hypertension guidelines for the treatment of patients whose blood pressure is greater than 20/​10 mm Hg above their goal blood pressure and therefore unlikely to achieve their goal blood pressure with monotherapy, and the 2018 European guideline has gone further than this by recommending that, with the exception of frail older patients and those at low risk and with Grade 1 hyper- tension (and particularly if SBP is <150 mm Hg), all patients should start treatment with a two drug combination, preferably in a single pill. It remains to be seen whether this recommendation will get traction in routine practice. The European guidelines are shown in Fig. 16.17.2.7 and the American guidelines in Fig. 16.17.2.8. section 16  Cardiovascular disorders 3770 Fig. 16.17.2.7  2018 European Society of Hypertension/European Society of Cardiology guideline recommendations for uncomplicated hypertension (Panel A), hypertension in patients with coronary artery disease (Panel B), and hypertension in patients with chronic kidney disease (Panel C). ACEi, angiotensin coverting enzyme inhibitor; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; CKD, chronic kidney disease; CVD, cardiovascular disease; MI, myocardial infarction; o.d., once daily. a CKD is defined as eGFR <60 ml/min/1.73 m2. b Use loop diuretic when eGFR <30 ml/min/1.73 m2. c Beware of the risk of hyperkalaemia. Reproduced from Williams B, et al. (2018). 2018 ESC/ESH guidelines for the management of arterial hypertension. J Hypertens, 36, 1953–2041, with permission from Wolters Kluwer. 16.17.2  Essential hypertension: Diagnosis, assessment, and treatment 3771 Adult aged ≥ 18 years with hypertension Implement lifestyle interventions (continue throughout management) Set blood pressure goal and initiate blood pressure lowering-medication based on age, diabetes, and chronic kidney disease (CKD) General population (no diabetes or CKD) Age ≥60 years Age <60 years All ages Diabetes present No CKD All ages CKD present with or without diabetes Blood pressure goal SBP <140 mm Hg DBP <90 mm Hg Blood pressure goal SBP <140 mm Hg DBP <90 mm Hg Blood pressure goal SBP <140 mm Hg DBP <90 mm Hg Blood pressure goal SBP <150 mm Hg DBP <90 mm Hg Nonblack Initiate thiazide-type diuretic or ACEI or ARB or CCB, alone or in combinationa Select a drug treatment titration strategy A. Maximize first medication before adding second or B. Add second medication before reaching maximum dose of first medication or C. Start with 2 medication classes separately or as fixed-dose combination Reinforce medication and lifestyle adherence. For strategies A and B, add and titrate thiazide-type diuretic or ACEI or ARB or CCB (use medication class not previously selected and avoid combined use of ACEI and ARB). For strategy C, titrate doses of initial medications to maximum. Reinforce medication and lifestyle adherence. Add and titrate thiazide-type diuretic or ACEI or ARB or CCB (use medication class not previously selected and avoid combined use of ACEI and ARB). Reinforce medication and lifestyle adherence. Add additional medication class (eg. β-blocker, aldosterone antagonist, or others) and/or refer to physician with expertise in hypertension management. Continue current treatment and monitoring.b Yes Yes Yes Yes No No No At goal blood pressure? At goal blood pressure? At goal blood pressure? No Initiate thiazide-type diuretic or CCB, alone or in combination Initiate ACEI or ARB, alone or in combination with other drug classa Black All races Diabetes or CKD present At goal blood pressure? Fig. 16.17.2.8  JNC8 hypertension guideline management algorithm. Note: (a) ACE inhibitor and ARBs should not be used in combination; (b) if blood pressure fails to be maintained at goal, re-​enter the algorithm where appropriate based on the current individual therapeutic plan. From James PA, et al. (2014). 2014 Evidence-​based guidelines for the management of high blood pressure in adults. Report from the panel members appointed to the Eighth Joint National Committee (JNC8). JAMA, 311, 507–​20. section 16  Cardiovascular disorders 3772 Choice of initial therapy There is some variation in the international guidelines with re- gard to the preferred initial therapy for essential hypertension. In the United States of America, the Joint National Committee 8 (JNC8) guideline recommends initial drug treatment with an ACE inhibitor, ARB, CCB, or TTD in non​black hypertensive patients, with a CCB or TTD preferred in black patients (Fig. 16.17.2.8 and Table 16.17.2.8). The 2018 European guideline makes recommendations based on the patient’s comorbidities, in particular coronary artery disease and chronic kidney disease, but for uncomplicated hypertension the recommendation is for an ACEi or ARB in combination with a CCB or TTD in a single pill combination (Table 16.17.2.7 and Fig. 16.17.2.7). The British Hypertension Society/​NICE guideline suggests that the most appropriate initial blood pressure lowering agent (1) for people 55 years or older (without type 2 diabetes), and for black people of African or Caribbean family origin of any age (without type 2 diabetes), is a CCB, with a thiazide-​like diuretic (e.g. indapamide) preferred if a CCB is not suitable; and (b) for people aged under 55 years, and any person with type 2 diabetes, an ACE inhibitor or a low-​cost ARB is preferred initial therapy (Fig. 16.17.2.9). The ra- tionale for this recommendation was founded on the observation that plasma renin levels fall as people age and are lower in blacks at any age. Therefore drugs that target the renin system are more likely to be more effective initial therapy in higher-​renin younger patients, whereas the converse is true with ageing. The argument against the use of β-​blockers as a preferred initial therapy (especially for older patients), unless there are compelling other indications (Table 16.17.2.7), is because they appear less effective at reducing the risk of stroke than the alternatives, are associated with an in- creased risk of developing diabetes, and are the least cost-​effective treatment option for essential hypertension. Combination therapy for controlling blood pressure All guidelines recognize that combinations of blood pressure lowering drugs are often required to achieve recommended blood pressure goals. If two drugs in a single pill combination are inad- equate the 2018 European guidelines recommend the use of a renin angiotensin system blocker, a calcium channel blocker and a diuretic in a single pill combination, followed if necessary by the intro- duction of spironolactone. The American JNC8 guidelines (Fig. 16.17.2.8 and Table 16.17.2.8) recommend selecting any two of the medications recommended as suitable for the particular patient as initial therapy. The British guideline (Fig. 16.17.2.9) provides ex- plicit guidance on preferred combinations of treatment as follows: • Step 2—​a CCB (C) combined with either an ACE inhibitor or ARB (A); • Step 3—​add a thiazide-​like diuretic (D); • Step 4—​add higher-​dose thiazide-​like diuretic, spironolactone, an α-​blocker or a β-​blocker. The preference for the combination of A + C at step 2 is based on data (e.g. the ACCOMPLISH study), suggesting that A + C may be more effective than A + D at preventing cardiovascular events, despite similarities in blood pressure control. Resistant hypertension Drug-​resistant hypertension can be defined as blood pressure that is not controlled despite treatment with an appropriate combination of three drug therapies (e.g. A + C + D—​see Fig. 16.17.2.9) prescribed at their maximum recommended and tolerated doses. In the ab- sence of evidence of target organ damage, white coat hypertension should be excluded by 24 h ambulatory monitoring if this has not already been done. Other causes for resistant hypertension include (1) secondary hypertension (e.g. renovascular or endocrine); (2) in- gestion of drugs that may raise blood pressure (e.g. non​steroidal anti-​inflammatory agents); (3) heavy alcohol intake; (4) sleep ap- noea; (5) sodium and fluid retention as a result of inadequate diur- etic therapy; and (6) poor patient adherence to treatment. Poor adherence to therapy is often difficult to detect in hyperten- sive patients and can lead to expensive investigations for secondary causes. One way of detecting effectiveness of treatment is to use ABPM to monitor blood pressure after directly observed consump- tion of medication. Although this may not resolve the problem of adherence to treatment, it will identify whether the treatment is effective if adhered to, thus avoiding the need for further investi- gations. Where adherence is obviously poor, certain manoeuvres can help to improve it. The treatment should be made as simple as possible, using once-​daily drugs and combination tablets, and a Table 16.17.2.8  Three strategies for the drug treatment of hypertension Strategy Description First step Second step Third (final) step A Start one drug, titrate to maximum dose, and then add a second drug Titrate the initial drug up to its maximum recommended dose to achieve goal BP. Move to second step if BP goal not achieved Add a second drug (ACE inhibitor, ARB, CCB, or thiazide-​type diuretic) and titrate this up to its maximum recommended dose to achieve goal BP. Move to third step if BP goal not achieved Add a third drug (ACE inhibitor, ARB, CCB or thiazide-​type diuretic), avoiding the combined use of an ACE inhibitor and ARB, and titrate this up to its maximum recommended dose to achieve goal BP. B Start one drug and then add a second drug before achieving maximum dose of the initial drug Start with one drug, then add a second drug before achieving the maximum recommended dose of the initial drug, then titrate both drugs up to their maximum recommended doses to achieve goal BP. Move to final step if BP goal not achieved C Start with two drugs at the same time, either as separate pills or a combination pill Start with two drugs simultaneously, either as two separate drugs or as a combination pill. Move to final step if BP goal not achieved 16.17.2  Essential hypertension: Diagnosis, assessment, and treatment 3773 carer needs to be involved in administering medication to those who are confused. Whenever possible, effective communication with full information and involvement of the patient in his or her treatment is essential. Nurses, pharmacists, and other health professionals can play a vital role in this process. Most patients with truly drug-​resistant hypertension (i.e. those who are taking their medications as prescribed) are likely to be re- taining sodium and will respond to further diuretic therapy. A sup- pressed plasma renin despite treatment with A + C + D would be indicative of sodium retention because these treatments would be expected to elevate plasma renin, hence the preferred initial ap- proach to treatment in this situation is further diuretic therapy, either with increased dosage of the thiazide diuretic, or using low-​ dose spironolactone (e.g. 25 mg/​day), or amiloride (10–​20 mg/​day), with careful monitoring of electrolytes. A recent randomized cross-​ over trial found the addition of spironolactone to be more effective than that of bisoprolol or doxazosin in this context. For some pa- tients with very severe drug-​resistant hypertension it may be neces- sary to use a combination of minoxidil, loop diuretic, and β-​blocker to improve blood pressure control. Follow-​up It is essential that patients are monitored regularly and it is im- portant that this message is conveyed to the patient. In the early stages of treatment, the frequency of monitoring will be deter- mined by the response to therapy, comorbidities, and the com- plexity of the treatment regimen required to control the blood pressure. Once blood pressure is controlled, patients should be re- viewed at least annually, and most will be reviewed every 6 months. Patients are increasingly monitoring their own blood pressure in the intervening period. Withdrawal of therapy Most patients with hypertension require lifelong therapy. Some with grade I  hypertension who make substantial adjustments to their lifestyle may obtain sufficient fall in their blood pressure to warrant withdrawal of monotherapy. However, patients with target organ damage or those at high cardiovascular disease risk should not usually have their therapy withdrawn, unless there is a compelling clinical reason to do so. It is also important to note that in patients with previously severe hypertension that has subsequently been well Adult under 55 years, and any patient with type 2 diabetes Adult over 55 years or black person of African or Caribbean family origin of any age (who do not have type 2 diabetes) Key A–ACE inhibitor or angiotensin II receptor blocker (ARB)1 C–Calcium-channel blocker (CCB) D–Thiazide-like diuretic, e.g. indapamide C2 A Step 1 Step 2 Step 3 Step 4 A + C2 A + C + D Resistant hypertension A + C + D consider further diuretic3, 4 or α- or β-blocker5 Consider seeking expert advice 1 Choose a low-cost ARB. 2 A CCB is preferred but consider a thiazide-like diuretic if a CCB is not tolerated or the person has oedema, evidence of heart failure or a high risk of heart failure. 3 Consider a low close of spironolactone4 or higher doses of a thiazide-like diuretic. 4 At the time of NICE consultation (March 2019) not all forms of spironolactone had a marketing authorisation for this indication. Informed consent should be obtained and documented. 5 Consider an α- or β-blocker if further diuretic therapy is not tolerated, or is contraindicated or ineffective. Fig. 16.17.2.9  British Hypertension Society/​NICE treatment algorithm for the treatment of essential hypertension. From National Institute for Health and Care Excellence (2011) CG 127 Hypertension: management of hypertension in adults in primary care. Available from https://​www.nice.org.uk/​CG127, with modification from National Clinical Guideline Centre (2019) CG 136 Hypertension in adults: diagnosis and management. Available from https://www.nice.org.uk/ng136. section 16  Cardiovascular disorders 3774 controlled, treatment withdrawal may not always result in an im- mediate increase in blood pressure. This can sometimes convey the false impression that treatment may no longer be required because blood pressure can sometimes take many months to progressively rise back to dangerously high pretreatment values. Thus, any patient who discontinues therapy must remain under review with regular monitoring of their blood pressure, and all but a very few will re- quire treatment again. Other issues Non​adherence with therapy Non​adherence to antihypertensive medication is common: after ex- clusion of white coat and secondary hypertension, 50% of patients with apparent resistance to antihypertensive drugs are partially or completely non​adherent to prescribed treatment. Indirect tests of adherence include asking patients to complete a structured, self-​reported medication adherence measure (e.g. Morisky), patient interview, pill counts, and prescription refill counts. Another approach is supervised administration of medi- cations and monitoring of blood pressure, but this requires appro- priate clinical staff and facilities and is therefore expensive, as well as being inconvenient for patients. An objective test is therapeutic drug monitoring in blood or urine. The latter has the advantages of being non​invasive, that sampling time is not important, and that a single assay can detect multiple drugs/​metabolites, the concen- trations of which are typically higher than in the blood. It is not, however, a panacea: it is difficult to develop an analytic method suitable for extraction and concentration of all drugs; the complex metabolism of some drugs means that the parent compound may not be present (particularly ACE inhibitors); and it does not allow judgement about when a patient took any drug that is found in their urine. A survey of UK hypertension specialists in 2016 reported that about 60% did not routinely check adherence, but awareness of the importance of this issue is increasing, and urinary testing is being more widely adopted. Factors responsible for non​adherence are shown in Table 16.17.2.9. To deal with the matter requires the physician to engage in an open and honest discussion with the patient to explore the reasons underlying their failure to take their medication as prescribed. It may be that an asymptomatic patient is unaware of the risks of per- sistent high blood pressure and the possible harmful consequences of it remaining so, and discussion may be helped by visual repre- sentations of risk. It will almost certainly be important to find out how the patient is managing their drugs, in particular the number of different drugs, their dosing frequency, and perceived side effects. Complicated dosing regimens are associated with lower adherence, hence use of single pill combination drugs may improve matters, and it may be appropriate to negotiate a reduction in the number of pills in the hope of achieving a higher but more realistic blood pressure target. Use of motivational interviewing techniques, which can be beneficial in encouraging lifestyle changes and managing substance abuse, has also been shown to improve medication adherence. Table 16.17.2.9  Factors contributing to non​adherence with antihypertensive drugs and possible solutions Factors Possible solutions Socioeconomic Poor socioeconomic status Illiteracy Unemployment Limited drug supply Cost of drugs Make patients aware of support from governmental and voluntary agencies such as the Citizens Advice Bureau in the UK Issue repeat prescriptions to cover a longer duration—​such as three months Healthcare system Clinician-​patient relationship Lack of knowledge and training for healthcare providers Inadequate time for consultation Book longer appointments Training of healthcare assistants, nurses, doctors, and pharmacists to discuss adherence Condition Lack of symptoms Chronic or incurable disease No immediate consequences of stopping the drugs Education through written and verbal information—​shared decision making Patient support groups Peer support and education Treatment Complex treatment regimens Duration of treatment Low drug tolerability and adverse effects of treatment such as dry cough with angiotensin converting enzyme inhibitors, ankle swelling with calcium channel blockers, and electrolyte disturbances and gout with diuretics Simplify the regimen and minimize side effects through use of monotherapy, single pill combination drugs, lower doses to prevent side effects, slow release formulations to reduce dose frequency, trying other drugs in the same class or changing the class Patient Patient’s knowledge of the disease Patient’s perception of risk and awareness of costs and benefits of treatment Non​acceptance of monitoring Psychiatric illness Patient education through written and verbal information Motivational interviewing Promoting self-​care through home monitoring Using smart phone applications to set medication reminders and record their home blood pressure, which could be shared electronically with their doctor Reproduced from Hammed MA, Dasgupta I, Gill P (2016). Poor adherence to antihypertensive drugs. BMJ, 354, i3268, with permission from BMJ Publishing Group Ltd. Adapted from WHO report on adherence to long term therapies (http://​apps.who.int/​medicinedocs/​fr/​d/​Js4883e/​) 16.17.2  Essential hypertension: Diagnosis, assessment, and treatment 3775 Indications for specialist referral There are circumstances when referral to a specialist centre is in- dicated for the management of hypertension. These include uncer- tainty about the decision to treat, investigations to exclude secondary hypertension, severe and complicated hypertension, and resistant hypertension, among others as detailed in Box 16.17.2.5. Medication to reduce cardiovascular risk Blood pressure should not be treated in isolation and should be considered as part of a comprehensive strategy to reduce cardiovas- cular disease risk. In this regard, patients at high risk, that is, those with established cardiovascular disease, target organ damage, and/​ or diabetes, or those with a calculated cardiovascular disease risk which is elevated (e.g. ≥10% over 10 years), should be offered add- itional interventions to reduce risk. These include reinforcement of lifestyle advice, especially smoking cessation, and treatment with statin therapy to further reduce their risk of stroke and coronary disease. The routine use of statins to reduce total cholesterol values by 1 mmol/​litre has been associated with a reduction in the risk of is- chaemic heart disease events by about one-​third and stroke by about one-​fifth, over and above the benefit already accrued from blood pressure lowering. Moreover, the relative risk reduction associated with statin therapy in higher-​risk hypertensive patients is not de- pendent on a high baseline cholesterol value. Once blood pressure has been controlled, higher-​risk hyperten- sive patients should also be considered for treatment with low-​dose aspirin (75 mg/​day). This has been shown to reduce the incidence of myocardial infarction in higher-​risk patients over 50 years old and should be offered routinely to patients who come into this category and who do not have contraindications. In view of the increased in- cidence of haemorrhage, it is not indicated in lower-​risk hyperten- sive patients. Intercurrent illness Patients who develop intercurrent illness that is likely to lead to volume depletion (e.g. diarrhoea, vomiting, high fever) should be told to stop taking their antihypertensive medications (particu- larly diuretics, ACEi, and ARBs) until they are able to eat and drink normally. This is very important if they develop postural dizziness, which is a marker of significant intravascular volume depletion in this clinical context. Other treatments for hypertension Device-​based therapies Renal denervation Initial uncontrolled and unblinded studies reported impressive re- duction in blood pressure in patients with resistant hypertension, but a subsequent blinded randomized trial (SIMPLICITY HTN-​3) failed to show benefit. A total of 535 patients were randomized in a 2:1 (active: sham) ratio: the mean reduction in office SBP at 6 months in the denervation group was 14 mm Hg, compared with 12 mm Hg in the controls, with 24 hr ambulatory SBP reduced by 7 mm Hg and 5 mm Hg, respectively. Following these findings several ongoing trials were stopped, but there has subsequently been a resurgence of interest. This treatment should not be offered to patients with hyper- tension in routine clinical practice. Baroreflex stimulation, carotid bulb expansion, and carotid body ablation In the Rheos Pivotal Trial 265 patients had a baroreflex activation therapy device implanted. One month after implantation they were randomized to receive baroreflex activation therapy immediately, or to have device activation delayed for 6 months. At 6 months, 42% of those whose device had been activated at 1 month had achieved SBP below 140 mm Hg, compared to 24% of those whose device had not been switched on; by 12 months over 50% of both groups had achieved this blood pressure target. Follow-​up over 22–​53 months suggested that the effect on blood pressure was maintained, and this persists at six years. However, the place of baroreflex activation therapy in the management of hypertension is not yet clear, and it should only be offered in the context of clinical trials. First-​in-​man studies of carotid bulb expansion using a dedicated carotid stent and of carotid body ablation using a transvenous cath- eter are ongoing. Arteriovenous anastomosis creation with a coupler In the ROX CONTROL HTN study patients were randomized to ar- teriovenous coupler therapy, which via an endovascular procedure created an arteriovenous anastomosis between an iliac artery and iliac vein, or to normal care. At 12 months office based SBP was re- duced by 25 mm Hg, DBP by 21 mm Hg and mean 24-hour ABPM by 13 mm Hg in 39 treated patients. This difference is clearly sub- stantial, but it is notable that the controls did not undergo any sham procedure (the importance of which has been well demonstrated in trials of renal denervation in hypertension), also that 30% of pa- tients in the intervention group required stenting or venoplasty for late ipsilateral venous stenosis. A randomized trial including a sham treated group (ROX CONTROL HTN-​2) was due to complete in May 2019, but as of September 2019 no results had been posted on Box 16.17.2.5  Recommended and possible indications for specialist referral for patients with hypertension • Urgent treatment needed: − Accelerated hypertension (severe hypertension with grade III—​IV retinopathy) − Particularly severe hypertension (>220/​120 mm Hg) − Impending complications (e.g. TIA, left ventricular failure) • Possible underlying cause: − Any clue in history or examination of a secondary cause, e.g. hypokalaemia with increased or high-​normal plasma sodium (Conn’s syndrome) − Elevated serum creatinine − Proteinuria or haematuria − Sudden-​onset or worsening of hypertension − Resistance to multidrug regimen, i.e. ≥3 drugs − Young age (any hypertension <20  years; needing treatment <30 years) • Therapeutic problems: − Multiple drug intolerance − Multiple drug contraindications − Persistent non​adherence • Special situations: − Unusual blood pressure variability − Possible white coat hypertension − Hypertension in pregnancy section 16  Cardiovascular disorders 3776 ClinicalTrials.gov. This treatment should only be offered in the con- text of clinical trials. Hypertension in specific groups of patients People of black African origin Hypertension is more prevalent in blacks, is associated with more target organ damage, and consequently carries a worse prognosis, with a particularly high risk of stroke. Black patients as a group tend to respond better to diuretics, CCBs, and dietary salt restriction than white patients. ACE inhibitors, ARBs, and β-​blockers are generally less effective as initial therapy, but become more effective when com- bined with diuretics and/​or CCBs. Older people Most people with hypertension are elderly, and elderly people have much higher absolute risk of cardiovascular events than younger people with hypertension. If a blood pressure of 140/​90 mm Hg or more is used to define hypertension, then over 70% of people over the age of 60 years will be hypertensive, with most of these having isolated systolic hypertension. Studies in patients aged more than 80 years confirm that treatment can be well tolerated and associated with impressive reductions in the risk of stroke, heart failure, and mortality. Surveys suggest that doctors consistently underestimate the risks and undertreat hypertension in older people, largely because of con- cerns about significant potential side effects, notably falls due to postural hypotension, and the belief that older patients recruited into trials are not representative of the patients that they care for. These concerns are real: analysis of a large database of individuals aged 70–​90 years showed a significant increase in hospitalizations for hip fracture in the 30 days after initiation of antihypertensive drug treatment. Other considerations when treating older people include eGFR declines with age and renal conservation of sodium and fluid in the face of depletion is impaired, thus elderly patients are more prone to dehydration as a result of diuretic therapy; clear- ance of drugs and their active metabolites is decreased as a result of declining hepatic and renal function; comorbidity is much more common; and communication and adherence with therapy may be more difficult with decline in cognitive function (and there is vari- able data from clinical trials as to whether this decline may be re- tarded or accelerated by antihypertensive treatment). With regard to very old and frail people, a European Society of Hypertension and European Union Geriatric Medicine Society working group have stated that: • Elderly patients should be monitored for the development of frailty using a validated tool, because change in treatment strategy may be needed if they become frail. • There is particular concern about polypharmacy in the very old and frail, hence combination of two antihypertensive drugs (whether or not they are in a single pill combination) should be considered if monotherapy fails to control BP, but only if the po- tential benefit of BP reduction is considered to outweigh the risk of hypotension, and use of more than three antihypertensive drugs should not be recommended in general. As a general rule, drug regimens should be as simple as possible and dosages increased gradually, the greatest danger resulting from lowering pressure too much and too rapidly. The low risk of fall injuries reported in clinical trials of healthy older adults may not reflect the risk in older adults with multiple chronic conditions. Physicians working in medical admission units will be all too fa- miliar with the scenario of the older patient, taking a plethora of antihypertensives, who is admitted after a collapse. Biological rather than chronological age should be the deciding factor in initiating antihypertensive treatment, but there is never any substitute for clin- ical common sense—​the elderly man with mild cognitive impair- ment, prone to falls, and with occasional dizziness on standing up, is not likely to be well served by the doctor who advocates medication to reduce marginally elevated blood pressure. Children Although secondary hypertension is more common in children than in adults, no specific cause is found for hypertension in most adoles- cents. The criteria for drug treatment, however, have to be modified because of the lower normal blood pressure range. The JNC guide- lines recommend that blood pressures above the 95th percentile—​ taking into account age, height, and sex—​should be considered elevated. In principle, treatment regimens are the same as those re- commended for adults, with appropriate dose adjustment. FURTHER READING Blood pressure measurement Agabiti-​Rosei E, et al. (2007). Central blood pressure measurements and antihypertensive therapy: a consensus document. Hypertension, 50, 1–​7. European Society of Hypertension (2008). Guidelines for blood pressure monitoring at home:  a summary report of the Second International Consensus Conference on Home Blood Pressure Monitoring. J Hypertens, 26, 1505–​26. Hodgkinson J, et al. (2011). Relative effectiveness of clinic and home blood pressure monitoring compared with ambulatory blood pres- sure monitoring in diagnosis of hypertension: systematic review. 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JAMA, 311, 507–​20. Kjeldsen SE, et al. (2016). Treatment of high blood pressure in eld- erly and octagenarians. European Society of Hypertension, Scientific Newsletter, Updated on Hypertension Management, 17, nr 63. Mancia G, et al. (2013). 2013 ESH/​ESC guidelines for the management of arterial hypertension: the task force for the management of ar- terial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J, 34, 2159–​219. Mendis S, et  al. (2007). World Health Organization (WHO) and International Society of Hypertension (ISH) risk prediction charts: assessment of cardiovascular risk for prevention and control of cardiovascular disease in low and middle-​income countries. J Hypertens, 25, 1578–​82. National Clinical Guideline Centre (2011). Hypertension—​the clinical management of primary hypertension in adults. Clinical guideline. http://​www.nice.org.uk/​guidance/​cg127. National Clinical Guideline Centre (2019). Hypertension in adults: diagnosis and management. NICE Guideline 136, https://www.nice. org.uk/ng136. The task force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension (2018). 2018 ESC/ESH guidelines for the manage- ment of arterial hypertension. J Hypertens, 36, 1953–2041. 16.17.3  Secondary hypertension Morris J. Brown and Fraz A. Mir ESSENTIALS The term ‘secondary hypertension’ is used to describe patients whose blood pressure is elevated by a single, identifiable cause, with an important subdivision being into reversible and irreversible causes: clinically, it is important to exclude the former, but not necessarily to find the latter. In the first two decades of life, the prevalence of secondary hyper- tension is greater than that of essential hypertension; thereafter, a patient is much more likely to have essential hypertension, but inves- tigations for secondary hypertension should still be assiduous in the twenties and thirties because the alternative entails so many years of tablet-​taking. Overall, it is estimated that about 10% of all patients with hypertension may have a secondary cause. All patients with hypertension should have a minimum set of in- vestigations (see Chapter 16.17.2). Common indications for further investigations are (1) any evidence of an underlying cause on his- tory or examination; (2) proteinuria, haematuria, or elevated serum creatinine (eGFR<30; CKD 4/​5); (3) hypokalaemia, even if caused by diuretics; (4) accelerated (malignant) hypertension; (5) documented recent onset or recent worsening of hypertension; (6)  resistant hypertension (not controlled with three antihypertensive drugs); (7) young age—​any hypertension at less than 20 years; any hyperten- sion needing treatment at less than 35 years. The minimum screen in younger patients should include serum electrolytes and bicarbonate, plasma renin and metanephrines to exclude phaeochromocytoma; 24-​h urinary sodium excretion should be measured either in all patients, or in those with ab- normal renin levels. Primary aldosteronism (Conn’s syndrome) Recent studies suggest that aldosterone-​producing adrenal aden- omas, which cause increased sodium retention through the epithe- lial sodium channel (ENaC) in the distal tubule and cortical collecting duct, are the single commonest known cause of hypertension. Diagnosis is usually on the basis of suggestive clinical biochemistry, radiological imaging showing an adenoma, and lateralization on selective adrenal sampling. Medical treatment is preferred for bilat- eral adrenal hyperplasia, control of hypertension and hypokalaemia before surgery for adenoma removal, older patients with adenomas who are well controlled, or where there is any doubt about diag- nosis or lateralization. Spironolactone is the treatment of choice but causes gynaecomastia in men. Elective surgery is indicated for younger patients with adenomas, and older patients intolerant of—​or uncontrolled by—​medical treatment. Renovascular hypertension This is most commonly due to intrinsic disease of the intima (e.g. atherosclerosis) or media (e.g. fibromuscular dysplasia). The main clinical clue is the finding in 50% of cases of a bruit anteriorly or pos- teriorly over a renal area. The diagnosis is made radiologically, most commonly by CT or MR angiography. In fibromuscular dysplasia, angioplasty is usually curative, with about three-​quarters of patients able to discontinue antihypertensive treatment. In atheromatous dis- ease, angioplasty is much less likely to be successful. Complete cure of hypertension is rare, and studies suggest no significant benefit in prevention of decline in renal function. Coarctation of the aorta Coarctation causes less than 1% of all cases of hypertension. The clas- sical clinical finding is radio–​femoral pulse delay or weak lower limb pulses. Diagnosis is confirmed by two-​dimensional echocardiog- raphy, or by CT or MR angiography. Treatment is by surgery, balloon dilatation, or stenting. 16.17.3  Secondary hypertension 3779 Phaeochromocytomas and paragangliomas Phaeochromocytomas are rare tumours of chromaffin tissue that account for 0.1 to 1% of cases of hypertension. About 40% of phaeochromocytomas and paragangliomas are associated with a single driver germline mutation, some with genetic syndromes, including von Hippel–​Lindau, multiple endocrine neoplasia type 2, and neurofibromatosis type 1. Hypertension, usually in associ- ation with one or more symptoms of headache, sweating, anxiety, and palpitations, is the most common presentation. Diagnosis is usually not difficult once the possibility of these conditions has been entertained, but excluding the diagnosis in patients who have clinical and/​or biochemical features of physiological catecholamine excess is problematic. The best screening test is to measure plasma normetanephrine (normetadrenaline) and metanephrine (metadrenaline) levels or, if unavailable, 24-​h urine metanephrines. CT or MRI scanning usually provides excellent imaging of the adrenal gland. Radioisotope scanning with the iodinated analogue of noradrenaline, m-​iodobenzylguanidine (mIBG), is usually helpful in localizing extra-​adrenal tumours. Surgery is the definitive treatment that cures hypertension in most patients. The offer of genetic counselling and screening ought to be considered in all patients. Introduction The term ‘secondary hypertension’ is used to describe patients whose blood pressure is elevated by a single, identifiable cause. Until the last decade there was an optimistic view that description of new causes of hypertension would mean that those regarded as having ‘essential hypertension’ would be an ever-​diminishing group. However, as discussed in Chapter 16.17.1, genome-​wide investiga- tion into the genetic bases of hypertension have shown that there are no common inherited susceptibility alleles that can explain more than 1–​2 mm Hg of a person’s blood pressure, and none has led to the discovery of inherited major gain-​ or loss-​of-​function mutations explaining hypertension in a small number of affected individuals. Hence it is now thought likely that essential hypertension differs from secondary hypertension not only in being unexplained, but in being, within each patient, due to a multiplicity of inherited and ac- quired characteristics. An important subdivision of secondary hypertension is into re- versible and irreversible causes: clinically it is important to exclude the former, but not necessarily to find the latter. Their elucidation may lead to improved medical therapy (e.g. by predicting the best diuretic in the monogenic causes of low-​renin hypertension), or help assess prognosis, as in the patient with proteinuria. However, the resource implications of finding causes, which can be consid- erable, need to be balanced against achievable gains. These in turn are influenced by the patient’s age, usually meaning that a search for secondary causes is easier to justify in young patients in whom small benefits are multiplied over many years. Age-​related prevalence of secondary hypertension Whereas essential hypertension is clearly an age-​related phenom- enon, the same is less true of secondary hypertension, although different causes predominate at different ages. The net likelihood of a given patient with hypertension having a secondary cause is higher at a young age (Fig. 16.17.3.1). In the first two decades of life, essential hypertension used to be so uncommon that even the absolute prevalence of secondary hypertension was greater than that of essential hypertension. However, this picture may now be changing in the second decade as a consequence of childhood obesity. After the teens, a patient is much more likely to have es- sential than secondary hypertension, but investigations for sec- ondary hypertension should still be aggressive in patients in their 0 10 20 30 40 50 60 70 80 90 100 5 75 65 55 45 35 25 15 Age Prevalence (% of all hypertension) Fig. 16.17.3.1  The age-​related prevalence of secondary hypertension. The red line shows the prevalence of essential hypertension by age (years), the dotted line the prevalence of secondary hypertension by age, and the bars show the percentage of all hypertensives with a secondary cause. section 16  Cardiovascular disorders 3780 twenties and thirties because the alternative entails so many years of tablet-​taking. In the first decade of life the main causes of secondary hyper- tension are (1)  the monogenic syndromes causing low-​renin (Na+-​dependent) hypertension, and (2)  congenital causes (e.g. coarctation). However, the rarity of blood pressure measure- ment or of complications in the first decade means diagnosis is often later, hence these are also the main causes of hypertension diagnosed in the second decade. Additional causes by this time are some acquired renal diseases, and the familial phaeochromo- cytoma syndromes. Primary aldosteronism (Conn’s syndrome) is probably the commonest reversible cause of hypertension in adults. From the fifth decade onwards, atheromatous renal artery stenosis is also an important cause of hypertension. The clinical approach to secondary hypertension All patients with hypertension should have a minimum set of inves- tigations, as described in Chapter 16.17.2, but ought to be guided by the clinical history and thorough examination. Common indi- cations for further investigations are shown in Box 16.17.3.1. If possible, patients with blood pressure requiring treatment in their twenties or thirties should be investigated before initiation of treatment because this is rarely pressing at a young age, and some of the tests are easier to interpret off treatment. The minimum screen in younger patients should include serum electrolytes, plasma bicarbonate, plasma renin, and metanephrines to exclude a phaeochromocytoma; 24-​h electro- lyte (sodium) excretion should be measured, either in all patients, or at least in those with suppressed renin levels. Sodium intake is most readily estimated at steady state (i.e. no recent change in diet or drugs) by measuring sodium excretion:  intakes be- tween 100 and 200 mmol (c.6–​12 g)/​day have little effect upon plasma renin, whereas outside this range there is a steep inverse relationship. Further investigations pursuing specific diagnoses that might be considered in particular cases (Table 16.17.3.1) are described in the following sections. Table 16.17.3.1  Evidence in history, examination, or routine investigations suggesting a secondary cause for hypertension Clinical Evidence Condition to consider History Paroxysmal features—​palpitations, sweating, pallor, panic, headache or chest pain, cool peripheries Phaeochromocytoma, paraganglioma Flushing, labile blood pressure Carcinoid syndrome Personal or family history of renal disease Renal hypertension Pregnancy Pre-​eclampsia, HELLP syndrome Drug history—​oestrogen-​containing oral contraceptives; corticosteroids; nonsteroidal anti-​inflammatory drugs; sympathomimetics (amphetamines, cocaine, cold cures, nasal decongestants); corticosteroids; ciclosporin; angiogenesis inhibitors, leflunomide; liquorice; caffeine; carbenoxolone; sodium bicarbonate (often found in excessive amounts in effervescent medications, antacids); ergotamine; triptans; monoamine oxidase inhibitors (with tyramine-​containing foods); erythropoietin; chronic arsenic exposure; long-​term alcohol use; smoking cessation therapies; tramadol (enhances serotonergic and adrenergic transmission) Drug-​induced hypertension Tetany, muscle weakness, fatigue Primary aldosteronism (Conn’s syndrome) Examination General appearance Cushing’s syndrome, acromegaly, thyroid disorders, obstructive sleep apnoea Palpable kidney(s) Adult polycystic kidney disease, tuberous sclerosis Abdominal or loin bruits Renovascular disease Delayed or weak femoral pulses Coarctation of the aorta Investigations (basic) Proteinuria, haematuria, or elevated serum creatinine (eGFR<30; CKD 4/​5) Renal or renovascular disease Hypokalaemia, metabolic alkalosis Primary aldosteronism (Conn’s syndrome) Hypercalcaemia Hyperparathyroidism Hyperglycaemia Phaeochromocytoma Box 16.17.3.1  Indications for investigation for secondary causes of hypertension • Any evidence of an underlying cause in the history or examination (Table 16.17.3.1) • Proteinuria, haematuria, or elevated serum creatinine (eGFR<30; CKD 4/​5) • Hypokalaemia, even if caused by diuretics • Hypercalcaemia • ‘Incidentalomas’ of the adrenal glands seen on radiological imaging • Accelerated (malignant) hypertension • Documented recent onset or recent worsening of hypertension • Resistant hypertension (not controlled with three antihypertensive drugs) • Young age—​any hypertension <20 years; any hypertension needing treatment <35 years 16.17.3  Secondary hypertension 3781 Primary aldosteronism (Conn’s syndrome) History In 1955, with the words ‘to our surprise and delight, a cortical ad- enoma was observed to be arising from the right adrenal gland’, Jerome Conn reported the first observation of the benign aldosterone-​secreting tumour that now bears his name. The patient had presented with severe hypertension and hypokalaemia, shortly after the discovery of aldosterone (‘electrocortin’) in London by the Taits in 1953. On detecting a high level of aldosterone in the patient’s urine, and in the absence of any easy method for imaging adrenals in the 1950s, Conn decided to remove both glands. There is an his- torical irony in this decision: not so much because the patient even- tually retained her left adrenal, but because the finding of unilateral disease in this patient has largely pre-​empted the same decision being made in patients with truly bilateral disease. Conn’s report led to a flurry of similar diagnoses and optimism that as much as 20% of hypertension might be due to his tumour. However, it soon became apparent that no adenoma could be found in perhaps 50% of patients with the clinical and biochemical fea- tures of primary aldosteronism, some being diagnosed instead as having bilateral nodular hyperplasia. With waning enthusiasm for finding a curable cause of hypertension, estimated prevalence fell to less than 1% of hypertension, but the picture again reversed with the recognition that not all patients with primary aldosteronism have an elevated plasma aldosterone concentration; indeed, it is now estimated that 5–​10% of hypertensive patients have a poten- tially curable cause. Whereas previously low-​renin hypertension was often considered a separate diagnosis, increasingly it is felt that even in such patients aldosterone drives the suppression of renin and that smaller adenomas are found when newer radiotracer imaging modalities are employed. Aetiology and pathology A Conn’s adenoma is a small (0.5–​3.5 cm), benign tumour. Although aldosterone is normally secreted selectively by the (outer) zona glomerulosa of the adrenal, classical Conn’s adenomas resemble the cortisol-​secreting zona fasciculata, and secrete more cortisol than aldosterone; occasionally, the extra cortisol may be sufficient to cause suppression of the contralateral adrenal. In recent years, it has become apparent that aldosterone-​producing adenomas of the zona glomerulosa are also common, but are often missed because of their smaller size. Adenomas arising in the two zones are character- ized by somatic mutations in different genes (KCNJ5, encoding a K+ channel, in zona fasciculata tumours; CACNA1D encoding Cav1.3, an L-​type Ca2+ channel; ATP2B3 and ATP1A1, encoding a Ca2+-​ and Na+/​K+-​ATPase, respectively, in zona glomerulosa tumours). Presentation in pregnancy and after the menopause of aldosterone-​ producing adrenal adenomas harbouring activating mutations of CTNNB1, encoding β-​catenin in the Wnt cell-​differentiation pathway, has also been described. Bilateral adrenal hyperplasia is a distinct condition in which either radiologically or histologically there are macro-​or micro-​ nodules in the adrenal cortex where the monolayered arcades of the normal zona glomerulosa are replaced by bi-​or multicel- lular layered arcades. In the one type of primary aldosteronism of known cause—​glucocorticoid-​remediable aldosteronism (see Chapter  16.17.4)—​there is no anatomical lesion in the adrenals other than expansion of the zona glomerulosa. It remains unknown whether some patients develop single adenomas on the background of nodular hyperplasia, with suppression of all but the dominant nodule, or whether unilateral adenomas are usually a different condition from hyperplasia. In favour of the latter are several bio- chemical and pharmacological differences, and the fact that patients with glucocorticoid-​remediable hyperaldosteronism never develop a super-​added adenoma. Patients with classical Conn’s adenomas show an exaggerated diurnal rhythm in aldosterone secretion, con- sistent with an enhanced ACTH-​dependent cAMP pathway. By contrast, patients with hyperplasia, and those with the small zona glomerulosa tumours, show exaggerated aldosterone response to stimulation by angiotensin II and therefore have higher erect than supine aldosterone levels. Primary aldosteronism causes increased sodium retention through the epithelial sodium channel (ENaC) in the distal tubule and cortical collecting duct. The chronic sodium retention leads to hypertension, which is an essential feature of Conn’s syndrome. Electroneutrality in the tubular cell is retained by secreting K+ and/​or H+ ions in exchange for the Na+ with consequent hypokal- aemic alkalosis. Epidemiology Adenomas are slightly commoner in women, bilateral hyper- plasia commoner in men. Conn’s syndrome is not a cause of child- hood hypertension, except for the rare monogenic syndrome of glucocorticoid-​remediable hyperaldosteronism. Hyperplasia is said to be commoner among older patients with hypertension. However, it is difficult clinically to distinguish hyperplasia from small zona glomerulosa adenomas. Since it is likely that the latter have been pre- sent for many years or decades before presenting with often resistant hypertension, the best and easiest time to look for them is in younger patients, where hyperplasia is less likely and surgical treatment is most rewarding. Another condition which needs distinguishing from aldosterone-​producing adenomas in older patients is non-​ functioning adrenal adenomas (‘incidentalomas’), which are present in at least 4% of people over 50. Overall prevalence remains contentious because of the detailed investigations required to establish presence or absence of func- tioning adenomas. In younger patients, where non​functioning adenomas and low-​renin hypertension are both uncommon, and response to surgery is more clear-​cut, a conservative estimate would be 2% of those with hypertension, but the discovery of the smaller zona glomerulosa tumours may double this number. The prevalence among older patients with hypertension is probably similar. At present, a higher proportion of the older age group are likely to be investigated, having presented with either resistant hypertension or an adrenal incidentaloma, but in reality a smaller proportion are likely to benefit from surgery. Whether investi- gations reduce or increase in coming years may depend on the success of less invasive modalities than in current use for both in- vestigation and treatment of adenomas, and extension of the latter into bilateral disease. Clinical features Patients with primary aldosteronism ‘escape’ from the effects of al- dosterone before sufficient Na+ is retained to cause overt oedema, section 16  Cardiovascular disorders 3782 hence the clues and confirmation of the diagnosis are largely bio- chemical. The classic picture in Conn’s syndrome is hypertension in which the plasma electrolytes show a low K+, elevated bicarbonate, and a Na+ typically at the upper end of the normal range, but some- times above this. The hypertension is often resistant to treatment with conventional treatment for the patient’s age group; for example, angiotensin converting enzyme (ACE) inhibition in a younger pa- tient, or to multiple drugs including a thiazide diuretic in the older age groups. It is important to mention, however, that the classical hallmark—​hypokalaemia—​is not always present, and yet the con- sequences of K+ depletion—​weakness, tiredness, U wave on ECG (Fig. 16.17.3.2)—​might still be manifest. The severity of hypo- kalaemia varies steeply with the Na+ load presented to the ENaC, this depending partly on dietary Na+ intake and partly on drugs—​ principally thiazide diuretics—​which affect the proportion of the filtered Na+ load reaching the distal tubule. The commonest reason for the biochemical features of Conn’s to be masked is concurrent treatment with a calcium channel blocker. Hence, when considering the possibility of Conn’s in a patient with hypertension apparently resistant to conventional treatment, it is important to look not just at the current plasma electrolytes but at an historical set of results for any finding of hypokalaemia or alkalosis, and also to reflect that hypokalaemia on a low dose of thiazide is a reason for pursuing (ra- ther than dismissing) the diagnosis of primary aldosteronism. Differential diagnosis The hypokalaemic hypertensive is an interesting diagnostic challenge that can usually be solved by a series of logical moves. The finding of a Conn’s adenoma is the most satisfying outcome because surgical ex- cision is most likely to lead to long-​term cure if the patient is young. The other curable cause is liquorice consumption which, taken in excess, inhibits the enzyme 11β-​hydroxysteroid dehydrogenase (11HSD) and permits cortisol access to the mineralocorticoid re- ceptor (see ‘Apparent mineralocorticoid excess’ in Chapter 16.17.4). Excess production of cortisol in Cushing’s syndrome can also mimic Conn’s. This is most likely to happen when there is ectopic ACTH production or with a malignant adrenocortical tumour, resulting in gross excess of cortisol and consequent saturation of the 11HSD en- zyme (Fig. 16.17.3.3). Cosecreting, or coexisting, aldosterone-​ and cortisol-​producing adenomas should also be considered, although generally the clinical picture is predominantly of one or the other. Clinical investigation Electrolytes The critical tests in the investigation of hypokalaemic hyperten- sion are plasma and urine electrolytes, and plasma renin and al- dosterone. If the recommendations described earlier for screening tests in young patients with hypertension have been observed, all but the plasma aldosterone should already have been performed. The urine K+ (which can be performed on a spot sample) is usu- ally in excess of 40 mmol/​litre if hypokalaemia is due to increased urinary loss, but this test is valuable only when performed when plasma K+ is low. Transient hypokalaemia is common, and hypo- kalaemia transient commonly even in Conn’s syndrome, hence it is important not to postpone urine K+ estimation and risk missing a one-​off opportunity for sparing a patient the further investigations required for renal K+ loss. Renin Of the triad of hypokalaemia, suppressed plasma renin, and ele- vated aldosterone, the renin is of most importance in the diagnosis of Conn’s—​although renin suppression is not invariable, even in un- treated patients. The diagnosis should be entertained in the absence of an elevated aldosterone, especially in patients where a suppressed renin is unexpected: the younger patient (aged <45 years), particu- larly if already on an ACE inhibitor or angiotensin receptor blocker (ARB); and the older patient with resistant hypertension, receiving multiple drugs which normally elevate renin. Fig. 16.17.3.2  A 12-​lead electrocardiogram (ECG) showing ‘u’ waves (arrowed) which may be indicative of hypokalaemia. 16.17.3  Secondary hypertension 3783 The main confounders in interpretation of the plasma renin level are excessive dietary salt intake and drugs. A low renin in the pres- ence of β-​blockade is of no significance, and a β-​blocker (which is unlikely to help with blood pressure control in Conn’s anyway) should be discontinued or substituted by an ACE inhibitor or ARB two weeks before renin measurement. Conversely, spironolactone or amiloride will ‘desuppress’ renin in most patients. Guidelines require these drugs to be stopped prior to hormone measure- ments, in the case of spironolactone for 6 weeks because of its long-​lived active metabolite. This can be clinically challenging in the common group of patients with primary aldosteronism with resistant hypertension. Empirically, a plasma renin found to be suppressed despite low-​dose spironolactone may be sufficient in- dication to investigate adrenal anatomy. Renin itself is very stable in blood, providing this is not chilled (which cryoactivates the renin precursor, prorenin). Although changes in posture and activity cause two-​to threefold changes in renin, the range of renin between high-​and low-​renin patients is some 1000-​fold, hence it is simple to interpret results taken in rou- tine outpatient clinics or surgeries, providing the blood sample (taken into an EDTA tube) reaches the laboratory for plasma separ- ation on the same day as the blood is taken. Aldosterone Plasma aldosterone is often elevated above the normal range (100–​400 pmol/​litre), and is generally higher in patients with macroadenomas (>1 cm) than in those with microadenomas or hyperplasia. In patients with adenomas there is an exaggerated influence of ACTH leading to pronounced diurnal variation in aldosterone levels, which are more likely to be normal when sampled in the afternoon. By contrast, patients with hyper- plasia have an exaggerated response to angiotensin II, so that levels may actually rise during the day in response to activity and be normalized by drugs blocking the renin system, particu- larly angiotensin receptor blockade. However, the most pro- found influences are serum K+ and the use of calcium channel blocker treatment, which (as already stated) is probably now the commonest reason for the diagnosis of Conn’s syndrome to be missed. Aldosterone/​renin ratio The recognition that aldosterone is often normal, despite correc- tion of hypokalaemia and withdrawal of confounding medica- tions, led to the concept of the aldosterone/​renin ratio. However, in practice, because renin is log-​normally distributed and aldos- terone distribution is normal, the aldosterone/​renin ratio is high in most low-​renin patients, except in the low-​renin, low-​aldosterone differential diagnoses considered earlier for hypokalaemic hyper- tension. Indeed, the suppression of plasma aldosterone in patients with liquorice-​induced hypertension is an important observation, showing that the appropriate aldosterone response to suppression of renin is suppression of aldosterone, unless aldosterone is itself the cause of Na+ retention and renin suppression. Because patients with a normal aldosterone but elevated aldosterone/​renin ratio are so numerous, the key question is how to avoid unnecessary inves- tigations in these cases. Until investigation and cure of primary al- dosteronism becomes simpler, the empirical answer is that in the absence of other clues—​hypokalaemia, high/​high-​normal plasma Na+, alkalosis—​investigation be undertaken only in young patients (aged <35) and those with resistant hypertension. Confirmatory tests In patients lacking the triad of plasma aldosterone more than 550 pmol/​litre, undetectable plasma renin, and spontaneous hypokal- aemia, a dynamic test is recommended before proceeding to radio- logical investigations, although the accuracy of such tests is disputed. The most commonly employed is a 4-​hour infusion of saline, after which plasma aldosterone should be more than 190 pmol/​litre in those with primary aldosteronism. An alternative is the captopril suppression test, requiring plasma aldosterone to be similarly unsup- pressed (>190 pmol/​litre) 4 hours after captopril 25 mg. Since patients with resistant hypertension are, by definition, already receiving a drug equivalent to captopril, the decision whether to look for an adrenal adenoma in this group need not be dependent on a confirmatory test Fig. 16.17.3.3  Coronal (a) and axial (b) CT scan images of a large right-​sided malignant adrenocortical tumour (horizontal arrow) that is invading the liver (vertical arrows). section 16  Cardiovascular disorders 3784 of their diagnosis. Its role in diagnosis can be reserved for a later stage in the diagnostic algorithm, in patients where the case for surgery is borderline, and when extra certainty about diagnosis is required. Genetic testing This is rarely required, but if there is a family history of early-​onset hypertension, and particularly of strokes at a young age, the patient should be screened for glucocorticoid-​remediable aldosteronism (see Chapter 16.17.4), of which there are only a few known families in the United Kingdom. Interestingly, research is increasingly providing fascinating insights into the genetics of aldosterone-​producing ad- enomas, which in turn may lead to improved diagnosis in future, without the need for adrenal venous sampling. Further discussion can be found in the ‘Aetiology and pathology’ section of this chapter. Scanning The adrenals are easily imaged by either CT or MRI, except when there is a dearth of intra-​abdominal fat (Fig. 16.17.3.4). There is no proven advantage of one of these two modalities over the other. MRI may be preferred in younger patients, to spare radiation, and the fat-​suppression sequence is useful for differentiating aden- omas both from other adrenal masses, and sometimes the adjacent normal adrenal. Resolution may be higher with CT, but the limit for both modalities is not so much inherent resolution as the existence of 0.3–​0.6-​cm adenomas that do not create a discrete bulge within an adrenal limb. Even 1-​cm adenomas at the bifurcation of the two limbs can be difficult to distinguish from a normal gland. It is valu- able to request coronal reconstructions, which may show or confirm adenomas less evident on the axial views. Neither MRI nor CT can differentiate functional from incidental adenomas. Functional lateralization This is the key but most difficult stage of diagnosis. Lateralization is essential in predicting that removal of one adrenal will have a substantial benefit, as well as indicating which adrenal to remove, although it might occasionally be omitted in younger patients (aged <35 years) with macroadenomas, or where the tumour is more than 3.5 cm in diameter and needs to be removed to exclude a mixed ad- renal carcinoma. At present, the only reliable form of lateralization available at most specialist centres is adrenal vein sampling. This is technically demanding and should be undertaken only by experienced radiolo- gists (Fig. 16.17.3.5). On the left side, the adrenal vein is the only vein to enter the renal vein superiorly, and cannulation is relatively straightforward. On the right, however, the adrenal vein is one of sev- eral small veins (<1 mm diameter) entering the inferior vena cava posteriorly. A  fish-​hooked ‘Cobra’ catheter with side-​holes maxi- mizes the chances of success at 80%, providing several veins are sam- pled, with reference samples also taken in the inferior vena cava above and below the adrenal veins. Centres vary in whether or not they ad- minister ACTH 250 micrograms as a 2-​hour infusion prior to the procedure. Confirmation of adrenal vein cannulation requires that the cortisol measurement is at least threefold higher than in the IVC. All samples need to be assayed for aldosterone and cortisol, with the ratio compared between the two sides: a ratio above 4 is considered diagnostic. Ratios of two-​to fourfold can be compatible with lateral- ization, but are best confirmed on repeat sampling. In such cases ac- curacy might be enhanced by simultaneous sampling from both veins, or—​if aldosterone levels were low on the first occasion—​by prior ACTH stimulation. When an adrenal vein (usually the right) cannot be cannulated, it is very risky to draw conclusions from the contra- lateral sample alone: concentrations of aldosterone can be very high, even from a normal gland, because adrenal vein blood flow is so low. Isotope scans can also be used for lateralization. 131I-​cholesterol (or 75Se-​methyl-​19-​norcholesterol) can be bought or generated for scanning in any nuclear medicine department, but 11C-​metomidate (Fig. 16.17.3.6) must be synthesized on site in centres with a cyclotron and positron emission tomography (PET) scanner. The cholesterol scans rely on its role as precursor of steroid synthesis, and the scan is performed 1 week after isotope administration to Fig. 16.17.3.4  Conn’s adenoma (arrow): CT transverse view (left), coronal view (middle), surgical specimen showing classical yellow, lipid-​rich adenoma (right). 16.17.3  Secondary hypertension 3785 permit cholesterol turnover and elimination from non​adrenal sites. However, the technique has a generally unreliable record, possibly because the dexamethasone taken during the week of in- vestigation has variable influence on zona glomerulosa as well as zona fasciculata uptake. Metomidate binds to synthetic enzymes in both the aldosterone and cortisol pathway, but its uptake is in- creased in aldosterone-​producing adenomas, compared to adjacent or contralateral normal adrenal cortex. This in vivo selectivity for aldosterone synthase probably reflects the higher concentration of the enzyme in adenomas—​especially those of the small zona-​ glomerulosa subtype—​due to their high density of mitochondria and inner membrane reduplication, as seen on electron microscopy. Treatment Medical Medical treatment is preferred for bilateral adrenal hyperplasia, before surgery for adenoma, in older patients with adenoma who are well controlled, or where there is any doubt about diagnosis or lateralization. Chronic medical treatment is by K+-​sparing diuretic, preferably spironolactone or amiloride. Spironolactone is a competitive an- tagonist of aldosterone, hence patients with very high aldosterone levels may require higher doses than used in resistant hypertension. While this is possible for preoperative use, long-​term administra- tion causes gynaecomastia. High-​dose amiloride (20–​40 mg daily) is better tolerated but may be less effective. Eplerenone also avoids the gynaecomastia of spironolactone, but again is less effective and more expensive. A possible strategy is to combine eplerenone or a low dose of spironolactone (≤25 mg daily) with amiloride, but vigi- lant monitoring of plasma electrolytes is required. It may not be possible to control blood pressure entirely by diur- esis, especially in older patients, where calcium channel blockers or α-​blockers can usefully be added. In patients who are difficult to con- trol, the maximum useful dose of diuretic can be found by titrating dose against plasma renin: once this is de-​suppressed it becomes lo- gical to add ACE inhibition or an ARB. In patients with bilateral hyperplasia, one of these classes is often required, even when renin is suppressed. This may reflect either the resistant nature of hyper- tension that often ensues with long-​standing hyperaldosteronism, or the increased sensitivity to angiotensin in salt-​loaded patients. Surgical Elective surgery is indicated for younger patients with adenomas, and older patients intolerant of medical treatment, or uncontrolled by it. A good blood pressure response to spironolactone may augur well for the blood pressure response to surgery, indicating that hypertension is largely due to excess aldosterone (rather than sec- ondary consequences of this). If lateralization has been correctly performed, most patients can expect cure of hypokalaemia, if pre- sent, and a substantial reduction in number of medicines required to control blood pressure. A bonus in many patients is alleviation of chronic fatigue, presumably attributable to total body K+ depletion. Surgery should be undertaken by a surgeon experienced in laparo- scopic adrenalectomy, but patients warned that anatomical anom- alies, or perioperative eventualities such as tear of the inferior vena Vein Aldosterone (pmol/litre) Cortisol (nmol/litre) Ratio 1 Left adrenal 3520 3440 1.02 2 Right adrenal 7520 4310 644 552 11.67 7.80 3 IVC 254 187 1.35 Fig. 16.17.3.5  Adrenal vein sampling for a right adrenal adenoma. CT PET PET/CT overlay Fig. 16.17.3.6  11C-​metomidate PET/​CT scan of a right adrenal aldosteronoma. Uptake correctly differentiated hot and cold nodules, as confirmed by presence and absence of aldosterone secretion from the nodules when cultured postoperatively. section 16  Cardiovascular disorders 3786 cava, may necessitate conversion to open adrenalectomy in about 1/​40 procedures. No special preoperative care is required, although it is sensible to undertake assessment to exclude hypercortisolism in those patients with large adenomas. Diuretics should be withdrawn from the time of surgery, but any additional antihypertensive treat- ment continued until any change in blood pressure becomes clear over the following weeks. Radiofrequency ablation of adenomas is starting to be reported, preserving the adjacent normal adrenal gland. To date, these have been undertaken percutaneously or via a laparoscope. However, left-​ side adenomas, sitting close to the stomach, are accessible for abla- tion, delivered using endoscopic ultrasound. A prospective study of this approach is in progress, which—​if successful—​should lower the bar at which intervention for a benign tumour is considered. Ablation also opens up the possibility of cure for the increasing number of pa- tients found to have bilateral aldosterone-​producing adenomas but in whom bilateral adrenalectomy would never be considered an option. Prognosis The average cure rate across reported studies is 30–​60%. Younger patients have a higher likelihood of cure than older, which probably reflects a shorter time of exposure to aldosterone excess. However, younger patients are also more likely to have larger KCNJ5-​mutant adenomas than smaller adenomas with other mutations. The latter appear more often on the background of multiple adenomas or hyperplasia and are perhaps less likely to be completely unilateral than binary clinical tests suggest. Hypokalaemia is usually cured by surgery, and either the number of medicines required is reduced and/​or there is improved blood pressure control. Renal hypertension The principal curable cause is renovascular hypertension. This is usu- ally due to a stenosis in one or both renal arteries, but can be due to a suprarenal aortic stenosis. Other curable causes include renal tumours (hypernephroma and, the rarest of all secondary causes, a juxtaglo- merular renin-​secreting tumour or reninoma); a unilateral, poorly functioning scarred or hydronephrotic kidney which hypersecretes renin, and can be removed without unacceptable loss of renal function; kidneys that are subject to long-​standing compression (e.g. by post-​ traumatic subcapsular haematoma or extrinsic mass; so-​called Page kidneys; Fig. 16.17.3.7); and various causes of acute/​subacute glom- erulonephritis, some associated with systemic disorders whose treat- ment by immunosuppression cures the hypertension and underlying disorder. Interestingly, aortic dissection, often itself a complication of arterial hypertension, may extend into the renal arteries and thereby ex- acerbate hypertension by causing increased secretion of renin. However, whatever the cause of renal hypertension, there is no evidence to sup- port renal denervation therapy, even in seemingly resistant cases. Renovascular hypertension This is most commonly due to intrinsic disease of the intima (ac- quired, as in atherosclerosis) or media (congenital, as in fibromuscular dysplasia). Extrinsic narrowing can be caused by ligamentous bands or by tumours (e.g. neurofibromas). Fibromuscular dysplasia (FMD) accounts for only 10–​20% of all patients with renovascular hypertension, but is the commonest cause under the age of 40. It is a non​atherosclerotic and non​inflammatory disease of small and medium arteries, usually affecting the media, less commonly the adventitia (<25%), and rarely the intima. The classical ‘string of beads’ appearance seen at arteriography results from pro- liferation of the extracellular matrix and disruption of the internal elastic lamina, causing multiple stenoses and poststenotic saccular aneurysms. The condition affects women more often than men, and there is usually no family history of hypertension. FMD involves extrarenal arteries in about one-​quarter of patients, with cerebral in- farction recorded due to relative hypotension and hypoperfusion of FMD-​affected carotid arteries following successful renal angioplasty. The typical medial form of FMD does not affect the proximal part of the renal arteries (Fig. 16.17.3.8) and is bilateral in about one-​ third of cases. Other vascular beds (e.g. the cerebral arteries), can be affected. Complications (other than renal ischaemia) are rare, whereas dissection or thrombosis can ensue in the rarer intimal or adventitial form of FMD. Rupture of renal artery aneurysms is rare. Fig. 16.17.3.7  A Page kidney. CT scan image showing a left-​sided neuroblastoma compressing the kidney (arrow). The compression impedes renal blood flow, resulting in excess secretion of the hormone renin and consequently hypertension. Named after Irvine Page (1901–​89) who demonstrated that wrapping cellophane tightly around an animal’s kidney caused arterial blood pressure to rise. The patient’s hypertension was cured after surgery to remove the tumour. Fig. 16.17.3.8  MR angiogram demonstrating fibromuscular dysplasia of the right renal artery causing stenosis (arrow). 16.17.3  Secondary hypertension 3787 Atheromatous renal artery stenosis has the same risk factors as atheromatous disease of other arteries, which often coexists. It is thus commoner in older men, and whereas FMD rarely causes renal impair- ment, atheromatous disease is often discovered in the context of inves- tigation of hypertension with chronic kidney disease. Apart from the obvious difference in biology of FMD and atheromatous renovascular hypertension, there is a difference in location of the stenosis, which is more likely to be proximal in atheromatous disease (Fig. 16.17.3.9). Mechanism of hypertension Unilateral renal artery stenosis gives rise to an endocrine disorder, because reduced pressure in the afferent arteriole causes juxtaglo- merular hyperplasia and increased renin secretion. The consequent increase in angiotensin II formation causes hypertension, partly by vasoconstriction, and partly through increased aldosterone se- cretion. Although secondary hyperaldosteronism is not usually a marked feature of renal artery stenosis, the combination of hypokal- aemia and hyponatraemia should raise suspicion of the diagnosis, the latter being dilutional and due to the inhibition by angiotensin II of free water clearance. The effect on renin secretion is less predict- able when renal artery stenosis affects both renal arteries: sometimes it is high, but sometimes bilateral reduction in GFR leads to suffi- cient sodium retention that renin is suppressed. Diagnosis Most cases of renovascular hypertension are probably not diagnosed because of the absence of sensitive clinical or biochemical markers. Lack of a family history of hypertension in younger patients, or re- cent onset (or exacerbation) of hypertension in older patients is more likely than in essential hypertension. Acute shortness of breath, due to flash pulmonary oedema, can be the presenting feature of bilateral renal artery stenosis. However, the main clinical clue is the finding, in about one-​half of the patients, of a bruit anteriorly or posteriorly over a renal area. It is important to remember, however, that such a bruit is never diagnostic: normal abdominal arteries can give rise to innocent flow murmurs in younger patients and in older pa- tients a bruit could arise from any of a number of arteries within the abdomen. The response to antihypertensive drugs can also give clues: in particular, poor response to β-​blockade in younger patients, or rapid worsening of renal function in older patients. The diagnosis of renal artery stenosis is made radiologically. The cheapest investigation is a nuclear medicine scan using technetium-​ labelled MAG3, both the uptake and elimination of this being delayed on the ischaemic side, with the difference in excretion rate between sides greatly increased following a single dose of captopril (25 mg) because of dilatation of the efferent arterioles in glomeruli and conse- quent reduction in filtration fraction. For this reason the scan is best performed initially with captopril; if abnormal, it is repeated on a sub- sequent visit without captopril, with partial or complete normaliza- tion being evidence that the previous abnormality was due to vascular rather than renal parenchymal disease. However, the MAG3 scan is not always positive, with chronic use of ACE inhibitors being a cause of some false negatives, and it may also miss bilateral renal artery sten- oses that do not cause significant asymmetry between the kidneys. Partly for these reasons, nuclear imaging is not performed for suspected renal artery stenosis in most centres, with investigation proceeding to direct imaging of the renal arteries by CT or MR angiography (Fig. 16.17.3.8 and Fig. 16.17.3.9). In patients under 20 years of age some form of angiography should always be under- taken, except in those with low-​renin syndromes, because of the high likelihood of a secondary cause being present, and that this will be a vascular abnormality. As well as providing an accurate estimate in most patients of the severity of any stenosis, angiography will also detect suprarenal aortic stenoses. False-​positive and false-​negative diagnoses still occur; for example, the poststenotic dilatations of FMD can—​if they expand proximally around the artery—​be a cause of stenoses being missed. However, the risk of diagnostic error can be reduced by careful review of images taken in more than one projec- tion, and it is useful to remember that stenoses are not usually isolated lesions in both FMD and atheromatous disease (Fig. 16.17.3.9). Some centres use Doppler flow measurements for diagnosis, but these are more user-​dependent than angiography, which is still re- quired subsequently for anatomical diagnosis. On the other hand, there are some patients in whom an anatomical diagnosis is made first, but the severity is in question. Here it can be useful to per- form Doppler or MAG3 scan as the second investigation before proceeding to treatment. Another investigation that is sometimes helpful at this stage is renal vein sampling for renin determination, the main use for which is before removing a kidney thought respon- sible for causing hypertension through elevated renin secretion. The contralateral—​anatomically normal—​kidney has often sustained microvascular damage as a consequence of prolonged hypertension and renin excess, and is found to secrete as much renin as (or more than) the diseased kidney. Nephrectomy should not normally be contemplated where significant renal function remains, but in any circumstance there would rarely be an indication for removing a Fig. 16.17.3.9  MRI scan image showing a left renal artery stenosis (yellow arrow at bottom of image) with concomitant left subclavian artery stenosis (yellow arrow at top of image) and also an infrarenal aortic stenosis (blue arrow). This patient presented with a subclavian steal syndrome and lower blood pressure readings in the left arm. section 16  Cardiovascular disorders 3788 kidney showing less than 25% excess renin secretion compared to the contralateral side. Treatment There are several options, one of which is simply to continue optimal drug treatment if for any reason the risks of other intervention appear excessive. Among interventions, the options are as for any other arterial stenosis, namely angioplasty, stenting, or surgery. For FMD, angio- plasty is usually curative, and about three-​quarters can discontinue antihypertensive treatment (Fig. 16.17.3.10). In atheromatous disease, angioplasty is much less likely to be successful, especially for lesions at the origin of the artery, and restenosis can occur. It is reasonable to rec- ommend stenting as a backup procedure when angioplasty has failed. Complete cure of hypertension is very much less likely than in FMD. In the past, the purpose of intervention was often to try to pro- tect or improve renal function. The ASTRAL and CORAL trials have largely rebutted this objective, although some argue the meth- odologies were flawed and that patients were excluded from partici- pation where clinicians were certain of benefit from intervention. Few nephrologists now pursue renal revascularization with the same vigour that was common ten or so years ago, although many still sup- port intervention in selected patients, such as those with renal artery stenosis of more than 80% with a significant translesional pressure gradient; younger patients with difficult to control blood pressure on more than three antihypertensives; and those with truncal rather than ostial stenosis, rapidly deteriorating renal function, flash pul- monary oedema, or post-​transplant renal artery stenosis. Sometimes angioplasty is unsuccessful because balloon infla- tion fails to dent the stenosis. Surgery is required in this situation, or when failure can be predicted because stenosis is due to external compression or there is complete occlusion. A  favoured surgical procedure is autotransplantation to the pelvis. Coarctation of the aorta Coarctation of the aorta, a congenital cause of hypertension, was described pathologically in the 1700s and recognized clinically in the early 1900s. The term describes a constriction of the aorta at the point where the fetal arterial duct originates, and the condi- tion should ideally be diagnosed in early childhood, with most cases treated before hypertension develops. Coarctation represents 5 to 8% of all causes of congenital heart disease, and 25% of patients with this condition will also have a bi- cuspid aortic valve, but coarctation causes less than 1% of all cases of hypertension. Diagnosis is often delayed until the patient presents Fig. 16.17.3.10  Renal angiography (Left panel), followed by balloon angioplasty (Right panel) of right-​sided renal artery stenosis secondary to fibromuscular dysplasia. (a) (b) Fig. 16.17.3.11  (a) Cross-​sectional CT image of a 52-​year-​old woman with aortitis. Note the increased inflammatory ‘cuffing’ around the aorta (arrow). (b) Cross-​sectional and sagittal PET CT images of the same patient. Note how the aorta ‘lights up’. 16.17.3  Secondary hypertension 3789 in adulthood with hypertension, and high blood pressure can some- times develop even after surgical cure of the coarctation. Stenosis may also develop at a lower level of the aorta as a consequence of aortitis (Fig. 16.17.3.11). The mechanism of hypertension is pre- dominantly the relative renal ischaemia consequent on low perfu- sion pressure in the aorta beyond the coarctation or stenosis. The classical clinical finding in coarctation is radiofemoral pulse delay or weak lower limb pulses, confirmed by measurement of reduced blood pressure in the legs. Of greater sensitivity and spe- cificity in the clinic is a bruit—​systolic or continuous—​over the front and back of the precordium, which arises in the intercostal collaterals. Rarely, subtle clues may be seen on plain chest radiog- raphy (Fig. 16.17.3.12). The diagnosis should be confirmed by two-​dimensional (2D) echocardiography (suprasternal view) or by CT or MR angiog- raphy (Figs. 16.17.3.13 and 16.17.3.14). Treatment is by surgery, balloon dilatation, or stenting. Surgery or balloon dilation are the preferred approaches in childhood, balloon dilation and stent im- plantation in adolescents and adults. Although upper limb hyper- tension is usually cured, recurrence has been attributed to a variety of unproven factors, including a systemic vasculopathy. Phaeochromocytoma and paragangliomas Aetiology and pathology Catecholamine biochemistry Catecholamine biochemistry is summarized in Fig. 16.17.3.15. The final step in the biosynthetic pathway is the N-​methylation of nor- adrenaline (norepinephrine) to adrenaline (epinephrine), which outside the brain occurs only in the adrenal medulla because the enzyme phenylethanolamine N-​methyltransferase in the adrenal is dependent for induction on glucocorticoids, secreted at high con- centration into the adrenal portocapillary circulation. The clinical importance of this is that extra-​adrenal phaeochromocytomas, or paragangliomas, rarely produce adrenaline. Fig. 16.17.3.12  Plain chest radiographs showing ‘rib-​notching’ in a patient with coarctation (Left panel, arrow) due to the formation of significant collateral intercostal arteries. The ‘3 sign’ in a different patient with coarctation (Right panel, arrows) is caused by pre and post-​stenotic dilatation of the aorta. Fig. 16.17.3.13  MR angiogram showing coarctation of the aorta (arrow). section 16  Cardiovascular disorders 3790 The metabolism of catecholamines is different from normal in phaeochromocytoma in that adrenaline and noradrenaline are lib- erated directly into the bloodstream, rather than mainly into the synaptic gap around sympathetic nerve endings. Noradrenaline re- leased from these is largely recaptured by neuronal and extraneuronal uptake, and metabolized before any free amine escapes into the bloodstream. Consequently, the proportion of parent amine (nor- adrenaline) to metabolite (adrenaline) is usually higher in blood and urine in the presence of a phaeochromocytoma than in any other cause of elevated catecholamine production. Pathology Phaeochromocytomas arise in chromaffin tissue and their anatom- ical distribution closely parallels the sites where this tissue is pre- sent at the time of birth. The term phaeochromocytoma reflects the dusky colour of the cut surface of the tumour, whereas the term chromaffin refers to the brownish colour caused by contact with di- chromate salts, which oxidize the catecholamines. Most phaeochromocytomas are benign, but the pathologist can rarely provide a clear distinction between those that are benign and those that are malignant: benign tumours can appear to be invading the capsule of the tumour, which is often ill-​defined, while malig- nant tumours may show no mitoses because of their slow rate of division. Yearly surveillance, or earlier if indicated clinically, with measurement of plasma metanephrine levels is recommended. Genetics At least 40% of phaeochromocytomas and paragangliomas (PPGLs) are now thought to be caused by a single driver germ line muta- tion, which makes such tumours among the most highly heritable in humans. Mosaic transmission may also occur, as well as a var- iety of well-​defined somatic mutations. As a result, genetic testing is increasingly being recommended in all patients, and over 15 dif- ferent susceptibility genes have been implicated in familial cases. Most are either involved in processes linked to angiogenesis and hypoxia-​induced cell proliferation, or to aberrant activation of kinase signalling pathways. Several mutations also cause syndromes that include PPGLs (Table 16.17.3.2), the clinical and biochemical features of Fig. 16.17.3.14  3D CT reconstruction of coarctation of the aorta (arrow). Tyrosine Hydroxylase HO CH2CHNH2 COOH CH2CHNH2 COOH CH2CH2NH2 CHCH2NH2 CHCH2NH2 OH OH HO HO HO HO HO HO HO HO Tyrosine DOPA Dopamine Noradrenaline Adrenaline DOPA Decarboxylase Dopamine β-hydroxylase Phenylethanolamine N-methyltransferase (PNMT) CHCOOH CH3O HO HO OH CHCH2NH2 HO OH CHCOOH OH CHCH2NH2 CH3O HO Dihydroxymandelic acid Noradrenaline Normetanephrine COMT COMT MAO MAO OH HO HO VMA Fig. 16.17.3.15  The biosynthetic pathway for epinephrine and norepinephrine (upper panel), and for metabolism of norepinephrine (lower panel). COMT, catechol-​O-​methyltransferase; DOPA, dihydroxyphenylalanine; MAO, monoamine oxidase; VMA, vanillylmandelic acid. 16.17.3  Secondary hypertension 3791 which are variable. Only tumours associated with mutations of succinate dehydrogenase (SDH, mainly subunits B or D) com- monly occur outside the adrenal. Paragangliomas in the head or neck are restricted to SDHD (or rarely SDHC) mutations. VHL and RET mutations may cause multiple tumour types, the site of these being determined by the site of mutation in the gene; for example, VHL type 2c missense mutations cause only phaeo- chromocytoma, while the gene deletions of type 1 cause renal cell carcinoma but not phaeochromocytoma. The main value of genotyping has become prediction of multiple (but usually be- nign) paragangliomas in patients with SDHD mutations, while patients with SDHB mutations have the highest incidence of as- sociation with malignancy or metastatic disease. There is also growing recognition of a link between susceptibility to renal cancer and PPGLs. As well as VHL, mutations in SDH, FH, and TMEM127 have been described in both. Gastrointestinal stromal tumours are known to be associated with germline SDH mutations. Epidemiology Phaeochromocytoma is a rare tumour, responsible for probably 0.1 to 1% of hypertensives, although it is possible that some of its non- ​blood-​pressure presentations are overlooked and that we select- ively detect patients in whom pressure natriuresis no longer com- pensates for the effect of vasoconstriction upon blood pressure. However, despite its rarity, phaeochromocytoma justifies the Table 16.17.3.2  Genes associated with phaeochromocytomas and paragangliomas (PPGLs) Gene Chromosome Exons Function % of mutations in PPGLs (mutation type: G—​germ line S—​somatic M—​mosaic) Frequency of malignant disease (if known) (%) SDHB 1p36.13 8 Tumour suppressor, Krebs cycle intermediate 8–​10 (G) 50 NF1 17qll.2 60 Encodes neurofibromin, suppresses cell proliferation by negatively regulating ras signal transduction 3 (G) 20–​25 (S) 11 SDHA 5p15.33 15 Conversion of succinate to fumarate in Krebs cycle <1 (G/​S) 10 TMEM127 2q11.2 4 Restricts mTORC1 activation 1–​2 (G) 10 VHL 3p25.3 3 Regulation of Hypoxia Inducible Factor (HIF) 8–​10 (G/​S) 5 RET 10qll.21 21 Cell growth and differentiation 4–​6 (G/​S) 3 SDHD 11q23.1 4 Electron transfer to ubiquinone in Krebs cycle 5–​7 (G) <3 KIF1B 1p36.22 48 Transport of mitochondria and apoptosis 4–​5 (G/​S) MEN1 11q13 14 Transcriptional regulation and cell proliferation <2 (G) 2–​10 (S) HRAS 11p15.5 7 Involved in ras signal transduction 7–​8 (S) EPAS1 2p21 17 Encodes HIF2α; involved in vasculogenesis and haematopoiesis during embryonic development 6–​12 (M/​S) ATRX Xq21.1 30 Telomere maintenance and chromosome integrity <5 (S) TP53 17p13.1 12 Gatekeeper for cell growth and division <5 (S) SDHC 1q23.3 6 Electron transfer to ubiquinone in Krebs cycle 1–​2 (G) FH 1q43 8 Hydration of fumarate to malate in Krebs cycle 1–​2 (G) BRAF 7q34 18 Involved in cell growth <2 (S) CDKN2A 9p21.3 12 Regulation of p53 and RB1 pathways <2 (S) EGLN1/​PHD2 1q42-​q43 5 Regulation of stability of HIF1 <1 (G/​S) FGFR1 8p11.23 24 Role in angiogenesis, neural and embryonic development 1 (S) H3F3A 1q42.12 4 Role in regulating transcription, DNA repair, and chromosomal stability <2 (M) IDH 2q34 12 Oxidative decarboxylation of isocitrate <1 (S) KMT2D 12q13.12 54 Regulation of accessibility to DNA <2 (G/​S) MAX 14q23.3 5 Regulates cell proliferation, differentiation, and apoptosis 1–​2 (G/​S) MDH2 7q11.23 10 Reversible oxidation of malate to oxaloacetate in Krebs cycle <2 (G) MERTEK 2q13 24 Regulation of cell survival and phagocytosis of apoptotic cells <2 (G) SDHAF2 11q12.2 4 Flavination of SDHA in Krebs cycle <1 section 16  Cardiovascular disorders 3792 disproportionate interest that it commands among physicians, combining the potential for being lethal if not diagnosed and treated, and for cure in most patients if diagnosed. The need for maintaining a high awareness of the condition is emphasized by the small number of deaths each year due to undiagnosed phaeo- chromocytoma in both anaesthetic and obstetric practice. Clinical features Hypertension is the most common presentation of phaeochromo- cytoma in clinical practice, but other rare presentations include unexplained heart failure or paroxysmal arrhythmias. Patients with large tumours occasionally remain asymptomatic, and this is the norm for small phaeochromocytomas detected through regular screening of patients with a genetic diagnosis. This is also true of many so-​called ‘incidentalomas’ seen on radiological imaging of the adrenal glands which subsequently turn out to be phaeochromocytomas. In hypertensive patients a spontaneous history or direct en- quiry will usually reveal at least one of a group of characteristic symptoms. The classical triad comprises headache, sweating, and palpitations; less frequent are episodes of pallor, a feeling of ‘impending doom’, and paraesthesiae. Spontaneous haemorrhage and infarction in the tumour can be associated with local pain and (on occasion) systemic features of tissue necrosis, and rarely the patient can present with the features of full-​blown retroperi- toneal haemorrhage, coupled to a pathognomonic swinging blood pressure. Most of the symptoms of phaeochromocytoma can be readily ascribed to the expected effects of catecholamine excess and dis- appear rapidly on initiation of appropriate treatment. Because large tumours principally secrete noradrenaline, even when arising within the adrenal gland, tachycardia is usually only modest, and can be replaced altogether by reflex bradycardia when episodes of hypertension are triggered by release of noradrenaline alone. The bradycardia can be severe enough—​if the hypertension is high enough—​to be misdiagnosed as asystolic cardiac arrest, and the correct treatment is not atropine but phentolamine to reduce the blood pressure. Severe bradycardia is also recorded in response to the paradoxical rise in blood pressure when patients with phaeo- chromocytoma are inadvertently given a non​selective β-​blocker such as propranolol. Often, however, the clinical features are less im- pressive than might be expected, possibly because the adrenoceptors have been down-​regulated by years of exposure before the diagnosis is first entertained. Examination may reveal a bruit over the tumour. A Raynaud’s type of discolouration over the extremities and the larger joints in the limbs can be caused by ischaemia. Clinical investigation The diagnosis of phaeochromocytoma is usually not difficult once the possibility has been entertained; often more difficult is excluding the diagnosis in patients who have clinical and/​or bio- chemical features of physiological catecholamine excess. There are two distinct questions to ask in order. ‘Does the patient have a phaeochromocytoma?’, and ‘Where is it?’. It is unwise to use radio- logical tests to answer the first question because of the risk of false positives and negatives. Biochemical analyses of catecholamines and their metabolites Twenty-​four-​hour urine samples measure integrated catecholamine release and provide a useful screening test, with catecholamine me- tabolites less temperamental to assay than the more unstable cat- echolamines themselves. Vanillylmandelic acid (VMA) measured by high-​performance liquid chromatography (HPLC) is least prone to interference, L-​DOPA and paracetamol being the main concerns, and although now regarded as less sensitive than some alternatives it is still the exception for VMA to be entirely normal in a patient with hypertension due to a phaeochromocytoma. Metanephrines (sometimes called metadrenalines) measured by radioimmuno- assay or gas chromatography–​mass spectrometry (GCMS) are more sensitive and more specific than VMA, with the assay of ‘frac- tionated metanephrines’ permitting separate evaluation of nor- adrenaline and adrenaline secretion. The ability to differentiate physiological release of noradrenaline from sympathetic nerve endings from pathological secretion from a phaeochromocytoma arises because of the presence of two different enzymes in the two locations: monoamine oxidase (MAO) in sympathetic nerves, and catechol-​O-​methyltransferase (COMT) in the adrenal medulla and phaeochromocytoma (Fig. 16.17.3.15). The measurement of free catecholamines in plasma (which have a very short half-​life) by HPLC with electrochemical detection allows short bursts of secretion during a possible phaeochromocytoma crisis to be detected. However, the technique is susceptible to interfer- ence, especially in the adrenaline peak, and the finding of an adren- aline concentration that is higher than that of noradrenaline should be regarded as suspect. Dopamine levels are usually undetectable in plasma, whereas it is the major catecholamine in urine as a product of renal decarboxylation of plasma dihydroxyphenylalanine. Only several-​fold increases in urinary dopamine are of diagnostic value, and are more likely to indicate neuroblastoma (in a child) or mel- anoma (which secretes dopamine as a by-​product of melanin syn- thesis) than phaeochromocytoma. Paragangliomas, particularly those of the head and neck area, tend not to secrete catecholamines. Up to 70% of those secondary to SDHB and SDHD mutations may have elevated levels of methoxytyramine, a dopamine metabolite. Most adrenal phaeochromocytomas secrete adrenaline (and there- fore metadrenaline), the exceptions being patients with very large tumours, which completely disrupt the portocapillary supply of cor- tisol required to induce phenylethanolamine N-​methyltransferase, and patients with von Hippel–​Lindau syndrome, who tend to secrete noradrenaline and often have normal adrenaline levels even when the tumour is small. By contrast, in patients with multiple endocrine neoplasia (MEN) an elevated plasma adrenaline concentration is the first biochemical abnormality. Usually the normal adrenal predom- inance of adrenaline over noradrenaline is reversed as the tumour enlarges. Occasionally even large tumours secrete mainly adrenaline if either the tumour’s centre is infarcted, leaving a rim still exposed to cortical cortisol supply, or the tumour itself is secreting ACTH or corticotrophin releasing factor. This secretion may be triggered by α-​blocker therapy, and typical Cushing’s features are then absent (as with any ectopic ACTH tumour). Phaeochromocytomas often secrete one or more neuropeptides: somatostatin may exaggerate the episodic nature of catecholamine discharge by inhibiting catecholamine release as soon as a discharge 16.17.3  Secondary hypertension 3793 starts, and it may also contribute to a reversible form of diabetes in phaeochromocytoma. Suppression tests The use of plasma or urine metanephrine measurements, in a re- liable laboratory, has reduced the number of patients with am- biguous results. In deciding which of the ‘grey zone’ patients need further investigations, it is also helpful to remember that modest increases in noradrenaline secretion are usually insufficient to cause severe hypertension. This is partly because of receptor (and postreceptor) desensitization, and partly volume depletion conse- quent on pressure natriuresis. Where doubt about the diagnosis re- mains, a pharmacological suppression test may be performed prior to imaging. Whereas physiological elevations of noradrenaline re- lease are temporarily suppressed by administration of the ganglion-​ blocking drug pentolinium, or the centrally acting α2-​agonist clonidine, these drugs do not suppress autonomous secretion by tumour. However, such pharmacological suppression tests have limited use nowadays given the increased diagnostic sensitivity of plasma and urinary assays for metanephrines. Localization of phaeochromocytomas A substantial clue to localization is provided by measurement of plasma adrenaline (or metadrenaline) or fractionated urinary metanephrines (as stated previously, extra-​adrenal tumours rarely produce adrenaline). CT or MRI scanning provides excellent imaging of the adrenal, where 90% of phaeochromocytomas are found (Fig. 16.17.3.16). They are usually much larger than Conn’s tumours, and may appear heterogeneous. It is best to withhold CT/​MRI scanning for extra-​adrenal phaeochromocytomas until the radiologist can be given some clue as to where to concentrate. This can be achieved by radio- isotope scanning with the iodinated analogue of noradrenaline, m-​iodobenzylguanidine (mIBG), in about 85% of patients. This may carry either an [123I] or [131I] label, the former being more sensi- tive but also more expensive, and may be misinterpreted if users are unaware that normal adrenal glands also accumulate mIBG. There is a case for undertaking mIBG scanning in addition to CT, even for patients found to have an adrenal phaeochromocytoma, to iden- tify extra-​adrenal secondary deposits when tumours are malignant, and because there may be coexisting adrenal and extra-​adrenal phaeochromocytomas. PET scans have been used and may be posi- tive when mIBG is unhelpful. 18F-​DOPA appears to be the most accurate of these, but available only when there is a centre doing neurological research for which a routine supply of this radiotracer is required. 68Ga-​DOTANOC, a somatostatin receptor analogue, is acquiring a reputation for higher sensitivity than mIBG, with good specificity. Selective venous sampling remains of occasional value when diagnostic problems persist. About 25 samples of blood are col- lected under fluoroscopic guidance from various sites, with an arterial sample invaluable for interpreting the results because it enables sites with a positive venoarterial difference to be readily detected. Because of the short half-​life of catecholamines in the circulation (c.1 min), the concentration at the tumour site is usu- ally several-​fold greater than elsewhere. This procedure should not usually be used for adrenal phaeochromocytomas, an exception being patients with von Hippel–​Lindau syndrome with small ad- renal masses, in whom all other biochemical tests may be normal, and the diagnosis of phaeochromocytoma is suggested by a re- versal of the normal excess of adrenaline to noradrenaline in the adrenal vein. Because phaeochromocytomas are vascular tumours, they pro- vide a good tumour blush, and occasionally angiography is required to resolve equivocal scans. Patients must be fully α-​blocked and preferably also β-​blocked prior to angiography. Other investigations It is important to check blood glucose in every patient as there may be α-​mediated inhibition of insulin release prior to effective treat- ment, and all patients should be screened for an associated medul- lary carcinoma of the thyroid. Routine slit lamp examination of the fundi has resulted in more frequent diagnosis of von Hippel–​Lindau syndrome, sometimes as a de novo occurrence. (c) (a) (b) Fig. 16.17.3.16  CT (Panel (a)) and m-​iodobenzylguanidine (mIBG) scan (Panel (b)) of a patient with a left adrenal phaeochromocytoma. Both scans illustrate typical non​homogeneous appearance due to large area of haemorrhage/​infarction at the centre of the tumour. Panel (c) shows the cut surface of a phaeochromocytoma, approximately 6 cm in diameter. Note the heterogeneous texture and dusky brown colour. section 16  Cardiovascular disorders 3794 Treatment Medical management before surgery The definitive treatment for phaeochromocytoma is surgical, with laparoscopic surgery possible for most adrenal tumours. Even the small number of phaeochromocytomas that are recognized to be malignant preoperatively (e.g. by the presence of bone or liver me- tastases) may still benefit from resection of the primary tumour. The task for the physician is to make surgery safe, for which the mainstay of medical treatment is α-​blockade, but not all patients—​especially those without elevated plasma adrenaline levels—​require β-​ blockade. Indeed, the inadvertent use of β-​blockers in patients with undiagnosed phaeochromocytomas may lead to a paradoxical rise in blood pressure due to unopposed α stimulation (Fig. 16.17.3.17). The objective of treatment is not solely control of blood pressure, but also the expansion of blood volume, which is invariably reduced. Without doubt, phaeochromocytomas represents the pure vaso- constriction end of the vasoconstriction-​volume spectrum, and the hypertensive patient is best seen as the exception where pressure natriuresis has failed to compensate adequately for vasoconstriction. Normotension is an indication, not contraindication, for the use of α-​blockade to restore volume preoperatively. The α-​blocker of choice is phenoxybenzamine, which is an irre- versible blocker that actually destroys the α-​receptor by alkylation. More modern α-​blockers, such as doxazosin, and the mixed α-​and β-​blocker labetalol (a much stronger β-​blocker than it is α-​blocker), cause competitive blockade, which can be overcome by a surge of noradrenaline release from the tumour. An additional advantage of phenoxybenzamine is that it will block both α1-​and α2-​receptors, with blockade of the latter possibly advantageous because extra-​synaptic α2-​receptors mediate some of the direct vasoconstriction caused by circulating (non​neuronal) catecholamines. The diabetogenic effect of catecholamines is also an α2-​mediated response. The starting dose of phenoxybenzamine is 10 mg once or twice daily, with increases titrated against blood pressure up to a maximum of 90 mg daily. The effect of irreversible antagonists is cumulative, with the effect of the drug—​and each subsequent dose increment—​taking several days to reach maximum. There is rarely any urgency for surgery, which should not nor- mally be considered in less than 1 month after initiation of treat- ment in patients with symptomatic phaeochromocytomas. Indeed, the more severe the initial clinical picture, the greater the need for prolonged α-​blockade to expand intravascular volume. In most pa- tients there is a low filling pressure at presentation, evident clin- ically as a jugular venous pressure visible only when the patient lies flat, and any postural hypotension should be assumed to re- flect continuing hypovolaemia, not excessive α-​blockade, until the venous pressure is normalized. Usually volume expansion will occur spontaneously with phenoxybenzamine treatment, but ex- pansion should be achieved with intravenous saline if there is per- sistent hypovolaemia. Preoperatively, the aim should be uptitration of phenoxybenzamine dose, concurrent with active volume re- placement, until there is at least a persistent 10 mm Hg postural drop in blood pressure. The need for β-​blockade is indicated by tachycardia, which may become apparent only after treatment with phenoxybenzamine, and the dose of β-​blocking drug necessary is generally lower than that used in the treatment of hypertension. It is usually better to use a β1-​selective agent so that the peripheral vasodilatation mediated by β2-​receptors is not affected. Occasionally, pronounced β2-​receptor mediated effects, including tachycardia or tremor, can oblige use of a non​selective β-​blocker, although blood pressure control may then be more difficult and require addition of a calcium blocker. The reason for using as low a dose of β-​blocker as possible is that there may be a period of hypotension immediately upon removal of the phaeochromocytoma, despite the preoperative preparation that has been outlined. This hypotension should normally be offset by the ability to mount a tachycardia. Otherwise, further volume replace- ment may be required, supplemented if necessary by β-​agonists, Facilitation Inhibition Presynaptic Extrasynaptic Norepinephrine Epinephrine α2 β2 β1 α1 Norepinephrine β–blockers β2 α2 VASODILATATION VASCOCONSTRICTION Postsynaptic Norepinephrine (a) (b) Facilitation α2 β2 β1 α1 β2 α2 Inhibition Presynaptic Postsynaptic Extrasynaptic VASCOCONSTRICTION VASODILATATION Norepinephrine Epinephrine Fig. 16.17.3.17  Paradoxical worsening of blood pressure by β-​blockers in the presence of excess catecholamines. Panel (a) shows the effects of epinephrine and norepinephrine on α and β receptors. Panel (b) shows that β-​blockers, particularly non​selective ones, negate vasodilatation mediated via β2 receptors and inhibit catecholamine reuptake, thereby augmenting α-​mediated vasoconstriction. 16.17.3  Secondary hypertension 3795 most vasoconstrictor drugs being ineffective because of the slow washout of phenoxybenzamine. Malignant phaeochromocytomas The treatment of malignant phaeochromocytomas remains uncer- tain and unsatisfactory. The rate of growth is usually slow, but the prognosis for affected individuals can vary between the extremes of local recurrence at intervals of many years, and rapid demise sometimes precipitated by surgery. The tumours are not particularly sensitive either to chemotherapy or to radiotherapy, although the variability of response may still make them worth trying. There has been interest in the use of therapeutic doses of mIBG as a means of targeting high doses of radioactivity to the tumour: some patients show considerable regression after such treatment, but long-​term results are less certain. It is rare for the pharmacological effects of the tumour to be the principal problem if the primary tumour has been removed or debulked. High doses of phenoxybenzamine are preferable to α-​methyltyrosine, used as an inhibitor of noradrenaline synthesis. There is anecdotal evidence that therapy with high doses of an ARB might slow progression through reflex activation of renin and hence AT2-​receptor mediated apoptosis. Prognosis and genetic screening The removal of a phaeochromocytoma cures hypertension in most patients, especially those that are young. Most (90%) phaeochromocytomas are benign, and the proportion is prob- ably even higher for adrenal tumours, whereas paragangliomas have a greater than 10% likelihood of proving malignant. The latter should all be screened for mutations in the SDHB gene, which carry greater than 50% risk of malignancy. Other genetic screening will be influenced by a mixture of clinical features and cost considerations. A history (or family history) of other relevant tumours will lead to a search for von Hippel–​Lindau syndrome or MEN type 2. Even so, there is increasing consensus that all patients should at least be considered for structured genetic counselling and screening, and this is particularly important in much younger patients. All patients should be followed indefinitely with at least an annual measurement of arterial blood pressure and analysis of one of the indices of catecholamine secretion. In patients at par- ticularly high risk of malignancy, annual (or earlier if indicated clinically) whole-​body MRI/​CT imaging and focal neck scanning ought to be considered. Other endocrine causes of hypertension Conn’s syndrome and phaeochromocytoma have been singled out for attention in this chapter as the two endocrine conditions most likely to present as hypertension. However, hypertension is a fea- ture of several other endocrinopathies: Cushing’s syndrome, acro- megaly, hyperparathyroidism, and is a common complication of type 2 diabetes. The hypertension of Cushing’s syndrome is usually modest, except in ectopic ACTH where there is saturation by high cortisol levels of 11β-​hydroxysteroid dehydrogenase 2 (which nor- mally converts cortisol to the inactive cortisone). The cause of the hypertension in other syndromes is less clear cut and often not cor- rected by surgical cure of the primary problem. FURTHER READING Primary aldosteronism Brown MJ, Hopper RV (1999). Calcium-​channel blockade can mask the diagnosis of Conn’s syndrome. Postgrad Med J, 75, 235–​6. Choi M, et al. (2011). K+ channel mutations in adrenal aldosterone-​ producing adenomas and hereditary hypertension. Science, 331(6018), 768–​72. De Sousa K, et al. (2019). Molecular mechanisms in primary aldoster- onism. J Mol Endocrinol, 242, R67–R79. Dluhy RG, Lifton RP (1999). Glucocorticoid-​remediable aldoster- onism. J Clin Endocrinol Metab, 84, 4341–​4. Gordon RD, et al. (1994). High incidence of primary aldosteronism in 199 patients referred with hypertension. Clin Exp Pharmacol Physiol, 21, 315–​18. Hood SJ, et  al. (2007). The Spironolactone, Amiloride, Losartan, and Thiazide (SALT) double-​blind crossover trial in patients with low-​renin hypertension and elevated aldosterone-​renin ratio. Circulation, 116, 268–​75. Mir FA, Brown MJ, Appleton DS (2007). Lessons in the diagnosis and management of Conn’s syndrome. Clin Med, 7, 530–​2. Mulatero P, et al. (2006). Comparison of confirmatory tests for the diagnosis of primary aldosteronism. J Clin Endocrinol Metab, 91, 2618–​23. Padmanabhan S, et al. (2015). Genetic and molecular aspects of hyper- tension. Circ Res, 116, 937–​59. Rossi GP, et al. (2006). A prospective study of the prevalence of primary aldosteronismin 1,125 hypertensive patients. J Am Coll Cardiol, 48, 2293–​300. Stewart PM (1999). Mineralocorticoid hypertension. Lancet, 353, 1341–​7. Stowasser M (2015). Update in primary aldosteronism. J Clin Endocrinol Metab, 100, 1–​10. Stowasser M, et al. (2003). High rate of detection of primary aldos- teronism, including surgically treatable forms, after ‘non-​selective’ screening of hypertensive patients. J Hypertens, 21, 2149–​57. Young WF Jr (2007). The incidentally discovered adrenal mass. N Engl J Med, 356, 601–​10. Renovascular hypertension and coarctation Caliezi C, Reber P (2006). Images in clinical medicine. Fibromuscular dysplasia of the renal artery. N Engl J Med, 355, 2131. Cooper CJ, et al. for the CORAL Investigators (2014). Stenting and medical therapy for atherosclerotic renal-​artery stenosis. N Engl J Med, 370, 13–​22. Rosenthal E (2005). Coarctation of the aorta from fetus to adult: cur- able condition or lifelong disease process? Heart, 91, 1495–​502. Safian RD, Textor SC (2001). Renal-​artery stenosis. N Engl J Med, 344, 431–​42. The ASTRAL Trial Investigators (2009). Revascularization versus medical therapy for renal-​artery stenosis. N Engl J Med, 361, 1953–​62. White CJ (2006). Catheter-​based therapy for atherosclerotic renal ar- tery stenosis. Circulation, 113, 1464–​73. Phaeochromocytoma Allison DJ, et al. (1983). Role of venous sampling in locating a phaeo- chromocytoma. BMJ, 286, 1122–​4. Brown MJ, et  al. (2009). Pheochromocytoma. Horm Metab Res, 41, 655–​7. 16.17.4 Mendelian disorders causing hypertension 3 16.17.4 Mendelian disorders causing hypertension 3796 Nilesh J. Samani and Maciej Tomaszewski section 16  Cardiovascular disorders 3796 Col V, et al. (1999). Laparoscopic adrenalectomy for phaeochromo- cytoma: endocrinological and surgical aspects of a new therapeutic approach. Clin Endocrinol (Oxf), 50, 121–​5. Jochmanova I, Pacak K (2018). Genomic landscape of phaeochromo- cytoma and paraganglionoma. Trends Cancer, 4, 6–9. Manger WM (1997). Pheochromocytoma. Springer Verlag, Berlin. Rednam SP, et  al. (2017). Von Hippel–​Lindau and hereditary pheochromocytoma/​paraganglioma syndromes:  clinical features, genetics, and surveillance recommendations in childhood. Clin Cancer Res, 23, 68–​75. Sisson JC, Shulkin BL (1999). Nuclear medicine imaging of pheochromocytoma and neuroblastoma. Q J Nucl Med, 43, 217–​23. Toledo RA, et al. for the NGS in PPGL (NGSnPPGL) Study Group (2017). Consensus Statement on next-​generation-​sequencing-​ based diagnostic testing of hereditary phaeochromocytomas and paragangliomas. Nat Rev Endocrinol, 13, 233–​47. 16.17.4  Mendelian disorders causing hypertension Nilesh J. Samani and Maciej Tomaszewski ESSENTIALS Several very rare mendelian disorders cause hypertension. Their predominant clinical features include a young age of onset, moderate to severe blood pressure elevation, strong family history, consan- guinity (for the autosomal recessive disorders), and electrolyte abnor- malities, particularly of potassium (although this is not invariable). The disorders include (1)  glucocorticoid-​remediable aldoster- onism—​caused by a chimeric gene where the regulatory elem- ents of the 11β-​hydroxylase gene become attached to the coding region of aldosterone synthase; (2)  apparent mineralocorticoid excess—​due to mutations causing loss of function in the type 2 11β-​hydroxysteroid dehydrogenase gene that normally inactivates cortisol in the kidney; (3) Liddle’s syndrome—​caused by activating mutations in genes encoding the β-​or γ-​subunits of the trimeric epi- thelial sodium channel; (4) pseudohypoaldosteronism type 2 (PHA2, Gordon’s syndrome)—​ caused by mutations in the WNK1 or WNK4 serine-​threonine kinases genes, the Kelch-​like 3 (KLHL3) gene or the cullin 3 (CUL3) gene, which regulate salt reabsorption by the Na-​Cl cotransporter (SLC12A3) and the linked process of potassium secre- tion by the renal outer medullary potassium channel (ROMK). Introduction Several rare mendelian disorders where hypertension is the pre- dominant manifestation have been characterized at the molecular level (Box 16.17.4.1). These include glucocorticoid-​remediable aldosteronism (or familial hyperaldosteronism type I), the syn- drome of apparent mineralocorticoid excess, Liddle’s syndrome, and Gordon’s syndrome. Hypertension and hypokalaemia are features of 11β-​hydroxylase and 17β-​hydroxylase deficiency—​two rare recessive gene disorders of adrenal steroid-​synthesizing enzymes that, among others, cause congenital adrenal hyperplasia. 11β-​Hydroxylase defi- ciency usually presents in infancy or early childhood with viriliza- tion of both sexes, while presentation of 17β-​hydroxylase deficiency may be delayed until adolescence or adulthood. Hypertension due to a phaeochromocytoma may be a feature of multiple endocrine neoplasia type 2 (MEN2), which when familial is inherited in an autosomal dominant pattern, Von Hippel-Lindau syndrome, or rarely to be a feature of neurofibromatosis (von Recklinghausen’s disease). Single mutations in more than 10 different genes are now recognised as the genetic defects underlying familial and sporadic pheochromocytomas and paragangliomas. Most recently, genetic causes of several types of familial hyperaldosteronism were identified including type II (CLCN2), type III (KCNJ5) and IV (CACNA1H). Glucocorticoid-​remediable aldosteronism Glucocorticoid-​remediable aldosteronism (GRA, OMIM 103900) is a form of mineralocorticoid hypertension that is inherited in an autosomal dominant fashion. The hypertension is accompanied by hypokalaemia (not invariably), a tendency to metabolic alkalosis, an elevated plasma aldosterone level and a suppressed renin level. Patients are usually suspected of having primary aldosteronism (Conn’s syn- drome, see Chapter 16.17.3), although the age of onset, usually in the first two decades of life, is younger than typical of primary aldoster- onism. Intracranial aneurysms are common, and the first manifest- ation may be a presentation with intracranial haemorrhage. The two hallmark features of GRA are the presence of large amounts of two abnormal steroids—​18-​hydroxycortisol and 18-​ oxocortisol—​in the urine, and the lowering of blood pressure, with return of plasma aldosterone to a normal level and disappearance of the abnormal steroids, following treatment over a few days with a low daily dose of exogenous glucocorticoid, for example, 0.5–​1.0 mg of dexamethasone (hence the name). Patients with GRA have a chimeric gene due to an unequal crossing-​ over event at meiosis between two adjacent and highly homologous genes involved in adrenocorticosteroid synthesis—​aldosterone Box 16.17.4.1  Mendelian forms of blood pressure variation Hypertension • Glucocorticoid-​remediable aldosteronism (GRA) • Syndrome of apparent mineralocorticoid excess (AME) • Liddle’s syndrome • Gordon’s syndrome (pseudohypoaldosteronism type II, PHA-​II) • Hypertension exacerbated by pregnancy • Hypertension with brachydactyly • 11β-​Hydroxylase deficiency • 17β-​Hydroxylase deficiency • Familial and sporadic phaeochromocytoma/paraganglioma • Familial hyperaldosteronism Hypotension • Pseudohypoaldosteronism type 1 • Gitelman’s syndrome • Bartter syndrome • 11β-​hydroxylase deficiency • Aldosterone synthase deficiency 16.17.4  Mendelian disorders causing hypertension 3797 synthase (CYP11B2) (normally expressed only in the zona glomerulosa, involved in aldosterone synthesis, and regulated by angiotensin II) and 11β-​hydroxylase (CYP11B1) (expressed in the zona fasciculata, involved in glucocorticoid synthesis, and regu- lated by ACTH). In the chimeric gene, the regulatory elements of CYP11B1 have become attached to the aldosterone synthase coding region of CYP11B2 (Fig. 16.17.4.1a). This leads to ACTH-​driven production of aldosterone (and the other abnormal hormones) in the zona fasciculata, hence the clinical syndrome and its suppression by glucocorticoids. Normal (b) AME Aldosterone synthase 11β-OHase Unequal crossing over (a) 3′5′ 3′ 3′ 5′ 5′ Aldosterone synthase Chimeric gene 3′5′ 3′ 5′ 3′ 3′ 5′ 5′ 11β-HSD β α γ 11β-OHase Cortisol Cortisone Aldosterone Mineralocorticoid receptor Mineralocorticoid receptor Cortisol Defective 11β-HSD (d) (c) Na Na Na Epithelial sodium channel intracellular extracellular Cl K lumen NCCT ROMK WNK1/WNK4 KLHL3/CUL3 normal Liddle’s syndrome Impaired channel internalization and degradation leads to higher surface channel density in Liddle’s syndrome Fig. 16.17.4.1  Mechanisms underlying four forms of monogenetic hypertension. (a) Glucocorticoid-​remediable aldosteronism (GRA). In GRA an unequal crossing event leads to a chimaeric gene where the coding region of aldosterone synthase becomes attached to the regulatory region for 11β-​hydroxylase. The chimaeric gene produces excess amounts of aldosterone under the regulation of ACTH. (b) Syndrome of apparent mineralocorticoid excess (AME). The mineralocorticoid receptor in the distal renal tubule is normally protected from stimulation by cortisol by the activity of the 11β-​hydroxysteroid dehydrogenase enzyme. In AME, mutations in the enzyme allow cortisol to gain access to the receptor. (c) Liddle’s syndrome. The trimeric epithelial sodium channel mediates sodium reuptake in the distal renal tubule. In Liddle’s syndrome, mutations in the β and γ subunits of the channel impair its intracellular biodegradation and lead to excessive channel density and activity on the surface of distal renal tubular epithelium. (d) Gordon’s syndrome. WNK1 and WNK4 regulate thiazide-​sensitive sodium-​chloride cotransporter (NCCT) and potassium secretion via ROMK in the distal nephron. Mutations in WNK1/​WNK4 or genes responsible for their intracellular degradation (KLHL3 and CUL3) lead to increased sodium reabsorption via overactive NCCT and impaired potassium secretion through ROMK. section 16  Cardiovascular disorders 3798 The mainstay of treatment for GRA is glucocorticoids, with physiological doses (or only slightly higher, e.g. 0.125 mg of dexamethasone or 2.5 mg of prednisolone daily) sufficing. Response can be monitored by measuring the suppression of aldosterone production. Selective mineralocorticoid receptor blockers, such as spironolactone, can provide useful adjunctive treatment. Syndrome of apparent mineralocorticoid excess The syndrome of apparent mineralocorticoid excess (AME, OMIM 218030) is an autosomal recessive disorder that usually presents in childhood with hypertension, hypokalaemia, and low renin activity. Despite the clinical features of mineralocorticoid excess, levels of all known mineralocorticoid hormones are low, yet the hypertension responds to spironolactone or amiloride. Patients with the disorder cannot metabolize cortisol to its in- active metabolite cortisone normally, resulting in a prolonged half-​life of cortisol and a characteristic increase in urinary cortisol (compound F) compared with cortisone (compound E) ratio. Elucidating the defect causing AME first required the solu- tion of another paradox—​why cortisol, which circulates at a level several-​fold greater than aldosterone, does not overwhelmingly activate the renal mineralocorticoid receptor in vivo despite the two having equal affinity in vitro. The reason relates to the enzyme 11β-​hydroxysteroid dehydrogenase (11β-​HSD), which has two isoforms. Type 1 11β-​HSD is located in the liver, adipose tissue, muscle, pancreatic islets, and gonad and converts cortisone to cor- tisol. Type 2 11β-​HSD is expressed in the mineralocorticoid target tissues—​kidney, colon, and salivary gland—​and inactivates cor- tisol to cortisone. In the kidney the enzyme plays the crucial role of protecting the mineralocorticoid receptor in the distal tubule from activation by cortisol. In subjects with AME a variety of loss-​of-​ function mutations in the type 2 11β-​HSD gene cause a deficiency of the enzyme, allowing cortisol access to the mineralocorticoid re- ceptor (Fig. 16.17.4.1b). The severe form of AME, due to disabling mutations in type 2 11β-​HSD, usually presents in childhood. Recently a milder form, termed AME type II, has been described, which is characterized by a later age of presentation (>30 years), a more variable degree of hypertension, and less impact on biochemical parameters. These patients have alterations in 11β-​HSD2 that produce a partial ra- ther than absolute decrease in enzymatic activity, hence classifica- tion into distinct subcategories may be inappropriate, with AME best regarded as a spectrum of mineralocorticoid hypertension with severity reflecting the underlying genetic defect. The main- stay of treatment of AME is spironolactone. A low-​salt diet is also important. AME resembles the syndrome observed in subjects ingesting large amounts of liquorice or taking the now redundant antiulcer drug carbenoxolone, both of which contain glycyrrhetinic acid, an inhibitor of type 2 11β-​HSD, thus explaining the hypertension and hypokalaemia observed with these compounds. Spillover access of cortisol to the mineralocorticoid receptor may also, at least partly, explain the hypertension accompanying some forms of Cushing’s syndrome and glucocorticoid resistance. Liddle’s syndrome Liddle described a family in which the siblings were affected by early-​onset hypertension and hypokalaemia, but with low renin and aldosterone levels (OMIM 177200). The clue to the nature of the mo- lecular defect underlying this autosomal dominant disorder came from the observation that the hypertension does not respond to spironolactone, the mineralocorticoid receptor antagonist, but does respond to direct inhibitors (such as amiloride or triamterene) of the trimeric epithelial sodium channel—​a key channel responsible for sodium reabsorption in the distal nephron. Subsequent work re- vealed activating mutations in genes (SCNN1B, SCNN1G) encoding the β-​or γ-​subunits of the channel (Fig. 16.17.4.1c), All mutations so far identified cause an alteration or deletion of a proline-​rich (PY) motif in the C-​terminal cytoplasmic tails of the subunits that is ne- cessary for regulatory proteins such as Nedd4 to bind and intern- alize the channel. When this mechanism is impaired, the number of channels located in the apical membrane is increased, leading to over-​reabsorption of sodium and water. Pseudohypoaldosteronism type 2 (Gordon’s syndrome) Pseudohypoaldosteronism type 2 (PHA2, OMIM 145260), also known as Gordon’s syndrome, is an autosomal dominant disorder that causes elevated blood pressure accompanied by hyperkalaemia, despite normal renal glomerular filtration. Mild hyperchloraemia, metabolic acidosis, and suppressed plasma renin activity are common associated findings. Hypercalciuria can also be a feature, leading to osteopenia, osteoporosis, and kidney stone disease. The hypertension and biochemical abnormalities are corrected by thiazide diuretics. Mutations in at least four genes are recognized causes of PHA2. Initially some cases of PHA2 were linked to mutations in two genes, WNK1 and WNK4, members of the WNK family of serine/​threo- nine kinases. The genetic defects in both WNK1 and WNK4, by increasing their expression/​activity in the distal nephron, lead to enhanced phosphorylation of two other enzymes, STE20/​SPS1-​ related proline-​alanine-​rich protein kinase (SPAK) and oxida- tive stress-​responsive kinase-​1 (OSR1). Both SPAK and OSR1 are key regulators of the Na-​Cl cotransporter, NCCT (encoded by the SLC12A3 gene), which is responsible for sodium reabsorption in the distal convoluted tubule and the linked process of potassium se- cretion by the renal outer medullary potassium channel (ROMK). Na-​Cl cotransporter overactivity is the chief biochemical abnor- mality of the syndrome and the primary driver of enhanced sodium reabsorption, volume expansion, inhibition of renin secretion, and hypertension. Decreased potassium excretion leading to hyperkalaemia in PHA2 results from two processes. Firstly, increased Na-​Cl cotransporter activity, by increasing sodium reabsorption in the distal convoluted tubule, leads to reduced sodium delivery to the connecting tubule, which results in a drop in electrochemical gradient necessary to maintain activity of ROMK channels that transfer K+ from blood to urine across the distal tubule epithelium. Secondly, enhanced in- ternalization of ROMK channels in PHA2 leads to their decreased expression/​activity on the surface of tubular epithelium. 16.17.4  Mendelian disorders causing hypertension 3799 More recently, mutations in two novel genes, Kelch-​like 3 (KLHL3) and Cullin 3 (CUL3), were reported to account for a majority (≈80%) of causal genetic defects in patients with PHA2. The mutations are inherited in either autosomal dominant (KLHL3 and CUL3) or re- cessive (KLHL3) manner. The products of both genes are a part of ubiquitin ligase complex responsible for intracellular degradation of more than 50 proteins, including WNKs. The most likely molecular mechanism by which genetic defects in these genes lead to PHA2 is disruption of WNKs intracellular degradation and accumulation of WNK4/​WNK1 and subsequent changes in the activity of Na-​Cl cotransporter/​ROMK channel. The Na-​Cl transporter is the target for thiazide diuretics, which explains the specific clinical response of PHA2 to this class of drugs. Defects in the Na-​Cl cotransporter lead to the salt-​losing Gitelman’s syndrome, which as described next is the mirror image of PHA2. Other monogenetic forms of hypertension A missense mutation in the ligand-​binding domain of the mineralo- corticoid receptor has been found to cause an autosomal dominant form of hypertension that is markedly accelerated in pregnancy. The mutation, MR S810L, causes partial, aldosterone-​independent activa- tion of the receptor, causing carriers to develop hypertension before age 20. Compounds such as progesterone that normally bind to but do not activate the mineralocorticoid receptor are all potent agonists of the mutant receptor, hence MR S810L carriers have dramatic accel- eration of hypertension during pregnancy stimulated by the 100-​fold rise in progesterone. Although the MR S810L mutation is extremely rare, the finding does raise the question of whether related mechan- isms may underlie other forms of hypertension in pregnancy. Most recently, several missense mutations in PDE3A (a gene that encodes phosphodiesterase 3A) were identified in families with a syndrome of hypertension and brachydactyly. The syndrome is characterised by severe salt-independent hypertension, abnormalities of rostral- ventrolateral medulla and high degree of stroke-related mortality. Genetic defects causing hypotension Certain mendelian syndromes where hypotension is a feature have recently been characterized at the molecular level (Table 16.17.4.1). Many are mirror images of the genetic abnormalities causing the mendelian forms of hypertension described earlier. Pseudohypoaldosteronism type 1 (PHA1) occurs in two forms, autosomal recessive and autosomal dominant. Both are charac- terized by life-​threatening dehydration in the neonatal period, hypotension, salt wasting, hyperkalaemia, metabolic acidosis, and marked elevation of renin and aldosterone. The autosomal reces- sive form (OMIM 264350) is due to inactivating mutations (com- pare with Liddle’s syndrome) in one of the genes SCNN1A, SCCN1B, or SCNN1G, encoding (respectively) the α, β, and γ subunits of the epithelial sodium channel, while the autosomal dominant form (OMIM 177735) is due to loss-​of-​function mutations in the gene NR3C2, encoding the mineralocorticoid receptor. Gitelman’s syndrome (OMIM 263800) is an autosomal recessive disorder characterized by hypotension, neuromuscular abnormalities, hypokalaemia, hypomagnesaemia, hypocalciuria, metabolic alkalosis, and an activated renin–​angiotensin system. It arises due to inactivating mutations in the gene encoding the renal thiazide-​sensitive Na-​Cl cotransporter (SLC12A3), and typically presents in adolescence or early adulthood with neuromuscular signs and symptoms. Bartter’s syndrome is caused by mutations in one or more of the genes that encode regulators of chloride transport within the thick as- cending limb of nephron. There are several types of Bartter’s syndrome. The gene defects responsible are in genes encoding bumetanide-​ sensitive sodium-​(potassium)-​chloride cotransporter 2 (SLC12A1) (type 1, OMIM 601678), ATP-​regulated potassium channel ROMK (KCNJ1) (type 2, OMIM 241200), chloride channel Kb (CLCNKB) (type 3, OMIM 607364), barttin (BSDN) (type 4a, OMIM 602522), and both CLCNKA and CLCNKB genes (type 4b, OMIM 613090). The manifestation of these autosomal recessive disorders is het- erogeneous, but the most typical clinical presentations include early onset (infancy or childhood), hypovolaemia and polyuria, low or normal blood pressure, elevated prostaglandin levels, and nephrocalcinosis. The recently identified Bartter-​like syndrome occurring in subjects with mutations in the CASR gene (which en- codes extracellular basolateral calcium sensing receptor) manifests as hypocalcaemic hypercalciuria. Does my patient have a recognized form of monogenetic hypertension? Identification that a patient has GRA, AME, Liddle’s syndrome, or Gordon’s syndrome has important consequences for treatment (Table 16.17.4.1) and family screening. Phenotypic expression is highly variable, but all of the syndromes are extremely rare and suspicion will usually go unrewarded. Features that may suggest a diagnosis of mendelian hypertension include a young age of onset, moderate to severe hypertension, strong family history, consan- guinity (for the autosomal recessive disorders), and electrolyte abnormalities, particularly of potassium (although this is not in- variable). A good starting point, as described in Chapter 16.17.3, is Table 16.17.4.1  Biochemical and therapeutic characteristics of glucocorticoid-​remediable aldosteronism (GRA), syndrome of apparent mineralocorticoid excess (AME), Liddle’s syndrome, and Gordon’s syndrome GRA AME Liddle’s Gordon’s Plasma electrolytes ↑Na ↓K ↑Na ↓K ↑Na ↓K ↑Na ↑K Plasma aldosterone ↑ ↓ ↓ ↑↓ Plasma renin ↓ ↓ ↓ ↓ Specific treatment Dexamethasone Spironolactone Amiloride Thiazide Note that while the biochemical changes are characteristic, they are not invariably present. 16.17.5 Hypertensive urgencies and emergencies 380 16.17.5 Hypertensive urgencies and emergencies 3800 Gregory Y.H. Lip and Alena Shantsila section 16  Cardiovascular disorders 3800 the measurement of plasma renin activity and plasma aldosterone. If the aldosterone is significantly elevated, then the differential diag- nosis lies between the various forms of Conn’s syndrome and GRA. Diagnosis of GRA would be supported by the finding of elevated 18-​hydroxycortisol and 18-​oxocortisol in the urine, and a positive dexamethasone suppression test, suppression of plasma aldosterone levels to less than 4 ng/​dl with 0.75 to 2.0 mg/​day for at least 2 days being reported to have a greater than 90% specificity and sensitivity for the diagnosis, and GRA can now also be relatively easily con- firmed by finding a chimeric gene fragment with DNA testing. If the aldosterone level is suppressed, then finding an in- creased ratio of cortisol/​cortisone metabolites in the urine would support a diagnosis of AME. The presence of hyperkalaemia, hyperchloraemia, and metabolic acidosis would suggest a diagnosis of Gordon’s syndrome. No biochemical abnormalities specifically support a diagnosis of Liddle’s syndrome, but it typically presents with hyporeninaemic hypoaldosteronism. Ultimately, diagnosis of AME, Liddle’s syndrome, and Gordon’s syndrome also requires DNA analysis, but this is not as straightforward as it is with GRA since several different mutations can give rise to each syndrome. FURTHER READING Boyden LM, et al. (2012). Mutations in kelch-​like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature, 482(7383), 98–​102. Geller DS, et al. (2000). Activating mineralocorticoid receptor muta- tion in hypertension exacerbated by pregnancy. Science, 289, 119–​23. Lifton RP, et  al. (1992). A chimaeric 11β-​hydroxylase/​aldosterone synthase gene causes glucocorticoid-​remediable aldosteronism and human hypertension. Nature, 355, 262–​65. Lifton RP, et al. (2001). Molecular mechanisms of human hyperten- sion. Cell, 104, 545–​56. Maass PG, et al. (2015). PDE3A mutations cause autosomal dominant hypertension with brachydactyly. Nat Genet, 47, 647–53. Mune T, et al. (1995). Human hypertension caused by mutations in the kidney isozyme of 11β-​hydroxysteroid dehydrogenase. Nat Genet, 10, 394–​9. Shimkets RA, et al. (1994). Liddle’s syndrome: heritable human hyper- tension caused by mutations in the β subunit of the epithelial so- dium channel. Cell, 79, 407–​14. Wilson FH, et al. (2001). Human hypertension caused by mutations in WNK kinases. Science, 293, 1107–​12. 16.17.5  Hypertensive urgencies and emergencies Gregory Y.H. Lip and Alena Shantsila ESSENTIALS Hypertensive urgencies and emergencies occur most commonly in patients with previous hypertension, especially if inadequately managed. About 40% of cases have an underlying cause, most com- monly renovascular disease, primary renal diseases, phaeochromo- cytoma, and connective tissue disorders. Hypertensive emergencies occur when severely elevated or sudden marked increase in blood pressure is associated with acute end-​organ damage. The key pathophysiological process is intense peripheral vasocon- striction, resulting in a rapid rise in blood pressure and a vicious circle of events, including ischaemia of the brain and peripheral organs. Hypertensive urgencies Malignant phase hypertension is a rare condition (1–​3 per 100 000 per year, more common in black people) characterized by very high blood pressure, with bilateral retinal haemorrhages and/​or exudates or cotton wool spots, with or without papilloedema. Presentation is typically with visual disturbance, with or without headaches. Urinalysis may demonstrate proteinuria and haematuria, even in the absence of primary renal disease. Some patients with mild renal impairment at first presentation may improve, or even re- gain normal renal function, but this is unlikely to occur in those with more severe renal impairment at presentation. Patients with severe hypertension who are asymptomatic require controlled reduction in blood pressure with oral antihypertensive agents. Over-​rapid blood pressure reduction may be hazardous, leading on occasion to ischaemic complications such as stroke, myocardial infarction, or blindness. The maximum initial fall in blood pressure should not exceed 25% of the presenting value, with the initial aim of treatment being to lower the diastolic pressure to about 100 to 105 mm Hg over a period of 2 to 3 days. The first-​line oral antihypertensive agent is either a short-​acting calcium antagonist (such as nifedipine, 10–​20 mg of the tablet formulation: sublingual or capsular preparations should never be used) or a β-​blocker (such as atenolol, 25 mg initial dose). Hypertensive emergencies Patients who are symptomatic with acute life-​threatening com- plications of severe hypertension, such as hypertensive enceph- alopathy, hypertensive left ventricular failure, or aortic dissection, require parenteral antihypertensive therapy to promptly reduce the blood pressure in a carefully controlled manner. Blood pres- sure should be reduced by 25% over several hours, depending on the clinical situation, usually with a target diastolic blood pres- sure of less than 100 to 110 mm Hg. The first-​line treatment for most hypertensive emergencies is either intravenous sodium nitroprusside or intravenous labetalol, with β-​blockade essential in patients with aortic dissection. Hypertensive emergencies and urgencies carry a poor short-​and long-​term prognosis unless adequately managed. Initial over-​rapid reduction of blood pressure to a normal value is dangerous, but—​in the long term—​blood pressure should eventually be reduced to ac- cepted blood pressure targets. Introduction Hypertensive emergencies occur when severe hypertension is associated with acute end-​organ damage. These can take a variety of forms and can occur at any age. They may be acute 16.17.5  Hypertensive urgencies and emergencies 3801 life-​threatening medical conditions, and are associated with ei- ther severe hypertension or sudden marked increases in blood pressure (Box 16.17.5.1). Symptomatic patients with complica- tions such as aortic dissection and hypertensive encephalopathy require parenteral antihyperten­sive therapy to reduce the blood pressure promptly, but in a controlled manner and with careful monitoring because over-​rapid treatment may in itself be haz- ardous, leading, on occasions, to ischaemic complications such as stroke, myocardial infarction, or blindness. Thus, in patients who have severe hypertension but are asymptomatic, slower, con- trolled, reduction in blood pressure should be achieved with oral antihypertensive agents, making such situations hypertensive ‘urgencies’ rather than ‘emergencies’. In general, there has been a decline in the incidence of hyper- tensive emergencies over the past 20 years in the Western world, which may possibly be the result of the more effective detection, diagnosis, and treatment of mild to moderate hypertension. If patients with hypertensive emergencies are not recognized or treated appropriately, the mortality and morbidity can be very high, with the 1-​year mortality being 70–​90%, and the 5-​year mortality 100%. With adequate blood pressure control, the 1-​year and 5-​year mortality rates decrease to 25 and 50%, respectively. Hypertensive emergencies occur most commonly in patients with previous hypertension, especially if inadequately managed. Nevertheless, some patients can present with hypertensive emergen- cies de novo, without any previous history of hypertension. Very severe and malignant hypertension are more likely to be as- sociated with underlying causes such as renovascular disease, pri- mary renal diseases, phaeochromocytoma, and connective tissue disorders, but malignant hypertension complicating primary hyperaldosteronism (Conn’s syndrome) is very rare. About 40% of patients with malignant hypertension have an underlying cause. Pathophysiology The common denominator in hypertensive emergencies is in- tense peripheral vasoconstriction, resulting in a rapid rise in blood Box 16.17.5.1  Hypertensive emergencies and urgencies Hypertensive emergencies • Hypertensive encephalopathy • Hypertensive left ventricular failure • Hypertension with myocardial infarction or unstable angina • Hypertension with aortic dissection • Severe hypertension with subarachnoid haemorrhage or stroke • Phaeochromocytoma crisis • Recreational drugs—​amphetamines, LSD, cocaine, MDMA (ecstasy), and so on • Perioperative hypertension • Severe pre-​eclampsia or eclampsia Hypertensive urgencies • Malignant hypertension • Chronic renal failure • Pre-​eclampsia • Severe non​malignant hypertension LSD, lysergic acid diethylamide; MDMA, 3,4-​methylenedioxymethamphetamine. Endothelial dysfunction Marked activation of renin-angiotensin system Malignant hypertension Juxtaglomerular ischaemia Thrombotic microangiopathies Platelet activation, fibrinogen elevation Lipid abnormalities • Thrombocytopenia • Neurological symptoms • Linear flame-shaped haemorrhages • Exudates • Cotton wool spots with or without papilledema • LVH • Fibrinoid necrosis of arterioles • Proliferative endarteritis of arteries • Deterioration of renal function (↑serum urea and creatinine, proteinuria) • Diastolic dysfuncction • White matter oedema • Haemolytic anaemia Microangiopathy: Brain: Hypertensive retinopathy: Heart: Kidney: Fig. 16.17.5.1  Main potential mechanisms and target organ involvement in the diagnosis of malignant hypertension. LVH, left ventricular hypertrophy. Modified from Shantsila A, Lip GYH (2017). Malignant Hypertension Revisited—​ Does This Still Exist? Am J Hypertens, 30, 543–​9. section 16  Cardiovascular disorders 3802 pressure and a vicious circle of events, including ischaemia of the brain and peripheral organs. This ischaemia stimulates neurohor- mone and cytokine release, exacerbating vasoconstriction and is- chaemia, further increasing blood pressure, and resulting in target organ damage. Renal ischaemia also leads to activation of the renin–​ angiotensin system (Fig. 16.17.5.1), causing further rise in blood pressure and microvascular damage with excessive endothelial in- jury. Myointimal proliferation in the vasculature may further ex- acerbate the situation, resulting in an intravascular prothrombotic state disbalance (agglutination/​ coagulation) and the development of thrombotic microangiopathies characterized by thrombocyto- penia and microangiopathic haemolytic anaemia (anaemia accom- panied by elevated serum lactate dehydrogenase and the presence of schistocytes in the peripheral blood smear), causing further micro- vascular dysfunction and organ ischaemia. With mild to moderate elevation of blood pressure, the initial re- sponse of the vasculature is arterial and arteriolar vasoconstriction— ​such autoregulation maintaining tissue perfusion at a relatively con- stant level and preventing the raised blood pressure from damaging smaller, more distal blood vessels. Later, arteriolar hypertrophy also minimizes the transmission of pressure to the capillary cir- culation. In normotensive subjects, the upper limit of autoregula­ tion can be a mean arterial pressure of 120 mm Hg (equivalent to 160/​100 mm Hg), but in chronic hypertension, where the vessels are hypertrophied by long-​standing hypertension, the lower limit of autoregulation of cerebral blood flow is shifted towards higher blood pressures (Fig. 16.17.5.2), with impairment of the tolerance to acute hypotension. However, the process of autoregulation fails with rapid and severe rises in blood pressure, leading to a rise in pressure in the arterioles and capillaries, causing vascular damage. Disruption of the endothelium allows plasma constituents (including fibrinoid material) to enter the vessel wall, narrowing or obliterating the lumen in many tissue beds, the level at which fibrinoid necrosis oc- curs depending upon the baseline blood pressure. In the cerebral circulation, this can lead to the development of cerebral oedema and the clinical picture of hypertensive encephalopathy. In addition to protecting the tissues against the effects of hyper- tension, autoregulation maintains perfusion during the treatment of hypertension via arterial and arteriolar vasodilatation. However, falls in blood pressure below the autoregulatory range can lead to organ ischaemia, and the arteriolar hypertrophy induced by chronic hypertension means that target organ ischaemia will occur at a higher pressure than in previously normotensive subjects. Malignant hypertension, a hypertensive ‘urgency’ The malignant phase of hypertension is a rare condition charac- terized by very high blood pressure, with bilateral retinal haem- orrhages and/​or exudates or cotton wool spots, with or without papilloedema (Fig. 16.17.5.3). Its pathophysiological definition is based on the histological hallmark of fibrinoid necrosis of arteri- oles in many tissues, particularly the kidney—​changes which are broadly similar to those seen in the haemolytic–​uraemic syndrome or scleroderma. Mucoid intimal proliferation in renal interlobular arteries and ischaemic collapse of the glomerular tufts may also be seen. Myointimal hyperplasia is a common finding in black pa- tients, with the consequent intrarenal vascular disease leading to ischaemia of the juxtaglomerular apparatus and activation of the renin–​angiotensin system with further vasoconstriction and wall damage, as well as exacerbation of hypertension. Epidemiology Malignant hypertension may be becoming rarer in some coun- tries, particularly among white populations, but it still remains a common problem in developing countries and in other popula- tions with health and social deprivation, where it is an important cause of end-​stage renal failure. In west Birmingham in the United Subepicardium Subendocardium Hypertensive subendocardium? 100 50 50 100 150 200 50 100 150 200 Mean arterial blood pressure (mm Hg) Myocardial blood flow (Percentage of control) Normotensive patients Treated hypertensive patients Hypertensive patients 100 50 Cerebral blood flow (Percentage of control) Fig. 16.17.5.2  Autoregulation of myocardial and cerebral blood flow in normotensive and hypertensive patients. Reprinted from The Lancet, Vol. 330, Strandgaard S and Haunsø S, Why does antihypertensive treatment prevent stroke but not myocardial infarction?, pp. 658–​60. Copyright (1987), with permission from Elsevier. Fig. 16.17.5.3  Ocular fundus in hypertension, showing papilloedema, exudates, and a few haemorrhages. 16.17.5  Hypertensive urgencies and emergencies 3803 Kingdom, the incidence of malignant hypertension is around 1 to 2 per 100 000 population per year, with no clear reduction between 1970 and 2011 in the number of new cases seen, the mean duration of known hypertension before presentation, presenting blood pressures, or the number of antihypertensive drugs that were being used. These data are reinforced by an analysis from Amsterdam of 122 patients with malignant hypertension in a multiethnic popu- lation, where the incidence rate was approximately 2.6 per 100 000 per year, and higher among blacks, approximately 7.3 per 100 000 of population per year. Increasing hospital admissions of pa- tients with either malignant hypertension or hypertensive enceph- alopathy has been observed in retrospective analysis of US data since 2007. These observations may reflect increasing diagnosis of malignant hypertension with encephalopathy, but at the very least there is no evidence of decline in the incidence of malignant hypertension. Although essential hypertension is usually the most common underlying cause of malignant hypertension in adults, secondary causes (especially renal disease) are more prevalent among younger patients, being identified in up to 40% of white and 10% of black subjects. In children (aged <16 years) with malignant hypertension, parenchymal renal disease is the commonest cause (63%), with 33% having renovascular hypertension (aortoarteritis and fibromuscular dysplasia), and only 5% with essential hypertension. There is an unexplained association between cigarette smoking and the use of oral contraceptive pill and the development of ma- lignant hypertension, that remains unexplained. Very rarely, the oral contraceptive pill may be implicated, consistent with the well-​ recognized increase in blood pressure in some women taking the combined oestrogen/​progesterone oral contraceptive pill. It is un- certain whether oral contraceptives cause malignant hypertension directly, or whether they simply exaggerate a pre-​existing tendency to raised blood pressure. Malignant hypertension can occur in older people, and is more common in Afro-​Caribbean than in white and Indo-​Asian popula- tions. Possible reasons for this include the relative resistance of black patients to some antihypertensive therapies and, perhaps, poorer drug compliance. In many series, black individuals had higher sys- tolic blood pressures and more renal dysfunction than whites. One reason for the failure of malignant hypertension to decline in some centres may be inadequate medical screening facilities among poorly educated people with a limited understanding of the nature of the disease and the need to comply with antihypertensive therapy. Any reported tendency towards reduction in the incidence of malignant hypertension may be because increasing use of drug therapy in milder grades of hypertension prevents progression to the malignant phase. Diagnosis The diagnosis of malignant hypertension is usually based on the asso- ciation of severely elevated blood pressure with a Keith and Wagener stage III or IV retinopathy. More recently, it has been suggested to consider that malignant hypertension with retinopathy is only one of several possible presentation(s) of acute hypertension with multiorgan damage (MOD). The presence of disturbance of at least three different target organs (kidney, heart, brain or microangiopathy) in association with acute blood pressure elevation is described as ‘hypertension MOD’, which would need to be managed as a hyper- tensive emergency, even though retinopathy is lacking. Clinical features The predominant presenting symptom is visual disturbances, ac- companied in some cases by headaches. Unfortunately, some patients with malignant hypertension remain asymptomatic, and others present at a late stage of their disease, this proportion ranging from 10% to 75% in one series from Nigeria. In the west Birmingham series, the presenting mean systolic and diastolic blood pressures have remained surprisingly similar over the 50 years surveyed (average blood pressure 229/​142 mm Hg), despite improvements in antihypertensive therapy. Heart failure, angina, or myocardial infarction are complicating features in approximately 20% of patients. The ECG shows that many patients have left ven- tricular hypertrophy, and many have cardiomegaly on chest radiog- raphy. However, some patients do have normal chest radiographs, ECGs, or echocardiograms despite very high blood pressure, sug- gesting that hypertension may have been of recent onset. The pro- portion of de novo diagnoses of malignant hypertension ranges from 55% to 60% in different registries. Investigation All patients with malignant hypertension need a detailed clin- ical history and examination, and investigation with blood tests (full blood count, serum biochemistry including electrolytes and renal function), 12-​lead ECG, chest radiography, and urinalysis. Fundoscopy and retinal photography are mandatory. Urinalysis may demonstrate proteinuria and haematuria, even in the ab- sence of primary renal disease, but the presence of proteinuria is a poor prognostic sign. The kidneys should be imaged by ab- dominal ultrasonography to assess renal size and appearance, with a low threshold for proceeding to renal angiography to look for renal artery stenosis if the kidneys are asymmetric. In all pa- tients a 24-​h urine collection is necessary for catecholamines (see Chapter  16.17.3), and urinary protein excretion should be esti- mated (most readily by measurement of urinary albumin/​cre- atinine ratio, ACR). These initial screening tests serve to identify patients in whom additional investigations may be appropriate to detect an underlying cause of hypertension. The full blood count and film may reveal the anaemia of chronic renal failure or occasionally a thrombotic microangiopathy, with thrombocytopenia and microangiopathic haemolytic anaemia—​ with red cell fragmentation and intravascular haemolysis—​possibly related to the degree of arteriolar fibrinoid necrosis, excessive endothelial injury, along with activation of the renin-​angiotensin-​ aldosterone system and an intravascular prothrombotic state. The presence of thrombotic microangiopathy is associated with worse recovery of renal function in the long term. Serum urea and creatinine should initially be measured daily: renal impairment may have significant prognostic implications. Mild hypokalaemia due to secondary hyperaldosteronism may be present, which usually resolves after control of the hyper- tension. Only very rarely does hypokalaemia indicate primary hyperaldosteronism (Conn’s syndrome), but if it is extreme or per- sists despite good blood pressure control, then the characteristic findings of low renin levels, but high aldosterone concentrations, section 16  Cardiovascular disorders 3804 may be present. More commonly, both plasma renin and aldosterone levels are high in malignant hypertension, usually attributed to juxta- glomerular ischaemia. The inflammatory markers erythrocyte sedi- mentation rate and C-​reactive protein are often modestly elevated in malignant hypertension, but measurement of autoantibodies (antinuclear antibodies and antineutrophil cytoplasmic antibodies) can be used to discern uncommon cases due to vasculitis. Renal bi- opsy is required to make a specific diagnosis in some instances, but should not be performed until blood pressure is controlled. The chest radiograph may show cardiomegaly and the presence of pulmonary oedema. In a recent series of patients with malignant hypertension undergoing echocardiography, features included left ventricular hypertrophy, impaired systolic and diastolic function, and a dilated left atrium, were evident. Systolic impairment, meas- ured by global longitudinal strain, improved significantly as early as 2 months after initiation of treatment and was usually restored completely at 1-​year follow-​up. Long-​term treatment with good blood pressure control results in regression of the left ventricular hypertrophy and improvement of diastolic dysfunction on tissue Doppler, although typically incomplete. These structural/​functional abnormalities may predispose patients to cardiovascular complica- tions including heart failure and cardiac arrhythmias, such as atrial fibrillation. Hypertension and atrial fibrillation commonly coexist, and both are additive to the risk of stroke. In particular, the presence of uncontrolled hypertension increases the risk of stroke and thromboembolism associated with this common arrhythmia. Atrial fibrillation can be regarded as another manifestation of hypertensive target organ damage. Complications Retinopathy As described earlier and in Chapter 16.17.2, the most widely used classification of hypertensive changes in the fundus is that of Keith, Wagener, and Barker—​the strength of this being the correlation in the original description between clinical findings and prog- nosis (Table 16.17.5.1). However, this classification has now been made obsolete by advances in the understanding of the patho- physiology of arterial hypertension and the availability of effective antihypertensive therapy. Ophthalmoscopic grading of the retinal changes in hypertension has been simplified into mild, moderate, and severe levels (see Chapter 16.17.2), and can be further reduced into two groups:  grade A  (non​malignant)—​arteriolar narrowing and focal constriction, which also correlate with age and general cardiovascular status as well as blood pressure; and grade B (malig- nant)—​linear flame-​shaped haemorrhages, and/​or exudates, and/​or cotton wool spots, with or without disc swelling. Papilloedema is an unreliable physical sign, and its presence or absence in the context of other grade B changes does not indicate a worse prognosis. Grades 1 and 2 are broadly similar and are related to age and gen- eral cardiovascular status as well as blood pressure. Grades 3 and 4 are much more alike and both are now considered to be ‘malignant’. See Chapter 16.17.2 for further discussion. Similar retinal appearances with haemorrhages and papilloedema can occur in severe anaemia, connective tissue disease, and in- fective endocarditis. Idiopathic intracranial hypertension with bilateral papilloedema is itself associated with hypertension and obesity but this is not indicative of hypertension entering its ma- lignant phase. Nevertheless, severe hypertension and lone bilat- eral papilloedema may be a variant of malignant hypertension, with similar clinical features and prognosis. The retinal features of malignant hypertension regress over a period of 2 to 3 months if good blood pressure control is achieved. There is an association between the degrees and dynamic of the retinal and renal function changes, thus emphasizing the fact that patients with malignant hypertension develop systemic microvascular damage/​dysfunc- tion involving several organs. Renal involvement Renal involvement in malignant hypertension has been referred to as malignant nephrosclerosis, manifest as haematuria, proteinuria, and (sometimes) acute renal failure. Renal failure is the commonest cause of death, with presenting urea and creatinine levels inde- pendent predictors of survival. When antihypertensive therapy is initiated and blood pres- sure control achieved, the effect on renal function is variable. In the short term, renal function stabilizes in 10% of cases, deteri- orates progressively in 30%, and deteriorates transiently before improving over a matter of weeks in the remainder. Renal failure is more frequent (two-​to threefold) in black, than in white, individuals (Fig. 16.17.5.4), but mainly because of higher serum creatinine levels at presentation. Table 16.17.5.1  The Keith, Wagener, and Barker classification of hypertensive retinopathy Grade 1 Grade 2 Grade 3 Grade 4 Retinal findings Mild narrowing or sclerosis of the retinal arterioles Moderate to marked sclerosis of the retinal arterioles Retinal oedema, cotton wool spots, and haemorrhages All the above and optic disc oedema Exaggerated arterial light reflex Sclerosis and spastic lesions of retinal arterioles Venous compression at arteriovenous crossings (‘nipping’) Macular star Percentage surviving in original series 1 year 90 88 65 21 3 years 70 62 22   6 5 years 70 54 20   1 16.17.5  Hypertensive urgencies and emergencies 3805 Isles and coworkers have suggested that the renal outcome of patients with malignant hypertension can be considered in three groups, each with a different renal prognosis: (1) patients whose serum creatinine is less than 300 µmol/​litre at presentation, who do well with effective antihypertensive therapy; (2) patients with chronic renal failure (serum creatinine >300 µmol/​litre) who do not require renal dialysis immediately, but are unlikely to main- tain or recover renal function, except possibly in the short term, and commonly progress to end-​stage renal failure; and (3) a small group with acute renal failure. It is possible that some of these pa- tients may have poststreptococcal acute nephritic syndrome, char- acterized by retinopathy, fluid retention, and usually complete renal recovery. In the west Birmingham series, Lip et al. did not find such a clear distinction based on serum creatinine and found that renal func- tion continued to deteriorate among many patients with malignant hypertension, despite good blood pressure control at follow-​up. About half of the patients with severe renal impairment at pres- entation demonstrated either static or improved renal function, and there was no evidence that those cases where renal function remained static were those with less renal impairment at presenta- tion. The severity of malignant hypertension at presentation did not predict outcome, but the quality of control of systolic blood pres- sure at follow-​up and the height of the serum creatinine at pres- entation did, suggesting that careful monitoring of renal function and aggressive treatment of blood pressure is mandatory in patients with this condition. End-​stage renal disease remains a significant cause of death in patients with malignant hypertension. High serum urate levels are associated with greater renal impair- ment at baseline, as well as higher diastolic blood pressures, but are not predictive of deterioration in renal function or overall survival in patients with malignant hypertension. There are varying reports of the frequency of renovascular disease in malignant hypertension, which may be due to the frequency with which renal angiography is performed. In older patients, renal artery stenosis is likely to be due to atheromatous disease, which itself may be a consequence of chronic hyperten- sion and chronic hyperlipidaemia, as well as cigarette smoking. In younger patients, and particularly in women, renal artery sten- osis may be due to fibromuscular dysplasia of the renal arteries, with the characteristic ‘string of beads’ appearance on renal angi- ography. The value of surgical or angioplastic correction of ather- omatous disease is debatable, possibly producing no better results than effective blood pressure control with antihypertensive drugs. In patients with fibromuscular dysplasia, however, renal angio- plasty with stenting is worthwhile and will often lead to a normal blood pressure level. Management All patients with malignant hypertension require assessment, in- vestigation, and commencement of therapy under supervision, preferably as an in-​patient. Blood pressure should be measured 4-​ hourly, with the initial aim of treatment being to lower the diastolic pressure near about 100–​105 mm Hg over a period of 2 to 3 days, with oral therapy and dose escalation at daily intervals, if necessary. The maximum initial fall in blood pressure should not exceed 25% of the presenting value, gradual reduction allowing adaptation of disordered tissue autoregulation and avoidance of target organ is- chaemia. More aggressive antihypertensive therapy is both unneces- sary and dangerous, as it may reduce the blood pressure to below the autoregulatory range, leading to ischaemic events such as strokes, heart attack, or renal failure. The first-​line oral antihypertensive agent is either a short-​acting calcium antagonist (such as nifedipine) or a β-​blocker (such as atenolol). An appropriate dose of nifedipine is 10–​20 mg of the tablet formulation, which can be repeated or increased, as ne- cessary, to bring about gradual reduction in blood pressure. Nifedipine is not absorbed from the oral mucosa, and there have been reports of complications including visual loss, cerebral in- farction, and myocardial infarction with nifedipine therapy using the short-​acting sublingual capsules, which produce unpredict- able falls in blood pressure and should never be used. β-​Blockers are useful alternatives, but should be avoided in patients with asthma or where there is a high suspicion of an underlying phaeo- chromocytoma. It is sensible to start with small doses, such as 25 mg of atenolol, increasing the dose as necessary. The combin- ation of oral atenolol and nifedipine is often a well-​tolerated and effective regime. Diuretics should be restricted to those with evidence of fluid overload. Some patients are volume depleted, presumably sec- ondary to a pressure-​related diuresis and activation of the renin–​ angiotensin system. Captopril and the other angiotensin converting enzyme (ACE) inhibitors can produce rapid and dangerous falls in blood pressure, particularly in patients with hypokalaemic sec- ondary hyperaldosteronism and hyponatraemia secondary to juxtaglomerular ischaemia or renovascular disease, which may be unrecognized in the acute situation. Over a period of about 1 to 2 weeks, further antihypertensive drugs should be added in to achieve a gradual reduction of blood pressure to less than 140/​85 mm Hg. Triple or quadruple drug regi- mens are invariably necessary in the long term. 1.0 0.8 0.6 Proportion with renal failure 0.4 0.2 White patients Black patients 0 1 2 3 4 5 6 Years from admission Fig. 16.17.5.4  Proportion with renal failure after presentation with malignant hypertension, stratified for ethnicity. From Van den Born BJ, et al. (2006). Ethnic disparities in the incidence, presentation and complications of malignant hypertension. J Hypertens, 24, 2299–​304. section 16  Cardiovascular disorders 3806 Drugs for the treatment of hypertensive emergencies and urgen- cies are summarized in Tables 16.17.5.2 and 16.17.5.3. Prognosis Historically, when malignant hypertension was left untreated, around 80% of patients died within 2  years, hence the name. In west Birmingham, between 1965 and 2006, after a median follow-​up of 103 months (range 1–​539 months), 40% were alive and not requiring renal replacement therapy, 3.2% were on long-​ term haemodialysis, and 40% were dead, with the remainder lost to follow-​up. The commonest causes of death were renal failure (39.7%), stroke (23.8%), myocardial infarction (11.1%), and heart failure (10.3%). The advent of effective and tolerable antihypertensive drug therapy has improved prognosis. For example, in the west Birmingham series, 5-​year mortality rates reduced from 76% prior to 1967 to 7% Table 16.17.5.2  Oral drugs for hypertensive emergencies and urgencies Category Example Comment β-​Blockers Atenolol (25–​50 mg) Safe unless contraindicated Calcium channel blockers Nifedipine capsules Dangerous Nifedipine tablets (10–​20 mg) Safe Amlodipine Onset of action is slow (c.5 days) Verapamil Useful if tachycardia or associated supraventricular arrhythmia Nicardipine Not better than nifedipine by mouth α-​Blockers Prazosin Little experience Doxazosin Little experience Phenoxybenzamine Phaeochromocytoma Diuretics Thiazides Slow onset Loop diuretics Only if heart failure ACE inhibitors Captopril (6.25–​50 mg, three times a day) If patient on diuretic, or if renal artery stenosis is undiagnosed, may cause rapid falls in blood pressure and acute renal failure Table 16.17.5.3  Parenteral drugs for the treatment of hypertensive emergencies Action Administration Use and adverse effects Comment Sodium nitroprusside Dilates both arterioles and veins via generation of cGMP which then activates calcium-​sensitive potassium channels in the cell membrane IV infusion; rapid onset and offset of action, minimizing the risk of hypotension Recommended starting dose is 0.25–​0.5 μg/​kg per min, increased as necessary to a maximum dose of 8–​10 μg/​kg per min, for up to 10 min Nitroprusside should not be given to pregnant women Can cause intrapulmonary shunting and coronary ‘steal’ Thiocyanate and cyanide toxicity manifest by clinical deterioration, muscle twitching, altered mental status, and lactic acidosis, and can be fatal The most effective parenteral drug for most hypertensive emergencies Easy to control on a minute-​to-​ minute basis Glyceryl trinitrate (nitroglycerin) Similar action to nitroprusside, but greater venodilatation IV infusion, 5–​100 μg/​min Onset of action is 2–​5 min, duration of action 5–​10 min Headache (due to direct vasodilatation) and tachycardia (reflex sympathetic activation) Vomiting Methaemoglobinaemia Most useful in patients with symptomatic coronary disease and in those with hypertension following surgery Labetalol Combined β-​and α-​blocker Rapid onset of action (5 min or less) Bolus of 20 mg initially, followed by 20–​80 mg every 10 min to a total dose of 300 mg The infusion rate is 0.5–​2 mg/​min Avoid in patients with contraindications to β-​blockers Safe in patients with active coronary disease since it does not increase the heart rate Also useful in the perioperative care of patients with severe hypertension Esmolol β-​Blocker Rapid onset and offset of action IV infusion, titrated to heart rate and blood pressure response Reduces myocardial ischaemia Avoid in patients with contraindications to β-​blockers Useful in tachycardias, hyperdynamic heart, arrhythmias (e.g. atrial fibrillation), perioperative hypertension, aortic dissection Nicardipine Dihydropyridine calcium channel blocker IV infusion at 5–​15 mg/​h Headache and flushing Tachycardia Becoming more popular Useful for most hypertensive emergencies, except acute heart failure 16.17.5  Hypertensive urgencies and emergencies 3807 for the years 1997 to 2011 (Fig. 16.17.5.5). The series by Scarpelli and coworkers reported a 12-​year survival rate of about 69%, al- though patients with malignant hypertension diagnosed after 1980 had a 100% survival rate. More contemporaneous data from the Amsterdam series, describing patient incidents between 1993 and 2005, showed that 10% had died and 19% needed renal replacement therapy after a mean follow-​up of 4 years. Hence, whatever the cause of malignant hypertension, progressive renal impairment is still a common complicating factor, with many patients needing dialysis in the long term. The importance of early diagnosis is emphasized as patients tend to develop clinical symptoms only at a late stage of their disease. Black men with malignant hypertension have a poor prognosis when compared with other ethnic groups or women; they also present with more severe hypertension and greater renal damage, which are independent predictors of outcome and explain the poorer prognosis. Hypertensive emergencies Hypertensive left ventricular failure Hypertension causes heart failure by a number of mechan- isms: these include pressure overload on the heart due to the raised peripheral vascular resistance, reduced left ventricular compliance (e.g. in left ventricular hypertrophy), an increased risk for cor- onary artery disease and the precipitation of cardiac arrhythmias (such as atrial fibrillation). Severe hypertension results in a signifi- cant increase in afterload and may result in decompensation of the failing heart. In very severe hypertension with marked pulmonary oedema, intravenous sodium nitroprusside may be necessary to reduce pre- load and afterload in addition to conventional management with opioids and loop diuretics. However, metabolism of nitroprusside to cyanide, possibly leading to the development of cyanide or (rarely) thiocyanate toxicity, may be a limitation. This manifests with altered mental status and lactic acidosis, and can be fatal. The risk of toxicity is increased in children, also with prolonged treatment (>24–​48 h), underlying renal insufficiency, and requirement for high doses (>2 µg/​kg per min). An infusion of sodium thiosulfate can be used in affected patients to provide a sulfur donor to detoxify cyanide into thiocyanate. Nitrates may also be used to treat hypertensive left ventricular failure, but they are less potent than sodium nitroprusside. ACE in- hibitors should be considered only after the patient’s condition is stabilized, when they are well established to be life-​saving in those with left ventricular systolic impairment, lead to long-​term regres- sion of left ventricular hypertrophy, and may also improve heart failure secondary to diastolic dysfunction. Hypertensive encephalopathy Hypertensive encephalopathy refers to the presence of signs of cerebral oedema caused by breakthrough hyperperfusion fol- lowing severe and sudden rises in blood pressure. There is failure of autoregulatory vasoconstriction with focal or generalized dila- tation of small arteries and arterioles and impaired macro-​and Action Administration Use and adverse effects Comment Diazoxide Arteriolar vasodilator that has little effect on the venous circulation IV bolus 50–​150 mg or infusion 2–​10 mg/​h Peak effect seen within 15 min, lasts for 4–​24 h Do not use in patients with angina pectoris, myocardial infarction, pulmonary oedema, or a dissecting aortic aneurysm Can cause marked fluid retention and a diuretic may be needed Give β-​blocker to block reflex activation of the sympathetic nervous system Rarely used nowadays as may cause excessive blood pressure reduction which is difficult to reverse Hydralazine Direct arteriolar vasodilator IV bolus Initial dose is 10–​20 mg Fall in blood pressure begins within 10–​30 min and lasts 2–​4 h Tachycardia, flushing, headache, vomiting Aggravation of angina Hypotensive response to hydralazine is less predictable Used in pregnant women Phentolamine α-​Adrenergic blocker IV bolus, 5–​10 mg every 5–​15 min as necessary Severe hypertension due to phaeochromocytoma and other syndromes of increased catecholamine activity, such as drug abuse, MAO-​ induced hypertension, and so on Tachyphylaxis means that doses need to be escalated IV, intravenous; MAO, monoamine oxidase. Table 16.17.5.3  Continued 80 76% 74% 26% 20% 7% 60 40 5-year mortality, % 20 0 1958–1966 1967–1976 1977–1986 Years of diagnosis 1987–1996 1997–2011 Fig. 16.17.5.5  Rates of 5-​year mortality in patients with malignant hypertension diagnosed in different time periods. From Shantsila A, Shantsila E, Beevers DG, Lip GYH (2017). Predictors of 5-​year outcomes in malignant phase hypertension: the West Birmingham Malignant Hypertension Registry. J Hypertens, 35, 2310–​14. section 16  Cardiovascular disorders 3808 microvascular function. This leads to high cerebral blood flow, dysfunction of the blood–​brain barrier, and the formation of brain oedema, which is thought to cause the clinical symptoms. The con- dition is now very rare, although recent retrospective analysis of the US data showed an increasing trend for the hospital admission of patients with either hypertensive encephalopathy or malignant hypertension after 2007. These observations could reflect improved recognition and diagnosis of malignant hypertension with enceph- alopathy, as admissions for essential hypertension fall. It is essential to perform a CT or an MRI scan to ensure that this hypertensive emergency is distinguished from other neurological syndromes as- sociated with high blood pressure, including intracerebral or sub- arachnoid haemorrhage, ischaemic stroke, or lacunar infarction. Hypertensive encephalopathy is usually associated with a history of hypertension that has been inadequately treated, or where pre- vious treatment has been discontinued. It is characterized by the in- sidious onset of headache, nausea, and vomiting, followed by visual disturbances, field loss, and fluctuating, non​localizing neurological symptoms such as restlessness, confusion, and—​if the hypertension is not treated—​seizures and coma. Severe retinopathy is frequently, but not always, present. CT or MRI may demonstrate white matter oedema, with the reso- lution of changes after patient stabilization. One of these tests is mandatory to exclude cerebral haemorrhage or infarction. Indeed, the increased use of CT scanning has demonstrated that almost all patients who appear to have hypertensive encephalopathy have cerebral infarction or haemorrhage with surrounding oedema and space-​occupying cerebral symptoms. Lumbar puncture is not indi- cated in the management of patients with malignant hypertension; but if obtained (perhaps in ignorance of the diagnosis) the cerebro- spinal fluid is usually normal, although at an increased pressure. The ECG may show variable transient, focal, or bilateral abnormalities. Sodium nitroprusside is the drug of choice for genuine hyperten- sive encephalopathy, but is not usually given if there is a cerebral infarct or haemorrhage. Parenteral labetalol and nitrates have also been used successfully. Rarely, diazoxide and hydralazine have been given, but they can cause precipitate and life-​threatening acute falls in blood pressure, and they require concurrent β-​blocker adminis- tration to minimize reflex sympathetic stimulation. Sublingual ni- fedipine capsules should never be used (see ‘Management’, earlier). Phentolamine is used only in patients with severe hypertension due to increased catecholamine activity, such as that seen in phaeo- chromocytoma, or after tyramine ingestion in a patient being treated with a monoamine oxidase inhibitor. ACE inhibitors are best avoided in the early stage as they may, even in a very low dose, cause precipitate falls in blood pressure and life-​threatening reduction in cerebral perfusion, particularly when patients are fluid depleted due to diuretic therapy or in the presence of renal artery stenosis. Severe pre-​eclampsia and eclampsia are discussed in detail else- where (see Chapter 14.4). They may present with clinical features similar to hypertensive encephalopathy, and treatment is broadly similar, with labetalol infusions, magnesium sulphate, and early de- livery of the fetus. Hypertension with unstable angina or acute myocardial infarction In a patient presenting with an acute coronary syndrome (unstable angina or acute myocardial infarction) and severe hypertension, a ‘true’ hypertensive emergency, such as aortic dissection, must first be ruled out. The risk of bleeding and stroke is significantly increased if anticoagulation with heparin, antiplatelet therapies (such as glyco- protein IIb/​IIIa inhibitors), or thrombolytic therapy is administered. The appropriate initial treatment of patients with severe hyper- tension (>180/​110 mm Hg) and an acute coronary syndrome should include the initiation of intravenous nitrates, with intravenous labetalol, sodium nitroprusside, or nicardipine as alternatives. The reduction of blood pressure should not be too abrupt: as with ma- lignant hypertension, a gradual reduction is recommended in an en- deavour to avoid further myocardial or brain ischaemia. As stated previously, sublingual nifedipine—​once considered as a first-​line drug—​should not be used in view of its negligible oral absorp- tion and the unpredictable hypotensive effects from later gastric absorption. Anticoagulation or thrombolytic therapy can be administered when the blood pressure is adequately controlled (<180/​110 mm Hg). In many centres, revascularization with primary percutaneous coronary angioplasty is increasingly the initial management option for acute ST-​segment elevation myocardial infarction (STEMI). Hypertension with acute stroke and after a stroke It is common to find modestly elevated blood pressure in patients ad- mitted to hospital following an acute stroke. Cerebral autoregulation is commonly impaired in this context, with flow becoming pressure dependent, hence excessive antihypertensive treatment may serve to worsen the cerebral damage resulting from intracerebral infarction or haemorrhage, and stroke physicians are very wary about lowering the blood pressure. There are few randomized controlled trials to inform the man- agement of this common problem. Current consensus only recom- mends acute blood pressure lowering where there is associated acute end-​organ damage—​for example, cardiac (acute myocardial infarc- tion, severe left ventricular failure) or vascular urgencies (aortic dissection), hypertensive encephalopathy, acute renal failure, con- current anticoagulant therapy (thrombolysis, intravenous heparin, and so on), or persistent blood pressure elevation with a threshold greater than 200/​120  mm Hg for ischaemic stroke and greater than 180/​105 mm Hg for haemorrhagic stroke. In these cases, oral therapy with small doses of nifedipine or atenolol may be required. Parenteral treatment or sublingual nifedipine is always contraindi- cated. The calcium antagonist nimodipine has beneficial effects on cerebral vasospasm following subarachnoid haemorrhage, but these effects are not related to the small fall in blood pressure with this drug. Severe hypertension after a stroke is a risk factor for further stokes, and long-​term treatment is worthwhile. It is unclear whether the immediate treatment of mild hypertension is of benefit. The role of antihypertensive medication before, during, and after a stroke can, therefore, be summarized as follows: • Before a stroke, it is of benefit to have blood pressure reduced to below 140/​85 mm Hg, as stroke prevention can be achieved. • During a stroke, it is detrimental to have hypertension treated ag- gressively, in view of the disordered cerebral autoregulation. • After a stroke, the epidemiological associations of hypertension with recurrent stroke have not been entirely consistent, with some studies showing no association or a J-​shaped relationship. 16.17.5  Hypertensive urgencies and emergencies 3809 In recent years, many studies have reported on the effects of antihypertensive drugs—​predominantly ACE inhibitors or angio- tensin receptor blockers—​in the early post-​stroke setting. The Heart Outcomes Prevention Evaluation (HOPE) study reported a subset of 1013 subjects with a previous history of stroke or tran- sient ischaemic attack (TIA), where there was a non​significant 15% reduction in total stroke recurrence with ramipril. In the PROGRESS trial, 6105 normotensive and hypertensive patients with a history of ischaemic or haemorrhagic stroke or TIA were randomized to perindopril (± indapamide), which reduced re- current stroke by 28% and major vascular events by 26% during 4 years of follow-​up. The Morbidity and Mortality after Stroke Eprosartan Study (MOSES) compared eprosartan (an angiotensin receptor blocker) to nitrendipine (a dihydropyridine calcium channel blocker) in hypertensive-​stroke survivors and found a 21% risk reduction in the primary endpoint of all cardiovascular and cerebrovascular events and a 25% reduction in recurrent cerebrovascular events in the eprosartan-​treated patients. In the CATIS Randomized Clinical Trial, patients with acute ischaemic stroke (n  =  2038) were randomly assigned to receive antihypertensive treatment (aimed at lowering systolic blood pressure by 10% to 25% within the first 24 h after randomization, achieving blood pressure less than 140/​90 mm Hg within 7 days, and maintaining this level during hospitalization) or to discon- tinue all antihypertensive medications (control) during hospi- talization (n = 2033). In this trial, blood pressure reduction with antihypertensive medications, compared with the absence of hyper- tensive medication, did not reduce the likelihood of death and major disability at 14 days or hospital discharge. Data from the large Safe Implementation of Thrombolysis in Stroke–​ International Stroke Thrombolysis Register (SITS-​ISTR) of 11 080 patients showed a U-​shaped relation of death and physical independency with post-​thrombolysis systolic blood pressure, with blood pressure of 141–​150 mm Hg associated with the most favour- able outcomes. The Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial pilot (INTERACT1) (n  =  404) and main INTERACT2 (n  =  2839) studies compared intensive (target <140 mm Hg) or guideline-​recommended (target <180 mm Hg) systolic blood pressure lowering treatment in patients with spon- taneous intracranial haemorrhage (<6 h). These showed favourable outcome on physical independency for intensive BP control (odds ratio 1.13, 95% confidence interval 1.00–​1.26; p = 0.042) over the early and later recovery periods. Management of blood pressure in a patient with aortic dissection The detailed presentation, diagnosis, and treatment of aortic dissection is discussed in Chapter 16.14.1. On suspicion of the diagnosis, whether or not surgery is indicated, all patients should be treated pharmacologically to reduce the systolic blood pres- sure to around 110 mm Hg and the heart rate to 60–​70 beats/​ min, thus reducing the force of systolic ejection to reduce aortic shear stress and limit the size of the dissection. Labetalol is an effective agent, or alternatively, sodium nitroprusside in con- junction with a β-​blocker may be used. Patients should ideally have haemodynamic monitoring with an arterial line in position. Diagnostic tests are then performed on an urgent basis to con- firm the dissection, identifying whether the ascending aorta is involved, and defining any vascular abnormalities resulting from the dissection. Acknowledgement We acknowledge the contribution of D. Gareth Beevers to previous editions of this chapter. FURTHER READING Bloxham CA, Beevers DG, Walker JM (1979). Malignant hyperten- sion and cigarette smoking. Br Med J, i, 581–​3. Cremer A, et al. (2015). From malignant hypertension to hypertension-​ MOD: a modern definition for an old but still dangerous emergency. J Hum Hypertens, 30, 463–​6. Gudbrandsson T, et  al. (1979). Malignant hypertension. Improving prognosis in a rare disease. Acta Med Scand, 206, 495–​9. Harvey JM, et al. (1992). Renal biopsy findings in hypertensive patients with proteinuria. Lancet, 340, 1435–​6. He J, et al. (2014). Effects of immediate blood pressure reduction on death and major disability in patients with acute ischemic stroke: the CATIS randomized clinical trial. JAMA, 311, 479–​89. Isles CG, McLay A, Boulton Jones JM (1984). Recovery in malignant hypertension presenting as acute renal failure. Q J Med, 212, 439–​52. Jhetam D, et al. (1982). The malignant phase of essential hypertension in Johannesburg blacks. S Afr Med J, 61, 899–​902. Kadiri S, Olutade BO (1991). The clinical presentation of malignant hypertension in Nigerians. J Hum Hypertens, 5, 339–​43. Keith NM, Wagener HP, Barker NW (1939). Some different types of essential hypertension: their course and prognosis. Am J Med Sci, 196, 332–​43. Kumar P, et al. (1996). Malignant hypertension in children in India. Nephrol Dial Trans, 11, 1261–​6. Lane DA, Lip GYH, Beevas DG (2009). Improving survival of malignant hypertension patients over 40 years. Am J Hypertens, 22, 1199–​204. Leishman AWD (1959). Hypertension—​treated and untreated: a study of 400 cases. Br Med J, i, 1361–​3. Lim KG, et al. (1987). Malignant hypertension in women of childbearing age and its relation to the contraceptive pill. BMJ, 294, 1057–​9. Lip GYH, et  al. (1995). Severe hypertension and lone bilateral papilloedema: a variant of malignant phase hypertension. Blood Press, 4, 339–​42. Lip GYH, et al. (1995). Malignant hypertension in the elderly. Q J Med, 88, 641–​7. Lip GYH, Beevers M, Beevers DG (1997). Does renal function improve following diagnosis of malignant phase hypertension? J Hypertens, 15, 1309–​15. Lip GYH, Beevers M, Beevers DG (2000). Serum urate is associated with baseline renal dysfunction but not survival or deterioration in renal function in malignant phase hypertension. J Hypertens, 18, 97–​101. Lip GY, et al. (2010). Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-​based approach: the Euro Heart survey on atrial fibrillation. Chest, 137, 263–​72. Mamdani BH, et al. (1974). Recovery from prolonged renal failure in patients with accelerated hypertension. N Engl J Med, 291, 1343–​4. section 16  Cardiovascular disorders 3810 Pitcock JA, et al. (1976). Malignant hypertension in blacks. Malignant intrarenal arterial disease as observed by light and electron micros- copy. Hum Pathol, 7, 333–​46. Scarpelli PT, et al. (1997). Accelerated (malignant) hypertension: a study of 121 cases between 1974 and 1996. Nephrology, 10, 207–​15. Schrader J, et al. (2005). Morbidity and mortality after stroke, eprosartan compared with nitrendipine for secondary prevention: principal results of a prospective randomized controlled study (MOSES). Stroke, 36, 1218–​26. Shantsila A, Lip GYH (2017). Malignant hypertension revisited—​does this still exist? Am J Hypertens, 30, 543–​9. Strandgaard S, Paulson OB (1996). Antihypertensive drugs and cere- bral circulation. Eur J Clin Invest, 26, 625–​30. Van den Born BH, et al. (2019). ESC Council on hypertension pos- ition document on the management of hypertensive emergencies. Eur Heart J Cardiovasc Pharmacother, 5, 37–46. Van den Born BJ, et al. (2006). Ethnic disparities in the incidence, pres- entation and complications of malignant hypertension. J Hypertens, 24, 2299–​304. Veriava Y, et al. (1990). Hypertension as a cause of end-​stage renal failure in South Africa. J Hum Hypertens, 4, 379–​83. Webster J, et al. (1993). Accelerated hypertension—​patterns of mor- tality and clinical factors affecting outcome in treated patients. Q J Med, 86, 485–​93. Zampaglione P, et al. (1996). Hypertensive urgencies and emer- gencies. Prevalence and clinical presentation. Hypertension, 27, 144–​7. 16.2 Clinical presentation of heart disease 3276 1 16.2 Clinical presentation of heart disease 3276 16.2.1 Chest pain, breathlessness, and fatigue 3276 Jeremy Dwight 16.2 Clinical presentation of heart disease CONTENTS 16.2.1 Chest pain, breathlessness, and fatigue  3276 Jeremy Dwight 16.2.2 Syncope and palpitation  3284 K. Rajappan, A.C. Rankin, A.D. McGavigan, and S.M. Cobbe 16.2.1  Chest pain, breathlessness, and fatigue Jeremy Dwight ESSENTIALS Chest pain, breathlessness, and fatigue are common diagnostic challenges, with a broad differential diagnosis that includes several life-​threatening pathologies. Chest pain The most reliable discriminating feature for angina, as opposed to other causes of chest pain, is its constricting nature, a fixed and pre- dictable relationship to exertion, and that is relieved, within a few minutes, by rest or glyceryl trinitrate. The pain in acute coronary syndromes is similar to exertional angina, but usually more severe and usually reaches maximal intensity over the course of a few min- utes: pain reaching its maximum intensity instantaneously suggests an alternative cause. Specific clues in history and physical examination are critical for diagnosis of aortic dissection and pericarditis. Breathlessness and fatigue Most patients find it impossible to distinguish between cardiac and pulmonary causes of dyspnoea. In the diagnosis of left ventricular failure the most helpful features in the history are exertional breath- lessness, orthopnoea, paroxysmal nocturnal dyspnoea, or a history of myocardial infarction. A displaced apex on palpation is helpful and relatively specific; a third heart sound has a high specificity but low sensitivity; basal inspiratory crackles are suggestive of pulmonary oedema but have low sensitivity and specificity. Other considerations The cardiovascular history routinely includes assessment of risk factors and those aspects of the patient’s past medical history that make cardiovascular disease more likely. The presence of numerous risk factors may, on occasion, prompt the physician to proceed to further investigation even in the face of a relatively unconvincing history. Most diagnoses are made on the basis of patient history, and the physician is always compelled to return to the initial history and examination to put the findings of any investigations into context and to plan therapy appropriate for the individual patient. Introduction The symptoms of chest pain, breathlessness, and fatigue present a frequent diagnostic challenge in the outpatient and acute medical departments, as well as the emergency department. They have a broad differential diagnosis that includes several life-​threatening pathologies. As with all clinical presentations, the initial presenting symptom will prompt a differential diagnosis that the physician must narrow down, using a thorough history, to one or two possibilities. The onset, nature, and precipitating causes of symptoms need to be ac- curately defined, with carefully directed questions used to assess their relevance. The process involves a partnership between the pa- tient and their doctor and is enhanced by explaining the reasoning behind the questions asked and their relevance to making a diag- nosis. In this way history-​taking is a useful opportunity to assist the patient to a better understanding of their symptoms and to improve their compliance with any management plan. The cardiovascular history routinely includes assessment of risk factors such as age, occupation, diabetes, hypertension, smoking, hypercholesterolaemia, drugs (both therapeutic and recreational), and a family history. It should also record those aspects of the patient’s past medical history that make cardiovascular disease more likely, such as stroke, transient ischaemic attack, claudica- tion, vascular surgery, renal disease, or connective tissue disease. The presence of numerous risk factors may, on occasion, prompt the 16.2.1  Chest pain, breathlessness, and fatigue 3277 physician to proceed to further investigation even in the face of a relatively unconvincing history. Armed with a differential diagnosis obtained from the history, the physical examination is directed to identifying further supporting evidence. In isolation, however, there are surprisingly few examin- ation findings that will provide a definitive diagnosis. The cardiologist has a large armamentarium of diagnostic tools available to assist in making a diagnosis—​ECG, echocardiog- raphy, coronary angiography, MRI, and so on. These may appear to threaten to displace history-​taking with the allure of high-​definition images and impressive software. However, most diagnoses are made on the basis of patient history, and the physician is always compelled to return to the initial history and examination to put the findings of any investigations into context and to plan therapy appropriate for the individual patient. Chest pain Chest pain accounts for up to 20% of all medical consultations and is one of the commonest presentations to the emergency depart- ment. In the community setting musculoskeletal or gastrointestinal causes are most common, whereas cardiac causes are more frequent in the emergency department (Table 16.2.1.1). The circumstances of chest pain Chest pain on exertion: Angina pectoris They who are afflicted with it are seized while they are walking (more especially if it be uphill and soon after eating) with a painful and most disagreeable sensation of the breast, which seems as if it would extinguish life, if it were to increase or continue, but the moment they stand still, all this uneasiness vanishes. (Heberden, 1768) Unfortunately for the physician, the descriptors used by patients with angina are highly variable and include burning, heaviness, tightness, pressure, squeezing, aching, and strangling. Patients may not describe pain and it is preferable to ask for symptoms of discomfort in the chest. Most patients with angina recognize the pain as being worrying or serious. The location of the discomfort is usually retrosternal and may radiate to the arms, neck, and jaw (Fig. 16.2.1.1). Less commonly, the pain may be felt in the back and upper abdomen. The most reliable discriminating feature for angina as opposed to other causes of chest pain is a fixed and predictable relationship to exertion that is relieved within a few minutes by rest or glyceryl tri- nitrate (nitroglycerin). The discomfort characteristically occurs when walking up an incline and compels the patient to stop. In some cases, the characteristic symptoms occur at the start of exertion and then ease, which is termed ‘walk-​through angina’. Surprisingly, patients may still be able to perform substantial anaerobic exercise without limitation. Angina is often worse in cold weather, in a cold wind, or after eating. Occasionally the pain is only present at the start of the day, when the patient is shaving or brushing their teeth. Symptoms of chest discomfort occurring after rather than during exertion, or which are present continuously throughout the day, are not due to angina. Taking a careful history of the time course of relief with rest and glyceryl trinitrate is important. Many patients mistakenly report a response to glyceryl trinitrate when their pain has taken more than 15 min to resolve, but a response to glyceryl trinitrate is only helpful diagnostically when it occurs within a few minutes. Oesophageal spasm also responds to glyceryl trinitrate and may produce similar discomfort, but the pain is not related to exertion and is nearly always associated with symptoms of reflux. The three key clinical features of anginal pain are that it is (1) a constricting discomfort in the front of the chest, neck, shoulders, jaw, or arms; (2) precipitated by exertion; (3) relieved by rest or GTN within about 5 min. These features are used to identify patients with typical angina (all three features), atyp- ical angina (two features), or non​cardiac pain (one or none of these features). In the United Kingdom this classification has been incorp- orated into National Institute for Health and Care Excellence (NICE) guidelines for management of recent onset chest pain. Chest pain at rest Chest pain due to ischaemia that occurs at rest has a broader dif- ferential diagnosis. The important life-​threatening differential diag- noses are myocardial infarction, aortic dissection, and pulmonary embolism. Rest pain due to angina without infarction is usually accompanied by a history of exertional angina, but there are a few exceptions. Arrhythmias (e.g. paroxysmal atrial fibrillation) may precipitate angina at rest and a history of palpitations should be sought in those with unpredictable symptoms. Emotional stress may also precipitate an attack. An important example of this is Takotsubo cardiomyopathy, where chest pain is accompanied by a character- istic pattern of left ventricular damage in the absence of significant coronary disease. Nocturnal angina may be precipitated by night- mares or the onset of pulmonary oedema, but a history of exertional angina is nearly always present. Where nocturnal chest pain is pre- sent in the absence of exertional symptoms, a history of acid reflux (relief on sitting up or with antacids, and discomfort on drinking hot fluids) should be sought. Reflux symptoms are common and may coexist with angina, and the patient may find it impossible to differ- entiate between the two. Table 16.2.1.1  Cardiovascular causes of chest pain and differential diagnoses Frequency as cause of chest pain Cardiovascular Non​cardiovascular Common Angina Oesophageal reflux Acute coronary syndromes Pleurisy Pericarditis Musculoskeletal, including osteochondritis Pulmonary embolism Syndrome X Uncommon Valvular heart disease Pneumothorax Pulmonary hypertension Herpes zoster Aortic dissection Peptic ulcer disease Myocarditis Pulmonary or mediastinal tumours Takotsubo cardiomyopathy Mediastinitis section 16  Cardiovascular disorders 3278 Particular causes of chest pain Acute coronary syndromes The term ‘acute coronary syndrome’ encompasses myocardial in- farction and unstable angina, conditions which are usually caused by a common pathology—​the rupture or erosion of an atheromatous plaque. Because of the need for rapid assessment and treatment, the ECG is often used to triage patients with chest pain on admission to the emergency department. Where there are classic features of ST elevation infarction, treatment is commenced with thrombolysis or angioplasty after a brief confirmatory history (see Chapter 16.13.4). However, patients with ST elevation represent only a small fraction of those presenting with chest pain, and those without ST elevation present the greater diagnostic challenge. Some will simply have dys- pepsia or musculoskeletal pain, whereas those at the other end of the spectrum will be at imminent risk of myocardial infarction. The history has two important roles: first to establish whether the pain is cardiac, and secondly to contribute to the risk stratification process that determines the nature and time course subsequent therapy and investigation. The character of pain in acute coronary syndromes is similar to exertional angina, but usually more severe. It usually reaches max- imal intensity over the course of a few minutes. Pain reaching its maximum intensity instantaneously suggests an alternative cause, in particular, aortic dissection. The patient should be asked to de- scribe exactly what they were doing at the onset of the pain: sudden onset during a specific movement will suggest a musculoskeletal origin. The classical description of the pain of myocardial infarction is of a heavy, crushing, or constricting pain. In comparison to angina the duration of pain in myocardial infarction is longer (>15 min), and with increasing duration myocardial infarction is more likely, but the pain rarely lasts more than a few hours. Infarction is more likely to be associated with systemic symptoms (breathlessness, sweating, nausea, and vomiting) and does not respond to glyceryl trinitrate. About one-​half of patients will have a history suggestive of worsening exertional angina, or short-​lived episodes of chest pain at rest before presentation. The pain of an acute coronary syndrome usually discourages the patient from attempting any exertion and does not improve with exercise. Although the history alone cannot definitively rule out myocardial infarction, it can be used to assess the probability of this condition (Box 16.2.1.1). During the examination, the patient should be asked to map out the distribution of the pain. Pain radiation to both arms is sug- gestive of acute coronary syndrome. Highly localized pain of less than a few centimetres in distribution is unlikely to ischaemic in origin. Tenderness on palpation of the chest wall or pain exacer- bated by rotation of the thorax or passive movements of the arms or neck suggest musculoskeletal pain but does not infallibly rule out cardiac ischaemia. Components of the history, the ECG, and markers of myocardial damage are used in non-​ST elevation acute coronary syndromes to determine the risk of subsequent events in the TIMI (Thrombolysis in Myocardial Infarction) risk score (Table 16.2.1.2) and a scoring system based on the GRACE (Global Registry of Acute Coronary Events) registry. Great emphasis has been placed on the use of troponin estimation in determining the risk of subsequent events in these patients and this is undoubtedly a useful tool. However, in the absence of definitive ECG changes or troponin rise, the patient may still score 5 on the TIMI risk score from the history alone, giving RETROSTERNAL INTERSCAPULAR Myocardial ischaemic pain Pericardial pain Oesophageal pain Aortic dissection Mediastinal lesions Pulmonary embolization SHOULDER Myocardial ischaemic pain Pericarditis Subdiaphragmatic abscess Diaphragmatic pleurisy Cervical spine disease Acute musculoskeletal pain Thoracic outlet syndrome ARMS Myocardial ischaemic pain Cervical/dorsal spine pain Thoracic outlet syndrome LEFT LOWER ANTERIOR CHEST Intercostal neuralgia Pulmonary embolization Myositis Pneumonia/pleurisy Splenic infarction Splenic flexure syndrome Subdiaphragmatic abscess Precordial catch syndrome Injuries EPIGASTRIC Myocardial ischaemic pain Pericardial pain Oesophageal pain Duodenal/gastric pain Pancreatic pain Gallbladder pain Distention of the liver Diaphragmatic pleurisy Pneumonia Myocardial ischaemic pain Musculoskeletal pain Gallbladder pain Pancreatic pain RIGHT LOWER ANTERIOR CHEST Gallbladder pain Distention of the liver Subdiaphragmatic abscess Pneumonia/pleurisy Gastric or duodenal penetrating ulcer Pulmonary embolization Acute myositis Injuries Fig. 16.2.1.1  Differential diagnosis of chest pain according to location and radiation. Serious intrathoracic or subdiaphragmatic diseases are usually associated with pains that begin in the central or left anterior chest, left shoulder or upper arm, the interscapular region, or the epigastrium. The scheme is not all inclusive (e.g. intercostal neuralgia occurs in locations other than the left lower anterior chest area). From Miller AJ (1988). Diagnosis of chest pain. New York, Raven Press (LWW), p. 175. 16.2.1  Chest pain, breathlessness, and fatigue 3279 a risk of 25% of major cardiovascular adverse events in the next 14 days. For further discussion, see Chapter 16.13.4. There are no specific findings on cardiovascular examination in acute coronary syndromes. In the context of severe coronary disease the patient may present with the clinical features of left ventricular failure (see ‘Particular causes of breathlessness’) or cardiogenic shock. Features of increased sympathetic tone, pallor, tachycardia, and sweating are often present in infarction, but are also features of all causes of severe chest pain. A pansystolic murmur may indicate the development of a ventricular septal defect or papillary muscle rupture and severe mitral regurgitation, complications which are usually associated with haemodynamic compromise and left ven- tricular failure. The presence of peripheral vascular disease increases the prob- ability of coexistent coronary disease and the patient should be examined for carotid, femoral, and renal bruits and an abdominal aortic aneurysm. The foot pulses should also be assessed. The presence of neck and/​or chest wall tenderness will point to alternative diagnoses such as cervical spondylopathy, costochondritis, or nerve entrapment. Hypochondrial tenderness suggests a gastrointestinal cause (e.g. peptic ulcer disease, pancrea- titis, or gallstones). Coronary spasm, Prinzmetal’s angina, syndrome X, atypical angina Patients with unpredictable angina due to the occurrence of cor- onary spasm, either in the context of coronary disease or with normal coronary arteries, have been described. The diagnosis should only be considered in the patient with a classical description of ischaemic chest pain that usually responds rapidly to glyceryl trinitrate, preferably in the context of ECG changes (ST elevation in the case of Prinzmetal’s angina). Cocaine abuse is a frequent cause of this presentation to the emergency department. Syndrome X, as its name suggests, is poorly understood. This label (whether it can properly be called a diagnosis is debatable) is often attached to patients with cardiac-​sounding chest pain and a normal angiogram. This finding is more common in women. The pain often has features atypical of angina. It is often of submammary location or radiation, and precipitating factors are highly variable. This diag- nosis should only be considered after other causes of chest pain have been carefully excluded, since it may expose the patient to a lifetime of inappropriate treatment and anxiety. The term ‘atypical chest pain’ is meaningless (especially for the patient) and is best avoided. There are, however, many patients for whom a confident diagnosis cannot be made. Serious pathology can be excluded and the patient reassured that they have an excel- lent prognosis. It is better to leave the diagnosis at ‘chest pain-​type symptom’ than to inappropriately label the patient as having ‘atyp- ical angina’ or syndrome X. Aortic dissection Aortic dissection is a rare but important cause of chest pain: up to one-​half of all patients with an untreated proximal aortic dissec- tion die within 48 h. The pain of aortic dissection is very sudden in onset, is usually described as tearing or ripping, and the pa- tient may report that it migrates from the front to the back of the chest. There should be a particularly high index of suspicion when chest pain is associated with neurological features such as hemi- plegia or paraplegia due to involvement of the carotid vessels and spinal arteries, but these are present in less than 20% of cases. Risk factors in the history include hypertension, Marfan syndrome, a bicuspid aortic valve, previous aortic valve replacement, cocaine usage, and the third trimester of pregnancy. Of the clinical fea- tures (see Box 16.2.1.2) aortic pain (as described earlier), loss of Box 16.2.1.1  Risk stratification for acute myocardial infarction and acute coronary syndrome according to components of the chest pain history Low risk: • Pain that is pleuritic, positional, or reproducible with palpation, or is described as stabbing Probably low risk: • Pain not related to exertion or that occurs in a small inframammary area of the chest Probably high risk: • Pain described as pressure, is similar to that of a prior myocardial infarction or worse than prior anginal pain, or is accompanied by nausea, vomiting, or diaphoresis High risk: • Pain that radiates to one or both shoulders or arms or is related to exertion Table 16.2.1.2  TIMI risk score for non-​ST elevation acute coronary syndromes Clinical feature Points Age ≥65 years 1 At least three risk factors for coronary diseasea 1 Prior demonstration of significant coronary artery stenosis 1 ST deviation on ECG 1 Severe anginal symptoms (e.g. ≥2 anginal events in the last 24 h) 1 Use of aspirin in previous 7 days 1 Elevated cardiac markers (e.g. troponin) 1 a Family history, hypertension, hypercholesterolaemia, diabetes, current smoking. From Antman EM et al. (2000). The TIMI risk score for unstable angina/​non-​ST elevation MI: a method for prognostication and therapeutic decision making. JAMA, 284, 835–​42. Box 16.2.1.2  Clinical features associated with aortic dissection • Sudden onset tearing, ripping chest pain that migrates to the back • Loss of peripheral pulses • Blood pressure difference more than 20 mm Hg between arms • Hemiparesis • Paraparesis • Diastolic murmur • Pleural effusion (usually left-​sided) • Hoarseness • Horner’s syndrome • Bilateral testicular tenderness • Pulsatile sternoclavicular joint • Superior vena cava obstruction • Pulsus paradoxus (with pericardial tamponade) section 16  Cardiovascular disorders 3280 peripheral pulses, blood pressure difference between the two arms (>20 mm Hg), and mediastinal widening on the chest radiograph are the most helpful. In the absence of these features the incidence of aortic dissection is less than 5%. The absolute level of blood pressure in unhelpful in discriminating aortic dissection from other causes of chest pain. Pericarditis Pericarditis occurs most commonly following a myocardial infarc- tion or viral infection. The patient may describe a preceding viral illness with fever and cough. The pain is usually sharp and precor- dial. The onset is often sudden. It is characteristically worse on in- spiration and relieved by sitting up and leaning forward, and it can be accompanied by classic pleuritic pain. A less typical description occurs when a pericardial effusion has developed and the pain arises from pericardial distension, when the pain may be a dull retro- sternal ache or pressure. Radiation of pericarditic pain occurs to all those areas associated with myocardial infarction, but radiation to the trapezius ridges is pathognomonic of the diagnosis. The patient is usually well and not compromised haemodynamic- ally (except where there is pericardial tamponade). Clinical examin- ation may initially be normal. A pericardial friction rub heard over the sternum may be positional and appear and disappear within hours. Repeated examination may be helpful, including auscultation of the patient lying flat in expiration. The ECG finding of concave ST elevation in multiple lead is helpful, but ECG findings are equivocal or normal in 40–​50% of cases. Breathlessness and fatigue Breathlessness (or dyspnoea, derived from Greek words meaning painful or difficult breathing) is the endpoint of a variety of path- ologies and is mediated by a series of neural pathways, the sensory inputs of which originate in the lungs, chest wall, and peripheral and sensory chemoreceptors (see Fig. 16.2.1.2). Patients may describe the sensation of breathlessness as tightness, wheeze, ‘inability to get enough air’, sighing, choking, or suffocating. Heart failure, asthma, and chronic obstructive airways disease account for about three-​ quarters of hospital admissions with breathlessness in industrialized nations. Symptom clusters have been described for these patholo- gies, but most patients find it impossible to distinguish between car- diac and pulmonary causes of dyspnoea. The time course of the illness is an important aid to the diagnosis in patients with dyspnoea but must be interpreted in the context of the patient’s day-​to-​day activities. Even when the disease progresses gradually the patient may report a recent onset of symptoms be- cause they have (often subconsciously) adapted their lifestyle over the course of many months. This is particularly true of patients with chronic heart failure. Efferent signals Motor cortex Effort? Sensory cortex Brain stem Air hunger Chemoreceptors Upper airway Ventilatory muscles Chest wall Chest tightness Upper airway Afferent signals Effort Fig. 16.2.1.2  Efferent and afferent signals that contribute to the sensation of dyspnoea. The sense of respiratory effort is believed to arise from a signal transmitted from the motor cortex to the sensory cortex coincidently with the outgoing motor command to the ventilatory muscles. The arrow from the brainstem to the sensory cortex indicates that the motor output of the brainstem may also contribute to the sense of effort. The sense of air hunger is believed to arise, in part, from increased respiratory activity within the brainstem, and the sensation of chest tightness probably results from stimulation of vagal-​irritant receptors. Although afferent information from airway, lung, and chest wall receptors most likely passes through the brainstem before reaching the sensory cortex, the dashed lines indicate uncertainty about whether some afferents bypass the brainstem and project directly to the sensory cortex. From Manning HL, Schwartzstein RM (1995). Pathophysiology of dyspnea. New England Journal of Medicine, 333, 1547–​53. http://​content.nejm.org/​cgi/​content/​extract/​333/​23/​1547. 16.2.1  Chest pain, breathlessness, and fatigue 3281 Until relatively recently, symptoms of fatigue and breathlessness in heart failure have been assumed to be due purely to a combin- ation of poor cardiac output and pulmonary congestion. However, in patients with heart failure the correlation between symptoms and left ventricular ejection fraction is very poor. Changes in skeletal and respiratory muscle function appear to contribute significantly to symptoms, a hypothesis that is supported by the response ob- served to exercise training programmes in patients with chronic heart failure, and which may account for part of the considerable variability in disability in patients with similar haemodynamic and echocardiographic findings. Because of the contribution of fa- tigue, it is more helpful to ask about a change in exercise tolerance in patients with suspected heart failure, since this may correlate more closely with the underlying pathology. The New York Heart Association (NYHA) classification is used to classify the extent of disability (Table 16.2.1.3). The time course of onset of breathlessness can be particularly useful in determining the underlying pathology (Table 16.2.1.4). Breathlessness of dramatic onset (over minutes) is suggestive of pul- monary embolism, pulmonary oedema, upper airway obstruction, or a pneumothorax. Chronic dyspnoea presents in the context of worsening breathlessness over a period of months or years is typical of chronic obstructive airways disease, interstitial lung disease, or anaemia, but may also be a feature of heart failure. Acute or chronic dyspnoea indicates an exacerbation of breathlessness in a patient with established disease. Chronic obstructive airways disease, asthma, and heart failure are common in the population of industrialized countries and most elderly patients presenting to the emergency department with breathing difficulties will have a prior history of pulmonary or car- diac disease. However, it is important not to automatically attribute any deterioration in symptoms as being due to progression of their underlying disease process. Alternative causes should be considered, and this situation is often a major diagnostic challenge. A common example is a sudden deterioration in the patient with long-​standing well-​controlled heart failure, which should prompt consideration of further pathology such as a silent myocardial infarction, pulmonary embolism, or arrhythmia. Breathlessness at rest occurs in pulmonary embolism or pul- monary oedema, and with a pneumothorax. Exertional dyspnoea occurs in left ventricular failure and chronic obstructive airways disease. Psychogenic breathlessness is frequently present at rest and is associated with sighing, features of hyperventilation such as perioral or peripheral paraesthesiae, and chest tightness. The pres- ence of breathlessness at rest but not on exertion strongly suggests a functional origin. Particular causes of breathlessness Left ventricular failure The incidence of left ventricular failure in the community is 1–​2%. It is important to attempt to identify the cause during the initial as- sessment. A history of ischaemic or valvular heart disease, alcohol abuse, smoking, diabetes, hypertension, and a family history are important. Patients with left ventricular failure commonly present to the out- patient clinic, but may present for the first time to the emergency Table 16.2.1.3  New York Heart Association classification of breathlessness according to severity Class I No limitation—​ordinary physical activity does not cause undue fatigue, dyspnoea, or palpitation Class II Slight limitation of physical activity—​comfortable at rest, but ordinary physical activity results in fatigue, dyspnoea, or palpitation Class III Marked limitation of physical activity—​comfortable at rest, but less than normal activity produces symptoms Class IV Inability to carry out any physical activity without discomfort Table 16.2.1.4  Conditions causing breathlessness classified by the rate of onset Acute Acute on chronic Chronic Asthma Infective exacerbation of COPD COPD Myocardial infarction Decompensated chronic heart failure Cardiac failure PE PE complicating congestive cardiac failure or COPD Anaemia Cardiogenic pulmonary oedema (secondary to ischaemia, valvular disease, arrhythmias) Pneumothorax complicating COPD or asthma Pulmonary vascular disease (PE, pulmonary hypertension) Pneumonia Atrial fibrillation/​flutter complicating COPD or cardiac failure Parenchymal lung disease, e.g. UIP, sarcoid Non​cardiogenic pulmonary oedema Chordal rupture in chronic non​rheumatic mitral regurgitation Pleural disease, e.g. effusion, asbestosis Pulmonary haemorrhage Chest wall disease, e.g. kyphosis, ankylosing spondylitis Spontaneous pneumothorax Neuromuscular disorders, e.g. muscular dystrophy, polio, myasthenia gravis Chest trauma Malignancy Upper airway obstruction Obesity/​deconditioning Hyperventilation syndrome Sleep apnoea Silent myocardial ischaemia COPD, chronic obstructive pulmonary disease; PE, pulmonary embolism; UIP, usual interstitial pneumonia. section 16  Cardiovascular disorders 3282 department. An acute presentation is more likely when there has been a rapid rise in the left atrial pressure generating pulmonary oedema. In severe cases this is associated with haemoptysis in the form of frothy pink sputum. This type of presentation occurs with myocardial infarction, mitral valve papillary muscle or chordal rupture, malignant hypertension, tachyarrhythmias, and endocar- ditis with major valve destruction. Where a rise in left atrial pres- sure occurs over a longer time course, sustained elevated left atrial pressures are compensated for by increased lymphatic drainage and structural changes in the pulmonary capillary and alveolar base- ment membrane and patients more commonly present with fatigue, exertional breathlessness, and orthopnoea. Prolonged increases in left atrial pressure are associated with pulmonary hypertension and the associated clinical features of right ventricular enlargement, tricuspid regurgitation, and a loud pulmonary second sound. This type of presentation is more frequently a feature of patients with an idiopathic, ischaemic, hypertensive, or alcoholic cardiomyopathy. Clinical findings that help in assessing impaired left ven- tricular function or elevated left atrial filling pressures are shown in Table 16.2.1.5. The most helpful features in the history are exertional breath- lessness, orthopnoea, paroxysmal nocturnal dyspnoea, or a his- tory of myocardial infarction. Breathlessness that is worse on lying flat and relieved promptly on sitting up is characteristic for orthopnoea. Patients with chronic obstructive airways disease may also describe orthopnoea, but this is usually present only in the setting of severe disease and chronic breathlessness at rest. Paroxysmal nocturnal dyspnoea is due to the development of interstitial oedema and typically occurs 2–​4 h after the onset of sleep. The patient usually stands up or sits on the side of the bed and symptoms resolve over the course of 10–​15 min. This is usu- ally a frightening and memorable experience for the patient, and to avoid these symptoms they will sleep propped up on pillows or, in severe cases, in a chair. However, a history of paroxysmal noc- turnal dyspnoea or orthopnoea is only present in 20% of patients with heart failure and its absence does not exclude the diagnosis. Ankle oedema is supportive of a diagnosis of heart failure, but de- pendent oedema is often present in older people and in patients with chronic obstructive airways disease, and the astute physician should avoid the common mistake of assuming that ‘ankle oedema means cardiac failure means diuretic prescription’. The clinical examination findings are used to support a sus- pected diagnosis of heart failure, but they are not always helpful. Tachycardia, cyanosis, and an elevated jugular venous pressure are features of heart failure, but they are also features of the major dif- ferential diagnoses, pulmonary embolism, and chronic obstructive airways disease. Although jugular venous pressure correlates with left atrial pressure it may be misleading in the presence of isolated right ventricular dysfunction, tricuspid regurgitation, and pul- monary hypertension. A displaced apex on palpation is helpful and relatively specific. Basal inspiratory crackles (rales) are suggestive of pulmonary oedema but can be present in fibrotic lung disease infection and chronic airways disease and have a sensitivity and specificity as low as 13% and 35%, respectively. The third sound is a low-​pitched sound heard in mid-​diastole, best with the bell of the stethoscope placed lightly over the apex. It can be confused with a split second sound but is later in diastole and has a much longer duration. It has a high specificity (90–​97%) but low sensitivity (31–​ 51%) for detecting left ventricular dysfunction. Fever and purulent sputum usually point to a diagnosis of an in- fective exacerbation of chronic bronchitis or chest infection. In older people, however, a chest infection may precipitate decompensation of heart failure. Left ventricular failure is highly unlikely in the presence of a genu- inely normal ECG. Evidence of a previous myocardial infarction on the ECG, in particular the presence of Q waves in the anterior chest leads is highly predictive of left ventricular dysfunction. The most useful finding on chest radiography is cardiomegaly, but heart size may be normal, particularly in diastolic heart failure. Changes of pulmonary venous distension, pulmonary oedema, and pleural effusion are more common in acute presentations, but are frequently absent in patients presenting with chronic breathlessness. Following clinical assessment, including ECG and chest radiog- raphy, there may still be considerable uncertainty about the diagnosis of the cause of breathlessness, particularly in patients presenting to the emergency department. Measurement of blood brain natriuretic peptide (BNP) may assist in a more rapid and accurate diagnosis in this circumstance, a level below 100 pg/​ml (>300 pg/​ml for NT-​ proBNP) making the diagnosis of left ventricular failure highly un- likely and alternative diagnoses should be considered. High levels (>500 pg/​ml) are strongly suggestive of heart failure. Intermediate levels are more difficult to interpret as there are certain confounding factors for BNP measurement (Table 16.2.1.6) As with troponin, BNP levels (see Chapter 16.5.3) must be inter- preted in the context of the history, clinical findings, and other inves- tigations. Scoring systems have been devised using BNP and other clinical and investigation findings in acute dyspnoea (Fig. 16.2.1.3). Given the relatively poor predictive value of the clinical history and physical signs in the diagnosis of left ventricular failure, open access to echocardiography may appear superior to clinical assess- ment. However, there are important arguments for careful clin- ical assessment. Firstly, echocardiography is not always available in the emergency setting. Secondly, cardiac and non​cardiac causes of dyspnoea, particularly chronic obstructive pulmonary disease (COPD), often coexist, and where there is dual pathology, deciding which treatment to escalate is more dependent on the appropriate interpretation of the symptoms, clinical signs, and chest radio- graphic findings than echocardiographic parameters. Thirdly, heart failure is frequently present in the presence of apparently preserved systolic function on echocardiography. Table 16.2.1.5  Helpful and relatively specific clinical findings for predicting heart failure in patients presenting with dyspnoea History Examination Orthopnoea Elevated jugular venous pressure Paroxysmal nocturnal dyspnoea Cardiomegaly Recent onset peripheral oedema Third or fourth heart sound Prior history of heart failure Basal crepitations Previous myocardial infarction Positive hepatojugular reflux Peripheral oedema beyond mid-​calf Source data from Badgett RG, Lucey CT, Mulrow CD (1997). Can the clinical examination diagnose left-​sided heart failure in adults? JAMA, 277, 1712–​19. 16.2.1  Chest pain, breathlessness, and fatigue 3283 Airways disease The clinical features of heart failure and airways disease are often difficult to distinguish. Patients with lung disease tend to use the terms ‘chest tightness’ or ‘restriction’, whereas the patient with heart failure is more inclined to describe the sensation of ‘not being able to get enough air’. Patients are more likely to have COPD if they have a self-​reported history of COPD, wheezing on examination (although this can be a feature of heart failure), a forced expiratory time of 9 s or more, and laryngeal descent. Clearly COPD is very unlikely in the absence of a smoking history and in patients under 45 years of age. Patients with COPD and left ventricular failure may suffer from a chronic cough, although in the case of heart failure this is usually a dry cough and more prominent at night. Fluid retention giving rise to an elevated jugular venous pressure and ankle oedema can occur in association with hypoxia, but only if saturations are persistently less than 93%. Ankle oedema may also be a feature of chronic CO2 retention. Although often cited as a cause of the clinical features of right heart failure in COPD, true right ven- tricular failure is relatively uncommon, and the mechanism of fluid retention is complex. COPD and heart failure often coexist. The chest radiograph may be unhelpful and patients with em- physema and left ventricular failure may not have any radiological features of pulmonary congestion or oedema. In these situations, systolic heart failure can only be ruled out by echocardiography. Pulmonary embolism Pulmonary embolism is a common differential diagnosis in patients with breathlessness and should be considered in any presenting with breathlessness without clinical signs of left ventricular failure. The acute presenting symptoms are of breathlessness (usually of sudden onset), chest pain (classically pleuritic, but central with large pulmonary em- boli), and less commonly haemoptysis, cough, and syncope. The differ- ential diagnosis depends on the predominant presenting feature, such as pleuritic pain (chest infection with pleurisy, pericarditis), central chest pain (myocardial infarction), dyspnoea (COPD), or heart failure. Chronic pulmonary embolic disease and pulmonary hypertension present with exertional breathlessness, and patients may complain of central chest pain that is due to right ventricular subendocardial is- chaemia. The diagnosis of pulmonary embolism cannot easily be ex- cluded without investigation and the exclusion of an alternative, more likely, cause of breathlessness is crucial to the initial assessment. Most patients with acute pulmonary embolism are breathless or tachypnoeic (respiratory rate >20/​min) and in the absence of these findings, haemoptysis and pleuritic chest pain are usually due to another cause. See Chapter 16.16.1 for further discussion of exam- ination findings and diagnostic strategy in patients with suspected pulmonary embolism. Dyspnoea with preserved left ventricular function Where breathlessness is present in the context of preserved left ven- tricular function, diastolic heart failure should be considered. This diagnosis can only be made in the context of an appropriate history and examination findings. Echocardiographic parameters of diastolic dysfunction (see Chapter  16.3.2) are common in the community setting, but more than 50% of individuals with such an echocardio- graphic diagnosis are asymptomatic and the presence of diastolic dysfunction in a patient with breathlessness should not automatically lead to a diagnosis of the clinical syndrome of diastolic heart failure. COPD, ischaemic heart disease, and obesity are common in indi- viduals with diastolic dysfunction, and diastolic heart failure can be overdiagnosed. Hypertension, coronary disease, and left ventricular hypertrophy are important causes of diastolic dysfunction and in their absence diastolic heart failure is rare. Alternative causes for dyspnoea should be always be excluded, in particular, chronic thromboembolic disease, airways disease, sleep apnoea, and silent ischaemia. FURTHER READING Badgett RG, Lucey CR, Mulrow CD (1997). Can the clinical examin- ation diagnose left-​sided heart failure in adults? JAMA, 277, 1712–​19. Bugiardini R, Merz CNB (2005). Angina with normal coronary ar- teries. A changing philosophy. JAMA, 293, 477–​84. Cayley WE (2005). Diagnosing the cause of chest pain. Am Fam Physician, 72, 2012–​21. Table 16.2.1.6  Confounding factors in the interpretation of BNP measurements Increased BNP Decreased BNP Increasing age Obesity Female sex Cardioactive drugs Pulmonary disease ACE inhibitors Systemic hypertension Spironolactone Hyperthyroidism β-​Blockers (long term) Cushing’s syndrome Diuretics Glucocorticoid usage Conn’s syndrome Hepatic cirrhosis with ascites Renal failure Paraneoplastic syndrome Subarachnoid haemorrhage < 3 0 20 40 60 80 100 % of patients with CHF 3-5 6-7 8-9 10-11 PRIDE acute CHF score 12-13 13-14 Derivation population Validation population Fig. 16.2.1.3  Scoring system to predict whether a patient presenting to the emergency department has congestive heart failure (CHF). The patient’s total score (maximum 14) is obtained by adding the points that they score for each clinical or investigation feature. Reprinted from Am J Heart, Vol 151(1), Baggish AL et al., A validated clinical and biochemical score for the diagnosis of acute heart failure: the Pro-​BNP Investigation of Dyspnoea in the Emergency Department (PRIDE) acute heart failure score, pp. 48–​54. Copyright (2006), with permission from Elsevier. 16.2.2 Syncope and palpitation 3284 K. Rajappan, A 16.2.2 Syncope and palpitation 3284 K. Rajappan, A.C. Rankin, A.D. McGavigan, and S.M. Cobbe section 16  Cardiovascular disorders 3284 Chunilal SD, et  al. (2003). Does this patient have pulmonary em- bolism? JAMA, 290, 2849–​58. Cooper A, Timmis A, Skinner J; Guideline Development Group (2010). Assessment of recent onset chest pain or discomfort of sus- pected cardiac origin: summary of NICE guidance. http://​guidance. nice.org.uk/​CG95/​Guidance/​pdf/​English Davie AP, et al. (1997). Assessing diagnosis in heart failure: which fea- tures are any use? Q J Med, 90, 335–​9. Fanaroff AC, et al. (2015). Does this patient with chest pain have acute coronary syndrome? The rational clinical examination systematic review. JAMA, 314, 1955–​65. Gehlbach BK, Geppert E (2004). The pulmonary manifestations of left heart failure. Chest, 125, 669–​82. Global Registry of Acute Coronary Events (GRACE). Center for Outcomes Research, University of Massachusetts Medical School. http://​www.outcomes-​umassmed.org/​grace/​ Hurst JW, Morris DC (2001). Chest pain. Futura, Armonk, NY. Klompas M (2002). Does this patient have acute thoracic aortic dis- section? JAMA, 287, 2262–​72. Mahler DA (1990). Dyspnoea. Futura, Armonk, NY. Manning HL, Schwartzstein RM (1995). Pathophysiology of dyspnea. N Engl J Med, 333, 1547–​53. Marcus GM, et al. (2005). Association between phonocardiographic third and fourth heart sounds and objective measures of left ven- tricular function. JAMA, 293, 2238–​44. McGee S (2018). Evidence-based physical diagnosis, 4th edition. Elsevier, Philadelphia, PA. Miller AJ (1988). Diagnosis of chest pain. Raven Press, New York. NICE Clinical Guideline (2010, updated 2016). Chest pain of recent onset: assessment and diagnosis. https://​www.nice.org.uk/​guidance/​cg95 NICE Guideline (2018). Chronic heart failure in adults: diagnosis and management. https://nice.org.uk/guidance/ng106 Pang PS, et al. (2008). A proposal to standardize dyspnoea measure- ment in clinical trials of acute heart failure syndromes: the need for a uniform approach. Eur Heart J, 29, 816–​24. Scano G, Stenardi L, Grazzini M (2005). Understanding dyspnoea by its language. Eur Resp J, 25, 380–​5. Swap CJ, Nagurney JT (2005). Value and limitations of chest pain history in the evaluation of patients with suspected acute coronary syndromes. JAMA, 294, 2623–​9. Wang CS, et al. (2005). Does this dyspnoeic patient in the emergency department have congestive heart failure? JAMA, 294, 1944–​56. 16.2.2  Syncope and palpitation K. Rajappan, A.C. Rankin, A.D. McGavigan, and S.M. Cobbe ESSENTIALS Syncope Syncope is a transient episode of loss of consciousness due to cerebral hypoperfusion. Its causes can be subdivided on the basis of pathophysiology, including (1)  neurally mediated—​or reflex—​syncope; (2)  orthostatic hypotension; (3)  cardiac causes; and (4) cerebrovascular or psychogenic causes. Neurocardiogenic syncope, or simple faint, is the commonest cause and is benign, but it is always important to exclude or establish the diagnosis of cardiac syncope, because this has an adverse prog- nosis that may be improved with appropriate treatment. Cardiac arrhythmia should be considered in all patients who have syncope associated with any of the following: (1) exertion, chest pain, or pal- pitations; (2) a past medical history of heart disease; (3) abnormal cardiovascular findings on examination; (4) an abnormal ECG; and (5) a family history of sudden cardiac death in people younger than 40 years old or with an inherited cardiac condition. Initial assessment of the patient with syncope by clinical his- tory, examination, and 12-​lead ECG will indicate a probable diag- nosis in most patients and guide further investigation (if required). Documentation of cardiac rhythm during syncope is extremely useful, especially if it is associated with palpitations, but this is usually diffi- cult to obtain because of the intermittent and typically infrequent na- ture of the symptom. External or implanted loop recorders, which can store the rhythm before, during, and after an episode, are increasingly used when the diagnosis remains unclear. In patients with structural heart disease in whom arrhythmia is suspected, programmed electrical stimulation of the ventricles may induce sustained monomorphic ven- tricular tachycardia: this is a relatively specific response, shows that the patient is at risk of recurrent ventricular arrhythmia, and makes an ar- rhythmic origin of syncope likely, but the diagnostic yield of electro- physiological testing is low in patients with a structurally normal heart. Palpitation Palpitation is the awareness of one’s heart beating—​it may be due to an awareness of an abnormal cardiac rhythm, or an abnormal awareness of normal rhythm. It is most commonly due to premature beats (ectopics) and is benign. Correlation between symptoms and cardiac rhythm is the initial aim of investigations in patients pre- senting with palpitations. Syncope Definition Syncope is defined as a transient loss of consciousness, with loss of postural tone, usually resulting in falling. It is often of sudden onset, with prompt spontaneous recovery. The underlying mech- anism is reduced cerebral perfusion, which may be due to a variety of cardiovascular—​or less commonly cerebrovascular—​causes. It is a common presentation, producing 1–​3% of emergency department visits and up to 6% of hospital admissions. Also, in some population studies up to 40% of people will experience a syncopal episode at some point in their lifetimes with only a small proportion repre- senting a sinister problem. The cause is often initially uncertain and assessment must first differentiate syncope from other causes of loss of consciousness, such as epileptic seizures. Prognosis The prognosis depends on the aetiology, with most patients having a benign condition, although recurrent syncope can produce anxiety 16.2.2  Syncope and palpitation 3285 and reduction in quality of life regardless of the underlying cause. The exceptions are cardiac causes of syncope, which have been re- ported to have 1-​year mortality rates as high as 18–​33%. An im- portant aim in the evaluation of syncope is to identify this subgroup of patients: clues may come from the history, examination, and the 12-​lead ECG (Box 16.2.2.1). Differential diagnosis The initial evaluation of the patient with possible transient loss of consciousness should include history, examination, supine and up- right blood pressure, and 12-​lead ECG (Fig. 16.2.2.1). It is important to establish that loss of consciousness (syncope) occurred to enable differentiation from non​syncopal causes such as falls, drop attacks, and transient ischaemic attacks. In the absence of ‘red flag’ features of cardiac syncope (Box 16.2.2.1) and with a normal 12-​lead ECG, a single episode of syncope requires no further investigation or treat- ment, other than reassurance. In patients with recurrent syncope, or a single episode in a high-​risk individual, further investigation and treatment will depend on the suspected diagnosis. The causes of syncope can be subdivided on the basis of patho- physiology, namely (1)  neurally mediated—​or reflex—​syncope, (2) orthostatic hypotension, (3) cardiac causes, and (4) cerebrovas- cular or psychogenic causes (Table 16.2.2.1). The patient history is most important. For example, it may strongly suggest a vasovagal origin, or an epileptic seizure. However, the diagnosis may be com- plicated by an overlap in features, such as convulsive movements during a vasovagal episode due to anoxic convulsive seizures. It is increasingly recognized that many patients who attend clinics for epilepsy have been misdiagnosed and are suffering from recurrent syncope: some of these patients have potentially lethal ventricular arrhythmias for which they should be receiving treatment. Neurally mediated syncope There are many disorders of autonomic control that can cause syn- cope. The most common is neurocardiogenic syncope, or simple faint, which is due to an increased sensitivity of normal reflex re- sponses. By contrast, autonomic dysfunction may produce abnormal neurovascular control that results in orthostatic hypotension. Vasovagal syncope Vasovagal syncope is the most common cause of syncope. It can affect all age groups and varies from infrequent episodes associated with obvious triggering factors to frequent unprovoked collapses, which may be debilitating. The pathophysiology most commonly involves venous pooling of blood and reduced venous return to the heart in response to upright posture. Reduced cardiac output and blood pressure stimulate arterial baroreceptors with resultant increased sympathetic activity and catecholamine levels. The vig- orous contraction of relatively empty ventricles results in the ac- tivation of mechanoreceptors that would normally respond to stretch in the left ventricular wall. Afferent nerve fibres conduct to the cerebral medulla and activate the reflex withdrawal of periph- eral sympathetic tone and activation of vagal parasympathetic ac- tivity. The resultant vasodilatation and bradycardia cause reduced cerebral perfusion and loss of consciousness. However, there is de- bate about these mechanisms and other factors may be involved in the aetiology of syncope, as illustrated by the documentation of neurocardiogenic syncope—​despite cardiac denervation—​in orthotopic heart transplant recipients. Certainly, it is well recog- nized that vasovagal syncope can result from other stimuli, such as pain, emotional shock, or the sight of blood: in these instances, the reflex activation is central in origin. The development of tilt testing has allowed the study of the patho- physiology of neurocardiogenic syncope. The patient is strapped to a tilt table and is tilted, head upright, usually at 70° for up to 45 min. Protocols that use additional provocation with isoprenaline or nitrates are commonly used. Blood pressure and cardiac rhythm are moni- tored throughout the tilt test. In neurocardiogenic syncope, the patient classically maintains normal blood pressure initially, until the sudden onset of syncope is associated with severe hypotension and brady- cardia, often preceded by tachycardia. These features resolve with re- turn to the supine posture. Some patients have a mainly vasodepressor response, with hypotension and little change in heart rate, while others have a marked cardioinhibitory response, with severe bradycardia or asystole of several seconds duration (Fig. 16.2.2.2). Most have a mixed response of hypotension and bradycardia. Carotid sinus hypersensitivity An abnormal sensitivity of a normal reflex is responsible for syn- cope. Activation of the carotid sinus baroreceptors (e.g. by phys- ical pressure, such as carotid sinus massage) results in sympathetic withdrawal and parasympathetic activation. Bradycardia is usually a prominent feature. Situational reflex-​mediated syncope In susceptible individuals, similar abnormal reflex sensitivity can result in syncope in response to afferent activity from some other Box 16.2.2.1  Features associated with cardiac syncope History of syncopal episode • Occurs during exertiona • Occurs when supinea • Lack of prodromal warninga • Associated palpitations (preceding syncope is higher risk)a • Associated chest pain • Traumatic injurya Past medical history • Known structural heart diseasea • Previous myocardial infarctiona • History of heart failurea • Valvular heart diseasea Family history • Family history of sudden deatha Examination • Presence of murmura • Signs of heart failurea • Carotid bruit 12-​lead ECG • Evidence of atrioventricular blocka • Bundle branch blocka • Evidence of previous infarctiona • Left ventricular hypertrophya • Long QTc intervala • Features of Brugada syndromea a Denotes a ‘red flag’ feature of the history or examination that suggests urgent assessment is required and that there is a high chance of recurrent syncope. section 16  Cardiovascular disorders 3286 mechanoreceptor activation. Syncopal responses to cough, mictur- ition, defecation, or swallowing have been reported. Orthostatic hypotension Hypotension may occur in patients in whom there are abnor- malities in the autonomic control of cardiovascular function. Abnormalities of afferent or efferent pathways, or of peripheral vascular control, can result in low blood pressure in the upright posture (i.e. orthostatic hypotension). The clinical presentation can be divided into four subgroups: • Initial orthostatic hypotension—​symptoms occurring within 30 s of standing diagnosed with active standing blood pressure meas- urement (syncope is rare). • Classical orthostatic hypotension—​symptoms occur between 30 s and 3 min diagnosed with active standing blood pressure meas- urement. It is usually due to classical autonomic failure or drug therapy (syncope is rare). • Delayed—​symptoms occur between 3 and 45 min of standing and there is a more prolonged prodrome with a gradual fall in blood pressure resulting in syncope with or without a reflex (abrupt blood pressure fall) component, usually diagnosed with tilt table testing. • Reflex syncope—​typically occurring in young healthy females, onset between 3 and 45 min; blood pressure is usually maintained until syncope and diagnosed by tilt table testing. Postural orthostatic tachycardia syndrome is not classically asso- ciated with syncope. TLOC present? (history) Presentation of patient with probable TLOC (may include ambulance or referral data) Initial syncose evaluation (H&P exam, ECG, supine, and standing BP) No TLOC (a) Syncope TLOC - non syncopal • Epileptic seizure • Psychogenic TLOC • TLOC, rare causes Certain or highly likely diagnosis High-risk of short-term serious events Early evaluation & treatment Ancillary tests followed by treatment Explanation, no further evaluation Low-risk but recurrent syncopes Low-risk single or rare recurrences Uncertain diagnosis (See panel (b)) Risk stratification (See panel (c)) Treat appropriately Act as needed Start treatment Fig. 16.2.2.1  (a) Flow diagram for the initial evaluation and risk stratification of patients with syncope. (b) Clinical features that can suggest a diagnosis on initial evaluation. (c) High-risk features (that suggest a serious condition) and low-risk features (that suggest a benign condition) in patients with syncope at initial evaluation in the emergency department. AF, atrial fibrillation; ARVC, arrhythmogenic right ventricular cardiomyopathy; AV, atrioventricular; BBB, bundle branch block; BP, blood pressure; bpm, beats per minute; ECG, electrocardiogram; ED, emergency department; H&P exam, history and physical examination; ICD, implantable cardioverter defibrillator; LQTS, long QT syndrome; LVEF, left ventricular ejection fraction; OH, orthostatic hypotension; SCD, sudden cardiac death; SVT, supraventricular tachycardia; TLOC, transient loss of consciousness; VT, ventricular tachycardia. From Brignole M, et al. (2018). 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J, 39, 1883–948. By permission of Oxford University Press. 16.2.2  Syncope and palpitation 3287 (b) Fig. 16.2.2.1  Continued section 16  Cardiovascular disorders 3288 (c) Fig. 16.2.2.1  Continued 16.2.2  Syncope and palpitation 3289 Orthostatic hypotension is more common in elderly patients, where it may be multifactorial, often exacerbated by drugs (Box 16.2.2.2). Nocturnal symptoms may occur, with a fall in blood pressure exacer- bated by sudden rising from a warm bed. Autonomic failure is an uncommon cause of syncope and patients may present with other features, including disturbances of bowel, bladder, or sexual function. Pure autonomic failure can be acute or chronic, primary (of unknown origin) or secondary to systemic dis- ease. Multiple system atrophy is characterized by autonomic dys- function, parkinsonism, and ataxia. Orthostatic hypotension may be a marked feature (the Shy–​Drager syndrome), with additional parkinsonian features or cerebellar symptoms. Secondary auto- nomic failure can result from the central or peripheral involvement of certain diseases, including multiple sclerosis, cerebral tumour, diabetes, and amyloidosis. Cardiac syncope Loss of consciousness of cardiac origin may result from some sub- stantial disturbance of cardiovascular function or from abnormal- ities of heart rhythm, with resultant reduced cerebral perfusion. The importance in establishing the diagnosis of cardiac syncope is the associated adverse prognosis, which may be improved with appro- priate treatment. The probability of cardiac syncope is increased in the presence of structural cardiovascular disease identified from the history, clinical examination, or the ECG (Box 16.2.2.1). Tachycardia Syncope may be caused by tachycardia, most commonly ventricular, but supraventricular tachycardia can also be associated with loss of consciousness if it is very fast or in patients with structural heart disease. Syncope, rather than cardiac arrest, may result from self-​ terminating ventricular tachycardia or from sustained tachycardia with hypotension at the onset, but with a subsequent recovery of blood pressure. Whether or not a tachycardia causes syncope is re- lated to its rate, underlying left ventricular function, and the patient’s baroreceptor sensitivity. Cardiac arrhythmia should be considered in all patients with structural heart disease presenting with syncope. Ventricular tachy- cardia most commonly occurs in patients with structural heart dis- ease (e.g. prior myocardial infarction) but may also occur in patients with structurally normal hearts. For example, torsades de pointes in a patient with the long-​QT syndrome is an important diagnosis to consider in young people with a history of loss of consciousness and possible epilepsy, in whom the episodes of collapse may be due to syncope caused by ventricular arrhythmia. Bradycardia A sudden decrease in heart rate, onset of ventricular standstill, or asystole may be a cause of syncope. When due to sinoatrial dysfunc- tion (sick sinus syndrome) this is not associated with a poor prog- nosis, but syncope due to intermittent complete atrioventricular block is. Syncope in a patient with a permanent pacemaker may in- dicate pacemaker malfunction. Structural cardiovascular disease Aortic stenosis may be associated with syncope, particularly during sudden exertion when the demand for increased cardiac output cannot be met because of the mechanical obstruction. Hypertrophic cardiomyopathy may also be associated with syncope, either because (a) (b) Fig. 16.2.2.2  Cardioinhibitory response to tilt testing. (a) After 6 min of head-​up tilting at 70° the patient complained of presyncope. Heart rate was 60/​min but blood pressure was 70 mm Hg. (b) By 7 min the patient had lost consciousness, associated with an asystolic pause of 10 s duration and an unrecordable blood pressure. Recovery was rapid following the patient’s return to the supine position. Table 16.2.2.1  Causes of syncope Neurally mediated Vasovagal or neurocardiogenic syncope Carotid sinus hypersensitivity Situational (micturition, defecation, cough, swallow) Orthostatic hypotension Primary autonomic failure Pure autonomic failure Multiple system atrophy (parkinsonian, cerebellar) Secondary autonomic failure (diabetic, amyloid neuropathy) Postural orthostatic tachycardia syndrome Drugs and alcohol Volume depletion (haemorrhage, diarrhoea) Cardiac syncope Bradycardia Atrioventricular block Sinoatrial disease Tachycardia Ventricular arrhythmia Structural heart disease Previous myocardial infarction Cardiomyopathy Structurally normal heart Long-​QT or Brugada syndrome Supraventricular arrhythmia Aortic stenosis Structural cardiovascular disease Hypertrophic cardiomyopathy Atrial myxoma or thrombus Pulmonary embolism Cerebrovascular or psychogenic Neurological Migraine Subclavian steal Vertebrobasilar disease Psychogenic Anxiety, depression, and hyperventilation section 16  Cardiovascular disorders 3290 of outflow obstruction or ventricular arrhythmia. Obstruction of blood flow through the mitral valve by an atrial myxoma or thrombus is an uncommon cause of syncope. Certain other cardiac diseases may be associated with loss of consciousness by a variety of mechanisms (arrhythmia, reflex-​mediated, or haemodynamic), including myocardial infarction, pulmonary embolism, congenital heart disease, or cardiac tamponade. Vascular diseases may also be involved, such as aortic dissection and extracranial vascular disease. Cerebrovascular or psychogenic causes of syncope When epilepsy is excluded, neurological conditions are rare causes of loss of consciousness, but possible diagnoses include migraine, vertebrobasilar vascular disease, and subclavian steal syndrome. However, in most cases these will not result in true syncope. A psychogenic origin of loss of consciousness implies the absence of neurally mediated, neurological, or cardiac abnormalities, and may occur in association with anxiety, depression, and conversion disorders. For instance, apparent syncope may occur during tilt testing but with normal pulse and blood pressure. Hyperventilation may be an associated mechanistic factor in psychogenic syncope. Assessment of the patient with syncope Careful assessment of the patient’s history, a full physical examin- ation and the 12-​lead ECG will indicate a likely diagnosis in over 50% of patients with a history of syncope. Further investigations will be prompted by the initial evaluation (Fig. 16.2.2.1). History The importance of the clinical history in assessing a patient with syn- cope cannot be overemphasized. If possible, an eyewitness descrip- tion of the patient during the syncopal event should be obtained. Features associated with an increased risk of cardiac syncope should be sought (Box 16.2.2.1). Provocative factors Vasovagal syncope is classically associated with upright posture, often with aggravating circumstances such as prolonged standing, a hot environment, or hunger. However, episodes may also occur when seated, including while driving. Specific stimuli may be re- sponsible for neurocardiogenic syncope in susceptible individuals. Ventricular arrhythmia, in particular torsades de pointes in the long-​QT syndrome, may be provoked by sudden stimuli such as a noise (e.g. an alarm clock), or exercise (particularly swimming). Exertional syncope is a feature of aortic stenosis or hypertrophic cardiomyopathy. Syncope may also be triggered by coughing, mic- turition, and more rarely, swallowing or laughing. Preceding symptoms Sweating and feeling hot or nauseated may precede vasovagal syn- cope. Cardiac arrhythmia may be associated with palpitation, chest pain, or breathlessness. Bradycardia, such as intermittent complete heart block, may produce no preceding symptoms and may cause loss of consciousness without warning. Sinoatrial dysfunction is a cause of symptoms of dizziness and light-​headedness in addition to syncope. A psychogenic origin may be suggested by multiple associ- ated symptoms including hyperventilation, paraesthesiae in fingers and lips, palpitation, and chest pain, which may precede syncope. Epilepsy may be preceded by a characteristic aura, which would strongly point away from cardiac syncope as the diagnosis. The syncopal episode In syncope the duration of loss of consciousness is usually short, with recovery after a few minutes. A longer duration of loss of con- sciousness suggests an alternative diagnosis. An exception to this is when the patient has remained upright during the attack, possibly aided by well-​meaning but misguided helpers. Incontinence is a feature of epileptic seizure but may also occur (uncommonly) with syncope. Description of the patient during the episode is of great value. The classic description of an episode of syncope due to car- diac arrhythmia—​in particular sudden-​onset severe bradycardia—​ is of a sudden loss of colour, becoming deathly pale, with flushing on recovery (Stokes–​Adams attack). Cyanosis may be a feature of an arrhythmic origin of syncope. Convulsive movements during the episode would raise the possibility of epilepsy, but they also occur with cardiac syncope. Although any cause of syncope can be associ- ated with injury, its absence may point to a non​syncopal or psycho- genic origin. The recovery period By contrast to the postictal phase following epilepsy, there is com- monly a rapid recovery of cerebral function following syncope. Vasovagal syncope may be followed by persisting nausea or vomiting and general malaise; in older people this phase may be prolonged. Family history There are a few specific causes of syncope in which a family history of syncope or sudden death may have prognostic significance. Long-​ QT syndrome is hereditary and may be associated with sudden death. A family history of syncope is of adverse prognostic signifi- cance in hypertrophic cardiomyopathy. Investigation The investigation of cardiac disease and arrhythmia are dealt with in the appropriate chapters, but the approach to the patient with syn- cope is described briefly here. Dependent on the history, further in- vestigations may not be necessary with the exception of a 12-​lead ECG. For example, the diagnosis of vasovagal syncope is a clinical one and other investigations are likely to have a low diagnostic yield. By contrast, if the history or examination points to a clear cause of Box 16.2.2.2  Common drugs that may cause postural hypotension • Diuretics • α-​Adrenergic receptor blockers • β-​Adrenergic receptor blockers • ACE inhibitors • Angiotensin II receptor antagonists • Calcium channel blockers • Nitrates • Opiates • Ethanol • Tricyclic antidepressants • Bromocriptine • Phenothiazines • Levodopa 16.2.2  Syncope and palpitation 3291 syncope, investigations appropriate to the underlying cause should be performed. Electrocardiogram An ECG should be performed on all patients with syncope. This may provide evidence of aetiology of syncope, such as the long-​QT syndrome, or of structural heart disease, such as prior myocardial infarction or left ventricular hypertrophy. An arrhythmia may be documented if it is sustained, and there may be evidence of sino- atrial disease or conduction system disease, such as ‘trifasicular’ block, bundle branch block, or first-​or second-​degree block. In those over the age of 40 carotid sinus massage (CSM) with digital pressure to the carotid artery for up to 5 s may cause marked bradycardia in carotid sinus hypersensitivity, with pauses of more than 3 s duration. Although it is recommended that CSM is avoided in patients with carotid bruits or a stroke or TIA within past 3 months, the incidence of adverse events is extremely rare. Active standing Measurement of lying and standing blood pressure is made using a sphygmomanometer (not an automated blood pressure cuff, as is commonly done) for a period of 3 min or until diagnostic criteria are reached. The test is diagnostic when there is a symptomatic fall in systolic blood pressure from baseline of 20 mm Hg or more or diastolic blood pressure of 10 mm Hg or more, or a decrease in sys- tolic blood pressure to less than 90 mm Hg. An asymptomatic fall, although suggestive, is not diagnostic when taken in context of the background incidence of postural hypotension which is up to 30% in the unselected elderly population and up to 60% in the hospital- ized population. Ambulatory monitoring Documentation of cardiac rhythm during syncope is extremely useful, especially if it was associated with palpitations, but is difficult to obtain because of the intermittent and usually infrequent nature of the symptom. In patients admitted with high-​risk syncope, in-​ hospital monitoring is recommended. Holter monitoring is usually only useful in individuals with recurrent syncope occurring more than once a week or in those where there are underlying ECG ab- normalities (in particular conduction abnormalities which do not automatically meet the criteria for bradycardiac pacing). Real-​time event recorders are of limited value in the investigation of syncope because they require a conscious patient to make the recording. Loop recorders, which have automatic rhythm detection algorithms and which can also be activated by the patient facilitating retro- spective rhythm analysis, can be used for periods of 1–​4 weeks and are useful for investigating syncope with an intermediate frequency. Implantable loop recorders have a greater diagnostic yield than con- ventional monitoring and can now be implanted in an outpatient setting. They are indicated in the evaluation and treatment of infre- quent (>4-​week interval), high risk, and recurrent syncope. Tilt testing When the history is suggestive of vasovagal syncope, the tilt test may be of value in confirming the diagnosis, but a negative test does not exclude the diagnosis. Adjuvant provocation (isoprenaline or ni- trate) may increase the sensitivity, but the incidence of false positive tests with tilt testing has been reported as 5–​20%. As such, its use is probably best limited to investigation of recurrent symptoms with an atypical history in patients in whom there are no features to sug- gest cardiac syncope. Electrophysiological testing Abnormal sinus node function or evidence of atrioventricular con- duction disease may be elicited by electrophysiological testing, but demonstrating bradycardia during ambulatory monitoring more reliably makes both of these diagnoses. In patients with structural heart disease in whom arrhythmia is suspected, pro- grammed electrical stimulation of the ventricles can induce sus- tained monomorphic ventricular tachycardia. This is a relatively specific response which shows that the patient is at risk of recurrent ventricular arrhythmia and makes an arrhythmic origin of syncope likely. However, recent guidelines on device implantation suggest that an electrophysiological study is no longer routinely required in a patient with impaired ventricular function and syncope likely to be cardiac in origin. If there is enough clinical suspicion, then implantable cardioverter defibrillators can be offered to these pa- tients without electrophysiological testing. It is important to note that the diagnostic yield of electrophysiological testing is low in pa- tients with a structurally normal heart. Other investigations Assessment for structural heart disease is important. Physical exam- ination will detect most significant valve disease, but other diag- noses, such as hypertrophic cardiomyopathy or atrial myxoma, may produce little in the way of clinical signs. An echocardiogram is therefore worthwhile in cases where the diagnosis remains un- clear. Exercise testing is useful in patients with a history of syncope during or immediately after exercise. Exercise testing is diagnostic if Mobitz II second-​degree or third-​degree atrioventricular block de- velop during exercise even without syncope. Troponin measurement is not indicated in patients with syncope in the absence of features suggestive of an acute coronary syndrome. Approximately 10% of patients over the age of 60 presenting to the emergency department with syncope will have an elevated troponin, and although this is an independent risk factor for subsequent ser- ious events, the finding rarely changes management appropriately or contributes to the final diagnosis. A strong suspicion of diagnoses other than syncope should lead to other investigations, including electroencephalography and brain imaging, but these have a low diagnostic yield in patients with syn- cope and should not be routine. Management Neurocardiogenic syncope may require no treatment other than re- assurance and avoidance of provocative factors. Syncope has several effects on lifestyle. Simple lifestyle measures may be employed to improve symptoms in specific situations: for example, increased fluid and salt intake. Where there is warning be- fore syncope occurs this may be used to prevent injury or complete syncope by adopting a position lying down or with feet elevated. It is crucial for those who suffer syncope to avoid situations that might put them at harm, such as swimming alone or bathing (showering is preferred). Management of vasovagal syncope, bradycardia, and cardiac ar- rhythmia are discussed in Chapters 16.4 and 24.5.4. In up to one-​third section 16  Cardiovascular disorders 3292 of patients, the aetiology of syncope may not be found: these patients have a good outcome unless they have underlying heart disease. Palpitation The symptom of palpitation is defined as an awareness of one’s heart beating. This may be due to an awareness of an abnormal heart rhythm, but it may also be due to an abnormal awareness of normal rhythm. A careful and detailed history can provide a likely diag- nosis. The most important aim in investigation is to correlate symp- toms with cardiac rhythm. History A description of the symptom should include an estimate of heart rate, duration of symptom, regularity of rhythm, suddenness of onset and offset. It may be helpful to ask the patient to tap with their finger to describe their palpitation. Trigger factors, including exer- cise, and aggravating factors such as alcohol and caffeine should be detailed. The length of history may be of interest. Sinus tachycardia An awareness of a rapid heart rate of gradual onset and offset is often associated with feelings of alarm and panic in patients with anxiety. Premature/​ectopic beats Symptomatic atrial and ventricular premature or ectopic beats com- monly occur in normal individuals, and often generate considerable anxiety resulting in consultation. In the absence of coronary disease, premature ventricular ectopic beats (PVCs) at a frequency of 1 per hour or more were recorded during Holter monitoring in the Framingham study in 33% of men and 32% of women. PVCs have also been recorded in 0.8% of a healthy military population during a standard 12-​lead ECG. These are im- portant factors to remember when discussing their significance with the patient. The patient may describe ‘missed beats’ or forceful beats. These symptoms relate to the pause that follows a premature beat. The premature beat produces a short diastolic filling interval and the low ventricular volume results in reduced ventricular contraction with a small stroke volume. However, the subsequent pause provides a long diastolic filling period and the resultant stretching of the ventricular walls is associated with an increased and forceful systolic contraction. The combination of the diminished premature beat and the enhanced postextrasystolic beat is responsible for the symptoms. Benign ectopy is indicated by the absence of a history of other cardiovascular symp- toms or family history of sudden death, their occurrence at rest and resolution with exercise, and a normal clinical cardiovascular exam- ination and resting ECG. Multifocal ventricular ectopy, and PVCs at a frequency of more than 20 000 in 24 h, are more indicative of poten- tially significant cardiac pathology and require further investigation. Atrial fibrillation This common arrhythmia may produce a variety of symptoms depending on ventricular rate, irregularity, and persistence. Paroxysmal atrial fibrillation is characterized by self-​terminating episodes of atrial fibrillation, when there may be a rapid and irregular ventricular response. The patient is aware of an increased heart rate and often describes the irregular nature of the symptom. The vari- ations in diastolic interval produce symptoms by similar mechan- isms to that described earlier for premature beats, with ‘missed’ and ‘forceful’ beats. Patients with sinoatrial dysfunction may be most symptomatic on termination of the atrial fibrillation, which can be followed by sinus bradycardia or prolonged sinus pauses. Atrial fib- rillation may be persistent or permanent, and the severity of symp- toms will be related to the ventricular rate and irregularity. Paroxysmal supraventricular tachycardia A history of sudden-​onset, rapid, regular palpitation in a healthy pa- tient with no underlying structural heart disease is suggestive of parox- ysmal supraventricular tachycardia. It may stop spontaneously or with vagotonic manoeuvres, or the patient may have had to attend hospital for intravenous therapy. In addition to palpitation, patients commonly report fatigue, malaise, light-​headedness, or dyspnoea, but because they have normal hearts such episodes of tachycardia are usually well tolerated. Polyuria is a common associated symptom, which results from the release of atrial natriuretic peptide secondary to atrial stretch. Ventricular tachycardia Ventricular arrhythmias can present with the symptom of palpita- tion, but more severe symptoms such as syncope or cardiac arrest also occur. Characteristically the symptom of palpitation would be the sudden onset and offset of a rapid regular heart rhythm. A his- tory of structural heart disease should be sought. Investigation Electrocardiogram The first aim is to document cardiac rhythm during symptoms. This may be possible with a standard ECG if the arrhythmia is sustained or persistent. Atrial or ventricular premature beats, or evidence of struc- tural heart disease (e.g. myocardial infarction), may be documented. The presence of pre-​excitation indicates the diagnosis of Wolff–​ Parkinson–​White syndrome and suggests symptoms due to episodes of atrioventricular re-​entry tachycardia. Other ECG signs indicative of primary electrical heart disease are: a corrected QT interval greater than 460 ms or less than 320 ms (long or short QT syndrome); right bundle branch block with ‘coved’ ST elevation (Brugada syndrome); epsilon waves and/​or T wave inversion with QRS duration greater than 100 ms in the right precordial ECG leads (arrhythmogenic right ven- tricular cardiomyopathy); and high voltages in the precordial leads with Q wave formation and ST changes (hypertrophic cardiomyopathy). Ambulatory monitoring The success of ambulatory monitoring in documenting the rhythm during symptoms will be dependent on the frequency of symptoms. If they occur daily, then a 24 or 48 h Holter recording should suffice. However, palpitation is often infrequent and other patient-​activated devices can be of more value. These include hand-​held, patient-​ activated event recorders that allow the telephonic transmission of recordings. These devices do not allow retrospective recording and require symptoms of sufficient duration to allow their use. However, there are now devices producing high quality single lead ECG re- cording that can be used with a smartphone and purchased directly by the patient. Shorter episodes may also be captured using loop re- corders: the newest devices are the size of a large plaster, are attached 16.2.2  Syncope and palpitation 3293 on the left upper part of the chest, can record for up to 2 weeks, and are waterproof. Ultimately, implantable loop recorders may be helpful where symptoms are infrequent, and they may also be effective in monitoring therapy once implanted for diagnostic purposes. The most recent devices are small enough to be classed as ‘injectable’, and they may even be implanted in the outpatient clinic setting. Other investigations Thyroid function and a full blood count are of particular importance in patients with atrial arrhythmias or sinus tachycardia, respectively. Electrolytes are routinely analysed. In patients with paroxysmal symptoms, a history of hypertension, sweating, and anxiety during attacks, urinary metanephrines for the investigation of phaeo- chromocytoma are indicated. Echocardiography is performed in most patients with palpitations and documented arrhythmias: in pa- tients with ventricular ectopy, however, it is usually indicated only in those with suspected structural heart disease, a very high burden of ectopy, or those at a high risk of development of serious ventricular arrhythmias or sudden cardiac death. Electrophysiological studies Invasive studies are of most value in determining the mechanism of a previously documented tachyarrhythmia, particularly with a view to treatments such as radiofrequency catheter ablation. Management Documentation of the cardiac rhythm during palpitation allows ap- propriate management, with reassurance as the only treatment in those with sinus tachycardia or premature beats. The treatment of other cardiac arrhythmias is discussed in Chapter 16.4. Lifestyle advice Advice regarding lifestyle with palpitations revolves around re- assurance where it is felt to be benign and avoiding precipitants where these can be identified. Although caffeine, other stimulants, alcohol, and stress are often quoted as potential triggers (and this may be true of ectopy, for example), it is much more common for many arrhythmias to occur without any avoidable trigger. Exercise as a trigger for palpitations is unusual and may signify adrenaline-​ dependent arrhythmias such as some forms of ventricular tachy- cardia (see Chapter 16.4). Driving restrictions may apply for both palpitations and syncope. In the United Kingdom clear guidance is provided by the Driver and Vehicle Licensing Agency (DVLA) as to who can and cannot drive with these symptoms, investigations that are required, and the dur- ation of driving bans for both a normal driving licence and heavy goods/​passenger vehicle licences. FURTHER READING Benditt DG, Sutton R (2005). Tilt-​table testing in the evaluation of syncope. J Cardiovasc Electrophysiol, 16, 356–​8. Brignole M, et al. (2018). 2018 ESC guidelines for the diagnosis and management of syncope. Eur Heart J, 39, 1883–948. Brignole M, et al. (2018). Practical instructions for the 2018 ESC guide- lines for the diagnosis and management of syncope. Eur Heart J, 39, e43–e80. Grubb BP (2005). Neurocardiogenic syncope and related disorders of orthostatic intolerance. Circulation, 111, 2997–​3006. NICE (2010). Transient loss of consciousness. Clinical guideline. https://​ www.nice.org.uk/​guidance/​cg109 Raviele A, et al. (2011). Management of palpitations: a position paper from the European Heart Rhythm Association. Europace, 13, 920–​34. Shen W-​K, et al. (2017). ACC/​AHA/​HRS Guideline for the evalu- ation and management of patients with syncope: a report of the American College of Cardiology/​American Heart Association Task Force on Clinical Practice Guidelines, and the Heart Rhythm Society. Circulation, 136(5), e60–​e122. 16.3 Clinical investigation of cardiac disorders 3 16.3 Clinical investigation of cardiac disorders 3294 16.3.1 Electrocardiography 3294 Andrew R. Houghton and David Gray 16.3 Clinical investigation of cardiac disorders CONTENTS 16.3.1 Electrocardiography  3294 Andrew R. Houghton and David Gray 16.3.2 Echocardiography  3314 James D. Newton, Adrian P. Banning, and Andrew R.J. Mitchell 16.3.3 Cardiac investigations: Nuclear, MRI, and CT  3326 Nikant Sabharwal, Andrew Kelion, Theodoros Karamitos, and Stefan Neubauer 16.3.4 Cardiac catheterization and angiography  3339 Edward D. Folland 16.3.1  Electrocardiography Andrew R. Houghton and David Gray ESSENTIALS The resting 12-​lead ECG The ECG has been recognized as a valuable diagnostic tool since the end of the 19th century. The normal ECG waveform consists of P, QRS, and T waves (and sometimes U waves)—​P waves result from atrial depolarization, QRS complexes from ventricular depolariza- tion, and T waves from ventricular repolarization. The standard 12-​ lead ECG utilizes four limb electrodes and six precordial electrodes to generate 12 leads or ‘views’ of the heart’s electrical activity. There are six limb leads (termed I, II, III, aVR, aVL, and aVF) and six precor- dial leads (termed V1, V2, V3, V4, V5, and V6). Supplementary ‘views’ can be obtained by using additional leads, such as V7, V8, and V9 to assess the posterior aspect of the heart and right-​sided chest leads to look for a right ventricular myocardial infarction. Assessment of the 12-​lead ECG—​this should be done in a method- ical manner, working through each aspect in turn. Conventionally, the heart rate, rhythm, and axis are assessed before inspection of each component of the waveform—​the P wave, PR interval, QRS complex, ST segment, T wave, QT interval, and U wave, with each component having its own range of normal attributes. Myocardial hypertrophy—​the ECG can be a specific but generally insensitive tool for detecting myocardial hypertrophy: (1) left ven- tricular hypertrophy can be assessed using certain diagnostic cri- teria, including the Cornell criteria and the Romhilt–​Estes scoring system; (2) right ventricular hypertrophy is indicated by a dominant R wave in lead V1 with right axis deviation; (3) left atrial hypertrophy is indicated by broad, bifid P waves; and (4) right atrial hypertrophy by tall P waves. Conduction blocks—​(1) left anterior hemiblock results from a block of conduction in the anterosuperior fascicle and is a cause of left axis deviation; (2) left posterior hemiblock results from a block of con- duction in the posteroinferior fascicle and is a cause of right axis devi- ation; (3) left and right bundle branch blocks both cause broadening of the QRS complexes by prolonging ventricular depolarization, and both exhibit characteristic diagnostic features. Ventricular pre-​excitation—​causes shortening of the PR interval and can result from Wolff–​Parkinson–​White-​type pre-​excitation, short PR-​type pre-​excitation, or Mahaim-​type pre-​excitation. Acute coronary syndromes The ECG is the most useful bedside triage tool in acute coronary syn- dromes, with utility in diagnosis, in location of the site of ischaemia/​ infarction, and as a prognostic indicator. ST elevation myocardial infarction—​the first indication of infarc- tion on the ECG is usually ST segment elevation, which occurs within a few hours. The J point (the origin of the ST segment at its junction with the QRS complex) is elevated by 1 mm or more in two or more limb leads, or by 2 mm in two or more precordial leads. The ST seg- ment returns to the baseline over the next 48–​72 h, during which Q waves and symmetrically inverted T waves appear. Some patients develop left bundle branch block, either transiently or perman- ently. The ECG of a completed infarct shows new Q waves greater than 2  mm, R waves reduced in size or absent, and inverted T waves. Non-​ST-​elevation myocardial infarction—​ECG changes are more variable than in ST-​elevation myocardial infarction. The ECG may be normal on first presentation and remain unchanged throughout the acute admission; there may be transient ST segment depression in- dicative of myocardial ischaemia; in 20–​30% the only change will be T-​wave inversion. Difficulties in interpretation of the ECG in acute coronary syndromes—​ the ECG diagnosis of acute myocardial infarction can pose challenges in the setting of right ventricular infarction, atrial infarction, coronary 16.3.1  Electrocardiography 3295 artery spasm, reciprocal changes, ‘stuttering’ infarction, non​infarct ST segment elevation, late presentation, left bundle branch block, prior infarction, pre-​excitation, and T-​wave inversion. Clinical decision-​making—​incorrect interpretation of an ECG can lead to inappropriate patient triage, either missing the opportunity to provide appropriate reperfusion therapy, or leading to inappro- priate treatment with attendant risk. Up to 12% of those with a high-​ risk ECG are missed on admission to the emergency department, yet pressure to provide treatment promptly to fulfil audit ‘targets’, for example, door-​to-​balloon time for primary percutaneous coronary intervention, should not replace accuracy in diagnosis. It is some- times better to repeat the ECG than to make an incorrect diagnosis. It is easy to place too much reliance on minor changes on the ECG; it is gross changes of ST elevation or depression within the parameters just outlined that should determine treatment. Exercise ECG testing Exercise ECG testing is better as an indicator of prognosis than as a diagnostic tool. The sensitivity of exercise ECG testing, the proportion with coronary disease correctly identified by the test, is 68% (range 23–​100) and specificity, the proportion free of disease correctly iden- tified by the test, is 77% (range 17–​100). In multivessel disease, these figures are 81% (range 40–​100) and 66% (range 17–​100), respectively. This means that exercise testing frequently yields both false-​positive results—​incorrectly diagnosing disease when coronary arteries are normal or minimally diseased—​and false-​negative results—​missing coronary disease when a flow-​limiting, even critical left main stem, coronary stenosis is present. Appearance of symptoms or ECG changes early in an exercise test is generally associated with more severe and extensive coronary dis- ease and a poor prognosis. Changes within the first 3 min usually indicate severe coronary disease affecting the left main stem or the proximal segments of at least one major coronary artery. Multivessel coronary disease is more likely with ST segment down-​sloping, de- layed ST normalization after exercise, increased number of leads af- fected, and lower workload at which ECG changes appear. The resting 12-​lead ECG History The first electrocardiogram (ECG), of an exposed frog’s heart, was performed by Marey in 1876 using the mercury capillary electrom- eter that had recently been invented by Gabriel Lippmann. Two years later the British physiologists John Burdon Sanderson and Fredrick Page demonstrated that recordings of the frog heart’s elec- trical activity consisted of two phases (which were subsequently to become known as the QRS complex and T wave). The first human ECG was published in 1887 by Augustus D Waller, who had worked under Sanderson in the Department of Physiology at the University College of London. While working at St Mary’s Hospital, London, Waller used a capillary electrometer to record the ECG of a labora- tory technician, Thomas Goswell. Electrocardiography was developed further by the Dutch physi- ologist Willem Einthoven, who witnessed a demonstration by Waller at the First International Congress of Physiology in Basle, Switzerland, in 1889. Although Einthoven made considerable im- provements to the technique of recording ECGs with the capillary electrometer, it was only with his invention of the string galvan- ometer at the turn of the century that high-​quality ECG recording became possible. Within a decade of Einthoven’s publication of the first string galvanometer ECG recordings in 1902, a commercial ECG machine became available. Manufactured by the Cambridge Scientific Instrument Company, the first machine was delivered to Sir Thomas Lewis, who would play a major role in developing the clinical application of electrocardiography. Einthoven’s invention led to him being awarded the Nobel Prize in 1924. Einthoven was also the first to use the PQRST notation to de- scribe the ECG waveforms. In the early ECG recordings, the wave- forms were named ABCD (four deflections were recognized). Mathematical correction, using differential equations, was used to correct and improve ECG recordings, and it was traditional that mathematical notation used letters from the latter half of the al- phabet. The letters N and O were already used elsewhere, so it was decided to begin the notation at P. Over the following years further refinements were undertaken, most notably in the 1930s when the use of the chest leads was first described. At around the same time Frank Wilson invented the ‘in- different electrode’ (also known as the ‘Wilson central terminal’). This led to the development of the ‘unipolar’ limb leads VR, VL, and VF (‘V’ stands for ‘voltage’). In 1942 the American cardiologist Emanuel Goldberger increased the voltage of these leads by 50%, leading to the term ‘augmented’ leads (aVR, aVL, and aVF), and the 12-​lead ECG which remains familiar today finally took shape. Although the format of the 12-​lead ECG has remained essen- tially unchanged since that time, there have nevertheless been other significant developments in electrocardiography over more recent years. Ambulatory ECG recorders and implantable cardiac moni- tors have gained a central role in the investigation of patients with suspected arrhythmias, and the use of intracardiac ECG recording has enabled the rapid development and widespread use of electro- physiological studies. Normal ECG appearances The ECG waveform The three fundamental deflections on the normal ECG are termed the P wave, the QRS complex, and the T wave (Fig. 16.3.1.1). The origins of each deflection are as follows. P wave The P wave results from depolarization of the atrial myocardium. Depolarization of the sinoatrial node itself, which triggers normal atrial depolarization, cannot be seen on the surface ECG (although it can be identified in intracardiac recordings). However, the presence of a P wave with normal morphology and orientation is generally taken to infer normal sinoatrial node depolarization. Repolarization of the atrial myocardium is represented on the ECG by the Ta wave (the atrial equivalent of the ventricular T wave). The Ta wave is seen as a small asymmetrical deflection after the P wave, with an opposite polarity to the preceding P wave. The Ta wave is often hidden within the QRS complex and is therefore not easily section 16  Cardiovascular disorders 3296 seen—​in fact, it is unusual to be able to appreciate the Ta wave at all. However, it can extend right through to the following ST segment, where it can be mistaken for the ST segment depression of myocar- dial ischaemia (particularly because the Ta wave is most likely to be seen extending into the ST segment during exercise-​induced sinus tachycardia). There is one case report of a positive Ta wave (after an inverted P wave) giving the erroneous impression of an acute ST seg- ment elevation myocardial infarction. QRS complex The QRS complex represents depolarization of the ventricular myocardium. Of all the deflections, the QRS complex can exhibit the greatest variability in appearance. As a result, the individual compo- nents of the QRS complex can be labelled in upper case (Q, R, or S) or lower case (q, r, or s) to represent the relative size of the compo- nent. For example, QRS complexes with a small Q wave deflection can be termed qRS complexes, and those QRS complexes with no Q wave component and a small R wave component can be termed rS complexes. T wave The T wave (together with the preceding ST segment) represents repolarization of the ventricular myocardium. The 12 conventional ECG leads Lead nomenclature It is important to emphasize that the term ‘lead’ does not refer to the electrode connecting the ECG machine to the patient. For a standard 12-​lead ECG recording, 10 electrodes are used to generate the 12 conventional ECG leads. The 12 leads can be categorized as limb (or frontal plane) leads (I, II, III, aVR, aVL, aVF) and chest (or precordial) leads (V1, V2, V3, V4, V5, V6). The 12 leads can also be categorized as bipolar (I, II, III) or unipolar (aVR, aVL, aVF, V1, V2, V3, V4, V5, V6). The leads aVR, aVL, and aVF can be further de- scribed as ‘augmented’ leads, as they are modified versions of the ori- ginal VR, VL, and VF leads, having a voltage amplification of 50%. The bipolar leads are generated by measuring the potential (voltage) between two electrodes. One electrode acts as a positive terminal and the other as a negative terminal. For instance, lead I measures the potential between the left arm electrode (positive) and right arm electrode (negative). Lead I is obtained by subtracting the right arm vector from the left arm vector. Similarly, lead II meas- ures the potential between the left leg electrode and the right arm electrode, and lead III measures the potential between the left leg electrode and the left arm electrode. The augmented unipolar leads measure the voltage between a single positive electrode and a ‘central’ point of reference generated from the other limb electrodes. Thus, aVR uses the right arm elec- trode as the positive terminal, aVL uses the left arm electrode, and aVF uses the left leg electrode. The three bipolar leads and the three augmented unipolar leads together comprise the six limb leads that view the heart in the frontal plane. The unipolar chest leads measure the voltage between six elec- trodes placed across the surface of the chest and a central point of reference, providing a view of the heart that is perpendicular to the frontal plane leads. For all 12 ECG leads, it is conventional that a wave of depolarization moving towards a lead generates a positive (upward) deflection on the ECG recording and vice versa. The six limb leads (frontal plane leads) Because the limbs act as linear conductors, it does not matter where- abouts the limb electrodes are attached on each limb. The six limb leads provide general spatial information (being less localized than the six chest leads). Fig. 16.3.1.2 shows the orientation of the six Fig. 16.3.1.1  Basic ECG waveform. aVR aVL aVF Left Right I II III Fig. 16.3.1.2  The six limb leads and their ‘view’ of the heart. Note that leads II, III, and aVF are inferior to the heart, I and aVL are anterolateral to the heart, and aVR looks into the cavity of the heart. 16.3.1  Electrocardiography 3297 limb leads in relation to the heart. In simple terms, one can visualize lead aVR as ‘looking’ at the heart from the right shoulder, lead aVL from the left shoulder, and lead aVF from the feet. Lead I ‘looks’ at the heart from the left horizontal position. Similarly, the ‘views’ of leads II and III are shown in Fig. 16.3.1.2. The six chest leads (precordial leads) For the chest (precordial) leads, each of the six electrodes is at- tached to a particular site on the chest wall. The chest electrodes act as positive terminals, and the indifferent terminal is formed from a combination of leads R, L, and F. The location of each electrode is important, in contrast to the limb leads. The surface positions of the chest electrodes are shown in Fig. 16.3.1.3, and the relation be- tween the chest leads and the heart in Fig. 16.3.1.4. The electrodes are placed as follows: • The V1 electrode is placed at the right sternal edge in the fourth intercostal space • The V2 electrode is placed at the left sternal edge in the fourth intercostal space • The V3 electrode is placed midway between the V2 and V4 electrodes • The V4 electrode is placed at the left midclavicular line in the fifth intercostal space • The V5 electrode is placed at the left anterior axillary line in a hori- zontal line with V4 • The V6 electrode is placed at the left midaxillary line in a hori- zontal line with V4 and V5 Reading a normal 12-​lead ECG Fig. 16.3.1.5 shows a normal 12-​lead ECG. As is conventional, this shows the leads arranged in four columns, each column containing three leads. In addition, a rhythm strip runs along the bottom of the ECG across its whole width. This is conventionally lead II, but any one of the 12 leads can be used for the rhythm strip as required. The ECG is recorded at a paper speed of 25 mm/​s, and at a sensitivity of 10 mm/​mV. The speed and sensitivity settings can also be adjusted on most ECG machines, if required, and so it is important that the actual recording speed and sensitivity are always noted on the ECG for future reference. In the following paragraphs we will describe the appearances of the normal ECG, looking at each wave, interval, and segment in turn. We will assume that the patient is in normal sinus rhythm, and that a standard paper speed (25  mm/​s) and calibration (10 mm/​mV) have been used—​this should always be checked be- fore reading any ECG. Identification details Before reading the ECG, check the patient’s details (the patient’s name and at least one other form of identification, such as date of birth or identification number, should be recorded on the ECG) and the date and time on which the ECG was recorded. It is good practice to note on the ECG any relevant clinical features. For instance, a note that the patient was experiencing chest pain or palpitations at the time the ECG was recorded can prove invaluable later on. Indeed, ECG interpretation should always take into account the appropriate clinical context. For instance, the ECG shown in Fig. 16.3.1.5 can be interpreted as showing normal sinus rhythm in a patient who is well. However, in a patient who is unconscious and pulseless, the same ECG would be interpreted as showing pulseless electrical activity, a cardiac arrest rhythm. Before interpreting any ECG, it is therefore appropriate (and important) to ask, ‘How is the patient?’ Rate A normal heart rate is between 60 and 100 beats/​min. A rate below 60 beats/​min is termed bradycardia; a rate greater than 100 beats/​ min is termed tachycardia. Heart rate normally applies to the ven- tricular rate, as shown on the ECG by the rate of QRS complexes. However, the atria have their own rate, as shown by the P wave rate. The atrial and ventricular rates are usually the same, and there is a 1:1 ratio between P waves and QRS complexes. However, the rates can differ; for instance, in complete heart block (Fig. 16.3.1.6), the atrial rate is usually greater than the ventricular rate, and both rates should therefore be quoted. Ventricular rate can be calculated in two different ways. One method necessitates counting the number of large (5 mm) squares between two adjacent QRS complexes. This figure is then divided into 300 to give the ventricular rate per minute. For instance, if there are five large squares between QRS complexes, the ventricular rate is 300/​5 = 60 V1 V2 V3 V4 V5 V6 Fig. 16.3.1.3  Surface positions of the chest electrodes. V1 V2 V3 V4 V5 V6 Fig. 16.3.1.4  The chest leads and their anatomical relationship to the heart. Return to the top. section 16  Cardiovascular disorders 3298 beats/​min. The same method can be used to calculate atrial rate, counting the large squares between two consecutive P waves. If the heart rhythm is irregular, the square-​counting method is not so useful. An alternative method is to count the number of QRS complexes in a certain time period, and then multiply the number up to obtain a rate per minute. Traditionally one counts the number of QRS complexes in a period of 30 large squares, which equates to 6 s of recording (a paper speed of 25 mm/​s covers five large squares per second, or 300 large squares per minute). One then multiplies the result by 10 to obtain the rate per minute. Thus, if there are 8 QRS complexes within 30 large squares, then the ventricular rate is 8 × 10 = 80 beats/​min. Once again, the same method can be used to calculate atrial rate. Rhythm A detailed description of arrhythmias can be found in Chapter 16.4. In general terms, the assessment of rhythm on the ECG requires careful attention to the following: • Whether there is ventricular activity (QRS complexes) and what is the ventricular rate; • Whether there is atrial activity (P waves) and what is the atrial rate; • Whether the heart rhythm is regular or irregular; • Whether the QRS complexes are normal or broad (broad com- plexes indicating either a ventricular origin to the rhythm or aber- rant conduction of a supraventricular rhythm); • Whether there is a relationship between P waves and QRS complexes. Assessing the ECG along these lines will provide a basis upon which to describe the rhythm and begin to identify the nature of the arrhythmia. Axis The concept of axis is often regarded as one of the hardest principles to grasp when learning ECG interpretation. The concept is, none- theless, straightforward: axis refers to the overall direction in which the wave of depolarization travels. There is a QRS (ventricular) axis, which is what most people refer to when discussing cardiac axis, but the P wave has its own axis too, representing the overall direction of depolarization in the atria. The T wave also has an axis, in this case referring to the overall direction of the wave of repolarization. In this section the discussion is confined to the QRS (ventricular) axis, but the same principles apply to P wave and T wave axes too. As the ventricles depolarize, the wave of depolarization travels through the atrioventricular node, into the bundle of His, and then to the ventricular myocardium via the Purkinje fibres. The overall direction of this depolarization wavefront is usually towards the apex of the heart. If, by convention, we regard the ‘view’ that lead I has of the heart (a horizontal line to the left of the heart) as 0°, and any angle clockwise from that line is positive (and any angle anti- clockwise from that line is negative), then the normal ventricular depolarization wavefront travels through the ventricles at an angle of approximately +60° (Fig. 16.3.1.7). As Fig. 16.3.1.7 illustrates, the six limb leads ‘view’ the heart from different angles. Lead I is taken as the horizontal reference point, 0°. Moving in a clockwise (positive) direction, lead II views the heart from an angle of +60°, lead aVF from an angle of +90°, and lead III from an angle of +120°. Moving anticlockwise from lead I, lead aVL views the heart from an angle of −30°, and lead aVR from an angle of −150°. This system of looking at axes, using the six limb leads, is known as the hexaxial reference system. The shaded area in Fig. 16.3.1.7 shows the normal range for the QRS axis, which lies between −30° and +90°. This does vary with Fig. 16.3.1.5  A normal 12-​lead ECG. Fig. 16.3.1.6  Complete heart block: complete dissociation of atrial (P waves) and ventricular (QRS complexes) rate. 16.3.1  Electrocardiography 3299 body morphology—​tall, slim individuals tend to have axes towards the rightward (+ 90°) end of the normal range; short, overweight individuals have axes towards the leftward (−30°) end of the normal range. An axis more negative (anticlockwise) than −30° is abnormal and termed left axis deviation. Similarly, an axis more positive (clockwise) than + 90° is abnormal and termed right axis deviation. Left axis deviation is seen in left anterior hemiblock (see next), in- ferior myocardial infarction, and also in ostium primum atrial septal defect. Right axis deviation is seen in left posterior hemiblock, right ventricular hypertrophy, lateral myocardial infarction, ostium secundum atrial septal defect, and Wolff–​Parkinson–​White (WPW) syndrome. There are several ways to calculate the QRS axis. One method is to look for which of the six limb leads has a QRS complex in which the R wave and S wave are closest to being equal (i.e. in which the positive and negative deflections cancel each other out). The QRS axis will be at right angles to this ‘equipolar’ lead, but could be pointing in either direction. For instance, if the equipolar lead is lead III (which looks at the heart from + 120°), then the QRS axis will be at right angles to this, namely either + 30° or −150° (refer back to Fig. 16.3.1.7). Next, find which lead is at right angles to the equipolar lead—​in this example, the answer would be lead aVR. Now, if the QRS axis is −150°, then you would expect a positive QRS complex in lead aVR (because the wave of depolarization would be travelling directly towards it). If, how- ever, the QRS complex in lead aVR is negative, the depolarization must be moving away from it and the QRS axis must be therefore be + 30°. This method works whichever limb lead is equipolar, as every limb lead has another lead at right angles to it. An alternative and quick method of checking whether the QRS axis is within the normal range is simply to look at leads I and II. If the QRS complex in lead I is positive (or at least equipolar), then the QRS axis must lie somewhere in the range of −90° to + 90°. Similarly, if the QRS complex in lead II is positive, then the QRS axis must lie somewhere in the range −30° to + 150°. Therefore, we can say that if the QRS complexes in leads I and II are both positive then the QRS axis must lie somewhere in the range −30° to + 90°. Thus, a posi- tive QRS complex in leads I and II means the QRS axis is within the normal range; a positive QRS complex in lead I and a negative QRS complex in lead II indicate left axis deviation; a negative QRS com- plex in lead I and a positive QRS complex in lead II indicate right axis deviation. More precise calculations of the QRS axis can be made by measuring the individual R and S waves in each of the limb leads and using vector analysis to plot out the overall direction of depolar- ization, but this degree of precision is usually unnecessary. P wave The P wave represents atrial depolarization. P waves are usually up- right except in leads aVR and V1 (and sometimes V2), where they can be inverted (or biphasic). P waves are seen most clearly in lead II and this is usually the lead of choice for the rhythm strip so that atrial activity can be assessed clearly. P waves can be inverted in other leads, indicating that atrial de- polarization has been initiated somewhere other than the sinoatrial node. For instance, an ectopic focus of depolarization near the atrioventricular node will give rise to inverted P waves in the in- ferior leads (II, III, and aVF) as the wave of atrial depolarization will spread upwards rather than downwards. P waves are normally no broader than three small squares (0.12 s) and no taller than 2.5 mm. The features of atrial hypertrophy are discussed later. PR interval The PR interval is measured from the beginning of the P wave to the beginning of the QRS complex. A normal PR interval is between 0.12 s and 0.20 s in adults. A long, fixed PR interval is termed first-​degree atrioven- tricular block and results from a delay in conduction between the atria and ventricles (Fig. 16.3.1.8). In second-​degree atrio- ventricular block the PR interval may gradually increase with each beat before a P wave is not conducted (Mobitz type I or Wenckebach phenomenon) or may be fixed and long (or normal) with intermittent non​conduction of P waves (Mobitz type II). In third-​degree atrioventricular block and also in atrioventricular dissociation, the PR interval will vary because of the absence of any association between atrial and ventricular activity. See Chapter 16.4 for further discussion. 150 III II I aVF aVL 120 90 60 30 0 −30 −60 −90 −120 −150 180 aVR Fig. 16.3.1.7  The standard convention for describing the orientation of cardiac axis, and the corresponding ‘views’ of each of the six limb leads. The shaded area represents the normal range for the QRS axis. Fig. 16.3.1.8  First-​degree atrioventricular block (long PR interval). section 16  Cardiovascular disorders 3300 A short PR interval is seen in ventricular pre-​excitation (see next) or when the focus of atrial depolarization arises not from the sino- atrial node but from the vicinity of the atrioventricular node. QRS complex The QRS complex represents ventricular depolarization. The first nega- tive deflection of the complex is termed the Q wave and the first positive deflection the R wave (whether or not it follows a Q wave). A negative deflection after an R wave is termed an S wave. If the deflections are small, lower-​case letters (q, r, and s) are used. Thus, it is possible to have QRS complexes, qRS complexes, rS complexes, and so on. Normal ‘physiological’ q waves are usually narrow (no more than 0.04 s in duration) and small (less than 25% the amplitude of the following R wave) and result from the left to right depolarization of the interventricular septum (‘septal q waves’). Larger Q waves may be pathological, although can be normal in leads III and aVR, and may also been seen in lead aVL if the QRS axis is greater than + 60°. The normal QRS complex duration is less than 0.12 s. The amp- litude of the QRS complex varies normally from lead to lead and, in the precordial leads, normally increases progressively from lead V1 to V6. At least one R wave in the precordial leads must be at least 8 mm in height, and the tallest R wave should be no more than 27 mm (and the deepest S wave no more than 30 mm), and the sum of the tallest R wave and the deepest S wave should be no more than 40 mm. In the limb leads, the R wave height should be no more than 13 mm in lead aVL and 20 mm in lead aVF. ST segment The ST segment should be horizontal and should not normally de- viate by more than 1 mm above or next the isoelectric line (which is the line between end of the T wave and the start of the subsequent P wave). T wave T waves in the limb leads are normally concordant—​if the QRS com- plex is positive, the subsequent T wave is upright, and vice versa. The T wave is normally inverted in lead aVR and upright in leads I and II. With regard to the precordial leads, normal T waves are always upright in leads V4 to V6. A flat or inverted T wave is found in lead V1 in 20% of adults, and in lead V2 in 5% of adults (in which case, the T wave should be inverted in lead V1 as well). An inverted T wave in lead V3 can, rarely, be found in normal young adults. T waves should not change their orientation—​an inverted T wave is not normal if previous ECGs show that it was previously upright. There are no strict criteria for normal T wave size, so ‘tall’ and ‘small’ T waves are not well defined and deciding on their presence tends to be a subjective judgement. ‘Tall’ T waves can occur in early acute myocardial infarction (‘hyperacute’ T waves) and in hyperkalaemia (‘tented’ T waves). Small T waves can be seen in hypokalaemia. QT interval The QT interval is measured between the start of the QRS complex and the end of the T wave. The normal range for the QT interval varies according to heart rate. It is therefore convenient to correct the measured QT interval to what it would be if the heart rate were 60 beats/​min. This is done most commonly using Bazett’s formula, in which the measured QT interval (in seconds) is divided by the square root of the RR interval (in seconds), to give the corrected QT interval (QTc). The normal range for the QT interval at a heart rate of 60 beats/​min, and thus for the QTc, is between 0.35 s and 0.45 s (men) or 0.46 s (women) (Fig. 16.3.1.9). U wave The T wave is occasionally followed by a U wave, most clearly seen in the right precordial leads, which has the same orientation as the T wave and is usually no more than one-​third of its size. The physio- logical origin of the U wave is still debated but is often said to relate to after depolarizations in the ventricles. Myocardial hypertrophy Left ventricular hypertrophy Evidence of left ventricular hypertrophy on the ECG is a significant risk factor for cardiovascular morbidity and mortality. Several diag- nostic ECG criteria for left ventricular hypertrophy have been de- veloped which, in general, are relatively specific (>90%) but not very sensitive (20–​60%). The diagnostic criteria shown in Box 16.3.1.1 are commonly used. The Cornell criteria involve measuring the S wave in lead V3 and the R wave in lead aVL. Left ventricular hypertrophy is indicated by a sum of more than 28 mm in men and more than 20 mm in women. The Romhilt–​Estes scoring system allocates points for the pres- ence of certain criteria, with a score of five indicating left ventricular hypertrophy and a score of 4 indicating probable left ventricular hypertrophy. Points are allocated as follows: • 3 points for (a) R or S wave in limb leads of 20 mm or more; (b) S wave in right precordial leads of 25 mm or more; or (c) R wave in left precordial leads of 25 mm or more; • 3 points for ST segment and T wave changes (‘typical strain’) in a patient not taking digitalis (1 point with digitalis); • 3 points for P-​terminal force in V1 greater than 1 mm deep with a duration greater than 0.04 s; • 2 points for left axis deviation (beyond −15°); • 1 point for QRS complex duration greater than 0.09 s; • 1 point for intrinsicoid deflection (the interval from the start of the QRS complex to the peak of the R wave) in V5 or V6 greater than 0.05 s. Fig. 16.3.1.9  A prolonged QT interval. Measurement can be difficult since the precise beginning and end of the interval may not be easy to determine, particularly if the end of the T wave is obscured by a superimposed U wave or the following P wave. 16.3.1  Electrocardiography 3301 A left ventricular ‘strain’ pattern (ST-​T wave abnormalities) is as- sociated with around double the risk of myocardial infarction and stroke as left ventricular hypertrophy in the absence of strain. Left ventricular hypertrophy cannot be assessed reliably using the ECG in patients with bundle branch block, previous myocardial in- farction, or WPW syndrome; visualization via echocardiography or cardiac MRI is required. An example of left ventricular hypertrophy is shown in Fig. 16.3.1.10. Right ventricular hypertrophy As with left ventricular hypertrophy, the ECG criteria for right ven- tricular hypertrophy tend to be relatively specific but not very sen- sitive. Right ventricular hypertrophy shifts the QRS complex axis rightwards as well as producing higher-​voltage QRS complexes in the right precordial leads. ECG criteria include: • a dominant R wave (R wave ≥ S wave) in lead V1, in the presence of a normal QRS duration; • a QRS complex axis of greater than + 90°. These criteria are supported by: • ST segment depression and T-​wave inversion in the right pre- cordial leads; • deep S waves in the lateral precordial and limb leads. It is not essential for all these criteria to be present, but the greater the number of features present, the greater the likelihood of right ventricular hypertrophy. It is prudent to remember that a dominant R wave in lead V1 can also be seen in right bundle branch block, WPW syndrome, and a posterior wall myocardial infarction. Atrial hypertrophy Left atrial hypertrophy Left atrial depolarization is responsible for the terminal portion of the normal P wave. Left atrial hypertrophy increases the voltage and duration of this depolarization, and thus usually evidences itself by abnormalities of the terminal portion of the P wave. The P wave dur- ation is prolonged, and it becomes bifid in lead II and biphasic, with a predominant negative component, in lead V1. So-​called ‘P mitrale’ can be seen in the left atrial enlargement that results from mitral valve stenosis (hence the term) and also in association with condi- tions that cause left ventricular hypertrophy, such as hypertension (most commonly) and aortic stenosis (Fig. 16.3.1.11). Right atrial hypertrophy Right atrial hypertrophy increases the voltage, but not the duration, of the P wave, and this is usually best seen in the inferior and right precordial leads. A P wave height greater than 2.5 mm is regarded as abnormal. So-​called ‘P pulmonale’ can result from right ventricular hypertrophy or from tricuspid valve stenosis (Fig. 16.3.1.12). The hemiblocks The left bundle branch divides into anterosuperior and postero­ inferior fascicles. A block of either fascicle (hemiblock) causes a deviation of the QRS axis. Left anterior hemiblock A block of the anterosuperior fascicle leads to a left anterior hemiblock. This causes a leftward shift in the QRS axis, as the Box 16.3.1.1  Diagnostic criteria for left ventricular hypertrophy Limb leads • R wave >11 mm in lead aVL • R wave >20 mm in lead aVF • S wave >14 mm in lead aVR • Sum of R wave in lead I and S wave in lead III >25 mm Precordial leads • R wave of ≥25 mm in the left precordial leads • S wave of ≥25 mm in the right precordial leads • Sum of S wave in lead V1 and R wave in lead V5 or V6 >35 mm (Sokolow–​Lyon criteria) • Sum of tallest R wave and deepest S wave in the precordial leads 45 mm Fig. 16.3.1.10  Left ventricular hypertrophy. section 16  Cardiovascular disorders 3302 right/​inferior region of the left ventricle depolarizes first (via the posteroinferior fascicle) and then the wave of depolarization spreads to the left/​superior region. Although this hemiblock introduces a minor delay in ventricular depolarization, the QRS duration re- mains within the normal range (up to 120 ms). The QRS axis shifts to the left (beyond −30°). As a similar axis shift can result from an inferior myocardial infarction, the diagnosis of an left anterior hemiblock requires the presence of left axis deviation in the absence of an abnormal q wave in lead aVF. Left posterior hemiblock Block of the posteroinferior fascicle leads to left posterior hemiblock. This causes a rightward shift in the QRS axis, as the left/​superior region of the left ventricle depolarizes first (via the anterosuperior fascicle) and then the wave of depolarization spreads to the right/​in- ferior region. As with a left anterior hemiblock, the QRS duration re- mains within the normal range (up to 120 ms). The QRS axis shifts to the right (beyond + 90°). However, right axis deviation can occur in several conditions (most commonly right ventricular hypertrophy, but also in lateral myocardial infarction and WPW syndrome). It is therefore not possible to diagnose left posterior hemiblock with cer- tainty from the 12-​lead ECG alone. Bundle branch block Left bundle branch block A left bundle branch block (LBBB) leads to a delay in left ventricular depolarization, as the left ventricle is depolarized via the right-​sided Purkinje system. In addition, the interventricular septum depolar- izes from right to left instead of the usual left to right. Thus, in LBBB: • The QRS duration is prolonged (≥120 ms); • The normal ‘septal’ q waves usually seen in the lateral leads are absent; • A secondary r wave is not seen in lead V1 (this distinguishes LBBB from right bundle branch block (RBBB) with clockwise cardiac rotation). These findings may be accompanied by ST segment depression and T-​wave inversion in the lateral precordial and limb leads, broad QS waves in the right precordial leads and broad R waves in the lat- eral leads, and R wave notching (‘M-​shaped’ QRS complexes). An example of LBBB is shown in Fig. 16.3.1.13. The extensive na- ture of the ECG changes means that further interpretation of the QRS complexes, ST segments, or T waves cannot be made. The dif- ficulties of diagnosing myocardial infarction in the setting of LBBB are discussed later. Right bundle branch block RBBB leads to a delay in right ventricular depolarization, as the right ventricle is depolarized via the left-​sided Purkinje system. However, the normal left to right activation of the interventricular septum is preserved. The ECG changes seen in RBBB are therefore not as ex- tensive as in LBBB. The QRS duration is prolonged (≥120 ms) and the right ventricular leads contain a second positive wave (and, con- versely, the left ventricular leads contain a second negative wave). Thus, in RBBB: • the QRS duration is prolonged (≥120 ms); • lead V1 contains a second positive wave (rsR); • lead V6 contains a second negative wave (qRs). These findings may be accompanied by deep slurred S waves in the lateral precordial and limb leads, and abnormal ST-​T wave changes in the right precordial leads. An example of RBBB is shown in Fig. 16.3.1.14. Ventricular pre-​excitation The normal progression of a wave of depolarization is from the sino- atrial node through the atria to the atrioventricular node, and then through the bundle of His and the Purkinje fibres to the ventricular myocardium. However, approximately 1 in 1000 of the population has an accessory pathway—​an alternative pathway from atria to ventricles that bypasses part of this normal route. Such a pathway initiates depolarization of the ventricles at a slightly earlier stage in the cardiac cycle than would otherwise be the case, hence the term ‘ventricular pre-​excitation’. This is because the accessory pathway lacks the inherent delay to conduction that is normally found in the atrioventricular node, thus allowing faster conduction of the wave of depolarization from atria to ventricles. There are several types of pathway that can give rise to ventricular pre-​excitation. WPW-​type pre-​excitation WPW-​type pre-​excitation is exemplified by WPW syndrome. In WPW syndrome an accessory pathway, the bundle of Kent, connects Fig. 16.3.1.11  Left atrial hypertrophy (‘P mitrale’). Fig. 16.3.1.12  Right atrial hypertrophy (‘P pulmonale’). 16.3.1  Electrocardiography 3303 the atria to the ventricles and bypasses the atrioventricular node al- together. This shortens the time between the onset of atrial depolar- ization and the onset of ventricular depolarization, and hence one of the ECG features of WPW syndrome is a short PR interval (<0.12 s). Because the accessory pathway leads directly to the ventricular myocardium, and not into the His–​Purkinje system, the subsequent initial ventricular depolarization progresses slowly, as conduction of the wave of depolarization cannot take advantage of the rapidly-​ conducting Purkinje fibres. This gives rise to a δ-wave—​a slurred initial upstroke of the QRS complex. These features can be seen in the ECG from a patient with WPW syndrome in Fig. 16.3.1.15. Conduction between atria and ventricles can be via the accessory pathway, or via the atrioventricular node, or via both routes, or can vary from one to another. If conduction does not occur via the acces- sory pathway, the ECG will appear normal and the pathway is said to be ‘concealed’. The appearances of the δ-wave can vary from patient to patient. Indeed, the ECG appearances of the QRS complex can be used, to a limited extent, to predict the likely location of the accessory pathway. However, the exact location can only be found with elec- trophysiological studies. The QRS complex morphology in WPW syndrome can mimic LBBB, RBBB, or acute myocardial infarction. WPW syndrome can also lead to repolarization (and therefore T wave) abnormalities. Great care must be thus taken in diagnosing these conditions in the presence of WPW syndrome. The existence of two atrioventricular pathways (the normal atrioventricular node and the abnormal bundle of Kent) provides a substrate for atrioventricular re-​entry tachycardia, which is dis- cussed in more detail in Chapter 16.4. Short PR-​type pre-​excitation A short PR interval in the absence of a δ-wave/​abnormal QRS complex is often referred to as Lown–​Ganong–​Levine syndrome, in which an atrio-​His accessory pathway bypasses the slow-​ conducting part of the atrioventricular node. Identical appearances can also be seen with a fast-​conducting atrioventricular node. The Fig. 16.3.1.13  Left bundle branch block. Fig. 16.3.1.14  Right bundle branch block. section 16  Cardiovascular disorders 3304 presence of an atrio-​His accessory pathway is a substrate for atrio- ventricular nodal re-​entry tachycardia. For further discussion, see Chapter 16.4. Mahaim-​type pre-​excitation Mahaim fibres, first described in the 1930s, are atriofascicular or atrioventricular accessory pathways that connect the atrioven- tricular node to the right bundle or the right ventricle. Patients with Mahaim-​type pre-​excitation have a normal PR interval with a LBBB QRS complex morphology and are prone to re-​entry tachycardia. For further discussion, see Chapter 16.4. Acute coronary syndromes Sudden disruption of existing coronary plaque may partially or to- tally occlude a coronary artery, causing myocyte necrosis. Symptoms of severe, centrally located chest pain develop suddenly, usually ac- companied by breathlessness due to left ventricular dysfunction and tachycardia, pallor, sweating, nausea, and extreme anxiety due to sym- pathetic drive. The American College of Cardiology and the European Society of Cardiology classification of myocardial ischaemia and in- farction recognizes that acute changes in coronary atheroma produce a spectrum of disease, the acute coronary syndromes (ACS): • Unstable angina, where coronary plaque has ruptured but stabilizes without major change in the lumen of the coronary ar- tery: the ECG may be normal, or indicate a previous myocardial infarction, or dynamic ST depression and/​or T-​wave inversion may appear. Serum troponin level, a marker of myocyte necrosis, is within normal limits. • Non-​ST elevation myocardial infarction (NSTEMI), where plaque is ruptured with partial occlusion of a major coronary artery: ECG signs are variable—​the ECG may be normal, or indicate a previous myocardial infarction, or ST depression may appear transiently, or symmetrically inverted T waves may appear. Troponin levels are elevated. • ST elevation myocardial infarction (STEMI) where thrombosis from a ruptured plaque completely occludes a coronary artery: the ECG shows ST segment elevation initially, then resolves within a day or two, with new Q waves and inverted T waves appearing in the leads subtending the infarcted area. Troponin levels are elevated. For discussion of the clinical features and management of ACS, see Chapters 16.2.1, 16.13.4, and 16.13.5. Role of the ECG in acute coronary syndromes The ECG remains the most useful bedside triage tool in the emergency setting, whether in the community, en route to hos- pital, or in the emergency department. Accurate interpretation is essential—​misinterpretation of the ECG can be as high as 12% and lead to inappropriate management. The ECG is used to diagnose ACS, to locate the site of ischaemia and infarction (see Table 16.3.1.1) and to identify areas of impaired perfusion (see ‘Reciprocal changes’). Of those who suffer a STEMI, the initial ECG is diagnostic in 50%, abnormal but not diagnostic in 40%, and normal in the re- mainder. Repeat ECGs may be necessary to confidently diagnose or exclude an acute coronary syndrome, as diagnostic changes may not appear for several hours. Serial recordings increase the sensi- tivity to 95%. The presenting ECG and prognosis in acute coronary syndrome About 22% of all patients with acute chest pain will present with T-​wave inversion, 28% with ST segment elevation, 35% with ST segment depression, and 15% with a combination of ST segment elevation and depression. T-​wave inversion is most likely to be as- sociated with angiographically normal coronary arteries. Those with ST segment depression are more likely to have three-​vessel disease. Mortality at 1 month is 1.7% in those with T wave changes, 5.1% with ST segment elevation or depression, and 6.6% with both depression and elevation. Severe ST segment depression (>2 mm Fig. 16.3.1.15  WPW syndrome, showing the short PR interval and δ-wave. 16.3.1  Electrocardiography 3305 in two contiguous leads) is associated with an increased risk of death at 1 year. The presenting ECG and probability of acute coronary syndrome New, or presumed new, ST segment deviation greater than 0.1 mV, however transiently, or T-​wave inversion in multiple precordial leads, is highly indicative of ACS. Q waves, ST segment depression of 0.05–​ 0.1 mV, or T-​wave inversion greater than 0.1 mV have an intermediate probability of ACS. T-​wave flattening or inversion less than 0.1 mV (in leads with dominant R waves) or a normal ECG has a low probability of ACS. The likelihood of NSTEMI is increased threefold in chest pain with ST segment depression in three leads or more than 0.2 mV. The presenting ECG and triage The presenting ECG can be used to triage patients with acute cardiac-​sounding chest pain: • ST elevation present—​immediate reperfusion should be con- sidered, by primary percutaneous coronary intervention (PCI) (or by intravenous thrombolysis if primary PCI unavailable). • ST elevation not evident—​immediate treatment with antiplatelet drugs and anti-​ischaemic drugs, with consideration of cor- onary angiography where appropriate. Risk stratification using tools such as GRACE or TIMI scoring, can help identify those most likely to benefit from early coronary angiography and revascularization. Table 16.3.1.1  Location of infarction and affected coronary artery ECG leads affected Site of infarction Most likely artery occluded (positive predictive value) V3 and V4 I, aVL and V1 to V6 (in extensive infarction) Anterior Left anterior descending (96%) V1 and V2 Septal V1 to V4 Anteroseptal I, aVL, and V3 to V6 Anterolateral II, III, and aVF Inferior Right coronary (80%) Right or circumflex (94%) I, aVL and V6 I and aVL (high lateral) Lateral Circumflex (75%) ST depression in V1 and V2 followed by development of prominent R waves in lead V1 or V2 Posterior Circumflex (75%) Lateral or posterior Right or circumflex (94%) II, III, and aVF with aVL, V5, and V6 Inferolateral Right coronary (93%) Fig. 16.3.1.16  Evolution of STEMI over several days. section 16  Cardiovascular disorders 3306 ST segment elevation myocardial infarction The ECG changes of myocardial infarction, first described in 1920, reflect myocardial ischaemia, injury, and myocyte necrosis. Within an hour or so of occlusion of a coronary artery, the T wave be- comes more prominent, exceeding one-​half the height of the pre- ceding R wave in the ECG leads subtending the infarcted area (see Fig. 16.3.1.16). Many patients present later than this, so these changes may pass unnoticed. In up to 50%, the presenting ECG is normal. The first documented indication of infarction is usually ST segment elevation which occurs within a few hours. The J point (the origin of the ST segment at its junction with the QRS complex) is elevated by 1 mm or more in two or more limb leads, or by 2 mm in two or more precordial leads. The ST segment returns to the baseline over the next 48–​72 h, during which Q waves and symmetrically inverted T waves ap- pear. Some patients develop LBBB, either transiently or perman- ently. The ECG of a completed infarct shows new Q waves greater than 2 mm, R waves reduced in size or absent, and inverted T waves. This classical evolution of STEMI is seen in about 50–​66% of patients. Reperfusion therapy, by primary PCI (or thrombolysis where primary PCI is unavailable) may alter this natural sequence of changes in the ECG. If treatment is given with thrombolysis, then an ECG performed 90 min after initiation should show that ST ele- vation has been reduced by at least 50% from pretreatment levels (Fig. 16.3.1.17). If chest pain persists and the ST segments remain elevated, coronary angiography and rescue PCI should be con- sidered. Where available, primary PCI should be offered in pref- erence to thrombolysis. Resolution of ST segment elevation predicts 30-​day mortality. With greater than 70% ST segment resolution, mortality is 2.1%; with 30–​70% ST segment resolution 5.2%; with no ST segment reso- lution 5.5%; and with worsening ST segment elevation 8.1%. Non-​ST elevation myocardial infarction ECG changes in NSTEMI are more variable than in STEMI. The ECG may be normal on first presentation and remain unchanged throughout the acute admission. There may be transient ST seg- ment depression indicative of myocardial ischaemia. In 20–​30%, the only change will be T-​wave inversion. Risk-​scoring systems have (b) (a) Fig. 16.3.1.17  (a) Acute inferolateral ST segment elevation myocardial infarction. (b) Substantial (but not complete) resolution of ST segment elevation 90 min after the initiation of thrombolysis. 16.3.1  Electrocardiography 3307 been developed, for example, by the Trials In Myocardial Infarction group (http://​www.timi.org), for use in patients with ACS. These are described in Chapter 16.13.4: with regard to NSTEMI, ST segment deviation greater than 0.5 mm is one of the recorded parameters. The extent of ST depression identifies those who are most likely to benefit from early revascularization (FRISC II trial). Mortality with early invasive therapy is 4% with ST segment depression, 2% with no ECG changes, and 0.2% with T-​wave inversion. Difficult diagnoses in acute myocardial infarction Right ventricular infarction The ECG provides prognostic as well as diagnostic information. An inferior infarction generally carries a good prognosis unless it is associated with a right ventricular infarction, when there is a six- fold increased risk of a major in-​hospital complication, including ventricular fibrillation, reinfarction, and death. The right ventricle is involved in about 50% of those with an inferior infarction, occurring with occlusion of the right coronary artery, causing a transmural in- farct of the inferoposterior wall and the posterior septum. To determine whether the right ventricle is involved in an in- ferior infarction, an ECG should be recorded with the anterior chest leads placed on the right side of the chest, in equivalent (but mirrored) positions to a standard 12-​lead ECG. The right ven- tricle is involved if there is greater than 1 mm ST segment eleva- tion in chest lead ‘right V4’ (RV4); this has a sensitivity of 100%, specificity of 87%, and positive predictive value of 92% for occlu- sion of the right coronary artery proximal to the right ventricular branch. If these changes are absent, the right ventricle has been spared (Fig. 16.3.1.18). Atrial infarction This occurs in up to 10% of myocardial infarcts in conjunction with ventricular infarction. A clue to its presence is PR segment (b) (a) Fig. 16.3.1.18  (a) Inferior ST segment elevation myocardial infarction. (b) Inferior ST segment elevation myocardial infarction with right ventricular involvement (note the right ventricular chest leads, with ST segment elevation in lead RV4). section 16  Cardiovascular disorders 3308 displacement but there may also be an abnormal P wave. It can cause rupture of the atrial wall and is frequently associated with atrial arrhythmias including atrial fibrillation, atrial flutter, and atrioventricular nodal rhythm. Coronary artery spasm The pain of Prinzmetal’s or variant angina is not usually triggered by exercise, emotion, cold, or a meal but tends to occur at rest, ac- companied by transient, marked ST segment elevation. This rapidly reverts to normal when the pain resolves spontaneously or with gly- ceryl trinitrate. Atrioventricular block or ventricular arrhythmia may accompany spasm-​induced myocardial ischaemia. Spasm suf- ficient to cause myocardial ischaemia, myocardial infarction, and sudden death can follow cocaine use. Reciprocal changes—​septal ischaemia or posterior infarction? ST or ‘reciprocal’ depression may be seen in leads remote from the site of a STEMI. For example, ST depression may be seen in leads V1 to V4 in an inferior STEMI. There are two explanations. First, in a right-​dominant system (70% of the population), the right cor- onary artery supplies the posterior interventricular septum, which becomes ischaemic with an inferior STEMI; the ischaemia resolves within a few days as septal perforating arteries from the left anterior descending artery dilate in response to ischaemic stress. Second, in a left-​dominant system, the circumflex supplies the posterior interventricular septum; if this occludes, a ‘true posterior infarc- tion’ follows. Difficulties in diagnosing STEMI ‘Stuttering’ infarction Symptoms of myocardial infarction are usually severe and of sudden onset. Occasionally, the onset of symptoms is not so clear cut and chest pain may resolve but recur at intervals over several hours. The time of arterial occlusion is at best a guess, but for prac- tical purposes is taken as the time that symptoms increase or are at their worst. Non​infarct causes of ST segment elevation Pericarditis may mimic the pain of myocardial infarction but is usu- ally relieved by sitting forward and is accompanied by a pericardial rub. The ST segments are elevated diffusely, do not fit the usual lead pattern for an inferior or anterior infarction, and, unlike the con- vexity of STEMI, are concave upwards (Fig. 16.3.1.19). Prinzmetal’s angina, caused by coronary artery spasm, can also mimic myocar- dial infarction. This usually occurs at rest, with marked ST eleva- tion during pain and a brisk response to glyceryl trinitrate. The ST segment can be elevated chronically in left ventricular aneurysm, left ventricular hypertrophy, LBBB, hypertrophic cardiomyopathy, acute cor pulmonale, hypothermia, and cocaine abuse. A normal variant is so-​called ‘high take-​off’ where serial ECGs show con- sistent ST elevation across most ECG leads; patients should be given a copy of the ECG to show to medical personnel to avoid unneces- sary investigations and treatment. Late presentation Patients who present to hospital outside the 12-​h time limit for reperfusion are sometimes diagnosed as ‘missed infarction’. The ECG may show signs characteristically seen later in the infarction process, with ST segments only slightly elevated, with established Q waves and inverted T waves. Over the next few days, the ST seg- ment fully returns to baseline and Q waves and T waves deepen. LBBB Recognition of acute STEMI in pre-​existing LBBB is challenging, but the Sgarbossa criteria help. Five points are scored for ST eleva- tion 1 mm or greater in at least one lead with a positive QRS com- plex, 3 points for ST depression 1 mm or greater in leads V1–​V3, and 2 points for 5 mm or greater ST elevation in leads with a negative QRS complex. A score of 3 points or greater has a 90% specificity (but a poor sensitivity) for acute myocardial infarction. ECG changes of ‘old’ infarction Q waves, once formed, usually persist indefinitely and so are a reli- able indicator of a previous myocardial infarction (Fig. 16.3.1.20). Fig. 16.3.1.19  Widespread elevation of the ST segments (concave upwards) in a case of pericarditis. 16.3.1  Electrocardiography 3309 However, there are several other causes of a Q wave that may cause confusion, the most common being hypertrophic cardiomyopathy and idiopathic cardiomyopathy. Rarer causes include myocarditis, cardiac amyloid, neuromuscular disorders (e.g. muscular dystrophy, myotonic dystrophy, Friedreich’s ataxia), scleroderma, sarcoidosis, and an anomalous coronary artery. Pre-​excitation WPW syndrome makes interpretation of the ECG more compli- cated. It may mask a myocardial infarction if conduction via the bypass tract is towards the left ventricle, as a Q wave will not be apparent. WPW may also simulate an infarction due to a negative δ-wave in the inferior leads producing Q waves. Serial or previous ECGs will reveal the true diagnosis. Patients with WPW syndrome should be given a copy of their ECG to avoid confusion and un- necessary future investigations. T-​wave inversion Atypical ECG features are seen in up to half of all infarctions in the early stages. Alone, these changes are not diagnostic. They can occur in ventricular aneurysm, electrolyte abnormalities, myocarditis, and subarachnoid haemorrhage, and with some drugs. Serial ECGs are necessary to establish a firm diagnosis. Deep, symmetrical ‘arrowhead’ T waves developing during an infarction are most often due to proximal occlusion of the left an- terior descending coronary artery (Fig. 16.3.1.21). Where errors occur Incorrect interpretation of an ECG leads to inappropriate patient triage and misses the opportunity to provide reperfusion therapy, whether by angioplasty or thrombolysis. In the worst-​case scenario, inappropriate thrombolysis might lead to a haemorrhagic stroke or ruptured aneurysm. Up to 12% of those with a high-​risk ECG (i.e. ST segment elevation of at least 0.1 mV, ST segment depression of at least 0.05 mV, or T-​wave inversion of at least 0.2 mV in two or more contiguous leads) are missed on admission to the emergency department. The ECG provides a ‘snapshot’ of electrical events within the heart, when the clinician really needs a ‘movie’ to monitor the dynamic changes of an acute coronary syndrome. If a diagnosis cannot be made on the presenting ECG but the history suggests an acute coronary syndrome, the patient should be admitted to a monitored area, a review by a specialist should be arranged, and the ECG should be repeated if symptoms get worse or if ST segment changes are seen on the monitor. This will ensure prompt and ap- propriate treatment. While it may be important to provide treatment promptly to fulfil audit targets (e.g. door-​to-​balloon time for primary PCI), speed should not replace accuracy in diagnosis. It is sometimes better to repeat the ECG than to make an incorrect diagnosis. It is easy to place too much reliance on minor changes on the ECG; it is clear changes of ST elevation or depression within the aforementioned parameters, that should determine treatment. Fig. 16.3.1.20  ‘Old’ inferior myocardial infarction: pathological Q waves in leads II, III, and aVF. Fig. 16.3.1.21  Recent anterior ST segment elevation myocardial infarction with ‘arrowhead’ T-​wave inversion. section 16  Cardiovascular disorders 3310 Exercise ECG testing ECG changes on exercise were first reported in patients with chronic stable angina in the early 1900s. Exercise testing was adopted into routine clinical practice soon after a standardized exercise protocol was developed. Cardiovascular responses to exercise in normal subjects and in coronary disease Normally on treadmill exercise, heart rate increases as a result of diminished vagal and increased sympathetic outflow. Heart rate in- creases on commencing exercise and reaches a plateau during each stage of the exercise test. A rapid increase may be due to lack of fit- ness, prolonged bed rest, anaemia, or dehydration. Systolic blood pressure increases in line with increased cardiac output, while dia- stolic pressure is near constant or falls slightly due to vasodilatation. On stopping the test, heart rate slows within a few minutes to pretest levels and both systolic and diastolic blood pressure falls, often to below pretest levels, as a result of vasodilatation. With cardiac disease, the maximum cardiac rate may be attenu- ated (even in the absence of a β-​blocker) due to sinus node dis- ease, coronary heart disease, or postinfarction (with or without β-​blockade). Failure to achieve the maximum predicted heart rate, calculated as 220 minus age, is suggestive of cardiac disease. Brady-​and tachyarrhythmias including atrial fibrillation may occur. Exercise-​induced hypotension, even a transient fall in blood pres- sure at (near-​)maximum heart rate, is indicative of severe heart dis- ease and increases the risk of ventricular fibrillation. On stopping exercise, systolic pressure falls to resting levels (or lower) within minutes, where it may remain for several hours. In some, venous pooling may cause a precipitous drop in systolic pressure. ECG changes with exercise in normal subjects and in coronary disease In normal subjects, exercise-​induced tachycardia causes short- ened PR, QRS, and QT intervals, increased P wave amplitude, and down-​sloping of the PR segment. R waves and T waves may di- minish, and S waves increase at maximum exercise. The J point (the isoelectric point where the S wave reaches the baseline) may become depressed in all leads and the ST segment may become up-​sloping. The most helpful ECG marker of exercise-​induced myocardial is- chaemia is the ST segment which becomes depressed with increasing heart rate. This is due to shortening of the action potential due to is- chaemia, setting up electrical gradients between endocardium and epicardium. Horizontal or down-​sloping ST depression, measured 60–​80 ms after the J point, of 1 mm (0.10 mV) or more for 80 ms in at least three complexes is considered significant (Fig. 16.3.1.22), but the leads in which ST depression appear do not reliably localize the site of myocardial ischaemia. Other indicators of myocardial ischaemia include: • ST segment elevation—​this indicates severe ischaemia due to proximal disease or coronary spasm, or an aneurysmal or dyskinetic left ventricle. Unlike exercise-​induced ST segment depression, the ECG site of ST segment elevation is relatively specific for the coronary artery involved. • T-​wave inversion—​this may occur with exercise-​induced hyperventilation. • Normalization of an inverted T wave—​this alone is not indicative of coronary disease. • U wave inversion—​this is relatively specific for coronary artery disease but is relatively insensitive; in precordial leads, it usually indicates left anterior descending coronary artery disease. Exercise protocols Various protocols have been developed but the most widely used are the following. Bruce protocol This is a multistage test with 3-​min walking periods during which a steady state is reached before the workload is increased by increasing the speed and slope of the treadmill. It is clearly only suitable for Fig. 16.3.1.22  ECG recorded during an exercise treadmill test, showing anterolateral ST segment depression after 3 min of exercise using the Bruce protocol. 16.3.1  Electrocardiography 3311 those whose walking is not limited by other considerations (e.g. musculoskeletal or neurological). For older patients or those with limited exercise capacity, the test can be modified to include two stages with lower workload demands. Bicycle ergometry This is often combined with radionuclide imaging (see Chapter 16.3.3), which increases the sensitivity and specificity of the test. Cycling avoids motion artefact, and so ECG recordings are clearer. The pa- tient pedals at a comfortable speed of between 60 and 80 revolutions/​ min; the test is terminated if speed cannot be maintained above 40 revolutions/​min. Exercise workload begins at 25 W and resistance is increased every 2 min in 25-​W increments by applying either an electronic or mechanical brake. The workload achieved during exercise is measured in metabolic equivalents or METs. This allows comparison of different protocols. A MET is 3.5 ml/​min per kg, the resting Vo2 for a 40-​year-​old 70 kg male. METs equivalent to normal daily activities have been esti- mated (Table 16.3.1.2). Conducting the exercise test Who should have an exercise test? Deciding who should and who should not undergo an exercise test requires clinical judgement and the test should not be organized as a routine. Exercise testing is used to: • assess functional capacity and estimate prognosis in the evalu- ation of chest pain; • assess patients with known coronary artery disease; • establish prognosis after myocardial infarction either predischarge (submaximal test) or 4–​6 weeks post-​discharge (symptom-​limited); • assess the effectiveness of coronary revascularization; • assess patients with symptoms of exercise-​induced cardiac arrhythmia; • risk-​stratify before non​cardiac surgery in patients with or at high risk of coronary disease; • determine the efficacy of rate-​responsive pacemakers. Exercise testing may also be indicated in selected asymptomatic individuals: • in specific occupations for licensing purposes (e.g. airline pilots, bus, or heavy goods vehicle drivers); • with more than two cardiovascular risk factors for risk stratification; • wishing to commence a strenuous exercise programme; • to assess cardiovascular risk due to prior to major surgery. Who should not have an exercise test? In its 2016 guideline on assessing chest pain of recent onset, the National Institute for Health and Care Excellence (NICE) recom- mended that exercise testing should no longer be used to diagnose or exclude stable angina in those without known coronary artery disease. Some conditions are considered to be absolute contraindi- cations to exercise testing but even in these patients a submaximal test may be informative. Exercise testing is inappropriate: • in healthy individuals with a low-​risk factor profile—​the false-​ positive rate is increased (see next); • with unstable medical conditions such as unstable angina; se- vere congestive cardiac failure; uncontrolled ventricular or supraventricular arrhythmia; myocarditis; severe pulmonary hypertension; drug toxicity; haemodynamic instability; symp- tomatic aortic stenosis; active thromboembolic disease; hyper- tension with systolic blood pressure more than 200 mm Hg or diastolic blood pressure more than 110 mm Hg; • in extreme obesity; • when taking specific medication—​digoxin depresses the ST seg- ment (Fig. 16.3.1.23); type 1 antiarrhythmics and tricyclic anti- depressants may be proarrhythmic; • in vasoregulatory disorders—​pulse and blood pressure changes are unpredictable. Patients with aortic stenosis may fail to report symptoms of an- gina, breathlessness, and syncope. Although severe symptomatic aortic stenosis is considered an absolute contraindication to exer- cise testing, a medically supervised symptom-​limited test in those who appear to be asymptomatic during their everyday activities may identify those who warrant cardiac catheterization and valve replacement. Who should supervise an exercise test—​cardiac technician, specialist nurse, or physician? Patients with new or recent-​onset chest pain thought to be angina are often referred to a rapid-​access chest pain clinic for assessment, where a specialist nurse carries out an initial assessment and then an exercise test. Experience shows that this approach is safe, provided a physician is available for consultation and advice. There are some high-​risk situations where the test, if it must be carried out, should Table 16.3.1.2  Table of MET equivalents Occupation METs Activity METs Receptionist 1–​2 Carrying a suitcase 7 Professional (active) 1.5–​2.5 Cleaning floor 4 Homemaker 1.5–​4 Washing clothes 5 Farm worker 3.5–​7.5 Cooking 3 Construction worker 4–​8.5 Gardening 4 Miner 4–​9 Push mower 5 Postal carrier 2.5–​5 Sex 5 Bed-​making 5–​6 Fig. 16.3.1.23  Depression of the ST segments caused by digoxin. section 16  Cardiovascular disorders 3312 be supervised by a physician. These include patients whose symp- toms are unstable, aortic stenosis, known severe coronary disease, severe or moderate systemic or pulmonary hypertension, severe left ventricular dysfunction, congestive or hypertrophic cardiomy- opathy, or a history of ventricular tachycardia, or second or third-​ degree atrioventricular block. Risks of exercise testing Exercise testing is generally considered a safe procedure but full resuscitation facilities, including defibrillator, emergency drug kit, airways management equipment, and oxygen are essential. Serious complications are rare. The risk of myocardial infarction and sudden death is less than 1 in 1000, more when testing pa- tients after myocardial infarction or with malignant ventricular arrhythmia. When to stop an exercise test Reasons for stopping a test include: • achieving 90% of the maximum predicted heart rate; • symptoms—​establish if these are typical symptoms of chest pain or breathlessness; exercise may continue provided that symptoms are not distressing or severe; • systolic blood pressure—​if systolic blood pressure falls below baseline levels or if systolic increases to greater 250 mm Hg or dia- stolic to greater than 115 mm Hg; • change in ECG—​if more than 2 mm ST segment depression or more than 1 mm ST segment elevation; or if LBBB (this may look remarkably like ventricular tachycardia at fast heart rate) or ar- rhythmia develops; • clinical signs—​if signs of poor peripheral perfusion such as cyan- osis appear; • symptoms of central nervous system dysfunction—​dizziness, near syncope, or ataxia; • serious arrhythmia—​ventricular tachycardia, multifocal ectopics, ventricular couplets; • technical difficulties—​failure of blood pressure recording or poor ECG trace; • patient request—​distressing symptoms of fatigue, breathlessness, wheeze, or claudication; maximal patient effort; or inability to maintain speed of treadmill. Recovery period It is important to observe the patient into the recovery period until the pretest heart rate and blood pressure have been restored. Minor ECG abnormalities early in recovery are common but late changes usually indicate myocardial ischaemia. Interpreting the results of an exercise test Like all medical tests, the exercise test is not a perfect indicator of the presence or absence of disease. Nevertheless, a test is often described as: • positive—​chest pain develops with or without ST displacement; blood pressure falls; arrhythmia occurs; the patient fails to com- plete the first two stages of the Bruce protocol or reach 90% of predicted maximum heart rate; • negative—​the patient completes uneventfully three stages of the Bruce protocol or reaches 90% of predicted maximum heart rate; • indeterminate—​90% predicted heart rate is not reached; symp- toms occur which are not typical of cardiac pain with a normal ECG throughout. A positive test does not necessarily mean that the patient has cor- onary disease, nor does a negative test mean the patient has some other, non​cardiac, cause for chest pain. The exercise test has limited use as a diagnostic test for coronary disease. Limitations and strengths of the exercise test The exercise test as a diagnostic tool The sensitivity of the exercise test, the proportion with coronary dis- ease correctly identified by the test, is 68% (range 23–​100) and spe- cificity, the proportion free of disease correctly identified by the test, is 77% (range 17–​100). In multivessel disease, these figures are 81% (range 40–​100) and 66% (range 17–​100), respectively. This means that exercise testing frequently yields false-​positive results, incorrectly diagnosing disease when coronary arteries are normal or minimally diseased; and false-​negative results, missing coronary disease when a flow-​limiting, even critical left main stem, coronary stenosis is present. Selection of patients for exercise testing is important as a false-​ positive result is more likely when an individual has few predisposing risk factors for coronary disease or the prevalence of coronary dis- ease prevalence in the population is low. Example 1 A positive test in a middle-​aged man with multiple coronary risk factors (smoking, dyslipidaemia, hypertension, diabetes mellitus, and family history) and typical chest pain on exertion (who is highly likely to have coronary disease) is most likely to be correct. Example 2 A positive test in a young woman with atypical chest pain and few or no cardiovascular risk factors is likely to be incorrect and may lead to other, more invasive tests including coronary angiography. The prevalence of coronary disease is lower in women than men and the specificity of exercise testing is lower in women, which means that the test is more likely to be positive in the absence of coronary disease, possibly due to increased catecholamine secretion during exercise contributing to coronary vasoconstriction. The exercise test as an indicator of prognosis Although the exercise test is of limited value as an aid to diagnosis, it is more reliable as a marker of prognosis. Generally, appearance of symptoms or ECG changes early in the test is associated with more severe and extensive coronary dis- ease and a poor prognosis (Table 16.3.1.3). Changes within the first 3 min usually indicate severe coronary disease affecting the left main stem or the proximal segments of at least one major cor- onary artery. Multivessel coronary disease is more likely with ST segment down-​sloping, delayed ST normalization after exercise, increased number of leads affected, and lower workload at which ECG changes appear. 16.3.1  Electrocardiography 3313 Difficulties with exercise testing Baseline ECGs that make interpretation of the exercise test difficult ECG patterns that may make exercise-​induced changes hard to recognize include: • ST depression or elevation at rest • Ventricular strain patterns—​left and right ventricular hypertrophy; • T wave changes—​inversion secondary to previous infarction or ‘strain’ • Conduction abnormalities—​LBBB affects ST segment and T wave; RBBB affects ST segment and T wave changes in V1, V2, and V3 • Prolonged QT interval Alternative tests that do not rely on the ECG to identify myo- cardial ischaemia are dobutamine stress echocardiography, radio- nuclide thallium, or myocardial perfusion imaging (MIBI) stress test, or cardiac MRI (see Chapters 16.3.2 and 16.3.3). Medication and exercise testing β-​Blockers and rate-​modifying calcium antagonists may mask myocardial ischaemia by limiting exercise-​induced tachycardia and so delay the appearance of ST depression. Blood pressure-​ lowering medication may blunt the normal exercise-​induced rise in pressure. Digoxin may induce or accentuate ST depression on the resting ECG. Medication may be continued if the indication for exercise testing is to assess the efficacy of treatment but should be temporarily stopped in all other circumstances. Specific rules apply if assessing for driving licensing purposes—​always check local rules, but gen- erally, antianginal drugs must be stopped at least 48 h prior to the assessment. ST segment depression in the absence of symptoms Asymptomatic, exercise-​induced ST segment depression, or ‘silent ischaemia’, is seen in 60% of patients with coronary disease but does not increase the risk of cardiac death compared with those who re- port angina. Technical issues Current ECG machines filter out motion and muscle artefact to facilitate measurement of the ST segment. Because leads placed on the limbs produce motion artefact, moving these to the torso exaggerates the degree of change and increases the amplitude of the R wave, potentiating exercise-​induced ST segment changes. It can be difficult to identify ST segment depression during exercise. If there is any doubt about the extent of ST segment depression on the running ECG, most automated machines will provide a filtered 12-​lead ECG for comparison with baseline. Exercise testing in special groups Peri-​and post-​myocardial infarction Exercise testing after myocardial infarction may be performed for risk stratification and selection for revascularization. A submaximal predischarge test to identify residual ischaemia appears to be safe, with 0.05% morbidity and 0.02% mortality. An abnormal blood pressure response or low exercise capacity predicts a poor outcome and is an indication for urgent revascularization. Evidence of myo- cardial ischaemia, especially at low workload, is an indication for referral for coronary angiography. Elderly patients Advanced age alone is not a contraindication to exercise testing, provided that the individual can walk at a reasonable speed. If mobility is limited, dobutamine stress echocardiography, radionuclide thallium, or MIBI stress test, or cardiac MRI are alternative means of identifying ischaemia (see Chapters  16.3.2 and 16.3.3). Asymptomatic individuals Testing may be undertaken in asymptomatic individuals, gener- ally a low-​risk population, as part of health screening, for insur- ance purposes, or for risk stratification. Up to 12% of middle-​aged men and up to 30% of women will have an abnormal exercise test in the absence of symptoms; the risk of a cardiac event is low unless the test result indicates a poor prognosis. The presence of cardiovascular risk factors increases the likelihood of coronary disease. Cardiac arrhythmia Exercise testing can be useful in evaluating cardiac arrhythmia, supplementary to ambulatory monitoring and electrophysiological studies. In about 10%, it may provoke an arrhythmia. Table 16.3.1.3  Prognostic indicators on treadmill testing Indicators of a good prognosis Indicators of a poor prognosis ST segment No displacement or up-​sloping 2 mm or more depression in stage 1 Bruce-​within 3 minutes Down-​sloping or horizontal Duration of exercise 9 minutes (>9 METs) Unable to complete stage 2 Bruce or equivalent (<6.5 METs) Heart rate at onset of limiting symptoms Reaches maximum predicted heart rate (220 –​ age) Unable to attain >120/​min off β-​blocker Systolic BP response Maintained or increased Sustained decrease >10 mm Hg or failure to rise with exercise Changes on exercise No changes Ventricular tachycardia U wave inversion T wave normalization Recovery Recovers normal heart rate <10 min Delayed recovery >10 min Symptoms None or atypical Test terminated due to increasing angina on exercise 16.4 Cardiac arrhythmias 3350 Matthew R. Ginks, D. 16.4 Cardiac arrhythmias 3350 Matthew R. Ginks, D.A. Lane, A.D. McGavigan, and Gregory Y.H. Lip ESSENTIALS The term cardiac arrhythmia (or dysrhythmia) is used to describe any abnormality of cardiac rhythm. The spectrum of cardiac arrhythmias ranges from innocent extrasystoles to immediately life-​threatening conditions such as asystole or ventricular fibrillation. The key to the successful diagnosis of cardiac arrhythmias is the systematic analysis of an ECG of optimal quality obtained during the arrhythmia. Continuous monitoring is necessary for identification when ar- rhythmias are intermittent. Ambulatory ECG recordings are of most value when they provide correlation between the patient’s symp- toms and the cardiac rhythm at that moment. Alternative strategies for the detection of infrequent arrhythmias include the use of a patient-​activated recorder, which is applied and activated during symptoms, or an external or implanted loop recorder. More detailed investigation of cardiac arrhythmias is under- taken by invasive cardiac electrophysiological testing. Multipolar electrodes are inserted transvenously to record electrograms from the atrium, ventricle, His bundle, and coronary sinus. Electrophysiological mapping is an essential part of radiofrequency ablation. Bradycardias Bradycardia is defined as a ventricular rate of less than 60 beats/​ min. The principal indications for active intervention in bradycardia are symptomatic (disturbances of consciousness, fatigue, lethargy, dyspnoea, or bradycardia-​induced tachyarrhythmias) or prognostic (prevention of sudden cardiac death). In the presence of haemodynamic compromise, immediate at- tempts to increase heart rate should be employed, using atropine, isoproterenol (isoprenaline), and/​or temporary cardiac pacing (transvenous or transcutaneous). Following stabilization, factors causing or contributing to the presentation should be sought and corrected—​especially acute ischaemia and infarction, concomitant drug therapy, hypothermia, or electrolyte disorders. Specific disorders causing bradycardia include: (1) sinoatrial dis- ease (‘sick sinus syndrome’); (2) neurocardiogenic syncope (e.g. ca- rotid sinus hypersensitivity); and (3) atrioventricular (AV) conduction disorders (‘heart block’). AV block—​the commonest cause of AV block is idiopathic fibrosis of the His–​Purkinje system, and the severity (degree) of block can be classified as (1) first-​degree—​defined as a PR interval greater than 0.2 s, which produces no symptoms and does not require treat- ment; (2) second-​degree—​when there is intermittent failure of con- duction from atrium to ventricle, either with a characteristic pattern of increasing PR interval duration preceding the non​conducted P-​wave (Mobitz type I, Wenckebach) or without (Mobitz type II). Pacemaker implantation is not necessary for Mobitz type I in most cases, but is usually required for Mobitz type II; (3) third-​degree (complete) AV block—​when there is complete dissociation between atrial and ventricular activity, which is an indication for permanent pacemaker implantation, except in the context of an acutely revers- ible condition. Tachycardias The principal mechanisms responsible for tachyarrhythmias are (1) abnormal automaticity; (2) triggered activity; or (3) re-​entry. Most clinically important sustained tachycardias appear to arise on the basis of re-​entry, which requires the presence of a potential circuit comprising two limbs with different refractoriness and conduction properties. The first and most important step in the diagnosis and manage- ment of tachycardias is to determine whether the arrhythmia arises within the atria and/​or AV junction, or from the ventricles, which can often be achieved by careful analysis of a 12-​lead ECG. Diagnosis—​it is safe to assume that virtually all narrow-​complex tachycardias have a supraventricular origin, but wide-​complex tachycardias (QRS duration ≥0.12 s) may arise either from the ven- tricle or from supraventricular mechanisms, and few areas in cardi- ology cause more difficulty—​or result in more mismanagement—​than the diagnosis of wide-​complex tachycardias. Careful scrutiny of the 12-​lead ECG may reveal diagnostic features, but the commonest reason for error is that the clinical context is not considered, or er- roneous conclusions are drawn from it: key issues to recognize are (1) elderly patients or those with a history of ischaemic heart dis- ease or heart failure are most likely to have ventricular arrhythmia; (2) the patient’s haemodynamic status is a poor predictor of the type of tachycardia; (3) ventricular tachycardia can present with a history of paroxysmal self-​terminating episodes. 16.4 Cardiac arrhythmias Matthew R. Ginks, D.A. Lane, A.D. McGavigan, and Gregory Y.H. Lip 16.4  Cardiac arrhythmias 3351 Treatment—​R-​wave synchronized, direct current (DC) cardio­ version under general anaesthesia or deep sedation is the most effective and immediate means of terminating sustained tachy­ cardias and should be employed when tachycardia is associated with haemodynamic compromise. In patients with tachycardia who are haemodynamically stable, manoeuvres that produce tran- sient vagal stimulation, such as the Valsalva manoeuvre or carotid sinus massage, may be employed. The response to intravenous ad- enosine, which will often terminate arrhythmias dependent on the AV node, may be of therapeutic or diagnostic value, and should be considered in all patients with tolerated regular tachycardia. In the long term, tachycardias can be treated with antiarrhythmic drugs (usefully categorized by the Vaughan Williams classification), implantable cardioverter–​defibrillators, radiofrequency catheter ablation, or arrhythmia surgery. In all cases an assessment of the underlying precipitating cause (i.e. ischaemic heart disease, elec- trolyte disturbance, structural heart disease, genetic predispos- ition, or drug therapy) is required before planning subsequent long-​term therapy. Atrial fibrillation Prevention of stroke—​this is the most important priority and requires individualized assessment of stroke risk using the CHA2DS2-​VASc score. Patients with one or more stroke risk factors should be con- sidered for oral anticoagulation. Formal assessment of a patient’s risk of bleeding with treatment should also be undertaken using the HAS-​BLED score. The SAMe-​TT2R2 scores can help inform treatment decisions between use of a vitamin K antagonist (VKA, e.g. warfarin) or a non-​VKA oral anticoagulant. Discussion and incorporation of patient preferences for treatment is advocated, and regular review of the treatment strategy over time is essential. Decisions on rhythm or rate control should be patient-​centred and symptom-​directed: a rate control strategy is non​inferior to a rhythm-​control strategy for long-​ term clinical outcomes. Rhythm or rate control management—​rhythm control is by cardioversion (electrical or pharmacological) or catheter abla- tion. Unless the patient has been therapeutically anticoagulated for several weeks, cardioversion should not be attempted without transoesophageal echocardiography unless the known dur- ation arrhythmia has been less than 48 h because of the risk of thromboembolism. If it is clinically appropriate to attempt chem- ical cardioversion, the drugs of choice are class  Ic agents (e.g. flecainide) for patients without significant underlying heart dis- ease; class III drugs (e.g. amiodarone) are safer in the presence of left ventricular dysfunction or ischaemic heart disease. For rate control, a β-​blocker or rate-​limiting (non​dihydropyridine) calcium channel blocker, sometimes in combination with digoxin, should be considered. Paroxysmal atrial fibrillation—​drug therapy may not be neces- sary for patients with infrequent paroxysms, or a ‘pill in the pocket’ approach can be used in those without structural heart disease, whereby they take a dose of an antiarrhythmic drug after the onset of arrhythmia. No drug is entirely satisfactory for recurrent parox- ysmal atrial fibrillation: although only modestly effective, a β-​blocker is often prescribed as first-​line therapy. Persistent atrial fibrillation—​usually requires electrical cardioversion to achieve sinus rhythm and has a high recurrence rate even after successful cardioversion. The key decision is whether to employ a rhythm or rate control strategy. In general, a rate control strategy (AV nodal blocking drug, e.g. β-​blocker, calcium channel blocker, or digoxin) should be considered in patients with few or minor symptoms, elderly patients, and those with contraindica- tions to antiarrhythmic therapy or cardioversion. A rhythm-​control strategy (elective cardioversion) may be best in more symptomatic or younger patients (especially in those with structurally normal hearts), or in those with recent-​onset atrial fibrillation due to a treated precipitant. If symptoms are clearly attributable to atrial fib- rillation and are refractory to antiarrhythmic drugs, then catheter ablation can be considered. Atrial flutter It is important to attempt to terminate atrial flutter since the ven- tricular rate is often poorly controlled by AV nodal blocking drugs: this may be achieved by electrical cardioversion (with pharmacological approaches being less effective), or by catheter ablation (which may be curative). Prophylaxis against thromboembolism should be given as for atrial fibrillation. Supraventricular tachycardias The term supraventricular tachycardia encompasses three types of arrhythmia:  AV nodal re-​entrant tachycardia (AVNRT), AV re-​ entry tachycardia, and atrial tachycardia (AT) in order of reducing frequency. Termination of an attack of AVNRT is achieved by producing transient AV nodal block by vagotonic manoeuvres, adenosine, or verapamil. Drug prophylaxis is undertaken with β-​blockers, a com- bined β-​blocker/​class  III agent such as sotalol, or with AV nodal blocking drugs such as verapamil or digoxin. Curative treatment is by radiofrequency ablation. Attacks of AV re-​entry tachycardia are treated in the same way as AVNRT. Antiarrhythmic prophylaxis may be effective, but radiofrequency ablation offers high success rates with low incidence of complications and should be considered early. Pre-​excitation syndromes The term ‘pre-​excitation’ (e.g. seen as a δ-wave on the ECG) refers to the premature activation of the ventricle via one or more accessory pathways that bypass the normal AV node and His–​Purkinje system. When seen in conjunction with palpitations this is Wolff-​Parkinson–​ White syndrome. The main prognostic concern is pre-​excited atrial fibrillation, which can be very rapid and degenerate into ventricular fibrillation. Patients with pre-​excitation should be offered a car- diac electrophysiological study as first-​line therapy, with a view to radiofrequency ablation. Ventricular tachycardia Ventricular tachycardia (VT) normally occurs in individuals with overt heart disease but is also seen in young and apparently healthy subjects, when occult cardiac disease or cardiac genetic syndromes should be considered. Sustained VT is a medical emergency. Immediate DC cardioversion is necessary if the patient is hypotensive; haemodynamically tol- erated VT may be terminated pharmacologically, with intravenous β-​blocker or amiodarone being the usual first-​choice options. Unless there is a clear precipitating factor, the risk of sudden death section 16  Cardiovascular disorders 3352 is high, and patients should be considered for an implantable cardioverter–​defibrillator. Polymorphic VT, of which torsades de pointes is a well-​recognized type associated with acquired or congenital prolongation of the QT interval, is an unstable rhythm with varying QRS morphology that undergoes spontaneous termination or degenerates into ventricular fibrillation. In patients with this condition, it is essential to discon- tinue predisposing drugs or other agents and to avoid empirical antiarrhythmic drug therapy. Intravenous magnesium sulphate is a safe and effective emergency measure. Intravenous isoprenaline or temporary pacing may also be required. Ventricular fibrillation The management of cardiac arrest due to ventricular fibrillation is discussed in this chapter. Patients who survive an episode should be assessed carefully to determine the risk of recurrence and may require an implantable cardioverter–​defibrillator or antiarrhythmic therapy as for patients with ventricular tachycardia. Genetic syndromes These are inheritable causes of cardiac arrhythmia and can be divided into ion channel diseases (‘channelopathies’) and heart muscle diseases. Ion channel diseases include the congenital long-​QT syndromes, short-​QT syndrome, Brugada syndrome, and catecholaminergic polymorphic VT. Heart muscle diseases include hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. General principles Definition The term cardiac arrhythmia (or dysrhythmia) is used to describe an abnormality of cardiac rhythm of any type. Normal cardiac electro- physiology is discussed in Chapter 16.3.1. The spectrum of cardiac arrhythmias ranges from innocent extrasystoles to immediately life-​ threatening conditions such as asystole or ventricular fibrillation. Arrhythmias may occur in the absence of cardiac disease but are more commonly associated with structural heart disease or external provocative factors. Symptoms of cardiac arrhythmias The symptoms produced by bradyarrhythmias depend on the ex- tent of cardiac slowing. They may include sudden death, syncope (Stokes–​Adams attacks), or dizziness/​presyncope. Continuous bradycardia without asystolic pauses may produce symptoms of fa- tigue, lethargy, dyspnoea, or cognitive impairment. The symptoms caused by tachyarrhythmias depend on a variety of factors including the heart rate, the difference between the rate during the arrhythmia and the preceding heart rate, the degree of ir- regularity of the rhythm, and the presence or absence of underlying cardiac disease. Symptoms of tachycardia include a feeling of rapid palpitation, chest discomfort or dyspnoea, syncope, or sudden death. The differential diagnosis of palpitation and syncope is dis- cussed in Chapter 16.2.2. Investigation of arrhythmias History-​taking must include a detailed description of the symp- toms associated with the arrhythmia. Evidence should be sought for factors that may precipitate the arrhythmia (e.g. exercise, al- cohol, or drug therapy) and for the presence of underlying car- diac disease, in particular valvular heart disease, myocardial ischaemia/​infarction, or congestive heart failure. Examination of the pulse may be unremarkable if the arrhythmia is intermittent. Physical examination for evidence of structural heart disease is essential. A 12-​lead ECG should be performed both during the arrhythmia and once it has resolved (if possible, when the patient presents acutely). A full blood count (in cases of sinus tachycardia), thyroid func- tion (sinus tachycardia and atrial arrhythmias), and electrolyte testing (potassium for both atrial and ventricular arrhythmias and calcium and magnesium for sustained ventricular arrhythmias) are routinely performed. Although troponin is often measured routinely in the patients presenting to the emergency department, a minor rise in troponin should not be regarded as diagnostic of an acute coronary syndrome as the precipitating cause. Further investigations to establish the presence of structural heart disease and to determine ventricular function may include chest radiog- raphy, echocardiography, exercise stress testing, coronary angiog- raphy, or MRI. Electrocardiography The key to the successful diagnosis of cardiac arrhythmias is the systematic analysis of ECG (see Chapter 16.3.1) of optimal quality obtained during the arrhythmia (Table 16.4.1). Ideally, this should be a 12-​lead ECG and may be compared to the ECG in intrinsic rhythm. Ambulatory electrocardiography Continuous monitoring is necessary for identification when arrhyth- mias are intermittent. Ambulatory (Holter) ECG is normally per- formed for periods of 24–​48 h using a portable recorder. High-​speed Table 16.4.1  Principles of ECG diagnosis of arrhythmias Obtain 12-​lead or multichannel recordings if possible Atrial activity P-​waves visible? Normal P-​wave morphology and axis? Flutter/​fibrillation waves? Atrial rate? Ventricular activity Ventricular rate? Regular or irregular? Normal QRS morphology and duration? Bundle branch block or bizarre QRS morphology? Variation in QRS morphology/​axis? Atrioventricular relationship PR interval—​fixed or varied? Retrograde P-​waves? Atrial versus ventricular rate? 16.4  Cardiac arrhythmias 3353 or automatic replay facilities enable the identification of intermit- tent arrhythmias, as well as the quantification of extrasystoles and assessment of parameters of heart rate variability. Interpretation of recordings requires knowledge of possible artefacts, such as those caused by movement or loss of electrode contact. It is important to allow for physiological variability in the sinus rate, also appreciating that minor abnormalities such as extrasystoles or brief (3–​4 beat) runs of supraventricular arrhythmias are usually of no significance. Ambulatory ECG recordings are of most value when they provide correlation between the patient’s symptoms and the cardiac rhythm at that moment. Patients should be issued with a diary card and asked to note any symptoms suggestive of arrhythmia during the recording. Alternative strategies for the detection of infrequent arrhythmias include the use of a patient-​activated recorder, which is applied and activated during symptoms, or an external or implanted loop re- corder. Loop recorders continually record the ECG signal, but only have sufficient memory to retain a few minutes of data. In the event of symptoms, the patient activates the device, thus ‘fixing’ the pre- vious few minutes of recording for subsequent analysis. External loop recorders are usually used for up to 7 days, while an implanted event recorder can last for up to 3 years. Cardiac electrophysiological study More detailed investigation of cardiac arrhythmias is under- taken by invasive cardiac electrophysiological testing. Multipolar electrodes are inserted transvenously to record electrograms from the atrium, ventricle, His bundle, and commonly from the coronary sinus (Fig. 16.4.1). The site of conduction delays within the heart may be identified, or accessory pathways lo- calized. Sustained arrhythmias may be initiated and their pat- tern of activation in the heart studied in detail; if necessary, the mechanism of the arrhythmia can be clarified using pacing manoeuvres (Fig. 16.4.2). Electrophysiological mapping is an es- sential part of radiofrequency ablation (see next), and modern three-​dimensional mapping systems have facilitated ablation of complex arrhythmias. Bradycardias Aetiology and mechanisms Bradycardia is defined as a ventricular rate of less than 60/​min, and results from a reduction in the rate of normal sinus pace- maker activity, or from disturbances of atrioventricular (AV) conduction. Sinus bradycardia may be physiological, for example, during sleep and in athletes. Pathological bradyarrhythmias can result from intrinsic degenerative disease of the sinus or AV node, or the conducting system. Bradycardia may also be due to extraneous factors such as sympathetic withdrawal, vagal stimu- lation, drug effects, myocardial ischaemia/​infarction, infiltra- tion, or surgical trauma, and also miscellaneous conditions such as hypothyroidism, hypothermia, jaundice, or raised intracranial pressure. General principles of management The principal indications for active intervention in bradycardia are symptomatic (disturbances of consciousness, fatigue, leth- argy, dyspnoea, or bradycardia-​induced tachyarrhythmias) or prognostic (prevention of sudden cardiac death). Particular at- tention should be given to the history and ECG documentation of the rhythm disturbance. Drugs interfering with sinoatrial or AV nodal function should be withdrawn if possible, although under certain circumstances (e.g. tachycardia–​bradycardia syndrome) it may be necessary to combine pacemaker implantation with con- tinued drug therapy. Acute management of bradycardia General principles can be applied to patients presenting with overt bradycardia, regardless of aetiology (Table 16.4.2). In the pres- ence of haemodynamic compromise, immediate attempts should be made to increase heart rate. Transient increases in sinus rate or the ventricular escape rate in complete AV block may be achieved with atropine or isoproterenol (isoprenaline). However, drug treat- ment is only of temporary value, and temporary or permanent car- diac pacing is indicated for persistent bradycardia (see ‘Pacemaker therapy’, later on). Temporary pacing is also indicated where ECG Right atrium His Right ventricle A H V 100 ms LV LA RA RV Fig. 16.4.1  Electrophysiological study. Illustration of lead placement (left). Quadripolar leads have been inserted from the femoral vein and the tips are shown positioned to allow recording and pacing from the high right atrium, His bundle, and the right ventricular apex. Intracardiac electrograms (right) show recordings from atrium (A), His bundle (H), and right ventricle (V). 1 s S1 S1 S2 S3 RV V1 aVF I Fig. 16.4.2  Induction of ventricular tachycardia by programmed stimulation. Ventricular pacing stimuli (S1) at 100 beats/​min are followed by two extrastimuli (S2 and S3). Sustained monomorphic ventricular tachycardia is induced. Surface leads I, aVF, V1, and the intracardiac electrogram from right ventricular apex (RV) are shown. section 16  Cardiovascular disorders 3354 frequent Stokes–​Adams attacks are occurring. Pacing can be per- formed transcutaneously using an external pacing system in the emergency situation if facilities for transvenous pacing are not im- mediately available. Following stabilization, factors causing or contributing to the presentation should be sought and corrected, especially acute ischaemia and infarction, concomitant drug therapy, or electro- lyte disorders. Analysis of the ECG will allow identification of the conduction disorder and plans for long-​term management can be instituted. Specific causes of bradycardia Sinoatrial disease Sinoatrial disease, often referred to as ‘sick sinus syndrome’, re- sults in inappropriate sinus bradycardia, sinus pauses, or junctional rhythm (Fig. 16.4.3) in the absence of extrinsic factors. The condi- tion is most commonly caused by idiopathic degeneration of the sinus nodal cells, particularly in older people, and is associated in about 20% of cases with idiopathic bundle branch fibrosis (see ‘Aetiology of atrioventricular block’). Occasionally, sinoatrial dis- ease is caused by ischaemia due to obstruction of the right coronary artery. Conduction block may occur between the sinus node and the atrium (sinoatrial exit block), resulting in ‘dropped’ P-​waves (Fig. 16.4.4). More prolonged suppression of sinus node activity results in periods of sinus arrest, which are terminated by an es- cape beat from the sinus node, AV node, or ventricle (Fig. 16.4.5a). Where the sinus rate is permanently slower than the junctional rate, continuous AV junctional rhythm will be present. Patients with sinoatrial disease have an increased predisposition to atrial tachyarrhythmias (tachycardia–​bradycardia syndrome), and pro- longed pauses may follow termination of tachycardia (Fig. 16.4.5b). Sinoatrial disease can cause symptomatic bradycardia, dizziness, or syncope, but may be asymptomatic. The diagnosis is normally made from 12-​lead or ambulatory ECG recording. Investigation should focus on excluding extrinsic causes of bradycardia, and on demonstrating the correlation between bradycardia or pauses and symptoms. Pacemaker implantation is indicated for the relief of symptoms (see next). Prognosis is not improved by pacemaker im- plantation in sinus nodal disease and thus pacemaker implantation in asymptomatic patients is not indicated. Neurocardiogenic syncope Conditions where patients suffer reflex-​induced attacks of brady- cardia or hypotension are described in Chapter 16.2.2. Patients with carotid sinus hypersensitivity and reproducible symptoms of presyncope or syncope on carotid sinus massage should undergo permanent pacemaker implantation (see ‘Permanent pace- maker therapy’). In patients with recurrent vasovagal syncope, it is recommended to maintain good hydration and salt intake. Isometric exercises may be helpful. Medical therapy with agents as diverse as α-​agonists, β-​blockers, vagolytic agents (disopyramide, hyoscine), ephedrine, mineralocorticoids, or antidepressants is often tried, but the evi- dence base for the efficacy of drug therapy is weak. Spontaneous resolution of symptoms occurs in many patients. There is little evi- dence to support pacemaker implantation even in those with pre- dominant bradycardia as the response to tilt testing, but it may be considered in selected individuals with intractable symptoms. Atrioventricular conduction disorders Impairment of AV conduction may occur either within the AV node (intranodal) or within the His–​Purkinje system (infranodal). Intranodal block is not associated with QRS abnormalities, while distal (infranodal) block is commonly associated with bundle branch block. Bundle branch block (particularly left bundle branch block) is a common finding in elderly patients with a history of fa- tigue, dizziness, and syncope. Although both left and right bundle branch block are associated with an increased risk of developing complete AV block, bundle branch block as an isolated finding is not sufficient evidence to attribute symptoms to conduction disease; fewer than one-​half of patients with bundle branch block and syn- cope have a final diagnosis of cardiac syncope. There are two ex- ceptions. Alternating left and right bundle branch block (although rare in the absence of higher-​grade AV block) is an indication for pacemaker insertion in the absence of documented symptomatic 2:1 Table 16.4.2  General principles of acute management of the patient with bradycardia Assess the patient Respiratory status Blood pressure Symptoms Examine the ECG Sinus rate Ventricular rate AV relationship QRS morphology and duration If haemodynamic compromise Atropine Isoproterenol Temporary pacing Look for precipitants Ischaemia/​infarction Vasovagal episode Thyroid status Electrolyte imbalance Hypothermia Drug therapy Fig. 16.4.3  Sinus bradycardia. The heart rate is less than 40 beats/​min, and the sinus rate is so slow that an escape junctional beat is seen (open circle), preceding the P-​wave. 16.4  Cardiac arrhythmias 3355 or third-​degree AV block. Trifascicular block (a triad of first-​degree heart block, left-​axis deviation, and right bundle branch block) may be considered sufficient evidence for symptomatic conduction dis- ease requiring pacing where no other cause for symptoms has been identified. However, further evidence of more advanced conduction disease with prolonged ECG monitoring is usually sought. Aetiology of atrioventricular block The causes of AV block are shown in Box 16.4.1. The commonest is idiopathic fibrosis of the His–​Purkinje system, which occurs with increasing frequency from the seventh decade of life onwards, is as- sociated with sinoatrial disease in up to 25% of cases, and results in progressive impairment of AV conduction. Atrioventricular block may occur acutely in myocardial infarction (Fig. 16.4.6). Inferior myocardial infarction predominantly affects AV nodal conduction by vagal overactivity, and possibly adenosine release from ischaemic myocardium. First-​degree, second-​degree, or third-​degree AV block may occur, but are commonly transient, particularly with the advent of primary percutaneous coronary intervention. Spontaneous recovery of normal conduction gener- ally occurs within 7–​10 days. By contrast, AV block secondary to anterior myocardial infarction is normally due to extensive infarc- tion of the interventricular septum involving both the left and right bundle branches. This may result in type II second-​degree block or complete AV block, with a low probability of recovery of normal conduction. Any drug-​slowing AV conduction may potentially produce AV block. The risk is greater when such drugs are used in com- bination. Intravenous verapamil in patients already receiving β-​adrenoceptor blockers is particularly hazardous. Vagally me- diated conduction disturbances occur as a physiological finding in highly trained athletes, and in young people during sleep, or in neurocardiogenic syncope. Atrioventricular conduction dis- turbances arise in structural congenital heart disease such as endocardial cushion defects, but also as an isolated congenital ab- normality, commonly in association with maternal systemic lupus erythematosus. First-​degree atrioventricular block First-​degree AV block is defined as a PR interval greater than 0.20 s (Fig. 16.4.7). This produces no symptoms and does not require treatment, although the risk of progression to higher-​degree AV block should be considered. Second-​degree atrioventricular block In second-​degree AV block, there is intermittent failure of conduc- tion from atrium to ventricle. In type I (Wenckebach) second-​degree block, a characteristic pattern of increasing PR interval duration followed by a non​conducted P-​wave is seen (Fig. 16.4.8). The QRS morphology is commonly normal. Type I (Wenckebach) second-​ degree AV block usually indicates block in the AV node, and is nor- mally associated with a reliable subsidiary pacemaker and a low risk of progression to complete heart block. In most instances pacemaker implantation is not necessary unless recurrent presyncope or syn- cope suggest the occurrence of an intermittent higher-​degree block. By contrast, in type II second-​degree AV block (commonly called Mobitz type II AV block) there is a sudden failure of conduction, without a preceding increase in the PR interval (Fig. 16.4.9). Regular non​conducted P-​waves may result in high-​degree block, with 2:1 or 3:1 conduction. Type II second-​degree AV block is generally indi- cative of extensive infranodal conduction abnormality, with a high risk of progression to complete AV block. Guidelines therefore (a) (b) Fig. 16.4.5  Sinus arrest. (a) A pause of 4 s results from failure of the sinus node to discharge. (b) Termination of atrial fibrillation is followed by a sinus pause of 2.5 s due to sinus arrest in a patient with bradycardia/​tachycardia syndrome. Fig. 16.4.4  Sinoatrial exit block. A pause occurred because of the absence of a P-​wave (open arrow). The timing of the sinus beats, however, is not interrupted, indicating that the sinus node discharged but the impulse failed to excite the atria. section 16  Cardiovascular disorders 3356 recommend permanent pacemaker implantation even in the ab- sence of symptoms. Third-​degree atrioventricular block The characteristic feature of third-​degree (complete) AV block is dissociation between atrial and ventricular activity (Figs. 16.4.6 and 16.4.10). The ventricular rate is regular and slower than the atrial rate. An escape rhythm arising above the bifurcation of the bundle of His will produce a narrow-​QRS morphology, commonly with a relatively stable escape rhythm (50–​60/​min). A more distal escape rhythm results in widened bundle branch block morphology complexes with a slower escape rate (20–​30/​min). Complete AV block in patients with atrial fibrillation is often missed. It is recog- nized by the presence of a slow, regular ventricular response. High-​ degree AV block can be intermittent, and the resting ECG may be normal or only show evidence of mild conducting system disturb- ance such as first-​degree AV block or bundle branch block. If there is clinical suspicion, ambulatory ECG recording is required, for pro- longed periods if necessary. The presence of complete AV block, except in the context of an acutely reversible condition, should be regarded as an indication for permanent pacemaker implantation. This is urgent in patients who are having Stokes–​Adams attacks; their prognosis is poor without pacemaker implantation, and markedly improved by permanent pacing, after which outcome will depend on the presence and extent of any underlying cardiac disease. Permanent pacing also improves prognosis in asymptomatic patients with complete AV block. One exception to this general rule is congenital complete heart block, where the escape rhythm is often relatively fast (50–​60/​min) with a narrow-​QRS morphology. Many patients remain asymptomatic well into adult life, although there is a small risk of syncope or sudden death. Pacemaker implantation should be considered if there are symptoms, if there are abrupt pauses, if the average heart rate is below 50/​min, or in patients over 40 years of age. Asystole The term asystole is used when the ECG shows a complete cessation of both atrial and ventricular activity. This appearance may be mim- icked by disconnected ECG cables or other artefacts, but since asys- tole causes cardiac arrest the distinction is virtually always obvious. Ventricular standstill occurs when there in ongoing ‘P’ wave activity without QRS complexes. Pacemaker therapy Basic principles The basis of pacemaker therapy is the local depolarization of the myocardium by an electric current passed through an electrode in contact with the heart (atrium or ventricle). Activation of the re- mainder of the atria or ventricles occurs by direct cell-​to-​cell conduc- tion. The minimum current necessary to stimulate the heart during diastole is known as the pacing threshold. Pacemaker systems con- sist of one or more intracardiac catheter electrodes, introduced into the heart via the venous system, and a pulse generator, which con- tains the circuitry for generating and timing the pacing stimulus, as well as for sensing spontaneous cardiac depolarizations. The pacing stimulus is delivered between the active pole at the tip of the elec- trode catheter and an indifferent electrode sited either on the same Box 16.4.1  Causes of atrioventricular block • Idiopathic conducting system fibrosis • Acute myocardial ischaemia/​infarction • Infiltration—​calcific aortic stenosis, sarcoidosis, scleroderma, syphilis, tumour • Infection—​diphtheria, rheumatic fever, endocarditis, Lyme disease • Drugs—​digoxin, verapamil or diltiazem, β-​blockers, antiarrhythmic drugs • Surgical trauma, radiofrequency ablation • Congenital heart block, congenital heart disease • Vagal—​athletic heart, carotid sinus, and vasovagal syndrome • Myotonic dystrophy Fig. 16.4.6  Complete heart block in a patient with acute myocardial infarction. There is a narrow-​QRS complex escape rhythm with ST-​ segment elevation, ventricular rate 45 beats/​min. Fig. 16.4.7  First-​degree heart block. The PR interval is prolonged (0.32 s). Fig. 16.4.8  Second-​degree heart block, type I (Wenckebach). The PR interval progressively prolongs until there is a failure of conduction following a P-​wave (arrow). Fig. 16.4.9  Second-​degree heart block, type II. A non​conducted P-​wave occurs without preceding prolongation of the PR interval. 16.4  Cardiac arrhythmias 3357 catheter 1–​2 cm proximal to the tip (bipolar pacing), or utilizing the can of an implanted pulse generator (unipolar pacing). Satisfactory pacing requires stable electrode contact with the myocardium. The standard sites for endocardial atrial and ventricular pacing are the right atrial appendage and the right ventricular apex, respectively (Fig. 16.4.11), although screw-​in active fixation leads allow place- ment at other atrial and ventricular sites. An external pulse generator is used for temporary pacing. For permanent pacing, it is usually implanted deep to the subcutaneous fat layer in the prepectoral region (Fig. 16.4.11). The generator con- tains a timer set to deliver pacing stimuli at a preset pulse interval (e.g. 1000 ms). Pacemakers normally operate in the demand mode, whereby if spontaneous activation of the cardiac chamber is sensed via the electrode, the delivery of a pacing stimulus is inhibited and the timer circuit of the generator is reset. Pacing in the fixed-​rate mode results in the delivery of stimuli regardless of the spontaneous activity of the chamber being paced. Temporary ventricular pacing Temporary pacing is indicated in patients with bradycardia causing haemodynamic compromise, or as a prelude to permanent pacemaker implantation in those with significant recurring symp- toms, or in high-​grade AV block (i.e. Mobitz II or complete heart block). It is recommended that in those patients with an indica- tion for a permanent system this should arranged urgently where possible to avoid the complications associated with temporary pace- maker insertion. In patients undergoing anaesthesia for non​cardiac surgery, the standard indications for pacing apply. Facilities for radiographic screening, continuous ECG moni- toring, and defibrillation are required. The pacing electrode is intro- duced under aseptic conditions via an intravascular sheath into the subclavian, internal jugular, or femoral vein and the tip advanced under radiographic guidance to the right ventricular apex. Non-​ sustained ventricular tachycardia, or occasionally ventricular fibril- lation, may occur during catheter manipulation. Once the electrode is at an acceptable site, pacing is initiated, and the minimum output necessary to achieve stable ventricular capture is determined. The pacing threshold should ideally be less than 1 V, at a pulse width of between 0.5 and 2 ms. If the pacing threshold is unsatisfactory, the electrode is repositioned until an acceptable site is found. Care should be taken to determine that the electrode is stable by asking the patient to take deep breaths or to cough while pacing at threshold. The electrode is then secured at the site of insertion and the pulse generator set to an output of at least 3 V above the pacing threshold. Permanent pacemaker therapy Indications for permanent pacing therapy are given in Table 16.4.3. Two scenarios are quite common and can cause confusion. Elderly patients presenting with symptomatic AV block (particularly in the context of permanent atrial fibrillation) or sinus node disease are fre- quently on rate-​slowing drugs. It is usual to withdraw these agents be- fore assessing the need for pacing therapy. This is particularly common where multiple agents (e.g. digoxin and β-​blockade) have been used. However, if patients have been on these agents for many years then the presentation with symptomatic bradycardia should be taken as an indication of progressive conduction disease and increasingly long-​ term pacing is required, particularly where these agents are required for control of tachyarrhythmias. The second scenario is the patient with evidence of conduction disease presenting with syncope where a class I indication is not met but there is a high index of suspicion and no other cause has been identified. These are patients with sinus node disease manifesting as pauses (>3 s) on a prolonged monitoring or advanced conduction disease (trifascicular block) on a 12-​lead ECG. It should be remembered that there is no prognostic benefit in per- manent pacing in patients with either of these conditions. Ideally an attempt should be made to correlate pauses with symptoms or iden- tify a more extensive conduction disease with prolonged monitoring. Nocturnal pauses are common in this population and are not an in- dication for pacing unless they are very prolonged, associated with Fig. 16.4.10  Third-​degree (complete) heart block. Atrial activity does not conduct to the ventricles, and there is a regular escape rhythm of 35 beats/​min. Fig. 16.4.11  Dual-​chamber permanent pacemaker. Chest radiograph showing the pacemaker generator (in a subcutaneous pocket in the pectoral region), which is connected to electrodes that pass via the left subclavian vein and superior vena cava to the heart. The tips of the electrodes are in the right atrial appendage and the right ventricular apex. section 16  Cardiovascular disorders 3358 symptoms, or the history is strongly suggestive of an arrhythmic cause for syncope (other causes having been excluded). Patients with sinus node disease have an increased susceptibility to neurally mediated bradycardia and hypotension, which may explain why some of these patients continue to have symptoms after pacemaker insertion. Pacing is not indicated in patients with unexplained falls; how- ever, there may be an argument for pacing in the context of conduc- tion disease and a classic history in selected cases, in an attempt to prevent further events. Permanent pacing electrodes are normally inserted via the left or right cephalic, axillary, or subclavian vein. Once the electrode is in a satisfactory position, it is secured and connected to the implanted pulse generator. Most pulse generators are powered by lithium batteries and have a life of approximately 8–​10 years, after which the generator is replaced. The rate, output voltage, pulse width, and other pacemaker parameters can be modified non​invasively using telemetry via a trans- mitter/​receiver placed on the skin over the pulse generator. The ampli- tude and pulse width of the pacing stimulus are usually set at nominal values (e.g. 3.5 V, 0.5 ms), but are adjustable and can be reduced to pro- long the life of the battery, provided there is a sufficient safety margin between the pulse generator output and the pacing threshold. Pacing mode selection The nomenclature used to describe pacing mode is given in Table 16.4.4, and ECG examples of the principal pacing modes are shown in Fig. 16.4.12. Atrial demand (AAI) pacing is used for sino- atrial disease in the absence of AV block. Ventricular pacing (VVI) is the simplest and technically easiest mode of pacing, and is required Table 16.4.3  Indications for permanent pacing therapy Indications for pacing Conducting tissue disease Details Class of indication Level of evidence In patients with persistent bradycardia Sinus node disease Pacing is indicated when symptoms can clearly be attributed to bradycardia I B Acquired AV block Pacing is indicated in patients with third-​or second-​degree type 2 AV block irrespective of symptoms I C Acquired AV block Pacing should be considered in patients with second-​degree type 1 AV block which causes symptoms or is found to be located at intra-​ or infra-​His levels at EPS IIa C In patients with intermittent (documented) bradycardia Sinus node disease (including brady-​tachy form) Pacing is indicated in patients affected by sinus node disease who have documentation of symptomatic bradycardia due to sinus arrest or sinus-​atrial block I B Intermittent/​paroxysmal AV block (including AF with slow ventricular conduction) Pacing is indicated in patients with intermittent/​paroxysmal intrinsic third-​or second-​degree AV block I C Reflex asystolic syncope Pacing should be considered in patients ≫40 years with recurrent, unpredictable reflex syncope and documented symptomatic pause/​s due to sinus arrest or AV block or the combination of the two IIa B Asymptomatic pauses (sinus arrest or AV block) Pacing should be considered in patients with a history of syncope and documentation of asymptomatic pauses >6 s due to sinus arrest, sinus-​atrial block, or AV block IIa C In patients with BBB BBB, unexplained syncope, and abnormal EPS Pacing is indicated in patients with syncope, BBB and positive EPS defined as HV interval of >70 ms, or second-​or third-​ degree His–​Purkinje block demonstrated during incremental atrial pacing or with pharmacological challenge I B Alternating BBB Pacing is indicated in patients with alternating BBB with or without symptoms I C In patients with undocumented reflex syncope Carotid sinus syncope Pacing is indicated in patients with dominant cardioinhibitory carotid sinus syndrome and recurrent unpredictable syncope I B AF, atrial fibrillation; AV, atrioventricular; BBB, bundle branch block; EPS, electrophysiology study. Table 16.4.4  Pacemaker mode nomenclature Chamber paced Chamber sensed Mode Additional features A Atrium A Atrium I Inhibited R Rate responsive V Ventricle V Ventricle T Triggered D Dual (A and V) D Dual (A and V) D Dual (I and T) O Neither O Fixed rate See text for examples. 16.4  Cardiac arrhythmias 3359 for AV conduction disturbances. However, VVI pacing does not permit AV synchrony or an increase in pacing rate in response to an increase in sinus (atrial) rate. Dual-​chamber (DDD) pacemakers have electrodes in both the right atrium and ventricle. If the sinus cycle length is greater than the pulse interval, atrial demand pacing occurs. Following the atrial stimulus, a programmable AV delay commences. If no spontaneous ventricular depolarization is sensed before the end of this interval, a pacing stimulus is delivered via the ventricular electrode. If the sinus cycle length is shorter than the pulse interval, no atrial stimulus is given, but the AV delay is trig- gered by the sensed atrial activity, followed by a paced ventricular beat, if a conducted ventricular activation does not occur. By this means, the ventricular rate tracks the atrial rate up to a program- mable maximum, allowing the heart to increase its rate in a physio- logical manner in response to metabolic demand. An alternative, and simpler, approach to achieve a rate response is the use of an ac- tivity sensor such as an accelerometer in the pulse generator. Such devices detect bodily movement and increase the pacing rate ac- cording to a programmable algorithm. Rate response can be utilized in either single-​or dual-​chamber pacemakers and is designated by the suffix ‘R’ (e.g. AAIR, VVIR, DDDR). The advantage of DDD pacing over VVI pacing lies in the maintenance of AV synchrony and rate responsiveness, but this is achieved at the expense of increased complexity, complications, and cost. DDD pacing reduces the risk of atrial fibrillation by virtue of pacing the atrium and avoiding retrograde atrial activation via the AV node and has a lower incidence of the pacemaker syndrome (see next). However, large-​scale randomized trials comparing DDD with VVI(R) pacing have failed to substantiate survival benefits from DDD pacing, at least during follow-​up periods of up to 3 years. Cardiac resynchronization pacing in patients with reduced ejec- tion fraction and an indication for permanent pacing is supported by evidence from several small randomized trials. The benefits have to be weighed against the added complexity of these devices and the complication rates. It should, however, be standard practice to perform an echocardiogram to assess left ventricular function in all patients undergoing permanent pacing, as up to 10% may have evi- dence of significant left ventricular dysfunction. Complications of pacemaker insertion Complications of temporary or permanent pacemaker implant- ation include those of central venous cannulation (e.g. bleeding, pneumothorax), perforation of the heart by the electrode tip leading to pericardial effusion and cardiac tamponade, and macroscopic or microscopic displacement of the electrode resulting in an increase in the pacing threshold or failure to capture. A chest radiograph should be taken after pacemaker insertion to exclude pneumothorax and to confirm that the electrode position is satisfactory. Permanent pacing may be complicated by the development of infection around the pulse generator, or by mechanical erosion of the generator through the skin. Once infection is established, or the skin is breached, it is almost never possible to eradicate infection with antibiotics: removal and replacement of the pacing system is required. The development of oedema and inflammation around the implanted electrode tip may result in a steady rise in the pacing threshold over the first few weeks, which can lead to an increase of the pacing threshold such that capture is lost (Fig.  16.4.13a), although the process is normally mild and self-​limiting. Lead dis- lodgement occurs in up to 4.2% of patients with a dual-​chamber and 1.4% with a single-​chamber system. Demand pacemakers require an adequate intracardiac signal to recognize activation of the chamber in question, to inhibit output. The pacing stimulus will not be suppressed (‘undersensing’) if the intracardiac signal is of insufficient amplitude, resulting in in- appropriate pacemaker firing (Fig. 16.4.13b). This phenomenon is commoner in atrial pacing, owing to the lower amplitude of atrial compared with ventricular electrograms. Conversely, detection of extraneous electrical activity (e.g. skeletal muscle activity) via the pacing electrode can result in inappropriate inhibition of the pace- maker output (oversensing; see Fig. 16.4.13c). Oversensing is com- moner with unipolar than bipolar pacing modes because of the inclusion of the pulse generator can in the electrical circuit, and its proximity to the pectoral muscles. For the same reason, unipolar pacemaker systems are more prone to the problem of local skeletal muscle stimulation. Damage to the conductor or insulation of the pacing electrode may occur due to trauma at the site of ligation or to compression between the clavicle and first rib. This may result in oversensing, skeletal muscle stimulation, or short-​circuiting leading to premature battery depletion. Patients receiving AAI pacemakers may subsequently develop AV block, resulting in a recurrence of syncope and requiring up- grade of the pacing system to a DDD unit. Some patients with VVI pacemakers, particularly those with sinoatrial rather than AV dis- ease, will manifest retrograde ventriculoatrial conduction during ventricular pacing. This sometimes causes symptoms of fatigue, dizziness, or hypotension (‘pacemaker syndrome’), which are asso- ciated with the presence of atrial cannon waves occurring as a result of simultaneous atrial and ventricular contraction. Upgrade of the system to a dual-​chamber unit is necessary if symptoms are trouble- some. Newer pacing systems allow DDD pacemakers to act as VVI DDD AAI Fig. 16.4.12  Permanent pacemaker modes. Ventricular demand pacing, VVI (upper) with broad-​complex ventricular complexes following the stimulus. Dissociated atrial activity can be seen. Atrial demand pacing, AAI (middle) with low amplitude bipolar pacing spike preceding the P-​ waves. Dual-​chamber pacemaker, DDD (lower) with paced ventricular complexes following each P-​wave (atrial tracking). section 16  Cardiovascular disorders 3360 single-​chamber atrial pacemakers, automatically switching to dual-​ chamber pacing should AV conduction fail, providing the benefits of atrial pacing with a lower risk of pacemaker syndrome. Follow-​up Many patients with long-​standing heart block treated by permanent pacing have no underlying cardiac rhythm, hence failure of the pacing system for whatever reason may be fatal and patients require follow-​up in a pacemaker clinic. As well as detection of the com- plications described here earlier, the function of such a clinic is to assess the status of the pulse generator battery, and to maximize its life by programming the pulse generator output to the minimum consistent with a satisfactory safety margin. The design of pulse gen- erators and the battery characteristics normally allow prediction of the expected replacement date several months if not years ahead. However, premature battery depletion or pacemaker failure does occur, and patients should therefore be assessed at least annually by the clinic. Managing patients with permanent pacemakers Patients with a permanent pacing system can usually lead a perfectly normal life without limitations regarding physical activity. Driving is usually allowed 1 week after implantation. Patients should avoid strong electromagnetic fields and specific risks (arc welding ma- chines). Domestic appliances are not usually a problem unless faulty, and mobile phones are safe unless used in close proximity (<15 cm) to the device. Electronic surveillance systems and metal detectors at airports can affect pacemaker function. A significant proportion of patients with pacemaker and CRT de- vices will subsequently develop an indication for investigation with MRI. This has led to the development of MRI-​compatible devices, which are now used routinely in younger patients or those where this form of imaging is likely to be required. Although the use of MRI in patients with pacemakers should be avoided, where the benefits of this investigation are thought to outweigh the risks, imaging can be relatively safely performed. Imaging should take place after consult- ation with the implanting cardiologist, and a cardiac physiologist or cardiologist should be in attendance during the procedure. Radiotherapy can also affect pacemaker function. Reprogramming is required before and after treatment in those patients who are pacing-​dependent. Where the device lies directly within the radio- therapy field the pacemaker needs to be repositioned. In patients presenting with recurrent syncope, palpitations, or falls with a pacemaker in situ the cause is rarely due to pace- maker malfunction, although a pacing check is usually performed. Interrogation of modern pacing devices may also provide useful in- formation in patients with suspected tachyarrhythmias. Tachycardias Mechanisms of arrhythmogenesis The principal mechanisms responsible for tachyarrhythmias are those of abnormal automaticity, triggered activity, or re-​entry (Fig. 16.4.14). There is a complex interaction between the under­ lying substrate, such as previous myocardial infarction, a trig- gering event such as an extrasystole, and modulating influences, of which sympathetic stimulation and myocardial ischaemia are the most important. Automaticity Abnormal automaticity is defined as an inappropriate increase in the rate of discharge of a tissue that has physiological pace- maker properties (sinus node, AV node, or Purkinje fibres) or the pathological development of automaticity in atrial or ventricular myocytes (Fig. 16.4.14a). Such abnormalities are most commonly seen in the presence of ischaemia, sympathetic stimulation, or drug toxicity, especially digoxin. Automatic tachycardias are character- ized by an absence of initiation by extrasystoles, either spontan- eously or during electrophysiological testing. (a) (b) (c) Fig. 16.4.13  Pacemaker malfunction. (a) Failure to capture. The fourth stimulus fails to capture the ventricle. (b) Undersensing. The atrial pacemaker has failed to sense the preceding atrial activity and therefore delivered the second stimulus. This has captured the atrium, with the P-​wave in the ST segment, and subsequent conduction to the ventricle. (c) Oversensing. This dual-​chamber pacemaker has sensed an electrical artefact through the ventricular lead and as a result has suppressed ventricular pacing, with the absence of ventricular activation following the third P-​wave. (a) (c) (b) (d) Fig. 16.4.14  Mechanisms of arrhythmia. (a) Increased automaticity. (b) Triggered activity due to early after-​depolarizations. (c) Triggered activity due to delayed after-​depolarizations. (d) Re-​entry circuit. See text for details. 16.4  Cardiac arrhythmias 3361 Triggered activity The term ‘triggered activity’ is used to define an impulse initiation asso- ciated with a preceding action potential, and can be induced in vitro in tissues that do not demonstrate physiological automaticity. Two char- acteristic forms of depolarization may cause triggered activity. Early after-​depolarizations These occur during the plateau phase of the action potential, prior to repolarization (Fig. 16.4.14b), and are more evident at slow heart rates, particularly in the presence of hypokalaemia and hypomag- nesaemia. Mutations in cardiac Na+ or K+ channels, or drugs that prolong myocardial repolarization by inhibiting one or more com- ponents of the outward potassium current, IK, (class IA and class III antiarrhythmics, tricyclic antidepressants, antihistamines, organo- phosphorus insecticides, and many others) predispose to the ap- pearance of early after-​depolarizations in vitro. These changes are associated with the congenital and acquired long-​QT syndromes and the arrhythmia torsades de pointes (see ‘Torsades de pointes and the long-​QT syndromes’). Delayed after-​depolarizations These are subthreshold depolarizations occurring after full repolari­ zation of the action potential (Fig. 16.4.14c). Their amplitude is in- creased by tachycardia or intracellular calcium overload and may reach a threshold at which an action potential is generated, potentially initiating a sustained tachycardia. Delayed after-​depolarizations can be induced experimentally by digitalis overload and are the likely mechanism of digitoxic arrhythmias. Re-​entry Most clinically important sustained tachycardias, whether of atrial, junctional, or ventricular origin, arise on the basis of re-​entry. The establishment of a re-​entry tachycardia requires the presence of a potential circuit comprising two limbs with different refractori- ness and conduction properties (Fig. 16.4.14d). A premature beat can be conducted in one limb of the circuit, but the other limb may still be refractory, resulting in unidirectional conduction block. If conduction is sufficiently slow, the tissue distal to the site of block in the refractory limb will have regained excitability before the ar- rival of the depolarizing wavefront, and conducts the activity retro- gradely. This results in reactivation of the initial conducting pathway and thus a circus movement tachycardia is established. Macro re-​ entry is defined as the occurrence of a re-​entry circuit over a large area of the heart, such as in the presence of an accessory pathway (Fig. 16.4.15a). Micro re-​entry occurs in a relatively small area of the heart, for example at the border zone of an old myocardial infarc- tion, where conduction velocity is markedly slowed (Fig. 16.4.15b). The characteristic feature of a re-​entrant tachycardia is that an ap- propriately timed extrastimulus can induce unidirectional block and initiate the arrhythmia. The tachycardia may be terminated by extrastimuli that depolarize the tissue ahead of the circulating wave- front and thus interrupt the circus movement. Differential diagnosis of tachycardias General principles The first and most important step in the diagnosis and manage- ment of tachycardias is to determine whether the arrhythmia arises within the atria and/​or AV junction, or from the ventricles. An essential element in the differential diagnosis is to distinguish be- tween tachycardias with normal QRS-​complex morphology and duration (‘narrow-​complex tachycardias’), and those where the QRS complexes are abnormal in morphology and increased in duration (‘broad-​complex tachycardias’). A guide to the differential diagnosis of tachyarrhythmias is provided in Fig. 16.4.16. Narrow-​complex tachycardias Narrow-​complex tachycardias arise through mechanisms that re- sult in ventricular activation via the AV node and His–​Purkinje system and therefore show normal QRS morphology and duration (≤0.12 s) during tachycardia. Careful study of all leads of the ECG is necessary to assess regularity of QRS complexes and to iden- tify the presence of atrial activity (P-​waves) (Fig. 16.4.16). The re- lationship of the PR to the RP interval is helpful in determining mechanism of narrow-​complex tachycardias. In supraventricular tachycardias (see ‘Supraventricular tachycardia’), P-​waves may not be visible, or may occur immediately following the QRS com- plex. A long RP interval is found in atrial tachycardia, atypical AV nodal re-​entry tachycardia and AV re-​entry involving a slowly conducting accessory pathway as the retrograde limb. Atrial flutter waves are most commonly evident in the inferior limb leads or in lead V1. Broad-​complex tachycardias Few areas in cardiology cause more difficulty, or result in more mis- management, than the diagnosis of broad-​complex tachycardias. Whereas it is safe to assume that virtually all narrow-​complex tachycardias have a supraventricular origin, broad-​complex tachycardias (QRS duration ≥0.12 s) may arise either from the ven- tricle or from supraventricular mechanisms, the latter occurring if there is bundle branch block, either pre-​existing or functional (ab- erration) as a result of the high rate (Fig. 16.4.16). An additional cause of aberrant conduction is activation of the ventricles via an accessory pathway. If the broad QRS morphology during tachycardia is identical to that in sinus rhythm, then a supraventricular origin is likely, with fixed bundle branch block. However, no ECG in sinus rhythm may be available, and difficulties in diagnosis and management arise when ventricular tachycardia is not recognized and is misdiagnosed as ‘SVT with aberration’. This usually happens as a result of certain Accessory pathway Infarct border zone ) b ( )a ( Fig. 16.4.15  Examples of re-​entry tachycardias. (a) Macro re-​entry circuit involving an accessory pathway, which results in atrioventricular re-​entry tachycardia. (b) Micro re-​entry circuit at the border zone of a myocardial infarction. section 16  Cardiovascular disorders 3362 failings and misconceptions, the commonest being that the clinical context is not considered: • Age of the patient—​middle-​aged or older individuals presenting with a recent history of broad-​complex tachycardia, and who give a history of myocardial infarction or congestive heart failure, are more likely to have ventricular than supraventricular tachycardia. However, ventricular tachycardia can also arise in young patients. • Haemodynamic status of the patient—​it is often assumed that ventricular tachycardia should cause haemodynamic collapse, whereas patients may in fact be haemodynamically stable if the rate is not excessively fast or if underlying cardiac function is good. Conversely, supraventricular tachycardias may cause syn- cope, hypotension, or shock if sufficiently rapid, or if there is underlying heart disease. • Nature of the episodes of palpitation—​it is often not appreciated that ventricular tachycardia can present with a typical history of paroxysmal self-​terminating episodes, just as in the case of supraventricular tachycardia. The importance of making a correct diagnosis in broad-​complex tachycardia is twofold. First, inappropriate acute therapy of the tachyarrhythmia can be avoided. In particular, the use of verapamil in ventricular tachycardia misdiagnosed as supraventricular tachy- cardia is associated with a high risk of haemodynamic collapse as a result of its negative inotropic effect, coupled with its lack of efficacy in terminating ventricular tachycardia. Secondly, if the original ar- rhythmia has been misdiagnosed, then the adverse prognostic sig- nificance of ventricular tachycardia will be overlooked. Appropriate investigation and long-​term management may not be instituted. It is therefore important that a diagnosis of SVT with aberration is made only if the ECG displays typical left or right bundle branch block with none of the features suggestive of VT listed in Fig. 16.4.16. In addition to attention to the history and 12-​lead ECG, the response to transient AV nodal blockade with adenosine will assist diagnosis in many patients (Table 16.4.5). General principles of management Many cardiac arrhythmias are benign and require no interven- tion. The main indications for treatment are to relieve symptoms, or to prevent complications such as myocardial ischaemia, cardiac failure, embolism, or arrhythmic sudden death. Precipitating fac- tors such as myocardial ischaemia/​infarction, infection, thyrotoxi- cosis, alcohol, electrolyte disorders, or drug toxicity must be sought and treated if possible. The therapy indicated will commonly be influenced by the presence of underlying structural heart disease such as myocardial ischaemia/​infarction or left ventricular dys- function and can include drug therapy, device implantation, or radiofrequency ablation. Acute management of tachycardia An algorithm for the treatment of tachyarrhythmias is shown in Fig. 16.4.17. Assessment of the patient’s cardiorespiratory status takes precedence. R-​wave synchronized, direct current (DC) QRS <120 ms Yes No Regular QRS Yes No Yes Atrial activity visible No • Atrial flutter • Atrial tachycardia Yes • Ventricular tachycardia No • AVNRT • AVRT • Atrial tachycardia No No Yes Yes A>V rate No RP > PR No • Atrial tachycardia • PJRT • Atypical AVNRT Yes • Atrial fibrillation • Atrial flutter • Atrial tachycardia • AF /Afl /AT with BBB* • Pre-excited AF • Polymorphic VT • Torsades de Pointes ECG features of VT** No QRS atypical for RBBB or LBBB* Yes or unknown 1:1 AV relationship Yes Regular QRS No or unknown No V>A rate Atrial activity visible No Yes Yes Yes *Atypical features of BBB favouring VT LBBB pattern: qR or qS in lead V6 R in V1 >30 ms Onset R to nadir of S >60 ms in V1 RBBB pattern: qR, Rs, or Rr in V1 Axis > +90 or < −90 **Features favouring VT In 12-lead ECG: Fusion or capture beats Extreme axis deviation In precordial leads: Concordance (all either positive or negative) Absence of RS pattern in any chest lead Onset R to nadir of S > 100ms QRS identical to that in sinus rhythm Fig. 16.4.16  Algorithm for diagnosis of tachycardia from 12-​lead ECG. A, atrial rate; AF, atrial fibrillation; Afl, atrial flutter; AT, atrial tachycardia; AVNRT, atrioventricular nodal re-​entrant tachycardia; AVRT, atrioventricular re-​entrant tachycardia; BBB, bundle branch block; LBBB, left bundle branch block; PJRT, permanent junctional reciprocating tachycardia; PR, PR interval; RBBB, right bundle branch block; RP, RP interval; V, ventricular rate; VT, ventricular tachycardia. See text for details. Table 16.4.5  Diagnostic use of intravenous adenosine Arrhythmia Response Atrial tachycardia Atrial flutter Atrial fibrillation Transient AV block reveals atrial arrhythmia Rarely terminated AVNRT AVRT Terminates tachycardia by anterograde (AV) block Ventricular tachycardia Not terminated 1:1 VA conduction may be blocked, revealing AV dissociation For abbreviations, see Fig. 16.4.16. 16.4  Cardiac arrhythmias 3363 cardioversion under general anaesthesia or deep sedation is the most effective and immediate means of terminating sustained tachycardias, and should be employed when the tachycardia is associated with haemodynamic compromise (Fig. 16.4.18). Although atrial flutter may respond to low-​energy cardioversion (50–​100 J), other arrhythmias normally require energies of 100–​ 360 J for termination (150–​200 J for biphasic shocks). The use of DC shock in the termination of ventricular fibrillation is discussed later in this chapter. In patients with haemodynamically stable tachycardias, manoeuvres that produce transient vagal stimulation such as the Valsalva manoeuvre or carotid sinus massage may be em- ployed. Similarly, adenosine is used pharmacologically to pro- duce transient slowing or block of the sinus node or AV node (see ‘Adenosine’). Vagal manoeuvres or adenosine will often terminate arrhythmias dependent on the AV node, and are also useful diagnostic tools, since transient interruption of AV nodal conduction may reveal the tachycardia mechanism (Table 16.4.5). Atrial tachyarrhythmias will not normally be terminated by vagal stimulation or adenosine, but an increase in AV block reveals the underlying atrial rhythm. Re-​entry tachycardias may be terminated by the delivery of appropriately timed extrastimuli that depolarize part of the re-​ entry circuit prior to the arrival of the wavefront and interrupt the arrhythmia. Simple overdrive pacing can be effective in the termination of atrial flutter, AV nodal re-​entry, AV (ortho- dromic) re-​entry tachycardia, or sustained ventricular tachycardia (Fig. 16.4.19). The cardiac chamber in question is paced for brief periods (e.g. 6–​12 beats), at a rate just above that of the tachy- cardia, with repeated attempts sometimes necessary at gradually increasing rates. Overdrive atrial or ventricular pacing may result in degeneration into atrial and ventricular fibrillation, respect- ively, hence facilities for immediate defibrillation must be avail- able. Implantable antitachycardia pacing facilities are incorporated into implantable cardioverter–​defibrillators (see ‘Implantable cardioverter–​defibrillators’). Haemodynamic compromise Yes No DC cardioversion Vagal manoeuvres IV adenosine* Terminated QRS <120ms Yes No IV amiodarone** IV lidocaine IV sotalol IV verapamil** IV β-blocker IV flecainide IV procainamide Overdrive pacing*** Persistent or re-initiated Terminated Terminated Persistent or re-initiated Caution with broad complex tachycardias or known pre-excitation. Adenosine is contraindicated in pre-excited AF and asthma ** Use only one drug from list *** If clinically appropriate, e.g. frequently recurring tachycardia Persistent or re-initiated Fig. 16.4.17  Algorithm for the acute management of tachyarrhythmias. 200 J I II III 1s Fig. 16.4.18  Synchronized DC cardioversion of atrial fibrillation. A 200 J DC shock is delivered during atrial fibrillation to coincide with the R-​wave of the QRS complex. This shock terminates the arrhythmia with restoration of normal sinus rhythm. I aVF V1 RV 1s S S S S S S S S Fig. 16.4.19  Termination of ventricular tachycardia by overdrive ventricular pacing. During ventricular tachycardia, a burst of eight stimuli (S) results in termination of the tachycardia and resumption of normal sinus rhythm. Surface leads I, aVF, V1, and intracardiac electrograms from the right ventricular apex (RV) are shown. section 16  Cardiovascular disorders 3364 Treatments for tachycardias Antiarrhythmic drug therapy The Vaughan Williams classification is based on the effects of antiarrhythmic drugs in isolated normal tissue, and although many drugs act by more than one mechanism, the classification is still in widespread use. The effects of the major classes of antiarrhythmic drug activity at the tissue level, and the associated electrocardio- graphic changes, are listed in Table 16.4.6. Individual drugs are de- scribed in Table 16.4.7. Class I activity Class I antiarrhythmic drugs act by inhibiting the rapid inward so- dium current. Class Ia agents (e.g. quinidine, procainamide, and disopyramide) increase the cardiac action potential duration and have intermediate effects on the onset and recovery kinetics of the sodium channel and hence on intracardiac conduction. Class  Ib agents (e.g. lidocaine and mexiletine) shorten the cardiac action potential duration and have very rapid offset kinetics that result in minimal slowing of normal intracardiac conduction. Class  Ic drugs (e.g. flecainide and propafenone) have no major effect on ac- tion potential duration, but produce the most long-​lasting effect on cardiac sodium channel kinetics and the most marked slowing of intracardiac conduction. Class II activity Class II activity is defined as antagonism of the arrhythmogenic effects of catecholamines. The commonest agents in this class are the competitive β-​adrenoceptor blockers. Other agents such as propafenone have a weak β-​receptor blocking activity, and amiodarone (see next paragraph) exhibits a non​competitive sym- patholytic effect. Class III activity The class III mode of antiarrhythmic activity comprises length- ening of the cardiac action potential duration and hence of the effective refractory period. Drugs in this class possess a broad spec- trum of activity against atrial, supraventricular, and ventricular arrhythmias. Currently available class III agents act by inhibiting the rapid component of the outward potassium current IKr. Dofetilide and ibutilide are examples of drugs with ‘pure’ class III antiarrhythmic actions. Sotalol is a non​selective β-​adrenoceptor antagonist that also possesses class III activity. Amiodarone pos- sesses antiarrhythmic activity in all four Vaughan Williams classes. Class IV activity Class IV drugs (e.g. verapamil and diltiazem) reduce the inward calcium current ICa in sinoatrial and AV nodal tissues. They are used to prevent or interrupt re-​entry arrhythmias involving the AV node (e.g. AV nodal re-​entry tachycardia), or to slow the ven- tricular response in atrial fibrillation or flutter. The dihydropyridine calcium antagonists, such as amlodipine and nifedipine, have no antiarrhythmic action. Digoxin The antiarrhythmic activity of digoxin is not explained within the Vaughan Williams classification and appears to be mediated pre- dominantly through vagal stimulation. It is used to slow ventricular rate in atrial fibrillation. Adenosine Adenosine, a naturally occurring purine nucleoside, is used pharmacologically to produce transient slowing or block of the sinus node or atrioventricular node. It is of particular value in view of its extremely short plasma half-​life (c.2 s), which confers safety. It must be administered by rapid intravenous bolus injection, using incremental doses usually from 6 to 18 mg, to achieve the desired therapeutic effect. Adenosine is contraindicated in pre-​excited atrial fibrillation or in severe asthma and cautioned in patients with known pre-​excitation syndrome (see ‘Pre-​excitation syndromes (Wolff–​Parkinson–​White syndrome)’). Non​pharmacological therapy Cardioversion External electrical cardioversion, as just described, can be used electively to restore normal rhythm in patients with persistent ar- rhythmia. Failure of external cardioversion of atrial fibrillation occurs in some patients as a result of various factors, including in- creased transthoracic impedance due to obesity, prolonged atrial fibrillation, left ventricular dysfunction, and left atrial dilatation. Internal cardioversion can be successful in many of these patients. Table 16.4.6  Classification of antiarrhythmic drug activity ECG effect Tissue effect HR PR QRS QT SA node Atrium AV node Ventricle Class Ia 0 0/​–​ + ++ 0 ++ –​ ++/​–​ Ib 0 0 0 0/​–​ 0 0 0 ++/​–​ Ic 0 + ++ + 0 ++ 0/​+ ++/​–​ Class II –​ + 0 0 ++ ++ ++ +/​0 Class III 0/​–​ 0/​+ 0 ++ 0/​+ ++ 0/​+ ++/​–​ Class IV 0/​–​ + 0 0 0/​+ +/​–​ ++ 0 Digoxin 0/​–​ + 0 0 0/​+ 0/​–​ ++ 0/​–​ Adenosine –​ + 0 0 ++ 0/​–​ ++ 0 ECG effect: +, increases; −, decreases; 0, no effect; HR, heart rate. Tissue effect: +, antiarrhythmic activity; −, potential adverse or proarrhythmic effect; 0, no effect. 16.4  Cardiac arrhythmias 3365 The procedure involves the introduction of specialized electrode catheters that permit DC shock delivery between electrodes in the right atrium and the pulmonary artery or coronary sinus, providing a current field that achieves depolarization of both atria. Implantable cardioverter–​defibrillators Patients identified as being at high risk of sudden cardiac death (e.g. a history of spontaneous ventricular arrhythmias, out-​of-​hospital cardiac arrest, or factors indicating high risk of developing a malig- nant arrhythmia) may be treated with an implantable cardioverter–​ defibrillator (ICD). A transvenous rate-​sensing/​shocking electrode is introduced via the subclavian vein to the right ventricular apex, with the generator implanted in the pectoral region (Fig. 16.4.20). If a heart rate above the threshold programmed by the device is recognized, a shock is delivered between the intracardiac shocking electrode and the generator casing. Some devices also include a right atrial electrode to sense atrial activation. A third lead lying in a tributary of the coronary sinus can be implanted to pace the left ventricle and help restore electromechanical synchrony in those with heart failure, reduced ejection fraction, and evidence of dyssynchrony (cardiac resynchronization therapy or ‘CRT’). An ICD can be programmed to deliver ventricular antitachycardia Table 16.4.7  Commonly used antiarrhythmic drugs Principal indication Dose Adverse effects IV Oral Class Ia Quinidine AF cardioversion –​ 1–​2 g/​day Hypersensitivity, GI symptoms, QT prolongation, hypotension Disopyramide AF prophylaxis VT termination 2 mg/​kg 300–​600 mg/​day Negative inotropy, QT prolongation, parasympathetic blockade (accelerated AV conduction, urinary retention, dry mouth, blurred vision) Procainamide AF cardioversion VT termination 100 mg/​5 min up to 1000 mg 1–​6 mg/​min 2–​6 g/​day Hypotension, QT prolongation, GI upset, lupus syndrome Class Ib Lidocaine (lignocaine) VT termination VT/​VF prophylaxis 100 mg bolus 1–​4 mg/​min Ineffective CNS—​confusion, dysarthria, fits Class Ic Flecainide AF cardioversion AF prophylaxis WPW prophylaxis 2 mg/​kg 100–​300 mg/​day Proarrhythmia, negative inotropy, CNS disturbance Propafenone AF cardioversion AF prophylaxis WPW prophylaxis –​ 450–​900 mg/​day Proarrhythmia, negative inotropy, CNS disturbance, bronchoconstriction Class II Various, e.g. bisoprolol AF prophylaxis AF rate control SVT prophylaxis Sudden death prophylaxis –​ 5–​10 mg/​day Bradycardia, -​ve inotropy, cold extremities, bronchoconstriction, lethargy Class III Sotalol AF termination AF prophylaxis WPW prophylaxis VT prophylaxis 2 mg/​kg 160–​320 mg/​day Bradycardia, negative inotropy, cold extremities, bronchoconstriction, lethargy, QT prolongation Amiodarone AF termination AF prophylaxis WPW prophylaxis VT prophylaxis 300 mg in 30–​60 min, then 900 mg/​24 h 0.6–​1.2 g/​day loading first 2 weeks, then 100–​400 mg/​day Bradycardia, photosensitivity, skin pigmentation, hypo-​or hyperthyroidism, alveolitis, hepatitis, peripheral neuropathy, epididymitis Class IV Verapamil SVT termination SVT prophylaxis AF rate control 5–​10 mg 240–​480 mg/​day Negative inotropy, AV block, flushing, constipation Other Digoxin AF rate control 0.125–​0.25 mg/​day Anorexia, nausea, vomiting, AV block, atrial and ventricular arrhythmias Adenosine SVT termination 6–​18 mg by incremental bolus Flushing, chest pain, bronchospasm, transient AV block AF, atrial fibrillation; SVT, supraventricular tachycardia (atrioventricular nodal and atrioventricular re-​entrant tachycardia); VT, ventricular tachycardia; WPW, Wolff–​Parkinson–​White syndrome. section 16  Cardiovascular disorders 3366 pacing for tolerated tachycardias, with shock delivery available for faster rates or if pace-​termination fails. ICDs are expensive, complex, and require regular specialist follow-​up. For patients without an indication for pacing, cardiac resynchronization therapy or requirement for antitachycardia pacing (i.e. sustained monomorphic ventricular tachycardia), a subcutaneous ICD (S-​ICD) is an alternative treatment option for prevention of sudden cardiac death. The lead is tunnelled super- ficial to the sternum and connected to a generator in an axillary pocket (Fig. 16.4.21). Radiofrequency ablation Selective ablation of part of a re-​entry circuit, an arrhythmic focus, or the AV node is used increasingly in the management of arrhythmias and offers the opportunity of curative treat- ment. Radiofrequency energy is delivered between the tip of an intracardiac electrode positioned at the appropriate site and an indifferent surface electrode placed over the lower back or thigh. The energy produces a localized necrotic lesion 2–​3 mm in diameter, which results in local conduction block. Current in- dications for radiofrequency ablation are listed in Table 16.4.8, and specific issues are discussed next in relation to individual arrhythmias. Arrhythmia surgery The ‘maze’ procedure for atrial fibrillation involves creating a series of lines of conduction block in the left and right atria, either by incisions or by ablation. This prevents the development of atrial re-​entry circuits while permitting AV conduction. Surgical man- agement of recurrent ventricular tachycardia by mapping and re- section of the re-​entry circuit is occasionally performed, but has been largely superseded by ablation or ICD therapy. Specific causes of arrhythmias Extrasystoles The term extrasystole is used to describe a premature beat arising from a focus other than the sinus node. Extrasystoles are also de- scribed as premature beats, premature contractions, premature de- polarizations, or ectopic beats. Atrial extrasystoles Atrial extrasystoles are recognized by a premature P-​wave of dif- ferent morphology from the sinus P-​wave (Fig. 16.4.22a), which can be hidden within the ST segment or T-​wave of the preceding sinus beat. Premature atrial extrasystoles that occur before full re- covery of the AV node will be followed by prolongation of the PR (a) (b) Shock VP VP Fig. 16.4.20  Implantable cardioverter–​defibrillator (ICD). (a) Chest radiograph showing the ICD generator in the left pectoral region, connected to a lead which passes via the left subclavian vein and superior vena cava to the heart. The tip of the lead is in the right ventricular apex. Cardiac rhythm is sensed from the electrodes at the tip of the lead, and shocks can be delivered between the metal casing of the generator and the right ventricular coil (thick portion of lead). (b) Discharge from an ICD. A rapid polymorphic ventricular tachycardia is terminated by a shock (typically 36 J) from the device. Electrograms shown are retrieved from the memory of the device, upper tracings from the shocking circuit (generator can to ventricular coil) and lower tracings from the sensing circuit (bipolar electrodes at the tip of the catheter in the right ventricle. The shock is followed by ventricular pacing (VP). Fig. 16.4.21  CXR showing subcutaneous ICD connected to a generator in an axillary pocket. 16.4  Cardiac arrhythmias 3367 interval, or, if sufficiently premature, complete failure of conduction (Fig. 16.4.22b). Non​conducted atrial extrasystoles must be distin- guished from sinus arrest or second-​degree AV block. An atrial extrasystole will commonly reset the sinoatrial node, such that the next sinus beat occurs earlier than expected with respect to the preceding sinus beat, and the pause is less than compensatory. Atrial extrasystoles are a common finding in healthy people, par- ticularly with increasing age, but are more frequent in the presence of increased atrial pressure or stretch such as in cardiac failure or chronic mitral valve disease. Patients should be reassured that the arrhythmia is benign, and that drug treatment is rarely necessary. If treatment is required on symptomatic grounds, β-​adrenergic blockers may be used, but class I antiarrhythmic drugs should be avoided in view of their proarrhythmic risk. Junctional extrasystoles Junctional extrasystoles are identified by the appearance of a premature, normal QRS complex in the absence of a preceding P-​wave. The atria as well as the ventricles may be activated, re- sulting in an inverted P-​wave simultaneous with the QRS com- plex, or inscribed within the ST segment. The significance and management of junctional extrasystoles are similar to those of atrial extrasystoles. Ventricular extrasystoles Ventricular extrasystoles are identified by the appearance of a bi- zarre, wide QRS complex not preceded by a P-​wave (Fig. 16.4.23). There is commonly ST-​segment depression and T-​wave inversion. Ventricular extrasystoles may be intermittent or occur with a fixed relationship to the preceding normal beats, that is, 1:1, 1:2 (bigeminy or trigeminy). Ventricular extrasystoles occur in otherwise normal hearts but are found particularly in the presence of structural heart disease. Benign ventricular ectopy is common and indicated by the following: normal resting 12-​lead ECG, structurally normal heart on echo, absence of other cardiac symptoms, resolution with ex- ercise, and the absence of a family history of early cardiac disease or sudden cardiac death. Ventricular ectopics occur commonly in the acute phase of myocardial infarction, but are also seen in the postinfarction phase, and in the presence of severe left ventricular hypertrophy or dysfunction of whatever cause. While the presence of frequent ectopy following myocardial infarction conveys an ad- verse prognosis, their suppression with class I agents (flecainide) actually increases mortality. Extrasystoles may produce symptoms that require treatment in a minority of cases. The safest option is β-​blockade. Atrial arrhythmias Atrial fibrillation Mechanisms Studies of patients with paroxysmal atrial fibrillation suggest that the arrhythmia may be triggered by one or more rapidly discharging foci, which are commonly situated in the pulmonary veins. Table 16.4.8  Indications for radiofrequency ablation Diagnosis Ablation target Success Comments AVRT Accessory pathway +++ Pre-​excited AF Accessory pathway +++ AVNRT Slow pathway +++ 0.5–​1 % risk of CHB Atrial flutter TVA–​IVC isthmus +++ Focal atrial tachycardia Tachycardia focus ++ Paroxysmal AF Pulmonary vein isolation ++ Moderate recurrence rate Persistent AF Extensive LA ablation + Often requires >1 procedure Permanent AF AV node +++ Requires permanent pacing, does not cure AF Scar-​related ventricular tachycardia Re-​entry circuit + High recurrence rate Focal ventricular tachycardia Site of origin ++ Especially RVOT focus AVRT, atrioventricular re-​entry tachycardia; AF, atrial fibrillation; AVNRT, atrioventricular nodal re-​entry tachycardia; LA, left atrial; CHB, complete heart block; TVA, tricuspid valve annulus; IVC, inferior vena cava; RVOT, right ventricular outflow tract. (a) (b) Fig. 16.4.22  Atrial extrasystoles. (a) An atrial extrasystole, with an abnormal P-​wave at the end of the preceding T-​wave, occurs following a sinus beat. (b) Blocked atrial extrasystoles. In the same patient, atrial extrasystoles occur following each sinus beat. They are earlier than those in (a), and the AV node is refractory because of the proximity of the atrial extrasystoles to the preceding beat, and conduction is blocked. Fig. 16.4.23  Ventricular extrasystole (open circle). No retrograde atrial activation occurs, and the P-​wave sequence is undisturbed (arrowed). section 16  Cardiovascular disorders 3368 In the presence of a heterogeneous substrate, it is thought that such a trigger gives rise to high frequency re-​entry in certain areas (rotors) which perpetuate fibrillatory conduction. Rapid atrial ac- tivation induces a process of electrical remodelling, which renders cardioversion and maintenance of sinus rhytshm more difficult (‘atrial fibrillation begets atrial fibrillation’). The initial mechanism of remodelling is thought to be intracellular calcium overload re- sulting in shortening of the atrial refractory period, although more prolonged atrial tachyarrhythmias result in downregulation of cal- cium entry and dedifferentiation of atrial myocytes. Structural changes, including interstitial fibrosis, also occur and further per- petuate the arrhythmia. Classification and aetiology Atrial fibrillation is a common arrhythmia affecting 1% of the popu- lation, the incidence increases with advancing age to 5–​10% in very elderly individuals. It is classified as paroxysmal (self-​terminating episodes <7 days duration but usually <48 h), persistent (termin- ates after 7 days or following intervention, e.g. electrical cardiover­ sion), and permanent (where there is no strategy to terminate the arrhythmia). There are numerous causes of the arrhythmia (Box 16.4.2), but in many instances no obvious aetiological factor can be identified, and the patient is described as having ‘lone’ atrial fibrillation. Atrial fib- rillation carries adverse prognostic significance, in part through its association with organic heart disease but also as an important risk factor for mortality and the development of stroke and systemic em- bolism due to stasis and thrombus formation in the left atrium. The risk of stroke is particularly high in patients with mitral stenosis or mitral valve replacement and permanent atrial fibrillation. Presentation Patients with structurally normal hearts with a relatively slow ven- tricular rate may be asymptomatic and only picked up during routine screening. The onset of atrial fibrillation may trigger palpitations, fatigue, breathlessness, or angina in patients with underlying cor- onary disease. Presentation with syncope is relatively uncommon but may occur in the context of sinus node disease where spontan- eous reversion to sinus rhythm is associated with prolonged sinus node recovery. Atrial fibrillation may be detected at the time of presentation or during the investigation of stroke. Atrial fibrillation results in loss of the atrial contribution to left ventricular filling, which can result in a worsening of heart failure. Symptoms and impairment of left ventricular function (‘tachycardiomyopathy’) arise as a result of a rapid uncontrolled ven- tricular rate. In addition, uncontrolled atrial fibrillation can cause further impairment of ventricular filling in mitral stenosis and con- ditions associated with left ventricular diastolic dysfunction such as hypertensive left ventricular disease and aortic stenosis. Diagnosis The characteristic ECG findings in atrial fibrillation of recent onset are of rapid, irregular ‘f’ waves at a rate of 350–​600/​min. These are associated with an irregular ventricular response because of variable conduction through the AV node (Fig. 16.4.24a). With increasing duration of persistent atrial fibrillation, the amplitude of the ‘f’ waves diminishes until they are no longer visible. Under these cir- cumstances, atrial fibrillation is diagnosed by the absence of P-​waves and the irregular ventricular response (Fig. 16.4.24b). Atrial fibrillation is classified into three patterns:  paroxysmal, persistent, or permanent. In paroxysmal atrial fibrillation, spontan- eously terminating attacks of palpitation last anything from a few seconds to a few days. The ventricular rate is often rapid and the patient may be severely symptomatic. The term ‘persistent atrial fib- rillation’ is used to describe instances where the arrhythmia is not self-​terminating, but where sinus rhythm can be restored by elec- trical or pharmacological cardioversion. Permanent atrial fibrilla- tion describes the situation where both patient and physician accept the arrhythmia and rhythm control (i.e. the restoration of sinus rhythm) is not being pursued. At this stage, the ventricular rate is often slower, and the patient may be unaware of the irregular pulse or of palpitations. General principles of management Appropriate management of atrial fibrillation depends on the pres- ence or absence of symptoms, haemodynamic status, duration of arrhythmia, and the presence of factors affecting the successful maintenance of sinus rhythm. Management is based on the pre- vention of thomboembolic complications as the initial priority, and the use of a rate-​or rhythm-​control strategy in a patient-​centred and symptom-​directed approach. Trials in asymptomatic patients have failed to demonstrate a mortality or morbidity benefit from re- storing and maintaining sinus rhythm with antiarrhythmic therapy. In the elderly asymptomatic or mildly symptomatic patient, particu- larly with long-​standing atrial fibrillation, a rate control strategy is sufficient. Box 16.4.2  Aetiology of atrial fibrillation • Increased atrial pressure—​mitral valve disease, congestive heart failure, left ventricular hypertrophy, restrictive cardiomyopathy, pulmonary embolism • Atrial volume overload—​atrial septal defect • Myocardial ischaemia/​infarction • Thyrotoxicosis • Alcohol • Sinoatrial disease • Infiltration—​constrictive pericarditis, tumour • Infection—​systemic, e.g. pneumonia; cardiac: myo/​pericarditis • Cardiac or thoracic surgery • Idiopathic—​‘lone’ atrial fibrillation (a) (b) Fig. 16.4.24  Atrial fibrillation. (a) Coarse atrial fibrillation of recent onset. (b) Fine atrial fibrillation in a patient with long-​standing valvular disease. Surface V1 leads are shown. 16.4  Cardiac arrhythmias 3369 Emergency presentation Atrial fibrillation of recent onset may terminate spontaneously, par- ticularly if associated with an acute febrile illness. Outside the con- text of an acute febrile illness, an attempt to restore sinus rhythm should be made unless the arrhythmia is obviously long-​standing (>48 h) or is associated with advanced organic heart disease. Underlying precipitating factors such as thyrotoxicosis should be corrected before attempting cardioversion. Chemical or pharmacological cardioversion may be achieved with class Ia, Ic, or III agents. Class Ia agents accelerate the ven- tricular rate by virtue of their anticholinergic action on the AV node and must be used in combination with AV nodal blocking agent (e.g. digoxin, β-​blocker, or calcium channel blocker). For patients without significant underlying heart disease, the current drugs of choice are the class Ic agents (e.g. flecainide 2 mg/​kg intravenously over 30 min). Class III drugs are safer in the presence of left ven- tricular dysfunction or ischaemic heart disease (e.g. amiodarone 300 mg intravenously over 30 min, followed by 900 mg/​24 h until cardioversion). The class III agents ibutilide and vernakalant have approval for this indication in some countries. Normally, only one drug should be tried in any individual patient. If drug therapy fails, DC cardioversion is commonly effective. Given that atrial fibrillation is a risk factor for the development of intracardiac thrombus formation, cardioversion, by chemical or electrical means, should not be attempted acutely if arrhythmia has clearly been present for longer than 48 h. Given that atrial fibril- lation may have developed asymptomatically, any doubt about the duration of arrhythmia onset should prompt thromboprophylaxis. Anticoagulation plus rate control with a β-​blocker, calcium channel blocker, or digoxin should be considered in these circum- stances. However, in the presence of haemodynamic compromise, the benefit of achieving sinus rhythm may outweigh the poten- tial risk of embolism and attempt to restore sinus should be made. Transoesophageal echocardiography is useful in this situation to ex- clude left atrial thrombus. The strategy used will therefore depend upon the clinical presen- tation and is summarized in Box 16.4.3. Paroxysmal atrial fibrillation Paroxysmal atrial fibrillation is a self-​terminating, recurrent ar- rhythmia, often associated with marked symptoms of palpitations. The goal of treatment is the maintenance of sinus rhythm and the amelioration of symptoms. In patients with infrequent paroxysms, drug therapy may not be necessary, or a ‘pill in the pocket’ approach can be used with selected patients without structural heart disease. For this, the patient takes a dose of an antiarrhythmic drug after the onset of arrhythmia (e.g. flecainide 100 mg), if this has previously been shown to be safe and effective under hospital supervision. In those with recurrent paroxysmal atrial fibrillation, prophylactic therapy should be considered. No drug is entirely satisfactory and a β-​blocker is often prescribed as first-​line therapy. If this is ineffective, other antiarrhythmic therapy should be started. Class  Ic agents (flecainide or propafenone) are effective and reasonably safe in the absence of underlying ischaemia, history of coronary artery disease, or left ventricular dysfunction, and are usually coprescribed with an AV nodal blocking drug. Amiodarone is effective but can be associ- ated with significant adverse effects and should be reserved for when the aforementioned measures fail. In the tachycardia–​bradycardia syndrome, implantation of a permanent pacemaker may be required to control bradycardia and to allow antiarrhythmic therapy for the treatment of tachycardia. Catheter ablation may be considered as first line or for those in whom pharmacological therapy has failed. The goal of catheter ablation is to achieve electrical isolation of the pulmonary veins; clinical success rates are 70–​80% from a single procedure. Persistent atrial fibrillation Persistent atrial fibrillation is not self-​terminating, usually requires electrical cardioversion to achieve sinus rhythm, and has a high recurrence rate even after successful cardioversion. The key deci- sion is whether to employ a rhythm or rate control strategy. The AFFIRM trial showed no overall mortality benefit of a rhythm-​ control strategy in patients in whom a rhythm-​control strategy in not indicated on the basis of symptoms. In general, a rate control strategy should be employed in asymptomatic or mildly symptom- atic individuals, in older people, and in those with contraindica- tions to antiarrhythmic therapy or cardioversion. This group should be treated as having permanent atrial fibrillation. In more severely Box 16.4.3  Cardioversion for atrial fibrillation 1 Defined onset <48 h with minor symptoms, haemodynamic stability, and no intercurrent illness 50% or more of patients will cardiovert spontaneously particularly in the context of prior paroxysmal symptoms. Rate control with oral β-​blockade (e.g. bisoprolol 5 mg) may be all that is required ini- tially. Administration of LMWH is indicated in case cardioversion does not occur spontaneously within 24 h. Early echocardiography is required to assess for structural heart disease. In the presence of normal LV function and absence of a history of ischaemic heart disease consider oral flecainide loading (300 mg) or IV flecainide (2 mg/​kg over 30 min). In the context of coronary disease or LV dys- function, consider oral amiodarone. 2 Defined onset >48 h/​no defined onset, with minor symptoms, haemodynamic stability, and no intercurrent illness Rate control with oral β-​blockade or rate-​limiting calcium channel blocker as first line. Oral digoxin if other agents are contraindicated. Commence warfarin. Outpatient review and decision regarding rate or rhythm control depending on symptoms. 3 Defined onset >48 h/​no defined onset, with haemodynamic in- stability, and no intercurrent illness Oral digoxin loading pending urgent echocardiographic assess- ment, then β-​blockade if required (in the absence of cardiogenic shock or severe LV dysfunction or aortic stenosis on echo). Consider IV amiodarone and TOE-​guided cardioversion in patients failing to respond (emergency cardioversion may be required without TOE in patients in imminent danger of cardiorespiratory arrest). 4 Rapidly conducted atrial fibrillation in conjunction with intercurrent illness In the context of a prior diagnosis of well-​controlled permanent atrial fibrillation, treatment should be directed at the underlying illness and continuing the current rate of control medication. Patients with new-​onset atrial fibrillation should be treated with rate control (as aforementioned) and anticoagulation with LMWH. Where haemodynamic compromise is felt to be due to atrial fib- rillation rather than the underlying illness, chemical or electrical cardioversion may be attempted depending on the duration of the arrhythmia (see earlier); however, the early recurrence rate is high. LMWH, low molecular weight heparin; LV, left ventricular; TOE, trans­ oesophageal echocardiography. section 16  Cardiovascular disorders 3370 symptomatic or younger patients, or in those with atrial fibrilla- tion due to a treated precipitant, a rhythm-​control strategy may be more appropriate. However, treatment choice has to be tailored to the individual and both options should be discussed with the patient. In patients with multiple comorbidities (e.g. chronic ob- structive pulmonary disease, heart failure, ischaemic heart disease), the contribution of atrial fibrillation to the patient’s limitation may not be immediately clear. In such cases an attempt at restoring sinus rhythm may be worthwhile to clarify whether a rhythm-​control strategy is justified. Prophylaxis of thromboembolism should be considered in both groups. If a rhythm-​control strategy is adopted, elective cardioversion should be scheduled. Given that cardioversion may be associated with embolism, patients undergoing this procedure should be treated with warfarin or a non-​VKA oral anticoagulants (NOAC) for at least 3 weeks beforehand, and this should be continued long term if warranted according to risk stratification, and for at least 4 weeks in those at low risk of thromboembolism, otherwise long-​ term anticoagulation is indicated irrespective of the apparent success of rhythm control. There is a high risk of recurrent atrial fibrillation (up to 50% at 1  year) and antiarrhythmic prophy- laxis should be considered. First-​line therapy is often a simple β-​ blocker followed by a class Ic agent if there is no structural heart disease. Amiodarone may also be considered, and treatment prior to cardioversion increases the likelihood of its success. Finally, radiofrequency ablation may be employed but this requires more extensive left atrial ablation compared to paroxysmal atrial fibril- lation (Fig. 16.4.25), with a lower success rate, and often requires more than one procedure. Permanent atrial fibrillation In permanent atrial fibrillation, restoration of sinus rhythm is not feasible or is unsuccessful and chronic management involves con- trol of ventricular rate. Traditionally, the mainstay of treatment has been digoxin, at a dose titrated to achieve adequate slowing in the ventricular rate at rest, with therapeutic plasma concentrations. Despite adequate rate control at rest, patients commonly have an uncontrolled heart rate on exercise. Control of rate response with other AV nodal blocking drugs such as β-​blockers or verapamil is associated with improved rate control which is especially important if the duration of diastole is critical, as in mitral stenosis or ischaemic heart disease. Often a combination of AV nodal blocking drugs is required. In cases where adequate rate control cannot be achieved despite combination therapy, radiofrequency ablation of the AV node and implantation of a permanent pacemaker (or cardiac resynchronization pacemaker) is an option, although this commits the patient to lifelong pacing therapy. Prevention of thromboembolism Atrial fibrillation patients have a fivefold increased risk of stroke compared to age-​and gender-​matched peers without atrial fibril- lation. However, individual stroke risk varies and is dependent upon the presence of other stroke risk factors such as increasing age, previous stroke, or transient ischaemic attack (TIA), hyper- tension, heart failure, diabetes mellitus, vascular disease (periph- eral artery disease, myocardial infarction), and female gender; the more risk factors that are present, the greater the risk of stroke. Importantly, when stroke occurs in the presence of atrial fibril- lation, the severity is greater, survival is poorer, residual neuro- logical deficit is greater, patients are more likely to require nursing home/​residential care, and risk of recurrent stroke within 12 months is increased. Oral anticoagulation for stroke prevention.  Anticoagulant therapy significantly reduces the risk of stroke and death in atrial fibrillation patients. Accordingly, current clinical guidelines (see Table 16.4.9) recommend effective stroke prevention with oral anticoagulation, either as a vitamin K antagonist (VKA, e.g. warfarin) or one of the non-​VKA oral anticoagulants, for all atrial fibrillation patients ex- cept those patients at extremely low risk of stroke (see Table 16.4.10). These low-​risk patients are defined as men and women aged under 65 years with no stroke risk factors. It is important to formally assess each patient’s individual risk of stroke to inform appropriate treat- ment decisions. Stroke risk assessment: CHA2DS2-​VASc.  The National Institute for Health and Care Excellence (NICE), American Heart Association/​ American College of Cardiology/​Heart Rhythm Society, and European Society of Cardiology (ESC) guidelines advocate the use of CHA2DS2-​VASc to assess stroke risk (see Table 16.4.9). CHA2DS2-​ VASc is an acronym for the stroke risk factors which comprise it (see Table 16.4.10): congestive heart failure, hypertension, age 75 years or more, diabetes mellitus, previous stroke or TIA, vascular dis- ease, age 65–​74 years, and female gender. The presence of each risk factor scores 1 point, except for age 75 years or over and previous stroke/​TIA, which score 2 points each; the maximum score is 9. The ACCP9 guidelines recommend assessing stroke risk using the older CHADS2 score: congestive heart failure, hypertension, age 75 years or more, diabetes mellitus (1 point for each), and previous stroke or Fig. 16.4.25  Virtual geometry of the left atrium using the Carto 3 system (Biosense Webster, Diamond Bar, CA, USA). The view is a posterior view. The pulmonary veins are shown and the veins are labelled (RSPV, right superior pulmonary vein; RIPV, right inferior pulmonary vein; LSPV, left superior pulmonary vein; LIPV, left inferior pulmonary vein). Lesions produced by sequential application of radiofrequency energy are shown by the red spheres, encircling the pulmonary veins to produce electrical isolation, which is confirmed using a circular mapping catheter, seen inside the RSPV. 16.4  Cardiac arrhythmias 3371 TIA (2 points); maximum score is 6. In those with a CHADS2 score of 0, the American College of Chest Physicians (ACCP) guidelines recommend consideration of ‘non-​CHADS2’ risk factors, that is, age 65–​74, female gender, and vascular disease. The CHA2DS2-​VASc score incorporates the CHADS2 score but offers a more compre- hensive assessment of stroke risk by including additional risk fac- tors (vascular disease, age 65–​74 years, and female gender, placing greater emphasis on age ≥75 years) and it also allows further risk stratification of patients with a CHADS2 score of 0. Indeed, patients designated as ‘low risk’ on the basis of a CHADS2 score of 0 are not truly low risk, and thus treatment decisions made on the basis of CHADS2 score of 0 (i.e. no therapy or aspirin monotherapy) may result in ineffective stroke prevention. The duration of paroxysms of atrial fibrillation required to in- crease the risk of thromboembolism in patients who are asymp- tomatic has been studied in the ASSERT trial where atrial arrhythmias were detected in patients with pacemaker implants. The annual incidence of stroke increased markedly from around 1% in those with episodes less than 17 h to approximately 5% per annum in those with episodes greater than 17 h. Bleeding risk assessment: HAS-​BLED.  Decisions regarding OAC or antithrombotic therapy also require formal assessment of the patient’s risk of bleeding with treatment, the purpose of which is to ‘flag up’ those at increased risk of bleeding for more careful review and follow-​up, and to address any modifiable bleeding risk factors. A high bleeding risk score should not necessarily lead to a decision to withhold anticoagulation, because for most patients the benefits of anticoagulation still outweigh the hazards. Appropriate and re- sponsible use of bleeding risk assessment is shown in Fig. 16.4.26. The NICE and ESC guidelines recommend the use of the HAS-​ BLED score to assess bleeding risk (see Table 16.4.9). The HAS-​ BLED acronym stands for uncontrolled hypertension, abnormal renal and/​or hepatic function, previous stroke, prior bleed or bleeding predisposition, labile INRs (if on VKA), elderly, concomi- tant interacting drugs, and alcohol (drink) excess; with 1 point for the presence of each risk factor (see Table 16.4.10), with a maximum score of 9. Many factors within the HAS-​BLED score are modifi- able and a patient’s HAS-​BLED score can be reduced by ensuring blood pressure is well controlled (<140/​90 mm Hg), maintaining INR control within the therapeutic range (INR 2.0–​3.0), omitting Table 16.4.9  Current guidelines for the antithrombotic management of atrial fibrillation Guidelines Assessment of stroke risk Assessment of bleeding risk Treatment recommendations Other recommendations NICE (2014) CHA2DS2-​VASc HAS-​BLED Offer OACa when CHA2DS2-​VASc ≥2, taking into consideration bleeding risk Consider OACa for men with CHA2DS2-​VASc ≥1, taking into consideration bleeding risk Review need for OAC at least yearly Do not offer aspirin monotherapy for stroke prevention in AF Only consider dual antiplatelet therapy if OAC contraindicated in patients with CHA2DS2-​VASc ≥2 OAC with VKA TTR ≥65% Assess TTR at each visit Correct modifiable reasons for poor INR controlc Consider alternative OAC if TTR cannot be improvedd NOACs In accordance with NICE STAs ESC (2016) CHA2DS2-​VASc No formal bleeding risk tool specified. Stresses attention to modifiable bleeding risk factors Consider patients’ treatment preferences No antithrombotic therapy if patient <65 years with lone AF (i.e. CHA2DS2-​VASc = 0 in males, 1 in females) OACa recommended if CHA2DS2-​VASc ≥2 in males, or ≥3 in females Consider OACa if CHA2DS2-​VASc 1 in males or 2 in females NOAC preferred to VKA in majority of AF patients initiating OAC NOACs Assess renal function before initiation (CrCl) Not recommended in those with severe renal impairment (CrCl<30 ml/​min) In accordance with licensed indications VKAs INR 2–​3; TTR control paramount ACCP (2012) CHADS2 but to consider other non-​CHADS2 risk factors (age 65–​74, vascular disease, female gender) No formal bleeding risk assessment or tool specified Tailor treatment decisions based on patients’ treatment preferences and bleeding risk No therapy if CHADS2 = 0 If patients with CHADS2 = 0 choose therapy, aspirin monotherapy or dual APT is recommended; if non-​ CHADS2 risk factors are present (age 65–​74, female gender, vascular disease), OAC recommended If CHADS2 = 1, OAC recommended over aspirin monotherapy or dual APT If CHADS2 ≥2, OAC recommended or aspirin monotherapy or dual APT if OAC refused/​ contraindicated Dabigatranb preferred over VKAs ACCP, American College of Chest Physicians; APT, antiplatelet therapy; CHADS2, congestive heart failure (recent), hypertension, age ≥75 years, diabetes mellitus, previous stroke, or transient ischaemic attack; CHA2DS2-​VASc, congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, previous stroke, or TIA, vascular disease, age 65–​74 years, female gender; CrCl, creatinine clearance; ESC, European Society of Cardiology; HAS-​BLED, uncontrolled hypertension, abnormal renal and/​or hepatic function, previous stroke, prior bleed, or bleeding predisposition, labile INRs (if on VKA), elderly, concomitant interacting drugs and alcohol (drink) excess; INR, international normalized ratio; NICE, National Institute for Health and Care Excellence; NICE STA, National Institute of Clinical Excellence single technology appraisal; NOAC, non​vitamin K antagonist oral anticoagulant; OAC, oral anticoagulation; TTR, time in therapeutic range, VKA, vitamin K antagonist. a Either vitamin K antagonist (most commonly warfarin) or non​vitamin K antagonist oral anticoagulant (apixaban, edoxaban, dabigatran, or rivaroxaban). b At the time the ACCP guidelines were published, dabigatran was the only NOAC approved by the US FDA. c Cognitive function; adherence to VKA; illness; drug interactions; lifestyle factors (diet and alcohol interactions). d If reason for poor TTR is non​adherence to OAC, switching to a NOAC is not recommended. section 16  Cardiovascular disorders 3372 nonessential antiplatelets or NSAIDs, and minimizing alcohol in- take (≤8 units/​week). A high HAS-​BLED score (≥3) does not indi- cate that OAC should be withheld, but warrants caution and should encourage more regular review and control of modifiable bleeding risks. In addition, OAC should not be withheld exclusively because of the risk of falls. Prediction of INR control: SAMe-​TT2R2.  Oral anticoagulation treatment options for stroke prevention in atrial fibrillation include VKAs and NOACs (see Fig. 16.4.27). The SAMe-​TT2R2 score (see Table 16.4.10), made up of routine demographic and clinical risk factors, can be used to identify upfront those newly diagnosed non-​ anticoagulated atrial fibrillation patients who are likely to have poor INR control on a VKA (SAMe-​TT2R2 score >2) and who may require more frequent INR monitoring and other interventions to help them achieve adequate time in therapeutic range (TTR) and for whom a NOAC might be a more effective option. Use of the SAMe-​TT2R2 score is recommended by an ESC Task Force on Anticoagulants in Heart Disease to aid decision-​making, rather than subjecting atrial fibrillation patients to a ‘trial of warfarin’ which may put such pa- tients at risk of stroke during the initial period of treatment. Patient preferences for treatment.  All of the most recent clinical guidelines advocate the importance of eliciting patients’ preferences regarding antithrombotic therapy and incorporating them into the decision-​making process. Central to informed decision-​making is patient education. The clinician’s role is to provide patients with in- formation about their own risk of stroke, the benefits of OAC in re- ducing this risk, and their risk of bleeding with such treatment to allow them to make appropriate treatment decisions, and to respect their views and beliefs. Patients with better knowledge about atrial fibrillation, who understand the necessity of OAC for stroke preven- tion, despite having awareness and/​or concerns about the bleeding risk associated with OAC, are more likely to adhere to treatment. Use of oral anticoagulation in the United Kingdom and globally.  Despite the overwhelming evidence of the benefit of OAC for stroke prevention in atrial fibrillation, two recent sizeable observational Table 16.4.10  Risk stratification scores to assess stroke risk (CHA 2DS 2-​VASc), bleeding risk (HAS-​BLED), and predict INR control (SAMe-​TT 2R 2) CHA 2DS 2-​VASc HAS-​BLED SAMe-​TT 2R 2 Definition Score Risk factor Definition Score Risk factor Definition Score Congestive heart failure Decompensated (i.e. hospitalized) HF irrespective of ejection fraction (i.e. HFrEF and HFpEF) and/​or objective evidence of moderate-​severe LV systolic dysfunction (on echocardiography) 1 Hypertension (uncontrolled) Systolic blood pressure 160 mm Hg 1 Gender Female 1 Hypertension Elevated blood pressure (>140/​90 mm Hg) or history of hypertension (receiving antihypertensive medication) 1 Abnormal renal function Chronic dialysis, renal transplantation, serum creatinine ≥200 mmol/​litre 1 Age <60 years 1 Age ≥75 years 2 Abnormal liver function Biochemical evidence of hepatic derangementa 1 Medical history ≥2 of the following: hypertension, diabetes, CAD/​MI, PAD, CHF, stroke, pulmonary dx, hepatic, or renal dx 1 Diabetes mellitus 1 Stroke Ischaemic or haemorrhagic 1 Treatment Interacting drugs (e.g. amiodarone) 1 Stroke/​TIA/​TE Previous stroke, transient ischaemic attack, or thromboembolism 2 Bleeding History of bleeding or bleeding predisposition (e.g. anaemia) 1 Tobacco use Current or ex-​smoker (within 2 years) 2 Vascular disease PAD, myocardial infarction, aortic plaque 1 Labile INR TTR <60% 1 Race Non​white ethnicity 2 Age 65–​74 years 1 Elderly E.g. >65 years, extreme frailty 1 Gender Female 1 Drugs or alcohol excess Concomitant antiplatelets or NSAIDs or excessive alcohol (≥8 units/​week (1 point for each) 1 or 2 Maximum score 9 9 8 CAD, coronary artery disease; CHF, congestive heart failure; dx, disease; HF, heart failure; HFrEF and HFpEF, heart failure with reduced or preserved ejection fraction; INR, international normalized ratio; LV, left ventricular; NSAIDs, non​steroidal anti-​inflammatory drugs; PAD, peripheral arterial disease; TTR, time in therapeutic range. a Bilirubin >2 upper limit of normal (ULN) in association with aspartate aminotransferase/​alanine aminotransferase/​alkaline phosphatase>3 ULN. 16.4  Cardiac arrhythmias 3373 Patient with atrial fibrillation; eligible for oral anticoagulation Bleeding risk assessment Review and address potentially reversible bleeding risk factors Uncontrolled hypertension Labile INRs (if receiving a VKA) Concomitant use of aspirin or NSAIDs in anticoagulated patient Alcohol excess Identifies ‘at-risk’ patients for more regular review and follow-up A ‘high-risk’ bleeding risk score is not a reason or execuse to withhold oral anticoagulation For patients with an increased risk of bleeding the benefit of oral anticoagulation usually, but not always, outweighs the bleeding risk; thus, regular review and careful monitoring of bleeding risk is important Do not withhold oral anticoagulation solely because the patient is at risk of falls EHR and ‘electronic alerts’ Low risk = no action High risk = patient ‘flagged up’ for review Fig. 16.4.26  Bleeding risk assessment in AF—​observations on the use and misuse of bleeding risk scores. EHR, electronic health record; INR, International Normalized Ratio; NSAID, non​steroidal anti-​inflammatory drug; VKA, vitamin K antagonist. From Lip GYH and Lane DA (2016). Bleeding risk assessment in atrial fibrillation: observations on the use and misuse of bleeding risk scores. J Thromb Haemost, 14, 1711–​4, © 2016 International Society on Thrombosis and Haemostasis, with permission from John Wiley and Sons. Fig. 16.4.27  The approach to decision-​making in the AF patient management pathway using the CHA2DS2-​VASc, HAS-​BLED, and SAMe-​TT2R2 scores. section 16  Cardiovascular disorders 3374 studies have demonstrated that large proportions of patients at risk of stroke (CHA2DS2-​VASc score ≥2 or CHADS2 score of ≥2) still do not receive OAC. In the first cohort from the Global Anticoagulant Registry in the FIELD (GARFIELD) study, of 10 614 AF patients in 19 countries, 40.7% of patients with a CHA2DS2-​VASc score of 2 or more did not receive OAC. More than one-​half of the reasons given for withholding OAC therapy for patients at risk of stroke in the GARFIELD registry were linked to physician choice (i.e. bleeding risk, concerns over patient adherence, falls risk). Perhaps a more worrying finding from the GARFIELD registry revealed that ap- proximately one-​quarter of patients with a CHA2DS2-​VASc score of 2 or more were receiving antiplatelet monotherapy. A  similar underuse of OAC in patients at high of stroke and overuse in those at low risk was seen in the Euro Heart Survey which was conducted a decade ago. The recent analysis in 1857 general practices in the United Kingdom, utilizing the GRASP-​AF tool (which assessed stroke risk on the basis of the CHADS2 score and recommends treatment based on the 2006 NICE guidelines), demonstrated that 34.0% of patients with a CHADS2 score of 2 or more, with no docu- mented contraindication to OAC, were receiving OAC and the use of antiplatelet therapy rose as stroke risk increased. Use of OAC de- clined significantly among patients aged 80 years or over (47.4% vs. 64.5%; p <0.001), while antiplatelet therapy increased in this age group. Consequently, those patients at greatest risk of stroke (i.e. elderly patients and those with multiple comorbidities) are the very patients who are least likely to receive adequate preventative therapy against stroke. This is despite very clear evidence from the Birmingham Atrial Fibrillation in The Aged (BAFTA) study which demonstrated that warfarin was more effective in preventing strokes than aspirin in patients aged 75 years or over (2.5% vs. 4.9% per year; RR 0.52 [95% CI 0.33–​0.80]), with a similar risk of major bleeding (1.9% vs. 2.0% per year; RR 0.96 [95% CI 0.53–​1.75]) and from an individual patient-​data meta-​analysis of approximately 9000 atrial fibrillation patients which confirmed that OAC was efficacious in reducing ischaemic stroke regardless of the patient’s age, whereas the protective effect of aspirin declined significantly with age. The lack of OAC prescription among atrial fibrillation patients at risk of stroke was not related to their bleeding risk or comorbidities. Guidelines for stroke prevention in atrial fibrillation.  Effective prevention of stroke for atrial fibrillation patients requires OAC, ei- ther with a VKA or one of the NOACs (see Table 16.4.9 and Fig. 16.4.27). If patients are prescribed a VKA, the most important con- sideration is their anticoagulation control (INR 2.0–​3.0), evidenced by a TTR of 65% or more. Patient education about factors that may affect their INR control (e.g. diet, alcohol intake, and interacting drugs) is important, and regular INR monitoring and assessment of the reasons for poor anticoagulation control is essential. Indeed, a recent trial demonstrated that a one-​off intensive education ses- sion significantly improved TTR 6 months after warfarin initiation in an inception cohort compared to usual care. Consideration and correction (where possible) of the reasons for poor anticoagulation need to be addressed (see Fig. 16.4.27 and Table 16.4.9). Currently four NOACs—​apixaban, dabigatran, edoxaban, and rivaroxaban—​ are NICE approved and available for stroke prevention in atrial fib- rillation (see Table 16.4.11 and Fig. 16.4.27). For patients who are OAC-​naive, the NOACs are broadly preferred over a VKA for most patients. Strict adherence to licensed indications is essential and a recent European Heart Rhythm Association document offers excel- lent practical guidance on the use of NOACs in practice. Renal func- tion must be assessed prior to initiating a NOAC and the creatinine clearance, using the Cockcroft–​Gault formula, must be calculated. NOACs should not be used in patients with severe renal impair- ment (CrCl <30 ml/​min), although rivaroxaban 15 mg once daily, edoxaban 30 mg once daily, and apixaban 2.5 mg twice daily can be used with caution in patients with CrCl 15–​29 ml/​min. Regular monitoring of a patients’ renal function for the duration of NOAC treatment is advocated; the frequency of renal function testing is de- pendent of the degree of renal impairment (see Table 16.4.11). Dose reductions are required in patients with moderate renal impairment and according to other factors (see Table 16.4.11 ‘Dose reductions’ for specific criteria for each NOAC). Aspirin monotherapy is not an effective treatment strategy for stroke prevention in patients with atrial fibrillation and conse- quently the clinical guidelines actively discourage its use. Dual antiplatelet therapy, with aspirin and clopidogrel, should only be considered in patients with a CHA2DS2-​VASc score of 2 or more in whom any OAC use is absolutely refused or contraindicated, given the increased risk of bleeding with dual antiplatelets and re- duced efficacy compared to OAC. Left atrial appendage occlusion devices should only be considered if OAC is absolutely contraindi- cated; they are not a first-​line alternative to OAC and the risks of LAAO need to be carefully discussed with the patient. Regardless of the stroke prevention treatment strategy selected after discus- sion with the patient, treatment decisions and stroke and bleeding risk assessments should be reviewed at least annually as a patients’ risk may change and treatment may need to be altered. One of the NICE 2014 recommendations is to offer patients with atrial fibrillation ‘a personalized package of care including measures to prevent stroke’. This involves matching the right OAC drug to the patient on the basis of their stroke and bleeding risk assessment and overall clinical background/​profile, which requires knowledge of the results of individual trials and of ‘real world’ observational studies supporting effectiveness or safety for particular patient profiles (Fig. 16.4.28). Net clinical benefit of OAC: NOACs versus warfarin.  The most ap- propriate stroke prevention strategy involves balancing the benefit of treatment (i.e. reduction in stroke) against the possibility of serious bleeding (i.e. intracranial haemorrhage) associated with treatment for each patient; an evaluation of the net clinical benefit. An analysis of the net clinical benefit of warfarin was undertaken in a large (>180 000) cohort of Swedish patients, with stroke and bleeding risk as- sessed by CHA2DS2-​VASc and HAS-​BLED, respectively. This study found that OAC treatment was associated with a positive net clinical benefit for all patients, except those with a CHA2DS2-​VASc score of 0, confirming their truly low-​risk status. Those with high stroke and high bleeding risk fared best from warfarin therapy; there were 12 fewer ischaemic strokes per 100 years at risk compared to not giving warfarin. What about the net clinical benefit of the NOACs against warfarin? There will never be a direct head-​to-​head comparison of the NOACs, therefore the next best option is an indirect comparison of the NOACs with warfarin. A similar analysis modelled the net clinical benefit of the NOACs apixaban, dabigatran, and rivaroxaban against warfarin in a real-​ world cohort of Danish atrial fibrillation patients. All four NOACs 16.4  Cardiac arrhythmias 3375 offered a net clinical benefit superior to warfarin among patients with a CHA2DS2-​VASc score of 2 or more or a CHADS2 score of 1 or more, despite the risk of bleeding. Among patients with a CHA2DS2-​ VASc score of 1, both doses of dabigatran and apixaban were associ- ated with better net clinical benefit. In patients with a CHADS2 score of 0 and a high risk of bleeding, only dabigatran 110 mg twice daily and apixaban displayed a beneficial net clinical outcome. If the risk of stroke and the risk of bleeding are high, the NOACs have a risk-​ benefit profile superior to that of warfarin. To streamline decision-​making for stroke prevention in patients with atrial fibrillation, a simple three-​step process in the patient pathway can be considered, as shown in Fig. 16.4.29. Atrial flutter Typical atrial flutter is caused by a macro re-​entrant circuit in the right atrium involving the cavo-​tricuspid isthmus (Fig. 16.4.30), which produces a typical electrocardiographic ‘sawtooth’ pattern of atrial activity with a rate close to 300/​min (Fig. 16.4.31). In the common form of the arrhythmia, flutter waves are negative in leads II, III, and aVF and positive in lead V1 and may be associated with either a regular or irregular ventricular response. Flutter with 2:1 AV conduction produces a regular tachycardia of 150/​min and should always be considered in the differential diagnosis of a regular, narrow-​QRS tachycardia of this rate. Occasionally, flutter occurs with 1:1 AV conduction producing a ventricular rate approaching 300/​min. Class I antiarrhythmic drugs may predispose to this by causing a relative slowing of the atrial rate and allowing 1:1 conduc- tion through the AV node. The flutter waves may not be seen easily with faster ventricular rates, and transient slowing of AV conduction may be necessary to make the diagnosis (Fig. 16.4.31). The underlying risk factors for the development of atrial flutter are the same as those of atrial fibrillation (Box 16.4.2) and likely represent different manifestations of an atrial electrical myopathy. Indeed, the conditions often coexist and patients may manifest ei- ther flutter or fibrillation at different times. Atrial flutter is often poorly tolerated due to fixed, fast ventricular rates, and it can be difficult to rate control with AV nodal blocking drugs. Termination may be achieved by chemical or electrical cardioversion, as just described here for atrial fibrillation. Drug prophylaxis against atrial flutter uses the same agents as in parox- ysmal atrial fibrillation, although some antiarrhythmic drugs may slow conduction and be proarrhythmic. Radiofrequency ablation is increasingly used as first-​line therapy, where a line of conduction block is created between the tricuspid valve annulus and the inferior vena cava, interrupting the isthmus through which the re-​entry cir- cuit must pass (Fig. 16.4.30). This achieves cure in 90–​95% of cases, Table 16.4.11  Novel oral anticoagulants for stroke prevention in atrial fibrillation Drug characteristics Apixaban Dabigatran Edoxaban Rivaroxaban Mechanism Oral direct factor Xa inhibitor Oral direct thrombin inhibitor Oral direct factor Xa inhibitor Oral direct factor Xa inhibitor Half-​life (h) 9–​14 12–​17 10–​14 5–​13 Excretion 25% renal; 75% faecal 80% renal 50% 66% liver, 33% renal Dose 5 mg twice daily 150 mg twice daily 60 mg once daily 20 mg once daily Dose in renal impairmentd (30–​49 ml/​min) 2.5 mg twice dailyc 110 mg twice daily 30 mg once dailya 15 mg once daily Dose reductions If ≥2 of following: serum creatinine >133 μmol/​l; age ≥80 years; body weight ≤60 kg ≥80 years; concomitant verapamil; HAS-​BLED score ≥3e ≥1 of the following: CrCl ml/​min 15–​50 ml/​min; body weight ≤60 kg; on ciclosporin, dronedarone, erythromycin, or ketoconazole No dose reduction except for renal function Drug interactions Anticoagulants, antiplatelets, NSAIDs; ketoconazole, itraconazole, voriconazole, posaconazole, HIV protease inhibitors (ritonavir), rifampicin, St John’s wort, phenobarbital, phenytoin, carbamazepine Anticoagulants, antiplatelets, NSAIDs; systemic ketoconazole, ciclosporin, tacrolimus, itraconazole, verapamil; quinidine, dronedarone, amiodarone, clarithromycin, rifampicin, St John’s wort, phenytoin, carbamazepine, SSRIs, SNRIs Anticoagulants, antiplatelets, NSAIDsb Ciclosporin, dronedarone, erythromycin, or ketoconazoleb Quinidine, verapamil, amiodarone Phenytoin, carbamazepine, phenobarbital, or St John’s Wort Anticoagulants, antiplatelets, NSAIDs; ketoconazole, fluconazole, itraconazole, voriconazole, posaconazole quinidine, HIV protease inhibitors (ritonavir), clarithromycin, erythromycin, dronedarone, rifampicin, St John’s wort, phenobarbital, phenytoin, carbamazepine Take with/​after food No Yes No Yes Check renal function Divide CrCl by 10; e.g. CrCl 60 ml/​min monitor every 6 months; if decline in renal function is suspected (e.g. hypovolaemia, dehydration) or concomitant use of certain medicinal products, check renal function a if CrCl 15–​50 ml/​min b Reduce dose to 30 mg once daily if use of concomitant use of ciclosporin, dronedarone, erythromycin, or ketoconazole. c Dose reduction if serum creatinine >133 μmol/​litre plus age ≥80 years and/​or body weight ≤60 kg. d Dabigatran not to be used if CrCl <30 ml/​min; edoxaban, rivaroxaban, and apixaban not be used if CrCl <15 ml/​min; rivaroxaban and apixaban only to be used if CrCl 15–​29 ml/​min with caution and regular review (at least 3 monthly). e On an individual basis based on stroke and bleeding risk. Adapted from Camm AJ et al. (2012) ESC Committee for Practice Guidelines (CPG). 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Eur Heart J, 33, 2719–​47; and Heidbuchel H et al. (2013) European Heart Rhythm Association. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non​valvular atrial fibrillation. Europace, 15, 625–​51. section 16  Cardiovascular disorders 3376 Recurrent stroke, systemic embolic event, or transient ischaemic attack despite good anticoagulation control (TTR > 70%) Dabigatran 150 mg BID Apixaban 5 mg BID*, rivaroxaban 15 mg once daily, dabigatran (if CrCl 30–49 ml/min)†, or edoxaban 30 mg once daily⧧ Apixabin 5 mg BID* or dabigatran 110 mg BID§ Apixaban 5 mg BID*, rivaroxaban 20 mg once daily¶, or edoxaban 60 mg once daily Dabigatran 110 mg BID§, apixaban 5 mg BID*, or edoxaban 60 mg once daily VKA, rivaroxaban 20 mg once daily¶, or edoxaban 60 mg once daily Apixaban 5 mg BID*, dabigatran†, or edoxaban 60 mg once daily VKA with additional education and more regular follow-up, dabigatran†, rivaroxaban 20 mg once daily¶, apixaban 5 mg BID*, or edoxaban 60 mg once daily Moderate-to-severe renal impairment (CrCl 15–49 ml/min) High risk of gastrointestinal bleeding Gastrointestinal symptoms or dyspepsia High risk of bleeding (HAS-BLED ≥3) Once daily dosing or preference to have a lower pill burden Asian patients (consider drugs with reduced risk of intracranial haemorrhage and major bleeding in Asian subgroups) Choosing the oral anticoagulant drug to fit the patient profile Less likely to do well on VKA with good TTR (SAMe-TT2R2 score >2) Fig. 16.4.28  Stroke prevention in atrial fibrillation: fitting the drug to the patient profile. CrCl, creatinine clearance; TTR, time in therapeutic range; VKA, vitamin K antagonist. *Reduced to 2.5 g BID with two or three criteria from age ≥80 years, bodyweight ≤60 kg, or serum creatinine concentration ≥133 μmol/​litre. †110 mg BID for patients with a CrCl 30–​49 ml/​min (most countries, but not in the United States); in the United States only, 75 mg BID (available in the United States only) for patients with CrCl 15–​29 ml/​min (and only 150 mg BID dose available in the United States for CrCl >30 ml/​min). ‡30 mg with CrCl 15–​49 ml/​min, P-​glycoprotein inhibitors, or weight <60 kg. §110 mg BID dose not available in the United States for atrial fibrillation. ¶ Reduced to 15 mg if CrCl 15–​49 ml/​min. ‖Dose to be halved if the patient has any of the following: CrCl 15–​49 ml/​min, bodyweight ≤60 kg, or concomitant use of P-​glycoprotein inhibitors. Reprinted from The Lancet, Vol. 388(10046), Freedman B, Potpara TS, Lip GY, Stroke prevention in atrial fibrillation, pp. 806–​17, Copyright 2016, with permission from Elsevier. Step 1 identify low-risk patients Low stroke risk CHA2DS2-VASc score: 0 in males 1 in females Calculate SAMe-TT2R2 score SAMe-TT2R2 score >2 Regular review/INR checks/ counselling for VKA users SAMe-TT2R2 score 0–2 VKA treatment (eg. warfarin) ... or try a NOAC Step 3 Decide on NOAC or VKA with high time in therapeutic range No antithrombotic treatment Also calculate the HAS-BLED score. If HAS-BLED ≥3, address the modifiable bleeding risk factors and plan a closer clinical follow-up. Step 2 consider stroke prevention (i.e. oral anticoagulant) in all AF patients with ≥1 additional stroke risk factors Fig. 16.4.29  The Birmingham ‘3-​step’ to streamline decision-​making for stroke prevention in patients with atrial fibrillation. Reprinted from Lip GYH (2017). Stroke prevention in atrial fibrillation. The Lancet, 38(1), 4–​5, by permission of Oxford University Press. 16.4  Cardiac arrhythmias 3377 but does not, however, alter the risk of future development of atrial fibrillation. With regards to thrombo-​prophylaxis, anticoagulation is indi- cated before and after cardioversion, as for atrial fibrillation. The role of longer-​term anticoagulation is less clear and is currently not mandated. However, given the close link between atrial flutter and atrial fibrillation, the presence of silent atrial fibrillation should be considered, especially in those with high CHA2DS2-​VASc scores. Finally, while it is important to note that although typical flutter accounts for more than 90% of all re-​entrant circuits occurring spontaneously in the atria (others include incisional or scar-​related re-​entry), iatrogenic left atrial flutters are increasing in frequency as a consequence of increased use of ablation to treat AF. Focal atrial tachycardia Focal atrial tachycardia is an automatic arrhythmia, usually re- sulting in an atrial rate between 120 and 250/​min. There may be a degree of AV block, although 1:1 AV conduction can occur. The ECG usually shows regular P-​waves which do not show the same ‘sawtooth’ appearance as in atrial flutter (Fig. 16.4.32). In contrast to most other forms of supraventricular tachycardia, focal atrial tachycardia usually has a long RP interval (defined as >50% of the RR interval). The rate characteristically accelerates or ‘warms up’ before reaching a rate of 125–​200/​min, and careful analysis of morphology of the P-​wave aids in localization of the source. Multifocal atrial tachycardia, in which rapid, irregular P-​waves of three or four different morphologies are seen, may occur in se- verely ill elderly patients, or in association with acute exacerbation of pulmonary disease. Acute management includes drug treatment or cardioversion, as for atrial fibrillation. Focal atrial tachycardia may be amenable to treatment with radiofrequency ablation with success rates ap- proaching 80%, although recurrence rate is high. Supraventricular tachycardia Although all atrial arrhythmias are (by definition) supraventricular in origin, the term supraventricular tachycardia is commonly re- served for those in whom the AV node is an obligate part of a re-​ entry circuit—​AV nodal re-​entrant tachycardia (AVNRT) or AV re-​entry tachycardia (AVRT). Correct recognition of these arrhyth- mias has achieved additional importance with the development of effective curative measures. Atrioventricular nodal re-​entry tachycardia Mechanism This is the commonest cause of paroxysmal re-​entry tachycardia manifesting regular, normal QRS complexes. The basis of the ar- rhythmia is the presence of two functionally distinct pathways in the region of the AV node (Fig. 16.4.33). The ‘fast’ pathway conducts more rapidly but has a longer refractory period. The ‘slow’ pathway has slower conduction properties but a shorter refractory period. During sinus rhythm, AV nodal conduction occurs via the fast pathway with a normal PR interval (Fig. 16.4.33a). If a sufficiently premature atrial extrasystole arises, conduction in the fast pathway is blocked, but slow pathway conduction may continue, resulting in an abrupt increase in the AH interval as recorded in the His bundle electrogram. This corresponds to an increased PR interval on the surface ECG (Fig. 16.4.33b). If conduction down the slow pathway is sufficiently delayed to allow the fast pathway to recover excitability before activation reaches the distal end of the pathways, retrograde activation occurs via the fast pathway. The stage is then set for a re-​ entry circuit with anterograde conduction via the slow pathway and retrograde conduction via the fast pathway (‘slow/​fast AV nodal re-​ entry’; Fig. 16.4.33c). Characteristically, anterograde activation of the ventricles and retrograde activation of the atria occur virtually simultaneously, resulting in the P-​wave being ‘buried’ within the QRS complex, or producing a very small distortion of the terminal TVA RA IVC Fig. 16.4.30  Mechanism of atrial flutter. Typical atrial flutter results from a counterclockwise re-​entry circuit in the right atrium. The isthmus between the tricuspid valve annulus (TVA) and inferior vena cava (IVC) forms a critical part of this circuit, and linear ablation to create block can prevent recurrent atrial flutter. Fig. 16.4.31  Atrial flutter with 1:1 AV conduction (top), 2:1 conduction (middle), and following adenosine administration (bottom) (6 mg intravenous injection 10 s previously). Fig. 16.4.32  Atrial tachycardia, with variable AV conduction. Lead V1. section 16  Cardiovascular disorders 3378 QRS, recognition of which requires careful comparison with the ECG during sinus rhythm (Fig. 16.4.34). A less common variant of AV nodal re-​entry tachycardia may arise where anterograde conduction during tachycardia is via the fast pathway with retrograde conduction via the slow pathway (‘fast/​ slow AV nodal re-​entry’, also termed ‘atypical AVNRT’). Under these circumstances, the atrium is activated well after the QRS com- plex, characteristically producing an inverted P-​wave, with the RP interval greater than the PR interval during tachycardia, termed ‘long RP tachycardia’ (Fig. 16.4.35). Clinical features Atrioventricular nodal re-​entry tachycardia commonly presents in young adults, although it may appear at any age. Episodes are char- acterized by sudden onset and sudden offset of symptoms of regular palpitations, which are normally well tolerated unless the tachy- cardia is particularly rapid, prolonged, or if the patient has other heart disease. The natural history is of episodic paroxysmal tachy- cardia, occurring at random intervals, although there may be clus- tering of attacks interposed with periods of relative freedom from symptoms. Atrioventricular nodal re-​entry tachycardia has no spe- cific association with other organic heart disease. Management Termination of an attack of AV nodal re-​entry tachycardia is achieved by producing transient AV nodal block. This may be achieved by vagotonic manoeuvres, by intravenous adenosine (3–​18 mg; see Fig. 16.4.34), or by intravenous verapamil (6–​18 mg). Drug prophylaxis of AV nodal re-​entry tachycardia is undertaken with β-​blockers, a combined β-​blocker/​class  III agent such as sotalol, or AV nodal blocking drugs such as verapamil or digoxin, although curative treatment of AV nodal re-​entry tachycardia by radiofrequency ablation is increasingly used as a first-​line therapy. Radiofrequency energy is delivered to the ‘slow’ pathway, which lies between the compact AV node and the tricuspid annulus. Ablation at this site is normally curative in over 95% of cases but carries a small risk (0.5–​1%) of inducing complete heart block. Atrioventricular re-​entry tachycardia Mechanism In contrast to AV nodal re-​entry tachycardia, the substrate for AV re-​entry is the presence of a second atrioventricular connection, separate from the AV node. This accessory pathway can lie any- where along the mitral or tricuspid annuli. Anterograde pathway conduction produces ventricular pre-​excitation and is discussed in the ‘Pre-​excitation syndromes’ section to follow. However, some ac- cessory pathways only conduct in the retrograde (ventriculoatrial) direction and are termed ‘concealed’, since there is no clue to their presence on the resting ECG. The anterograde limb of the re-​entrant circuit is the AV node, with retrograde atrial activation occurring over the accessory pathway (see Fig. 16.4.36). This is termed ortho- dromic tachycardia and normally produces a narrow-​complex QRS morphology. Retrograde atrial activation can be identified by the presence of a characteristic inverted P′-​wave early in the ST seg- ment, an important diagnostic feature of AV re-​entry tachycardia (Fig. 16.4.37). Rarely, an accessory pathway with slow retrograde Fig. 16.4.33  Atrioventricular nodal re-​entry tachycardia. Mechanism of initiation by atrial extrasystole. See text for details. Fig. 16.4.34  Atrioventricular nodal re-​entrant tachycardia. Rapid narrow-​ complex tachycardia with no apparent P-​waves (upper) responding to 6 mg adenosine with restoration of sinus rhythm (lower). Close inspection reveals a positive deflection of the terminal QRS during tachycardia (pseudo R′, arrowed) which is absent during sinus rhythm. This is due to retrograde atrial activity coincident with ventricular activation. Lead V1. Fig. 16.4.35  Atypical atrioventricular nodal re-​entry tachycardia (‘long RP’). Inverted P-​waves precede the QRS complex during tachycardia (compare with preceding sinus beats). 16.4  Cardiac arrhythmias 3379 conduction may allow a stable, incessant re-​entrant circuit with a long RP interval, referred to as permanent junctional reciprocating tachycardia. Clinical features Features are similar to AV nodal re-​entry tachycardia, although ac- cessory pathways are the more common tachycardia substrate in children. Patients have a similar relapsing course of symptoms inter- spersed with periods of relative quiescence. Multiple pathways can be present within the same patient and are more common if there is coexisting structural heart disease such as Ebstein’s anomaly (see Chapter 16.12). Management As with AV nodal re-​entry tachycardia, the AV node is an obligate part of the circuit and attacks may be aborted by vagotonic man- oeuvres or with intravenous adenosine. Antiarrhythmic therapy may be effective, but radiofrequency ablation offers high success rates with low incidence of complications and should be considered early in a patient’s treatment. Pre-​excitation syndromes (Wolff–​Parkinson–​White syndrome) The term ‘pre-​excitation’ refers to the premature activation of the ventricle via one or more accessory pathways that conduct in the antegrade direction (from atrium to ventricle), bypassing the normal AV node and His–​Purkinje system. Accessory pathways with elec- trophysiological properties of normal myocardium may lie at any point in the AV ring, the commonest sites being in the left free wall or the posteroseptal region (Fig. 16.4.36). The characteristic electrocardiographic appearance is due to the fusion of wavefronts progressing down the normal His–​Purkinje system and the antegradely conducting accessory pathway. Early ventricular activation through the pathway occurs more quickly than conduction through the AV node, producing a short PR interval, but thereafter intraventricular conduction is slow, resulting in slurred initiation of the QRS complex (the δ-wave; Fig. 16.4.38), before the remainder of the ventricle is excited via the normal His–​Purkinje system. QRS morphology therefore reflects fusion of AV nodal and accessory pathway conduction. As such, the degree of pre-​excitation during sinus rhythm is variable: it may be intermittent if the re- fractory period of the accessory pathway is close to the sinus cycle length (Fig. 16.4.38), or inapparent if the δ-wave is obscured due to rapid AV nodal conduction. In such instances, transient slowing of AV nodal conduction (e.g. by adenosine) will enhance the pro- portion of the ventricle excited by the accessory pathway and reveal pre-​excitation. The ECG appearances of a δ-wave occur in approximately 1.5 per 1000 of the population, but many individuals never experience paroxysmal tachycardias. The Wolff–​Parkinson–​White syndrome describes the combination of the symptoms of palpitation and the presence of pre-​excitation on the ECG. (a) (c) (b) Fig. 16.4.36  Atrioventricular re-​entry tachycardia. Mechanism of initiation by atrial extrasystole. See text for details: if the accessory pathway were concealed the ECG in sinus rhythm would not show the characteristic δ-wave. Fig. 16.4.37  Initiation of atrioventricular re-​entry tachycardia. The third sinus beat is followed by the onset of narrow-​complex tachycardia, initiated by an atrial extrasystole (obscured by T-​wave). Retrograde atrial activation, with inverted P-​waves in the ST segment (arrows), are seen during tachycardia. section 16  Cardiovascular disorders 3380 Mechanisms of orthodromic and antidromic tachycardia The mechanism for orthodromic AV re-​entry tachycardia is illus- trated in Fig. 16.4.35. A premature atrial extrasystole may find the pathway refractory but be conducted through the AV node to the ventricles (Fig. 16.4.36b). If sufficient delay has occurred by the time the ventricular insertion of the accessory pathway is depolarized, the pathway may have recovered excitability and allow retrograde activation from the ventricle to atrium, with the establishment of a re-​entry circuit (Fig. 16.4.36c). Since the circuit involves activation of the ventricles via the His–​Purkinje system, the QRS morphology during re-​entry tachycardia is normal, unless a rate-​related bundle branch block develops. If a bundle branch block is seen at a lower heart rate than a documented narrow-​complex tachycardia, this is diagnostic of an accessory pathway ipsilateral to the bundle branch block (Coumel’s sign). A rare form of AV re-​entry tachycardia has anterograde conduc- tion via the accessory pathway and retrograde conduction via the AV node (antidromic tachycardia). The QRS morphology of this tachycardia is broad and grossly abnormal, with appearances de- pendent upon the site of insertion of the accessory pathway. Pre-​excited atrial fibrillation The major prognostic concern in Wolff–​Parkinson–​White syn- drome is pre-​excited atrial fibrillation. Conduction via an acces- sory pathway with a short refractory period, bypassing the normal AV nodal slowing, may result in very rapid conduction to the ven- tricle (Fig. 16.4.39) that can degenerate into ventricular fibrilla- tion. The degree of pre-​excitation during atrial fibrillation varies, giving a characteristic pattern of an irregular ventricular response with QRS morphology ranging from normal to fully pre-​excited. The risk of sudden death is increased if the shortest R-​R interval is less than 250 ms during pre-​excited atrial fibrillation, and is an indication for urgent cardioversion and early radiofrequency ablation. Management of the symptomatic patient with ventricular pre-​excitation The AV node is a part of the re-​entry circuit in both ortho-​and anti- dromic tachycardia, and adenosine and other AV nodal-​blocking drugs may be effective. However, adenosine may precipitate pre-​ excited atrial fibrillation and should be used with caution. In pa- tients with known Wolff–​Parkinson–​White syndrome presenting with AV re-​entrant tachycardia, drugs which also act on the acces- sory pathway such as flecainide or sotalol may be preferred. In pre-​ excited atrial fibrillation, AV nodal blocking drugs such as digoxin or verapamil should be avoided, because of the risk of ventricular fibrillation; treatment should be with antiarrhythmic therapy such as flecainide or by DC cardioversion. Patients with Wolff–​Parkinson–​ White syndrome should be offered radiofrequency ablation as first-​ line therapy. This abolishes the risk of pre-​excited atrial fibrillation as well as preventing further attacks of AV re-​entry tachycardia. Careful mapping of the AV annulus using an electrode catheter is necessary to identify the site of the accessory pathway, at which the interval between the atrial and ventricular electrograms is at a min- imum. Passage of the radiofrequency current causes heating of the catheter tip and results in the disappearance of accessory pathway conduction within a few seconds (Fig. 16.4.40). The success rate of Fig. 16.4.38  Intermittent pre-​excitation in Wolff–​Parkinson–​White syndrome. The first two beats show the characteristic short PR interval and δ-wave. The middle two beats, however, show that the pre-​excitation was intermittent. The pathway has become refractory, with normal PR interval and QRS morphology. Pathway conduction returns to cause pre-​excitation in the final two beats. 1s Fig. 16.4.39  Pre-​excited atrial fibrillation. Conduction via an accessory pathway results in an irregular broad-​complex tachycardia. The third and fourth beats show less pre-​excitation, with activation mainly through the normal conducting system, with more normal QRS-​complex morphology. Lead V1. RF I V1 CS Map s 2 s 1 0 Fig. 16.4.40  Radiofrequency ablation of an accessory pathway. The patient had Wolff–​Parkinson–​White syndrome with evidence of ventricular pre-​excitation on the surface electrogram during sinus rhythm (short PR interval, δ-wave). One beat after switching on the radiofrequency (RF) current the QRS becomes normal, indicating successful ablation of the accessory pathway. This was a left-​sided accessory pathway, as shown by the short interval between left atrial and left ventricular activation recorded from the coronary sinus (CS). This interval is prolonged following ablation of the pathway. Surface leads I, V1, and intracardiac electrograms from CS and mapping catheter (Map) are shown. 16.4  Cardiac arrhythmias 3381 ablation varies according to the location of the pathway, but is usu- ally over 90%. Approach to the asymptomatic patient with ventricular pre-​excitation Patients with Wolff–​Parkinson–​White syndrome should be evalu- ated carefully for the risk of pre-​excited atrial fibrillation, even in the absence of symptoms. The risk of sudden death due to rapid pre-​excited atrial fibrillation is very low among adults who have not had any symptomatic tachycardias, but is higher in symptom- atic patients. If pre-​excitation is intermittent, this indicates a long refractory period of the pathway and a low risk of life-​threatening tachycardias. Abrupt disappearance of the δ-wave in response to exercise testing, or during Holter monitoring, or with the admin- istration of a class Ia or Ic antiarrhythmic drug, also suggests a low risk. Some centres advocate diagnostic electrophysiological studies to identify a high-​risk group with short pathway refractory periods and inducible tachycardia or pre-​excited atrial fibrillation. The gen- eral tendency is for accessory pathway conduction to become slower with increasing age, and spontaneous disappearance of conduction is well documented. Other pre-​excitation syndromes Other forms of pre-​excitation include the Mahaim pathway, a direct AV, or atriofascicular connection with decremental conduction properties similar to AV nodal tissue. Ventricular tachycardia Definitions Ventricular tachycardia is defined as the presence of three or more consecutive ventricular beats at a rate of 120/​min or greater. It is considered to be sustained if an individual salvo lasts for 30 s or more, and non​sustained if the duration is between 3 beats and 30 s.  Monomorphic ventricular tachycardia has a consistent QRS morphology, whereas polymorphic ventricular tachycardia dem- onstrates a constantly changing QRS morphology, often without discrete QRS complexes. Polymorphic ventricular tachycardia may degenerate into ventricular fibrillation and the ECG distinction be- tween the two is difficult. Torsades de pointes is a polymorphic VT in association with QT interval prolongation and is discussed in more detail later in the chapter. ECG characteristics The presence of AV dissociation is a particularly important feature to seek in a broad-​complex tachycardia as it makes the diagnosis of ventricular tachycardia virtually certain (Fig. 16.4.41a). A careful search for P-​waves perturbing the QRS complex or T-​waves is ne- cessary, ideally using multilead recordings. Occasionally, a for- tuitously timed P-​wave allows the development of a capture beat of normal QRS morphology without interrupting the tachycardia. A fusion beat occurs when activation of the ventricle is partly via the normal His–​Purkinje system and partly from the tachycardia focus (Fig.  16.4.41b). Fusion and capture beats are diagnostic of ven- tricular tachycardia but are commonly present only if the ventricular rate is relatively slow. Although AV dissociation is diagnostic of ven- tricular tachycardia, it is not invariable. Retrograde ventriculoatrial conduction may occur, giving either 1:1 conduction or higher de- grees of block (Fig. 16.4.41c). The QRS duration in ventricular tachycardia is commonly greater than 120 ms, and values greater than 140 ms are particularly sug- gestive of ventricular tachycardia. Although the QRS morphology may superficially resemble left or right bundle branch block, the morphology is commonly atypical (see Fig. 16.4.16). Ventricular tachycardia arising from the right ventricular free wall has a left bundle branch block-​like pattern, whereas left ventricular free wall tachycardias show right bundle branch block morphology. The pres- ence of concordant positive or negative QRS complexes across the chest leads is suggestive of ventricular tachycardia, as is the existence of extreme axis deviation. ECG features consistent with VT are listed in Fig. 16.4.16. Aetiology Sustained monomorphic ventricular tachycardia commonly occurs in the presence of structural heart disease, but also arises in struc- turally normal hearts. It rarely occurs in the acute phase of myo- cardial infarction, but may be seen in the subacute phase (>48 h), or may arise many years later, particularly in association with left ventricular scar or aneurysm formation. The arrhythmia also occurs in other forms of structural heart disease associated with ventricular dilatation or fibrosis such as dilated cardiomyopathy, hypertrophic cardiomyopathy, or previous ventricular surgery (e.g. following re- pair of Fallot’s tetralogy). Ventricular tachycardia may degenerate into ventricular fibrillation. Sustained monomorphic tachycardia can occur as a proarrhythmic response to antiarrhythmic drugs, particularly class I agents. Although ventricular tachycardia normally occurs in individ- uals with overt heart disease, it is also seen in young and apparently healthy subjects. In these, occult cardiac disease or cardiac genetic syndromes should be considered (see ‘Genetic syndromes’). There (a) (b) (c) Fig. 16.4.41  Sustained monomorphic ventricular tachycardia. (a) Ventricular tachycardia with atrioventricular dissociation. P-​waves (arrowed) are seen to have no relationship to the ventricular activation. Lead V1. (b) Ventricular tachycardia with fusion beat (arrow). Lead V1. (c) Ventricular tachycardia with 2:1 ventriculoatrial conduction. Lead III. P-​waves (arrows) follow every second ventricular complex. section 16  Cardiovascular disorders 3382 remain a few patients with documented ventricular tachycardia in whom no structural heart disease is evident on clinical, ECG, or echocardiographic examination. The tachycardia may arise from the outflow tract of the right or left ventricle, or from one of the fas- cicles of the left bundle branch, and is amenable to radiofrequency ablation. Acute management of ventricular tachycardia Rapid ventricular tachycardia may present with cardiac arrest, syn- cope, shock, anginal chest pain, or left ventricular failure, but slower tachycardias in patients with preserved cardiac function may be well tolerated. Sustained ventricular tachycardia is a medical emer- gency. If the patient is pulseless or unconscious, immediate DC cardioversion is necessary. If the patient is conscious but hypoten- sive, urgent DC cardioversion under general anaesthesia or deep sedation is used. Haemodynamically tolerated tachycardias may be terminated by drug therapy (see Fig. 16.4.17). Adenosine may be ad- ministered in the presence of haemodynamic stability to exclude the differential diagnoses of SVT with aberrancy or antidromic AVRT, but is likely to be ineffective in terminating VT (see Table 16.4.6). Amiodarone 300 mg over 20 min (ideally via a central vein) followed by 900 mg/​24 h may be effective in restoring sinus rhythm. Second-​ line drugs for the termination of ventricular tachycardia include intravenous lidocaine (lignocaine) 100 mg, sotalol, procainamide, and disopyramide, although all may be proarrhythmic. Flecainide is contraindicated in view of the risk of developing incessant tachy- cardia. Verapamil should be avoided as it may cause clinical deteri- oration. The only exception to this is in the rare instance of patients with structurally normal hearts who have ventricular tachycardia that is known to respond to verapamil (e.g. LV fascicular tachy- cardia). All antiarrhythmic drugs have significant negative inotropic actions that may further impair the haemodynamic status of the pa- tient if sinus rhythm is not restored. For this reason, no more than one antiarrhythmic drug should normally be given before recourse to alternative therapy, usually DC cardioversion. Overdrive termin- ation of ventricular tachycardia following insertion of a temporary pacing lead may be effective, particularly if the tachycardia is rela- tively slow. Facilities for cardioversion must be available in view of the risk of acceleration or degeneration into ventricular fibrillation. Secondary prevention Ventricular tachycardia is a potentially life-​threatening condition. Unless the acute episode was clearly precipitated by some transient or reversible factor, there is a high probability of recurrent attacks, which may result in sudden death. Prognosis is worse if the ar- rhythmia was poorly tolerated, or if there is severe left ventricular dysfunction. Clinical evaluation of the patient after restoration of sinus rhythm should be supported by ECG, echocardiography, cardiac magnetic resonance imaging, and/​or radionuclide ventriculography. Coronary angiography should be considered to identify the presence of sig- nificant coronary artery disease, which may act as a trigger to ven- tricular tachycardia. Unless there is a clear precipitating factor such as drug toxicity, electrolyte abnormality, or acute ischaemia, the risk of sudden death is high and patients should be considered for a sec- ondary prevention ICD (see Fig. 16.4.20). A meta-​analysis of three secondary prevention trials of patients resuscitated from ventricular fibrillation or ventricular tachycardia causing haemodynamic compromise showed defibrillators to be better than antiarrhythmic drug therapy in preventing death from any cause (Fig. 16.4.42a). Primary prevention Patients with left ventricular dysfunction of any cause are at risk of sudden death from ventricular tachycardia or fibrillation and implantable defibrillators are appropriate for a subgroup of these patients as part of a primary prevention strategy. Those with non-​ sustained ventricular tachycardia, in whom sustained tachycardia can be induced at electrophysiological testing, have a better survival with defibrillator implantation compared with drug therapy. Primary prevention trials such as the Sudden Cardiac Death in Heart Failure Trial (SCD-​HeFT) have expanded the indication to include patients with class II/​III heart failure and an ejection fraction less than 30%, even in the absence of known arrhythmia (Fig. 16.4.42b). Antiarrhythmic therapy Implantable defibrillator therapy is not affordable in all countries, and not appropriate for patients with New York Heart Association (NYHA) class  IV heart failure or other conditions causing a se- verely limited prognosis. Medical therapy is necessary for many patients, but is limited by a relative lack of evidence from random- ized controlled trials. β-​Adrenoceptor blockers are comparable to conventional antiarrhythmic agents in the prevention of recurrent ventricular tachyarrhythmias. Since they have been shown to reduce the risk of sudden death in unselected survivors of myocardial in- farction and in patients with chronic heart failure, they should be used routinely in the prophylaxis of ventricular tachycardia if toler- ated. Amiodarone did not improve mortality compared to placebo in the SCD-​HeFT trial. The class I antiarrhythmics should not be used for this indication as they were associated with a higher rate of arrhythmic deaths in the Cardiac Arrhythmia Suppression Trial. Other therapies Radiofrequency ablation is used in the management of ventricular tachycardia, particularly in those with no structural heart disease. Right or left ventricular outflow tract tachycardia and fascicular tachycardia are particularly amenable to ablation. Radiofrequency ablation of critical areas of slow conduction in scar-​related ven- tricular tachycardias is now frequently undertaken but success rates are lower than for other types of ablation and this approach is often reserved for the treatment of recurrent tachycardia in patients with implantable defibrillators. Direct surgical management of recurrent ventricular tachycardia involves aneurysmectomy, endocardial mapping, and resection of the area containing the micro re-​entry circuit. The indications for surgery have been reduced considerably since the advent of the ICD and the emergence of catheter ablation, since the surgical mor- tality is up to 10–​15%. Where medically intractable ventricular tachyarrhythmias are associated with very poor left ventricular function, cardiac transplantation should be considered if catheter ablation fails. Non​sustained ventricular tachycardia The mechanism and causes of non​sustained ventricular tachy- cardia (Fig. 16.4.43) are similar to those of sustained ventricular tachycardia. There is often slight variation in the R-​R interval, particularly if the salvo involves only a few beats. Short salvos of 16.4  Cardiac arrhythmias 3383 ICD Death Amio 50 40 30 20 10 0 1 2 3 Years Number at risk ICD: 934 715 467 273 159 104 Amio: 932 664 427 248 128 82 4 5 ICD Arrhythmic death Amio 50 40 30 20 10 0 1 2 3 Years 934 715 467 273 159 104 932 664 427 248 128 82 4 5 (a) (b) 0 0.0 0.1 0.2 0.3 0.4 Amiodarone (240 deaths; 5-yr event rate, 0.340) Amiodarone vs. placebo ICD therapy vs. placebo Hazard ratio (97.5% CI) 1.06 (0.86–1.30) 0.77 (0.62–0.96) P value 0.53 0.007 Placebo (244 deaths; 5-yr event rate, 0.361) ICD therapy (182 deaths; 5-yr event rate, 0.289) 12 24 36 Months of follow-up Mortality rate 48 No. at risk Amiodarone 845 772 715 484 280 97 Placebo 847 797 724 505 304 89 ICD therapy 829 778 733 501 304 103 60 Fig. 16.4.42  Improved survival with the implantable cardioverter–​defibrillator (ICD). (a) Cumulative risk of fatal events for ICD or amiodarone (amio) from a meta-​analysis of trials of secondary prevention, showing reduced death with ICD (left panel), due to reduced arrhythmic death (right panel). (b) Improved survival with ICD compared to amiodarone or placebo in a study of primary prevention in patients with heart failure. (a) Reproduced from Connolly SJ, et al. (2000). Meta-​analysis of the implantable cardioverter defibrillator secondary prevention trials. Eur Heart J, 21(24), 2071–​8, by permission of Oxford University Press; (b) Bardy GH, et al. (2005), New Engl J Med, 352, 230. Copyright ©2005 Massachusetts Medical Society. All rights reserved. Fig. 16.4.43  Non​sustained ventricular tachycardia. section 16  Cardiovascular disorders 3384 non​sustained ventricular tachycardia are often asymptomatic. Apart from the instances where non​sustained ventricular tachycardia pro- duces troublesome symptoms, the major clinical significance of the arrhythmia is as a risk marker for sustained ventricular tachycardia or sudden cardiac death in patients with left ventricular dysfunction or hypertrophy. Patients with structural heart disease, in particular those with severe left ventricular dysfunction, with QRS duration greater than 120 ms or heart muscle disease, should be considered for an implantable defibrillator as primary prevention of sudden car- diac death. If no structural heart disease or ion channel disease is present, and the patient is asymptomatic, no treatment is indicated as long-​term follow-​up of such patients indicates a good prognosis with no excess risk of sudden death. Polymorphic ventricular tachycardia Polymorphic ventricular tachycardia is an unstable rhythm with varying QRS morphology. It is most commonly seen in the acute phase of myocardial infarction. It either undergoes spontaneous ter- mination or degenerates into ventricular fibrillation. If episodes of polymorphic ventricular tachycardia are frequent in the early hours of myocardial infarction, they can be suppressed by β-​blockade. Torsades de pointes and the long-​QT syndromes Torsades de pointes is a characteristic type of polymorphic ven- tricular tachycardia with a typical undulating variation in QRS morphology as a result of variation in axis. It occurs in association with a prolonged QT interval during sinus rhythm. Long-​QT syn- dromes may be acquired or congenital; the latter are discussed later in the chapter. Aetiology Although class Ia and III antiarrhythmic drugs are the best-​known causes of acquired long-​QT syndrome, a very large number of non-​ cardiac drugs inhibit the outward potassium current IKr, and may cause significant lengthening of the QT interval either singly or in combination (Table 16.4.12). Episodes of torsades de pointes are often multifactorial in origin, with prolongation of the QT interval by an IKr inhibitor in association with predisposing factors such as bradycardia or pauses, hypokalaemia, or hypomagnesaemia. All of these predispose to early after-​depolarizations in vitro and this mechanism appears to be the likely cause of torsades de pointes in the acquired syndromes. The prognosis of the acquired long-​QT syndromes is excellent, provided the underlying predisposing fac- tors are identified and corrected. However, it is increasingly rec- ognized that there is a genetic predisposition to the development of acquired long-​QT syndrome in the face of predisposing factors, leading to the concept that patients developing acquired long-​QT syndrome have reduced ‘repolarization reserve’ as a result of a forme fruste of the congenital syndrome. ECG characteristics Torsades de pointes is an atypical ventricular tachycardia charac- terized by a continuously varying QRS axis (‘twisting of points’; see Fig. 16.4.44). Episodes of torsades are commonly repetitive and normally self-​terminating, although they may degenerate into ven- tricular fibrillation. Paroxysms of torsades de pointes are associated in the preceding beats with evidence of marked QT prolongation, and frequently with morphological abnormalities of the T-​wave such as T-​U fusion, gross increases in T-​wave amplitude, or T-​wave alternans. In the acquired long-​QT syndromes a slowing of the heart rate, and in particular a postextrasystolic pause, is often associated with initiation of the arrhythmia. This produces a characteristic ‘short–​long–​short’ sequence of initiation (Fig. 16.4.44). Acute management The common clinical presentation is of recurrent dizziness or syncope, and the condition may easily be misdiagnosed as self-​ terminating polymorphic ventricular tachycardia or ventricular fib- rillation unless the characteristic morphology of torsades de pointes and the associated QT interval prolongation is recognized. It is es- sential to discontinue predisposing drugs or other agents and to avoid empirical antiarrhythmic drug therapy, which may worsen the arrhythmia. Individual paroxysms of torsades de pointes are nor- mally self-​limiting, but if they are persistent, cardiac arrest will occur and emergency defibrillation is necessary. Intravenous magnesium sulphate (8 mmol over 10–​15 min, repeated if necessary) is a safe and effective emergency measure for the prevention of recurrent parox- ysms of tachycardia. If torsades de pointes is associated with brady- cardia and pauses, the heart rate should be increased to between 90 Table 16.4.12  Causes or contributory factors in acquired long-​QT syndromes Drug induced Antiarrhythmic drugs—​classes Ia, III Macrolide antibiotics—​erythromycin Antifungals—​ketoconazole Psychotropics—​tricyclic/​tetracyclic antidepressants, antipsychotics Antihistamines—​terfenadine, astemizole Antiemetics—​domperidone, ondansetron Synthetic opioid—​methadone Electrolyte disturbances Hypokalaemia, hypomagnesaemia, hypocalcaemia Metabolic Hypothyroidism, starvation, anorexia nervosa, liquid protein diet Bradycardia Sinoatrial disease, AV block Toxins Organophosphorus insecticides, heavy metal poisoning Fig. 16.4.44  Torsades de pointes. Note the marked QT interval prolongation in the sinus beats, and the ‘short–​long’ pattern of R-​R intervals immediately prior to initiation of the arrhythmia. Ambulatory monitoring recording is shown (continuous tracing). 16.4  Cardiac arrhythmias 3385 and 100/​min by atrial or ventricular pacing or isoproterenol (iso- prenaline) infusion. Hypokalaemia and hypomagnesaemia should be sought and corrected if necessary. Accelerated idioventricular rhythm The term ‘accelerated idioventricular rhythm’ is used to describe a continuous ventricular rhythm with a rate less than 120/​min. Idioventricular rhythm commonly occurs in the setting of acute myocardial infarction and appears to be a marker of successful reperfusion therapy. No active treatment is necessary. Ventricular fibrillation Ventricular fibrillation is defined as a chaotic, disorganized ar- rhythmia with no identifiable QRS complexes (Fig. 16.4.45). The mechanism is of multiple, unstable re-​entry circuits. The electrocar- diographic pattern depends on the duration of fibrillation: recent-​ onset fibrillation is described as ‘coarse’, with a peak-​to-​peak amplitude of around 1 mV (1 cm). With increasing duration of car- diac arrest, the amplitude of ventricular fibrillation diminishes and such ‘fine’ ventricular fibrillation is less likely to be amenable to suc- cessful electrical defibrillation. Ventricular fibrillation may occur during acute myocardial is- chaemia often initiated by an R on T extrasystole, and is the principal cause of death in the first 2 h following acute myocardial infarction (Fig. 16.4.45). Ventricular fibrillation during myocardial infarction is subdivided into primary, occurring without warning in an otherwise stable patient, and secondary, where fibrillation occurs in the context of left ventricular failure or cardiogenic shock. Ventricular fibrillation occurring in chronic heart disease is most commonly a result of de- generation of rapid ventricular tachycardia, whose causes have been described earlier. Rarer causes of fibrillation are listed in Box 16.4.4. Ventricular fibrillation is rarely self-​terminating, and normally causes cardiac arrest with the rapid onset of pulselessness, uncon- sciousness, and apnoea. The management of cardiac arrest due to ventricular fibrillation is discussed in Chapter 17.2. Patients who survive an episode of ventricular fibrillation should be assessed carefully to determine the risk of recurrence. If ven- tricular fibrillation has occurred in the first few hours of a typical ST-​elevation myocardial infarction, the risk of recurrent cardiac arrest is low, and no specific prophylactic therapy other than as- sessment and treatment of residual ischaemia and conventional postinfarction β-​blockade is indicated. However, in many instances ventricular fibrillation arises as a result of acute ischaemia in pa- tients with known, extensive heart disease who have not sustained an acute infarction. These patients remain at high risk of recurrent ventricular fibrillation, and should be evaluated fully by exercise testing and coronary arteriography with a view to revascularization, and managed with an ICD or antiarrhythmic therapy as discussed in the section on ventricular tachycardia. Genetic syndromes Ion channel diseases Congenital long-​QT syndromes The congenital long-​QT syndromes (LQTS) are inherited conditions due to mutations in genes encoding ion channel proteins. They are mainly autosomal dominant and are subclassified according to the underlying gene defect (Table 16.4.13). Most cases are either LQT1 or LQT2, due to mutations affecting either the slow (IKs) or rapid (IKr) components of the outward potassium current. In the less common LQT3, the inward sodium current (INa) is affected. Lengthening of ventricular repolarization, and hence of the QT interval, occur as a result either of reduced outward current flow via IKr or IKs or in- creased duration of current flow via INa. The arrhythmia, torsades de pointes, has characteristics consistent with triggered activity. Attacks of torsades de pointes in the congenital syndromes are commonly associated with sympathetic stimulation such as exercise, waking, or fright, and are associated with increases in sinus rate. Cardiac events are particularly associated with exercise in LQT1, with auditory stimulation in LQT2, and can occur during sleep in LQT3. Paroxysms may produce syncope, which if prolonged may be complicated by convulsion, leading to misdiagnosis as epilepsy. A  family history of recurrent syncope or sudden death may be obtained. Sinus bradycardia is commonly seen in these syndromes. The diagnosis of long-​QT syndrome can be challenging and is not based on the ECG characteristics alone. The finding of a long QT interval on an ECG in patients with a history of syncope or palpi- tations or a routine ECG in asymptomatic patients can cause con- siderable anxiety among clinicians. The probability of LQTS can be assessed using the Schwartz score, with a score more than 3.5 sup- porting the diagnosis (Table 16.4.14). The prognosis of untreated congenital long-​QT syndrome is poor, with a high incidence of sudden death in childhood. Factors associ- ated with high risk include personal history of aborted sudden cardiac death or syncope, and corrected QT interval greater than 500 ms. Males with LQT3 are at increased risk regardless of the degree of QT interval prolongation. LQT1 has a better prognosis than other subtypes. Episodes of torsades de pointes and T-​wave alternans on Holter monitoring also confer a higher risk. Fig. 16.4.45  Ventricular fibrillation complicating acute myocardial infarction. The arrhythmia is initiated by an ‘R on T’ ventricular extrasystole. Box 16.4.4  Causes of ventricular fibrillation • Acute myocardial ischaemia • Acute myocardial infarction—​primary or secondary • Advanced organic heart disease with poor LV or RV function • Severe LV hypertrophy • Ventricular tachycardia/​torsades de pointes • Electrical—​electrocution, lightning, unsynchronized DC shock, com- petitive ventricular pacing • Pre-​excited atrial fibrillation • Profound bradycardia • Hypoxia, acidosis • Genetic syndromes (e.g. long-​QT syndrome, Brugada syndrome) section 16  Cardiovascular disorders 3386 Table 16.4.13  Genetics of congenital long-​QT syndromes Subtype Chromosome Gene Product Ion current affected Frequency LQT1 11 KCNQ1 KvLQT1 ↓IKs c.50% LQT2 7 KCNH2 HERG ↓IKr 30–​40% LQT3 3 SCN5A Nav 1.5 ↑INa 5–​10% LQT4 4 ANKB Ankyrin-​B ↓Multiple Rare LQT5 21 KCNE1 minK ↓IKs Rare LQT6 21 KCNE2 MiRP1 ↓IKr Rare LQT7 17 KCNJ2 Kir2.1 ↓IK1 Rare LQT8 12 CACNA1C Cav1.2 ↑ICaL Rare LQT9 3 CAV3 Caveolin 3 ↑INa Rare LQT10 11 Sodium channel β4 SCN4B ↑INa Rare LQT11 7 AKAP9 Yotiao ↓IKs Rare LQT12 20 Syntrophin α1 SNTA1 ↑INa Rare LQT13 11 KCNJ5 Kir3.4 ↓IKr Rare LQT14 14 CALM1 Calmodulin 1 N/​A Rare LQT15 2 CALM2 Calmodulin 2 N/​A Rare LQT16 19 CALM3 Calmodulin 3 N/​A Rare Table 16.4.14  Schwartz score for the diagnosis of long-​QT syndrome Clinic features Points ECG findingsa A QTcb ≥480 ms 3 460–​479 ms 2 450–​459 ms (male) 1 B QTcb 4th minute of recovery from exercise stress test ≥480 ms 1 C Torsade de pointesc 2 D T-​wave alternans 1 E Notched T-​wave in three leads 1 F Low heart rate for aged 0.5 Clinical history A Syncopec With stress 2 Without stress 1 B Congenital deafness 0.5 Family history A Family members with definite LQTSe 1 B Unexplained sudden cardiac death 5 litres) is the dominant feature. Management is principally with bed rest, loop diuretics (usually by intravenous infusion), and, where appropriate, mineralocorticoid receptor antagonists. Thiazide diuretics can be added in resistant cases. Prophylactic low molecular weight heparin should be pre- scribed. Careful monitoring of fluid balance with daily weights and section 16  Cardiovascular disorders 3398 daily electrolytes is essential. Angiotensin-​converting enzyme in- hibitors and subsequently β-​blockade can be introduced once a satisfactory diuresis has been achieved. Management of cardiogenic shock is usually determined by the cause. Fluid status should be assessed, and an adequate left ventricular filling pressure ensured by the administration of intra- venous fluids where required (particularly in the case of right ven- tricular infarction). Revascularization is the mainstay of therapy in acute myocardial infarction. Circulatory support with intra-​ aortic balloon counterpulsation, inotropic agents, ventricular as- sist devices, and extracorporeal membrane oxygenation should be considered for reversible causes (e.g. ventricular septal rup- ture, papillary muscle rupture, acute myocarditis, and peripartum cardiomyopathy). Prognosis Hospital admission with acute heart failure caries a poor prognosis with an average in-​hospital mortality of 10–​15% rising to up to 60% at 30 days in cases of cardiogenic shock. Introduction Although the term ‘acute heart failure’ often conjures up an image of a patient with acute pulmonary oedema, in extremis, struggling to breathe and producing pink, frothy sputum, such a dramatic pres- entation is not common. Admissions to hospital for heart failure, on the other hand, are extremely common, and most patients admitted are not breathless at rest, only becoming breathless on mild exer- tion. It is better to think of acute heart failure as being a worsening of symptoms and/​or signs leading the patient, carer, or primary care physician to seek urgent expert advice—​leading, in turn, to an ur- gent admission to hospital for investigation and/​or treatment. Many patients will be able to walk, albeit slowly, from their wheelchair to their hospital bed. Patients admitted with heart failure usually have a problem with oedema (i.e. fluid in the wrong place). The old-​fashioned term ‘anasarca’ describes a state of severe generalized oedema. It can be helpful to think of patients as being on a spectrum between pul- monary oedema at one end, in which the fluid is predominantly in the lung, and anasarca on the other, in which patients have an abso- lute excess of fluid, usually manifesting as peripheral oedema. This notion is similar to the classification system used for patients with chronic airways disease and emphysema: patients with pulmonary oedema can be termed ‘puffers’, and those with anasarca as ‘bloaters’ or having dropsy (Table 16.5.2.1). Patients with pulmonary oedema usually present with a short his- tory of deterioration. There is often an obvious acute precipitating factor such as acute coronary syndrome or atrial fibrillation, par- ticularly with a rapid ventricular response. They often have hyper- tension and a high peripheral vascular resistance. The patient has had no time to retain a substantial excess of body fluid. In contrast, patients with dropsy (‘bloaters’) usually have a history of deterior- ation over a period of weeks and no acute precipitating factors (al- though the development of atrial fibrillation with a slow ventricular response, anaemia, and chronic kidney disease (CKD) could be considered chronic precipitants). They have a low blood pressure and have had time to retain many litres (sometimes ≥20 litres) of excess fluid. The distinction is important in interpreting the results of clinical trials: an agent that is designed to improve acute breath- lessness, but given to someone who is already comfortable at rest (perhaps rendered so by standard background therapy) is likely to appear ineffective, even if it is highly effective in the appropriate pa- tient at the appropriate time. There is little evidence from randomized controlled trials in acute heart failure syndromes to guide management. Much of what follows in terms of management advice thus reflects the balance of expert opinion rather than definitive recommendations. The lack of evidence reflects a constellation of difficulties. The reasons for hospital admission may be misunderstood and patients often present at inconvenient hours of the night when it is least likely they will encounter people with the time or inclination to do research (funding nocturnal research can be expensive). Protocol procedures often cause delays which allow standard therapies to be effective before a new intervention can be started. Indeed, the effect- iveness of oxygen, nitrovasodilators, and diuretics for the short-​term management of symptoms suggests that the needs for managing acute pulmonary oedema are largely satisfied. The big problems for ‘acute’ heart failure really appear 2–​3 days after admission when it is clear that diuretics alone have not solved the immediate problem. For most patients, the problem then is per- ipheral oedema and exertional breathlessness rather than breath- lessness at rest. In the longer term, the big problems are recurrent exacerbations and death. Thankfully, the vast majority of patients who survive to discharge attain a reasonable quality of life in the intervening period. There are guidelines to help guide practice, but those relating to acute heart failure tend to focus most on the patients with acute pulmonary oedema. The European Society of Cardiology’s (ESC) guidelines of 2016 are helpful, but it is noteworthy that the only treatment to receive a class I, level A recommendation was the use of prophylaxis against thromboembolism. The National Institute for Health and Clinical Excellence clinical guideline of 2014 covered both patients with pulmonary oedema and the more common presentation with fluid retention. This placed a great deal of emphasis on the importance of organization of care and the need for patients with acute heart failure to be managed in the appropriate environment, but was notably frank regarding the ab- sence of good trial evidence and gave a series of helpful recom- mendations for future research. Table 16.5.2.1  The spectrum of acute heart failure ranges from patients with acute pulmonary oedema, perhaps 15% of patients presenting to hospital with acute pulmonary oedema, to those with fluid retention. Differences between the two groups are highlighted Pulmonary oedema Anasarca Syndrome Puffers Bloaters Acute precipitant Yes Usually no Oedema In lungs Predominantly peripheral Absolute fluid excess No Yes Time course Minutes to hours Days to weeks 16.5.2  Acute cardiac failure 3399 Cardiogenic pulmonary oedema Pathophysiology In patients with pulmonary oedema, fluid from the lung capillaries collects in the extravascular spaces of the lung. The Starling equa- tion describes the forces acting on fluid in the pulmonary capil- laries (Fig. 16.5.2.1). Hydrostatic pressure tends to force fluid out of the capillaries while the colloid osmotic pressure (largely pro- vided by proteins) tends to maintain the fluid within the capillary. The balance between the forces varies between arteriole and venule; however, there is net filtration along the length of the capillary. Some resistance to fluid movement is provided by the alveolar–​capillary membrane and any fluid entering the interstitium is removed by the lymphatics. Problems with any of these components can lead to (or worsen) pulmonary oedema. Pulmonary lymphatic flow may increase substantially in heart failure, reducing the risk of pulmonary oe- dema. However, the lymphatics drain into the venous circulation and so a rise in venous pressure may inhibit lymphatic clearance. Lymphatic occlusion, as occurs in lymphangitis carcinomatosa, and disruption to the alveolar capillary membrane, as happens in adult respiratory distress syndrome, can cause pulmonary oedema. Hypoalbuminaemia causes peripheral oedema and reduces the hydrostatic pressure at which pulmonary oedema occurs. In the normal circulation, the Frank–​Starling relation describes the relation between the load on the left ventricle at the end of dia- stole, usually expressed as the end-​diastolic pressure, and the work subsequently performed by the ventricle during systole. The end-​ diastolic pressure is the same as the left atrial and hence pulmonary venous pressure. In patients with heart failure, the curve relating the two is shifted to the right: for any given cardiac output, the filling pressure required is greater in the failing ventricle (see Fig. 16.5.2.2). An acutely failing ventricle needs a higher and higher filling pressure to maintain cardiac output. The rising end-​diastolic pressure is re- flected in a rise in left atrial, pulmonary venous, and pulmonary ca- pillary pressure, resulting in faster rates of fluid filtration. Ultimately, fluid is filtered faster than the rate at which the lymphatics can re- move it, and pulmonary oedema results. This sequence cannot be quite the full explanation: a rise in pres- sure (including left ventricular filling pressure) can only arise from an input of energy. In acute pulmonary oedema, the energy for the rise in left ventricular pressure can only come from the right heart. When the left ventricle fails, there is a fall in left ventricular stroke volume and consequent mismatch between left and right ventricular stroke volumes. The higher right ventricular stroke volume causes the increase in left ventricular filling pressure and restoration of car- diac output, but an inevitable consequence is some accumulation of fluid in the pulmonary circulation. The greater the fall in stroke volume of the left in relation to the right ventricle, the higher the left ventricular filling pressure will be and the greater the pulmonary fluid volume. Note that the total amount of fluid in the body does not increase and the effect is brought about by fluid moving to the ‘wrong’ body compartment. The fluid extravasation into the alveoli results in a reduction in blood volume during acute pulmonary oedema, which then increases back to normal levels during successful treatment. The fluid accumulation in the lungs starts with peribronchial swelling/​oedema, followed by distension of the alveolar walls; only then does fluid enter the alveoli, initially at the alveolar angles, and eventually flooding the alveoli. The accumulation starts at the lung bases as the hydrostatic pressure is greatest here. Clinical presentation Acute pulmonary oedema is a dramatic medical emergency. The typical patient presents with very severe shortness of breath that has developed abruptly over minutes or hours. He or she has to sit up- right (and might indeed die if forced to lie flat) and may be unable to speak or gasp only a few words. Patients are usually very frightened and often certain that they are dying. Coughing may be prominent and will often produce blood-​tinged oedema fluid. There may be some clues in the history as to the precipitant of pulmonary oedema. Sympathetic nervous system activation usually results in a tachy- cardia and a rise in blood pressure; the skin is white, cold, and clammy. The patient usually exhibits central cyanosis. Heart sounds may be inaudible but a gallop rhythm is common. The lung fields Fig. 16.5.2.1  The forces acting on fluid in a pulmonary capillary. Fig. 16.5.2.2  The Frank–​Starling relation. As preload increases, so does cardiac output. In the failing ventricle, the relation is shifted to the right so that to deliver any given cardiac output, the ventricle requires a higher filling pressure. section 16  Cardiovascular disorders 3400 are usually filled with crackles and sometimes wheezes (so-​called ‘cardiac asthma’). Given how sick the patient with pulmonary oedema is, the initial investigations and management have to be carried out at speed. The ESC guidelines for the management of acute heart failure empha- size the need to investigate and treat simultaneously (Fig. 16.5.2.3). There are three strands: making the diagnosis, identifying the imme- diate precipitant, and initiating treatment. Identifying precipitating factors is particularly important as it will influence subsequent man- agement (see Table 16.5.2.2). Initial investigation A 12-​lead electrocardiogram (ECG) will often show grossly ab- normal QRS complexes, including evidence of acute myocardial infarction, or abnormal heart rhythm, including atrial fibrillation with a rapid ventricular response and ventricular tachycardia (see Fig. 16.5.2.4). A chest radiograph gives vital information. At early stages in the development of pulmonary oedema, the patient may have septal (or Kerley B) lines (Fig. 16.5.2.5), fluid in the lung fissures, and pleural effusions. There is peribronchial cuffing and upper lobe blood diver- sion. As oedema worsens, confluent shadows spreading out from the hila develop (Fig. 16.5.2.6). Near-​patient testing for cardiac markers is becoming more widely available. Natriuretic peptide measurement can be helpful in making the diagnosis where there is clinical uncertainty: a patient with a normal natriuretic peptide level is extremely unlikely to have heart failure. A raised troponin suggests that there might be an acute Patient with suspected AHF Cardiogenic shock? Urgent phase after first medical contact Immediate phase (initial 60–120 minutes) Respiratory failure? Identification of acute aetiology: acute Coronary syndrome Hypertension emergency C H A M P Arrhythmia No Yes Immediate initiation of specific treatment Diagnostic work-up to confirm AHF Clinical evaluation to select optimal management Follow detailed recommendations in the specific ESC Guidelines acute Mechanical cause’ Pulmonary embolism No No Yes Circulatory support Ventilatory support • pharmacological • mechanical • oxygen • noninvasive positive pressure ventilation (CPAP, BiPAP) • mechanical ventilation Immediate stabilization and transfer to ICU/CCU Yes Fig. 16.5.2.3  The treatment algorithm recommended by the European Society of Cardiology. Note that investigations and active management have to be undertaken simultaneously. From Ponikowski P, et al. (2016). 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Eur Heart J, 37(27), 2129–​200. 16.5.2  Acute cardiac failure 3401 coronary syndrome (ACS) in progress, but troponin is commonly raised in acute heart failure even in the absence of ACS. A full blood count, biochemical screen, and thyroid function are important investigations. Anaemia is common, often due to iron defi- ciency but exacerbated by plasma volume expansion. Glucose is very commonly raised due to the high sympathetic drive, and does not ne- cessarily mean that diabetes is present. Other appropriate investiga- tions may include CT pulmonary angiography and a septic screen. Echocardiographic assessment early in the course of admission is very useful in confirming the cause of presentation and guiding subsequent therapy. Management Patients with acute pulmonary oedema should be managed in a high-​dependency unit. Whether this should be cardiac care or a unit where intubation and ventilation is available will depend upon the degree of respiratory distress. Ventilatory support The lowest dose of oxygen needed to restore normal oxygenation should be used. Care should be taken in patients with chronic air- ways disease who are at risk of developing CO2 retention (which may be exacerbated by the use of opiates). In a patient who is tiring or whose gas exchange is worsening despite treatment, positive pres- sure ventilation provides immediate relief. Non​invasive ventilation should be tried first: there is good evidence that both continuous positive airway pressure ventilation and bilevel positive airway pres- sure ventilation are safe. Medical treatment Opiates are commonly prescribed to relieve the distress of acute pul- monary oedema, but there is no evidence that they are safe and some data suggest that their use is associated with adverse outcomes. They should be used cautiously, if at all. Table 16.5.2.2  Common precipitants of acute pulmonary oedema, helpful investigations, and possible immediate treatment options. ECG is electrocardiogram; CXR is chest X-​ray; (N)STEMI is (non) ST elevation myocardial infarction Precipitant Examples Investigation Immediate management Acute ischaemia STEMI NSTEMI ECG, troponina Immediate cardiology review Arrhythmia Atrial fibrillation Ventricular tachycardia ECG DC cardioversion Mechanical disaster Rupture of: interventricular septum Mitral papillary muscle Sinus of Valsalva Echocardiogram Cardiac surgery Hypertensive crisis Renal artery stenosis Salt load During recovery Vasodilators Intercurrent illness Pneumonia Urinary infection Sepsis CXR, septic screen As appropriate Pulmonary embolus CT pulmonary angiogram Thrombolysis, anticoagulation Environment Lack of compliance with medication/​diet High salt intake History Education a often elevated in acute or chronic heart failure in the absence of any other evidence of ACS. An elevated troponin in patients with heart failure is a bad prognostic sign. Fig. 16.5.2.4  A 12-​lead electrocardiogram from a 76-​year-​old man presenting with acute pulmonary oedema. His ventricular tachycardia had been precipitated by an acute coronary syndrome. section 16  Cardiovascular disorders 3402 Diuretics Diuretics are almost universally used in patients with acute pul- monary oedema, although trials to prove efficacy are lacking. As patients are usually not fluid overloaded, diuretics may not be the most logical therapy, although by reducing circulating volume, they do reduce filling pressure and relieve oedema. There is a firmly held view that furosemide is a vasodilator, but its haemodynamic effects coincide with the onset of diuresis. Vasodilators Nitrovasodilators are a more logical approach to the treatment of pulmonary oedema. They reduce both preload and afterload, as well as helping to relieve any myocardial ischaemia. Small studies suggest that nitrates may be more helpful than diuretics, but the evidence is not definitive, and clinical surveys suggest that they are used in few patients. The National Institute for Health and Care Excellence (NICE) guideline does not recommend their routine use. Other vasodilators have been tried. Despite early promise (and, indeed, licensing in some countries), nesiritide (human re- combinant B-​type natriuretic peptide) had no effect on outcome in a large trial, and no patient subset obtained a striking benefit. Serelaxin (human recombinant relaxin, a vasoactive peptide pro- duced in pregnancy) was again promising, but a definitive trial, RELAX-​AHF-​2, was again neutral. In TRUE-​AHF, patients with acute heart failure were randomized to receive either ularitide (an- other natriuretic hormone) or placebo, and the results were again neutral both for longer term cardiovascular mortality and for short-​ term symptom relief. Patient selection is part of the reason for the neutral studies of vasodilators. By the time a patient has been through the processes required for study entry, several hours have typically passed since presentation and the worst may by then be over. Severely ill pa- tients may be excluded as not being able to consent, and most studies exclude patients with many of the precipitants of acute pulmonary oedema, such as acute myocardial infarction. Indeed, it can be difficult to tell who, precisely, the criteria for the trials are targeting for inclusion. They usually appear to be trying to recruit patients with pulmonary oedema, who perhaps may have most to gain from a vasodilator, but in are in practice predominantly recruiting those with fluid retention, and if a patient is not breath- less at rest, then a treatment targeting breathlessness is unlikely to be helpful. Inotropes Inotropic support is often used, particularly as a ‘last ditch’ attempt to help very sick patients, more in despair than hope. Such evidence as there is from randomized trials suggests that all positive inotropic drugs working through adrenergic pathways are associated with an adverse outcome. Investigational approaches include cardiac my- osin activators and inhibitors of sarcoplasmic calcium re-​uptake. Mechanical support In selected patients, there may be a role for intra-​aortic balloon pumping to buy time, particularly when there is a potentially revers- ible cause for the pulmonary oedema. Similarly, a left ventricular assist device and extracorporeal membrane oxygenators may have a role when there is a potential either for recovery or for heart transplantation. Prognosis The clinical course of acute pulmonary oedema is usually very brisk: the patient usually recovers rapidly after treatment, or deteri- orates rapidly and dies. Overall, in-​hospital mortality is around 15%, but strongly age-​related; it is less than 10% in those aged less than 65 years and much higher in those aged more than 85 years, but these figures do not include those dying before reaching hospital. Fig. 16.5.2.5  A plain postero-​anterior chest X-​ray in a breathless patient showing Kerley B lines–​multiple short horizontal lines visible towards the lung peripheries. There are also small pleural effusions. Fig. 16.5.2.6  More severe pulmonary oedema on supine antero-​ posterior film showing confluent shadowing spreading out from the hila. Note the relatively small heart shadow suggesting that this is an acute event in a previously normal heart. 16.5.2  Acute cardiac failure 3403 The recovery from pulmonary oedema is in part an active process in which cells take up fluid and return it to the capillary or lymphatic circulation. Novel agents designed to enhance this process are being developed. Cardiogenic anasarca Pathophysiology At the other end of the scale from pulmonary oedema are patients with fluid retention. Two processes result in oedema: the retention of sodium and water, and the transfer of fluid into the tissues. To take the second first: fluid collects in the tissues as a consequence of a rise in intravascular hydrostatic pressure or fall in osmotic pressure. As with the lungs, there is continuous filtration of fluid from the ca- pillaries to the tissues: if extravasation exceeds lymphatic drainage, oedema develops. The effect of gravity means that the hydrostatic pressure is highest in the feet, so ankle swelling is usually the first sign of fluid retention. In a patient confined to bed, though, the fluid will collect around the sacrum. The reasons why the body retains water are less certain. Sodium and water are retained by the kidneys, presumably in response to de- creased renal perfusion or deviation from the kidney’s set-​point for renal perfusion pressure (i.e. the blood pressure the kidney ‘wants’). The consequence is renin production by the juxtaglomerular appar- atus leading to conversion of angiotensinogen to angiotensin I and ultimately to aldosterone production, which in turn causes salt and water retention by the kidney. In addition, antidiuretic hormone (or arginine vasopressin) is released in increased quantities, stimulating fluid retention and, importantly, thirst, and thus greater fluid intake. However, antagonists of each of these systems, even when used in combination, do not seem sufficient to prevent salt and water reten- tion and do not obviate the need for diuretics, although they might reduce the dose required. The stimulus leading to neuroendocrine activation is not clear. A common assumption is that it is a fall in blood pressure due to the failing heart. The body responds in the same way as it would to any other cause of a fall in blood pressure, such as dehydration or haem- orrhage, with avid salt and water retention to maintain blood pres- sure. Although some patients have a normal or high blood pressure compared to healthy people, this blood pressure may be below their individual set-​point. If the set-​point could be changed, then perhaps salt and water retention would not occur. Clinical presentation The typical picture is of a patient with gradual weight gain, often in the context of previous coronary disease, hypertension, atrial fibril- lation, and CKD. Around 5 litres of fluid (weighing 5 kg) are needed before oedema first appears. As the process is often very gradual, patients will often present only once they have retained many litres of fluid and have pitting oedema affecting the abdominal wall, and sometimes even the thoracic wall. Pleural and pericardial effusions and ascites are common in this situation. In some patients, the oe- dema causes obvious ballooning of the ankles. However, in many patients the oedema does not grossly distort the shape of the leg, and oedema of the trunk may develop and go unobserved by the patient or a careless doctor. Symptoms such as ‘I can’t get my shoes on’ or ‘I have had to loosen my belt’ or ‘I have increased a waist size’ in a pa- tient with increasing breathlessness should alert the clinician to the possibility of oedema. The oedema is usually very obvious on examination. Cardiogenic oedema is pitting. The highest level of pitting oedema should be sought. The jugular venous pressure will be raised: however, when it is very high, the top of the column of the blood may not be visible in the neck, even with the patient sitting upright. There is usually a tachycardia and often hypotension. The apex beat is displaced and dyskinetic and there is almost always a third sound or gallop rhythm. Mitral regurgitation is very common. There are commonly signs of ascites and pleural effusions, with basal crackles in some patients who have pulmonary congestion. Differential diagnosis It is important to consider the differential diagnosis of peripheral oedema (Table 16.5.2.3). Once a firm diagnosis of cardiogenic oe- dema is made, the next step is to consider the possible causes of the ‘right heart’ failure. Although the commonest cause is left heart failure, other cardiac conditions, particularly constrictive pericar- ditis, can result in severe fluid overload and be difficult to diagnose (see Table 16.5.2.4). Pulmonary hypertension leading to right ven- tricular dysfunction appears increasingly common in frail elderly patients with right heart failure, many of whom also have lung and left heart disease. Initial investigations Patients presenting with anasarca should be investigated as patients presenting with chronic heart failure (see Chapter 16.5.3) with the aim of making the diagnosis, unmasking any treatable cause, and identifying any associated comorbidities. • Common ECG abnormalities include previous myocardial in- farction, left bundle branch block, atrial fibrillation. • A chest radiograph will show a large heart shadow and evidence of pulmonary venous congestion. It may also exclude other causes of breathlessness. • Urinary dipstick testing will help pick up infection and gross proteinuria. • Anaemia is common in anasarca due to heart failure. Patients may benefit from an iron infusion should they have iron deficiency. • Renal dysfunction and electrolyte abnormalities are common in patients with heart failure and are major determinants of outcome. Regular testing during treatment (see next) is vital. Table 16.5.2.3  Differential diagnosis of peripheral oedema. Note that anasarca is easily overlooked without careful examination Oedema fluid Cardiogenic Hypoalbuminaemia Fluid overload Pregnancy Lymphatic obstruction Idiopathic Medicines Dihydropyridines/​glitazones Venous insufficiency Varicose veins Previous DVT Chronic stasis Fat (Obesity) section 16  Cardiovascular disorders 3404 • Natriuretic peptide levels are usually grossly raised. • An echocardiogram is essential (see Fig. 16.5.2.7). The key elem- ents to look at are: ■ Left atrial size—​mitral valve disease or chronic elevation in left ventricular filling pressure will cause left atrial dilation. It is probably the best guide to the chronic health of the left heart but may not be enlarged with severe acute-​onset disease. ■ Left ventricular size and contractility—​the left ventricle is com- monly dilated with reduced systolic function but sometimes small, hypertrophied, and ‘stiff’. Regional wall motion abnor- malities suggest a possible underlying diagnosis of ischaemic heart disease. ■ Valve disease. • More sophisticated investigation may reveal pulmonary hyper- tension, right ventricular disease, and dilated venae cavae. Ultrasound can also be used to identify ‘lung comets’ indicating pulmonary congestion. Management The problem is one of an absolute excess of fluid, and initial man- agement is directed at fluid removal. General care is important: the patient should be managed with bed rest with prophylactic low molecular weight heparin used to reduce the (high) risk of venous thrombosis. The only way to monitor progress accurately is with strict fluid balance monitoring and daily weights. The urea and elec- trolytes should be measured at least daily, and the patient should be reviewed daily by an experienced member of the team. Oedema is due to retention of water, not salt: in 1 litre of oedema fluid, there are 991 g of water and 9 g of salt. There is no good evi- dence that sodium restriction is useful, although restricting a very high intake may be useful in the occasional patient. Salt restric- tion may lead to hyponatraemia. Aquaresis may be greater (and hyponatraemia less likely) when moderate salt intake is allowed. Fluid intake is often restricted to around 1.5 litres per day, but the evidence for this is weak. The aim should be to try and induce a net diuresis of around 2 litres per day. Diuretic management is key. Diuretics work by preventing the re- absorption of some of the filtered sodium from the tubular lumen. • Loop diuretics block the sodium–​potassium–​chloride cotransporter in the thick ascending loop of Henle. As they reach their site of ac- tion from the lumen of the nephron, they only work if there is at least some glomerular function. Once their effects are over, the kidney goes into overdrive to restore the lost salt and water. • Thiazide diuretics work at the distal convoluted tubule. They in- duce a small but persistent diuresis; over a 24-​hour period loop and thiazide diuretics may have the same natriuretic effect. • Mineralocorticoid receptor antagonists block the effects of aldos- terone at the sodium–​potassium exchanger in the distal convo- luted tubule, resulting in potassium retention. A typical approach is to use intravenous loop diuretic. Oral ab- sorption is very erratic in patients with cardiogenic oedema because of bowel oedema. An infusion of 10 mg per hour of furosemide is Table 16.5.2.4  Differential diagnosis of cardiogenic peripheral oedema Possible cause Examples Raised left atrial pressure (left heart failure) Impaired left ventricular  Contraction  Ischaemic heart disease (IHD)  Dilated cardiomyopathy  Relaxation  Left ventricular hypertrophy (hypertension)  Hypertrophic cardiomyopathy  Amyloid Mitral valve disease Raised right atrial pressure (right heart failure) Chronic left atrial hypertension Pulmonary hypertension IHD Tricuspid valve disease (often tricuspid regurgitation due to dilated right ventricle) Right ventricular cardiomyopathy Congenital heart disease Left-​to-​right shunts Right ventricle in systemic position Pulmonary hypertension Chronic left atrial hypertension Lung disease (cor pulmonale) Thromboembolic disease Pericardial disease Constrictive pericarditis Fig. 16.5.2.7  Echocardiogram of a patient presenting with anasarca. Long axis parasternal view. The left ventricular internal diameter is approximately 8 cm, and there is little difference between systolic and diastolic frames. 16.5.2  Acute cardiac failure 3405 often used. Data from small studies suggests that an infusion causes a greater natriuresis than repeated boluses to the same dose, but the biggest study of infusion versus bolus dosing showed no difference between the two strategies. Particularly after chronic loop diuretic usage, the cells of the distal convoluted tubule hypertrophy and increase their capacity to reabsorb sodium. The addition of a thiazide will block the distal convoluted tubule (so-​called ‘progressive nephron blockade’) which may lead to a profound diuresis. Metolazone is often used for this purpose although there is no convincing evidence that it is more potent than other thiazides. Combination therapy can be very helpful, but patients having the two diuretics must be monitored very closely. Potentially nephrotoxic drugs, such as non​steroidal anti-​ inflammatory drugs (including aspirin) should be stopped. It is not certain whether pre-​existing β-​blocker (or angiotensin-​converting enzyme inhibitor or ACE) therapy should be stopped: the evidence available suggests that those patients whose pre-​existing therapy is not stopped are less likely to be discharged without these life-​saving treatments. Towards the end of intravenous therapy, ACE inhibitors and β-​blockers should be started simultaneously at low doses. If not al- ready being used, a mineralocorticoid (aldosterone) receptor antag- onist (MRA) should also be started (see Fig. 16.5.2.8). The dose of ACE inhibitor should be titrated rapidly to target with careful moni- toring of blood pressure and renal function. β-​Blockers are titrated more slowly and often only after discharge. Intravenous diuretic therapy should be continued until the oe- dema has resolved unless an oral diuretic regimen is clearly having the desired results. It is not uncommon for renal function to im- prove following diuresis and diuretic therapy should not be with- held or reduced in patients with impaired renal function at the time of presentation where there is clear evidence of fluid overload. For some patients, however, complete resolution of oedema cannot be achieved due to worsening renal impairment and a balance has to be struck between some peripheral oedema and a raised creatinine. Ideally, a patient finishing intravenous therapy will be moni- tored for 48 h to make sure that the fluid does not re-​accumulate immediately. Some patients may fail to respond adequately to intravenous di- uretics. It is important to reconsider the diagnosis: has constrictive pericarditis been missed? Is there some correctable cause of renal dysfunction, such as renal artery stenosis? Other therapeutic options include the use of digoxin, which has a diuretic effect, although the evidence base for its use in acute heart failure is poor. Positive inotropic drugs, particularly in hypotensive patients, are sometimes used. There is no evidence to support the practice, and no evidence that ‘renal dose dopamine’ has anything to offer. Ultrafiltration can be used to remove fluid rapidly from patients with anasarca (see Table 16.5.2.5). Veno-​venous filtration is possible in a cardiac care unit setting with small devices. There is conflicting evidence as to its value: in one study, its use was associated with a reduction in the need for subsequent emergency care, but in pa- tients with worsening renal function, a second study suggested that ultrafiltration was associated with a higher creatinine, although this finding may simply have reflected haemoconcentration. The most recent study was terminated early by the sponsoring company: al- though the primary endpoint was not met, several of the secondary endpoints suggested a benefit for ultrafiltration. The role of ultra- filtration in routine practice is still uncertain, but there is no doubt that as much as 5 litres can safely be removed from a patient in 24 h, and it is useful in selected patients who are unresponsive to com- bined diuretic therapy or when diuresis is limited by renal dysfunc- tion (Fig. 16.5.2.9). Fig. 16.5.2.8  Time course of diuresis for a patient presenting with approximately 25 litres of anasarca. Note the brisk response once the furosemide infusion was started, and the timing of introduction of long-​ term medication. ACEi is angiotensin-​converting enzyme inhibitor and βB is beta adrenoceptor antagonist. Table 16.5.2.5  Diuretics commonly used in the management of anasarca. DCT is distal, and PCT, proximal, convoluted tubule. MRA is mineralocorticoid antagonist Class Example Route Site of action Comments Loop Furosemide, bumetanide Intravenously Na+/​K+/​Cl–​cotransporter in thick ascending loop of Henle High ceiling; short duration of action Shorter half-​life than thiazides Thiazide Bendroflumethiazide By mouth DCT Low ceiling; longer period of action Combined with loop may cause profound diuresis ‘Thiazide-​like’ Metolazone By mouth DCT (and PCT) Combined with loop may cause profound diuresis MRA Spironolactone, eplerenone By mouth DCT–​Mineralocorticoid receptor antagonists Essential component of long-​term management section 16  Cardiovascular disorders 3406 Cardiogenic shock Shock occurs when there is tissue hypoperfusion despite adequate ventricular filling. There is no blood pressure level that can be used to define shock, with the consequence that the incidence and prog- nosis quoted varies from study to study. Pathophysiology Cardiogenic shock most commonly arises from an acute myocar- dial insult which results in sufficient reduction in cardiac output that the perfusion to vital organs is insufficient to maintain organ function. By far the commonest cause is acute myocardial infarc- tion, although patients with acute presentation of cardiomyopathy, including peripartum cardiomyopathy, may develop shock. The result is massive sympathetic nervous system activation as the body tries to restore blood pressure. The consequent increase in afterload cannot be met by the failing left ventricle. Reduced cor- onary artery perfusion results in worsening myocardial function, perpetuating the problem. Clinical presentation The patient is hypotensive, usually tachycardic, pale, and sweaty. Reduced cerebral perfusion results in confusion and agitation, and the patient becomes oliguric or anuric. Except for those patients with predominant right ventricular infarction, some degree of pul- monary oedema is invariably present. Differential diagnosis and investigations Making the correct diagnosis is fundamental: investigations should be directed at finding any reversible cause for the patient’s state. Making certain that the left ventricle is adequately filled is essential to make the diagnosis of shock: if the left ventricle is underfilled, then fluid replacement should result in rapid reso- lution of symptoms. If there is doubt, then fluid challenges with rapid infusion of 100–​200 ml fluid can be helpful. In some cases, pulmonary artery catheterization is used to determine the pulmonary capillary wedge pressure and hence confirm adequate filling. There is no evidence that using the catheter to guide fur- ther management is helpful. An ECG with right-​sided leads will help make the diagnosis of a predominantly right-​sided myocardial infarct. An echocardiogram to confirm the extent of left and right ventricular damage and to exclude a mechanical problem (free wall rupture, papillary muscle rupture, ventricular septal rupture) is a vital early investigation. Bladder catheterization will confirm that the patient is genu- inely oliguric rather than confused due to retention of urine. Sepsis should be excluded. Management Dealing with any treatable cause of shock is the most important step. Revascularization in patients presenting with acute myocardial in- farction may relieve shock, although if shock develops following or despite a successful procedure, the outlook is particularly poor. Patients with mechanical problems tend to have smaller and more localized infarctions than those without: although it is very high risk, early surgery may be life-​saving. For those patients with right ventricular infarction as the cause, fluid loading may improve the patient’s condition, but at a cost of high central venous pressure. Trying to sustain the circulation in patients with no readily revers- ible cause is rarely successful. • Positive inotropic drugs, such as catecholamines and phospho- diesterase inhibitors, may improve cardiac output and blood pres- sure: however, their use has not been shown to improve prognosis. Indeed, dobutamine in randomized trials is associated with a worse outcome. • Intra-​aortic balloon counterpulsation (IABP) can improve the situation, at least temporarily. Trial evidence suggests that the IABP does not improve prognosis in patients with cardiogenic shock due to acute infarction, but it can certainly help patients with acute mechanical causes such as septal rupture and mitral regurgitation. In some patients with potentially reversible causes, such as peripartum cardiomyopathy, IABP has been used success- fully to sustain the circulation for many weeks. • Advanced therapies with ventricular assist devices (VADs), extra- corporeal membrane oxygenation (ECMO), and even heart trans- plantation have been successful in selected patients. VADs and ECMO are only available in the United Kingdom in transplant centres, but there is a move to make them more widely available as a temporizing measure before patients are transferred to the centres. The prognosis of cardiogenic shock is bleak. Unless there is a readily correctable cause, the mortality rate approaches 60% at 30 days. Once treatable causes of shock have been excluded, conser- vative management and an easy death may be preferred rather than transfer to the intensive care unit for valiant, desperate, protracted, but ultimately futile, intervention. FURTHER READING Chen HH, et  al. for the NHLBI Heart Failure Clinical Research Network (2013). Low-​dose dopamine or low-​dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial. JAMA, 310, 2533–​43. Clark AL, Cleland JG (2013). Causes and treatment of oedema in pa- tients with heart failure. Nat Rev Cardiol, 10, 156–​70. Fig. 16.5.2.9  A patient receiving ultrafiltration. There is a two-​lumen right internal jugular venous line from which blood is continuously removed, pumped through a filter (black arrow) and then returned to the body. Filtrate is seen collecting in the bag (white arrow). 16.5.3 Chronic heart failure Definitions, investig 16.5.3 Chronic heart failure: Definitions, investigation, and management 3407 John G.F. Cleland and Andrew L. Clark 16.5.3  Chronic heart failure 3407 Costanzo MR, et  al. (2017). Extracorporeal ultrafiltration for fluid overload in heart failure: current status and prospects for further research. J Am Coll Cardiol, 69, 2428–​45. Gray A, et al. 3CPO Trialists (2008). Noninvasive ventilation in acute cardiogenic pulmonary edema. N Engl J Med, 359, 142–​51. Harris P (1983). Evolution and the cardiac patient. Cardiovasc Res, 17, 313–​19, 373–​8, 437–​45. MacIver DH, Clark AL (2015). The vital role of the right ventricle in the pathogenesis of acute pulmonary edema. Am J Cardiol, 115, 992–​1000. MacIver DH, Dayer MJ, Harrison AJ (2013). A general theory of acute and chronic heart failure. Int J Cardiol, 165, 25–​34. National Institute for Health and Care Excellence (2014). Acute heart failure: diagnosis and management. Clinical guideline. https://​nice. org.uk/​guidance/​cg187 Ponikowski P, et al. (2016). 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J, 37, 2129–​200. Tharmaratnam D, Nolan J, Jain A (2013). Management of cardio­genic shock complicating acute coronary syndromes. Heart, 99, 1614–​23. Thiele H, et al. IABP-​SHOCK II Trial Investigators (2012). Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med, 367, 1287–​96. 16.5.3  Chronic heart failure: Definitions, investigation, and management John G.F. Cleland and Andrew L. Clark ESSENTIALS Heart failure is a common clinical syndrome, predominantly a disease of older people, often presenting with breathlessness, fatigue, and per- ipheral oedema. Its pathophysiology is complex, with a common fea- ture being salt and water retention, possibly triggered by a relative fall in renal perfusion pressure. Common aetiologies include ischaemic heart disease, hypertension, and valvular heart disease. New treatments have improved prognosis substantially over the past two decades. Early diagnosis relies on a low threshold of suspicion and screening of people at risk. Low plasma concentrations of BNP/​NT-​ proBNP exclude most forms of heart failure, and intermediate or high concentrations should prompt referral for echocardiography to identify possible causes and determine the left ventricular ejection fraction (LVEF), leading to classification as heart failure with reduced LVEF (<40%, HFrEF), normal LVEF (>50%, HFnEF), or borderline LVEF (40–​50%, HFbEF). HFbEF and HFnEF are managed similarly by cur- rent guidelines. Treatable causes for heart failure (e.g. valvular disease, tachyar­ rhythmias, thyrotoxicosis, anaemia, or hypertension) should be iden- tified and corrected. Pharmacological therapy is given to improve symptoms and prognosis. Diuretic therapy is the mainstay for control of congestion and symptoms, but its effect on long-​term prognosis is un- known. For patients with HFrEF, either angiotensin-​converting enzyme inhibitors, angiotensin receptor blockers, or angiotensin receptor–​ neprilysin inhibitors, combined with β-​blockers and mineralocor- ticoid receptor antagonists (triple therapy) provide both symptomatic and prognostic benefit. Other treatments that may be appropriate in particular cases include ivabradine, digoxin, cardiac resynchronization therapy, and implantable defibrillators. Heart transplantation or assist devices may be options for highly selected patients with end-​stage heart failure; many others may benefit from palliative care services. Introduction Heart failure is the most common malignant disease in the United Kingdom. Heart failure in its various manifestations now causes or complicates twice as many hospital admissions (about half a million deaths and discharges each year in the United Kingdom) as do all cancers or acute coronary syndromes combined. This is likely to be a gross underestimate of total activity as the diagnosis of heart failure is often missed or ignored during admission. In the community, heart failure syndromes are almost as common as diabetes mellitus and far more deadly. For some cardiac phenotypes (e.g. left ventricular systolic dys- function), treatment is often highly effective and may even be cura- tive, but diagnostic awareness is low and care, when given, is often fragmented and disorganized. The reasons for the current clinical neglect of heart failure are not entirely clear but may reflect the lack of a robust definition, the difficulty and uncertainties of its clinical diagnosis, the relative complexity of its treatment, all combined with ageism and fatalism on the part of both the clinician and patient. Definition No consensus has been reached on a simple, practical universal definition of heart failure. Indeed, it may be better to consider the diagnosis of heart failure across a spectrum of certainty based on clinical acumen supported by blood tests (particularly natriuretic peptides) and cardiac imaging. Until now, most experts and guidelines have required that the pa- tient should have symptoms before a diagnostic label of heart failure is applied. Of course, a sedentary lifestyle and liberal use of diuretics may mask symptoms. Simply asking the patient to take a walk will often reveal how poor their effort tolerance is, and stopping diuretics will often lead to the diagnosis becoming obvious. Other specialties use biochemical definitions to define organ failure (kidney, pancreas, liver). Central to the concept of heart failure is congestion, indicating that the heart is unable to sustain a normal filling (atrial) pressure for the required cardiac output. Cardiac output is usually fairly normal at rest until the late stages of heart failure. How then should congestion be measured? Natriuretic pep- tides, hormones that are secreted by the stressed heart and designed to counter sodium retention, provide a simple objective method of detecting congestion, even before it becomes clinically overt (Fig. 16.5.3.1). Thus, heart failure could be considered cardiac dys- function leading to an increase in natriuretic peptides. Natriuretic section 16  Cardiovascular disorders 3408 peptides are now an essential tool for the early detection and con- firmation of a diagnosis of heart failure in any modern health service. Broadening the definition of heart failure has many consequences, the most obvious being a great increase in the number of patients. About 3% of the adult population is taking loop diuretics for no obvious reason other than symptoms or signs suggestive of heart failure. Currently, most cases of heart failure are diagnosed during a hospital admission, suggesting that the diagnosis is usually missed until the problem is bad enough to provoke severe symptoms. The onset of symptomatic heart failure may well be precipitated by an acute event, but usually on a back- ground of chronic cardiac dysfunction. Earlier diagnosis will increase identification in the community before the onset of severe symptoms and at a time when therapy might be more effective. Clinical physiology Heart failure can be considered as a sequence of unfortunate events (Fig. 16.5.3.2), starting with cardiac (usually left ventricular) dys- function leading to haemodynamic changes that are often initially subtle, including a rise in atrial pressures and a fall in blood pressure below the set-​point for renal sodium retention. This triggers acti- vation of neuroendocrine systems such as the renin–​angiotensin–​ aldosterone and sympathetic nervous system in an attempt to restore blood pressure by vasoconstriction and blood volume expansion. This has long-​term deleterious effects on the heart. Fortunately, there is also activation of counter-​regulatory mechanisms, most not- ably the natriuretic peptides, which attempt to prevent sodium re- tention and delay the onset of symptomatic congestion. Eventually, counterregulatory systems are overwhelmed, and clinical evidence of congestion appears, manifest either as breathlessness (loosely re- lated to left atrial pressure) or peripheral oedema (loosely related to right atrial pressure). The treatment of heart failure revolves around preventing or reversing congestion and avoiding sudden death due either to arrhythmias or vascular events, which can arise at any time. Cardiac (imaging) phenotypes Cardiac phenotype is strongly linked to the aetiology of cardiac dys- function and is a key determinant of management. For some cardiac phenotypes there is little evidence that treatment alters outcome. Fig. 16.5.3.1  Natriuretic peptides are the earliest and most sensitive sign of congestion but do not distinguish between cardiac and renal causes. Cardiac imaging is less sensitive and accurate (i.e. abnormal cardiac function may not cause congestion) for detecting congestion but, along with tests for heart rhythm and renal function, it helps to determine the cause of congestion. Symptoms and signs are late manifestations of congestion and usually only first detected when they have deteriorated sufficiently to precipitate a hospital admission. Left ventricular dysfunction Rise in left atrial pressure At rest During stress Volume (fluid load, exercise) • Pressure (hypertension, exercise) • • Pulmonary congestion • Breathlessness • Pulmonary arteriolar hypertrophy & vasoconstriction • Pulmonary hypertension • Rise in right atrial pressure • Peripheral oedema • Peripheral congestion • Tricuspid valve regurgitation • Right ventricular dysfunction • • Mitral regurgitation Fig. 16.5.3.2  Development and progression of heart failure. 16.5.3  Chronic heart failure 3409 Few patients have a single pure phenotype; most patients manifest several phenotypes, but usually one is dominant (Table 16.5.3.1). When heart failure is associated with a reduced left ventricular ejection fraction (LVEF) this is often termed HFrEF or left ven- tricular systolic dysfunction (LVSD). Patients with heart failure and a normal or preserved LVEF are termed HFnEF and HFpEF, respect- ively. Left ventricular diastolic dysfunction (LVDD) is a subset of HFnEF as it is possible to have HFnEF without LVDD (e.g. patients with isolated right ventricular dysfunction). Various authorities suggest different LVEF thresholds for defining HFnEF, with the cut-​off ranging from less than 40% to over 50%. Since echocardiographers usually refer to a LVEF of under 50% as LVSD the terminology is confusing, and some believe that patients with an LVEF of 40–​50% should be considered a separate group HFbEF (heart failure with a borderline LVEF), which seems a helpful concept. LVEF measured by conventional echocardiography is only accurate to within about 10%, although more advanced imaging techniques such as cardiac MRI (CMRI) may have greater precision. Each of the phenotypes is heterogeneous, particularly HFnEF (Fig. 16.5.3.3). HFrEF is the predominant cardiac phenotype in men and patients aged less than 75 years and is often due to ischaemic heart disease. HFnEF is the predominant phenotype in older women and is often due to hypertension. In patients with HFrEF, it is im- portant to consider to what extent contractile dysfunction is due to dysfunction of viable myocardium, which may be reversible, or to consolidated scar that is likely to be irreversible using existing tech- nology. The relative contribution of extracellular matrix and fibrosis and impaired cardiac myocyte relaxation to HFnEF is uncertain, and the therapeutic target at the myocardial level is unclear. Heart failure due to valve disease may occur at any age, but degenerative valve disease is an increasingly common cause in older people. Risk factors and aetiology The most important risk factor for heart failure is age. It is likely that everyone will develop heart failure if they live long enough. Biological rather than chronological age may account for the link between physical frailty and the risk of developing heart failure. Currently, one in five people is expected to develop heart failure be- fore they die, which may be a gross underestimate given the diag- nostic gap outlined earlier. The most important medical risk factors for developing heart failure are hypertension and ischaemic heart disease, and their combination may confer more than additive risk (Table 16.5.3.1). Both may go undetected and untreated for years; the onset of symptoms of heart failure may be the first time the patient seeks help. There is a wealth of evidence that hypertension, even when detected, is often poorly man- aged. Alarmingly, studies suggest that most myocardial infarctions, perhaps especially among older people, do not provoke symptoms sufficient for the person to seek immediate medical assistance. Good treatment of hypertension and other risk factors for coronary artery disease will undoubtedly delay the onset of disease. Poor lifestyle and inferior medical care probably account for the association between social deprivation and the onset of heart failure at an earlier age. Among patients aged under 50 years, cardiomyopathies and con- genital heart disease account for a large proportion of heart failure. Table 16.5.3.1  Common cardiac phenotypes in heart failure HFrEF HFbEF HFpEF/​HFnEF LVEF <40% 40–​50% 50% Ischaemic heart disease XXX XX X Hypertension X XX XXX Atrial fibrillation XX XX XXX Dilated cardiomyopathy XXX ? NA Aortic stenosis X XX XXX Mitral regurgitation XX XX XX Number of crosses reflects strength of association (although not necessarily proportion affected or prevalence). HFrEF = heart failure with a reduced left ventricular ejection fraction. HFbEF = heart failure with a borderline left ventricular ejection fraction. HFpEF/​HFnEF = heart failure with a preserved or normal left ventricular ejection fraction. Fig. 16.5.3.3  Heterogeneity of heart failure with normal left ventricular ejection fraction. Conceptually, the diagnosis of heart failure requires evidence of congestion: for example, elevated natriuretic peptides, evidence of a cardiac abnormality, and (retrospectively) an increased risk of cardiovascular events. section 16  Cardiovascular disorders 3410 In patients aged over 50 years, ischaemic heart disease is the dom- inant cause of HFrEF and hypertension the dominant cause of HFnEF. There are many rare causes of heart failure (Table 16.5.3.2), but collectively these affect a substantial number of patients. Diagnosis Most heart failure is first diagnosed at a late stage in the disease, subsequent to a hospital admission. This is unlikely to change until screening the population at risk with natriuretic peptides becomes routine. There are six diagnostic steps: Step 1: Case ascertainment The first and most important step is suspecting that something might be wrong. The patient may complain of breathlessness, but this is a late manifestation of disease in a sedentary population. By the time orthopnoea, paroxysmal nocturnal dyspnoea, or breathlessness on mild exertion have developed, the disease is far advanced. Walking with the patient at a brisk pace may well provoke symptoms but does not lend itself to the organization of conventional clinics in primary or secondary care. Ankle oedema due to rising systemic venous pres- sure is also a late manifestation of disease and carries low specificity. Symptoms and signs may be abolished by diuretic therapy, but there is concern that such treatment may accelerate the progression of dis- ease by deleterious activation of neuroendocrine systems. Earlier detection of heart failure requires a provocative test of cardiac reserve (e.g. a corridor walking test) or identification of ac- tivated compensatory mechanisms (e.g. natriuretic peptides) in pa- tients deemed at risk of heart failure by virtue of age or medical risk factors. Any patient prescribed a loop diuretic should be presumed to have heart failure until proven otherwise. Table 16.5.3.2  Some rarer causes of heart failure Causes Comments Phenotype and specific therapy Amyloidosis Due to plasma cell expansion/​myeloma (AL), transthyretin (ATTR) gene mutation or chronic infection/​inflammation (AA). TTR mutations may cause 10% of HFpEF in older people Increased LV wall thickness, HFbEF, or HFpEF. Often atrioventricular conduction delay Poor prognosis for AL. Most patient die within a year of diagnosis. ATTR better prognosis. Specific therapies in discovery (e.g. tafamidis) Haemochromatosis High serum ferritin and transferrin saturation. Often diabetic. Affects c.0.05% of Northern Europeans HFrEF or HFbEF. Often a restrictive picture Treat with phlebotomy and iron chelation therapy. Early detection important Haemosiderosis Usually associated with multiple blood transfusions due to haemolytic or aplastic anaemia. Carcinoid syndrome Caused by hepatic or more rarely pulmonary metastasis of serotonin secreting tumours Tricuspid regurgitation and pulmonary stenosis leading to low output and peripheral congestion. Sarcoid heart disease Often associated with pulmonary disease HFrEF or HFpEF. Arrhythmias and conduction defects common Tachy-​cardiomyopathy Ventricular rate usually persistently >150 bpm. Usually supraventricular but rarely ventricular tachycardia. Lower rates suggest that tachycardia is a consequence of heart failure Dilated cardiomyopathy. Resolves usually within a few weeks when arrhythmia is corrected Thyrotoxicosis May be iodine/​amiodarone induced. Weight loss, tachycardia, and other features of thyroid hormone excess High output Phaeochromocytoma Due to catecholamine secreting tumours—​usually adrenal HFrEF. Care with the use of adrenergic antagonists. Requires surgical correction Genetic DCM More than a dozen genetic mutations, notably of the titin gene HFrEF Lamin A/​C gene mutation Rare HFbEF. Atrioventricular conduction defects, ventricular arrhythmias, and sudden death Muscular dystrophy Duchenne, Becker, and myotonic dystrophy HFrEF often with conduction defects Hypertrophic cardiomyopathy May be genetic or sporadic HFpEF or HFbEF Left ventricular non​compaction May be familial HFrEF or HFbEF Endomyocardial fibrosis Usually a tropical disease possibly due to parasitic disease. Consider if eosinophilia HFpEF or HFbEF. Restrictive defect Iatrogenic Cancer chemotherapy, radiation, calcium channel blockers, hypoglycaemic therapies Anthracycline and radiation induced damage may be irreversible. May be HFrEF or HFpEF Nutritional deficiency Thiamine, iron, selenium Rare unless severe deficiency Peripartum Cardiomyopathy Usually in last trimester or within a few weeks of delivery May only be recognized when severe. Usually recovers if patient survives. May recur with further pregnancy Myocarditis May be viral, including HIV, or due to borrelia (Lyme disease) or trypanosomiasis (Chagas disease). Giant cell myocarditis has a particularly poor prognosis HFrEF HIV—​often pulmonary hypertension Chagas disease—​arrhythmias Borrelia—​consider doxycycline Giant cell—​steroids?/​immunosuppression? 16.5.3  Chronic heart failure 3411 Step 2: Proving that cardiac dysfunction and heart failure are present Once heart failure is suspected, objective evidence of cardiac dys- function is required. Breathlessness and ankle swelling are not specific to heart failure. Signs of heart failure, such as jugular venous distension, are relatively specific but insensitive, often dif- ficult to elicit, and not easily recorded in a way that convinces colleagues. Chest radiography is no longer regarded as essential. A normal chest radiograph is not uncommon in patients with heart failure, and radiographic cardiomegaly is frequently a spurious finding. The electrocardiogram (ECG) is almost universally abnormal in heart failure and if genuinely normal places the diagnosis in doubt. Until recently, echocardiography was considered the practical gold-​standard measure for cardiac dysfunction and focused al- most exclusively on identifying valve disease and HFrEF. However, there is growing awareness of the limitations of echocardiography, especially when not interpreted by experts. Reproducibility of LVEF estimation is poor, and measurements of diastolic function are complex and often contradictory. Probably the best echocar- diographic guide to cardiac dysfunction, at least when chronic, are atrial volumes. Natriuretic peptides provide a simple approach to diagnosis and are more closely associated with atrial volumes than many other measures of cardiac dysfunction. They are not only more sensitive than cardiac imaging but a better guide to the patient’s prognosis. Natriuretic peptides are also more specific than imaging when the question is ‘Does this patient have serious disease requiring further investigation?’ rather than ‘Does this patient have cardiac dysfunction?’ A normal plasma concentration of a natriuretic pep- tide in the absence of a diuretic effectively excludes heart failure with one uncommon exception—​constrictive pericarditis. Gross obesity is associated with somewhat lower plasma concentrations of natriuretic peptides and diuretics may reduce them as they im- prove congestion. The N-​terminal fragment of pro brain natri- uretic peptide (NT-​proBNP) is stable for days in blood samples and therefore can be measured easily and inexpensively in primary or secondary care. Interpretation of results requires additional information. Atrial fibrillation and renal dysfunction are other common reasons for an increase in plasma natriuretic peptides concentrations. Clinical acumen supported by a measurement of natriuretic peptide is usually sufficient to make or refute a diag- nosis of heart failure. Step 3: Differential diagnosis If a patient has symptoms, merely excluding or diagnosing heart failure is not enough. Alternative causes of symptoms should be sought. The common differential diagnoses for breathlessness are lung disease, obesity, and being unfit, all of which may coexist with heart failure. Determining how much each is contributing to symp- toms will help guide use of diuretics; dehydrating patients with lung disease is unlikely to make them better and may make them worse. Spirometry may help identify lung disease, but low values may re- flect general frailty and poor technique rather than lung disease. Natriuretic peptides can help; a slim patient who is very breath- less but only has moderately elevated NT-​proBNP is likely to have lung disease as the dominant pathology. Cardiopulmonary exercise testing aids differential diagnosis but requires special equipment and expertise. Echocardiographic evidence of mild diastolic dysfunction is very common in elderly people and heart failure can be readily overdiagnosed. A diagnosis of HFnEF made on the isolated echocar- diographic finding of diastolic dysfunction should always be regarded with caution, and only following exclusion of alternative pathology. Conditions that may masquerade as ‘diastolic heart failure’, either in isolation or in combination, are listed in Table 16.5.3.3. Step 4: Cardiac phenotype and cause(s) of cardiac dysfunction Clinical acumen combined with natriuretic peptides may be enough to make a diagnosis of heart failure, but is a poor guide to cardiac phenotype. The workhorse of cardiac phenotyping is the echocardiogram. The echocardiogram provides an approxi- mate guide to LVEF and therefore differentiates HFrEF from HFnEF, identifies abnormal heart valves, and quantifies atrial vol- umes. Of the many parameters of diastolic function, increased left atrial size is probably the simplest and most reliable, and is an im- portant prognostic indicator regardless of baseline left ventricular function. For patients with HFrEF, the amount of myocardial scar is an important determinant of the response to treatment and is best as- sessed by CMRI. However, many heart failure services have little access to this investigation. Radionuclear imaging is an alternative. A diagnosis of coronary disease can usually be made based on the clinical history or, failing that, by CMRI, stress echo, or radionuclear imaging. In the absence of symptomatic angina there is no evidence that revascularization improves outcome in patients with chronic heart failure. The presence or absence of coronary disease should have little influence on the choice of pharmacological or device treatment, and there is no evidence that antiplatelet agents are safe or effective in this setting. Angiography should therefore be reserved for patients with limiting angina despite pharmacological therapy, and those presenting with heart failure in the context of an acute cor- onary syndrome. CT angiography can be used if it is felt necessary to exclude left main-​stem disease or that of another proximal coronary artery. There is little information to be gained from heart catheter- ization that cannot be obtained more pleasantly, safely and at lower cost by non​invasive methods, which may also supply information that an angiogram cannot. Table 16.5.3.3  Conditions masquerading as diastolic heart failure COPD/​Cor pulmonale (without RV dysfunction) Obesity-​hypoventilation syndrome Obstructive sleep apnoea Severe renal disease Anaemia Thyrotoxicosis Nephrotic syndrome Silent myocardial ischaemia Venous insufficiency Lymphatic obstruction section 16  Cardiovascular disorders 3412 Step 5: Comorbidity—​what other problems might exacerbate or complicate heart failure? Patients rarely only have heart failure. Identifying important cardio- vascular and non​cardiovascular comorbidity provides additional therapeutic targets (Table 16.5.3.4). Step 6: Diagnostic tests required to achieve therapeutic aims The therapeutic goals should first be defined. If it is palliative care, then only treatments designed to control symptoms are appropriate (this may include diuretics, ACE inhibitors, mineralocorticoid antagonists (MRA), cardiac resynchronization therapy, and pos- sibly digoxin and intravenous iron). If the goal is to improve prog- nosis through ‘disease-​modifying’ interventions, then β-​blockers, ivabradine, and implantable cardiac defibrillators should be added to the list. Preventing patients with atrial fibrillation from developing the misery of a stroke might be considered appropriate regardless of other therapeutic aims. The small amount of information (10 items) routinely required to use these agents safely and effectively is shown in Table 16.5.3.5. Prognosis The prognosis of heart failure depends on the clinical context. Incident heart failure is associated with a 30% mortality at 6 months. The annual mortality of chronic stable patients is now probably less than 5% per annum, but admission to hospital with worsening heart failure has a mortality of about 10–​15%, with mortality in the 6 months after discharge from an admission being in the range of 15–​25%. Age is an important determinant of mortality, with the in- fluence of treatments shown in Fig. 16.5.3.4. Readmission rates are also high; most patients with heart failure will be admitted at least once in a 3-​year period, and following a re- admission, 15–​25% will have a further readmission within 30 days without expert support. Age is not such a good predictor of readmis- sion, perhaps because older people have a higher mortality. A pragmatic prognostic scoring system for chronic heart failure can be found at http://​www.heartfailurerisk.org/​, and may be im- proved by some simple additional pieces of information, such as whether the patient has had a recent exacerbation of symptoms, the dose of diuretic, and plasma concentration of NT-​proBNP. Knowing prognosis can help with management, both in terms of advice to the patient and choice of therapy. Management Modern management of patients with heart failure requires the co- ordinated input of a multidisciplinary team of dedicated cardiolo- gists, specialist heart failure and rehabilitation nurses, primary care physicians, and palliative care specialists. The key to the successful Table 16.5.3.4  Common problems (comorbidities) complicating the diagnosis and management of heart failure Problem Comment Obesity (and lack of fitness) Alternative cause for breathlessness creating diagnostic uncertainty and problems with judging diuretic dose. Diuresis will not help breathlessness due to obesity. Obesity is consistently associated with a better prognosis in a broad spectrum of patients with cardiovascular disease, including heart failure. Cachexia Ominous sign in heart failure. Exclude cancerous malignant disease. If patient is a candidate for transplant or mechanical assist, consider urgent referral. COPD Alternative cause for breathlessness creating diagnostic uncertainty and problems with judging diuretic dose. Diuresis will not help breathlessness due to COPD. Patients with heart failure and COPD have a worse prognosis. Atrial fibrillation AF may cause heart failure and vice versa. Optimal ventricular rate control may be about 80 bpm at rest. Need for anticoagulation. Ischaemic heart disease Common cause of a reduced LVEF. Little evidence that revascularization improves prognosis. Coronary angiography only indicated if patient has angina. Ongoing research into revascularization of viable myocardium but randomized controlled trials neutral so far. Hypertension A sign that the left ventricle still has some reserve. Most treatments for heart failure reduce blood pressure, so in this context hypertension is a good sign! Hypotension Often limits amount of pharmacological treatment and is a poor prognostic sign. Cardiac resynchronization will increase systolic blood pressure in appropriately selected patients. Anaemia Often associated with iron deficiency although not always corrected by oral or even intravenous iron. Some anaemia is dilutional (plasma volume expansion) and some caused by renal dysfunction and deficient erythropoiesis. Folate and B12 deficiency are rarely important causes of anaemia in heart failure. Diabetes mellitus Indicates a worse prognosis, possibly because of associated renal problems. Treatment for diabetes may make heart failure worse. Optimal HbA1c in patients with heart failure being treated for diabetes may be around 7.5% (lower if ‘prediabetic’). Chronic kidney disease Often due to pre-​existing renal damage and exacerbated by hypotension and low renal blood flow. Often limits the doses of medication that can be given. Renal function is a powerful prognostic marker (more powerful than LVEF). Stroke Related mainly to pre-​existing hypertension, atherosclerosis, and atrial fibrillation. Dementia Age often brings deterioration in cognitive as well as cardiac function. Dementia reduces ability for self-​care and adherence to advice and medication. Worsening heart failure may impair cognitive function. Aortic stenosis Common in older people. Diuretics may reduce congestion and symptoms, but other medication may be of little help and may cause hypotension. Consider aortic valve surgery or transcutaneous procedure. Mitral regurgitation Common in all forms of heart failure. May improve with treatments that reduce ventricular volume, especially cardiac resynchronization. Patient selection for surgery often difficult. Transcutaneous repair may be considered. 16.5.3  Chronic heart failure 3413 management of these patients is prompt identification in the com- munity and following admission to hospital, and access to follow-​up and management by a specialist team. Lifestyle Patients with heart failure should be advised to lead a healthy lifestyle, avoiding smoking and excessive alcohol consumption, eating a balanced diet, and taking regular exercise (http://​www. heartfailurematters.org/​en_​GB). There is little evidence that such advice makes a difference to prognosis, but it probably improves well-​being. Attention to psychological health is important. Keeping socially active, taking holidays (with adequate health insurance; http://​www.bhf.org.uk/​heart-​health/​living-​with-​aheart-​condition/​ living-​with-​heart-​failure.aspx) and investing in hobbies and recre- ations are more important than pharmacological treatments for anxiety and depression that are, however, mostly safe. There is no evidence that complementary medicine can alter the course of heart failure but, provided the patient is not tempted to stop conventional therapy, it may provide them with psychological support. Patients should know what medication to take and be advised to have a system to ensure that they do so. Excessive dietary salt and fluid consumption should be avoided, but there is scant evidence that severe restriction of dietary salt is helpful and it might do harm. Fluid restriction (to <1.5 litres/​day) may be required in patients with advanced, diuretic-​resistant heart failure. The ideal body mass index for a patient with heart failure is probably about 30 kg/​m2. Dieting to lose weight might improve symptoms, but there is no evidence that it will improve prognosis and it may be harmful. Patients with severe heart failure may develop cachexia (in the context of heart failure, this may mean achieving a normal body mass index) that may be partly due to reduced cal- orie intake. Trying to improve appetite seems reasonable, although of uncertain prognostic value and may not reverse weight loss. There is no evidence that supplementing the diet with vitamins or trace elements helps. Patients with heart failure are at increased risk of dying from in- fluenza and pneumococcal pneumonia and should receive these vaccinations, although there is no specific evidence that they alter outcome in patients with heart failure. It is important to be sensitive to the patient’s view of their illness. Many patients will not want to discuss how they are likely to die, others will. Developing counselling skills that allow patients to raise issues such as death and identifying when a patient has run out of therapeutic options and requires palliative care is an important part of a heart failure service. It is also important to address the worries and concerns of carers and the patient’s social network as this may help them to support the patient with issues such as adherence to medicine, keeping appoint- ments, or doing monitoring tests. Drug treatment of HFrEF The change in prognosis resulting from pharmacological and device therapy for patients with HFrEF (Table 16.5.3.5) is among the most remarkable success stories for any disease in the last quarter century (see Fig. 16.5.3.4). Loop and thiazide diuretics Diuretics are the most effective method of dealing with congestion, regardless of cardiac cause. They are also the most abused and least evaluated class of medication for heart failure. They are generally given at a fixed daily dose, but many patients can do without their diuretics for several days at a time, and others for much longer. Diuretic-​free days may allow the patient greater freedom of activity. Some advocate adjusting the diuretic dose to maintain an ideal weight, which suits some patients. Reliable daily weight monitoring with accurate scales, potentially as part of a telemonitoring pro- gramme, may facilitate this strategy. In most countries, diuretics acting on the loop of Henle, which produce a powerful diuresis lasting a few hours, are preferred. Once the diuresis is over, avid renal salt and water retention occur. In some countries, thiazide diuretics acting on the distal convoluted tubule are preferred first-​line agents. They produce a less powerful but much longer natriuresis, which may result in similar 24 h so- dium excretion to loop diuretics, but some patients will complain Table 16.5.3.5  Indications for therapy and information required for choosing and monitoring key treatments in heart failure HISTORY EXAMINATION ELECTROCARDIOGRAM BLOOD TESTS ECHOCARDIOGRAM (evidence base for use) SOB (NYHA CLASS) BP OEDEMA HR AF QRS K GFR BNP HFrEF HFpEF (>40%) Loop diuretics II-​IV X X X X Symptomatic Symptomatic ACE/​ARB II-​IV X X X Symptomatic/​Prognostic Symptomatic ARNI II-​IV X X X X Symptomatic/​Prognostic ? β-​Blocker II-​IV X X X Prognostic ? MRA II-​IV X X X Symptomatic/​Prognostic (<35%) ? Ivabradine II-​IV X X Symptomatic/​Prognostic (<35%) ? Digoxin III-​IV X X X X X Symptomatic ? Hydralazine/​ Nitrates III-​IV X Symptomatic/​Prognostic ? ICD I-​III 120 msec Prognostic (<35%) ? CRT II-​IV X X 120 msec/​LBBB Symptomatic/​Prognostic (35%) ARNI, angiotensin receptor neprilysin inhibitor; MRA, mineralocorticoid receptor antagonist; ICD, implantable cardiodefibrillator; CRT, cardiac resynchronization therapy; X indicates where information is required to guide treatment. section 16  Cardiovascular disorders 3414 of an increase in nocturia and the rate of hypokalaemia and hyponatraemia may be higher. Thiazides are said to be ineffective when renal function is substantially impaired. In patients with hypertension, thiazide diuretics have repeatedly been shown to re- duce myocardial infarction, stroke, heart failure, and death. Similar evidence for loop diuretics is lacking. Typically, a patient will be initiated on 40 mg of furosemide or 1 mg of bumetanide per day. The patient should be warned that the first few doses are likely to provoke a marked diuresis, but that this will subside as pathophysiological signals for salt and water reten- tion intensify (the ‘braking’ effect). Diuretics may provoke urinary retention in patients with prostatic disease. Serum electrolytes and renal function should be monitored. If serum potassium drops below 4.0 mmol/​litre, then a potassium-​sparing diuretic should be given; usually an MRA. Patients with severe congestion may be treated with high doses of loop diuretics or with a combination of loop and thiazide diuretics. It is unclear which is the better strategy. An MRA may be added to either combination to prevent hypokalaemia and further enhance natriuresis. Angiotensin-​converting enzyme inhibitors, angiotensin receptor blockers, and renin inhibitors Angiotensin-​converting enzyme inhibitors Angiotensin-​converting enzyme (ACE) inhibitors are one of the cornerstones of contemporary therapy for HFrEF. The onset of heart failure provokes the production of renin and, in turn, angiotensin II, which stimulates AT1 receptors that cause vasoconstriction, secre- tion of aldosterone, and sodium retention. Activation of the renin–​ angiotensin–​aldosterone system (RAAS) is subtle until diuretics are given. ACE inhibitors block the production of angiotensin II. The ACE is also responsible for the breakdown of bradykinin, which may be responsible for side effects such as cough (much more common in women) and angioneurotic oedema. Bradykinin also stimulates the production of prostacyclin, which may be an important part of the mode of action of ACE inhibitors. Aspirin blocks the production of prostacyclin and may detract from benefit. ACE inhibitors improve symptoms and exercise capacity, have favourable effect on ventricular remodelling (disease progression), reduce the risks of atrial fibrillation and hospitalization for heart failure, and delay death by reducing the rate of both sudden death and death from progressive heart failure. In addition to idiosyncratic side effects such as cough and angio- neurotic oedema, ACE inhibitors usually reduce blood pressure and increase serum potassium and creatinine, each of which may be dose limiting. In patients with renal artery stenosis, the rise in serum creatinine may be marked. ACE inhibitors are contraindicated in pregnancy or during breastfeeding and in patients with a history of angioneurotic oe- dema. They should be used with caution in patients with a low blood pressure, high serum potassium, or marked renal dysfunction. ACE inhibitors should be started at a low dose, typically enalapril 2.5 mg bd or ramipril 1.25 mg bd. If the patient has well-​maintained blood pressure and renal function and frequent monitoring is possible (e.g. in hospital), then doses may be doubled every 48 h up to a target of 10–​20 mg bd for enalapril or 5 mg bd for ramipril. Patients who do not achieve guideline target doses quickly may never achieve them unless the continuity of care is excellent. For more fragile patients, titration of ACE inhibitors at 2-​week inter- vals with a blood test at each step is recommended. Having said this, dose-​ranging studies of ACE inhibitors have failed to show a striking advantage to higher doses, although patients at the milder end of the spectrum may benefit more from higher doses, perhaps because they can tolerate them. Asymptomatic low blood pressure should not deter attaining guideline target doses, but excessive in- creases in potassium and creatinine require dose reduction or may occasionally prevent use of ACE inhibitors. See section on blood Fig. 16.5.3.4  Cumulative effect of drugs and device therapy on mortality in patients with symptomatic heart failure and LVEF less than 40% between the ages of 50 and 70 years (baseline mortality represented by that on diuretic therapy only). CRT-​D, cardiac resynchronization therapy—​defibrillator; ARA/​ARB, angiotensin receptor antagonist/​angiotensin receptor blocker; BB, β-​blocker; ACEi, angiotensin converting enzyme inhibitor. 16.5.3  Chronic heart failure 3415 pressure in ‘Practical aspects of monitoring and management’ for further details. Angiotensin receptor blockers Angiotensin receptor blockers (ARBs) inhibit the binding of angio- tensin II to the AT1 receptor. The AT2 receptor is not blocked and there is some evidence that this may be beneficial. Bradykinin deg- radation is not blocked, hence ARBs do not cause cough or angio- neurotic oedema. Overall, ARBs appear to have similar benefits to ACE inhibitors, but the evidence is somewhat less convincing and so they are a second choice (e.g. for patients who have troublesome cough with an ACE inhibitor). It is possible that ARBs are only ef- fective when used in high doses. In general, dual therapy with ARB and ACE inhibitors should be avoided. Renin inhibitors A large trial of a renin inhibitor (aliskiren) as an alternative to or in addition to an ACE inhibitor (enalapril) did not support its use in either capacity, indeed the addition of aliskiren to enalapril led to more adverse effects without benefit. Angiotensin receptor–​neprilysin inhibitors LCZ696 (valsartan/​sacubitril) is a hybrid of an ARB (valsartan) and a neutral endopeptidase or neprilysin inhibitor, an enzyme respon- sible for inhibiting the degradation of both natriuretic peptides and bradykinin. A clinical trial comparing LCZ with enalapril in more than 8000 patients with HFrEF was stopped due to substantial benefit (about 20% reduction) on a composite end point of risk of death and hospitalization for heart failure. In terms of incorporation of valsartan/​sacubitril into routine clinical practice, an analysis pub- lished in 2017 indicates that it is cost-​effective. A trial of this drug combination in HfpEF is underway. Mineralocorticoid receptor antagonists Addition of an MRA to either an ACE inhibitor or an ARB has be- come another cornerstone of the contemporary management of HfrEF. Although ACE inhibitors and ARBs reduce the secretion of aldosterone, suppression is incomplete. MRAs block the effects of aldosterone much more effectively, and they improve symptoms and reduce hospitalizations and death due to worsening heart failure, re- duce the incidence of atrial fibrillation (presumably by treating con- gestion), and reduce the risk of sudden death (possibly by preventing hypokalaemia). All the benefits of MRAs may be explained by their ability to reduce urinary potassium and increase urinary sodium excretion and the associated fall in blood pressure. However, some believe that MRAs may also reduce myocardial fibrosis, but there is little evidence that MRAs improve underlying myocardial function or remodelling. Spironolactone stimulates oestrogen receptors that may cause gy- naecomastia and testicular atrophy that become clinically problem- atic in about 10% of men. Eplerenone is more selective and does not cause these problems. MRAs should not be given to patients with a serum potassium greater than 4.9 mmol/​litre and should be used with caution in pa- tients with substantial renal dysfunction or low blood pressure, also in frail elderly patients. Spironolactone and eplerenone should generally be started at 25 mg/​day. Lower initial doses may be appropriate in older patients with impaired renal function (e.g. 25 mg on Monday, Wednesday, Friday—​daily doses are unnecessary and splitting tablets can be problematic). The dose should be adjusted according to the effects on serum potassium, renal function, and blood pressure. The ideal serum potassium is around 4.5 mmol/​litre. Doses of MRA should be increased to get serum potassium to this target, but reduced if potassium rises above 4.9  mmol/​litre. Titration at 2-​week inter- vals is generally appropriate unless the serum potassium is below 3.5 mmol/​litre, in which case more urgent action is required. β-​Blockers The sympathetic nervous system is activated in heart failure, leading to increases in heart rate, cardiac myocyte dysfunction, and weight loss (cachexia). Blockade of adrenergic receptors re- duces heart rate and reverses cardiac myocyte dysfunction, often leading to a remarkable recovery in myocardial function (although not scar), and it may retard, prevent, or reverse the development of cardiac cachexia. These effects lead to a reduction in mortality from worsening heart failure. Adrenergic receptor blockade also reduces the risk of supraventricular and ventricular arrhythmias, coronary events, and sudden death. How much of the benefit of β-​blockers is mediated by reduction in heart rate or by other mechanisms is unclear. Recent analyses suggest that β-​blockers may not be effective in patients with HFnEF and atrial fibrillation (see section on heart rate in ‘Practical aspects of monitoring and management’). Addition of a β-​blocker to ACE inhibitor or ARB and an MRA (triple therapy) is the third cornerstone of the contemporary man- agement of HFrEF. Typically, an ACE inhibitor and β-​blocker will be started in low doses at the same time. The dose of ACE inhibitor will be increased every day, week, or fortnight, but the β-​blocker more slowly at 2–​4-​week intervals. MRAs are then added when titration of the ACE inhibitor and β-​blocker are complete, but sooner if po- tassium is low or congestion is severe. β-​Blockers are contraindicated in patients with bradycardia, im- paired atrioventricular conduction (unless the patient has a pace- maker), asthma (although not in most patients with chronic lung disease, who have little reversibility with sympathomimetic bron- chodilators), and in patients with severe uncontrolled congestion. Initiation of a β-​blocker may cause some initial worsening of con- gestion and symptoms, but overcautious clinicians are probably a substantial reason for patient side effects and intolerance. There are many different β-​blockers, but only four have been shown to be effective for HFrEF. Three are selective for the β1-​receptor (bisoprolol, metoprolol succinate—​not available in the United Kingdom—​and nebivolol) and one is a non​selective agent (carvedilol). There is some evidence that carvedilol may be superior, and it is best studied in trials. β-​blockers should be started at a low dose (e.g. carvedilol 3.125 mg bd or bisoprolol 1.25 mg once daily) and titrated upwards at 2–​4-​ week intervals to target doses (carvedilol 25–​50 mg bd or bisoprolol 10 mg/​day). The optimal resting heart rate for patients in sinus rhythm appears to be 50–​60 bpm, and doses should be adjusted to try to achieve this target. Achieving optimal heart rate appears more important than the dose of a β-​blocker. In atrial fibrillation a ventricular rate of 75–​85 bpm is associated with the best prog- nosis. Aggressive titration should be avoided if a β-​blocker is used in atrial fibrillation. Fatigue and hypotension, or perhaps prescribing section 16  Cardiovascular disorders 3416 inertia on the part of doctors, prevent many patients from achieving target doses. Ivabradine Ivabradine slows the rate of discharge of the sinus node, slowing heart rate only when the patient is in sinus rhythm. In patients with HFrEF and a resting sinus rate in excess of 70 bpm, ivabradine im- proves cardiac function and symptoms, and reduces hospitalization and death from worsening heart failure. It does not reduce arrhyth- mias or prevent sudden death. Ivabradine is indicated only when β-​blockade has failed to re- duce sinus rate below 70 bpm. Many patients are perceived to be in- tolerant of doses of β-​blockers required to control heart rate, but this can often be overcome by extra care and persuasion. Most patients with chronic lung disease tolerate β-​blockers. Unlike β-​blockers, ivabradine does not reduce blood pressure and has little or no effect on atrioventricular conduction. Younger patients with dilated car- diomyopathy may obtain larger benefits from ivabradine. Ivabradine is effective in patients who are unable to tolerate β-​blockers, but they should be strongly encouraged to take at least a low dose of β-​ blocker in addition. Ivabradine is usually started at 5 mg bd and adjusted down to 2.5 mg bd or up to 7.5 mg bd to attain a resting heart rate of 50–​60 bpm. Regarding side effects, the channels that ivabradine acts on are also present in the retina. Distortion of colour vision may occur, espe- cially while driving at night, but usually settles in a few weeks. Alternative vasodilators There is no certain place for other vasodilator agents in patients with heart failure. Although venous and arteriolar vasodilatation may have beneficial haemodynamic effects, there is little evidence that this improves symptoms or outcome. Vasodilatation may provoke further renal sodium retention and merely shunt blood through tis- sues, thereby reducing the useful work of the heart. For instance, there is evidence that both sildenafil and endothelin antagonists may increase pulmonary shunting in patients with heart failure, leading to a fall in arterial oxygen saturation, and similar shunting of blood may occur through peripheral tissues. Neither nitrates nor hydralazine used alone has been shown to improve symptoms or outcome in patients with heart failure, but when used in combination there is some evidence of benefit similar to that of ACE inhibitors, but potentially with less adverse effects on renal function. This combination is therefore sometimes used as an alternative to ACE inhibitors in patients with severe renal dysfunc- tion (e.g. eGFR <20 ml/​min), but few patients are able to tolerate the high doses required. A study in patients of African-​American origin suggested an improvement in morbidity and mortality when added to contemporary medical therapy including ACE inhibi- tors, β-​blockers and MRA, but this finding has not been repeated in other racial groups. Vasodilator calcium antagonists have also failed to improve out- come, and other agents of this class, such as diltiazem and verapamil, have an adverse effect on outcome. Inotropic agents There is no firm place for any inotropic agent in patients with chronic heart failure. Whether digoxin has a contemporary role is uncertain because the trials of digoxin demonstrating modest benefit were conducted before the widespread introduction of β-​ blockers and MRA. These agents might have rendered digoxin ob- solete, but also might have made it safer and more effective. Digoxin has vagomimetic effects, slowing sinus rate and prolonging atrio- ventricular conduction, and therefore slowing ventricular rate in pa- tients with sinus rhythm or atrial fibrillation. It is also a diuretic. It does not drop and may increase blood pressure. For digoxin-​naive patients with severe heart failure, an initial loading dose that does not need to be adjusted for renal dysfunction is appropriate. Maintenance doses should be adjusted according to renal function, erring on the side of caution in older people. The contemporary fashion is to use lower maintenance doses of digoxin, typically 125 micrograms/​day for a middle-​aged patient of average build and with good renal function, and 62.5 micrograms/​day for older, frailer patients. Monitoring of serum digoxin is rarely ne- cessary, but it is important to check for and prevent hypokalaemia, which increases the risk of digoxin-​induced arrhythmia. Antiarrhythmic agents Amiodarone and dronedarone should only be given after expert advice and should be discontinued unless there is a clear need. In patients with moderate or severe HFrEF, addition of these agents to contemporary therapy increases mortality. They have a limited role in maintaining sinus rhythm in atrial fibrillation, and for the symptomatic treatment of ventricular tachycardia. Side effects such as pulmonary fibrosis or hepatitis are rare, pro- vided the maintenance dose of amiodarone is 200 mg/​day or less. Photosensitivity and hypothyroidism are problems with long-​ term treatment. Other antiarrhythmic agents should generally be avoided in heart failure as they have adverse effects on cardiac function and prognosis. Lipid-​modifying therapies There is no established role for lipid-​modifying therapies in patients with heart failure. Two large trials of rosuvastatin failed to show a reduction in mortality, although some reduction in hospitalizations was observed. Considering all of the evidence, it is likely that pa- tients with less severe cardiac dysfunction (e.g. NT-​proBNP <1000 ng/​litre) do benefit from statins, but that patients with more ad- vanced disease do not. Some argue that treatment should be ration- alized and statins withdrawn. Others argue that there is no evidence of harm and some evidence for a reduction in morbidity, and that they should be continued. Informed patients may wish to express an opinion. One large trial suggested a small reduction in mortality with the addition of omega-​3 fatty acids to contemporary heart failure therapy, but this awaits confirmation. Anticoagulants and antiplatelet agents Patients with heart failure and paroxysmal or persistent atrial fib- rillation should be anticoagulated. Warfarin has been the mainstay for many decades, but newer agents that do not require thera- peutic monitoring may be less likely to cause intracranial bleeding. Antiplatelet therapies are not effective in reducing emboli and markedly increase the risk of bleeding when used concomitantly with anticoagulants. They should usually be withdrawn when anti- coagulants are introduced, unless the patient has had a recent car- diac procedure. 16.5.3  Chronic heart failure 3417 There is no evidence that anticoagulant or antiplatelet agents, including aspirin, improve outcome in patients with heart failure in sinus rhythm, whether or not they have coronary artery disease. There are theoretical concerns about the safety of aspirin in patients with heart failure, but no robust evidence to refute or support its use. Aspirin might be partly responsible for iron deficiency anaemia now frequently observed in patients with heart failure. Medicines to avoid Some medicines should be avoided because evidence of benefit is lacking. Aspirin, statins, and omega-​3 fatty acids might fall into this category. Other agents are harmful. For patients with HFrEF, rate-​ limiting calcium channel blockers increase morbidity and mortality. Oral hypoglycaemic agents may cause fluid retention, probably by increasing renal insulin sensitivity, or exacerbate heart failure in other ways. Metformin is relatively contraindicated in chronic kidney disease (eGFR <30) in heart failure because of an increased risk of lactic acidosis, although this is rare. Non​steroidal anti-​ inflammatory drugs, including aspirin, may cause worsening renal function and hyperkalaemia. Paracetamol and opioids are the pre- ferred analgesics. Many cancer chemotherapies are associated with cardiac toxicity. Amiodarone and dronedarone should be avoided unless there is a clear indication. Other medicines in development The failing heart has a shortened ejection time. Omecamtiv mecarbil is a cardiac myosin activator that prolongs the duration of systole and therefore increases stroke volume and efficiency. Positive results have been reported in Phase I and Phase II studies. The effects on vascular events and mortality in patients with heart failure of adding a low dose of rivaroxaban (a factor Xa antagonist) to background therapy (usually including aspirin) is being studied. Soluble guanylate cyclase inhibitors and stimulators, novel MRAs, vaptans, nitroxyl donors, ryanodine channel stabilizers, agents acting on the mitochondrial respiratory chain, and superabsorbent polymers are among a substantial array of compounds under investigation. Gene therapy and stem cells The potential to improve cardiac myocyte function by transfecting cells with the SERCA2a (to improve calcium uptake of the sarco- plasmic reticulum), ribonucleotide reductase (to increase synthesis of dATP), and a variety of other genes is being explored. Similarly, efforts are being made to use a variety of stem cells to induce cardiac regeneration. Such approaches have met with little success thus far. Treatment of HFrEF with devices Implantable cardioverter–​defibrillators Most patients with mild to moderate heart failure will die sud- denly rather than progress gradually to terminal disease. Sudden death is often due to a ventricular arrhythmia, either spontaneous or provoked by myocardial ischaemia or infarction. Implantable cardioverter–​defibrillators (ICDs) deliver pacing and shock therapy to terminate ventricular arrhythmias. ICDs reduce the rate of sudden death by about 70% and lead to a 1–​2% absolute annual reduction in all-​cause mortality, hence a pa- tient has to avoid dying of other things for quite a long time before benefiting substantially from an ICD, which does not improve and may impair symptoms and quality of life. The risk of inappro- priate shocks has declined dramatically after much longer device-​ diagnostic delays were introduced prior to delivering ICD therapy. Forcing ICDs to hesitate before they intervene has revealed that most ventricular tachycardia self-​terminates. The ideal candidate for an ICD has mild heart failure, a low ejec- tion fraction, and a QRS duration exceeding 120 ms, which is similar to the criteria for implanting a cardiac resynchronization therapy (CRT) device. Indeed, it is possible that patients who are not can- didates for CRT have little to gain from an ICD. Implanting a CRT device rather than an ICD in an appropriate patient may increase the benefit of the ICD component of therapy, although CRT alone can reduce sudden death. In summary, there is no doubt that ICDs reduce sudden death and all-​cause mortality, but there are grave doubts about their cost-​effectiveness in the absence of a concomi- tantly implanted CRT. Cardiac resynchronization therapy In appropriately selected patients, CRT improves ventricular func- tion, reduces mitral regurgitation, raises blood pressure, improves symptoms and quality of life, reduces recurrent hospitalization for heart failure, and increases longevity substantially by reducing the rate of both sudden death and end-​stage heart failure. Adding an ICD function to a CRT device may prevent some sudden deaths and provide modest incremental benefit to CRT alone. Current evidence suggests that patients with HFrEF (up to an LVEF of 40%) in sinus rhythm with a QRS duration of more than 140 ms, who have been stabilized on optimal medical therapy, are likely to benefit from CRT regardless of the severity in symptoms. Patients with a QRS duration between 130 and 140 ms may get some benefit, but patients with a QRS duration of less than 130 ms may be harmed by CRT. Patients with ischaemic heart disease have less improvement in cardiac function than patients with dilated cardio- myopathy but similar prognostic benefit. It is not clear whether QRS morphology is important, although left bundle branch block is associated with longer QRS duration which is, in turn, associated with a better response to CRT. Whether patients with atrial fibrillation (AF) benefit from CRT is controver- sial, although some advocate CRT with atrioventricular node abla- tion. There are many uncertainties about the optimal programming of devices. Expert advice should be sought for patients who have had a disappointing response to CRT. Comorbidity and its impact on management of heart failure Valve disease Valve repair or replacement should be considered for all patients with heart failure and substantial mitral or aortic valve disease. Pharmacological treatment, other than for the treatment of conges- tion, will make little difference to symptoms, disease progression, or prognosis in the presence of substantial aortic or mitral stenosis. Patients with aortic stenosis should be considered for aortic valve surgery or transarterial aortic valve implantation. Mitral regurgita- tion is often functional due to left ventricular dysfunction. Although severe mitral regurgitation due to structural disease may benefit from surgical repair, the results of surgery for functional mitral section 16  Cardiovascular disorders 3418 regurgitation are less certain. Transcutaneous procedures to reduce mitral regurgitation have met with some success, but surgical cor- rection of tricuspid regurgitation is of dubious benefit and carries substantial risk. Pulmonary valve disease is not common. Diuretics may relieve the symptoms of congestion in patients with aortic or mitral regurgitation for long periods, allowing the disease to pro- gress beyond the optimal timing of surgery. Renal dysfunction Renal dysfunction is a bad prognostic sign in heart failure and yet many agents that improve prognosis cause a decline in glomerular filtration rate. Clearly, at some point there will be a trade-​off between the benefits of therapy and their adverse effect on renal function. Precisely where that point lies is unknown. Patients with renal dys- function are prone to developing hyperkalaemia. Renal dysfunction often precedes the development of heart failure, perhaps reflecting the damage that hypertension has done to both heart and kidney. Many patients will have renal artery ath- eroma. Low arterial and high venous pressures conspire to produce a low net renal perfusion pressure, which is a major determinant of renal function. The introduction of an ACEi or ARB often causes a rise in serum creatinine, and an increase of up to 30% is generally regarded as ­acceptable provided renal function subsequently stabilizes. Many medicines are excreted by the kidney and therefore lower doses are required to obtain plasma concentrations similar to those in people with normal renal function. Improving the net renal perfusion pressure, avoiding non-​ steroidal anti-​inflammatory drugs (NSAIDs; including aspirin), stopping non-ACEi/​ARB antihypertensive agents, and—​if this fails—​allowing efferent renal arteriolar tone to increase by re- ducing or stopping ACE inhibitors or ARBs are the best hope of improving renal function. Methods of increasing blood pressure are discussed later in the chapter. Diuretics and nitrates can reduce both arterial and venous pressure and their effects on renal func- tion are unpredictable, but usually adverse unless venous pressure is high and falls substantially with treatment. In practice, if con- gestion is not severe, reducing the dose of diuretic should be the first response to declining renal function. Only if this fails or is inappropriate should the dose of ACE inhibitor/​ARB be reduced or stopped. Ultrafiltration or renal dialysis can be used to lower serum creatinine and potassium, but neither intervention is proven to prolong survival, although they may bridge a patient to a de- finitive procedure (e.g. mechanical circulatory support), which can also improve renal function when this is due to severe heart failure and itself be a bridge to a more permanent solution (i.e. transplantation). Respiratory disease Patients who have a definite diagnosis of asthma should avoid β-​ blockers; ivabradine may be similarly effective to β-​blockers for patients in sinus rhythm. Most patients with chronic obstructive pulmonary disease tolerate and benefit from β-​blockers. Monitoring of airways obstruction by spirometry may be appro- priate when in doubt. This may also provide an opportunity to with- draw unnecessary bronchodilator therapy. Patients with pulmonary fibrosis may have persistent fine crepitations at the lung bases that may be confused with pulmonary oedema and lead to overaggressive diuretic therapy. Sleep-​disordered breathing Patients with heart failure are prone to both obstructive and cen- tral sleep apnoea, and many will have both. The severity of sleep-​ disordered breathing may vary according to the severity of congestion or the reduction in cardiac output, sleeping posture, or the effects of alcohol or hypnotic or anxiolytic agents. Simple ambu- latory equipment is available for diagnosis. Arterial oxygen desat- uration is probably the key manifestation of important disease, but arrhythmias induced by airways obstruction may also be important. Studies of continuous positive airways pressure ventilation have been disappointing, possibly because high intrathoracic pressures can reduce cardiac output and increase right-​sided congestion. A major trial using adaptive servoventilation showed that this treat- ment increased mortality. Angina and myocardial ischaemia There is no evidence that revascularization reduces morbidity or mortality in patients with heart failure and coronary artery disease. Pharmacological treatment of angina is appropriate in the first in- stance, which may include β-​blockers, ivabradine, and short-​and longer acting nitrates. Ranolazine may also be used, although the evidence base is limited. Vasodilator calcium antagonists should be used cautiously and avoided if blood pressure is low. For patients with persistent, limiting angina, coronary angiog- raphy and revascularization should be considered. There is anec- dotal evidence that revascularization of silent myocardial ischaemia or viable but dysfunctional myocardium may have striking benefits for cardiac dysfunction and symptoms of heart failure, but two ran- domized trials have failed to show that this strategy is generally su- perior to pharmacological therapy. There is no imperative, based on current evidence, to investigate for ischaemia or to do a coronary angiogram that may set in train a series of events that the patient and clinician may regret. Atrial fibrillation About 50% of patients with AF also have heart failure, and at least 25% of patients with heart failure have AF. Patients with AF and heart failure should be anticoagulated (see ‘Anticoagulants and antiplatelet agents’, earlier). Clinical trials show no benefit from β-​blockers in patients with AF and HFrEF, perhaps due to excessive reduction in ventricular rate. The optimal resting ventricular rate (measured at clinic rather than by ambulatory monitoring) in AF may be 75–​85 bpm. Digoxin can improve ventricular rate control but is rarely required. Its vagomimetic properties provide better resting and nocturnal ven- tricular rate control, while β-​blockers reduce the rise in ventricular rate during exercise. There is little evidence to support pulmonary vein ablation to re- store sinus rhythm in chronic heart failure. Patients in AF cannot benefit from atrioventricular (AV) resynchronization, and there is no good evidence that CRT is effective when AF is present. Patients who require a pacemaker or a defibrillator should be considered for AV node ablation and biventricular pacing, although the evidence for this strategy is not robust. CRT should be considered an inter- vention of last resort in the setting of AF. 16.5.3  Chronic heart failure 3419 Anaemia Anaemia in heart failure is often due to iron deficiency, which affects up to 50% of patients with this condition and is associated with poor quality of life, impaired exercise tolerance, and increased mortality. Serum ferritin may be elevated due to the fact that inflammation is part of the heart failure syndrome, hence in this patient group iron deficiency is typically recognized by serum ferritin less than 100 ng/​ ml, or serum ferritin 100–​300 ng/​ml along with transferrin satur- ation less than 20%. The reasons for iron deficiency are unclear and may be related to reduced iron intake (anorexia), impaired intestinal absorption (mu- cosal oedema, reduced intestinal blood flow, disrupted iron uptake processes), increased gastrointestinal losses (gastritis, perhaps ex- acerbated by aspirin) and frequent venepuncture. Trials that have given oral iron alone (as the control arm of studies giving both oral iron and erythropoiesis stimulating agents) have shown that this has no effect on haemoglobin level, symptom se- verity, or exercise tolerance. By contrast, in randomized studies, intravenous iron has been shown to improve exercise capacity, car- diac function, symptom severity, and quality of life. Patients with symptomatic heart failure should be monitored regularly for the presence of iron deficiency and given intravenous iron if this is present. Anaemia is rarely due to folate or B12 deficiency. Many patients have impaired renal function and are either deficient in or resistant to erythropoietin, or have plasma volume expansion leading to ‘dilutional’ anaemia. Administration of erythropoiesis-​stimulating agents increases haemoglobin and produces modest improvement in ejection fraction, exercise duration, quality of life, and heart failure-​related hospitalizations, but is not proven to affect mortality. Gout Gout is common in patients receiving diuretics for heart failure. Acute attacks should be treated with colchicine or steroids. NSAIDs should be avoided if at all possible. High-​dose paracetamol or even opiates are preferred analgesics. Once an acute attack has settled, allopurinol may be used to reduce the formation of uric acid and the risk of recurrent attacks. Particular circumstances End-​stage heart failure For patients with severe intractable heart failure, palliative care, mechanical circulatory support with left ventricular assists devices, or heart transplantation should be considered. Early referral of patients potentially appropriate for the latter therapies to an expert centre is warranted. Usually, these patients will be aged less than 70 years with no other serious, irreversible disease. Always consider the following: • Review pharmacological and device therapy; ensure optimal treat- ment and withdraw what is unnecessary or harmful. • Check for anaemia and iron deficiency. • Consider adding digoxin (a rapid loading dose may be appropriate). • Opiates might improve breathlessness. Exacerbation of chronic heart failure Heart failure is often portrayed as an inexorably progressive condi- tion with a poor prognosis. This is no longer true for many patients receiving modern treatment. Stabilization for a decade or more, remission and—​for a lucky few—​medical cure is now well docu- mented. However, many patients do deteriorate, even if well man- aged. The reasons are diverse and often remediable. Sudden acute deterioration in a previously stable patient may be due to infection, myocardial ischaemia or infarction, arrhythmias (especially AF), or (rarely) catastrophic failure of a heart valve. Failure to comply with advice on diet or to take prescribed medi- cines, anaemia, renal dysfunction, or poorly controlled hyperten- sion are more often subacute and should be detected long before the patient reaches an acute crisis. Treatment of heart failure with a normal ejection fraction (HFnEF) No treatment has been conclusively shown to alter the natural his- tory of HFnEF. However, diuretics relieve congestion and congestion can kill. Indeed, treatments directed predominantly at congestion, such as ACE inhibitors and MRA, may produce similar benefits in patients with HFnEF and HFrEF, provided the patient with HFnEF does have evidence of congestion (i.e. a raised plasma concentration of natriuretic peptides). The same may not be true of β-​blockers: re- duction in heart rate will increase the duration of diastole that may be advantageous when the problem is impaired cardiac myocyte re- laxation, but deleterious when the problem is myocardial fibrosis and restriction. There is some evidence that digoxin reduces the risk of hospitalization for heart failure. There is little evidence for the safety or efficacy of calcium channel blockers. Hypertension and anaemia are common in this population, and are therapeutic tar- gets. The effects of angiotensin receptor–​neprilysin inhibitors, sol- uble guanylate cyclase inhibitors, and interatrial septal shunt devices and many other interventions are currently being explored in this population. Practical aspects of monitoring and management Regular monitoring of symptoms, weight, and vital signs is essen- tial for good management, especially in sicker, unstable patients. Patients should be encouraged to do this for themselves, potentially assisted by a home telemonitoring system linked to expert clin- ical surveillance and advice, and supported by family and informal carers. Serum electrolytes and renal function should be measured at least every 6 months, and much more frequently in patients with ad- vanced or unstable disease. QRS duration and haemoglobin should be measured on at least an annual basis. There is little evidence to support routine serial echocardiography. There is some evidence to support serial monitoring of natriuretic peptides to identify patients who are in need of more intensive therapy. Symptoms and signs The clinical trials on which guidelines are based focus on morbidity and mortality, but symptoms are usually the reason why the patient seeks medical help. Fortunately, treatment can usually control symp- toms for most patients for most of the time. Less than 5% of patients with heart failure have severe end-​stage symptoms at any time; most of these patients either improve or die within a few weeks. Heart rate A reduction in parasympathetic and increase in sympathetic tone are responsible for the increase in heart rate in heart failure. β-​blockers section 16  Cardiovascular disorders 3420 and digoxin will reduce ventricular rate regardless of heart rhythm; ivabradine only if the patient is in sinus rhythm. For patients with HFrEF, the target range for resting heart rate in sinus rhythm is 50–​ 60 bpm, but for AF it is 75–​85 bpm. Blood pressure High blood pressure is an important risk factor for developing heart failure, especially HFnEF. Low blood pressure is a bad prognostic sign, perhaps because it reflects more severe impairment in the pumping action of the heart (cardiac power output). Many medi- cines that reduce morbidity and mortality also lower blood pressure. Identifying the appropriate blood pressure for the individual patient, and achieving it, is a key aspect of managing heart failure. For most patients, treatment of heart failure will reduce systolic blood pressure below 140 mm Hg. Treatment of hypertension may cause the features of heart failure to disappear and may account for much of the confusion and uncertainty surrounding HFnEF as a clinical entity. A patient may be admitted in florid heart failure with a systolic blood pressure greater than 200 mm Hg, but after treatment, usually with diuretics and ACE inhibitors, there may be little residual evidence for heart failure even when diuretics are withdrawn. A low blood pressure that is not causing problems should not deter the patient or clinician from titrating medication to guideline-​ indicated doses. Patients may tolerate a systolic blood pressure of 80 mm Hg or less, but postural hypotension is likely to become a limiting factor, also rise in serum creatinine presumably attribut- able to reduced glomerular filtration due to reduced renal perfusion. When low blood pressure is a problem, then treatments for heart failure that increase blood pressure may be added, or treatments that reduce blood pressure reduced in dose or withdrawn. If the patient’s symptoms and signs of heart failure are well controlled, the preferred action is to reduce the dose of diuretic. If symptoms and signs are not well controlled, then digoxin or CRT (if appropriate) will increase systolic blood pressure. If the aforementioned are in- appropriate or fail, then reducing the dose of disease-​modifying therapies should be considered, with the potential benefits and risks explained to the patient. If the patient is oedematous, then the dose of β-​blocker should be reduced, allowing heart rate to rise to around 80/​min if in AF or, if in sinus rhythm, using ivabradine to keep resting heart rate at 50–​60 bpm. If serum creatinine is in excess of 200 μmol/​litre, then the dose of ACE inhibitor should be reduced. If serum potassium is in excess of 5 mmol/​litre, then the dose of MRA should be reduced. If appropriate, referral for assess- ment for mechanical circulatory support or heart transplantation may be considered. Blood tests Patients with heart failure receiving diuretics should have a blood test at intervals not exceeding 6 months. Serum potassium For patients with HFrEF, mortality climbs steeply when potassium drops below 4.0 mmol/​litre or rises above 4.9 mmol/​litre. Aiming for a serum potassium of about 4.5 mmol/​litre, usually by manipulating the dose of MRA, appears ideal. Potassium supplements are rarely necessary and should be used only short term. Patients with HFnEF may benefit similarly from this strategy. Renal function Serum urea and creatinine are stronger markers of prognosis than measures of cardiac dysfunction such as LVEF. As already noted, most treatments that improve the prognosis of heart failure cause a decline in renal function. Advice on manipulation of therapy to optimize renal function is provided in the section on blood pressure. Haemoglobin Anaemia, often due to iron deficiency, is common in patients with heart failure and indicates a poor prognosis. Treatment may improve symptoms and perhaps prognosis. Haemoglobin should be meas- ured at least annually. The electrocardiogram Most patients with HFrEF will have a QRS duration greater than 100 ms, and each year some of these will develop a QRS duration greater than 140 ms, indicating the need for CRT. Treatment with β-​blockers will often mask the onset of AF, requiring anticoagulation and a change in strategy of heart rate control. Patients should gen- erally have an annual ECG. Table 16.5.3.6  Example care plan context: recovering in hospital from episode of worsening heart failure Mandatory information (Unchanging) • Date of birth: 07/​01/​1943 • Sex: female • Height: 160 cm Mandatory information (most recent with date) • Aetiology: ischaemic heart disease • Most recent MI: yes: anterior 09/​11/​2005 • Comorbidity: type 2 diabetes, arthritis • LVEF: 32% (HFrEF) • Mitral regurgitation: moderate • Other important valve disease: no • Heart rhythm: sinus • PR interval: 210 msec • QRS duration: 110 msec • Device: none • FEV1: 2.1 (83% of predicted) • FEV1/​FVC: 75% • Haemoglobin: 10.8 g/​dl • Haematinic screen: to be done • HbA1c: 7.4% • Sodium: 138 mmol/​litre • Potassium: 4.0 mmol/​litre • Urea: 11.5 mmol/​litre • Creatinine: 137 umol/​litre • Albumin: 44 g/​dl • NT-​proBNP: 3742 ng/​litre 16.5.4 Cardiorenal syndrome 3421 Darren Green and 16.5.4 Cardiorenal syndrome 3421 Darren Green and Philip A. Kalra 16.5.4  Cardiorenal syndrome 3421 Organization of care Good management requires organization to ensure that appropriate treatment is delivered safely and effectively in order to • gain and maintain clinical stabilization; • recognize when patients are deteriorating, and do something about it before they reach a crisis; • identify patients who need more specialized services. This is greatly facilitated by the use of electronic health records (EHRs), especially if they are enhanced by decision support systems. EHRs and home telemonitoring have a synergistic role in improving healthcare. Increasingly, patients, their carers, and their social net- work are becoming involved with long-​term care, and any good or- ganization will use them as part of the care team. Delivering good care requires a care plan that is shared with the patient and all the services that support them. These should provide enough informa- tion about the patient to deliver the treatments and doses specified in the care plan safely and effectively (Table 16.5.3.6). FURTHER READING Burnett H, et al. (2017). Thirty years of evidence on the efficacy of drug treatments for chronic heart failure with reduced ejection frac- tion: a network meta-​analysis. Circ Heart Fail, 10, e003529. Kassi M, Hannawi B, Trachtenberg B (2018). Recent advances in heart failure. Curr Opin Cardiol, 33, 249–​56. McMurray JJ, et al. ESC Committee for Practice Guidelines (2012). ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail, 14, 803–​69. Erratum in: Eur J Heart Fail, 2013, 15, 361–​2. NICE guideline (2018). Chronic heart failure in adults: diagnosis and management. https://www.nice.org.uk/guidance/ng106 Yancy CW, et  al. (2018). 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology Task Force on expert consensus decision pathways. J Am Coll Cardiol, 71, 201–​30. 16.5.4  Cardiorenal syndrome Darren Green and Philip A. Kalra ESSENTIALS Concurrent renal and cardiovascular disease is common. Renal dis- ease is a potent cardiovascular risk factor and consequently cardio- vascular disease is the most important cause of mortality in patients with end-​stage renal disease. This increased risk is mediated by vascular disease (coronary calcification, endothelial dysfunction, dyslipidaemia, and others), left ventricular hypertrophy, risk of ar- rhythmias, and left ventricular systolic and diastolic dysfunction. These interactions are further complicated by the presence of an- aemia in advanced renal disease. The coexistence of renal disease and heart failure presents a major therapeutic challenge and requires careful attention to fluid status and renal function. Diuretic resistance is common and the important prognostic benefit of angiotensin-​converting enzyme inhibition in this high-​risk group is often neglected. Cardiovascular drugs, particu- larly antiarrhythmic agents such as digoxin, sotalol, and flecainide, should be used with caution in patients with renal disease. Patients with severe cardiac and renal disease require a multidisciplinary ap- proach to their management. Instructions • Double carvedilol every 2 wks until target achieved • Delay titration if heart rate <65 bpm or systolic BP <110 mm Hg • Down titrate if heart rate <55 bpm • Add ivabradine 5 mg bd if heart rate remains >70 bpm despite achieving carvedilol target • Double enalapril in one week to achieve target • Reduce dose if systolic BP <90 mm Hg • Check renal function and electrolytes in 10 days. Reduce dose if serum creatinine >180 μmol/​litre (c.30% increase). Re-​check in 10 days if 150 μmol/​litre (c.10% increase) • If serum potassium >5.5 mmol/​litre stop spironolactone and re-​check potassium in 10 days. Reinitiate at half-​dose if potassium <5 mmol/​litre • Stop ferrous sulphate in 3 months and re-​check haemoglobin and iron status • Advise on diet and exercise • Increase bumetanide in one month if: • Systolic BP not at target and the patient is not at dry weight • Remains symptomatic and the patient is not at dry weight • Reverse this decision if patient does not like the change • Further cardiology review in six weeks Discharge Target Carvedilol 3.125 mg bd 25 mg bd Enalapril 2.5 mg bd 5 mg bd Spironolactone 25 mg/​d 25 mg/​d Bumetanide 1 mg/​d 1 mg/​d Aspirin 75 mg/​d stop Clopidogrel —​ 75 mg/​d Metformin 500 mg bd 500 mg bd Lansoprazole 30 mg/​d Stop Ferrous sulphate 200 mg tid Re-​assess Exercise for 10 min × 3/​wks Now Target Symptoms (NYHA class) Recent IV I/​II Resting heart rate (bpm) 73 55–​65 Systolic BP (mm Hg) 114 110–​130 Weight (kg) 68.7 67.0–​69.0 Potassium (mmol/​litre) 4.5 4.0–​4.9 Creatinine (µmol/​litre) 134 <150 section 16  Cardiovascular disorders 3422 What is the cardiorenal syndrome? The term ‘cardiorenal syndrome’ was first introduced to describe the frequent finding of worsening renal function in response to acute decompensation of heart failure or the up-​titration of nephrotoxic agents used in its treatment. However, this definition is criticized for focusing only on the few patients in whom specific diseases of the heart and kidney lead to concurrent morbidity in the other organs. Indeed, most patients who have evidence of adverse cardiorenal interaction will not fall into this category, and likewise acute kidney injury (AKI) will not be a precipitant of major cardiac morbidity in most patients with this condition. Further attempts to classify different interactions of renal failure and heart disease into subtypes of cardiorenal syndrome have yielded the Acute Dialysis Quality Initiative classification system found in Table 16.5.4.1. This acknowledges the wider spectrum of cardiac disease that may be precipitated by renal impairment, such as sudden cardiac death and the impact of heart failure on chronic kidney disease (CKD) as well as AKI. However, its use in clinical practice is very limited as it provides no mechanistic, therapeutic, or prognostic guidance, and does not accommodate the complex interactions of acute and chronic illness when coexisting. For this reason, both clinical and experimental terms and definitions relating to cardiorenal syndrome are likely to change as under- standing evolves. In this chapter, rather than simply outlining the purported different types of cardiorenal syndrome (1–​5) that have been repeatedly described elsewhere, we instead concentrate on the important structural abnormalities and pathophysiological inter- actions which result from the interplay of diseased kidneys, heart, or both. Epidemiology of concurrent cardiac and renal disease Difficulties in classifying cardiorenal syndrome arise from the broad disease categories implicated and their overlapping inter- actions. Cardiovascular mortality is disproportionate in CKD compared to the general population. Annual mortality for dialysis patients is 15% in Europe and 19% in North America, and 46% of these deaths are due to cardiovascular disease. The most common cause of death in dialysis patients is sudden cardiac death, likely due to arrhythmia. The event rate far exceeds that of the general population (70–​120 versus 1–​2 events per 1000 patient years, see Table 16.5.4.2), and accounts for a greater proportion of all deaths (26% vs. 11%). The period of highest mortality is actually the first 6 months after initiation of chronic haemodialysis therapy. Left ventricular hypertrophy (LVH) is present in 74% of new haemodialysis pa- tients, and reduced ejection fraction is present in 36%. That these abnormalities are already present at the initiation of dialysis in- dicates that the high cardiovascular risk to which these patients are exposed is a function of progression of cardiac disease during predialysis CKD, as well as an effect of dialysis itself. The increased risk of cardiovascular events and death persists after renal transplant, albeit at a reduced event rate. New-​onset cor- onary artery disease after transplant occurs at approximately 10 events per 1000 patient years, and cardiovascular death accounts for more than 50% of all post-​transplant mortality. This risk is greatest in diabetic transplant recipients, who have a threefold greater risk of cardiovascular disease than their non​diabetic coun- terparts. Indeed, in the latter group, post-​transplant infection and malignancy cause more deaths than cardiovascular disease. Renal disorders are also common in patients presenting with car- diac disease. Only 17% of patients seen in heart failure clinics will have normal renal function, and up to 55% will have CKD stage Table 16.5.4.1  Acute Dialysis Quality Initiative classification of cardiorenal syndrome Type Onset Precipitant Secondary effect Examples 1 Acute CARDIAC Acute cardiac dysfunction RENAL AKI Cardiogenic shock causing rapid rise in serum creatinine, decompensated heart failure leading to AKI 2 Chronic Chronic cardiac dysfunction CKD Chronic heart failure leading to long-​term decline in eGFR 3 Acute RENAL Acute kidney injury CARDIAC Acute cardiac event Acute glomerulonephritis with oliguria leading to pulmonary oedema, AKI causing hyperkalaemia leading to arrhythmia 4 Chronic CKD Cardiac remodelling Renal artery stenosis and CKD leading to LVH, CKD associated vascular calcification with chronic ischaemia 5 Secondary OTHER Systemic condition BOTH Cardiac and renal dysfunction Diabetes mellitus, hypertension, SLE AKI, acute kidney injury; CKD, chronic kidney disease; LVH, left ventricular hypertrophy; SLE, systemic lupus erythematosus. Table 16.5.4.2  Comparison of event rates for sudden cardiac death (SCD) in the general population and high-​risk clinical groups including patients with heart failure and receiving dialysis SCD events (per 1000 patient years) General population <85 years 1–​2 General population >85 years 40 Post-​myocardial infarction 40 Heart failure, ejection fraction <35% 90–​200 Predialysis CKD 7 CKD on dialysis 70–​120 CKD, chronic kidney disease. 16.5.4  Cardiorenal syndrome 3423 3 to 5 (for CKD stages, see Table 16.5.4.3) and mortality risk in- creases as renal function worsens (Fig. 16.5.4.1). Similarly, AKI oc- curs in 27–​45% of hospitalizations for decompensated heat failure depending on definition. Inpatient mortality, critical care admis- sion, and total length of stay are all independently associated with AKI in this population. Although definitions of AKI have differed between studies this is a consistent finding, even after a fall in serum creatinine of just 9 μmol/​litre. In one study of 1007 non​elective hos- pital heart failure admissions, the relative risks of adverse outcomes if AKI supervened compared to normal renal function were 7.5 for death, 2.1 for major complication, and 3.2 for length of stay greater than 10 days (here, AKI was defined as an increase in serum cre- atinine >26.5 μmol/​litre). The predictive power of AKI to recognize adverse outcome in decompensated heart failure has a high degree of specificity (>80%) but is poorly sensitive (<70%). In fact, AKI is as predictive of adverse outcome in acute heart failure as left ventricular ejec- tion fraction and blood pressure. AKI is also most common in heart failure patients with pre-​existing CKD. A summary of fac- tors predisposing to AKI after decompensation of heart failure is given in Box 16.5.4.1. Haemodynamic effects of cardiorenal interaction in disease Systemic blood pressure is dependent on the actions of both the heart and kidneys, which regulate body fluid volumes by changes in vascular tone, diuresis, and natriuresis. Dysregulation of one may lead to dysfunction of the other. For example, a fall in blood pressure associated with heart failure will activate the renin–​angiotensin–​ aldosterone (RAAS) pathway to retain salt and water, and increase vascular tone via sympathetic pathways. Subsequent volume expan- sion will help maintain renal perfusion but may paradoxically lead to further decompensation of heart failure. Activation of the RAAS system will also have other deleterious actions such as increasing oxidative stress, inflammation, and tissue fibrosis. Reduced cardiac output may also in turn lead to reduced cardiac filling and increased central venous pressures. Should such pressures increase in the renal vasculature, glomerular filtration may become compromised by a reduction in the pressure difference between af- ferent and efferent vessels. This will lead to CKD or AKI. This vicious cycle of worsening chronic cardiorenal deterioration is summarized in Fig. 16.5.4.2. A specific example of where RAAS overactivation is implicated in cardiorenal disease is the association between atherosclerotic renovascular disease (ARVD) causing renal artery stenosis and acute and chronic heart failure. Renal artery stenosis is classically linked to flash pulmonary oedema, but this phenomenon most probably represents no more than decompensation of heart failure, given that 75% of patients with ARVD have left ventricular hyper- trophy and diastolic dysfunction (far greater than in age and eGFR matched controls). Furthermore, ARVD is common, being found in half of patients attending secondary care heart failure clinics and in one in three hospital admissions with heart failure decompensation. Haemodynamically significant ARVD leads to increases in cir- culating angiotensin II, which as well as promoting salt and water retention contributes to the fibrotic, hypertrophic cardiac remod- elling seen in ARVD by stimulating production of FGF-​23, PDGF, Table 16.5.4.3  The stages of chronic kidney disease Stage eGFR (ml/​min/​1.73 m2) 1 90a 2 60–​89 3a 45–​60 3b 30–​44 4 15–​29 5 <15 Suffix T = transplant; suffix D = dialysis. a Evidence of damage without change in function (e.g. proteinuria). 40 35 30 25 20 15 10 0.76 2.11 1.03 3.65 4.76 11.29 11.36 21.8 14.14 36.6 5 0 60 45–59 30–44 eGFR (ml/min/1/73m2) Age-standardized event rate per 100 patient years 15–29 <15 Death Cardiovascular events Fig. 16.5.4.1  The increasing cardiovascular burden of declining renal function. Adapted from Go SG, et al. (2006). Hemoglobin level, chronic kidney disease, and the risks of death and hospitalization in adults with chronic heart failure. The Anemia in Chronic Heart Failure: Outcomes and Resource Utilization (ANCHOR) study. Circulation, 113(23), 2713–​23. Box 16.5.4.1  Risk factors for acute kidney injury in hospital admissions for heart failure • Laboratory parameters • Underlying CKD • Anaemia • Hyponatraemia • Echocardiographic parameters • Diastolic dysfunction • Pulmonary hypertension • Atrioventricular valvular incompetence • Haemodynamic factors • Hypotension on admission • Underlying hypertension • Comorbidities • Older age • Diabetes • Previous acute heart failure admissions • Previous AKI or dialysis • Nephrotoxic polypharmacy section 16  Cardiovascular disorders 3424 and TGF​ß. Importantly, renal artery revascularization leads to sig- nificant reductions in circulating angiotensin II, and there is a case report of improvement in left ventricular mass from 161 g before revascularization to 108 g one year after, and in left ventricular end diastolic volume from 193 ml to 124 ml (estimated using cardiac magnetic resonance imaging). On a broader scale, in a case control study of 100 patients with ARVD and heart failure, revascularization was associated with a fivefold reduction in heart failure hospitalization compared to medical management alone. A further study, also of 100 patients, has shown that patients with ARVD and chronic heart failure who have never previously suffered acute pulmonary oedema may also benefit from revascularization. Here, the hazard ratio for death in the revascularization group was 0.76 (0.58–​0.99, p = 0.04) compared to medically managed patients. This latter finding may indicate that ‘flash pulmonary oedema’ as the current indication for ARVD revascularization could yet be extended to encompass a broader phenotype of heart failure patients. On a cautionary note, however, these two studies were both conducted in an observational setting, and prospective randomized evidence will be required to justify a change in routine practice. See Chapter 21.10.10 for further discus- sion of atherosclerotic renovascular disease. Other factors implicated in cardiorenal syndrome are the rela- tionship between nitric oxide and reactive oxygen species, both of which affect haemodynamic regulation and endothelial function, and both of which are under partial control by the heart and kid- neys. The relative importance of each factor is unknown and is likely to be different in different cardiorenal syndrome settings. This complexity of pathways leading to cardiorenal syndrome means that the search for biomarkers of cardiorenal syndrome risk or a common signalling pathway, such as interleukin-​6, has thus far not been fruitful. Nephrotoxicity and other adverse drug effects The problem of mechanism is further confounded by the effect of external factors, most notably prescribed medication. Perhaps most obviously, AKI may be caused directly by contrast agents used in coronary angiography. This risk can be quantified based on weighted scoring of risk factors for contrast nephropathy, as shown in a cohort study of 8357 patients (Table 16.5.4.4). This is a useful tool in clinical decision-​making and for the process of obtaining informed consent. The use of RAAS blockade, particularly angiotensin-​converting enzyme (ACE) inhibitors, is associated with improved survival in heart failure. ACE inhibitors are also known to affect glomerular filtration and may lead to AKI during decompensated heart failure Decompensation of heart failure Reduced blood pressure RAAS activation Increased sympathetic tone Vasoconstriction Increased renal perfusion Preservation of renal function Deterioration of renal function vs. Salt and water retention Relative volume expansion Increased glomerular efferent pressure Increased venous pressure Reduced glomerular filtration Fig. 16.5.4.2  The competing haemodynamic response to heart failure in causing and preventing deterioration in renal function. 16.5.4  Cardiorenal syndrome 3425 with resultant uncertainty as to how best manage these drugs during the episode. However, the extent to which ACE inhibitors are impli- cated in AKI may be overstated. In the Studies of Left Ventricular Dysfunction (SOLVD) trial, 16% of patients treated with enalapril (mean daily dose 16.6 mg) developed a rise in serum creatinine in excess of 44 μmol/​litre. However, the figure for the placebo arm was 12%. Also, such studies do not usually report improvements in GFR, but it is estimated that 10% may have comparable improvements in renal function due to improved cardiac output. Furthermore, as demonstrated in Fig. 16.5.4.2, RAAS overactivation may lead to acute worsening of both cardiac and renal function and so cessation of ACE inhibitors is of possible detriment in such cases. Fear of deteriorating renal function is often a reason for underprescribing ACE inhibitors for long-​term cardioprotection in CKD patients. However, ACE inhibition is protective against renal deterioration even in CKD stage 4, and deterioration in the pres- ence of renovascular disease is much less common than anticipated at approximately 11%. A rise in creatinine with the introduction of ACE inhibitors in patients with heart failure of up to 50% above baseline or to a creatinine of 200 μmol/​litre is accepted in some guidelines provided renal function subsequently stabilizes. What may be required is a different approach to ACE inhibitor dosing for heart failure where CKD is present. The ATLAS trial compared high versus low dose lisinopril in 3164 patients with heart failure (>30 mg per day versus 2.5–​5 mg). Overall, there was a reduction in mortality (12%) and heart failure hospitalization (24%) in the high-​dose arm. However, in a post-​hoc analysis of study patients with advanced CKD (n = 988) there was no difference in mortality or heart failure outcomes, but the high-​dose arm suffered significantly more ad- verse effects in respect of hypotension, hyperkalaemia, and decline in renal function. This supports patients with advanced CKD being given ACE inhibitors for heart failure, but at low dose. Long-​term monitoring of renal function in patients with CKD on ACE inhibitors is vital, as is adequate counselling about the risk of AKI and the importance of seeking medical advice in the event of a dehydrating illness such as diarrhoea. There are now reports of medico-​legal disputes involving such cases, akin to those relating to anticoagulation and chemotherapeutic agents. There is also a reluctance to prescribe high-​dose loop diuretics in patients with renal disease. This is based on a fear of renal toxicity and prerenal failure due to intravascular volume depletion. It is fre- quently not appreciated that in fluid-​overloaded patients with heart failure the adverse effects on renal function due to an elevated right atrial pressure and renal congestion are greater than the impact of re- duced cardiac output. Inducing a significant diuresis with high-​dose diuretics in this situation may result in a significant improvement ra- ther than deterioration in renal function. Key to the assessment of the likely impact of diuretic therapy on renal function in these patients is a careful assessment of the intravascular volume status of the patient. Determining the most appropriate action in respect of these drugs is poorly evidence based, but the key message is that monitoring of renal function is vital in both chronic and acute care of cardiac dis- ease, and although suspension of ACE inhibitors during acute illness is often the safest action, their timely reintroduction is also necessary. As noted earlier, the most common cause of mortality in CKD is sudden cardiac death, and certain drugs commonly prescribed in nephrology clinics have the potential to exacerbate arrhythmia. The three most common pathways for this are (1) electrolyte dis- turbances; (2)  drugs affecting repolarization manifesting as QT prolongation; or (3)  altered metabolism of antiarrhythmic drugs leading to toxicity. Table 16.5.4.5 summarizes familiar drugs impli- cated in each of these scenarios. Table 16.5.4.4  Risk prediction for nephropathy after intravenous contrast for coronary angiography Factor Component score NHYA III/​IV HF 5 Hypotension <80 mm Hg/​invasive support 5 Diabetes mellitus 3 Age >75 years 4 Anaemia (haematocrit <39%[M]‌, <36% [F]) 3 IV contrast (per 100 ml contrast used) 1 eGFR (ml/​min/​1.73 m2) 40–​60 2 20–​40 4 <20 6 Combined score Risk (%) Nephropathy Dialysis 0–​5 8 0.04 6–​10 14 0.12 11–​16 26 1.09 17+ 57 12.6 Reprinted from the Journal of the American College of Cardiology, Vol 44, Issue 7, Mehran et al., A simple risk score for prediction of contrast-​induced nephropathy after percutaneous coronary intervention: development and initial validation. 1393–​9. Copyright (2004) with permission from Elsevier. Table 16.5.4.5  Prescribed medication that may exacerbate cardiorenal disease via arrhythmia Cardioprotective drugs that cause hyperkalaemia Renin–​angiotensin blockade Causes hypoaldosteronism and reduced eGFR Digoxin Impairs renal excretion and prevents cellular uptake β-​Blockade Supresses cellular uptake of potassium mediated by β2 receptors Unfractionated heparin Hypoaldosteronism Low molecular weight heparin Mechanism not certain Drugs that cause QTc prolongation Indication for use Calcineurin inhibitors Transplant immunosuppression Midodrine Refractory hypotension Quinolones Antibiotics Macrolides Antibiotic Benzodiazepines Anxiolytic SSRIs Antidepressant Potentially arrhythmogenic drugs requiring dose adjustment in dialysis Flecainide Use 50% normal dose Sotalol Avoid in CKD5D, use at 25% normal dose in eGFR <15 ml/​min Digoxin Start at 62.5 micrograms daily section 16  Cardiovascular disorders 3426 Antiarrhythmic therapy is further complicated in dialysis patients, as many of these drugs are not removed from the body by dialysis. Those that would normally be excreted via the kidneys can there- fore accumulate in such patients, and the timing of dosing of short-​ acting drugs may need to accommodate the timing of haemodialysis sessions. Managing antiarrhythmic drugs may require the input of a specialist renal pharmacist. Certain drugs, such as sotalol, ought to be avoided completely in dialysis patients where possible. Sotalol may predispose to QTc prolongation and torsades de pointes in toxic doses. It is over 90% absorbed after oral intake, undergoes almost no hepatic first-​pass metabolism, and is excreted via the kidneys. Diuretic resistance in chronic renal disease The use of thiazide diuretics in patients with cardiovascular disease is usually limited to hypertension in older people and patients with heart failure. Thiazides are effective in inducing a natriuresis in patients with a GFR less than 30 ml/​min. Patients with a GFR below this level will usually require loop diuretics to achieve a satisfactory diuresis. Loop diuretics are progressively less effective at lower GFR and pro- portionately higher doses given in a once-​daily regimen are required to induce a diuresis. Activation of the RAAS in conjunction with distal tubular cell hypertrophy induces diuretic resistance. A combination of thiazide diuretic and loop diuretic may be helpful in overcoming diuretic resistance in these patients. Diuretic resistance is particularly prominent in diabetic proteinuric renal disease where protein binding of loop diuretics within the renal tubules reduces bioavailability. Arrhythmia in chronic kidney disease Sudden cardiac death is the most common cause of death in dialysis patients. Although this has been presumed to be predominantly due to ventricular tachyarrhythmia, as for sudden cardiac death in the general population, there is emerging evidence that bradycardia and asystole are implicated more often than is the case in non​renal pa- tients. In one study, implanted loop recorder devices were used to capture arrhythmia in 50 maintenance haemodialysis patients over 18 ± 4 months. Eight patients (16%) suffered sudden cardiac death, all due to bradyarrhythmia or asystole, and all occurring during the long interdialytic interval. Although arrhythmia was common in this and other similar studies, there was no prodrome of asymp- tomatic bradyarrhythmia or heart block in such patients during the period of in vivo monitoring prior to the fatal event. This means that the use of such devices does not yet allow for risk stratification in a way that could lead to pre-​emptive pacemaker implantation to pre- vent future potentially fatal bradyarrhythmia. Medications commonly prescribed in CKD may also predispose to arrhythmia. These are listed in Table 16.5.4.5. There is also a high prevalence of ECG conduction abnormalities that may indicate risk. In one cross-​sectional analysis of 323 prevalent dialysis patients, 34% had QRS duration in excess of 100 ms, 19% first-​degree heart block, and 10% atrial fibrillation or flutter. Other studies have shown high rates of QTc prolongation and increased QT dispersion as well as loss of heart rate variability in CKD populations. Such abnormalities are associated with worse outcome. The best ECG predictor of mortality appears to be left bundle branch block, with an increased hazard ratio for death of 4.6 compared to normal QRS morphology. Equally, the impact of supraventricular arrhythmia on mortality cannot be overstated. The absence of sinus rhythm on ECG is associated with an 89% increased risk of death in diabetic dialysis patients, and atrial fibrillation is associated with an 80% 5-​year mortality in dialysis pa- tients. Importantly, current evidence suggests that anticoagulation with warfarin leads to worse outcome for dialysis patients with atrial fibrillation, albeit that this evidence comes from observational studies and not randomized trials. The increased risk is thought to result from increased bleeding and vascular calcification. The substrates for arrhythmia in CKD are manifold and Fig. 16.5.4.3 summarizes these. Myocardial ischaemia is likely to play a role via coronary atheroma, medial calcification, and poor coronary perfusion due to diastolic dysfunction and pathological LVH with fibrosis and capillary rarefaction. The process of haemodialysis also induces arrhythmia, but it is not clear whether this is directly due to dialysis-​induced myocardial ischaemia, autonomic effects, or the rapid electrolyte and fluid shifts that occur during dialysis. The role of Fig. 16.5.4.3  Potential triggers to sudden cardiac death in chronic kidney disease. 16.5.4  Cardiorenal syndrome 3427 LVH is likely to be an important one as endomyocardial biopsies from dialysis patients demonstrate abnormal remodelling with interstitial fibrosis and myocyte hypertrophy. These changes affect conduction through the myocardium and potentially will lead to arrhythmia. Vascular calcification Although 40% of dialysis patients have coronary artery disease, lipid-​ lowering drugs are less efficacious in this setting than in the wider population. One reason is that arterial disease in CKD is not typically due to atheroma: 50% of CKD patients have significant diffuse medial arterial calcification at the initiation of chronic dialysis. There is a fivefold increase in calcification of the coronary arteries in dialysis patients compared to non-​CKD patients with coronary atheroma where calcification tends to be focal and found in the intimal layer. Calcification in CKD is associated with hyperphosphataemia, hypercalcaemia, and hyperparathyroidism, all of which can stimulate calcification of vascular smooth muscle cells and matrix. CKD also leads to a reduction in endogenous inhibitors of calcification, such as fetuin A. Vascular calcification and renal bone abnormalities are to- gether termed ‘chronic kidney disease–​mineral bone disorder’ (CKD-​ MBD), acknowledging the wide spectrum of associated disease. Aortic stiffness, a surrogate of calcification, can be measured non-​ invasively with pulse wave velocity (PWV). An increase in PWV is as- sociated with LVH and increased left ventricular myocardial infarction (and with reduced coronary filling), all of which may eventually pre- dispose to heart failure. Indeed, increased PWV has been shown to be more important than hypertension in the development of LVH in CKD. Left ventricular hypertrophy The mechanism of LVH development in CKD is likely to be multi- factorial, but evidence is emerging that the association of vascular stiffness with LVH may be concurrent pathological manifestations of CKD-​MBD, as well as demonstrating a cause-​and-​effect response to increased afterload. Fibroblast growth factor 23 (FGF-​23) is pro- duced by osteocytes as renal function declines. Its role in this setting is to induce phosphaturia and to inhibit hydroxylation of vitamin D to its active form. Elevated FGF-​23 levels are independently associ- ated with LVH in CKD, intracardiac administration of FGF-​23 leads to LVH in wild type mice, and in vitro administration of FGF-​23 to isolated rat myocytes results in pathological hypertrophy. LVH may yet become a therapeutic target in CKD given its high prevalence and implications for worse outcome. The relative risk of cardiac death in dialysis patients with LVH is 2.7 compared to those without. Above a mean arterial pressure of 106 mm Hg, small in- creases in blood pressure are associated with significant increases in the rate of de novo heart failure in CKD. On a more optimistic note, tight control of blood pressure is associated with regression of LVH, slowing progression of CKD may slow progression of LVH, and tight control of CKD-​MBD is also likely to positively impact on patho- logical cardiac remodelling. Multidisciplinary approach to renal disease in cardiac patients The high prevalence of coexistent cardiac and renal disease, and the high risk of major morbidity this combination brings, will often necessitate referral to nephrology services outside the usual guidelines. A list of potential circumstances triggering referral is listed in Table 16.5.4.6. Importantly, such referrals provide access to a multidisciplinary team beyond renal physicians, such as an- aemia services, specialist psychologists, dietetic services, pharma- cists, palliative care teams, and dialysis-​planning specialist nurses, each of whom can provide care which may improve the quality of life and prognosis for patients. Indeed, being aware of and moni- toring for the possibility of these problems in the likes of heart failure clinics may lead to earlier diagnosis and intervention for significant renal disease in many cases. Table 16.5.4.6  Suggested indicators for referral to renal services for cardiology patients with chronic kidney disease, and investigations to request on referral Problem Diagnosis Investigations Diuretic resistant peripheral or pulmonary oedema/​ recurrent acute decompensation of heart failure Renal artery stenosis; consider peritoneal dialysis for heart failure therapy Renal tract ultrasound Unexplained anaemia Renal anaemia Rule out gastrointestinal bleeding, ferritin, Fe/​TIBC/​B-​ vitamins, PTH, CRP Electrolyte or acid–​base disturbance Tubular or pararenal disease, renal adverse drug effects Serum bicarbonate, chloride, calcium, magnesium, urine salts Hyperphosphataemia (particularly with valvular annular calcification on echocardiography or radiographic evidence of aortic/​arterial calcification) CKD-​MBD Serum phosphate, calcium, PTH, food diary Proteinuria or haematuria Nephropathy/​glomerulonephritis not cause by vascular disease Urine microscopy, urine culture, urine PCR, renal tract ultrasound, electrophoresis, ESR, HIV, HCV, autoantibody screen if haematuria (ANA, ANCA, GBM, C3, C4) Progressive decline in eGFR Drug effect, renal artery stenosis/​occlusion, progressive CKD, approaching dialysis, palliation Send full medication list/​dose changes and historical eGFR with referral ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibody; C3, C4, complement components; CKD, chronic kidney disease; CKD-​MBD, chronic kidney disease–​mineral bone disorder; CRP, C-​reactive protein; ESR, erythrocyte sedimentation rate; GBM, glomerular basement membrane; HCV, hepatitis C virus; PCR, polymerase chain reaction; PTH, parathyroid hormone; TIBC, total iron binding capacity. 16.5.5 Cardiac transplantation and mechanical circ 16.5.5 Cardiac transplantation and mechanical circulatory support 3428 Jayan Parameshwar and Steven Tsui section 16  Cardiovascular disorders 3428 Summary The interaction between heart and kidneys in acute and chronic disease leads to poorer survival and greater hospitalization for patients. The pathophysiology of the cardiorenal illness differs according to clinical scenario and between cases, from CKD-​ induced arrhythmia to decompensated heart failure causing dialysis-​dependent AKI. The management of each scenario is fur- ther complicated by potential nephrotoxicity and altered renal drug clearance. This means that a general guideline for care in cardiorenal syndrome is not applicable, and patients must be as- sessed on a case-​by-​case basis. FURTHER READING Bongartz LG, et al. (2005). The severe cardiorenal syndrome: ‘Guyton revisited’. Eur Heart J, 26(1), 11–​17. Braam B, et al. (2014). Cardiorenal syndrome—​current understanding and future perspectives. Nat Rev Nephrol, 10(1), 48–​55. Faul C, et al. (2011). FGF 23 induces left ventricular hypertrophy. J Clin Invest, 121(11), 4393–​408. Green D, et  al. (2011). Sudden cardiac death in hemodialysis pa- tients: an indepth review. Am J Kidney Dis, 57(6), 921–​9. Green D, Kalra PA (2012). The heart in atherosclerotic renovascular disease. Front Biosci, 4, 856–​64. Green D, et al. (2017). Revascularization of atherosclerotic renal artery stenosis for chronic heart failure versus acute pulmonary oedema. Nephrology, doi: 10.1111/​nep.13038. Kane GC, et al. (2010). Renal artery revascularization improves heart failure control in patients with atherosclerotic renal artery stenosis. Nephrol Dial Transplant, 25(3), 813–​20. Kumar U, Wettersten N, Garimella PS (2019). Cardiorenal syndrome: pathophysiology. Cardiol Clin, 37, 251–65. McCullough PA, et al. (2013). A DQI consensus on AKI biomarkers and cardiorenal syndromes. Contrib Nephrol, 182, 82–​98. Mehran R, et al. (2004). A simple risk score for prediction of contrast-​ induced nephropathy after percutaneous coronary intervention. J Am Coll Cardiol, 44(7), 1393–​9. Roberts PR, Green D (2011). Arrhythmias in chronic kidney disease. Heart, 97(9), 766–​73. 16.5.5  Cardiac transplantation and mechanical circulatory support Jayan Parameshwar and Steven Tsui ESSENTIALS Cardiac transplantation Cardiac transplantation is the treatment of choice for selected pa- tients with advanced heart failure: median survival exceeds 12 years and recipients enjoy an excellent quality of life, but availability is se- verely limited by shortage of donor organs. The need for lifelong immunosuppression is associated with side effects, including an increased incidence of malignancy. Newer immunosuppressive agents reduce nephrotoxicity and delay the onset of cardiac allograft vasculopathy, but may produce other side effects. Mechanical circulatory support Ventricular assist devices are mechanical blood pumps that work in parallel or series with the native ventricles. First-​generation volume-​displacement pulsatile ventricular assist devices have been superseded by rotary blood pumps that generate continuous flow. Significant complications include bleeding, thromboembolism, de- vice failure due to pump thrombosis, and infection. Temporary support—​several devices are available for use in pa- tients who require support for days to weeks in the intensive care unit: these are invaluable in post-​cardiotomy cardiogenic shock and in patients who present in extremis with uncertain viability. Chronic support—​implantation of a durable ventricular assist device in patients with chronic heart failure can either be as a bridge to heart transplantation or as permanent support, sometimes referred to as destination therapy. There is evidence that patients with end-​stage heart failure randomized to implantation of a ventricular assist de- vice (HeartMate XVE) have improved survival (52% vs. 25% at 1 year) compared to those receiving best medical therapy. A subsequent study randomizing similar heart failure patients between a newer continuous-​flow left ventricular assist device (the HeartMate II) and the pulsatile HeartMate XVE showed that survival with continuous-​ flow ventricular assist devices was even better. Heart transplantation Introduction In 1964 James Hardy transplanted a chimpanzee heart into a 68-​ year-​old man with ischaemic heart failure, but the patient did not survive surgery. The first human-​to-​human heart transplant was per- formed in Cape Town on 3 December 1967 by Christiaan Barnard; the patient died 18 days afterwards of infective complications. By the end of 1968, 102 patients had received heart transplants in 50 hos- pitals in 17 countries: mean survival was only 29 days and there was widespread disenchantment with the procedure. Only a few institu- tions continued clinical cardiac transplantation during the 1970s, the team at Stanford University under the leadership of Norman Shumway being pre-​eminent among them. By the late 1970s, 1-​year survival at Stanford had increased to 65%, establishing the place of heart transplantation. The introduction of new immunosuppressive drugs in the 1980s led to further improvement in outcome and an explosion of activity around the world, but during the 1990s there was a decline in the number of heart transplants performed owing to a shortage of donor organs. However, heart transplant activity has slowly increased again in recent years, probably due to increased use of extended criteria donors. Before transplantation Recipient selection Heart transplantation is the treatment of choice for selected pa- tients with end-​stage heart failure. However, the limited number of available donor hearts restricts this treatment to a small fraction of 16.5.5  Cardiac transplantation and circulatory support 3429 potential recipients. Careful selection of patients is therefore cru- cial to make best use of this scarce resource. Patients with New York Heart Association (NYHA) class IIIB and class IV heart failure are best discussed with the local heart failure/​transplant centre to opti- mize medical management and to consider high-​risk non​transplant cardiac surgery where appropriate (see Chapter 16.13.6). Patients with chronic heart failure should be referred before they develop significant end-​organ dysfunction (renal and hepatic) or irrevers- ible secondary pulmonary hypertension. Box 16.5.5.1 summarizes criteria used to select patients for trans- plantation. Haemodynamic assessment, measurement of natriuretic peptides, and the use of cardiopulmonary exercise testing to object- ively quantify functional capacity are all important in estimating prognosis. Box 16.5.5.2 outlines the important contraindications. Matching of donor and recipient Donor and recipient blood groups need to be compatible. Appropriate size matching is also generally thought to be necessary to minimize the risk of donor organ failure. HLA matching is not routinely car- ried out, but there is some evidence that HLA-​DR matching results in fewer episodes of acute rejection. The presence of preformed antibodies to HLA antigens is an important consideration, hence selection of an appropriate donor includes ruling out those with the relevant HLA antigens and sensitized patients are likely to have a much longer wait for a suitable donor organ. After transplantation Most patients spend 2 to 3 weeks in hospital after a heart transplant and are fit to return to work after 4 to 6 months. In the first year they need to return to the transplant centre at set intervals to monitor immunosuppression, and to have surveillance endomyocardial biopsies to screen for acute rejection. There is data suggesting that, at least for low-​risk patients, a non​invasive monitoring strategy involving gene-​expression profiling of peripheral blood mono-​ nuclear cells may be a safe alternative to endomyocardial biopsy. Immunosuppression Immunosuppression is commenced at surgery and continued for life. The intensity of immunosuppression is greatest early post-​ transplant, with a staged reduction in the dosage of drugs over the first year. Box 16.5.5.3 lists the agents commonly used for mainten- ance immunosuppression: some units routinely deploy induction therapy with an antibody for the first few days after the transplant. At least 50% of patients can be safely weaned off prednisolone in the first 2 years after heart transplant. Episodes of acute cell mediated rejection (usually confirmed by endomyocardial biopsy) are treated with intravenous methyl­ prednisolone and are almost always reversible. The importance of antibody-​mediated rejection has been increasingly recognized in recent years. Treatment includes antibody removal, intravenous immunoglobulin, and various monoclonal antibodies, but there is no convincing evidence for the efficacy of these regimes. When antibody-​mediated rejection is associated with ventricular dys- function, medium-​term prognosis is compromised. The presence of donor specific antibodies in the serum may be associated with an adverse prognosis, including early cardiac allograft vasculopathy. Outcome Fig. 16.5.5.1 shows the survival of patients after heart transplant- ation. Median survival now exceeds 12 years in most large centres. Annual mortality after the first year is approximately 2.5% per year. Most patients enjoy an excellent quality of life, with minimal or no functional limitation. Successful pregnancy is possible, with management requiring close collaboration between transplant and obstetric teams. Maternal morbidity is higher than in the general population and there is a higher incidence of small-​for-​date babies. Teratogenicity does not seem to be a significant problem with the immunosuppressive regimens used in the 1980s and most of the 1990s (steroids, azathioprine, calcineurin inhibitors), but patients receiving mycophenolate mofetil or sirolimus/​everolimus should be Box 16.5.5.1  Indications for heart transplantation • History: recurrent hospital admissions for worsening heart failure • Recurrent symptomatic ventricular arrhythmia associated with severe impairment of ventricular function • Refractory ischaemia not amenable to revascularization and associ- ated with severe impairment of left ventricular function • Functional capacity: persistent symptoms of heart failure at rest or minimal exertion despite optimal medical therapy. Functional capacity measured by peak oxygen uptake on exercise <14 ml kg−1 min−1 (or 50% predicted). For patients receiving β-​blockers, a value of <12 ml kg−1 min−1 has been recommended • Biomarkers: persistent elevation of natriuretic peptides • Prognostic scores (e.g. Seattle Heart Failure Model indicating 1-​year mortality >20% on optimal medical therapy) Box 16.5.5.2  Relative contraindications to heart transplantation • Active infection—​but note that patients with chronic viral infection (e.g. hepatitis B, HIV) may be considered if viral titres are undetectable and there is no organ damage other than to the heart • Symptomatic cerebral or peripheral or vascular disease • Diabetes mellitus with end-​organ damage (e.g. nephropathy, neur- opathy, proliferative retinopathy) • Coexistent or recent neoplasm • Severe lung disease—​FEV1 and FVC <50% predicted and evidence of parenchymal lung disease • Renal dysfunction with creatinine clearance less than 40 ml min−1 (combined cardiac and renal transplantation may be considered) • Recent pulmonary thromboembolism • Pulmonary hypertension-​pulmonary artery systolic pressure >60 mm Hg, transpulmonary gradient ≥15 mm Hg, and/​or pulmonary vascular resistance >5 Wood units • Psychosocial factors including history of noncompliance with medica- tion, inadequate support, drug, or alcohol abuse • Obesity (body mass index >35 or weight >140% of ideal body weight) Box 16.5.5.3  Immunosuppressive agents • Calcineurin inhibitor: ciclosporin or tacrolimus • Antimetabolites: mycophenolate mofetil or azathioprine • Corticosteroid: usually prednisolone • Proliferation signal inhibitors: sirolimus or everolimus • Antibody therapy:  antithymocyte globulin (ATG), basiliximab, alemtuzumab section 16  Cardiovascular disorders 3430 strongly advised not to become pregnant and arrangements made to switch to alternative drugs if pregnancy is planned. Complications General complications related to immunosuppression include an increase in opportunistic infection and malignancy, in particular squamous cell carcinoma of the skin and non-​Hodgkin’s B-​cell lymphoma (which affects 2–​4% of heart transplant recipients). Calcineurin inhibitors can cause headaches, tremor, hypertension, nephropathy, and peripheral neuropathy, and exacerbate myalgia/​ myositis associated with statin use. Corticosteroids are associated with osteoporosis and diabetes. Ciclosporin can cause hirsutism and gum hypertrophy. Issues particular to cardiac transplantation are described next. Hyperlipidaemia Abnormalities in lipid levels have been reported in up to 80% of pa- tients on standard immunosuppressive drug regimes. Pretransplant abnormalities are common in patients transplanted for ischaemic cardiomyopathy. Use of statins early post-​transplant has been shown to delay the onset of cardiac allograft vasculopathy thus increasing late survival, and is now standard practice in most units. Renal dysfunction The most serious side effect of calcineurin inhibitors (CNI) is renal toxicity. Data from the International Society for Heart and Lung Transplantation indicate that about 20% of patients have some de- gree of renal dysfunction at 1 year after transplantation. Afferent renal arterial vasoconstriction is believed to be the cause of early renal dysfunction and is reversible. Late renal dysfunction is re- lated to tubular damage and tends to be progressive, even when the offending drug is discontinued. At least 5–​6% of heart transplant recipients progress to require renal replacement therapy in the first 10 years post-​transplant, and their prognosis on dialysis is poor. Judicious use of CNI-​free regimes slows the progression to end-​ stage renal disease and, if introduced early, renal function may im- prove significantly. Selected heart recipients who have developed renal failure but maintained good cardiac allograft function can be considered for renal transplantation. Cardiac allograft vasculopathy This term is used to describe concentric narrowing of the coronary arteries (and sometimes veins) of the transplanted heart. It is be- lieved to be an immune-​mediated disease and is also referred to as ‘chronic rejection’, although non​immune mechanisms probably contribute to pathogenesis. It is the commonest cause of late death after heart transplantation but occasionally presents as a fulminant process that causes death within the first year. Conventional risk fac- tors like smoking and hyperlipidaemia are associated with earlier disease, but cardiac allograft vasculopathy occurs in children and in the absence of other risk factors. The basic pathological lesion is a diffuse and progressive thick- ening of the intima that occurs in epicardial and intramyocardial arteries (Fig. 16.5.5.2). The disease tends to affect the arterial tree diffusely, although there is heterogeneous involvement of different parts of the arteries. The degree of intimal thickening that occurs in the first year (measured by intravascular ultrasonography) is a predictor of the development of angiographic disease and death or retransplantation for cardiac allograft vasculopathy, the risk factors for which are shown in Box 16.5.5.4. Most patients with cardiac allograft vasculopathy present with signs and symptoms of heart failure, although angina can be ex- perienced despite denervation. The disease is commonly first seen during surveillance coronary angiography. Revascularization is rarely feasible because the disease is diffuse, but occasionally pa- tients have focal proximal lesions that are amenable to angioplasty. Intravascular ultrasonography (IVUS) is the most sensitive tech- nique for diagnosis of early disease and most clinical trials of new immunosuppressive drugs include IVUS-​derived parameters as an endpoint. The only definitive treatment for cardiac allograft 0 25 50 75 100 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Survival (%) Years 1982–1991 (N = 21482) 1992–2001 (N = 40097) 2002–2008 (N = 26046) 2009–6/2016 (N = 30824) Adult Heart Transplants Kaplan-Meier Survival by Era (Transplants: January 1982–June 2016) All pair-wise comparisons were significant at p < 0.0001. Median survival (years): 1982–1991 = 8.6; 1992–2001 = 10.5; 2002–2008 = 12.4; 2009–6/2016 = NA Fig. 16.5.5.1  Survival was calculated using the Kaplan–​Meier method, which incorporates information from all transplants for whom any follow-​up has been provided. Since many patients are still alive and some patients have been lost to follow-​up, the survival rates are estimates rather than exact rates because the time of death is not known for all patients. The median survival is the estimated time point at which 50% of all of the recipients have died. Survival rates were compared using the log-​rank test statistic. Adjustments for multiple comparisons were done using Scheffé’s method. Source data from The International Society for Heart and Lung Transplantation (JHLT 2018 Oct:37 (10): 1155–1206). Fig. 16.5.5.2  Cross-​section of coronary artery at autopsy showing marked intimal hyperplasia and obliteration of the lumen. 16.5.5  Cardiac transplantation and circulatory support 3431 vasculopathy is retransplantation, which—​given the shortage of donor organs—​is an option for only a few patients. Proliferation signal inhibitors may delay the onset and slow the progression of cardiac allograft vasculopathy. Mechanical circulatory support The concept of arterial counterpulsation to unload the heart in sys- tole was introduced in the early 1960s. This led to the development of the intra-​aortic balloon pump, which was first applied clinically by Kantrowitz in 1967. In 1966 DeBakey reported the first suc- cessful clinical application of a true ventricular assist device (VAD) in a 37-​year-​old woman who could not be weaned from cardiopul- monary bypass following aortic and mitral valve replacement. In 1969 Cooley supported a patient with a total artificial heart for 64 h until a donor heart was available. In 1984 Stanford University re- ported the first successful heart transplant following bridging with a left ventricular assist device (LVAD). VADs are mechanical blood pumps that work in parallel or series with the native ventricle. An LVAD draws oxygenated blood from the left atrium or ventricle and returns it to the aorta; a right ven- tricular assist device (RVAD) draws venous blood from the right atrium or ventricle and returns it to the pulmonary artery. Contexts for using mechanical circulatory support Bridge to transplantation Successful cardiac transplantation provided the stimulus for the de- velopment of devices that could be used to support patients until a suitable donor organ became available. The availability of donor hearts is unpredictable, hence the patient with acute haemodynamic deterioration requires other means of circulatory support when intravenous inotropic therapy cannot maintain adequate perfusion to vital organs. Renal and hepatic functions improve on mechan- ical support, pulmonary vascular resistance falls, nutritional status and muscle strength recover. This buys time for the patient until a suitable donor heart is identified and reduces the risk of subsequent transplantation. Box 16.5.5.5 outlines guidance for use of a LVAD as a bridge to transplantation and factors affecting risk of perioperative complications. Permanent support Depending on definition, the prevalence of severe heart failure be- tween the ages of 65 and 75 years is 0.5–​1.2%. Most of these patients will not be candidates for heart transplantation by virtue of age and comorbidity. VADs were originally developed as a long-​term treat- ment for heart failure and patients who are not transplant candidates can be considered for this form of therapy. The REMATCH study (Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure) random- ized patients with end-​stage heart failure to best medical therapy or the implantation of the pulsatile HeartMate assist device. Survival at 1 year was 52% in the device group and 25% in the medical group; at 2 years it was 23% and 8%, respectively. Quality of life was sig- nificantly improved at 1 year in the device group, but with a higher frequency of serious adverse events. In the HeartMate II study, patients with end-​stage heart failure were randomized to undergo implantation of the pulsatile HeartMate XVE or a continuous-​flow LVAD (HeartMate II). The quality of life and functional capacity improved significantly in both groups. Patients implanted with the continuous-​flow LVAD had superior ac- tuarial survival rates at 2 years (58% vs. 24%, p = 0.008) and signifi- cantly lower adverse event rates. This provides compelling evidence that LVAD therapy can increase life expectancy and quality of life in selected patients with advanced heart failure. Similar outcomes have been reported in the ENDURANCE Study with the HeartWare heart ventricular assist device (HVAD). In a com- parison with the HeartMate II in patients ineligible for transplant- ation, survival at 2 years free of disabling stroke or device removal Box 16.5.5.4  Risk factors for cardiac allograft vasculopathy Immunological • Number of episodes of acute rejection • HLA-​DR mismatch between donor and recipient • Anti-​HLA donor specific antibodies in the recipient (associated with the deposition of antibody and complement in the vasculature of the allograft) Non​immunological • Donor age • Recipient age and gender • Coronary artery disease as the cause for transplantation in the recipient • Cytomegalovirus infection • Smoking • Obesity • Hyperlipidaemia Box 16.5.5.5  Guidelines for the use of LVAD as a bridge to transplantation Inclusion criteria • The patient is a candidate for transplantation, or is likely to become a candidate after a period of mechanical circulatory support (bridge to candidacy) • Haemodynamics (usually on IV inotropic therapy); cardiac index <2.0 litres min−1 m−2; systolic blood pressure <80 mm Hg; pulmonary capil- lary wedge pressure >20 mm Hg • Progressive end-​organ dysfunction (renal or hepatic) due to reduced perfusion • More than two heart failure hospitalizations in previous 12 months without an obvious precipitating cause Exclusion criteria • Active endocarditis • Multiorgan failure • Life-​limiting comorbidities: systemic disease that limits 1-​year survival (e.g. advanced or irreversible pulmonary disease), advanced hepatic disease (cirrhosis and portal hypertension), severe peripheral vascular disease, metastatic cancer, and irreversible neurological or neuromus- cular disorders • Severe right ventricular failure (would need BIVAD) Factors increasing the risk of perioperative complications • Age • Prolonged prothrombin time or raised INR • Hypoalbuminaemia • Era of implantation (lower mortality for implants after May 2007) • Centre experience (>15 implants associated with decreased mortality). section 16  Cardiovascular disorders 3432 for malfunction was 55.4% in the HVAD group and 59.1% in the HeartMate II group. The HeartMate 3 device has shown promising results at 6-​month follow-​up (86.2% for a similar endpoint), with a lower rate of pump thrombosis when compared with HeartMate II, but longer-​term data are not available as yet. The ADVANCE Study com- pared the HeartWare HVAD with the HeartMate II; two-​year survival free of disabling stroke was over 55% in both groups. The Momentum study compared the HeartMate 3 device with the HeartMate II. Two year survival free of disabling stroke was 79.5% in the former and 60.2%. There was also a much lower incidence of pump thrombosis leading to pump exchange in the HeartMate 3 group. Bridge to recovery Patients dying from fulminant myocarditis can be supported with mechanical circulatory support and it is not uncommon to see re- covery of myocardial function to the point where the device can be removed. Recovery has also been reported in patients with idiopathic dilated cardiomyopathy. LVADs unload the ventricle to a degree that cannot be achieved by drug therapy, and there is a considerable body of evidence to show that the myocardium recovers at the cellular and molecular level with mechanical circulatory support. Structural improvement detectable by echocardiography occurs much less fre- quently, and clinical recovery to the point where the device can be re- moved safely is rarer still (<10% of patients in most series, although there are intriguing reports of higher rates of clinical recovery from a few centres). Studies are ongoing, but at present implantation of a device in patients with chronic heart failure should be viewed as a bridge to heart transplantation or as permanent support. Short-​term support Several devices are available for use in patients who need support for days or weeks. These are invaluable in post-​cardiotomy cardiogenic shock and in patients who present in extremis with multiorgan failure. In the latter group, a short-​term device may be a bridge to a longer-​term device or to heart transplantation, but occasionally patients may improve to the point where the device can be removed and they can be stabilized on medical therapy. This is sometimes described as ‘bridge to decision’. To support patients for periods of a few weeks to several months, the CentriMag device has been widely used with reasonable success. Veno-​arterial extracorporeal membrane oxygenation (ECMO) can be introduced at the bedside in critically ill patients to maintain systemic circulation and to afford the opportunity to assess the appropriateness of further therapy. It may also be used to stabilize patients for transport to an advanced heart failure centre for further evaluation. Patients with any of these devices are confined to critical care or a high-​dependency area and cannot be discharged from hospital. Types of ventricular assist devices There are many devices available for clinical use. Box 16.5.5.6 shows a classification of devices and examples of each type: a brief descrip- tion of selected devices in each category follows. Rotary ventricular assist devices Rotary devices deploy an impeller spinning at high speed to generate blood flow. An inflow cannula carries blood from the apex of the left ventricle to the device, while the outflow graft is anastomosed to the ascending aorta. They are smaller than the original pulsatile devices, have a limited blood contact surface with a single moving part, and are silent in operation. Newer pump designs have eliminated mech- anical bearings altogether with the hope that these will be even more durable. Implantation is generally easier than for pulsatile devices and infections are less common, probably because of the less inva- sive surgery and thinner drive line. Rotary devices provide continuous flow and are therefore not ‘physiological’; patients usually do not have a palpable pulse and blood pressure measurement with a sphygmomanometer requires a Doppler probe to detect blood flow. Rotary pumps are preload de- pendent and afterload sensitive. Adequate left ventricular filling is re- quired to ensure sufficient preload and avoid ventricular ‘suckdown’. The absence of valves makes them simpler to operate. However, in the event of pump stoppage, free regurgitation from the ascending aorta back into the left ventricle may occur. Depending on native left ventricular function, some pulsatility may be seen as more blood is delivered to the VAD during ventricular systole. The impeller spinning at speed results in high sheer stress to blood components which can cleave the von Willebrand factor, resulting in an acquired von Willebrand disease. Pump thrombosis is another potential com- plication of continuous-​flow devices and all rotary pumps currently require anticoagulation with warfarin and antiplatelet agents. The Thoratec Heartmate II (Fig. 16.5.5.3) is a second-​generation device which consists of an axial-​flow blood pump with a percutan- eous lead that connects the pump to an external computer controller and power source. The blood pump is a 12 mm diameter straight tube made of titanium alloy containing an internal rotor with helical blades that curve around a central shaft. When the rotor spins on its axis, blood is drawn from the left ventricular apex through the pump and into the ascending aorta. The pump requires a pump pocket in the anterior abdominal wall, has an implant volume of 63 ml, and weighs 350 g. It operates at approximately 8000–​10 000 rpm and can generate up to 10 litres of flow per minute. The controller and two batteries are wearable, providing 4–​6 h of power. The HeartMate II is approved for clinical use in Europe and the United States of America for bridging to transplant as well as for destination therapy. It has been implanted in over 20 000 patients worldwide, representing the benchmark against which other continuous-​flow devices are being compared. Box 16.5.5.6  Classification of devices for mechanical circulatory support Temporary devices • Thoratec CentriMag • Abiomed Impella 2.5; 4.0; 5.0 • TandemHeart • Venoarterial Extra Corporeal Membrane Oxygenation (VA-​ECMO) Long-​term devices Pulsatile (volume displacement) • Berlin Heart Excor • NuPulse iVAS (investigational device) Continuous flow • Jarvik 2000 • Berlin Incor • HeartMate II and HeartMate 3 • HeartWare HVAD 16.5.5  Cardiac transplantation and circulatory support 3433 The HeartWare HVAD (Fig. 16.5.5.4) is a third-​generation cen- trifugal blood pump which contains a wide-​bladed impeller with a hydrodynamic suspension. This pump weighs only 160 g, has an implant volume of 70 ml, and does not require an abdominal pump pocket, allowing intrapericardial placement. It operates at 2400–​3800 (a) (b) Fig. 16.5.5.3  (a) HeartMate II. (b) Stylized picture of a patient with a HeartMate II LVAD. (a) and (b) Courtesy of Thoratec. (a) (b) Fig. 16.5.5.4  (a) The HeartWare HVAD. (b) Stylized picture of a HeartWare HVAD showing inflow drainage from left ventricular apex and outflow graft anastomosed to ascending aorta. (a) and (b) Courtesy of HeartWare Inc. section 16  Cardiovascular disorders 3434 rpm and can generate flows of up to 10 litres/​min. The HeartWare HVAD is approved for clinical use in Europe and for bridging to transplant in the United States of America. The HeartWare HVAD has been implanted in nearly 10 000 patients worldwide and has pro- duced very favourable clinical outcomes. The HeartMate 3 is a third-​generation centrifugal pump in which the rotor is suspended using magnetic forces. Like the HeartWare HVAD it is placed intrapericardially (Fig. 16.5.5.5). It has been de- signed with large blood flow pathways to minimize shear stress on the blood cells. It also provides some artificial pulsatility. In a ran- domized trial against the HeartMate II device, the HeartMate3 was superior with regard to survival free of disabling stroke and need for pump exchange due to pump thrombosis at 2 years. Outcome of ventricular assist device treatment Clinical outcomes of patients treated with implantable VADs have improved significantly over the last decade. This is a result of better understanding of patient selection criteria, the develop- ment of clinical strategies to minimize perioperative complica- tions, and improvements in device technology. Algorithms have been developed to risk stratify patients preoperatively, allowing targeted medical optimization of high-​risk patients before VAD implantation. The introduction of the INTERMACS registry in the United States of America created a template for rigorous data monitoring and audit. Actuarial survival following implantation of continuous-​flow LVADs is 80% at 1 year and 70% at 2 years across all indications (Fig. 16.5.5.6). The commonest causes of 30-​day mortality are right ventricular failure, multiorgan failure, and neurological events. In the longer term, device-​related infec- tion, stroke, and pump thrombosis emerge as the most important cause of death. Multivariate analysis identified older age, greater severity of right ventricular failure, and cardiogenic shock at im- plant as risk factors for death. External battery pack Outflow graft Skin entry site Centrifugal-flow LVAS Left ventricle From left ventricle Inflow cannula Motor Motor Rotor with internal magnet Pump chamber Blood flow To aorta Slide lock Aorta Percutaneous lead System controller Fig. 16.5.5.5  Stylized picture of a HeartMate 3 device, with a fully magnetically levitated centrifugal-​flow pump. Courtesy of Abbott Laboratories. 100% Intermacs - Kaplan–Meier survival for continuous flow LVADs (with or without RVAD implant at time of LVAD operation) by device type primary prospective implants: 23 June 2006 to 30 September 2017 Device type LVAD (n = 18745, Deaths = 5895) BiVAD (n = 690, Deaths = 348) 90% 80% 70% 60% 50% % Percent survival 40% 30% 20% At risk 690 18745 231 10288 125 5875 72 3325 46 1891 31 983 10% 0% 0 Shaded areas indicate 70% confidence limits p (log-rank) = <.0001 Event: Death (censored at transplant or recovery) 3 6 9 12 15 18 21 24 27 Months after device implant 30 33 36 39 42 45 48 51 54 57 60 Fig. 16.5.5.6  Kaplan–​Meier survival for continuous-​flow LVADs (with or without RVAD implant at time of LVAD operation). Primary prospective implants: 23 June 2006 to 30 September 2017. From Kirklin KJ (2017). Intermacs Quarterly Statistical Report 2017 Q3. Exhibit 17: p. 26 http://​www.intermacs.org. 16.5.5  Cardiac transplantation and circulatory support 3435 Complications of ventricular assist devices With long-​term requirement for anticoagulation therapy and the need for a percutaneous driveline, bleeding and infection re- main the most common adverse events following LVAD implant. Other common complications include arrhythmias, respiratory failure, renal dysfunction, and right heart failure. Patients receiving continuous-​flow devices appear to experience significantly reduced incidences of device malfunction, infection, and hepatic dysfunc- tion, but there appears to be a significantly increased risk of gastro- intestinal bleeding with the use of rotary devices, which may be associated with an acquired form of von Willebrand’s disease and reduced pulsatility of the systemic circulation. Stroke remains a sig- nificant complication (ischaemic and intracerebral bleeding) as does pump thrombosis. Recent data suggests that optimal blood pressure control may reduce the risk of stroke. FURTHER READING Barnard CN (1967). A human cardiac transplant: an interim report of a successful procedure performed at Groote Schuur Hospital, Cape Town. S Afr Med J, 41, 1271–​4. Berry GJ, et al. (2013). The 2013 International Society for Heart and Lung Transplantation Working Formulation for the standardization of nomenclature in the pathologic diagnosis of antibody-​mediated rejection in heart transplantation. J Heart Lung Transplant, 32, 1147–​62. Billingham ME (1992). Histopathology of graft coronary disease. J Heart Lung Transplant, 11, S38–​44. Birks EJ, et al. (2006). Left ventricular assist device and drug therapy for the reversal of heart failure. N Engl J Med, 355, 1873–​84. Cowger J, et al. (2013). Predicting survival in patients receiving con- tinuous flow left ventricular assist devices: the HeartMate II risk score. J Am Coll Cardiol, 61, 313–​21. Kapadia SR, et al. (1998). Development of transplantation vasculopathy and progression of donor-​transmitted atherosclerosis. Circulation, 98, 267–​78. Kirklin J, et al. (2015). Eighth INTERMACS annual report: 15,000 pa- tients and counting. J Heart Lung Transplant, 34, 1495–​504. Leitz K, et al. (2007). Outcomes of left ventricular assist device im- plantation as destination therapy in the post-​REMATCH era: impli- cations for patient selection. Circulation, 116, 497–​505. Lund LH, et al. (2016). The Registry of the International Society for Heart and Lung Transplantation: Thirty-​third Official Adult Heart Transplant Report-​2016. J Heart Lung Transplant, 35, 1149–​57. Mancini DM, et al. (1991). Value of peak oxygen consumption for op- timal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation, 83, 778–​86. Mehra MR, et  al. (2016). The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: a 10-​year update. J Heart Lung Transplant, 35, 1–​23. Mehra et al. (2018). Two year outcomes with a Magnetically Levitated Cardiac Pump in Heart Failure. New Eng J Med, 378, 1386–95. Pham MX, et al. (2010). Gene-​expression profiling for rejection sur- veillance after cardiac transplantation. N Engl J Med, 362, 1890–​900. Rogers JG, et al. (2017). Intrapericardial left ventricular device for ad- vanced heart failure. New Eng J Med, 376, 451–​60. Rose EA, et al. (2001). Long-​term use of a left ventricular assist device for end-​stage heart failure. N Engl J Med, 345, 1435–​43. Slaughter M, et al. (2009). Advanced heart failure treated with continuous-​ flow left ventricular assist device. N Engl J Med, 361, 1–​11. Stevenson LW, et al. (2009). INTERMACS profiles of advanced heart failure: the current picture. J Heart Lung Transplant, 28, 535–​41. 16.6 Valvular heart disease 3436 Michael Henein 16.6 Valvular heart disease 3436 Michael Henein ESSENTIALS Rheumatic valve disease remains prevalent in developing countries, but over the last 50 years there has been a decline in the incidence of rheumatic valve disease and an increase in the prevalence of de- generative valve pathology in northern Europe and North America. In all forms of valve disease, the most appropriate initial diagnostic investigation is almost always the echocardiogram. Mitral stenosis The most common cause is rheumatic valve disease. Other causes include mitral annular calcification, congenital mitral stenosis, in- fective endocarditis (very rarely), and systemic lupus erythematosus (Liebman–​Sachs endocarditis). The important consequences of mitral stenosis are its effect on left atrial pressure, size, and the pulmonary vasculature; it com- monly causes atrial fibrillation. Presenting symptoms are typically exertional fatigue and breathlessness; systemic embolism can occur. Characteristic physical signs are irregular pulse, tapping apex beat, loud first heart sound, opening snap, and an apical low-​pitched rum- bling mid-​diastolic murmur. Management—​the only medical treatments in mitral stenosis are (1) prophylactic measures against rheumatic fever and endocarditis; (2)  anticoagulation to prevent systemic thrombo-​embolism; and (3) diuretics for raised left atrial pressure. Patients who are symp- tomatic need intervention by either surgical valvotomy or catheter balloon valvuloplasty, whether or not they have pulmonary hyper- tension. Early intervention—​before the development of atrial fib- rillation and an enlarged left atrium—​is recommended, provided a conservative operation is possible. Mitral valve replacement is re- served for cases where the mitral valve cannot be repaired. Mitral regurgitation The most common causes are ischaemic myocardial dysfunction, mi- tral valve prolapse, and dilated cardiomyopathy. Other causes include congenital valve disease, infective endocarditis, endomyocardial fi- brosis, and connective tissue diseases (including Marfan syndrome). Mitral regurgitation is an isolated volume overload on the left ven- tricle, providing the physiological equivalent of afterload reduction so that a normal forward cardiac output is maintained by the com- bination of increased ejection fraction and higher preload. Patients with mild regurgitation may not have any symptoms: those with se- vere regurgitation are likely to present with dyspnoea. Characteristic physical signs are an apex beat that may be prominent and dis- placed, an apical pansystolic murmur, and a third heart sound (in severe cases). The loudness of the murmur generally correlates with severity of regurgitation. The cardinal signs of mitral prolapse are a mid-​systolic click followed by a murmur. Endocarditis prophylaxis may be recommended to high-​risk pa- tients with regurgitation. Patients in atrial fibrillation should be given anticoagulants. The development of symptoms suggests the need for surgical correction to avoid development of irreversible left ventricular dysfunction. Assessment during routine follow-​up should identify those likely to need surgical intervention even in the absence of symp- toms, with an effective regurgitant orifice of over 40 mm2 being one proposed indication. It is generally considered that a left ventricular end-​systolic dimension more than 50 mm indicates a poor prognosis and that surgical intervention is unlikely to be of benefit. If technically possible, mitral valve repair results in a much better clinical outcome than does valve replacement, but mitral replacement by a mechanical valve or bioprosthesis is the only option for irreparable valves. Aortic stenosis Aortic stenosis may be at subvalvar, valvar, or supravalvar level, the commonest being valvar stenosis. Age-​related degenerative calcific disease is the commonest cause in western Europe and the United States of America. Other causes include congenital bicuspid aortic valve and rheumatic disease (always associated with aortic regurgi- tation, ‘mixed aortic valve disease’, and usually with rheumatic mitral disease). With the increase in outflow tract resistance in aortic stenosis, left ventricular wall stress increases and hypertrophy develops, preserving overall ventricular systolic function, but potentially at the expense of subendocardial ischaemia. Patients with mild disease may be asymp- tomatic, and even severe stenosis may be silent, but breathlessness, angina, and syncope are typical. Characteristic physical signs are a slowly rising, low-​amplitude pulse, a narrow pulse pressure, a sus- tained apex beat, and a long and harsh ejection systolic murmur that is loudest at the base (second right intercostal space, also known as the aortic area) of the heart, and in most cases radiates to the carotids (where a thrill may be palpable). 16.6 Valvular heart disease Michael Henein 16.6  Valvular heart disease 3437 Management—​patients with moderate or severe disease should be advised to avoid strenuous exercise. Prophylaxis against endocar- ditis may be recommended to high-​risk patients. Asymptomatic pa- tients with mild or moderate aortic stenosis require follow-​up; those with severe disease (pressure gradient >70 mm Hg) need aortic valve replacement. Aortic regurgitation Aortic regurgitation is caused by leaflet disease or aortic root dilata- tion, the commonest causes being isolated medionecrosis, rheum- atic disease, infective endocarditis, and Marfan syndrome. The left ventricular stroke volume is significantly increased, which is accommodated by an increase in left ventricular cavity size. As dis- ease progresses, end-​systolic volume increases out of proportion to stroke volume, and eventually these changes lead to irreversible damage. The onset of symptoms, particularly breathlessness, coin- cides with the onset of left ventricular disease. Characteristic phys- ical signs of chronic severe aortic regurgitation are a large amplitude ‘collapsing’ pulse (which when severe can induce pulsations in many parts of the body), a low diastolic blood pressure (<50 mm Hg) and/​ or a high pulse pressure (>80 mm Hg), an apex beat that is sustained and/​or displaced, and an early diastolic, decrescendo murmur, loudest at the left sternal border. Acute aortic regurgitation causes the patient to be cold and shut down, with tachycardia, hypotension, and a short early diastolic murmur that is easily missed. Management—​medical treatment of chronic aortic regurgita- tion includes angiotensin converting enzyme (ACE) inhibitors and/​ or calcium channel blockers to reduce afterload. Patients with a di- lated aortic root should be given β-​blockade with ACE inhibition/​ angiotensin receptor blockers. Prophylaxis against endocarditis may be recommended to high-​risk patients. Although patients with se- vere chronic aortic regurgitation may remain asymptomatic, valve replacement should be offered when there is progressive increase in left ventricular end-​systolic dimension, which should not be allowed to reach more than 40 mm. Right heart valve disease Many of the conditions that cause right-​sided valve diseases are congenital, and are excluded from further discussion here (see Chapter 16.12). Tricuspid stenosis—​this is rare, but most often caused by rheum- atic disease that almost invariably simultaneously affects the mitral valve. Symptoms include fatigue, dyspnoea, and fluid retention. On auscultation at the left or right sternal edge, a mid-​diastolic murmur is heard and a tricuspid opening snap may be present. Diuretics can help to minimize fluid retention. Severe tricuspid stenosis needs sur- gical repair, or replacement if additional regurgitation is present. Tricuspid regurgitation—​significant disease is most commonly sec- ondary to pulmonary hypertension and/​or right heart dilatation; the commonest non​congenital primary cause is infective endocarditis. Symptoms include fluid retention and hepatic congestion. A raised venous pressure with prominent V-​wave is expected. Other signs include a pansystolic murmur at the left or right sternal edge (in one-​third of cases), expansile pulsation of the liver (in most), and peripheral oedema/​ascites. Diuretics and ACE inhibitors may reduce systemic venous pressure and right ventricular size, even restoring valve competence in some cases. Valve repair or replacement may be advised in some cases. Pulmonary stenosis—​a rare condition usually caused by rheumatic disease or carcinoid syndrome. Fatigue and dyspnoea are the main symptoms. Characteristic physical signs are a prominent venous ‘a’ wave in the neck and an ejection systolic murmur loudest at the upper left sternal edge. Balloon valvuloplasty is the procedure of choice if intervention is warranted. Pulmonary regurgitation—​significant disease is rare, but is usu- ally caused by rheumatic disease, carcinoid, and endocarditis. The characteristic physical sign is a soft early diastolic murmur in the left upper parasternal region. Arrhythmia or progressive right ventricular dilatation are indications for surgery, using homograft or conduit and valve. Introduction Over the last 50 years there has been a significant shift in the causes of heart valve disease in northern Europe and North America, with a decline in the incidence of rheumatic valve disease and an increase in the prevalence of degenerative valve pathology. Rheumatic valve disease remains prevalent in the developing countries, particularly in areas with limited clinical services. The commonest valve in- volved with rheumatic pathology is the mitral valve, but the aortic and tricuspid valves can also be involved. The apparent increase in the diagnosis of valve disease could be due either to ageing of the population or to the extensive use of echocardiography in car- diology clinics. Age affects the valves, making leaflets thicker with fibrous strands and adipose tissue deposition at the closure lines of the leaflets. Isolated myxomatous changes may also occur in the valve fibrosa. In patients with a suspected diagnosis of endocarditis these changes can add to diagnostic difficulty since they may look like small vegetations, and they also need to be distinguished from papillary muscle fibroelastoma. Medical treatment of valve disease is limited, focusing mostly on prophylaxis against endocarditis and ventricular dysfunction as well as optimizing haemodynamics. Although surgical repair is the main conventional treatment of severe valve disease, the need for this is 5 to 10 times less than that for coronary artery disease. Valve-​related mortality is more common in aortic valve disease than mitral valve disease, largely due to the frequent development of left ventricular dysfunction that causes congestive heart failure. Other causes of death in valve disease are additional pathologies such as coronary artery disease, endocarditis, or arrhythmia. The mitral valve Normal mitral valve anatomy and function Optimum function of the mitral valve depends on the intact func- tion of all its components—​leaflets, chordae, annulus, and pap- illary muscles, in addition to the left atrium and the left ventricle. A normal mitral valve does not close passively. In addition to the pressure difference between the ventricle and atrium in systole, the annular contraction and papillary muscle contraction play an important role in the competence of the mitral valve. The anterior mitral valve leaflet represents a continuation of the posterior aortic root wall. The annular fibrous ring is located mainly posteriorly; it section 16  Cardiovascular disorders 3438 is usually D-​shaped but there is significant variability in different individuals. The normal diameter of the mitral annulus is around 3 cm with a circumference of 8–​9 cm: it is not a passive structure, so in addition to its normal movement towards the apex in systole, the contraction of the posterior myocardial muscle shortens its diam- eter by 25%, with such movement being a very important compo- nent in the mechanism of mitral valve competence. Change in the size and shape of the left atrial cavity is a cause for incompetence of the mitral valve by enlarging the annular diameter. Loss of atrial mechanical function may contribute significantly to the development of mitral regurgitation in patients with atrial fibril- lation. Likewise, atrial fibrillation itself has been shown to contribute to the enlargement of the left atrium and consequently the develop- ment of mitral regurgitation. The two leaflets of the mitral valve meet at the medial and lat- eral commissures. The area of the U-​shaped anterior leaflet is larger than that of the posterior leaflet, which is wider and shorter than the anterior leaflet. The posterior leaflet is made up of several scallops, commonly three. The two leaflets coapt at the zone of apposition, leaving an overlapping segment 5 mm long. The chordal anatomy of the mitral valve is complicated, with around 12 primary chordae rising from each papillary muscle. These divide into secondaries and numerous tertiary branches that attach themselves to the margins of the two leaflets. In addition, a number of basal chordae also attach themselves to the ventricular surface of the leaflets and to the commissures. The location of the chordae follows that of the papillary muscles anterolaterally and posteromedially. Any rupture or redundancy of the chordae or extra tissue in the leaflets results in mitral regurgitation. Mitral stenosis Causes The most common cause of mitral stenosis, which affects women more than men (2:1), is rheumatic valve disease. The rheumatic pro- cess involves not only the leaflets but may also affect the chordae and the annulus, causing fibrosis and superimposed calcification. The rheumatic leaflets become thickened and fibrosed, and the commis- sures fuse. The end result of this pathology is a reduction in mitral valve area, the rigid movement of the leaflets and the commissural fusion together contributing to the limited flow across the mitral valve orifice and hence stenosis. It is not uncommon for the fibrotic process to involve the subvalvar region in an aggressive way, thus causing flow to be limited at the level of the subvalvar apparatus. In such cases the chordae become short and the inflow tract of the left ventricle becomes tunnel-​like. Mitral annular calcification is another cause of raised filling vel- ocities; this is seen in older people with the calcification limited to the annulus and the proximal segments of the leaflets, but the leaflets themselves are normal. A very uncommon cause of mitral stenosis is congenital mitral stenosis, which may be associated with other cardiac abnormalities. Infective endocarditis with bulky vegetations may rarely cause restriction of mitral flow, and patients with sys- temic lupus erythematosus can develop fibrosis of the mitral cusps with commissural fusion following Liebman–​Sachs endocarditis. Pathophysiology and complications The important consequence of mitral stenosis is its effect on left atrial pressure and size and on the pulmonary vasculature. As the valve area falls progressively, left atrial pressure rises, its size increases, and the pulmonary venous pressure also increases. In most patients with rheumatic mitral valve disease the left ventricle is normal in size and systolic function unless the valve stenosis is severe and making the ventricle underfilled. With a mild degree of mitral stenosis, reduced orifice area is com- pensated by increased flow during atrial systole. As the valve stenosis becomes more severe, the left atrial pressure increases, the pressure difference between the atrium and the ventricle increases, and the filling occurs throughout diastole. In severe mitral stenosis the pres- sure difference may be as high as 25–​30 mm Hg. Long-​standing dis- ease may result in irreversible pulmonary hypertension secondary to the raised left atrial pressure. Atrial fibrillation also develops, with loss of mechanical atrial function. The area of a normal mitral valve area is of the order of 5 cm2, compared to less than 1 cm2 in a patient with severe mitral sten- osis. Effective mitral valve area changes very little with increase in heart rate compared to aortic valve area (which increases), the reason probably being the smaller number of commissures that as- sist opening of the mitral valve compared to the aortic valve. During exercise, particularly in atrial fibrillation, diastolic time falls and the fixed valve area causes raised left atrial pressure and pulmonary venous pressure. Left atrial dilatation Progressive reduction in mitral valve orifice area causes progres- sive increase in left atrial pressure and size and pulmonary venous pressure. Left atrial dilatation is associated with reduction in its mechanical function that slows down intra-​atrial blood circulation (swirling). With progressive disease and development of atrial fib- rillation, the circulation in the atrium becomes very sluggish and echocardiography may demonstrate spontaneous echo-​contrast, particularly on transoesophageal images. Such patients are given anticoagulants in order to avoid clot formation and hence the risk of transient ischaemic attacks or strokes. Almost one-​fifth of the patients undergoing surgery for mitral stenosis have left atrial thrombus, and in one-​third of them the thrombus is restricted to the atrial appendage. Atrial fibrillation This is the most common complication of mitral stenosis and its prevalence increases with age; it is found in 70% of patients in their thirties and in 80% of those in their fifties. The presence of pul- monary hypertension raises the prevalence of atrial fibrillation. The Framingham study estimated a 20-​fold increase in risk of stroke in patients with atrial fibrillation and mitral stenosis compared to only 5-​fold increase in those without mitral valve disease. Left atrial thrombus may also form in patients with a dilated left atrium with spontaneous echo-​contrast who are in sinus rhythm. The loss of left atrial appendage mechanical function has been proposed as a possible mechanism behind blood stagnation and thrombus formation. Left ventricular dysfunction Although in most cases of mitral stenosis the left ventricle is normal in size and systolic function, in some patients diastolic function may be impaired and end-​diastolic pressure raised. This could be related to additional pathology (e.g. systemic hypertension and 16.6  Valvular heart disease 3439 diabetes). The left ventricle is dilated only in the presence of add- itional coronary artery disease. Primary rheumatic myocardial dis- ease was proposed years ago, but no convincing evidence has ever come to light. Pulmonary hypertension With the increase in left atrial pressure, the pulmonary venous pres- sure increases and hence pulmonary arterial pressure also rises. Although pulmonary artery pressure corresponds to the degree of increase in left atrial pressure, a discrepancy between the two may reflect a raised pulmonary vascular resistance. A normal pressure drop across the pulmonary bed is of the order of 10–​15 mm Hg. The pulmonary hypertension is not always reversible after valve surgery. For any degree of mitral stenosis patients can display a variety of pulmonary pressures, but it is very rare for secondary pulmonary hypertension to develop with left atrial pressure less than 20 mm Hg in the setting of isolated mitral stenosis. Right heart disease With the development of pulmonary hypertension, the right ven- tricle becomes hypertrophied and its cavity dilates. This is also reflected in right atrial size. Patients with rheumatic mitral valve dis- ease may have additional tricuspid valve involvement; in particular, with the annulus dilating and causing significant tricuspid regur- gitation. Patients with severe tricuspid regurgitation may complain of fluid retention that needs careful management in order to main- tain the left-​sided cardiac output and obtain tissue perfusion. Long-​ standing significant tricuspid regurgitation and raised right atrial pressure may cause further deterioration of right ventricular func- tion and congestive heart failure. By that stage, the damage is usually irreversible despite any successful mitral valve surgery. Clinical presentation Symptoms Patients may remain asymptomatic with mild mitral stenosis. As the disease progresses, early symptoms are exertional fatigue and breathlessness. With severe mitral stenosis shortness of breath is accompanied by orthopnoea and paroxysmal nocturnal dyspnoea. With the development of pulmonary hypertension, right ventricular dysfunction, and tricuspid regurgitation, patients may present with fluid retention as well as recurrent chest infection. Atrial fibrillation may be an early symptom in patients with mitral stenosis, particu- larly palpitations on exercise. Major systemic embolus can also be a presenting symptom, and the condition may be detected for the first time during pregnancy as patients complain of disproportionate dyspnoea. Physical examination Long-​standing mitral stenosis characteristically causes weight loss and a malar flush. The pulse character is normal, but pulse volume may be reduced and atrial fibrillation is likely. The jugular venous pressure is usually normal unless there is tricuspid regurgitation and/​or pulmonary hypertension. The apex is not displaced, but the first heart sound is sometimes palpable (‘tapping apex’), and less fre- quently the opening snap is also. The characteristic auscultatory features of rheumatic mitral sten- osis are an opening snap in early diastole, a mid-​diastolic murmur, and a loud first heart sound. The opening snap is caused by the abrupt tension that develops in the fibrosed leaflets at the termination of the opening movement. It is best heard at the lower left sternal edge or apex, becoming closer to the second heart sound as left atrial pres- sure rises, and it is absent with leaflet calcification. The diastolic murmur is low pitched and maximal at the apex. It is caused by in- creased blood flow velocity between the left atrium and left ventricle and is accentuated in late diastole by atrial contraction in patients in sinus rhythm. The loud first heart sound is associated with fibrosis of the anterior leaflet and is lost with leaflet calcification. Many patients with mitral stenosis have some degree of mitral regurgitation, which is not significant in the presence of severe stenosis. In the presence of pulmonary hypertension the jugular venous pressure is raised, there may be a palpable right ventricular heave, and the second heart sound is usually loud. In patients with sig- nificant tricuspid regurgitation, whether secondary to pulmonary hypertension or due to rheumatic tricuspid valve, there is a clear V-​ wave and deep Y descent in the jugular venous pulse, and expansile pulsation of the liver. The murmur of tricuspid regurgitation is not usually prominent. Investigations Chest radiograph and electrocardiogram Early in the disease a chest radiograph may show a completely normal cardiac silhouette. Later, as the disease progresses, left atrial enlargement appears and a prominent left atrial appendage contour becomes very evident (Fig. 16.6.1). Left atrial double-​density and elevation of left main bronchus may also be evident. In patients with Fig. 16.6.1  Chest radiograph from a patient with pure mitral stenosis. The heart size is normal, but the left atrial appendage is enlarged. The upper lobe vessels are dilated and there are Kerley lines at both bases. section 16  Cardiovascular disorders 3440 raised left atrial pressure, pulmonary vascular redistribution mani- fest as ‘dilated upper lobe veins’ and interstitial pulmonary oedema (‘Kerley B lines’) may be seen. The central pulmonary arteries be- come prominent as pulmonary hypertension develops, and upper lobe deviation is also seen. Finally, right-​sided dilatation may also be seen as tricuspid regurgitation develops. The electrocardiogram can show a broad and notched P-​wave due to left atrial hypertrophy and enlargement (‘P mitrale’) as a classical finding in mitral stenosis, and its progressive broadening predicts the occurrence of atrial fibrillation, which is common in mitral stenosis. Echocardiography Echocardiography is the investigation of choice in mitral valve dis- ease. A typical picture of rheumatic valve disease is a short, fibrosed, and stiff posterior leaflet; a fibrosed anterior leaflet that bows down towards the ventricle in diastole; and narrow valve area (Fig. 16.6.2). Short-​axis images clearly demonstrate the fused commissures and two-​dimensional images show the extent of chordal fibrosis. Planimetry of the mitral valve area in diastole gives an estimate of the degree of stenosis. Continuous-​wave Doppler assesses the blood flow velocity across the valve. In mild stenosis, transmitral Doppler demonstrates a peak velocity in late diastole compared to in early diastole in severe stenosis. With atrial fibrillation there is a single early diastolic filling component to the left ventricle. A transmitral mean pressure gradient of more than 4 mm Hg suggests a moderate degree of stenosis (Fig. 16.6.3), and a mean pressure gradient of more than 8 mm Hg suggests severe stenosis. Colour-​flow Doppler can provide a quantitative approach for assessing mitral stenosis se- verity using the proximal isovelocity surface area (PISA) method or the vena contracta method (the vena contracta being the narrowest region of the stenotic jet, just downstream of the valve orifice and reflecting the size of that orifice). Although the latter is easy to use, it has its limitations since it varies more with deformation of the mitral orifice area and shape. Colour-​flow Doppler will also show any mi- tral regurgitation jet and give some indication of its severity. Echocardiography also assesses any involvement of the aortic valve or the tricuspid valve by the same or other pathologies. It is now common practice that most patients with mitral valve dis- ease are studied by transoesophageal echo because this provides more detailed assessment of the mitral valve, the subvalvar ap- paratus, and the presence of left atrial spontaneous contrast and appendage clots. Cardiac catheterization Echocardiography has replaced cardiac catheterization in making the diagnosis of mitral stenosis. Catheterization may provide add- itional information on pulmonary vascular resistance and coronary artery disease before surgery. Differential diagnosis The diagnosis of mitral stenosis is usually straightforward on the basis of clinical findings supported by echocardiography, which should distinguish the presence of an Austin–​Flint murmur caused by aortic regurgitation and the rare conditions of left atrial myxoma (see Chapter 16.10) and cor triatriatum (see Chapter 16.12). Management There is a significant time lag between the acute event of rheumatic fever and the presentation of mitral stenosis with mild symptoms, which could be up to 15 years. Patients may need another 10 years to develop signs and symptoms of severe stenosis. The likely reason behind this delay is the time needed for rheumatic leaflet fibrosis and calcification to develop and cause raised left atrial pressure. This time lag between acute rheumatic fever and clinical presentation varies significantly between developed and developing countries. In Europe and North America patients need valve surgery for mitral stenosis in their fifties, whereas those in developing countries need it in their thirties. The clinical outcome of patients with unoperated rheumatic mitral stenosis has changed significantly over time, with 20-​year follow-​up mortality dropping from historically 85% to re- cently 44% in those who refuse surgery. Fig. 16.6.2  Transoesophageal echocardiogram from a patient with severe rheumatic mitral stenosis showing a dilated left atrium (LA) with spontaneous echo-​contrast. 1 m/s Fig. 16.6.3  Continuous-​wave Doppler of left ventricular filling from a patient with mitral stenosis, showing raised velocities (>2 m/​s, arrowed) across the mitral valve as the ventricle fills in diastole. A mean velocity of more than 1.3 m/​s at the mitral valve leaflet tips is abnormal. 16.6  Valvular heart disease 3441 Medical The only medical treatments in mitral stenosis are the prophy- lactic measures against rheumatic fever (penicillin prophylaxis, see Chapter 16.9.1) and endocarditis (considered for high-​risk cases, see Chapter 16.9.2), anticoagulation to prevent systemic embolism, and diuretics for raised left atrial pressure. There is no medication that has a direct effect on slowing disease progress. Patients with mitral stenosis should be followed up clinically using non​invasive investigations, particularly Doppler echocardiography. The frequency of follow-​up should be tailored according to indi- vidual patient’s clinical condition and the severity of disease: this could be every 2 years in a patient with mild stenosis and regur- gitation, but closer attention is required for the patient with severe stenosis and evidence of pulmonary hypertension. Particularly close follow-​up is advised for pregnant women who have mitral stenosis. In patients who develop atrial fibrillation, attempts to restore sinus rhythm are usually unsuccessful unless associated with surgery. To maintain sinus rhythm the organic mitral lesion should be dealt with either interventionally or surgically. In addition to heart rate con- trol, digoxin may keep a patient with a modestly dilated left atrium in sinus rhythm. However, once atrial fibrillation is established, at- tention should be diverted to rate control with digoxin, β-​blockers, or calcium channel blockers. With persistent atrial fibrillation anticoagulation is essential and INR level should be monitored and maintained at 2.5–​3.5. Patients recommended for percutaneous mitral valvuloplasty should receive stable anticoagulation therapy for at least 3 months before the procedure and transoesophageal echo should exclude left atrial clot. Those who need surgical inter- vention may receive a maze procedure as a means for restoring the sinus rhythm, which involves surgically creating a single electrical pathway from the sinus node to the atrioventricular node, while isolating the abnormal electrical activity of the left and right atrial tissue. Recently, electrophysiological mapping with isolation of pul- monary veins has offered an alternative procedure. The success of the maze procedure varies considerably, ranging between 25% and 80% even after an initially successful procedure. See Chapter 16.4 for further discussion. Patients who are symptomatic need intervention by either surgical valvotomy or catheter balloon valvuloplasty, whether or not they have pulmonary hypertension. Early intervention is highly recom- mended before the development of atrial fibrillation and an enlarged left atrium, provided a conservative operation is possible. The percu- taneous mitral valvuloplasty procedure involves inserting an Inoue balloon into the mitral valve orifice and inflating it until an increase in mitral valve area is achieved (Fig. 16.6.4). Contraindications to this procedure are left atrial appendage thrombus, calcified subvalvar apparatus, and/​or mitral regurgitation. Early results of this technique are satisfactory, particularly if patients are well selected (e.g. those with relatively mobile, non​calcified leaflets that are not greatly thickened, and without subvalvular thickening). Mitral sten- osis may recur following this procedure after the healing period of the split of the fused commissures. Surgical Closed mitral valvotomy has been replaced by percutaneous mitral valvuloplasty, but its results are not optimal in low-​workload centres in developed countries. There is thus still room for surgical repair of the mitral valve. This is better suited to patients with minimal calcifi- cation and those with short chordae. The technique offers the advan- tage of avoiding replacement of the mitral valve, which has effects on left ventricular function. However, in a patient with an irreparable mitral valve, the only remaining option is mitral valve replacement. Closed mitral commissurotomy This historic procedure aimed at opening the mitral valve by ap- plying a dilator through the ventricular apex, with the surgeon using a finger to feel the valve leaflets and orifice to judge when the desired valve area was achieved. The first successful operations were carried out in 1948. It has been intensively used in the United Kingdom and other countries, with an average mortality of 3–​4%. Open mitral valvotomy This operation requires the use of an extracorporeal circulation and aims at direct visualization of the mitral valve through a medial sternotomy, with careful dissection of the fused commis- sures under direct vision. In contrast to the closed operation, the surgeon is able to deal with the subvalvar apparatus and the fused chordae, and correct chordal shortening if required. The left atrial appendage can also be visualized, and if there is thrombus pre- sent it can be removed. With appropriate patient selection and preoperative evaluation open commissurotomy is feasible in most patients, with an operative mortality of approximately 1%; how- ever, most cases not suitable for balloon valvotomy require mitral valve replacement. Mitral valve repair Lack of access to anticoagulation medications and monitoring in low income countries, also the religious cultural bias regarding type of prosthetic valve in some countries, necessitates an increase in the proportion of patients undergoing repairs of rheumatic mi- tral valves. Fig. 16.6.4  Inoue balloon catheter, as used for mitral valvuloplasty, partially (left) and completely (right) inflated. section 16  Cardiovascular disorders 3442 Mitral valve replacement Mitral valve replacement involves either a mechanical or a tissue valve substitute. Surgical mortality varies according to other comorbidities: it is of the order of 3% in patients with isolated mitral valve stenosis but can be as high as 12% in patients with additional pulmonary hypertension. The life of biological mitral valve substi- tutes, particularly porcine xenografts, is limited to less than 10 years in most adults, hence their use tends to be restricted to very elderly patients. Cryopreserved mitral homografts have been proposed re- cently as a better option, as has the use of a pulmonary autograft in a Dacron tube, but experience is limited. Mitral regurgitation Causes The most common causes of mitral regurgitation are ischaemic myocardial dysfunction, mitral valve prolapse, and dilated cardio- myopathy. Other causes are given in Table 16.6.1. Ischaemic mitral regurgitation The posteromedial papillary muscle is predisposed to ischaemic dysfunction and infarction because it is supplied by a single branch of the posterior descending artery and tends to have only a few collaterals. The anterolateral papillary muscle receives blood from branches of both the left anterior descending artery and the cir- cumflex artery, so it is less susceptible to ischaemia. Ischaemic dis- turbances of left ventricular function contribute to the development of mitral regurgitation through several mechanisms: (1) regional wall motion abnormalities with adverse ventricular remodelling and systolic tenting of the valve leaflets; (2) left ventricular dilata- tion and shape change that alters normal alignment of the papillary muscles and results in leaflet tethering and inadequate closure; and (3) annular dilatation leading to inadequate annular contraction. These mechanisms may contribute to further enlargement of the left ventricle and deterioration of its function, which itself would add to the severity of mitral regurgitation. Four clinical presentations are seen in ischaemic mitral regurgitation: acute myocardial infarction; papillary muscle rupture; reversible ischaemic myocardial dysfunc- tion in the presence of preserved left ventricular systolic function; and end-​stage ischaemic cardiomyopathy with reduced function. Acute myocardial infarction Significant mitral regurgitation complicates 3–​16% of acute myo- cardial infarctions. Most present within the obvious context of acute myocardial infarction, but some with pulmonary oedema from the acute development of mitral regurgitation. Most patients presenting with myocardial infarction complicated by mitral re- gurgitation have right and circumflex coronary artery disease that causes inferior wall dysfunction. Mitral regurgitation does not therefore seem to be related to infarct size, but to the extent of is- chaemic dysfunction and involvement of the posteromedial pap- illary muscle. The resulting poor support to the posterior leaflet, referred to as tethering, causes lack of leaflet coaption and valve incompetence. When severe mitral regurgitation develops it carries a poor prognosis, with mortality rising to 25% at 30 days and over 50% at 1 year. The effect of reperfusion on mitral regurgitation re- mains controversial. Papillary muscle rupture Complete papillary muscle rupture causes severe mitral regurgita- tion and cardiogenic shock that is usually fatal (70% within 24 h without emergency surgery). Surgical repair of the papillary muscle is not feasible in most cases because tissues are necrotic: valve re- placement is necessary, with risk influenced by other factors including the severe left ventricular disease that is usually present. Ischaemic mitral regurgitation in a normal left ventricle Patients with long-​standing ischaemic myocardial dysfunction usu- ally have exertional reversible ischaemia. If this affects the posterior wall of the left ventricle it leads to further deterioration of pos- terior wall function and consequently the posterior leaflet function with the development of mitral regurgitation. Exertional breath- lessness in these patients does not always have to be due to raised end-​diastolic pressure and may be caused by a sudden increase in left atrial pressure through the development of mitral regurgitation with exercise, particularly in those with a dilated left atrium. Stress echocardiography is ideal for demonstrating the stress-​induced is- chaemic ventricular dysfunction and the development of mitral re- gurgitation and raised left atrial pressure, when antianginal therapy and afterload reduction may be beneficial. Patients who develop sig- nificant mitral regurgitation with stress and who are accepted for coronary artery bypass surgery should receive mitral valve repair and a ring insertion at the time of surgical revascularization. Ischaemic mitral regurgitation in ventricular dysfunction Mitral regurgitation is very common in patients with long-​standing ischaemic left ventricular dysfunction and/​or end-​stage ventricular disease. Since the valve leaflets appear morphologically normal, the mitral regurgitation is described as ‘functional’. However, three-​ dimensional echocardiographic assessment of the mitral valve Table 16.6.1  Common causes of mitral regurgitation Structure primarily affected Anatomical defect Cause Valve cusps Congenital cleft Primary atrial septal defect Isolated Redundant cusp Mitral valve prolapse Marfan syndrome Perforation Infective endocarditis Scarring Rheumatic fever Ergot-​derived dopamine receptor agonists Chordae Redundant Mitral valve prolapse Marfan syndrome Other connective tissue disease Rupture Acute myocardial infarction Mitral valve prolapse Marfan syndrome Other connective tissue disease Infective endocarditis Rheumatic fever Shortening Rheumatic fever Endomyocardial fibrosis Papillary muscle Dysfunction Ischaemia Valve annulus Dilatation Severe left ventricular disease of any cause—​‘dilated cardiomyopathy’ 16.6  Valvular heart disease 3443 proves that it is not entirely normal, with long-​standing progres- sive changes in the interleaflet relations and subvalvar apparatus. Reducing ventricular pressures may improve left ventricular geom- etry, and lowering blood pressure may reduce mitral regurgitation severity. Mitral valve prolapse Mitral valve prolapse is a genetic connective tissue disorder that affects the mitral leaflets, chordae, and annulus, with an auto- somal dominant pattern of inheritance and variable penetrance. Histologically the leaflets show thickening of the spongiosa and dis- ruption of the fibrosa with fragmentation. Collagen is also abnormal with high rate of synthesis, deficiency in type III collagen, and split- ting of collagen with fibre disarray. The cause has not yet been iden- tified: defects in a collagen gene or in a gene encoding a component of microfibrils, similar to that involved in Marfan syndrome, have obviously been considered. The condition is common: 1.5–​6% of adults have mitral prolapse, depending on definition, and screening of first-​degree family members demonstrates prolapse in approxi- mately 30% of cases. Mitral prolapse can be classified into two types: a benign condi- tion seen in young people, commonly women, that does not always progress; and the ‘myxomatous mitral valve disease’ seen in older people, often causing significant mitral regurgitation that needs sur- gical repair. Overall survival in patients with mitral prolapse is 97% at 6 years and 88% at 8 years, but those with myxomatous mitral valve disease and a flail leaflet have a 10-​year survival much less. With posterior leaflet myxomatous prolapse, progressive chronic mitral regurgitation is associated with progressive dilatation of the left atrium and left ventricle. The commonest site for posterior mitral prolapse is the middle scallop (P2). Significant mitral regurgitation occurs in less than 10% of patients with posterior prolapse compared to 25% of those with anterior leaflet prolapse. In contrast, the incidence of atrial fibril- lation and heart failure is significantly higher in posterior leaflet prolapse than in anterior leaflet prolapse. In general, severe mitral regurgitation is associated with redundant leaflets, a longer pos- terior leaflet, and a larger annulus. Chordal distribution may also be abnormal, and there may be a relative scarcity of chordae to the central scallop of the posterior leaflet, increased chordal division, or a higher incidence of chordal rupture. There is a clear relationship between mitral valve prolapse, ar- rhythmia, and sudden death. The annual rate of sudden death in mitral prolapse is approximately 2%, which significantly falls after surgical repair. The risk of endocarditis is estimated at three to eight times that of the general population, the substrate being that leaflet prolapse causes significant turbulence of the blood flow across the valve orifice, disrupting platelet and fibrin deposition on the valve surface, and subsequently resulting in vulnerability to infection. There is controversy regarding the relationship between mitral pro- lapse and embolic events. Dilated cardiomyopathy Mitral regurgitation is common in dilated non​ischaemic cardiomy- opathy. Dilatation of the left ventricle disturbs the normal closure of the mitral valve, the leaflets fail to coapt, and hence mitral regurgi- tation occurs. Pathophysiology and complications Regurgitant orifice and jet The regurgitant volume of mitral regurgitation is calculated as the regurgitant flow over the regurgitant area. The flow velocity through the orifice is related to the ventricular–​atrial systolic pres- sure difference. A high left ventricular systolic pressure (e.g. sys- temic hypertension) increases mitral regurgitation volume, and low left ventricular pressure reduces it. Left atrial pressure in acute mitral regurgitation is raised, with a V-​wave in late systole due to the increased volume and the velocity of blood entering it (al- though the absence of such a wave on the left atrial or pulmonary wedge pressure trace does not exclude the diagnosis of severe mi- tral regurgitation). Mitral regurgitation is often a dynamic lesion, with the size of the regurgitant orifice and regurgitant volume varying with the pressure gradient across the valve and with changes in left ventricular volume and geometry. The use of medical therapy to reduce left ventricular volume and improve its systolic function may therefore assist in re- ducing the severity of mitral regurgitation. Left atrium Left atrial volume increases in patients with mitral regurgitation in response to the increase in its pressure, to the transmission of the mitral regurgitation kinetic energy to the left atrial wall, and also to the development (in some cases) of atrial fibrillation. These ef- fects balance those of the mitral regurgitation jet on left atrial pres- sure, which is normal in compensated patients. In contrast to mitral stenosis, the fast regurgitant jet in the left atrium reduces the risk of thrombus formation. Afterload Mitral regurgitation is an isolated volume overload on the left ven- tricle, providing the physiological equivalent of afterload reduc- tion so that a normal forward cardiac output is maintained by the combination of increased ejection fraction and higher preload. Therefore, unlike the situation with pressure overload, the coronary blood flow is normal and the increase in myocardial oxygen con- sumption in mitral regurgitation is only mild. Left ventricular dys- function, manifest by increased end-​systolic diameter, is one of the most important determinants of outcome. Right heart The risk of right heart disease and dysfunction in mitral regurgita- tion is very similar to that in mitral stenosis. The raised left atrial pressure and pulmonary venous pressure are directly reflected on right ventricular systolic pressure. Right ventricular dysfunction as a complication of pulmonary hypertension is an important deter- minant of outcome. Clinical presentation Symptoms Patients with mild mitral regurgitation may not have any symp- toms:  those with severe regurgitation are likely to present with dyspnoea. It is sometimes reported that mitral valve prolapse may be associated with non​specific symptoms such as chest pain and fa- tigue, but this is debatable. section 16  Cardiovascular disorders 3444 Physical examination The patient with non​rheumatic mitral regurgitation is usually in sinus rhythm; but with severe mitral regurgitation of any cause, pa- tients may present in atrial fibrillation. The pulse is likely to be of normal character, but is sometimes reported as ‘jerky’, meaning of normal amplitude but rapid upstroke. The venous pressure is normal unless there is significant pulmonary hypertension or associated tri- cuspid disease. The apex beat may be prominent and displaced, it may be double due to a palpable third heart sound, and there may be a palpable sys- tolic thrill in severe cases. A palpable left parasternal heave may be due to systolic expansion of the left atrium and/​or right ventricular hypertrophy. The first heart sound is normal or soft, the most prominent find- ings on auscultation being an apical pansystolic murmur and a third heart sound. The loudness of the murmur generally correlates with severity of regurgitation, a murmur of less than grade 2/​6 (meaning that it can be heard only with special effort) indicating mild disease, with the notable exception that no murmur may be audible with acute mitral regurgitation (when the mitral valve may effectively be absent). The cardinal signs of mitral prolapse are the mid-​systolic click, due to the backward movement of the mitral leaflet into the left atrium, and the late systolic mitral regurgitation that occurs after the click. The murmur extends throughout systole as mitral regurgi- tation becomes severe. The radiation of a mitral regurgitant murmur depends on the direction of the regurgitant jet. A  posterolateral jet—​seen in is- chaemic mitral regurgitation, anterior leaflet disease, and dilated cardiomyopathy—​radiates from the apex to the axilla, and even to the back. An anterosuperior jet due to posterior leaflet prolapse is heard better at the lower left sternal edge or cardiac base (second right intercostal space, also known as the aortic area), and even on the carotids. Other physical signs depend on the severity of mitral regurgita- tion and possible complications (e.g. pulmonary hypertension). Investigations Chest radiography and electrocardiogram The chest radiograph reflects the haemodynamic disturbance (Fig. 16.6.5). The overall heart size is often normal or only moderately enlarged, with selective enlargement of the left atrium, although not to the same extent as with mitral stenosis (see Fig. 16.6.1). However, considerable cardiac enlargement develops due to secondary left ven- tricular disease if mitral regurgitation is severe and long-​standing. The electrocardiograph (ECG) usually shows sinus rhythm. There may also be evidence of left atrial hypertrophy, left ventricular hypertrophy, and frequent ventricular ectopic beats. Echocardiography Two-​dimensional echocardiography provides a thorough assess- ment of the anatomy and function of the mitral valve apparatus, including the leaflets and annular diameter, as well as left ventricular size and function, left atrial size, and pulmonary artery pressure. The echocardiographic criterion for mitral prolapse is the presence of at least 2 mm of late systolic posterior displacement of the leaflets across the mitral annular plane (Fig. 16.6.6). Severe myxomatous degeneration is associated with thickening of the leaflets and the appearance of extensive folding or redundancy of the leaflets in dia- stole, chordal elongation, and systolic anterior motion of the leaflets. Secondary mitral prolapse can easily be distinguished from primary prolapse in patients such as those with Marfan syndrome, where the leaflets (particularly the anterior) are thin and long, and also in hypertrophic cardiomyopathy, with long leaflets and anterior mo- tion of the mitral valve. Transthoracic echocardiography is perfectly adequate, but transoesophageal echocardiography is recommended if images are limited in quality. Because it is non​invasive, echocardiography is an ideal tool for the follow-​up of patients to allow early identification of worsening of regurgitation or deterioration in ventricular function. Many Fig. 16.6.5  Chest radiograph showing acute pulmonary oedema due to acute mitral regurgitation resulting from ruptured chordae tendineae. Fig. 16.6.6  Transoesophageal echocardiogram from a patient with posterior mitral leaflet prolapse (arrow). LA, left atrium. 16.6  Valvular heart disease 3445 echocardiographic methods for determining the severity of re- gurgitation have been described (Fig. 16.6.7), three-​dimensional reconstruction of the mitral regurgitation jet being a very prom- ising tool for obtaining accurate regurgitant volume assessment since it avoids the conventional cross-​sectional limitations. The extent of left ventricular cavity activity directly reflects the se- verity of volume overload, thus limiting the accuracy of using ejection fraction as a measure of ventricular function in such patients, hence changes in left ventricular end-​systolic volume or dimensions should be taken as a marker of ventricular dys- function. Patients recommended for surgical repair need detailed transthoracic and transoesophageal echocardiographic assess- ment of the anatomy of the valve and subvalvular apparatus to assist surgeons in planning. Findings that support pulmonary hypertension, in particular en- largement of the right side of the heart and increase in the retrograde pressure drop across the tricuspid valve, are easily obtained from a conventional Doppler echocardiographic study. Tricuspid leaflet prolapse is seen in 20% of patients with mitral valve prolapse, but aortic involvement is much less frequent. Cardiac catheterization This is not indicated for diagnostic purposes but may be required for preoperative assessment of the coronary arteries. Differential diagnosis Mitral regurgitation needs to be distinguished from ventricular septal defect (VSD), aortic valve disease, and tricuspid regurgitation. Congenital VSDs are discussed in Chapter 16.12, but the com- monest scenario in adult practice where distinction between mitral regurgitation and VSD needs to be made is the patient who deteri- orates shortly after a myocardial infarction and is found to have a pansystolic murmur. It is impossible to distinguish reliably between the two by physical examination, although if the murmur is heard over the back VSD is most likely. Echocardiography and/​or right heart catheterization with measurement of oxygen tension in the various cardiac chambers are required (see Chapter 16.3.4). The systolic murmur of aortic valve disease can radiate to the apex, and sometimes be louder there than at the base (aortic area). The latter can lead to misdiagnosis of mitral valve disease, and the former can lead to confusion as to whether both aortic and mi- tral valves are diseased. Aside from looking for other evidence of aortic valve disease, the key thing is to establish the precise timing of the murmur. Mitral valve disease should only be diagnosed if the murmur is pansystolic, extending right up to and even obliterating the second heart sound (or right up to the onset of the early diastolic murmur of aortic regurgitation). The murmur of tricuspid regurgitation is typically loudest at the lower left sternal border, is loudest during inspiration, and is associ- ated with elevation of the venous pressure with systolic waves. Management Patients with chronic mitral regurgitation may survive for a long time with no limiting symptoms. Once symptoms develop they suggest the need for surgical correction of valve regurgitation to avoid development of irreversible left ventricular dysfunction. Assessment during routine follow-​up identifies those likely to need surgical intervention even in the absence of symptoms, with an effective regurgitant orifice of over 40 mm2 being the cut-​off recommended value. Although patients with acute regurgitation secondary to papillary muscle rupture need emergency surgery, this does not necessarily apply to those with ruptured chordae or chronic ischaemic regurgitation. Such patients need to be stabilized and other risk factors and comorbidities identified and optimally managed. Medical There is no medical therapy that cures mitral regurgitation or mitral valve prolapse. Endocarditis prophylaxis is recommended for high-​ risk patients with regurgitation, although isolated mitral prolapse in Fig. 16.6.7  Apical four-​chamber views from a patient with coronary artery disease and ischaemic mitral regurgitation at rest (left) and stress (right). Note the significant increase in mitral regurgitation severity with stress as the ventricle became ischaemic. section 16  Cardiovascular disorders 3446 the absence of regurgitation might not be counted as a definite indi- cation. Symptomatic supraventricular arrhythmia needs optimum therapy, usually with β-​blockers, and patients with ventricular tachycardia and syncope should be evaluated for implantable defib- rillator (see Chapter 16.4). Those in atrial fibrillation should be given anticoagulants and INR adjusted at 2.5 to 3.5. Appropriate pacing for dilated cardiomyopathy has been reported as reducing the severity of mitral regurgitation. Vasodilators im- prove prognosis and also reduce preload and the venous return, which improves leaflet coaption and reduces mitral regurgitation. Their effect on the afterload improves the forward flow and also reduces the retrograde flow across the mitral valve. Carvedilol has been shown to reduce long-​axis length over diameter ratio (‘car- diac index’) and reduce mitral regurgitation severity. Similar find- ings have been documented in patients receiving ACE inhibitors or angiotensin receptor antagonists. Surgical Certain factors predict surgical outcome after correction of mitral regurgitation. As might be expected, the more complex the sur- gical procedure the higher the surgical risk. Age-​related opera- tive mortality is of the order of 12% in patients over 75 years of age and 1% in younger patients. Symptoms related to mitral re- gurgitation are important predictors: patients in New York Heart Association (NYHA) classes I and II carry a mortality of 0.5%, but for those in classes III and IV it is 10% or more. The aetiology of mitral regurgitation is another determinant, with 1–​3% mortality in rheumatic mitral valve disease, compared to 9% in ischaemic mitral regurgitation. Ventricular dysfunction adds to the surgical risk, in par- ticular having an end-​systolic dimension greater than 45–​50 mm. However, recent data suggest that even significant left ventricular dysfunction should not be used as an exclusion criterion for cor- rection of mitral regurgitation, although the general belief re- mains that a systolic dimension of more than 50 mm indicates a poor prognosis and that surgical intervention is unlikely to be of benefit. Pulmonary hypertension is another important predictor of outcome that carries a poor prognosis: correction of mitral regur- gitation does not always guarantee normalization of pulmonary artery pressure, particularly if long-​standing, which indicates that surgical intervention should be considered before development of this complication. Mitral valve prolapse accounts for approximately 25% of mitral valve surgical procedures. The benefit of surgical intervention and ring insertion into patients with dilated cardiomyopathy remains controversial. Mitral valve repair The intention of mitral valve repair is to preserve the integrity of the valve, which—​if successful—​results in a much better clinical out- come for patients with mitral regurgitation than does valve replace- ment. Preservation of the chordal attachment is crucial, keeping the continuity between the mitral leaflets and the papillary muscles which control the long-​axis function of the left ventricle. This itself also affects the sphericity of the left ventricle and hence overall per- formance of the cavity. Mitral valve repair avoids the use of anticoagulants that are needed for life in patients with mechanical prostheses, and even those who develop atrial fibrillation from mitral valve repair might not need the higher dose of anticoagulants necessary for those who receive a mechanical valve. The risk of endocarditis is much lower from mitral valve repair compared to replacement. As for any operation, patient selection for mitral valve repair is important. Although historical results of mitral valve repair for rheumatic regurgitation showed a success rate of 50%, better re- sults have been reported recently, with a reoperation in approxi- mately 20% of patients at 10 years. Surgical repair for rheumatic mitral valve disease is also affected by rheumatic aortic and tri- cuspid valve disease. The most common procedure is the quadrilateral resection of the posterior leaflet, removing excess valve tissue, reapproximating the scallops, and reducing the annulus, with or without mitral annuloplasty. The success rate of this technique is of the order of 90%. Although historically anterior leaflet repair was not so easy as that of the posterior leaflet, recent advances have made it as suc- cessful. An alternative approach (not widely accepted in the surgical community) is the Alfieri repair, which involves suturing the pos- terior and anterior leaflets together in the central section and cre- ating a double-​orifice mitral valve. Non​surgical mitral-​clip insertion has emerged as a replacement for repair procedures where the surgical risk is high. This procedure involves transcatheter implantation of a clip that hooks the tips of the anterior and posterior leaflets, thus creating a double-​orifice mitral valve and reducing the extent of regurgitation. Early post-​ procedure results are satisfactory, but patients may continue to com- plain of breathlessness secondary to left ventricular stiffness rather than mitral regurgitation. It is now routine practice to use intraoperative transoesophageal echocardiography to provide detailed assessment and detect signs of valve dysfunction immediately on completion of surgery on the valve:  residual regurgitation can be dealt with before closure of the chest. In addition to mitral repair, patients with atrial fibrillation may be considered for arrhythmia ablation—​surgically or by radiofrequency—​to restore sinus rhythm. Results of the combined procedure have been satisfactory, even with chronic atrial fibrilla- tion before surgery. Mitral valve replacement Mitral valve replacement has a higher operative mortality than aortic valve replacement for aortic stenosis or regurgitation, or con- servative operation for mitral stenosis. Although survival from mi- tral valve replacement surgery has improved significantly over the years, probably because of the better selection, improved myocardial preservation, and surgical techniques, it remains of concern, par- ticularly in patients with ischaemic mitral regurgitation, where 5-​ year survival is 75%. The ideal valve would be a homograft in the mitral position, but this can only be achieved by use of a composite including the mitral valve and related structures and placing it attached to the annulus, which avoids cutting the papillary muscle heads and the chordae and preserves the continuity between the mitral valve apparatus and the left ventricle. However, such attempts have proved uniformly un- successful. Pulmonary autograft has been used in the mitral position with satisfactory results, but in only a small group of patients in one or two centres. 16.6  Valvular heart disease 3447 Mitral replacement by a mechanical valve or bioprosthesis is the only option for irreparable valves. It has a very satisfactory success rate, particularly when papillary muscles and chordae are preserved. Bileaflet or tilting disc are currently the most commonly used mech- anical valves. Mixed mitral valve disease Mixed mitral disease is nearly always due to rheumatic valve disease. In general, it occurs in older patients than pure mitral stenosis, and the valve is more likely to be calcified with limited cusp mobility and scarred subvalve apparatus. The mitral regurgitation is not usually severe, but the increased stroke volume increases the diastolic pres- sure drop across the valve. Symptoms are the same as for mitral stenosis or regurgitation. On examination the first heart sound is not palpable or loud, the pansystolic murmur is usually loudest towards the axilla, and there is a mid-​diastolic murmur. The chest radiograph (Fig. 16.6.8) may show more advanced changes than in pure mitral stenosis (see Fig. 16.6.1):  the left atrium can be extremely large. Echocardiography is likely to show thickened cusps with reduced motion in addition to mitral re- gurgitation. When symptoms merit, valve replacement is usually required. Aortic valve disease Aortic stenosis Causes Aortic stenosis is caused by congenital, rheumatic, or senile disease. It may be at subvalvar, valvar, or supravalvar level, the commonest being valvar stenosis. Age-​related degenerative calcific disease is now the commonest cause of aortic stenosis in western Europe and the United States of America. The commonest congenital valvar aortic disease is the bi- cuspid aortic valve, which may remain completely silent for years, but as age advances the leaflets become thickened and calcified re- sulting in significant reduction in valve area, raised transvalvar vel- ocities, and pressure drop (gradient) across the valve. Rheumatic aortic stenosis is nearly always associated with aortic regurgitation (‘mixed aortic valve disease’) and with rheumatic mitral disease. Symptomatic valvar aortic stenosis is more prevalent in men. Subvalvar aortic stenosis is caused by a membrane (shelf) or a hypertrophied upper septal segment bulging into the outflow tract. Subaortic membrane is a congenital anomaly that commonly pro- gresses with age. Hypertrophy of the upper septum is an acquired syndrome that affects older people, particularly those with long-​ standing hypertension. Supravalvar aortic stenosis is rare:  when found it is commonly part of Williams’ syndrome (OMIM 194050; ‘elfin’ facies with low nasal bridge, unusual behaviours and mental retardation, transient hypercalcaemia; supravalvar aortic stenosis). Pathophysiology and complications In addition to the anatomical narrowing of the aortic valve, left ventricular function plays an important role in determining the transvalvar velocities. Patients with severe aortic stenosis and poor left ventricular function may have underestimated velocities and pressure drop. By contrast, those with mild valve narrowing but a hyperactive ventricle (e.g. hyperdynamic circulation) may present with overestimated velocities across the valve; in particular, signifi- cant aortic regurgitation can lead to overestimation of the degree of valve stenosis because of increased stroke volume. Despite various attempts to determine the most sensitive marker of aortic sten- osis, valve gradient (pressure drop) remains the most appropriate measure in clinical practice. Left ventricular response With the increase in outflow tract resistance in aortic stenosis, left ventricular wall stress increases and hypertrophy develops. This compensatory mechanism preserves overall ventricular systolic function. Most patients develop concentric left ventricular hyper- trophy and increased mass, which regresses after removal of the stenosis. Patients with untreated aortic stenosis may present very late with left ventricular cavity dilatation, reduced ejection fraction, and dyssynchrony. Left ventricular subendocardial ischaemia may result from long-​standing ventricular hypertrophy and outflow tract obstruction, and diastolic left ventricular function also become im- paired, resulting in increased end-​diastolic pressure and left atrial pressure. Most patients with aortic stenosis who are allowed to reach this degree of ventricular dysfunction complain of progressive breathlessness and finally pulmonary oedema. Fig. 16.6.8  Chest radiograph of a patient with mixed mitral valve disease, showing gross cardiac enlargement, mainly due to dilatation of the left atrium. section 16  Cardiovascular disorders 3448 Coronary circulation Even in the absence of significant coronary artery disease (ath- erosclerosis), the coronary circulation plays an important role in the pathophysiology and clinical presentation of aortic stenosis. Proximal coronary artery size is often increased, probably as a com- pensatory mechanism for the increased myocardial oxygen demand because of left ventricular hypertrophy, but coronary flow reserve re- mains suboptimal. This limited coronary flow reserve is manifested in the subendocardium, which may become irreversibly damaged, and the more severe the aortic stenosis, the greater the impairment of subendocardial function. Furthermore, left ventricular relaxation is usually prolonged in left ventricular hypertrophy, which further reduces coronary flow. The combination of hypertrophy-​related altered coronary flow and increased myocardial work probably contributes to the angina-​like symptoms, even in the absence of epi- cardial coronary disease. Regression of left ventricular hypertrophy after aortic valve replacement improves coronary flow reserve. Clinical presentation Symptoms Mild aortic stenosis does not give any symptoms, and even severe stenosis may be silent. Breathlessness or exercise intolerance is the most common symptom. Progressive deterioration of left ven- tricular function and increased end-​diastolic pressure leads to acute pulmonary oedema and florid heart failure. Angina is the second most frequent symptom, but less common than breathlessness. When it happens, it represents a significant mismatch between myo- cardial oxygen supply and demand, and it may be exercise limiting even in the absence of epicardial coronary artery disease. The third symptom is syncope, which in some patients is clearly related to ex- ertion. This can be caused by reduced cardiac output due to out- flow tract obstruction, or by arrhythmia (transient atrioventricular block, ventricular arrhythmia, and carotid sinus hypersensitivity have all been described), with exercise-​induced peripheral vasodila- tation in the face of a fixed cardiac output the likely explanation for those who collapse when exercising. Physical examination The physical signs of significant aortic stenosis are very character- istic. Proper examination of the character of the pulse is crucial: a slowly rising, low-​amplitude carotid (or brachial) pulse has high specificity for diagnosing severe aortic stenosis, and there may be a carotid thrill. Arterial pulse pressure is narrow. The venous pressure is usually normal until late in the disease, but a small ‘a’ wave is often present. This is known as a Bernheim ‘a’ wave and appears to be related in some poorly understood way to the presence of left ventricular hypertrophy and atrial cross- talk: it should not be taken in isolation as evidence of pulmonary hypertension. The apex beat is often sustained and may be double, due to an add- itional left atrial impulse. On palpation of the precordium there may be a systolic thrill over the aortic area in severe cases. On auscultation the first heart sound is normal or soft, and may be preceded by a fourth heart sound. The characteristic long and harsh ejection systolic murmur is loudest at the base (second right intercostal space, also known as the aortic area) of the heart, and in most cases it radiates to the carotids. The murmur is often heard at the lower left sternal border, and in a minority the ejection sys- tolic murmur may also be referred to the apex. A systolic ejection click may be heard, typically in patients with an uncalcified bicuspid valve. The second heart sound in aortic stenosis is typically single because of the limited cusp movement in a heavily calcified valve, but in young patients with severe aortic stenosis and mobile leaf- lets the splitting of the second sound is reversed. A normal split-​ second heart sound is a reliable sign for mild aortic stenosis. A third heart sound may be heard when left ventricular cavity dilatation and raised left atrial pressure have developed. A soft early diastolic murmur is often present, which does not necessarily imply haemo- dynamically significant aortic regurgitation. It is important to note that these physical signs are modified as ventricular disease progresses and stroke volume falls. Pulse volume drops and the pulse loses its slow rising quality, the systolic murmur becomes shorter and softer and may even disappear, and a func- tional mitral regurgitant murmur can appear along with a third heart sound. Such ‘silent’ but critical aortic stenosis cannot be diagnosed reliably on the basis of physical signs: a high index of suspicion and a good-​quality echocardiogram are required to prevent misdiagnosis of ‘congestive cardiomyopathy, cause unknown’. Investigations Chest radiograph and electrocardiogram The chest radiograph may be completely normal in patients with uncomplicated aortic stenosis. Post-​stenotic dilatation of the as- cending aorta may be seen. Associated left ventricular disease leads to pulmonary venous congestion. In most patients the ECG shows evidence of left ventricular hypertrophy based on voltage criteria, but in some cases it can be completely normal. Advanced hypertrophy may be associated with non​specific T-​wave changes. With progressive left ventricular dys- function, QRS duration broadens and left bundle branch block may develop. Inverted U wave may be seen in patients with severe left ventricular disease. Echocardiography Echocardiography is the investigation of choice for patients with aortic stenosis, providing comprehensive information on valve anatomy and function and left ventricular size and function, as well as other associated cardiac abnormalities that may contribute to patient’s symptoms (e.g. mitral valve regurgitation). Transthoracic echocardiography is mandatory in all patients with suspected aortic stenosis. Transoesophageal echocardiography may assist in exam- ining the aortic root and the proximal ascending aorta. The most clinically valuable measure of severity of aortic sten- osis is transvalvular velocity using continuous-​wave Doppler. The blood flow sounds under two-​dimensional echocardiographic guid- ance assist in deciding on the optimum positioning of the probe for velocity recordings, with the beam as parallel as possible to the jet direction. Peak velocities across the aortic valve are converted into a pressure drop (pressure gradient) using the modified Bernoulli equation, P = 4V2. Timing of peak velocity across the valve is a good indicator of the degree of aortic stenosis: in mild stenosis velocities peak in early sys- tole, but in severe stenosis velocities peak in mid-​systole, in parallel with the rise in aortic pressure. 16.6  Valvular heart disease 3449 Aortic stenosis can be quantified as valve area, which can be cal- culated from Doppler velocity data using the continuity equation based on the fact that the flow rate across the stenotic valve and the normal subvalvar area are equal. Valve area is therefore calculated from the relative increase in blood velocity across the aortic valve with respect to the subvalvar region, in conjunction with an estimate of the subvalvar cross-​sectional area. Thus, an increase in peak vel- ocity across the aortic valve by five times that of subvalvar velocity, with a pressure gradient of at least 35 mm Hg, is consistent with a fivefold drop in aortic valve area and suggests severe aortic stenosis (Fig. 16.6.9). An important application of this principle is seen in patients who have a moderate aortic pressure drop and in whom it is not clear whether this is simply because stenosis is not severe, or because stroke volume is low due to impaired left ventricular function. Stress echocardiography is a useful investigation in these circumstances (Fig. 16.6.10). With increase in heart rate, the increased blood flow across the valve differentiates between severe valve narrowing and severe left ventricular disease. A significant increase in transvalvular velocities and pressure gradient reflects fixed valve area and hence the diagnosis of severe aortic stenosis. By contrast, failure of aortic velocities to increase significantly with stress suggests impaired left ventricular function as the cause of the low cardiac output and symptoms rather than aortic stenosis. Colour-​flow Doppler will reveal the presence of mild aortic re- gurgitation in most patients with aortic stenosis, and in those with 0.2m/s 1 m/s Fig. 16.6.9  Parasternal long-​axis views from a patient with severe calcific aortic stenosis (arrow) and poor left ventricular function showing a dilated cavity with increased end-​systolic dimension (LV). Transvalvar peak velocity of 3.0 m/​s (upper right panel) and subvalvar velocity of 0.6 m/​s (lower right panel). 1 m/s 55 mm Hg 120 mm Hg Fig. 16.6.10  Continuous-​wave Doppler of transaortic valve velocities at rest (left panel) and peak stress (right panel) showing significant increase in velocities and consequently gradient from 55 to 120 mm Hg. section 16  Cardiovascular disorders 3450 impaired left ventricular function and raised end-​diastolic pressure Doppler recordings of aortic regurgitation should be assessed care- fully to avoid overestimating the degree of regurgitation because of raised left ventricular end-​diastolic pressure. Echocardiography can also provide accurate measurements of left ventricular dimensions and systolic function, as well as left ventricular hypertrophy and mass, from which mass index can be calculated. Left ventricular filling pattern guides the assessment of left atrial pressure. Most patients with aortic stenosis and left ventricular hypertrophy have a small early diastolic filling com- ponent and a dominant late-​diastolic one. With progressive left ventricular disease and increase in end-​diastolic pressure, the left atrial pressure increases and ventricular filling becomes of the re- strictive pattern, with a dominant early diastolic filling component with short deceleration time and a very small late-​diastolic filling component with flow reversal in the pulmonary veins. Most pa- tients presenting with this pattern of physiology have a dilated left atrium and some may even present with atrial arrhythmia. The ex- tent of the commonly found mitral regurgitation can also be as- sessed, and other parameters enable estimation of the presence and degree of pulmonary hypertension. Mitral annular calcification is a very common finding in patients with severe aortic stenosis but rarely contributes to any increase in atrial pressure or results in mitral stenosis. Cardiac catheterization High-​standard echocardiographic estimation of the severity of aortic stenosis is clinically very reliable and does not need to be reconfirmed by catheterization. The traditionally measured aortic pressure gradient during cardiac catheterization, using a pull-​back technique to record the difference between peak left ventricular and aortic pressure, is a less satisfactory measure than that possible echocardiographically because the two peaks do not occur simul- taneously. A further problem with estimation of aortic gradient by cardiac catheterization occurs because left ventricular pressure may not be uniform, hence the measured pressure difference depends on the location of catheter tip in the ventricle, particularly in the pres- ence of significant hypertrophy as in most cases of aortic stenosis. The difficulty increases since aortic pressure also depends on its dis- tance from the valve leaflets and the aortic wall, as well as the pres- sure recovery process in the aortic root. Such estimates should thus be regarded as semiquantitative. Cardiac catheterization is needed only to assess possible coronary artery disease, which frequently accompanies aortic stenosis. CT coronary angiography can now provide similar information. Differential diagnosis The commonest differential diagnosis that needs to be considered is aortic sclerosis, when examination of an elderly patient reveals an ejection systolic murmur at the cardiac base or left sternal edge. Other features of aortic stenosis—​slow rising pulse, narrow pulse pressure, radiation of the murmur to the carotids, presence of a thrill—​are not present. Most often in a younger patient the possibility of hypertrophic cardiomyopathy needs to be considered, but here the carotid pulse is normal or jerky rather than slow rising (see Chapter 16.7.2). Fixed subaortic stenosis also needs to be considered in children and young adults (see Chapter 16.12). All of these differential diagnoses can be distinguished from aortic stenosis by echocardiography. Management Progression of aortic stenosis is generally slow. Symptoms are vari- able but overall reflect left ventricular disease. Patients with a con- genital bicuspid aortic valve tend to develop symptoms at an average age of 50 years, whereas those with senile valve disease do so at the age of 70–​80 years. Patients with significant congenital aortic valve stenosis may develop symptoms earlier in life. Some 50% of patients with severe aortic stenosis die suddenly. Raised aortic velocities and gradient, and the rate of increase in velocities over time, are the most accurate predictors of outcome, the rate of deterioration being faster in senile disease than rheum- atic aortic stenosis. Once symptoms develop the outcome is poor without surgical intervention, with 5-​year survival less than 50%. Autopsy series showed that the average time from symptom de- velopment to death is 2 years in patients with exertional syncope, 3 years in those with dyspnoea, and 5 years in those with angina. It should be highlighted that prognosis is much better in patients with a high valve gradient rather than those with low gradient due to severe left ventricular disease. Recent data suggests that patients presenting with an ejection fraction below 20% fail to thrive even after successful aortic valve replacement surgery. Approximately 50% of adults with aortic stenosis who need sur- gery have additional coronary artery disease. Patients with angina-​ like symptoms who have only mild aortic stenosis are likely to have significant epicardial coronary disease, but a new onset of angina in patients with severe aortic stenosis may reflect a further deterior- ation of the degree of aortic stenosis and subendocardial ischaemia. A particularly difficult group of patients to manage is those with moderate aortic stenosis and angina-​like symptoms. Medical There is no medical treatment for aortic stenosis that will stop dis- ease progression. Asymptomatic patients with mild or moderate aortic stenosis require follow-​up; those with severe aortic stenosis need aortic valve replacement. It is prudent to advise those with moderate or severe disease to avoid strenuous exercise. A pressure gradient of more than 70 mm Hg across the aortic valve is a good indication for surgery, particularly in those who are symptomatic. Patients with severe aortic stenosis and left ventricular disease who present with heart failure should be stabilized before referral for sur- gery: diuretics are important, as well as β-​blockers for controlling the heart rate; vasodilators, including ACE inhibitors, are contra- indicated. Once a patient develops raised left atrial pressure and pulmonary hypertension the outcome is less than satisfactory, even with surgery. Instructions on endocarditis prophylaxis and the use of antibiotics before dental and surgical procedures should be given to high-​risk patients. Patients with other comorbidities and risks, in particular hyperlipidaemia, should have these addressed. The effect of statins on the rate of progression of aortic stenosis seems to be negligible. Surgical Recent advances in aortic valve surgery—​earlier intervention, changes in the procedures used, improved methods of myocardial preservation—​have resulted in a significant fall in surgical mortality, 16.6  Valvular heart disease 3451 to 2.0% in adults under 70 years of age. Concurrent coronary artery disease, ventricular dysfunction, and pulmonary hypertension are important surgical risks. Older patients with aortic stenosis, particu- larly those over the age of 80 years, tend to have a higher mortality, but age is not a contraindication to surgery. Surgical intervention in octogenarians has been shown to provide improvement in quality of life, with a 5-​year postoperative survival compared to only 1 year for the unoperated. Aortic valve repair  In young people aortic valvotomy is an ac- ceptable procedure, but the option of valve repair in adults remains uncertain. It may provide a medium-​term solution for a clinical problem, but further surgical intervention will definitely be required in the long term. Aortic valve replacement  • Tissue valves Tissue valves do not need anticoagulants in the absence of atrial fib- rillation. Although their durability is significantly lower than that of mechanical valves, indications for their use are clear: older people, young pregnant women, and patients with limited access to anti- coagulant therapy. Over the years the durability of tissue valves has significantly improved: for patients over the age of 60, modern, third-​generation, glutaraldehyde-​preserved valves provide 90% survival at 15 years. Stentless tissue valves have better durability and are associated with faster recovery of ventricular function, but they are more difficult to implant. • Homografts The best option to replace a native valve is a human valve (homo- graft), but availability is limited. An aortic valve homograft replace- ment is particularly indicated in patients with endocarditis that involves the aortic root and is associated with abscess formation, be- cause a mechanical valve replacement in this scenario compromises eradication of the infection. Aortic homograft implantation tech- niques have evolved from a two-​layer subcoronary implantation to conduit implantation, which involves replacing the valve and sinus of Valsalva by a full root and valve. This still is considered more chal- lenging than mechanical or tissue valve implantation. Under the age of 30 years aortic homografts tend to fail within 10 years: in older patients the mean survival of the valve is 15 to 18 years. • Pulmonary autograft An alternative procedure is the pulmonary autograft or ‘Ross pro- cedure’. This goes back to 1967 when Donald Ross transferred a patient’s own living pulmonary valve to the aortic position and inserted a homograft in the pulmonary position. In children these autograft valves, unlike any other valve substitute, are capable of growth. A pulmonary homograft is placed in the right ventricular outflow tract, where because of the lower pressures on the right side of the circulation the mean survival of the valve is 20 years. • Mechanical valves Over the years, technical improvement in valve design has been remarkable, providing larger orifice area and greater resistance to thrombosis. In the long term the commonest problem, affecting less than 5% of patients with mechanical prostheses, is paravalvular dehiscence. While this may not always be haemodynamically significant, it may be responsible for haemolytic anaemia due to shear stress on red blood cells, and it is a focus for infective endocar- ditis. Valve dysfunction due to subvalvar tissue ingrowth that influ- ences valve opening and closure remains a problem. • Transcutaneous aortic valve implantation A transcatheter stent-​mounted bioprosthesis is an alternative to surgical aortic valve replacement in patients with impaired left ven- tricular function, prior coronary artery bypass surgery, or other comorbidities (e.g. renal impairment or chronic obstructive pul- monary disease). The procedure has proved a great success in pa- tients with heavily calcified aortic root and valve. Long-​term clinical results of the transcatheter aortic valve implantation (TAVI) pro- cedure are similar to those of surgical aortic valve replacement, des- pite a slightly higher prevalence of stroke. Aortic regurgitation Causes Aortic regurgitation is caused by either leaflet disease or aortic root dilatation (Table 16.6.2), the commonest causes being iso- lated medionecrosis, rheumatic disease, infective endocarditis, and Marfan syndrome. Pathophysiology and complications The left ventricular stroke volume, which equals the forward stroke volume plus the regurgitant volume, is significantly increased in aortic regurgitation. This is accommodated by an increase in left ven- tricular cavity size, a process that is progressive in a similar fashion to mitral regurgitation, although the degree of ventricular dilata- tion is greater. Another difference between the two conditions is the peripheral vascular resistance, which is significantly raised only in patients with aortic regurgitation. This combination of volume over- load and raised peripheral resistance results in a progressive increase in left ventricular wall thickness and mass. In uncomplicated aortic regurgitation, the left ventricular ejection fraction is maintained, but as the disease progresses end-​systolic volume increases out of pro- portion to stroke volume, and eventually these changes lead to irre- versible damage which persists even after surgical correction of the aortic regurgitation. Table 16.6.2  Causes of aortic regurgitation Structure primarily affected Anatomical defect Cause Cusp Distortion Rheumatic Rheumatoid Ergot-​derived dopamine receptor agonists—​ pergolide, cabergoline (treatments for Parkinson’s disease) Fenfluramine, phentermine (appetite suppressants) Perforation Infective endocarditis Root disease Dilatation Isolated medionecrosis Marfan syndrome Syphilis Ankylosing spondylitis or other connective tissue disease Loss of support Dissecting aneurysm of aortic root Subaortic ventricular septal defect section 16  Cardiovascular disorders 3452 Whether or not aortic regurgitation is accompanied by some degree of aortic stenosis due to intrinsic valve leaflet disease, the increase in stroke volume causes high systolic velocities across the aortic valve. Pressure relations between the aorta and the left ventricle in diastole are of great importance, in particular the end-​ diastolic pressure difference that depends not only on aortic but also on left ventricular end-​diastolic pressure: the higher the left ventricular end-​diastolic pressure, the lower the pressure difference across the valve. In mild aortic regurgitation the pressure drop between the aorta and the left ventricle is maintained throughout diastole. By contrast, with acute aortic regurgitation the pressure difference between the aorta and the left ventricle falls to 15 mm Hg or even less before end of diastole, either because of the very low resistance at the valve level or because the left ventricle is stiff, hence a relatively small regurgitant volume causes a disproportionate rise in left ventricular diastolic pressure. This disturbed physiology has major implications because the aortic–​left ventricular diastolic pressure gradient is the pressure head supporting the coronary flow. Coronary autoregulation stops at a perfusion pressure difference between the aorta and the left ven- tricle of 40 mm Hg, and with acute aortic regurgitation—​or even severe chronic aortic regurgitation—​the gradient is less than this, resulting in significant myocardial ischaemia and progressive ven- tricular dysfunction. This disturbed physiology may be tolerated in chronic severe aortic regurgitation, but in acute severe aortic regur- gitation it may contribute to rapid clinical deterioration. The limitation of coronary flow by a raised ventricular end-​ diastolic pressure is further exacerbated by the increased oxygen demand of the myocardium as a result of the hyperdynamic ven- tricular state, as well as (in chronic regurgitation) the hypertrophy resulting from the volume overload. This causes subendocardial is- chaemia, particularly with stress. Clinical presentation Symptoms Patients with aortic regurgitation may remain asymptomatic for a long time. The onset of symptoms, particularly breathlessness, co- incides with the onset of left ventricular disease, a significant rise in end-​diastolic pressure, and development of pulmonary venous hypertension. Angina is an uncommon symptom in chronic aortic regurgitation, but when it occurs it should suggest significant subendocardial ischaemia as a result of the mismatch between the coronary artery flow and myocardial mass. It is more common in those with acute aortic regurgitation. Any sudden worsening of symptoms may reflect acute deterioration of the degree of aortic re- gurgitation or impairment of left ventricular function. Physical examination The physical signs of significant chronic aortic regurgitation are characteristic. The pulse has large amplitude and is ‘collapsing’ in nature (‘water hammer’, Corrigan’s pulse) due to the increased stroke volume and rapid fall-​off in aortic pressure during diastole. When severe, this can induce pulsations in many parts of the body, generating many eponyms that describe what is effectively a single physical finding. Among the better known of these are Quincke’s ca- pillary pulsations (best demonstrated by blanching a portion of a fingernail by applying gentle pressure and observing the pulsating border between the white and the red segments), de Musset’s sign (bobbing of the head in time with the arterial pulse, named after the French poet who had the condition), and pulsations of various organs or their parts (uvula—​Muller’s sign, retinal arteries—​Becker’s sign). The same pathophysiology underlies two peripheral arterial signs. Pistol shot sounds are short, loud sounds that can be heard over large peripheral arteries if the stethoscope is lightly applied: they occur because of sudden expansion and tensing of the walls during sys- tole. Duroziez’s sign is a double to-​and-​fro (systolic and diastolic) murmur heard over the brachial or femoral artery if the stethoscope is firmly applied: the diastolic component results from reversal of flow in the artery during diastole. A diastolic blood pressure of less than 50 mm Hg and/​or a pulse pressure of 80 mm Hg or more suggest moderate or severe regurgi- tation in patients who have a characteristic murmur (but are of no significance with regard to the aortic valve if no murmur is present). The venous pressure is normal until late in the course of disease, although a dominant Bernheim ‘a’ wave may be seen. The apex beat is sustained and/​or displaced because of the left ventricular hyper- trophy and/​or dilatation. On auscultation the classical murmur of aortic regurgitation is diastolic, starting immediately after the second heart sound, de- crescendo in nature, and loudest at the left sternal border. It may be short, or extend throughout diastole. It may radiate to the right sternal border if it is caused by aortic root dilatation, and rarely it is loudest at the apex or even in the left axilla. The louder the murmur, the more severe is the regurgitation. The heart sounds may not dem- onstrate any specific change in aortic regurgitation, or—​as with aortic stenosis—​the aortic component of the second heart sound may be absent. An ejection systolic murmur due to increased stroke volume is nearly always present. At the apex, a low-​pitched mid-​ diastolic murmur (Austin–​Flint murmur) mimicking that of mitral stenosis may be heard: it is usually assumed that this is due to the aortic regurgitant jet striking the anterior leaflet of the mitral valve, but other hypotheses have been advanced. In acute aortic regurgitation—​usually caused by infective endo- carditis, thoracic aortic dissection, or disintegration of a tissue valve replacement—​the physical signs are quite different, based on the fact that the stroke volume in acute regurgitation does not increase by the same magnitude as in chronic regurgitation. The patient is cold and shut down due to a low cardiac output, with tachycardia, a low systolic blood pressure and low pulse pressure, and a short early dia- stolic murmur that is easily missed. The apex is not displaced and peripheral signs are absent. There may be a loud third heart sound. Investigations Chest radiograph and electrocardiogram The chest radiograph may show increased cardiothoracic ratio and dilatation of the aortic root (Fig. 16.6.11). In isolation these appear- ances cannot be taken as diagnostic, but they are very useful for follow-​up of a known case. The 12-​lead ECG may demonstrate increased voltage and a ‘strain’ pattern that correlates with increase in left ventricular cavity dimen- sions, hypertrophy, and wall stress. The voltage pattern may fall sig- nificantly after correction of the aortic regurgitation and regression of left ventricular mass. Non​specific T-​wave changes may occur with exercise, reflecting either the development of subendocardial 16.6  Valvular heart disease 3453 ischaemia or increase in systolic left ventricular volume. Increased QRS duration is a marker of left ventricular disease. A  long PR interval may indicate aortic root abscess, particularly in those with other clinical suspicion of endocarditis. Echocardiography Doppler echocardiography is an invaluable investigation in the assessment of patients with aortic regurgitation (Fig. 16.6.12). Two-​dimensional images can identify the exact cause of regurgi- tation, revealing the valve anatomy, leaflet number, calcification, or evidence of infection. The diameter of the aortic root and prox- imal ascending aorta can also be measured. Transoesophageal examination is always recommended if this is not achievable on transthoracic images, particularly in patients with Marfan syn- drome or those presenting with suspected dissection. Left ven- tricular size, dimensions, wall thickness, and ejection fraction can easily be measured, and muscle mass calculated using simple for- mulae. Colour Doppler detects the presence of aortic regurgita- tion and gives some idea of its severity: the finding of large vena contracta, a large regurgitant orifice area, and jet diameter more than 50% of the aortic root diameter are all consistent with signifi- cant regurgitation. Continuous-​wave Doppler is ideal for assessing regurgitation severity as well as pressure differences between the aorta and the left ventricle (Fig. 16.6.13): in general, the faster the pressure decline on the aortic regurgitation trace, the more severe is the regurgitation likely to be, although this does not apply in patients with raised end-​diastolic pressure. Doppler can also con- firm severity of aortic regurgitation by demonstrating flow re- versal in the descending aorta or femoral arteries. In patients with symptoms disproportionate to the degree of aortic regurgitation, a diagnosis of left ventricular disease should be considered (e.g. hypertension or coronary heart disease). In acute aortic regurgitation echocardiography clearly demon- strates the cause of the disease; endocarditis with its complications or disintegrating homograft or bioprosthesis. M-​mode echocardi- ography shows premature mitral valve closure which, together with the left ventricular activity, support the diagnosis of acute aortic regurgitation. Fig. 16.6.11  Chest radiograph of a patient with chronic aortic regurgitation showing cardiac enlargement and dilatation of the ascending aorta. Fig. 16.6.12  Transoesophageal echocardiogram from a patient with aortic regurgitation on colour-​flow Doppler. Fig. 16.6.13  Continuous-​wave Doppler from the same patient as shown in Fig. 16.6.12, showing significant regurgitation based on the rate of transvalvar pressure decline in diastole (between the arrows). section 16  Cardiovascular disorders 3454 Cardiac catheterization Cardiac catheterization is not needed to assess the severity of aortic regurgitation: it is only needed to confirm the presence of additional coronary artery disease, particularly before surgical intervention. Differential diagnosis It can sometimes be difficult to distinguish the early diastolic murmur of aortic regurgitation from that caused by pulmonary re- gurgitation (Graham Steell murmur). In this circumstance no other features of aortic regurgitation are expected, and pulmonary regur- gitation is usually associated with other signs indicating the presence of significant pulmonary hypertension (including a large pulmonary artery on the chest radiograph). Other causes of aortic run-​off, including persistent ductus arteriosus, ruptured sinus of Valsalva aneurysm, and coronary ar- teriovenous fistula, can also produce auscultatory findings that can be confused with aortic incompetence. However, they all cause a continuous murmur, rather than one confined to diastole. Management It is uncommon for mild aortic regurgitation to progress rapidly to severe regurgitation, hence the importance of Doppler echocardi- ography in the follow-​up of patients. Identification of the cause of aortic regurgitation helps in determining how often patients should be reviewed: those with mild aortic regurgitation due to aortic root or ascending aorta disease should be followed up more closely than those with stable valve disease. Patients with moderate or severe aortic regurgitation may have no symptoms for years. As symptoms always reflect ventricular dysfunction, a progressive increase in end-​systolic dimension/​volume should be taken as an indication for serious consideration of surgery, even in the absence of symptoms. Ejection fraction cannot be taken as a marker of ventricular function in aortic regurgitation because of the volume overload and overesti- mation of the ejection performance: an end-​systolic dimension up to 40 mm carries a good prognosis, whereas a dimension more than 50 mm is associated with 20% possibility of developing ventricular dysfunction, symptoms, or even death over a course of 5 years. In the same way that patients with aortic regurgitation secondary to aortic valve disease are managed, those with aortic regurgitation associated with or causing aortic root dilatation should be followed up to assess the aortic root dimensions, with the aim of preventing progressive dilatation and the potential risk thereof. Some patients with a bicuspid aortic valve develop progressive dilatation of the aortic root and ascending aorta because of the eccentric jet, as well as the accompanying aortopathy. Another group of patients who need regular follow-​up and careful aortic root assessment are those with Marfan syndrome, in whom aortic root aneurysmal dilatation and dissection are the major causes of morbidity and mortality. In addition to using conventional Doppler echocardiography, CT scan- ning and MRI can play a useful role in the follow-​up of patients with aortic root or ascending aorta disease, and three-​dimensional echo- cardiography for assessment of left ventricular size and function (see Chapters 16.3.2 and 16.3.3 for further discussion). Medical Medical management in aortic regurgitation aims at slowing down its progression, supporting the left ventricle, and determining the optimal time of surgical intervention. The increased afterload in patients with aortic regurgitation should be managed medically to reduce the wall stress and the diastolic driving pressure across the valve. Doing so decreases the pressure and the volume overload on the left ventricle and prevents progressive left ventricular dilatation and systolic dysfunction, and can delay the need for surgery. This effect has been demonstrated using ACE inhibitors and calcium channel blockers, the choice of the pharmacological agent for left ven- tricular afterload reduction depending on the other comorbidities (e.g. coronary artery disease), as well as patient tolerance. Patients with aortic root dilatation should not be treated with vasodilators alone. In this instance β-​blockers are recommended because they decrease aortic wall stress, blood pressure, and the rate of pressure increase in systole. Although patients with Marfan syn- drome may remain completely asymptomatic, the rate of aortic root dilatation is the most important risk factor. It may be that the com- bination of β-​blockade with ACE inhibition/​angiotensin receptor blockers (possibly acting through inhibition of TGF​β signalling) may prove effective in retarding or even preventing dilatation. However, when dilatation does occur, previous guidelines have suggested that aortic root dimension larger than 55 mm is a good indication for surgical intervention, although recent recommenda- tions have advocated an earlier surgical approach, particularly in the presence of family history of dissection. See Chapter 16.11 for further discussion. As is the case with all valve disease, oral hygiene should be en- couraged in patients with aortic regurgitation and prophylactic antibiotics prescribed to cover dental, proctological, urological, and gynaecological surgeries for patients at risk. Surgical Although patients with severe chronic aortic regurgitation may re- main asymptomatic, surgical intervention should be offered when there is progressive increase in systolic dimension. A left ventricular end-​systolic dimension of 40 mm is a cut-​off value for preserved left ventricular systolic function, particularly for an active ventricle. Predictors of outcome after valve surgery are severe aortic regur- gitation, age, severe symptoms, exercise intolerance, and evidence for left ventricular hypertrophy on echocardiography. Raised left ventricular end-​diastolic pressure and the ratio of wall thickness to chamber dimension have also been identified as potential predictors of outcome. An additional risk is the presence of coronary artery disease. These patients should be carefully evaluated by preoperative cardiac catheterization and receive myocardial revascularization surgery and coronary grafting at the same setting with aortic valve replacement surgery. There is evidence to suggest that patients with aortic regurgitation and ventricular dysfunction develop faster re- verse remodelling and fall of left ventricular mass index following successful valve replacement if they receive a stentless rather than a stented valve. Details of surgical procedures for aortic regurgitation are as described in the preceding section on aortic stenosis. Acute aortic regurgitation, irrespective of its aetiology, should be managed as an emergency with surgical intervention. While diag- nostic evaluation is in progress, the patient should be treated with afterload reduction. Aortic balloon counterpulsation is contra- indicated because it increases afterload. Cases caused by infective endocarditis should receive optimal antibiotic therapy following blood culture and emergency valve replacement, which could be life-​saving. 16.6  Valvular heart disease 3455 Mixed aortic disease Mild to moderate aortic regurgitation often accompanies aortic stenosis but does little to alter the overall clinical picture. The com- bination can result from a bicuspid aortic valve or chronic rheum- atic heart disease, or be the result of endocarditis or conservative surgery on a stenosed valve. The main haemodynamic disturbance is increased resistance to ejection, but the superimposition of even a moderately increased stroke volume due to regurgitation on the small, stiff left ventricle of pure aortic stenosis can lead to high filling pressures, left atrial enlargement, and even pulmonary hyperten- sion. Breathlessness and chest pain are the most prominent symp- toms. The arterial pulse is bisferiens, and typical ejection systolic and early diastolic murmurs are expected. Patients with symptoms are likely to require valve replacement. Right heart valve disease Many of the conditions that affect right-​sided valves are congenital: these are discussed in detail in Chapter 16.12. Particularly pulmonary and tricuspid valve diseases that develop later in life are discussed here, after general discussion of effects of abnormal right-​sided haemodynamics on right heart function and diagnostic techniques. Pathophysiology and complications Right ventricular response to valve disease The right ventricle responds to chronic pressure overload (e.g. caused by pulmonary stenosis or pulmonary hypertension) by hypertrophy and early dilatation. With increased afterload and right ventricular dilatation the ventricle adapts by making the intraventricular septum function as part of the right heart. This can be identified by studying septal movement during various phases of the cardiac cycle using M-​mode echocardiography, revealing that it becomes reversed in systole and in diastole. Right ventricle dilatation includes the tri- cuspid annulus and results in tricuspid regurgitation. Eventually right ventricular systolic function deteriorates, and this may become irreversible even after correcting the volume or pressure overload. With right ventricular volume overload the ventricle is very active, readily apparent on recording its free-​wall movement at the level of the tricuspid ring. However, assessing right ventricular ejection frac- tion and overall systolic function is difficult because of its complex anatomy, being made up of an inlet portion and an outlet portion that are at a significant angle to each other, and a trabecular portion at the apex. Assessment of right ventricular size and function A three-​dimensional approach to the assessment of right ven- tricular systolic function is the ideal method, but other cross-​ sectional echocardiographic and MRI techniques have developed over the years and proved sensitive in assessing right ventricular ejection fraction. Right ventricular inlet diameter can be used as a marker of cavity dilatation. Free-​wall long-​axis movement studied by M-​mode and tissue Doppler imaging from the lateral angle of the tricuspid annulus is an easy measure of systolic function and correlates closely with right ventricular ejection fraction. Likewise, right ventricular outflow tract diameter has been shown a sensi- tive measure of systolic function. In patients with reversed septal movement, it is crucial to exclude any shunt as a cause for volume overload on the right ventricle. Estimation of pulmonary artery pressure is an essential compo- nent in the evaluation of patients with right-​sided valve disease. The retrograde flow velocity across the tricuspid valve gives an indica- tion of systolic right ventricular pressure by use of the simplified Bernoulli equation. In all patients systolic pulmonary artery pres- sure equals the retrograde peak pressure drop across the tricuspid valve added to the estimated right atrial pressure, according to the collapsibility of the inferior vena cava. These measurements are clin- ically useful in patients without pulmonary stenosis. Investigation of valve stenosis and regurgitation The methods used in clinical practice for investigating possible tri- cuspid and pulmonary valve stenosis and regurgitation are the same as those used in assessment of conditions affecting the left side of the heart. Colour Doppler detects the level at which there are increased velocities as a sign of valve narrowing, which can be confirmed by continuous-​wave Doppler. In patients with valve regurgitation, colour Doppler assesses the jet diameter, direction, and area which, with respect to the right atrial area in cases of tricuspid regurgita- tion, gives some indication of the severity of tricuspid regurgitation. Transoesophageal echo images, particularly in tricuspid valve dis- ease, provide detailed assessment of valve pathology. Transthoracic images of the pulmonary valve can be somewhat limited technically, but in most cases Doppler studies can exclude significant valve disease based on forward and backward velocities and pressure drop. Transoesophageal echo provides a clearer image of the pulmonary valve and so is best suited for determining the level of valve stenosis. The degree of pulmonary stenosis and regurgita- tion severity is assessed by continuous-​wave Doppler, with timing of reversal of regurgitant pulmonary flow being another confirmation of its severity. Mild pulmonary regurgitation occupies the whole of diastole, while in severe regurgitation there is early pressure equal- ization between the two chambers. A jet diameter of 7 mm or more also supports the diagnosis of severe pulmonary regurgitation. MRI is another good non​invasive technique for assessment of right-​sided chamber size and valve function, in particular the pul- monary valve. The level of narrowing can easily be determined, the degree of stenosis by velocity mapping, and severity of regurgitation by estimating the regurgitant volume. Tricuspid stenosis Tricuspid stenosis is a rare condition, most often caused by rheum- atic disease, which almost invariably simultaneously affects the mitral valve. Other (even rarer) causes are carcinoid disease, in- fective endocarditis, and Whipple’s disease. A right atrial myxoma or extension of hypernephroma into the inferior vena cava and right atrium can in very rare instances present with signs and symptoms of right ventricular inflow tract obstruction, similar to tricuspid stenosis. Symptoms include fatigue, dyspnoea, and fluid retention. In pa- tients with chronic rheumatic heart disease the problem is to rec- ognize that the tricuspid valve has been affected in addition to the mitral valve (and perhaps the aortic valve as well). If the patient is in sinus rhythm, there may be an ‘a’ wave in the venous pulse, which would be unusual in the presence of pulmonary hyperten- sion and mitral stenosis alone (when the patient is very likely to be in atrial fibrillation). On auscultation at the left or right sternal edge a mid-​diastolic murmur (usually higher in pitch than the murmur section 16  Cardiovascular disorders 3456 of mitral stenosis) is heard, and a tricuspid opening snap may be present (later in the cardiac cycle than a mitral opening snap, and varying in timing in relation to P2 with respiration), although it is not possible to differentiate this reliably from the mitral opening snap that is likely to coexist. The chest radiograph shows a large right atrium with normal pul- monary artery size and clear lung fields. Echocardiography shows a dilated right atrium and demonstrates clearly the valve anatomy and function, as well as other intracardiac pathologies. The echo- cardiographic signs of rheumatic tricuspid disease are similar to those of the mitral valve, including commissural fusion, fibrosed leaflets that dome in diastole, short and fibrosed chordae, and raised transtricuspid forward flow velocities. Tricuspid valve disease progresses very slowly and needs careful follow-​up. Medical treatments are not satisfactory:  diuretics can help to minimize fluid retention, but at the expense of reduced car- diac output if pushed too hard. Mild and moderate tricuspid stenosis is generally tolerated; severe tricuspid stenosis needs surgical repair, or replacement if additional regurgitation is present. Tricuspid regurgitation Mild tricuspid regurgitation is found in 50% of normal individ- uals. Causes of significant tricuspid regurgitation are shown in Table 16.6.3, the commonest being secondary to either pulmonary hypertension or right heart dilatation. Endocarditis is commonly caused by intravenous access, either in those who abuse drugs intravenously, or in patients who required prolonged right heart catheters for medical therapy. Endomyocardial fibrosis, which is prevalent in tropical Africa, causes fibrosis of the papillary muscle tips and thickening and shortening of tricuspid valve leaflets and chordae. Permanent pacemaker wires across the tricuspid valve may rarely cause leaflet adhesions and dysfunction. Blunt trauma to the chest may be complicated by tricuspid regurgita- tion through the papillary muscle or chordal lacerations. Metastatic carcinoid tricuspid valve disease is rare, but echocardiographic find- ings of carcinoid involvement of the tricuspid valve are very charac- teristic, showing short, fibrosed, and thickened leaflets resulting in larger areas of incomplete coaption and severe tricuspid regurgita- tion. Tricuspid valve prolapse is occasionally seen in patients with mitral valve prolapse. The symptoms of tricuspid regurgitation are usually non​specific. When it develops in a patient with mitral stenosis it is often associ- ated with increased fatigue rather than breathlessness. Some patients will present with increasing peripheral oedema, and hepatic conges- tion may cause nausea or upper abdominal pain exacerbated by ex- ercise. Diarrhoea caused by a protein-​losing enteropathy (thought to be secondary to venous congestion of the gut) has been reported. The main physical sign is a raised venous pressure with prom- inent V-​wave, without which the diagnosis of significant tricuspid regurgitation is very difficult to sustain. In about one-​third of cases a pansystolic tricuspid regurgitation murmur can be heard at the left or right sternal edge: this tends to increase in intensity with in- spiration as the venous return increases, and it can radiate into the epigastrium. Expansile pulsation of the liver is present in most cases, but hepatic fibrosis (and jaundice) can occur if regurgitation is long-​ standing and this physical sign then disappears. Most patients with severe regurgitation have peripheral oedema, ascites, or both. The findings on a chest radiograph depend mainly on whether or not the patient has any other cardiac disease, but there may be enlargement of the heart shadow towards the right. The ECG may show right atrial hypertrophy. Echocardiography is the best way to make the diagnosis (Fig. 16.6.14). Cardiac catheterization is not re- quired for assessment of tricuspid regurgitation but may be indi- cated for diagnosis or assessment of other concurrent heart disease. Many patients tolerate tricuspid regurgitation for a long time, but some present with symptoms that significantly limit their exercise Table 16.6.3  Causes of tricuspid regurgitation Cause Type of condition Disease Primary Congenital Ebstein’s anomaly Atrioventricular defect Prolapsing cusp Acquired Rheumatic fever Infective endocarditis Permanent pacemaker wires Endomyocardial fibrosis Blunt trauma to the chest Carcinoid syndrome Ergot-​derived dopamine receptor agonists Following radiotherapy to the chest Secondary Functional Pulmonary hypertension or right heart dilatation Ischaemic right ventricular disease Fig. 16.6.14  Apical four-​chamber view from a patient with tricuspid regurgitation secondary to left-​sided dilated cardiomyopathy and mitral regurgitation: regurgitation into both left atrium (LA) and right atrium (RA) can be seen. 16.6  Valvular heart disease 3457 capacity and lifestyle. Medical treatment with diuretics and ACE in- hibitors may reduce systemic venous pressure and right ventricular size, even restoring competence to the tricuspid valve in some cases. Attempts should be made to treat pulmonary hypertension if this is the primary cause of right ventricular dilatation and tricuspid regur- gitation. If fluid retention is severe and refractory to medical treat- ment, careful consideration should be given to surgical correction of tricuspid regurgitation before the patient develops irreversible right ventricular damage. Repair and replacement of the tricuspid valve are problematic operations, with the former sometimes failing to prevent regurgitation and the latter leading to a significant dia- stolic pressure drop between the right atrium and ventricle, creating a problem of iatrogenic tricuspid stenosis, but in specialist centres the current approach is less conservative than it used to be. Tricuspid valvuloplasty is often performed at the time of mitral valve surgery for rheumatic disease. Annuloplasty involves a full ring, incomplete ring, or suture plication of the annulus. A semicir- cular ring has the advantage of maintaining annular flexibility and avoiding conduction disturbances, but residual tricuspid regurgi- tation occurs less often with a circular angioplasty ring than with a semicircular one. Tricuspid valve replacement by a mechanical prosthesis has a potential risk for endocarditis, particularly in drug abusers. Bioprostheses have a much lower thrombogenicity and re- sistance to flow in the tricuspid position and are therefore the pre- ferred choice. The surgical mortality of tricuspid valve surgery depends par- ticularly on the degree of preoperative hepatic congestion. Survival following tricuspid valve replacement is not purely related to the surgical procedure itself or to valve function, but is significantly af- fected by right ventricular dysfunction that is almost always masked by the volume overload before surgery. Pulmonary stenosis Pulmonary stenosis is congenital in 95% of cases (see Chapter 16.12): rarely it is caused by rheumatic valve disease or carcinoid syn- drome. Patients can tolerate moderate pulmonary stenosis (gra- dient <50 mm Hg) for years, fatigue and dyspnoea due to reduced cardiac output being the main symptoms in those with severe dis- ease. Physical examination reveals a prominent venous ‘a’ wave in the neck and an ejection systolic murmur at the upper left sternal edge that radiates to the suprasternal notch and left side of the neck. With severe pulmonary stenosis the pulmonary component of the second sound may be delayed, but it is often inaudible. An ejection click may be heard at the upper left sternal edge. Echocardiography and MRI show the level of stenosis. Doming leaflets are consistent with congenital valve disease. MRI imaging is particularly good for demonstrating supravalvar stenosis. Event-​free survival is related to the pressure gradient across the pulmonary valve. Balloon valvuloplasty is the procedure of choice for chil- dren and adults with significant pulmonary stenosis. On average transpulmonary gradient drops by two-​thirds of the baseline value without development of significant pulmonary regurgita- tion. Additional subvalvar stenosis may underestimate the success of the procedure. Surgical valvotomy may be considered if balloon valvuloplasty fails, and valve replacement may be needed for those with iatrogenic significant pulmonary regurgitation, especially after repair of tetralogy of Fallot. Homograft replacements might be ad- vantageous to avoid anticoagulation and thrombogenicity. Pulmonary regurgitation A small amount of pulmonary regurgitation is common. Significant pulmonary regurgitation is very rare and most commonly preceded by intervention to the pulmonary valve during childhood. Although the outcome of repair of tetralogy of Fallot is excellent in most cases, many of its complications are related to pulmonary regurgitation. Rare causes of pulmonary regurgitation are rheumatic disease, car- cinoid, and endocarditis. Many patients with pulmonary hyper- tension and dilatation of the right ventricular outflow tract will demonstrate some degree of pulmonary regurgitation. The typical murmur of pulmonary regurgitation is a soft early dia- stolic murmur that is best heard in the left upper parasternal region. It begins after the pulmonary component of the second sound and may be accompanied by an ejection systolic murmur caused by in- creased stroke volume. Most patients have enlarged neck veins and other evidence of pulmonary hypertension. Most patients with mild pulmonary regurgitation remain com- pletely asymptomatic for years. Although those with severe regurgi- tation may remain asymptomatic, correction of valve incompetence may save them irreversible damage of the right ventricle. Arrhythmia or progressive right ventricular dilatation are indications for sur- gery, using homograft or conduit and valve. Normalization of right ventricular size and function following pulmonary homograft inser- tion occurs in some but not all patients, probably depending on pre- operative ventricular dysfunction that could be masked by volume overload. FURTHER READING Henein MY (2009). Valvular heart disease in clinical practice. Springer, London. Henein MY (2012). Clinical echocardiography, 2nd edition. Springer, London. Mitral valve disease Alpert JS (1999). Mitral stenosis. In: Alpert JS, Dalen JE, Rahimtoola SH (eds) Valvular heart disease. Lippincott Williams & Wilkins, Philadelphia, PA. Baumgartner H, et al. (2017). 2017 ESC/​EATS guidelines for the man- agement of valvular heart disease. Eur Heart J, 21, 2739–​91. 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Mason and Heinz-​Peter Schultheiss ESSENTIALS Myocarditis can be acute, subacute, or chronic and may affect either focal or diffuse areas of the myocardium. It has many infectious and non​infectious aetiologies, but viral infections are the main cause in most regions, with notable exceptions such as Chagas myocarditis in South America. The condition often results in congestive heart failure and is a common cause of chronic dilated cardiomyopathy, also called in- flammatory cardiomyopathy. It can present with (a)typical chest pain, palpitations, ventricular arrhythmias, syncope, or even ful- minant heart failure. Patients with lymphocytic myocarditis are usu- ally young (average age in the forties) and often report an antecedent viral illness. The disease can be diagnosed by demonstration of lymphocyte infiltration and adjacent myocyte damage on endomyocardial bi- opsy, and molecularly by the detection of viral genomic material and tissue markers of immune activation in biopsy specimens. MRI and other imaging techniques are helpful in making the diagnosis, but their sensitivity and specificity is not sufficient in the chronic phase; hence endomyocardial biopsy remains the gold standard for defini- tive diagnosis and the basis for guiding clinical management in un- explained heart failure. Adverse immune activation is the primary cause of myocardial damage in most cases, hence appropriately timed immunosup- pressive therapy, most commonly with a steroid (prednisolone) and azathioprine, improves outcome in a significant number of cases. Antiviral therapies with interferon β in coxsackie-​ and adenovirus positive myocarditis are promising, although prospective random- ized studies have not been done. Specific forms of myocarditis include peripartum myocarditis, Lyme carditis, cardiac sarcoidosis, giant cell myocarditis, eosinophilic myocarditis, and Chagas carditis, each of which requires specific diagnostic and therapeutic measures. Introduction Myocarditis has captured the interest of clinicians and scientists because of its varied aetiology, its diagnostic and therapeutic chal- lenges, and the possibility that myocarditis may be the primary cause of so-​called dilated cardiomyopathy. Scientific study of myo- carditis is facilitated by the availability of numerous easily manipu- lated animal models of the disease and by new molecular probes. Epidemiology Myocarditis affects young people:  the average age of patients in the United States Myocarditis Treatment Trial was 42 years. There was a slight male predominance (62%) in that trial, but other series have not demonstrated a gender predilection. The true incidence of myocarditis is unknown: autopsy studies have reported figures of up to 3%, but varying histological criteria were used, and myocar- ditis may occur as an incidental complication of other fatal illnesses. About 10% of patients with influenzal infections have electrocar- diographic abnormalities, but it is not known if these are the result of myocarditis. The incidence of fatal myocarditis was estimated in a retrospective review of United States Air Force recruits under- going boot camp training: there were eight such deaths over 1 606 167 person days, which yields an estimate of 4/​100 000 per year in people aged 17–​28 years, perhaps somewhat greater than would be expected in the general population in the United States of America, who would not be exposed to similar levels of intense exercise or high probability of transmission of viral illnesses. A recent study section 16  Cardiovascular disorders 3460 using International Classification of Diseases Codes estimated the global prevalence of myocarditis to be 22 of 100 000 people annu- ally. Studies addressing the issue of sudden cardiac death in young people report a high but variable autopsy prevalence of myocarditis, ranging from 2% to 40% cases. Aetiology and pathogenesis The most common form of myocarditis in Europe and North America is known as lymphocytic myocarditis or autoimmune myocarditis. Other frequently applied terms are viral or post-​viral myocarditis, because an antecedent viral infection is common (Table 16.7.1.1). Indeed, some experts believe that nearly all Table 16.7.1.1  Aetiologies of myocarditis Infection Viruses Adenovirus Arbovirus Arenavirus Coronavirus Coxsackievirus (A, B) Cytomegalovirus Dengue virus Echovirus Encephalomyocarditis Epstein–​Barr Hepatitis B Hepatitis C Herpes simplex Human herpesvirus-​6 Human immunodeficiency Influenza (A, B) Junin Metapneumovirus Mumps Parvovirus (B19, bocavirus-​2) Polio Rabies Respiratory syncytial virus Rubella (German measles) Rubeola (measles) Vaccinia Varicella-​zoster virus Variola Zika virus Bacteria, spirochaetes, and bacteria-​like organisms β-​Haemolytic streptococci Borrelia burgdorferi (Lyme disease) Brucella spp. Campylobacter jejuni Chlamydia (psittaci, trachomatis, pneumoniae) Clostridia spp. Corynebacterium diphtheriae Francisella tularensis (tularaemia) Gonococcus Haemophilus influenza Legionella pneumophila Leptospira spp. Listeria monocytogenes Mycobacterium spp. Mycoplasma pneumoniae Neisseria meningitides Salmonella (berta, typhi) Streptococcus pneumoniae Staphylococcus spp. Treponema pallidum (syphilis) Tropheryma whipplei Rickettsia Coxiella burnetii (Q fever) Orientia tsutsugamushi (scrub typhus) Rickettsia rickettsii (Rocky Mountain spotted fever) Rickettsia prowazekii (typhus) Protozoa Entamoeba histolytica Leishmania spp. Plasmodium vivax Toxoplasma gondii Trypanosoma cruzi (Chagas disease) Helminths Cysticercus Echinococcus spp. Schistosoma spp. Toxocara spp. Trichinella spp. Fungi Actinomyces spp. Aspergillus spp. Blastomyces dermatitides Candida spp. Coccidioides immitis Cryptococcus neoformans Fusarium Oxysporum Histoplasma capsulatum Mucor Nocardia spp. Sporothrix schenckii 16.7.1  Myocarditis 3461 lymphocytic myocarditides are the result of viral infections, pre- sumed to be subclinical in those patients with no awareness of a viral prodrome. In the past, cardiotrophic enteroviruses including echoviruses and coxsackieviruses were the predominant aetiological agents, but new data has demonstrated the following genomic distribu- tion: parvovirus B19 (36.6%), enterovirus (32.6%), human herpes virus 6 (10.5%), and adenovirus (8.1%). However, dozens of viruses have been implicated and many more undoubtedly cause myocar- ditis in humans; hence in clinical practice it is impractical to exclude them all. However, the knowledge of a specific virus (e.g., influenza A, Coxsackie-​, Adeno-​, or HHV6 virus), as the cause in a given case of myocarditis may have significant therapeutic relevance if viricidal therapy is being considered. In animal models, enteroviruses such as coxsackie B3 can cause three phases of myocarditis. The first is the result of direct injury of myocytes by viral entry, resulting in activation of innate immunity. During the second phase, which can last several weeks to several months, viral replication and activation of the acquired immune response occur. Phase three is characterized either by recovery or development of dilated cardiomyopathy. The underlying mech- anisms are complex and incompletely understood, but most hy- potheses suggest that autoimmune phenomena play a major role. In some instances molecular mimicry may be involved, in which the similarity of a viral antigen to a myocardial protein triggers an autoimmune reaction. In others an autoimmune response to cellular proteins released during the viral replication phase may occur, and myosin has been implicated in this regard. Cytokines arising from immune activation and cellular necrosis probably play a role in some cases, bringing about further cellular damage, such as through activation of matrix metalloproteinases. Viral persist- ence appears to induce a chronic adverse immune response and, as a result, to correlate with a poor prognosis. However, although these mechanisms have been well delineated in murine models, they have not been proven to cause myocarditis in humans, nor has their delineation generated therapies proven to be effective by prospective randomized studies. It also has to be emphasized that some viruses can cause myocar- ditis by the infection of endothelial cells. For example, parvovirus B19 primarily infects endothelial progenitor cells which then leads to an infection of cardiac endothelial cells. This can increase the cor- onary resistance, trigger coronary vasospasm, and induce myocyte necrosis. Myocarditis may also result from a hypersensitivity reaction to a drug or other agent (see Table 16.7.1.1). In these cases, eosino- phils accompany the inflammatory lymphocytic infiltrate. A  few patients, perhaps about 10%, present with a secondary form of myo- carditis: these special presentations are discussed next. Recently human-​induced pluripotent stem cell-​derived cardio­ myocytes were introduced as a way to model the cardiomyocyte’s interaction with cardiotropic viruses, which offers an opportunity to examine possible prevention and treatment candidates directly in the infected human cell, even though the immune system is excluded. Drugs and chemicals Toxicity 2-​Interferon Amphetamines Animal and insect toxins Anthracyclines Arsenic Cannabis Catecholamines, endogenous and exogenous Cocaine 5-​Fluorouracil Interleukin 2 Lithium Paracetamol Paraphenylene diamine (hair dye) Hypersensitivity Aminophylline 5-​Aminosalicylic acid Ampicillin Azithromycin Benzodiazepines Clozapine Dapsone Digoxin Ephedrine Furosemide Hydrochlorothiazide Methyldopa Olanzapine Penicillin Phenytoin Quetiapine Sulfasalazine Tetracycline Tricyclic antidepressants Autoimmunity Antigenic mimicry Autoimmune disease associated Cardiac myosin Checkpoint inhibitor therapy Cytokines Dolutegravir therapy Dressler’s syndrome Post-​cardiotomy syndrome Post-​infection Post-​radiation section 16  Cardiovascular disorders 3462 Relationship to idiopathic dilated cardiomyopathy Classic lymphocytic myocarditis can resolve, with resultant im- provement in cardiac function over weeks or months: 50% of pa- tients presenting with significant left ventricular dysfunction will have complete recovery, but 25% will go on to have chronic systolic dysfunction and about 25% will progress towards end-​stage heart failure. In the United States Myocarditis Treatment Trial, the mean left ventricular ejection fraction improved during the year after ini- tial presentation by more than 10 ejection fraction units (from 24% to 36%; normal >55%). However, residual cardiac dilatation and dysfunction were common, and mortality was high, reaching 55% at 5 years. In those patients who do not recover fully, the ensuing clin- ical picture cannot be distinguished from that of idiopathic dilated cardiomyopathy. The possibility that myocarditis may occur without an obvious viral prodrome therefore raises the interesting possibility that viral myocarditis may be a common covert cause of idiopathic dilated cardiomyopathy. In the United States trial, only 10% of patients with suspected myocarditis had positive biopsies according to the Dallas classification. The fact that the histological evaluation of endomyocardial biopsy usually does not reveal myocarditis in pa- tients with idiopathic dilated cardiomyopathy may be the result of timing of the biopsy after resolution of the lymphocytic infiltrate, sampling error, or the inability to detect the inflammatory process. Immunohistochemistry using a large panel of monoclonal anti- bodies for characterization and quantification of infiltrating immune cells provides additional information and is regarded as obligatory today. Retrospective analysis has shown that the characterization and quantification of different infiltrative cell types (e.g. perforin-​ positive cytotoxic cells) are of high prognostic value and essential for deciding whether or not a patient should be treated. The presence of viral genomic material in endomyocardial biopsies—​particularly persisting viral genome in follow-​up biopsies—​was associated with progressive left ventricular dysfunction and a higher mortality rate, whereas spontaneous viral clearance was associated with a signifi- cant improvement of left ventricular dysfunction. Absence of viral genome does not, however, eliminate post-​viral autoimmune pro- cesses, proceeding despite complete viral clearing, as a possible aetiology. The fact that immunomodulatory therapy can improve cardiac function in patients with inflammatory cardiomyopathy, and even in dilated cardiomyopathy without lymphocytic myocardial infil- trates, adds indirect evidence that dilated cardiomyopathy has an inflammatory origin in a significant percentage of cases. Even in patients with so-​called genetic cardiomyopathy, a genetic predis- position can interact with intrinsic or environmental factors. In this context a robust proinflammatory response in dilated cardio- myopathy hearts, likely in response to cellular damage triggered by MYBPC3 mutation and resultant contractile dysfunction, could be shown. This explains why patients with the same genotype develop different phenotypes, and vice versa. Clinical features In Europe and North America most cases of myocarditis present with congestive heart failure of unknown cause. In many instances there is a history of recent upper respiratory tract infection or of a ‘flu-​like’ illness. This is followed by symptoms of cardiac decom- pensation, usually fatigue, breathlessness, and cough. Chest pain occurs in a substantial minority of patients, and—​when com- bined with regional ST-​segment shifts on the electrocardiogram (ECG)—​can mimic acute myocardial infarction. A  few patients present with ventricular tachyarrhythmias and minimal or no car- diac dilatation. The usual duration of symptoms due to infection is brief, less than 1 month in approximately 50% of patients and nearly always less than 1 year. Myocarditis should always be suspected when a pa- tient presents with unexplained congestive heart failure with a rapid onset, especially if there is a viral prodrome. In adults under the age of 40, the combination of typical chest pain and a significant rise in troponin I is more likely due to myocarditis than to myocardial in- farction, and fever or a viral prodrome are usually reported by those with myocarditis. Clinical examination typically reveals signs of cardiac failure. Investigation The ECG may show conduction abnormalities, ST/​T-​wave changes (including persistent ST-​segment elevation that does not proceed to Q-​wave development), or arrhythmias (atrial or ventricular). The chest radiograph shows cardiomegaly and—​in acute fulminant cases—​pulmonary oedema. The echocardiogram reveals four-​ chamber dilatation and reduced contractility, and is notable for the fact that valvular disease is absent or minimal. Speckle tracking imaging is a new and promising method which gives additional information regarding regional contractility. Global longitudinal strain and strain rate are significantly impaired in patients with biopsy-​proven myocarditis. Cardiac scintigraphy with indium-​111 antimyosin antibodies and single photon emission computed tom- ography (SPECT) have been used to detect myocarditis. Cardiac MRI is the most reliable non​invasive method for diag- nosis, and can be used to distinguish acute myocardial infarction, acute myocarditis, and healed myocarditis. Contrast-​enhanced MRI allows assessment of the regional extent of myocardial involvement. Detection of a pericardial effusion on the MRI increases the prob- ability of a diagnosis of myocarditis, and injection of fluorine-​19, which is taken up by inflammatory cells, is a promising method for MRI detection of localized inflammation due to myocarditis. However, it must be emphasized that the diagnostic performance of MRI is significantly worse in chronic myocarditis, with a sensi- tivity and specificity of around 50%. In this context, it also has to be underlined that MRI is not able to detect viral persistence, which is a prerequisite for deciding if and how the patient should be treated. Furthermore, the nature and intensity of the inflammatory pro- cess, which is important for estimation of the prognosis, cannot be analysed. Endomyocardial biopsies (which have a complication rate of below 1% in experienced centres) using the standardized histopathological, immunohistological, virological, and molecular methods therefore remain the gold standard by which the diagnosis of the different forms of myocarditis is made and by which thera- peutic decisions can be made. Should coronary angiography be per- formed, the vessels are normal or show only minor abnormalities. 16.7.1  Myocarditis 3463 Elevation of serum cardiac biomarkers (e.g., troponin, creatine phosphokinase) is common. Dozens of viruses can cause myocarditis in humans, and it is im- practical to exclude them all. Some patients may present in the acute phase of the viral illness, as has recently been described in patients with influenza A  (H1N1), but they usually present a substantial length of time after the viral infection has cleared, making it diffi- cult or impossible to document an acute rise in titre. However, the knowledge of a specific virus (e.g., influenza A, coxsackie-​, adeno-​, or HHV6 virus), as the cause in a given case of myocarditis may have significant therapeutic relevance if viricidal therapy is being considered, and in this context it should be restated that negative titres for the common viral agents do not exclude a viral aetiology. Management Virus-​negative lymphocytic myocarditis/​autoimmune myocarditis/​inflammatory dilated cardiomyopathy As stated earlier, lymphocytic myocarditis is believed by most to have a viral aetiology, even in the absence of a clinically apparent viral pro- drome. In the acute phase of viral myocarditis, the direct cytolytic effect of viral myocyte infection may lead to congestive heart failure, although this is uncommon. In this early phase, the immune response is likely, on balance, to be beneficial. Thus, antiviral therapy might be expected to be helpful, but on theoretical grounds immunosup- pressive therapy would not. However, though antiviral therapies have shown promise, none have been adequately tested in humans with acute myocarditis, although it is routine practice to administer neur- aminidase inhibitors such as oseltamivir to those with influenza A. In the second stage of myocarditis, thought to result from an ad- verse immune response to previous infection, immunosuppressive therapy has appeared to be beneficial in several trials. However, no benefit was demonstrated in the United States Myocarditis Treatment Trial, a prospective randomized trial performed in pa- tients with myocarditis defined histologically. In that trial the ‘Dallas’ criteria defined myocarditis histologically as a lymphocytic infiltrate with associated myocyte necrosis (Fig. 16.7.1.1). However, it must be emphasized that neither immunohistology nor viral gen- omic analyses were performed, and we now recognize these as an essential prerequisite for the decision as to whether a patient should be treated. Notwithstanding these concerns, it has become increasingly clear that immunosuppressive treatment in cases of viral–​positive myo- carditis is not beneficial. Treatment with prednisone combined with either ciclosporin or azathioprine does not improve outcome, as de- fined by change in left ventricular ejection fraction. It is therefore appropriate to consider other diagnostic criteria, such as presence of viral genomic material and human leucocyte antigen upregulation on biopsy, circulating antiheart antibodies, and imaging, in the diag- nosis and treatment of myocarditis. RNA microarray analysis on bi- opsy specimens has been found to be highly sensitive and specific in differentiation of myocarditis from idiopathic dilated cardiomyop- athy, myocardial infarction, and other myocardial disorders associ- ated with inflammation. An algorithm for the diagnosis and treatment of suspected myo- carditis is shown in Fig. 16.7.1.2. This algorithm differs somewhat from recently published recommendations of the European Society of Cardiology (ESC), primarily in the use of endomyocardial biopsy, which is more liberally applied in the ESC consensus statement. Spontaneous improvement in left ventricular function can be antici- pated in about 50% of the patients. Thus, in the beginning it is rea- sonable to use standard therapy for congestive heart failure, without performing a biopsy or administering steroids, and to observe the patient, using echocardiography to monitor left ventricular function. However, in patients who do not improve in 8–​12 weeks or even de- teriorate, or who present with cardiogenic shock, an endomyocardial biopsy should be performed as early as possible. As many experts would base a diagnosis of myocarditis on proven imaging techniques, such as contrast-​enhanced MRI, in combination with a circulating biomarker such as cardiac-​specific antibodies, it has to be empha- sized that endomyocardial biopsies remain the current gold standard for the diagnosis of myocarditis. Beside histological examination, more sophisticated techniques of immunohistology and molecular biology/​virology are essential for a clear-​cut diagnosis and the deci- sion whether and how the patients should be treated. If chronic, virus-​negative myocarditis is present in patients with heart failure, immunosuppressive therapy should be administered, typically beginning with prednisone at 1.25 mg/​kg per day, and azathioprine (Fig. 16.7.1.3). It must be admitted, however, that the efficacy of such treatment has not been proved by multicentre, pro- spective randomized studies, although Frustaci et al. clearly showed in a randomized placebo-​controlled trial the positive impact of immunosuppression on recovery of left ventricular dysfunction in biopsy-​proven virus-​negative inflammatory cardiomyopathy. These data were confirmed by Escher et al. who could show the effect- iveness and beneficial haemodynamic effects of immunosuppres- sive therapy after 6-​months, and in a long-​term follow-​up period up to 10  years. If the patient worsens despite this therapy, then endomyocardial biopsy should be repeated because of the sampling error regarding viral persistence. Viral positive myocarditis and inflammatory cardiomyopathy An algorithm for management after endomyocardial biopsy is shown in Fig. 16.7.1.3. Direct antiviral treatments that have been Fig. 16.7.1.1  An example of acute myocarditis, with lymphocytic infiltration adjacent to frayed myocytes. section 16  Cardiovascular disorders 3464 tested or proposed include interferon β, aciclovir, ganciclovir, foscarnet, and amantadine. Using polymerase chain reaction (PCR) technology and in-​situ hybridization, viral RNA and DNA—​ mainly parvovirus B19, entero-​ and adenovirus, and human herpes virus 6—​can be detected in endomyocardial biopsies of patients with myocarditis and inflammatory cardiomyopathy. In cocksackie-​ and adenovirus infection it has been shown that spontaneous and treatment-​related viral clearance with interferon Usual presentation Ventricular tachyarrhythmia cardiogenic shock Continue standard treatment of CHF Monitor with echo Aggressive therapy of arrhythmia if present (e.g., ICD) Endomyocardial biopsy Patient improves haemodynamically MRI Echo & HM CHF treatment observe Suspected viral myocarditis or post-viral autoimmunity/inflammatory dilated cardiomyopathy Patient does not improve or worsens haemodynamically Negative for myocarditis Positive for myocarditis Differential diagnosis and differential therapies–see Figures 16.7.1.3 and 16.7.1.4 Fig. 16.7.1.2  Algorithm for diagnosis and treatment of suspected myocarditis. CHF, congestive heart failure; echo, echocardiogram; HM, Holter monitor; ICD, implantable cardioverter–​defibrillator; MRI, magnetic resonance imaging. Endomyocardial biopsy Inflammation +/− Virus + Inflammation + Virus − Inflammation− Virus− Healed myocarditis LVEF >55% LVEF <55% Symptomatic therapy Risk stratification and heart failure therapy Dilated cardiomyopathy Genetic testing CD3 >10 cells/mm2 CD45R0 >45 cells/mm2 -Perforin + cytotoxic T-cells 2.9 cells/mm2 Characterization Quantification Immunosuppressive therapy: corticosteroids & azathioprine Repeat EMB after six months Coxsackie virus + Adenovirus + Antiviral therapy Interferon-β Parvovirus B19 + Telbivudine or new drugs Immunohistology ci HHV6 + Viral load+ mRNA − Viral load + mRNA + Ganciclovir or valganciclovir No therapy Repeat EMB after six months Viral load+ mRNA − Immunohistology + Immuno- suppressive therapy: corticosteroids & azathioprine Repeat EMB after six months Fig. 16.7.1.3  Differential diagnosis and therapeutic options for endomyocardial biopsy-​proven chronic myocarditis, inflammatory dilated cardiomyopathy, and dilated cardiomyopathy. EMB, endomyocardial biopsy; HHV6, human herpes virus 6; LVEF, left ventricular ejection fraction. 16.7.1  Myocarditis 3465 β is associated with clinical and haemodynamic improvement, but a prospective randomized study of this treatment in parvovirus B19 in- fection found it not to be effective. Retrospective analyses regarding the prognosis of parvovirus B19 have shown that the viral load is not important, but that active replication (evidenced by mRNA posi- tivity) and an accompanying inflammation in mRNA-​negative pa- tients seem to be important. However, it has to be emphasized that up to now there are no useable or proven clinical data for the specific treatment of parvovirus B19 indicated in Fig. 16.7.1.3. Regarding HHV6 infection, it has been shown that chromo- somal integrated (ci) HHV6 reactivation causes symptomatic pro- gressive heart failure symptoms, and that antiviral treatment with ganciclovir abolished viral mRNA and ameliorated cardiac symp- toms. Although there are no large prospective randomized studies to establish the efficiency of antiviral treatment, the clinical data clearly show that chronic viral infections and virus-​associated in- flammatory processes cause myocardial damage and consequently ventricular dysfunction. An early biopsy-​based diagnosis and timely treatment may therefore prevent disease progression and improve the clinical outcome. Immunomodulatory treatments including the application of intravenous immune globulins or immunoadsorption show conflicting results. They might be an option in individual cases, but the routine use of these methods cannot be recommended. Management of ventricular tachyarrhythmias in patients with myocarditis Lymphocytic myocarditis, with or without a viral prodrome, may present with ventricular tachyarrhythmias and little or no cardiac dilatation and dysfunction. An endomyocardial biopsy should be considered in all cases of ventricular tachycardia of recent onset if no aetiology is apparent, because the presence of myocarditis can substantially change treatment strategy. Since myocarditis is often a self-​limited disorder, the patient’s risk of recurrent ventricular tachyarrhythmias may resolve, and it may be unnecessary to subject them to electrophysiological study and/​or cardioverter–​defibrillator implantation. If arrhythmia does not improve spontaneously, a trial of immunosuppressive therapy should be considered. In such cases it is difficult to know how long to continue with antiarrhythmic drugs. The risks of ventricular arrhythmia should not be under- estimated, but nor should those of long-​term treatment with agents such as amiodarone. If 24-​h ECG monitoring at 6 months shows no sinister abnormalities, then many would withdraw antiarrhythmic treatment at that point, but others advocate repeat endomyocardial biopsy to document complete resolution of myocarditis before taking this step. In the case of severe ventricular tachycardia and an endomyocardial biopsy-​based therapeutic option—​for ex- ample, immunosuppressive therapy—​the indication for a Life-​Vest should be discussed before the implantation of an implantable cardioverter–​defibrillator. Specific forms of myocarditis Specific forms of myocarditis and their treatments are shown in Fig. 16.7.1.4. Peripartum myocarditis Dilated cardiomyopathy developing during the last trimester of pregnancy or within 6 months of delivery is known as peripartum or postpartum cardiomyopathy. In some series the dominant cause is myocarditis. When heart failure develops rapidly in the first few weeks after delivery, myocarditis is more likely to be found on endomyocardial biopsy than when the onset is insidious and de- layed, and patients with early, rapid onset are more likely to recover quickly and completely. While steroid therapy has been used and is recommended by some, its efficacy has not been proved, and spon- taneous resolution of peripartum cardiomyopathy is well docu- mented. Bromocriptine, a dopamine D2 receptor agonist which blocks prolactin, seems to be a disease-​specific treatment for this condition in addition to standard heart failure therapy. The usual prohibition against future pregnancy has been debated; it is very clear that some women risk recurrent heart failure, while others Peripartum Lyme Sarcoid Giant cell Eosinophilic Chagas • CHF at term or within six months of delivery Steroids recommended by some, but unproven Bromocriptine Amoxicillin or tetracycline indicated, but may not alter course • Tick exposure • Typical rash • AV block common • Dilatation rare • Pulmonary or systemic disease • Increased serum ACE Steroids unequivocally indicated • Autoimmunity • Rapid course Steroids + Ciclosporin + Azathioprine • Autoimmunity • Rapid course Steroids + Azathioprine • Central or South American residence or travel • Complement fixation test Nifurtimox or benznidazone (probably only effective in acute Chagas) Therapeutic options for specific forms of acute myocarditis Acute myocarditis Autoimmune/ viral (Dallas criteria) Specific treatment – follow up biopsy Fig. 16.7.1.4  Suspected specific forms of myocarditis and their treatments. ACE, angiotensin converting enzyme; CHF, congestive heart failure; Comp fix, complement fixation; EMB, endomyocardial biopsy; AHA, antiheart antibody; PCR, polymerase chain reaction. section 16  Cardiovascular disorders 3466 do not. In those women in whom severe heart failure persists, car- diac transplantation is an appropriate therapy. After transplant- ation, successful pregnancies have occurred without recurrence of cardiomyopathy. Lyme carditis Borrelia burgdorferi, a spirochete, infects humans following Ixodes tick bites. Lyme disease, which results from this infection, has been reported in 48 of the 50 United States, as well as in Europe and Asia (see Chapter 8.6.33). It is characterized by an erythema migrans rash and flu-​like symptoms, followed by arthritis, carditis, and neuro- logical disorders in some patients. Carditis is detected in approxi- mately 8% of cases. Both lymphocytic infiltration and the bacterium itself can be demonstrated by endomyocardial biopsy. The usual car- diac manifestation is varying degrees of atrioventricular block, with cardiac dilatation occurring infrequently. Atrioventricular block is usually transient, though permanent complete heart block has been reported. The site of block appears to be the atrioventricular node in most cases, but block within the His bundle has been docu- mented by electrophysiological study, and the common occurrence of intraventricular conduction delays suggests that bundle branch block may also occur. Temporary pacing is usually sufficient, though recovery of antegrade conduction may take a week or longer. Lyme carditis should be considered in any case of heart block of unknown cause, especially in young people. Antibiotic therapy is recommended in Lyme carditis, but it is not known if this alters the course of carditis and atrioventricular block. Cardiac sarcoidosis Less than 10% of patients with pulmonary or systemic sarcoid- osis have clinically manifest cardiac involvement, ranging from conduction disturbances and arrhythmias to cardiac dilatation. Endomyocardial biopsy reveals typical sarcoid granulomas. The most serious complications of cardiac sarcoidosis are complete heart block, ventricular tachyarrhythmias, and dilated cardiomy- opathy. Cardiac sarcoidosis accounts for as much as 19% of all cases of unexplained atrioventricular block requiring pacemaker implantation in adults under 55 years of age. The relatively high incidence of sudden death in patients with sarcoidosis is thought to result from sudden complete heart block or ventricular fibril- lation. Patients with sarcoidosis who develop significant conduc- tion disease, arrhythmias, or congestive heart failure should receive steroids. Occasionally, cardiac involvement will occur without detectable systemic manifestations of sarcoidosis; thus, cardiac sarcoidosis is in the differential diagnosis of any undiagnosed ven- tricular arrhythmia, dilated cardiomyopathy, or atrioventricular block. See Chapter 16.7.3 for further discussion. Giant cell myocarditis Early recognition of this rapidly progressive form of myocarditis is required as it has a prognosis considerably worse than that of non-​ specific lymphocytic myocarditis. The endomyocardial biopsy is dis- tinguished by the presence of multinucleated giant cells and scattered lymphocytic infiltrates with eosinophils, but matters are made diffi- cult by sampling error due to the focal appearance of multinuclear giant cells. A new molecular method—​myocardial gene expression profiling—​facilitates the prediction of the presence of giant cells in the myocardium, even without a direct histological proof in single small endomyocardial biopsy sections, and thus reduces the risk of a sampling error. The aetiology of giant cell myocarditis is unknown, but thought to be autoimmune given its association with myasthenia gravis, thymoma, Crohn’s disease, and other immune disorders. It should be suspected in patients—​particularly those with a history of an auto- immune condition—​who present with disease which progresses un- usually rapidly, without viral prodrome, and who do not respond to standard therapy of congestive heart failure. Endomyocardial biopsy should be performed if giant cell myocarditis is suspected, because combined immunosuppressive therapy with antithyroglobulin, cyclosporine, and corticosteroid appears to be helpful. Patients with giant cell myocarditis should be considered for early cardiac trans- plantation if they do not respond to therapy. Giant cell infiltration can be isolated to the atria, producing atrial enlargement and ar- rhythmias; this form of the disease is more benign. Eosinophilic myocarditis Eosinophilic myocarditis is a rare form of myocardial inflammation. The aetiological factors are hypersensitivity or allergic reactions, in- fectious, malignancies, hypereosinophilic syndromes, and vasculitis, notably Churg–​Strauss syndrome. The clinical presentation varies from asymptomatic forms to life-​threatening conditions. Many pa- tients have significant increased eosinophilic cells in the peripheral blood, but diagnosis depends on endomyocardial biopsy. Treatment differs significantly regarding the underlying aetiology, but im- munosuppressive therapy represents the mainstay of treatment. Chagas disease Chagas disease, caused by Trypanosoma cruzi, is the leading cause of myocarditis and dilated cardiomyopathy in some Central and South American countries, but uncommon in the United States of America (see Chapter 8.8.12). Overt acute myocarditis with congestive heart failure, arrhythmias, and conduction disease may develop, but car- diac involvement in early Chagas disease is usually subclinical. Years later, chronic Chagas disease may develop and may involve the heart. In the chronic phase, right bundle branch block and biventricular failure are present, and right heart failure predominates. Myocarditis occurs in both the acute and chronic phases, when immune medi- ation of myocyte injury is well documented. Antiprotozoal treat- ment with nifurtimox or benznidazole is beneficial in the acute phase. These agents are also indicated in the chronic phase, but—​ while they do reduce or eliminate serological immune markers of disease—​it is not known if they improve outcome. Likely future developments The use of endomyocardial biopsy for diagnosis of myocarditis is es- sential at present, with a combination of morphological, molecular, and genetic analyses necessary to improve prognosis by a specific causal treatment. In the future it might be replaced gradually by other methods, including molecular assessments of biopsy tissue and non​invasive methods. In addition to diagnosis, new techniques like microRNA cluster analysis, gene expression profiles, analysis of genetic predisposition, or other aspects of immune response, will identify more accurately subsets of patients likely to respond to specific therapies. Relevance of animal models to clinical forms of 16.7.1  Myocarditis 3467 myocarditis will be improved by a fuller analysis and understanding of the disorder in humans. The most important advances will lead to prevention of the causative infections through vaccination and other prophylactic measures. These developments could profoundly re- duce the incidence of dilated cardiomyopathy throughout the world. FURTHER READING Aretz HT, et al. (1987). Myocarditis. A histopathologic definition and classification. Cardiovasc Pathol, 1, 3–​14. Baughman KL (2006). Diagnosis of myocarditis: death of Dallas cri- teria. Circulation, 113, 593–​5. Blauwet LA, Cooper LT (2010). Myocarditis. Prog Cardiovasc Dis, 52, 274–​88. Caforio, AL, et al. (2013). Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis:  a pos- ition statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Euro Heart J, 34, 2636–​48. Cooper LT (2009). Myocarditis. N Engl J Med, 360, 1526–​38. Cooper LT, Berry GJ, Shabetai R (1997). Idiopathic giant-​cell myocarditis—​natural history and treatment. N Engl J Med, 336, 1860–​6. Corsten M, et al. (2015). The microRNA-​221/​-​222 cluster balances the antiviral and inflammatory response in viral myocarditis. Eur Heart J, 36, 2909–​19. Escher F, et al. (2014). Presence of perforin in endomyocardial biopsies of patients with inflammatory cardiomyopathy predicts poor out- come. Eur J Heart Fail 16, 1066–​72. Escher F, et al. (2015). Aggravation of left ventricular dysfunction in patients with biopsy-​proven cardiac human herpesvirus A and B in- fection. J Clin Virol, 63,1–​5. Escher F, et  al. (2016). Long-​term outcome of patients with virus-​ negative chronic myocarditis or inflammatory cardiomyopathy after immunosuppressive therapy. Clin Res Cardiol, 105, 1011–​20. Felker GM, et  al. (2000). Myocarditis and long-​term survival in peripartum cardiomyopathy. Am Heart J, 140, 785–​91. Francone M, et al. (2014). CMR sensitivity varies with clinical pres- entation and extent of cell necrosis in biopsy-​proven acute myocar- ditis. JACC Cardiovasc Imaging, 7, 254–​63. Felix SB, Staudt A (2008). Immunoadsorption as treatment option in dilated cardiomyopathy. Autoimmunity 41, 484–​9. Frustaci A, et  al. (2003). Immunosuppressive therapy for active lymphocytic myocarditis: virological and immunologic profile of re- sponders versus nonresponders. Circulation, 107, 857–​63. Frustaci A, et al. (2009). Randomized study on the efficacy of immuno- suppressive therapy in patients with virus-​negative inflammatory cardiomyopathy: the TIMIC study. Eur Heart J, 30, 1995–​2002. Gauntt CJ, et al. (1995). Molecular mimicry, antcoxsackievirus B3 neu- tralizing monoclonal antibodies, and myocarditis. J Immunol, 154, 2983–​95. Heymans S, et al. (2009). Inflammation as a therapeutic target in heart failure? A  scientific statement from the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail, 11, 119–​29. Holzmann M, et  al. (2008). Complication rate of right ventricular endomyocardial biopsy via the femoral approach: a retrospective and prospective study analyzing 3048 diagnostic procedures over an 11-​year period. Circulation, 118, 1722–​8. Kasner M, et al. (2017). Multimodality imaging approach in the diag- nosis of chronic myocarditis with preserved left ventricular ejection fraction (MCpEF):  the role of 2D speckle-​tracking echocardiog- raphy. Int J Cardiol, 243, 374–​8. Knowlton KU (2017). Myocarditis: an intersection between genetic and acquired causes of human cardiomyopathy. J Am Coll Cardiol, 69, 1666–​8. Kühl U, et al. (2005). Viral persistence in the myocardium is associated with progressive cardiac dysfunction. Circulation, 112, 1965–​70. Kühl U, et al. (2013). A distinct subgroup of cardiomyopathy patients characterized by transcriptionally active cardiotropic erythrovirus and altered cardiac gene expression. Basic Res Cardiol, 108, 372. Kühl U, et al. (2012). Interferon-​beta improves survival in enterovirus-​ associated cardiomyopathy. J Am Coll Cardiol, 60, 1295–​6. Kühl U, et al. (2015). Chromosomally integrated human herpesvirus 6 in heart failure: prevalence and treatment. Eur J Heart Fail, 17, 9–​19. Lassner D, et al. (2014). Improved diagnosis of idiopathic giant cell myocarditis and cardiac sarcoidosis by myocardial gene expression profiling. Eur Heart J, 35, 2186–​95. Leone O, et al. (2011). 2011 Consensus statement on endomyocardial biopsy from the Association for European Cardiovascular Pathology and the Society for Cardiovascular Pathology. Cardiovasc Pathol, 21, 245–​74. Lurtz P, et al. (2012). Diagnostic performance of CMR imaging com- pared with EMB in patients with suspected myocarditis. JACC Cardiovasc Imaging, 5, 513–​24. Maleszewski JJ, et al. (2015). Long-​term risk of recurrence, morbidity and mortality in giant cell myocarditis. Am J Cardiol, 115, 1733–​8. Mason JW (1997). Arrhythmias associated with myocarditis. Cardiac Electrophys Rev, 1, 268–​9. Mason JW, et al. (1995). A clinical trial of immunosuppressive therapy for myocarditis. N Engl J Med, 333, 269–​75. Mason JW (2013). Basic research on myocarditis: superb but unre- quited. J Am Coll Cardiol, 62, 1746–​7. McManus BM, et al. (1993). Direct myocardial injury by enterovirus: a central role in the evolution of murine myocarditis. Clin Immunol Immunopathol, 68, 159–​69. McNamara DM, et al. (2001). A controlled trial of intravenous im- mune globulin in recent-​onset dilated cardiomyopathy. Circulation, 103, 2254–​9. Pauschinger M, et  al. (1999). Enteroviral RNA replication in the myocardium of patients with left ventricular dysfunction and clinic- ally suspected myocarditis. Circulation, 99, 889–​95. Pauschinger M, et al. (1999). Detection of adenoviral genome in the myocardium of adult patients with idiopathic left ventricular dys- function. Circulation, 99, 1348–​54. Pollack A, et al. (2015). Viral myocarditis—​diagnosis, treatment op- tions, and current controversies. Nat Rev Cardiol, 12, 670–​80. Rose NR, Hill SL (1996). The pathogenesis of postinfectious myocar- ditis. Clin Immun Immunopath, 80, S92–​9. Rose NR (2014). Learning from myocarditis: mimicry, chaos and black holes. F1000Prime Rep, 6, 25. Schultheiss H-​P, et al. (2016). Betaferon in chronic viral cardiomyop- athy (BICC) trial: effects of interferon-​β treatment in patients with chronic viral cardiomyopathy. Clin Res Cardiol, 105, 763–​73. Sharma A, et al. (2014). Human induced pluripotent stem cell-​derived cardiomyocytes as an in vitro model for coxsackievirus B3-​induced myocarditis and antiviral drug screening platform. Circ Res, 115, 556–​66. Skouri HN, et al. (2006). Noninvasive imaging in myocarditis. J Am Coll Cardiol, 48, 2085–​93. Van Linthout S, Tschope C (2018). Viral myocarditis: a prime example for endomyocardial biopsy-guided diagnosis and therapy. Curr Opin Cardiol, 33, 325–33. 16.8 Pericardial disease 3501 Michael Henein 16.8 Pericardial disease 3501 Michael Henein ESSENTIALS The most common clinical presentations of pericardial disease are pericarditis, effusion, tamponade, and constriction. Acute pericarditis The most common proven causes are viral infection or as a compli- cation of myocardial infarction, but a wide range of other conditions including autoimmune rheumatic disorders and tuberculosis need to be considered. No firm cause is established in many cases, which are regarded as ‘idiopathic’ (presumed viral). The main clinical features are chest pain, the presence of a peri- cardial rub, and widespread ST segment elevation on the ECG. Idiopathic disease is self-​limiting: treatment is with analgesics and/​or non​steroidal anti-​inflammatory agents and colchicine. Pericardial effusion Acute rapid collection is usually caused by traumatic injury, iatro- genic ventricular puncture, or aortic dissection. Presentation is with pericardial tamponade. Chronic fluid accumulation is most commonly caused by viral in- fection, uraemia, autoimmune rheumatic disease, myocardial infarc- tion, myxoedema, or malignancy. Patients may remain asymptomatic despite the presence of a large volume of fluid in the pericardium due to corresponding increase in the capacity of the pericardial cavity. Examination may reveal distant heart sounds and increase in the area of cardiac dullness to percussion. The chest radiograph typically shows a large globular heart and clear lung fields. Echocardiography is the investigation of choice for confirming the presence of effusion and for assessing its volume. Pericardial tamponade Pericardial tamponade is a condition of haemodynamic instability caused by chamber compression, because increased intrapericardial pressure is greater than the filling pressure of the right and left ventricles. Presentation is typically with shortness of breath or circula- tory collapse. The key physical findings are tachycardia, pulsus paradoxus (an exaggeration of the normal fall in systolic blood pressure on inspiration) of greater than 10 mm Hg, and elevation of the venous pressure. Echocardiography is the most important investigation, providing clear evidence of fluid collection around the heart and presence of diastolic right ventricular or right atrial collapse. Immediate management is by pericardial aspiration. Pericardial constriction A stiff pericardium loses its stretching ability to accommodate normal changes in intracardiac pressures. Most patients present with leg or abdominal swelling and dyspnoea. The key physical find- ings are elevated venous pressure (with a characteristic ‘M’ or ‘W’ waveform), a pericardial knock, hepatomegaly, ascites, and oedema. Investigation and diagnosis—​Doppler echocardiography is the best non​invasive investigation. Cardiac catheterization demon- strates a difference of less than 5 mm Hg between end-​diastolic pressures in the two ventricles, persisting with respiration and fluid loading; a peak right ventricular pressure of less than 50 mm Hg; and a ratio of end-​diastolic to peak right ventricular pressure of more than 0.33. Management—​fluid retention in early pericardial constriction can be managed by diuretics, with pericardiectomy recommended for patients who are resistant. Anatomy and physiology The pericardium consists of two layers, a visceral layer lined by mesothelial cells and a parietal or fibrous layer also lined by meso- thelial cells, but with attached fat and fibrous tissue. The mesothelial layer secretes about 50 ml of clear pericardial fluid that allows both surfaces to slide together during the cardiac cycle. The innermost layer of the visceral pericardium is adherent to the outer myocardial layer, the epicardium. The fibrous layer is usually 1 mm in thick- ness, and the visceral layer is a transparent membrane on the surface of the heart. The fibrous pericardium attaches the heart to the dia- phragm below and the great vessels above. Intrapericardial pressure normally ranges between −2 and 2 mm Hg, thus it is less than that of the right heart. It falls with the intrapleural pressure during inspiration, resulting in a fall in right-​ sided cardiac pressures. This causes a modest increase in right heart filling velocities with inspiration. These effects are often exaggerated in patients with clinically significant pericardial disease. 16.8 Pericardial disease Michael Henein section 16  Cardiovascular disorders 3502 The most common clinical presentations of pericardial disease are pericarditis, effusion, tamponade, and constriction. Pericarditis Causes Infection The most common causes of acute viral pericarditis are coxsackie B, flu, mumps, hepatitis B, rubella, echovirus 8, and HIV. The typical presentation is with ‘flu-​like’ upper respiratory tract infection along with chest pain that is related to breathing. Sending blood tests for viral titres is not usually conclusive in routine clinical practice. The condition is usually self-​limiting. Bacterial infection (other than tuberculous) is a very rare cause of pericarditis, usually caused by staphylococci, pneumococci, or streptococci spreading directly from the lungs or pleura, particu- larly in patients with impaired immunity. Tuberculous infection is an important cause of bacterial peri- cardial disease, particularly in developing countries. It may take the form of acute pericarditis, pericardial effusion, or constric- tion. The primary response is an acute pericarditis due to allergic reaction. Chronic pericardial effusion and constriction both re- flect granulomatous disease complicated by fibrosis and calcifi- cation. Both parietal and visceral layers of the pericardium may be involved, including the epicardial layer of the myocardium. In sub-​Saharan Africa, most patients (>80%) with tuberculous peri- carditis will be HIV positive. This needs to be established before treatment: antituberculous chemotherapy is the first line of man- agement for all, but if there is pericardial effusion or constriction steroids are used for the first few weeks to limit the development of adhesions and hence the need for pericardiectomy in those who are HIV-​negative. Actinomycosis, coccidioidomycosis, histoplasmosis, and hydatid disease can rarely cause pericarditis in endemic areas. Myocardial infarction This may be complicated by acute pericarditis in 15% of cases, par- ticularly in patients with transmural infarction, when electrocardi- ography (ECG) demonstrates ST and T-​wave changes that are more generalized than the segmental distribution of the infarct. A friction rub may be heard and a small effusion may be seen on transthoracic echocardiographic examination. A delayed response 3 to 4 weeks after an acute infarct may present as Dressler’s syndrome, with fever and pericardial rub. Although this condition is self-​limiting it may respond to non​steroidal anti-​inflammatory medications (NSAIDs) and (if needed) steroids. Autoimmune diseases Pericardial involvement can be a serious manifestation of rheuma- toid disease, systemic lupus erythematosus, systemic sclerosis, and Churg–​Strauss syndrome. Presentation can be with pericardial pain, effusion, or even constriction. A small pericardial effusion is seen in most cases of rheumatic fever, but this hardly ever develops into a significant problem. If adhesions develop they may later mature in the form of constriction, a pathology which can be confirmed at the time of valve surgery. Other medical conditions Inadequately treated chronic renal failure may be complicated by pericarditis and pericardial effusion. Pericardial tamponade may develop if the effusion remains untreated. Hypothyroidism may be complicated by pericarditis, usually accompanied by a small fluid collection that is unlikely to require drainage. Irradiation Irradiation can cause pericarditis soon after treatment, with typical ECG presentation, fluid collection, or even constriction. Late pres- entation can be seen years after irradiation, when the pericardium is thickened and fibrosed. Clinical features and management There are three main features of the clinical syndrome of acute pericarditis—​chest pain, pericardial rub, and ECG changes. The chest pain occurs at rest and varies with posture and respir- ation. It is typically sudden in onset (although often preceded by the non​specific symptoms of a viral illness), retrosternal, continuous, sharp, or ‘raw’ in character, worse on inspiration, radiating to the tra- pezius ridge, and relieved by sitting up. It needs to be distinguished from ischaemic cardiac pain (particularly in the context of recent myocardial infarction), oesophageal pain, and musculoskeletal pain. On examination the main feature is the presence of a pericardial rub. This scratching or creaking sound, variably described as being like ‘walking on fresh snow’ or the ‘creaking of new leather’, is usually loudest at the left sternal border, but may be heard anywhere in the chest. It often changes with posture, may be louder with inspiration, and can be fleeting, recurring in hours. In isolated pericarditis, other elements of the cardiovascular examination are usually normal un- less pericarditis is associated with the presence of significant peri- cardial fluid to cause tamponade, or with pericardial constriction. The typical ECG change is generalized ST elevation, usually con- cave upwards, by 1 mm or more. The extent of ST change (unlike that of myocardial infarction) does not usually conform to a single coronary artery territory. Similar ECG features may be seen in indi- viduals with early repolarization and in cases without a typical pres- entation it is important to repeat the ECG in the convalescent phase to ensure that the changes are not fixed to avoid over diagnosis of the condition. Depression of the PR segment is a subtle but char- acteristic feature. Non​specific T-​wave changes may follow after the acute episode has resolved. ST changes usually resolve, but T-​wave changes may persist for years afterwards in some cases. A minor troponin rise reflecting myocardial involvement is not uncommon. Inflammatory markers—​C-​reactive protein and erythrocyte sedi- mentation rate (ESR)—​are also commonly raised. The chest radiograph is not usually helpful in diagnosis:  it may show cardiac enlargement, but may be completely normal. Echocardiography is the best technique to show any fluid collection around the heart and to assess its physiological significance. Similar findings can be shown by cardiac MRI, if available. Although the underlying cause of pericarditis should always be sought, the final diagnosis is often ‘idiopathic’ or ‘presumed viral’. Idiopathic pericarditis is self-​limiting and needs only analgesics. Small effusions due to other causes rarely need drainage, but with symptoms the patient may benefit from NSAIDs. Colchicine is trad- itionally used as second line therapy in patients with recurrent or 16.8  Pericardial disease 3503 persistent pericarditis. However recent evidence suggests that the use of colchicine as a first-​line agent (at a dose of 0.5 mg twice daily for 3 months for patients weighing >70 kg or 0.5 mg once daily for patients weighing ≤70 kg) may also reduce the rate of symptom persistence and recurrence. Pericardial effusion The diagnosis of pericardial effusion is only made when the volume of the fluid in the pericardial space is more than the physiological amount of 50 ml. Two-​dimensional echocardiography can detect 100 ml fluid in the pericardial space. Pericardial effusion can be secondary to cardiac or non​cardiac causes. Acute rapid collection is usually caused by traumatic injury, iatrogenic ventricular puncture, or aortic dissection. The common causes of chronic fluid accumulation are viral infection, uraemia, autoimmune rheumatic disease, myocardial infarction, myxoedema, and malignancy. Conditions associated with generalized salt and water retention such as congestive cardiac failure, renal failure, and hepatic cirrhosis may also be complicated by pericardial effusion. A small, rapidly accumulated effusion may result in raised peri- cardial pressure and development of symptoms (see ‘Pericardial tamponade’), whereas with a slowly accumulating effusion patients may remain asymptomatic despite the presence of a large volume of fluid because of the corresponding increase in the capacity of the pericardial cavity. Symptoms in uncomplicated pericardial ef- fusion are non​specific—​reduced exercise tolerance or dull aching chest pain—​but patients may develop symptoms of mediastinal syn- drome: cough caused by bronchial compression, dyspnoea due to lung compression, or hoarseness of voice caused by recurrent laryn- geal nerve compression. On examination distant heart sounds and increase in the area of cardiac dullness to percussion may be the only physical signs until tamponade develops. The chest radiograph does not always confirm the presence of pericardial effusion if it is less than 250 ml, but when the effusion is large there is an increased cardiothoracic ratio and the cardiac shadow is globally enlarged (Fig. 16.8.1). The ECG may show low-​ voltage QRS complexes, and electrical alternans may be present if the effusion is large, with the heart swinging to and fro within it (Fig. 16.8.2). Echocardiography is the investigation of choice for confirming the presence of pericardial effusion and for assessing its volume (Fig. 16.8.3). An echo-​free space in the pericardium, on both M-​mode and two-​dimensional images, should be distinguished from anterior pericardial fat pad. Quantitation of pericardial ef- fusion is quite reliable from two-​dimensional echocardiographic images: a 1-​cm global collection around the heart suggests an ap- proximate amount of 200 ml. With localized effusion, a compara- tive assessment of the effusion size with that of the left ventricle gives a rough estimation of the collection volume. The haemo- dynamic effects of pericardial effusion depend on the pressure–​ volume relation of the pericardium, the speed of fluid collection and the volume of the effusion. Changes in ventricular compliance may also influence the haemodynamic effects of pericardial effu- sion in patients with ventricular disease. Pericardial tamponade Pericardial tamponade is a condition of haemodynamic instability caused by chamber compression because increased intrapericardial pressure is greater than the filling pressure of the right and left ventricles. Pathophysiology Provided the pericardium can stretch slowly, more than 2000 ml of fluid can be accumulated without a significant increase in pres- sure, but rapid accumulation of as little as 200 ml increases peri- cardial pressure. Inability of the pericardium to distend acutely causes its pressure to rise above right atrial pressure, followed by Fig. 16.8.1  Posteroanterior chest radiograph of a patient with a large pericardial effusion. The heart shadow is greatly enlarged and globular in shape. The parts of the lung fields that can be seen are normal. Fig. 16.8.2  ECG from a patient with a massive malignant pericardial effusion. All QRS complexes are sinus beats with a constant PR interval, but the QRS axis alternates, hence the term ‘electrical alternans’. section 16  Cardiovascular disorders 3504 right ventricular pressure, and eventually results in right ventricular collapse. Intrapericardial and intrapleural pressures normally fall equally during inspiration, but with tamponade intrapericardial pressure does not fall as much, resulting in a reduced pressure gra- dient between intrathoracic pressure/​pulmonary veins and left atrium/​left ventricle. This results in reduced left-​sided filling veloci- ties during inspiration and hence stroke volume. On the right side of the heart the normal increase in right ventricular dimensions during inspiration enhances right-​sided filling and ejection. Progressive in- crease in pericardial pressure and right ventricular pressure may affect the left heart further, adding to the compromise of its filling during inspiration and exacerbating reduction in stroke volume. The combined effect of these two mechanisms eventually comprom- ises cardiac output. Pericardial pressure greater than 10 mm Hg results in right ven- tricular collapse and raised diastolic pressures of both ventricles as well as increased capillary wedge pressure. This leads to inspiratory fall of aortic pressure and hence hypotension with pulsus paradoxus (see ‘Clinical features’). Left ventricular and left atrial collapse are much less commonly seen with tamponade. Causes The most common cause of tamponade is malignant effusion or acute fluid collection after cardiac surgery. Intrapericardial clot for- mation after cardiac surgery or as a complication of an interven- tional procedure (e.g. trans-​septal puncture) may result in signs of tamponade due to the rapid increase in intrapericardial pressure, even in the absence of a significantly large fluid volume. Left ven- tricular invagination caused by localized collection around the free wall has been reported after open heart surgery. Significant localized posterior effusion is usually caused by anterior adhesions between the right ventricle, the right atrium, and pericardium. Clinical features Patients with cardiac tamponade present with shortness of breath or circulatory collapse. The key physical findings to make the diagnosis are tachycardia, pulsus paradoxus of more than 10 mm Hg, and ele- vation of the venous pressure. Tachycardia (>100 beat/​min) is almost invariable, but clearly not specific for tamponade. Pulsus paradoxus describes an exaggeration of the normal fall in systolic blood pressure (up to 10–​12 mm Hg) on inspiration. With the patient breathing normally, the best way to detect this sign is to stop deflation of the blood pressure cuff as soon as the first Korotkoff sound is heard, in which case in the presence of pulsus paradoxus the sound will disappear on every inhalation and reappear on every exhalation. After noting the systolic pressure reading, the cuff is then gradually deflated until the Korotkoff sound is heard throughout the respiratory cycle, at which point the pres- sure is again noted—​the difference between the two readings is the measurement of the amount of paradox. A pulsus paradoxus greater than 10 mm Hg is found in 98% of patients with tamponade, greater than 20 mm Hg in 78%, greater than 30 mm Hg in 49%, greater than 40 mm Hg in 38%, and total (pulse not palpable on inspiration) in 23%. The most common reason for pulsus paradoxus to be absent in tamponade is compromised stroke volume. However, although pulsus paradoxus is a sensitive sign of tamponade, it must be noted that it is not specific: it can be seen not infrequently in severe asthma, also (uncommonly) in constrictive pericarditis, right ventricular in- farction, and pulmonary embolism. The venous pressure is always high in cardiac tamponade: if it is not, then the diagnosis is wrong. Usually it is very high, which can make it difficult to see the top. The venous pressure normally falls on inspiration because right heart pressures drop as intrathoracic pressure decreases. Kussmaul’s sign is an increase in venous pres- sure during inspiration, which can be observed (infrequently if at all in most series) in tamponade because of the inability of the right atrium and ventricle to accommodate greater influx of blood. Abnormalities of the venous wave form are not helpful in making the diagnosis of tamponade. In addition to tachycardia, pulsus paradoxus, and elevated venous pressure, patients with tamponade will usually have tachypnoea and cool peripheries, and they may have a pericardial rub. Differential diagnosis The main requirement is for the doctor to consider the diagnosis, even if only briefly, when confronted with any patient in unex- plained circulatory shock. Tamponade must be distinguished from the common causes of such a presentation, namely hypovolaemia, overwhelming sepsis, severe ventricular disease (e.g. acute myocar- dial infarction), and pulmonary embolism. If the patient is shocked with a high venous pressure, then par- ticular consideration needs to be given to pulmonary embolism, right ventricular infarction, and (less commonly) pericardial constriction. Investigations The chest radiograph typically shows a large globular heart, which unlike congestive heart failure, is not associated with pulmonary venous congestion (Fig. 16.8.1): if pulmonary oedema is present, it suggests additional myocardial disease. The ECG shows tachycardia, often with low-​voltage QRS complexes, and may reveal electrical alternans (Fig. 16.8.2). Echocardiography is the most important investigation. It provides clear evidence for fluid collection around the heart, which is usu- ally large with tamponade (Fig. 16.8.3), and is likely to show evi- dence for diastolic right ventricular or right atrial collapse. Right ventricular collapse is a sensitive (92%) and highly specific (100%) PE LV LA Fig. 16.8.3  Parasternal long axis echocardiographic view from a patient with a large pericardial effusion (PE), located mostly posteriorly to the left ventricle (LV). LA, left atrium. 16.8  Pericardial disease 3505 diagnostic sign for tamponade, reflecting transient negative trans- mural early diastolic pressure as pericardial pressure exceeds right ventricular pressure. Right atrial collapse is less sensitive (82%) but equally specific (100%). In the absence of a haemodynamically sig- nificant pericardial effusion, right ventricular diastolic collapse may be caused by bilateral large pleural effusions (Fig. 16.8.4). Right ven- tricular collapse may be delayed by myocardial hypertrophy, pul- monary hypertension, or free wall adhesions, commonly associated with malignant effusions. Swinging of the heart inside the pericar- dial fluid may be seen. Doppler recordings of right and left cardiac filling and ejection show inspiratory dominance in the right with re- ciprocal changes in the left (Fig. 16.8.5). Finally, echocardiography can exclude the presence of large pleural effusion as a potential cause of the clinical and physiological disturbances: it is essential for the echocardiographer to identify the high-​intensity echo of the fibrous pericardium posterior to the left ventricle on the left parasternal image—​a pericardial effusion is inside this layer and a pleural effu- sion outside it. Management Pericardial tamponade is a medical emergency, particularly when there is clear evidence for arterial paradox, or if the effusion is col- lecting rapidly. Pericardial aspiration should be performed in an area where resuscitation facilities are available. Echocardiography is used to determine where to insert the needle and to estimate the depth and direction of advancement. The subcostal route is the most popular because it avoids possible injury to the coronary artery (left anterior descending). After administration of a local anaesthetic a larger needle or polythene cannula is introduced into the effusion, followed by a pigtail catheter inserted over a guide wire. An injec- tion of agitated saline through the drain can help to confirm that it is in the pericardial space. A maximum of 500 ml of fluid is removed initially to relieve haemodynamic instability: rapid withdrawal of a larger volume can provoke cardiovascular collapse. Continuous drainage is then commenced and the rest of the effusion drained over the next few hours. Many pericardial effusions are heavily bloodstained, particularly those that are malignant. The aspirated fluid can be distinguished from blood (usually to the great relief of the doctor performing the procedure) by its colour (dark because very desaturated) and failure to clot (because defibrinated). Fluid should be sent for culture and cytological analysis. Biochemical analysis (glucose and protein) can sometimes be useful but is diagnostically less reliable than for pleural effusions. Surgical creation of a pericardial window (usually with video-​ assisted thoracoscopy) is recommended for recurrent or rapidly accumulating effusions and permits therapeutic pressure relief, fluid drainage, and pericardial biopsy (for culture and histological examination). Constrictive pericarditis Pericardial constriction is a pathological condition characterized by pericardial thickening and fibrosis that results in adhesion of its two layers. Chronic constrictive pericarditis frequently proves to be ‘idiopathic’; a (presumed) viral aetiology is frequently invoked when no other cause is found. Tuberculosis is currently an uncommon cause, particularly in developed countries. Other causes include ra- diation, autoimmune rheumatic disease, chronic renal failure, neo- plastic disease, and previous cardiac surgery. Pathophysiology The stiff pericardium loses its stretching ability to accommodate normal changes in intracardiac pressures. This is demonstrated by equalization of a raised end-​diastolic pressures in the right and left ventricles, with the dip–​plateau pattern a cardinal sign for diagnosing pericardial constriction (see Fig. 16.3.4.1). Pericardial constriction also leads to characteristic abnormalities in the venous pressure waveform, with prominent ‘x’ and ‘y’ des- cents. The ‘x’ descent, which occurs after atrial contraction (‘a’ wave), is caused by two processes: (1) right atrial relaxation (followed by a positive ‘c’ wave that is not visible on inspection), and (2)  the atrioventricular tricuspid valve ring moving downwards during LA Pleural Fig. 16.8.4  Parasternal long axis view showing pleural effusion posterior to the left ventricle. Expiration Inspiration I E Fig. 16.8.5  Transmitral pulsed Doppler velocities from a patient with large pericardial effusion and tamponade demonstrating significant fall in left ventricular filling velocities with inspiration (arrow, I) compared to expiration (arrow, E). section 16  Cardiovascular disorders 3506 systole, increasing the volume of the right atrium. A fibrosed and unstretchable pericardium, being adherent to the epicardial layer of the myocardium, can limit its normal movement during the cardiac cycle along the ventricular transverse axis, particularly in systole. It cannot, however, affect shortening and lengthening of the longi- tudinal myocardial fibres that are located in the subendocardium, hence the downward displacement of the tricuspid ring and valve in systole is preserved, allowing a column of blood to enter the atrium rapidly, thereby producing a characteristic exaggerated ‘x’ descent (Fig. 16.8.6). Following the ‘x’ descent the ‘v’ wave represents right atrial filling, with the ‘y’ descent beginning the moment that the tri- cuspid valve opens at the beginning of diastole and allows blood to enter the ventricle. In pericardial constriction the ‘y’ descent is prominent because, from a high venous pressure, diastolic filling is not impaired at the beginning of diastole, only when the relaxing ventricle meets the rigid pericardium. Similar features can be seen in the left heart physiology. It should be noted that simply the presence of a thickened peri- cardium on imaging techniques (echo or MRI) is not a sufficient diagnostic criterion for constrictive physiology. Furthermore, in rare cases of rapidly increasing ventricular volumes, as in dilated cardiomyopathy, the pericardium may be completely normal and yet demonstrate an external constricting effect, thus adding to the deterioration of the clinical condition. Clinical features Most patients with constrictive pericarditis present with leg or ab- dominal swelling and dyspnoea. Rarely the patient can present with jaundice, or with features of nephrotic syndrome or protein-​losing enteropathy. The key physical findings are elevated venous pressure, a pericardial ‘knock’, hepatomegaly, ascites, and oedema. As with pericardial tamponade, the venous pressure is always high; if it is not, then the diagnosis is almost certainly wrong. However, unlike with pericardial tamponade, the form of the venous waveform is characteristic, with exaggerated ‘x’ followed by ‘y’ des- cent (for reasons explained earlier) that create two conspicuous dips per cardiac cycle, making the waveform appear to follow an ‘M’ or ‘W’ pattern with each arterial pulse (Fig. 16.8.6). Kussmaul’s sign (an increase in venous pressure during inspiration) is seen in 50% of cases. Sometimes the changes in venous pressure are transmitted to the liver, which then pulses twice with each cardiac cycle. A pericardial knock is a loud, high-​frequency sound, typically best heard between the left lower sternal border and the apex. It is caused by sudden cessation of ventricular filling as it meets the con- striction and is reported in about 50% of cases in most series. Other common findings are atrial fibrillation, a mild degree of pulsus paradoxus (≤20 mm Hg), and systolic retraction of the apical impulse. A pericardial rub can be heard in some cases. Differential diagnosis The main differential diagnosis of constrictive pericarditis is restrictive myocardial disease (see Chapters  16.7.2 and 16.7.3). Distinction between these can be difficult. In restriction, ventricular filling becomes limited to early diastole, with high acceleration and deceleration frequently associated with right-​sided third heart sound. Respiratory variation of ventricular filling and ejection vel- ocities may be present in constriction but is absent in restrictive right ventricular disease. Imaging can help to determine if the main abnormality is likely to be pericardial or myocardial. Pericardial constriction also needs to be distinguished from other causes of raised venous pressure, including obstruction of the su- perior vena cava, tricuspid stenosis, or tricuspid regurgitation. Investigations The chest radiograph is usually normal but may show pericardial calcification, either as multiple plaques or as a rim covering the dia- phragmatic and anterior surfaces of the heart. The ECG is not diag- nostic, but can show low-​voltage QRS complexes and non​specific T-​wave changes. On CT or MRI, the pericardium may appear thick- ened, but this is an insensitive marker for constriction. Doppler echocardiography is the best non​invasive investigation to demonstrate the systolic descent in the jugular venous pressure and systolic filling of the right atrium from the superior and in- ferior vena cavae during ventricular systole. Ventricular filling is non​specific, depending on additional myocardial disease. In con- strictive pericarditis there is less intracardiac than extracardiac re- spiratory variation, particularly on the right side, when compared to that seen with pericardial tamponade. A raised right atrial pressure during inspiration (Kussmaul’s sign) and dilated inferior vena cava are non​specific signs of constriction. Spontaneous contrast in the inferior vena cava, resulting from the limited venous return, may also be an additional finding in favour of constrictive pericarditis. Cardiac catheterization demonstrates the following diagnostic features for constriction: • a difference of less than 5 mm Hg between end-​diastolic pressures in the two ventricles, persisting with respiration and fluid loading; X X Y Y Y X X Y Fig. 16.8.6  Systemic venous pulse from a patient with constrictive pericarditis before (top) and after (bottom) pericardiectomy. Note the ‘M’ or ‘W’ pattern, with deep ‘x’ descent that disappears after pericardiectomy. 16.8  Pericardial disease 3507 • a peak right ventricular pressure of less than 50 mm Hg; • a ratio of end-​diastolic to peak right ventricular pressure of more than 0.33. Management Fluid retention in early pericardial constriction can be managed by diuretics, with pericardiectomy recommended for patients who are resistant. After surgical removal of the pericardium, which is often very difficult, the venous pressure drops and the ‘x’ descent disappears from the jugular venous pressure (Fig. 16.8.6). This is not always in- stantaneous and may take up to a few days or even weeks to settle. Pericardial complications after open heart surgery Apart from the commonly seen pericardial collection, other signifi- cant complications may occur that have a major impact on clinical management. Pericardial clot A collection of clots in the pericardial space, with or without pericar- dial effusion, is often associated with delayed postoperative clinical recovery. It may have an important physiological effect on overall cardiac function, irrespective of the amount present. The clinical presentation is typically with cooling of the peripheries, hypoten- sion, and fall in urine output over minutes to hours, and the con- dition should be suspected particularly in any patient who has bled rather heavily at operation, especially if the blood flow from the chest drains suddenly falls. There are no specific abnormalities on the chest radiograph or ECG; transthoracic echocardiography rarely gives good images immediately postoperatively; transoesophageal echocardiography may show clotting alongside the heart. Reopening the chest to remove the clot surgically is the best management, with early detection and removal securing complete recovery. ‘Tight’ pericardium In the absence of postoperative pericardial effusion, intrapericardial pressure may be raised to the extent that it affects right-​sided physi- ology so that superior vena caval flow occurs only during inspir- ation. This condition mimics left ventricular disease and may lead to inappropriate administration of inotropic agents. The jugular venous pressure is raised, and right-​sided filling and ejection is pre- dominantly inspiratory. On two-​dimensional echocardiographic images there is no evidence for right atrial or ventricular collapse. Although these signs usually resolve with time, delayed sternal closure has proved beneficial when the clinical manifestations are severe. The condition tends to settle within days or weeks after sur- gery, with complete normalization of venous pressure. Restrictive pericarditis This is a rare clinical presentation that has been documented after open heart surgery, presenting with resistant fluid retention and raised venous pressure. Two-​dimensional echocardiographic images may not show any specific abnormality, although MRI may demon- strate a thickened pericardium. The underlying pathology seems to be chronic combined pericardial and epicardial inflammation that results in massive fibrosis and adhesions between the two layers, with myocardial involvement. Patients with this condition are usu- ally resistant to medical therapy, demonstrating signs of restrictive physiology on both sides of the heart with a dominant early dia- stolic filling component and short deceleration time. Cases resistant to medical therapy may respond to surgical decortication of the pericardium. Pericardial tumours The commonest tumours of the pericardium are secondaries from elsewhere, most frequently carcinoma of the breast and lung, ma- lignant melanoma, lymphoma, and leukaemia. They invade the pericardium either directly, or via lymphatics, or by haematogenous dissemination. Primary tumours are rare but include malignant mesothelioma and sarcomas. Whereas carcinomas metastasize in the pericardium in the form of localized masses, lymphomas, and leukaemia present in the form of uniform pericardial infiltration and thickening, which may cause tumour incarceration of the heart and hence the clinical syndrome of ‘constrictive physiology’. A mild degree of pericardial thickening can easily be missed on echocardi- ography, but the pattern of ventricular wall motion is characteristic. MRI or CT may be better at showing pericardial thickening. Recurrent pericardial effusion of unknown aetiology should al- ways suggest malignancy until otherwise proved, as should pericar- dial effusion in the presence of an intracardiac mass. Congenital pericardial disease Congenital anomalies of the pericardium are rare. Pleuropericardial defect, either complete or partial (80% of cases), is the most common form. The left side is most commonly involved in the partial form, allowing the left atrial appendage or part of the left ventricle (if the defect is large) to herniate through the defects. The chest radiograph is characteristic, demonstrating a shift of the heart to the left and prominent main pulmonary artery. Defects in the diaphragmatic portion of the pericardium are extremely rare. In most instances pericardial defects are asymptomatic, but about one-​third of cases are associated with congenital abnormalities of the heart and lungs. Pericardial cysts are very rare, difficult to diagnose, and if present do not cause any clinical problem. Their presence can only be con- firmed when found surgically and removed. Pericardial constriction due to fibrosis of unknown cause may contribute to the clinical picture of Mulibrey (muscle, liver, brain, eye) nanism (OMIM 253250), which is an autosomal recessive condition characterized by growth failure, a triangular face (often with a hydrocephalus), hypotonia, a peculiar voice, large liver, and yellowish dots and pigment dispersion in the optic fundi. FURTHER READING Athappan G, Sorajja P (2017). Invasive hemodynamics of pericardial disease. Interv Cardiol Clin, 6, 309–​17. Callahan JA, et  al. (1985). Two-​dimensional echocardiographically guided pericardiocentesis: experience in 117 consecutive patients. Am J Cardiol, 55, 476–​9. section 16  Cardiovascular disorders 3508 Cameron J, et al. (1987). The etiologic spectrum of constrictive peri- carditis. Am Heart J, 113, 354–​60. Chang SA (2017). Tuberculous and infectious pericarditis. Cardiol Clin, 35, 615–​22. Guberman BA, et al. (1981). Cardiac tamponade in medical patients. Circulation, 64, 633–​40. Henein MY, et al. (1999). Restrictive pericarditis. Heart, 82, 389–​92. Henein MY (2012). Clinical echocardiography, 2nd edition. Springer, London. Imazio M, et al. (2013). A randomized trial of colchicine for acute peri- carditis. N Engl J Med, 369, 1522–​8. Imazio M, Gribaudo E, Gaita F (2017). Recurrent pericarditis. Prog Cardiovasc Dis, 59, 360–​8. McGee SR (2001). Evidence-​based physical diagnosis. W. B. Saunders, Philadelphia, PA. Miranda WR, Oh JK (2017). Effusive-​constrictive pericarditis. Cardiol Clin, 35, 551–​8. Murashita T, et  al. (2017). Experience with pericardiectomy for constrictive pericarditis over eight decades. Ann Thorac Surg, 104, 742–​50. Reddy PS, et al. (1978). Cardiac tamponade: hemodynamic obser- vations in man. Circulation, 58, 265–​72. Sagrista-​Sauleda J, et  al. (2004). Effusive-​constrictive pericarditis. N Engl J Med, 350, 469–​75. Shabetai R, et al. (1965). Pulsus paradoxus. J Clin Invest, 44, 1882–​98. Shabetai R, Oh JK (2017). Pericardial effusion and compressive disorders of the heart: influence of new technology on unrav- eling its pathophysiology and hemodynamics. Cardiol Clin, 35, 467–​79. Welch TD, Oh JK (2017). Constrictive pericarditis. Cardiol Clin, 35, 539–​49. Xu B, Kwon DH, Klein AL (2017). Imaging of the pericardium:  a multimodality cardiovascular imaging update. Cardiol Clin, 35, 491–​503. 16.9 Cardiac involvement in infectious disease 350 16.9 Cardiac involvement in infectious disease 3509 16.9.2 Endocarditis 3519 James L. Harrison, John L 16.9.2 Endocarditis 3519 James L. Harrison, John L. Klein, William A. Littler, and Bernard D. Prendergast 16.9.2  Endocarditis 3519 Parks T, et al. (2017). Association between a common immunoglobulin heavy chain allele and rheumatic heart disease risk in Oceania. Nat Commun, 8, 14946. Quinn RW (1989). Comprehensive review of morbidity and mor- tality trends for rheumatic fever, streptococcal disease, and scarlet fever: the decline of rheumatic fever. Rev Infect Dis, 11, 928–​53. Remenyi B, et al. (2012). World Heart Federation criteria for echocar- diographic diagnosis of rheumatic heart disease-​an evidence-​based guideline. Nat Rev Cardiol, 9, 297–​309. RHD Australia (ARF/​RHD writing group), National Heart Foundation of Australia, and the Cardiac Society of Australia and New Zealand (2012). Australian guideline for prevention, diagnosis and manage- ment of acute rheumatic fever and rheumatic heart disease, 2nd edi- tion. Menzies School of Health Research, Darwin. Roberts K, et al. (2014). Echocardiographic screening for rheumatic heart disease in high and low risk Australian children. Circulation, 129, 1953–​61. Robertson KA, Volmink JA, Mayosi BM (2005). Antibiotics for the primary prevention of rheumatic fever:  a meta-​analysis. BMC Cardiovasc Disord, 5, 11. Seckeler MD, Hoke TR (2011). The worldwide epidemiology of acute rheumatic fever and rheumatic heart disease. Clin Epidemiol, 3, 67–​84. Shulman ST, et al. (2012). Clinical practice guideline for the diagnosis and management of group A streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America. Clin Infect Dis, 55, 1279–​82. Stollerman GH (2001). Rheumatic fever in the 21st century. Clin Infect Dis, 33, 806–​14. Tubridy-​Clark M, Carapetis JR (2007). Subclinical carditis in rheum- atic fever: a systematic review. Int J Cardiol, 119, 54–​8. Veasy LG, Tani LY, Hill HR (1994). Persistence of acute rheumatic fever in the intermountain area of the United States. J Pediatr, 124, 9–​16. Watkins D, et  al. (2017). Global, regional, and national burden of rheumatic heart disease, 1990–​2015. N Engl J Med, 377(8), 713–​22. WHO Expert Consultation on Rheumatic Fever and Rheumatic Heart Disease (2004). Rheumatic fever and rheumatic heart di- sease: report of a WHO Expert Consultation, Geneva, 29 October–​1 November 2001. WHO Technical Report Series 923, World Health Organization, Geneva. Zuhlke L, et al. (2016). Clinical outcomes in 3343 children and adults with rheumatic heart disease from 14 low-​ and middle-​income coun- tries: two-​year follow-​up of the Global Rheumatic Heart Disease Registry (the REMEDY Study). Circulation, 134(19), 1456–​66. 16.9.2  Endocarditis James L. Harrison, John L. Klein, William A. Littler, and Bernard D. Prendergast ESSENTIALS Endocarditis predominantly affects the aortic and mitral valves; in- volvement of the tricuspid valve occurs in approximately one-​fifth of cases and pulmonary valve involvement is rare. In the developing world rheumatic heart disease is the most common predisposing factor. In developed countries endocarditis is more common in older people with native valve disease and in patients with prosthetic valves and intracardiac devices (pacemakers and defibrillators). In these countries up to 50% of cases have no predisposing cardiac lesion and more cases are related to intravenous drug abuse and nosoco- mial infection related to invasive procedures. Mortality remains high (30%) despite advances in antimicrobial therapy and surgery, and at least 50% of cases require valve surgery. Early diagnosis, specialist management, and timely intervention are key to successful outcome. Clinical features Presenting symptoms and signs include those of a bacteraemic illness, tissue destruction (heart valve(s) and adjacent structures); phenomena thought to be related to circulating immune com- plexes (e.g. splinter and conjunctival haemorrhages, Osler’s nodes, Janeway lesions, vasculitic rash, Roth spots, and nephritis; and sys- temic and septic pulmonary emboli in left-​ and right-​sided lesions, respectively). Blood culture is the most important laboratory investigation, with prolonged incubation requested in circumstances where endocar- ditis is strongly suspected. Serological tests can aid in the identifi- cation of organisms that are difficult to isolate. Echocardiography should be performed as soon as possible when endocarditis is sus- pected: its principal role is to detect vegetations, but it is not suf- ficiently sensitive to allow the clinician to exclude the diagnosis confidently on the basis of a negative result. Diagnosis is based on pathological criteria (demonstration of microorganisms by cul- ture or histological examination, or histological evidence of active endocarditis) or—​more usually—​a combination of major and minor clinical criteria, with the major clinical criteria relating to (1) positive blood cultures of ‘typical’ or ‘consistent’ organisms, and (2) evidence of endocardial involvement detected on physical examination (new murmur) or with echocardiography. Causes and management Worldwide the principal causes of endocarditis are viridans strepto- cocci (up to 58%) and Staphylococcus aureus (30% of community-​ acquired and 46% of hospital-​acquired disease) with Streptococcus bovis, enterococcus species, fungi, coagulase-​negative staphylo- cocci, and the HACEK group of organisms making up the remainder. However, in developed countries the epidemiological profile has changed in recent decades: rheumatic heart disease is now rare, and with more cases related to prosthetic valves (20% of all cases) device therapy and nosocomial infection, Staph. aureus has overtaken oral streptococci as the most common pathogen. Best management is provided by a multidisciplinary team involving cardiologists, microbiologists, infectious disease specialists, and car- diac surgeons. Bactericidal antibiotics are the mainstay of treatment. Recommended empirical therapy for the patient with suspected na- tive valve endocarditis is amoxicillin or ampicillin (12 g/​day IV in four divided doses) plus gentamicin (1 mg/​kg body weight IV 8-​hourly, modified according to renal function), substituting vancomycin for amoxicillin/​ampicillin in patients with penicillin allergy. This should be modified to a definitive antibiotic treatment regimen when the pathogen is known. Surgery is required in about 50% of cases, with the main indications being haemodynamic instability, persistent in- fection, annular or aortic abscesses, and significant residual valve re- gurgitation once antibiotic therapy is complete. section 16  Cardiovascular disorders 3520 Prevention Until recently, antibiotic prophylaxis in at-​risk patients—​meaning any with a wide variety of cardiac lesions undergoing a wide var- iety of dental, medical, and surgical procedures—​was accepted as reasonable, but there is no good evidence to support this prac- tice. Recommendations from relevant United Kingdom, European, and American professional bodies are now much more restrictive. National Institute for Health and Clinical Excellence (United Kingdom) guidelines state that antibiotic prophylaxis should only be given to high-​risk patients (including those with prosthetic car- diac valves or other prosthetic material within their hearts, previous endocarditis, and some forms of congenital heart disease) if they are undergoing a gastrointestinal or genitourinary procedure at a site where there is suspected infection. Most cardiologists feel that this is too restrictive and prefer European and American guidelines that recommend prophylaxis before dental and non​dental procedures for patients at high risk. When prophylaxis is recommended for dental and other pro- cedures, regimens typically include amoxicillin (or clindamycin if penicillin-​allergic), with the addition of gentamicin if risks are thought to be high, and substitution of vancomycin (or teicoplanin) for amoxicillin if the patient is penicillin-​allergic (or has taken more than a single dose of penicillin in the previous month). Historical background Lazarus Riverius recorded the first case of what is now known as endocarditis in 1723. He described a French magistrate with an ir- regular pulse, oedema, and congestion, who at autopsy had fleshy masses ‘the size of hazelnuts’ obstructing the aortic ostia. Some 50  years later, Morgani (1769) made the link between infection (fulminating gonorrhoea) and ‘whitish polypus concretions on the upper part of the aortic valve near its borders’. The clinical picture of endocarditis was first described by Jean Baptiste Bouillard, in 1835: ‘fever, an irregular pulse, cardiomegaly (by percussion) and a bellows murmur in the heart’. He gave the dis- ease the name ‘endocarditis’, or an inflammation of the inner mem- brane of the heart and fibrous tissues of the valve, and was the first to use the term ‘vegetations’ for the valvular lesions. Winge used the term ‘mycoses endocardi’ for the groups of microorganisms that he saw when he examined vegetations under the microscope in 1870. In 1886, Wyssecokowitch cultured Staphylococcus aureus from an endocardial vegetation. Lenthartz, in 1901, was the first to use blood cultures in the diagnosis of endocar- ditis. ‘Infective endocarditis’ was the term used by Thomas Horder, in 1901, to describe the syndrome consisting of (1) the presence of valvular disease, (2) the occurrence of systemic embolism, and (3) the discovery of microorganisms in the bloodstream. Epidemiology Endocarditis was universally fatal before the advent of antibiotic therapy. Despite significant advances in diagnosis and treatment, it remains a dangerous disease, particularly for people at risk (prosthetic valves, congenital heart disease, previous endocarditis), in whom morbidity and mortality approach 50%. About 200 deaths are recorded each year in the United Kingdom, but this is almost certainly an underestimate. A recent review of papers published be- tween 1993 and 2003 found the mean age of patients varied between 36 and 69 years, the median incidence being 3.6 per 100 000 popu- lation per year (range 0.3–​22.4), increasing from 5 or less per 100 000 population per year in individuals aged younger than 50 years to 15 or more per 100 000 population per year in those older than 65 years. The median in-​hospital mortality rate was 16% (range 11–​ 26%). The incidence is greater in men, in those over 65 years of age, and in those with prosthetic heart valves. In intravenous drug users, the incidence of endocarditis is estimated as 150–​200 per 100 000 person years. Pathogenesis Normal vascular endothelium is resistant to microbial infection and very few patients potentially at risk actually develop endocar- ditis. Bacteraemia may occur spontaneously during chewing, tooth brushing, and other normal activities. Since low-​grade bacteraemia occurs frequently in everyone, a defence mechanism must exist that can eradicate microbes adherent to fibrin-​platelet aggregates at the site of injured endothelium. Platelets play a pivotal role in the antimicrobial host-​defence mechanism and human platelets have been found to contain at least 10 different bactericidal proteins or ‘thrombocidins’. Damage to the endothelial surface of the heart or blood vessels induces platelet and fibrin deposition producing a sterile thrombotic vegetation; endocarditis is initiated by the binding of microbes, dis- charged into the general circulation from a peripheral site, to these vegetations. These microbes become rapidly encased in further de- positions of platelets and fibrin, and multiply. The pathogenesis of endocarditis involves complex interactions between microbes and the host-​defence mechanisms, both circu- lating and at the site of endothelial damage. An essential step is the activation of the clotting system and the formation of a fibrin clot on the endothelial surface. Experimental evidence suggests that the main pathogens in endocarditis (streptococci and staphylococci) can bind to endothelial cells and induce functional changes within these cells causing monocyte adhesion. The endothelial cells respond to local inflammation by expressing β1-​integrins which promote the adhesion of pathogens that carry fibronectin-​binding proteins on their surface. The combination of damaged endothelial cells, bac- teria, and endothelial bound monocytes results in the induction of tissue-​factor-​dependent procoagulant activity which initiates clot formation. Polymorphonuclear leucocytes which are recruited to the infected endothelial site may be subsequently involved in the disease progression, with the contents of lysosomes released by the activated leucocytes probably causing softening and separation of valve tissue, leading to its destruction. In endocarditis, the vegetations are found predominately on the left side of the heart (85%). In a large autopsy series of more than 1000 cases reported over 50 years ago, the mitral valve was involved in 86%, the aortic in 55%, the tricuspid in 20%, and the pulmonary valve in only 1%. The predominance of left-​sided lesions has led to the belief that the higher pressures and velocities encountered in the 16.9.2  Endocarditis 3521 left side of the heart and the proximal aorta must impose a greater mechanical stress on the valves and endocardium, which in turn leads to local damage. Endocarditis is classically associated with ‘jet lesions’, where blood flowing from a high-​pressure area through an orifice to an area of lower pressure produces a high-​velocity jet. Vegetations are usually found in the lower-​pressure area (e.g. on the atrial surface of the mitral valve in mitral regurgitation, or the ventricular surface of the aortic valve in aortic regurgitation). This particular deposition of vegetations has been explained on the basis of the Venturi effect. Once a vegetation is established, it determines the subsequent clinical picture by four basic processes: bacteraemia, local tissue de- struction, embolization, and the formation of circulating immune complexes. Clinical features Early reports of endocarditis described a low-​grade, febrile illness caused by viridans streptococci from the mouth in a patient with chronic rheumatic heart disease. Night sweats, anorexia, and weight loss were followed by the development of splinter haemorrhages and Osler nodes, finger clubbing, and splenomegaly. The infection pro- gressed relentlessly with increasing cachexia, and the patient died from cardiac failure or a major embolic episode. The term ‘subacute bacterial endocarditis’ was used to describe this illness. ‘Acute or malignant endocarditis’ described an aggressive form of the disease, usually caused by Staph. aureus or other virulent bacteria. During the past 50 years, there has been a striking change in the pattern of endocarditis. The proportion of patients in developed countries with endocarditis who have no known pre-​existing car- diac lesion has risen to almost 50%. This change is related both to the decline in rheumatic heart disease and to the increase in extracardiac predisposing factors, including intravenous drug abuse, haemodi- alysis, and the use of intravascular devices. Prosthetic heart valves are an important predisposing factor and cardiac surgery for com- plex congenital lesions has increased the lifespan of patients who would previously have died prematurely. Antibiotic-​resistant organ- isms have emerged. The longevity of the populations of developed countries has resulted in an increasing age of patients with endo- carditis, with mean age rising from under 40 years before 1940, to 60–​70 years today. For the general physician, the diagnosis of endocarditis is de- pendent upon a high index of suspicion. In the older population, with a high incidence of degenerative valvular disease, an early pres- entation of endocarditis may often be misdiagnosed and treated as a urinary or upper respiratory tract infection with an incidental finding of a heart murmur. Routine investigation with blood cultures of all patients with a history of valvular heart disease presenting with fever, sepsis, or malaise is therefore recommended. Features of a bacteraemic illness Discharge of the infecting agent into the circulation produces constant bacteraemia which may present as pyrexia, rigors, mal- aise, anorexia, headache, confusion, arthralgia, and anaemia. Some cases of endocarditis, particularly in older people, may present without fever. Features of tissue destruction Endocarditis initially affects valve cusps, leaflets, or chordae tendineae. Tissue destruction results in valvular incompetence, cusp perforation, or rupture of the chordae, producing an appropriate cardiac murmur that may change in character during the course of the illness: 80% of patients present with a murmur, and 15–​20% develop one during their hospital stay. Large vegetations rarely ob- struct a native valve, but mechanical obstruction of prosthetic valves is more common and clinically more difficult to detect. As the infective process progresses, it may extend beyond the valve into the paravalvular structures. Aortic root abscess is a serious complication: extension through the aortic wall into other tissues or cavities can create a fistula or pseudoaneurysm. Particular prob- lems can include the development of a sinus of Valsalva aneurysm and involvement of the coronary ostia. Septal abscesses can lead to progressive conduction defects evidenced by prolongation of the PR interval on the electrocardiogram (ECG) and, eventually, complete heart block. Paravalvular abscess is more common in native aortic valve endo- carditis than in mitral valve infection. Infection of a mechanical valve involves the sewing ring and may lead to valve dehiscence. In the case of a mechanical aortic valve, where infection is often local- ized to the junction between the sewing ring and the aortic annulus, a large false aneurysm may develop in this area. Free-​wall myocar- dial abscesses may rupture and cause sudden death. Features of systemic or pulmonary emboli Fragments of an infected vegetation may be dislodged into the sys- temic or pulmonary circulation, producing emboli in 20–​40% of cases (up to 50% reported in autopsy series). These may lodge in any part of the circulation and present as a cerebrovascular accident, limb arterial occlusion, myocardial infarction, sudden unilateral blindness, or infarction of the spleen or a kidney. Septic embolism from the left side of the heart may result in the formation of a cere- bral abscess. In right heart endocarditis, recurrent septic pulmonary emboli may be misinterpreted as ‘pneumonia’. Mycotic aneurysms arise from embolism of the vasa vasorum that weakens the arterial wall: these have been reported in almost 3% of clinical cases but are found in up to 15% at autopsy. In the cerebral circulation, such aneurysms may produce subarachnoid haemor- rhage or intracerebral haemorrhage. The popliteal artery is also a common site for mycotic aneurysms. Emboli are characteristic of Staph. aureus infections and large em- boli are a feature in HACEK and fungal endocarditis. They usually occur before or within the first few days after starting antimicro- bial therapy. Anterior mitral valve-​leaflet vegetations are more likely to embolize than aortic valve vegetations, especially if they are highly mobile. Vegetation size does not predict systemic embolism, but large vegetations (>10  mm) are associated with poor overall outcome. After an embolic complication, recurrent episodes are likely to follow, especially if vegetations persist on echocardiography. In more than 50% of cases, such recurrence occurs within 30 days of the first episode. The risk of embolism falls rapidly after the initiation of anti- biotic therapy but is not reduced by treatment with anticoagulants or antiplatelet therapy: both may increase the risk of bleeding and should be avoided unless they are essential. section 16  Cardiovascular disorders 3522 Features of circulating immune complexes The infected vegetation acts as an antigen that triggers an im- mune response. Chronic antigenaemia stimulates generalized hypergammagloblinaemia such that after several weeks of infection a variety of autoantibodies can be detected. Immune complex de- position probably causes many of the extracardiac manifestations of endocarditis, but these classical signs are relatively uncommon and frequently absent in acute presentations. • Splinter haemorrhages (5–​15% of cases)—​found in the nail bed of the fingers and, less commonly, the toes (Fig. 16.9.2.1). • Conjunctival haemorrhages. • Osler’s nodes (5–​10% of cases)—​transient painful erythema- tous nodules that are found at the ends of fingers and toes and the thenar and hypothenar eminences which may be due to mi- nute infected emboli rather than immune complex deposition (Fig. 16.9.2.2). • Janeway lesions—​irregular painless erythematous macules found in roughly the same distribution as Osler’s nodes (Fig. 16.9.2.3); they tend to blanch with pressure. • Vasculitic rash—​due to immunoglobulin and complement de- posits in the walls of skin capillaries (Fig. 16.9.2.4). • Roth spots (5% of cases)—​boat-​shaped haemorrhages in the retina are often called Roth spots, but true Roth spots are white retinal exudates that may be surrounded by haemorrhage that consist of perivascular lymphocyte collections. • Splenomegaly—​clinical splenomegaly is less common than was reported in earlier literature (20% of cases); however, abdominal CT scanning demonstrates splenomegaly in at least 50% of cases, often with associated splenic infarcts (Fig. 16.9.2.5). Splenic ab- scesses may occur, and splenic rupture can be fatal. • Nephritis (10–​15% of cases)—​immune complexes can cause glomerulonephritis, manifest as proteinuria, haematuria, and de- cline in renal function, with immunoglobulin and complement deposition within glomeruli on renal biopsy. Key investigations are simple dipstick testing of the urine (with microscopy if more than 1 + positive for blood and/​or protein) and measurement of serum creatinine. • Arthralgia—​joint manifestations may result from immune com- plex deposition in the synovial membrane. Fig. 16.9.2.1  Splinter haemorrhages. Fig. 16.9.2.2  Osler’s nodes involving the fingers and the thenar and hypothenar eminences. Fig. 16.9.2.3  Janeway lesions on the under surface of the left big toe. Fig. 16.9.2.4  Vasculitic rash of the lower limb. 16.9.2  Endocarditis 3523 Other features Up to 30% of patients with endocarditis present with neurological symptoms: these are most common in staphylococcal infection, in which one-​third present with the clinical features of menin- gitis. Headaches, confusion, and toxic psychosis can be present as well as encephalomyelitis. It is not certain whether some of these neurological manifestations result from repeated small emboli or from a vasculitic process within the cerebral circulation as a consequence of immune complex deposition. The cerebrospinal fluid can show an increase in white cells, but is usually sterile on culture. Very occasionally it may be positive for staphylococcal infection. Although immune-​mediated glomerulonephritis has been re- garded as the typical renal lesion of endocarditis, this assumption was based on small series predating modern treatment regimens. More recent work indicates that the most common histological finding is renal infarction. Circulatory compromise can rarely cause severe renal impairment as a result of renal cortical necrosis. Finger clubbing is one of the classical features of endocarditis, usually seen after 1 or 2 months of the illness. It is seldom seen now, but when present is still a useful sign because it rarely occurs in con- ditions with which endocarditis can be confused. Specific types or circumstances of endocarditis Prosthetic valve endocarditis Patients with prosthetic heart valves have a small, but constant, risk of endocarditis, estimated at 0.2–​1.4 events per 100 patient years. The incidence of prosthetic valve endocarditis is about 3% in the first postoperative year, with the highest risk during the first 3 months. Prosthetic valve endocarditis is five times more common in the aortic area than the mitral area and may involve mechanical, xeno- graft, and homograft valves. Prosthetic valve endocarditis has been classified as early or late ac- cording to its temporal relationship to surgery. Early prosthetic valve endocarditis usually occurs within 60 days of open heart surgery and accounts for 30% of cases. It is caused either by contamination of the prosthetic valve at implantation or by perioperative bacter- aemia from intravenous catheters, arterial lines, urethral catheters, or endotracheal tubes. The most common organisms are coagulase-​ negative staphylococci. Late prosthetic valve endocarditis accounts for 70% of cases and usually occurs 60 days or more after surgery. The pathogens are those seen in native valve endocarditis, with a preponderance of viridans streptococci and staphylococci, but with a higher incidence of other organisms. Some patients with late prosthetic valve endocarditis will have acquired the infection at the time of surgery, but a bacteraemia is usually the principal cause. Bacteraemia in a patient with a prosthetic valve must always be taken seriously, but it may not always be the result of endocarditis. The clinical picture of prosthetic valve endocarditis is typically fever, malaise, and weakness, with the more classical signs usually absent. The condition is often insidious and clinically difficult to diagnose. A new murmur may appear, and heart failure and embolic phenomena cause high mortality (20–​50%). Infection in a mech- anical valve is located in the sewing ring, from which the infection can spread into the host tissues producing annular/​myocardial ab- scesses, paravalvular leak, and prosthetic dehiscence. Infection of a tissue valve usually involves the valve leaflets, resulting in destruc- tion or perforation and valvular incompetence. Vegetations may cause obstruction with all forms of prosthetic valve. The diagnosis of prosthetic valve endocarditis requires a high index of clinical suspicion, blood cultures, and transoesophageal echocardiography, which is far superior to the transthoracic ap- proach for detecting vegetations and identifying periprosthetic spread of infection. Vegetations are more difficult to identify in pa- tients with mechanical valves than those with bioprostheses. Right-​sided endocarditis Right-​sided endocarditis accounts for only 5% of cases overall, but centres that treat large numbers of intravenous drug users will have a higher incidence. The clinical picture differs significantly from left-​sided disease. It is usually associated with intravenous drug ad- diction or indwelling intravascular devices, including pacemakers, implantable defibrillators, central venous lines of all types, and septal occluder devices. Staph. aureus is the most common pathogen and the tricuspid valve is more commonly affected (80%) than the pul- monary valve. Fever is almost always present and a cardiac murmur is found in 80% of cases. There may be septic pulmonary emboli (Fig. 16.9.2.6) and the resultant pulmonary infarcts may cavitate. Symptoms include cough, haemoptysis, and pleuritic chest pain; a chest radiograph shows pulmonary infiltrates, which are often mis- interpreted as ‘patches of pneumonia’. Renal involvement (most commonly abscess formation or diffuse pyelonephritis) has been described in over one-​half of cases. Myocarditis is more common in right-​sided involvement than left. Peripheral stigmata, spleno- megaly, and central nervous system involvement are rare (no more than 5% of cases). Death is most commonly due to sepsis, rarely to heart failure. Fig. 16.9.2.5  CT scan showing multiple splenic infarcts within an enlarged spleen. section 16  Cardiovascular disorders 3524 Endocarditis in intravenous drug users Endocarditis is a serious complication of intravenous drug abuse. The right side of the heart is affected most commonly, but the left may also be involved in a substantial number of patients (37%), and both right and left side in a few (7%). On the left side, mitral and aortic valves are equally infected. A history of previous heart disease is found only in some 25% of cases. Staph. aureus is responsible for 40% of all cases. Streptococci and enterococci are the next most common pathogens. Less com- monly, fungi and Gram-​negative bacilli can cause endocarditis in intravenous drug users, and polymicrobial endocarditis accounts for 5% of cases. The skin is the most common site from which pathogens enter the bloodstream via needles. Gram-​negative bacilli are rarely recovered from needles or the drug itself, and it has been suggested that these organisms come from tap water, sinks, or lavatory pans. The clinical picture of endocarditis associated with intravenous drug use depends on which side of the heart is affected. Right-​sided disease is described earlier; left-​sided disease behaves like that seen in non​drug cases, with a high incidence of heart failure, arterial embolism, central nervous system involvement, and peripheral stigmata. The overall mortality depends on when the patient presents: it is high if they present late, reflecting among other things the frequent challenges in dealing with intravenous drug users, because of poor compliance and failure to discontinue drug use. The principles of management are similar to those in patients who are not drug users. The duration of intravenous antibiotics should be at least 4 weeks, but this is frequently impossible in practice. Furthermore, there are often legitimate concerns regarding the risk of reinfection of a pros- thetic valve and surgery requires very careful consideration in this patient group. Endocarditis in children Endocarditis does occur in children but is rare, especially in the first decade of life. In the early literature, tetralogy of Fallot was the cardiac problem most commonly associated with endocarditis. Complex cyanotic disease, congenital heart disease corrected with prosthetic material, and small ventricular septal defects now make up the bulk of cases. Diagnosis of endocarditis Laboratory methods Blood culture This is the most important laboratory investigation in the diag- nosis of endocarditis (Table 16.9.2.1). Isolation of the pathogen enables an effective antibiotic treatment regimen to be devised. Optimal technique is necessary to avoid false-​positive cases due to contaminating skin organisms. The recommended regimen for obtaining blood cultures is that three sets of blood cultures should be taken from a separate venepuncture sites over 24 h at least 1 h apart, with at least 10 ml of blood injected into one aerobic and one anaerobic culture bottle. Blood cultures should be taken be- fore antibiotics are given; if they have already been given, cultures should still be done and, if possible, the administration of further antibiotics delayed for a few days. However, previous antibiotics may render the blood sterile for some time, and the chances of re- covering the pathogen, particularly when it is a sensitive organism such as viridans streptococcus, are very low. Much mystique has been attached to the number and timing of blood cultures in cases of suspected endocarditis. What is known is that the bacteraemia is usually constant and in most cases all bottles will grow the pathogen whenever the blood is obtained for culture and however many sets are taken. There are, of course, rare exceptions when only a few bottles taken are positive, and this is one reason why it is conventional to take three sets. Another reason for several cultures is to assess the relevance of the common skin contaminants (par- ticularly coagulase-​negative staphylococci and Corynebacterium) that can cause endocarditis. In most laboratories, blood culture systems are automated, with continuous monitoring to flag up growth for further investiga- tion. Most cultures become positive within 48 h and after this the chances of isolating the pathogen recede (with the exception of fas- tidious organisms of the HACEK group that may take much longer to recover). In most laboratories, blood cultures are incubated for 5–​7 days, but this may not be long enough for the rare fastidious slow grower. The onus is on the clinical microbiologist or clinician to request prolonged incubation for blood cultures from patients in whom endocarditis is strongly suspected, who have not had pre- vious antibiotics, and whose blood cultures are sterile after a week’s incubation. Other routine blood tests In endocarditis, an elevated erythrocyte sedimentation rate (ESR) and C-​reactive protein (CRP) are almost invariable, and these in- flammatory markers are used most commonly to monitor the ac- tivity of the disease. A normochromic normocytic anaemia is often present and a polymorphonuclear leucocytosis is found in most cases. Hypergammaglobulinaemia and a low serum complement may be present, together with a false-​positive rheumatoid factor. Circulating immune complexes may be detected. Fig. 16.9.2.6  CT scan of the chest showing multiple pulmonary infarcts in a case of right-​sided endocarditis of the tricuspid valve in an intravenous drug abuser. 16.9.2  Endocarditis 3525 Serological tests aid in the identification of organisms that are difficult to isolate, including bartonella, coxiella (Q fever), myco- plasma, legionella, brucella, and fungi. Candida antibodies are of no diagnostic value. Echocardiography In suspected cases of endocarditis, transthoracic echocardiography should be performed as soon as possible and interpreted by an ex- perienced cardiologist. Its principal role is to detect vegetations (Fig. 16.9.2.7), but it is not sufficiently sensitive to allow the clin- ician to exclude the diagnosis confidently on the basis of a negative result. The sensitivity depends on the size of the vegetations and the time course of the disease: it can resolve vegetations as small as 1–​2 mm, but confident identification is more difficult with pros- thetic than native valves and more difficult with mechanical than biological prostheses. Vegetations appear as thick, ragged, non​uniform echoes oscillat­ ing on or around a cardiac valve or in the path of a regurgitant jet. They need to be differentiated from other conditions which produce echo-​density on cardiac valves, including calcification, myxoma- tous degeneration, and atrial myxoma. Vegetations do not usually restrict leaflet mobility and exhibit valve-​dependent motion. On na- tive valves, vegetations are usually attached to the ventricular side of the aortic valve and the atrial side of the mitral and tricuspid valves (Fig. 16.9.2.8). Vegetations tend to be larger on the right side and can be demonstrated in 80–​100% of cases. Transoesophageal echocardiography improves the rate of diag- nosis of endocarditis over that of transthoracic echocardiography, particularly in the presence of a prosthetic valve. It also makes it easier to recognize many complications of prosthetic valve endocar- ditis, such as abscesses, fistulae, and paravalvular leak. Table 16.9.2.1  Microbiological diagnosis of endocarditis Organism Proportion of cases Relevant clinical history Blood cultures Serology Staphylococcus aureus 30% of community community-​acquired; 70% of hospital-​acquired IVDU/​IV access devices Usually positive Not routinely available (antilipid S antibodies have shown some promise) Coagulase-​negative staphylococci 5–​10% Prosthetic valves/​cardiac devices Usually positive Not available Viridans group streptococci 20–​30% Dental abscess/​poor oral hygiene Positive, if no recent antibiotics Not available Streptococcus bovis group 5–​10% Gastrointestinal neoplasia//​older patient population Positive, if no recent antibiotics Not available HACEK group 3% Dental treatment/​URTI Most positive in 6 days Not available Fungal <5% Prosthetic valves/​IVDU/​ immunosuppression/​long-​term IV lines Filamentous fungi rarely positive, candida usually positive Galactomannan and β-​D glucan tests may have a role, but few studies in endocarditis Enterococcus spp. 10% Urological procedures/​urinary catheterization/​older patients Positive, if no recent antibiotics Not available Brucella spp. <% Endemic area/​contaminated milk or dairy product consumption Positive in 80%. May need prolonged incubation Reference assay = tube agglutination Coxiella burnetii (Q fever) 1% Farming background/​exposure to domestic ruminants/​raw milk consumption/​previous valvulopathy Rarely positive. Tissue cell culture reported as optimal method Major criteria for modified Duke criteria: Antiphase 1 IgG >800 and IgA antibody 100 is highly sensitive Reference assay = microimmunofluorescence Bartonella spp. 13% Homelessness (body lice)/​ alcoholism/​exposure to cats Rarely positive Reference assay = microimmunofluorescence Legionella spp. <1% May be associated with an outbreak Rarely positive. Urinary antigen. Bronchial washings/​sputum High antibody levels Reference assay = microimmunofluorescence IV, intravenous; IVDU, intravenous drug use; URTI, upper respiratory tract infection. Fig. 16.9.2.7  A transthoracic echocardiogram showing a large vegetation involving the mitral valve. section 16  Cardiovascular disorders 3526 Examination of the heart valve and other tissues Histology Histology remains the gold standard for explanted valves. When valve replacement is undertaken, valvular tissue (including vegeta- tion) should be examined histologically and cultured for the pres- ence of microorganisms, which may allow postoperative antibiotics to be tailored accordingly. However, the isolation of microorganisms by valvular culture is infrequent: only 15% in one large series, with staphylococci being most common. Fastidious and rare microorgan- isms have been demonstrated on heart valves by various staining techniques and, more recently using tissue polymerase chain reac- tion techniques. Nucleic acid-​based techniques Polymerase chain reaction (PCR) techniques are now widely used for samples obtained from heart valves and embolic tissue in pa- tients with suspected endocarditis. Most laboratories use a broad range strategy, with primers designed to capture all bacteria (e.g. targeting the 16s rRNA gene). Such tests have a sensitivity of around 80% due to the high concentration of bacteria, and hence bacterial DNA, in vegetations. Where available, PCR-​based tests should be applied routinely to explanted heart valves in cases of endocarditis of unknown aetiology. By contrast, broad range PCR tests applied to whole blood have a much lower sensitivity and hence are not rou- tinely recommended. Criteria for the diagnosis of endocarditis In 1994, Durack and colleagues introduced criteria for the diag- nosis of endocarditis that have been accepted as the ‘Duke criteria’ and categorize patients into definite, possible, and rejected groups. Although these criteria have been shown to be superior to previous diagnostic tools, they have limitations: in particular, there is a pos- sibility of misclassification when blood cultures remain negative or echocardiography is inconclusive. Negative blood cultures occur in 5–​31% of cases of endocarditis, commonly due to prior antibiotic therapy, but also as a result of infection with fastidious and atyp- ical microorganisms. Transthoracic echocardiography visualizes vegetations in only about 50% of cases: transoesophageal echocar- diography has a higher sensitivity for detection on both native and prosthetic valves, but will only be diagnostic in 50–​94% of cases. These issues mean that the number of patients who may be incor- rectly diagnosed as having possible endocarditis, as opposed to def- inite, could be as high as 24%. Modification of the Duke criteria to increase their sensitivity has been suggested by several authors (Table 16.9.2.2). Positive serology for typical microorganisms and the use of polymerase chain reaction techniques have been suggested as major criteria, and the following additional minor criteria have been proposed:  newly diagnosed clubbing; splenomegaly; splinter haemorrhages and petechiae; microscopic haematuria; a high ESR or CRP; and the presence of central non​feeding lines and peripheral lines. Microbiology Although almost any microorganism can cause endocarditis, par- ticularly when this involves a prosthetic valve, certain species do so much more commonly than others. The predominant species involved in the infection have not changed significantly in their incidence in the past three decades. Overall, viridans streptococci and staphylococci account for about two-​thirds of cases. However, endocarditis cannot be considered as a microbiologically homo- geneous entity as the incidence of any specific organism depends (1) on the patient, whether an intravenous drug user or not; (2) on the valve, whether native or prosthetic—​and if native, whether pre- viously abnormal or not, and if prosthetic whether mechanical or a bioprosthesis, and whether the infection was acquired early or late; and (3) where (and how) the infection was acquired, whether in the community or (as increasingly these days) in hospital, usually via an infected intravascular device. The more common species encountered are considered individually. Streptococci The genus Streptococcus includes species of differing virulence and pathogenicity as well as differing normal habitat in humans. Viridans streptococci For many years, it has been conventional to refer to a group of streptococci that produce greening (α-​haemolysis) on blood agar as viridans streptococci; indeed, many still refer (inaccurately) to a microbe ‘Streptococcus viridans’. Although most of these strepto- cocci are virtually specific to the normal oropharyngeal flora and are rarely encountered at other sites, some are not found in the oro- pharynx at all (e.g. Strep. bovis), and others are found at many sites including the oropharynx (e.g. the milleri group of streptococci). The most common species of the viridans streptococci specific to the oropharynx are Strep. sanguis, Strep. oralis, and Strep. mutans, but there are others. Dextran formation may be a virulence factor in these streptococci. Contrary to popular belief, they do not re- quire a dental extraction to enter the bloodstream and cause fre- quent bacteraemias after chewing, tooth brushing, and so on. They are organisms of low virulence and thus usually only infect previ- ously abnormal heart valves. Whereas Strep. oralis and Strep. sanguis are occasionally isolated from blood cultures of patients who do not have endocarditis, the isolation of Strep. mutans from the blood is virtually synonymous with endocarditis. Fig. 16.9.2.8  Bacterial vegetations on the mitral valve—​the patient had died as a result of a large cerebral embolism. 16.9.2  Endocarditis 3527 Streptococcus bovis This streptococcus, which may appear ‘viridans’ on blood agar, is part of the normal intestinal flora, but may initially be mistaken for an oral streptococcus. In common with the enterococci, it bears the Lancefield group D antigen and thus can also be mistaken for Enterococcus faecalis, though it is sensitive to penicillin whereas the latter is resistant. There is a significant association between Strep. bovis bacteraemia (and hence endocarditis) and colonic pathology, and any patient with Strep. bovis endocarditis thus warrants appro- priate investigation. Strep. bovis endocarditis is much less common than that caused by oral streptococci. Pyogenic streptococci These organisms, often referred to as β-​haemolytic streptococci, cause endocarditis less frequently than the viridans strepto- cocci, but are more aggressive microbes and likely to affect (and often rapidly destroy) a previously normal valve. The commonest pyogenic streptococcus to cause endocarditis is the Lancefield group B β-​haemolytic streptococcus (GBS), sometimes referred to as Strep. agalactiae. This organism is found as normal flora in the genital and gastrointestinal tracts. As with Staph. aureus, any patient with community-​acquired group B β-​haemolytic strepto- coccus bacteraemia should be assumed to have infection in bone, Table 16.9.2.2  Duke criteria for the diagnosis of endocarditis and proposed modifications Duke criteria Suggested modifications Pathological criteria Microorganisms demonstrated by culture or histological examination Active endocarditis demonstrated by histological examination Major criteria Positive blood cultures To be added: Typical microorganisms consistent with endocarditis from two separate blood cultures Positive serology for Coxiella burnetii Microorganisms consistent with endocarditis from persistently positive blood cultures Bacteraemia due to Staph. aureus Positive molecular assay for specific gene targets and universal loci for bacteria and fungi Positive serology for Chlamydia psittaci Positive serology for Bartonella spp. Evidence of endocardial involvement Echocardiography—​oscillating structures, abscess formation, new partial dehiscence of prosthetic valve Clinical—​new valvar regurgitation Minor criteria Predisposing heart disease To be omitted: Fever >38 °C Suspect echocardiography (no major criterion) Vascular phenomena To be added: Immunological phenomena Elevated CRP, elevated ESR, splenomegaly, haematuria, clubbing, splinter haemorrhages, petechiae, purpura Microbiological evidence (no major criterion) Identified IE organism from metastatic lesions Suspect echocardiography (no major criterion) Categories Definite: Pathological criteria positive or 2 major criteria positive or 1 major and 2 minor criteria positive 1 major and 1 minor criterion positive or 5 minor criteria positive 3 minor criteria positive Possible: All cases which cannot be classified as definite or rejected Rejected: Alternative diagnosis Resolution of the infection with antibiotic treatment for <4 days No histological evidence CRP, C-​reactive protein; ESR, erythrocyte sedimentation rate; IE, infective carditis. Reproduced from Heart, Prendergast BD, Vol 92, pp. 879–​85. The changing face of infective endocarditis. Copyright (2006) with permission from BMJ Publishing Group Ltd. section 16  Cardiovascular disorders 3528 joint, or on a heart valve until proved otherwise. Groups C and G β-​haemolytic streptococci occasionally cause endocarditis, and group A even more rarely. The milleri group of streptococci are best regarded as pyogenic streptococci:  they form part of the normal flora of all mucous membranes and occasionally cause endocarditis, though much more often cause abscesses at many different sites. The milleri group consists of three species, Strep. constellatus, Strep. intermedius, and Strep. anginosus. Streptococcus pneumoniae (pneumococcus) Pneumococcal endocarditis accounted for about 10% of cases of endocarditis in the preantibiotic era, but is now rarely seen, although it is sometimes diagnosed at autopsy of patients with fatal pneumo- coccal infection. The pneumococcus is a virulent pathogen and attacks normal heart valves. Patients with endocarditis generally have pneumonia and sometimes meningitis. Enterococci Enterococci form part of the normal gastrointestinal flora. They are more virulent than viridans streptococci and more resistant to anti- biotics. The incidence of enterococcal endocarditis is increasing, particularly in older people, but this infection is still much less common than that caused by viridans streptococci. While there are many species of enterococci, those causing endocarditis are usually E. faecalis and occasionally E. faecium. Most cases are community acquired, but the infection can sometimes be acquired in hospital as a result of urological instrumentation. Any patient admitted from the community with E. faecalis in the blood should be investigated for endocarditis. Staphylococci Staphylococci now account for about one-​third of cases of community-​acquired endocarditis and are the most common cause of hospital-​acquired endocarditis. Most of these staphylococci are Staph. aureus, but an increasing proportion are now coagulase-​ negative staphylococci. All staphylococci are skin organisms and patients become infected from their own skin flora, or in the case of methicillin-​resistant Staph. aureus (MRSA) from that of others by cross-​infection. Staphylococcus aureus Staph. aureus is an important and aggressive pathogen in community-​ acquired native valve endocarditis. Sometimes a trivial skin lesion can be identified as the source of the organism, but there is often no obvious lesion. Staph. aureus, and increasingly now MRSA, is the most common cause of hospital-​acquired endocarditis. Prosthetic valves can become infected with Staph. aureus, both early as result of sternal wound sepsis and late as with native valves. Staph. aureus is the commonest pathogen causing endocarditis in intravenous drug users. Coagulase-​negative staphylococci Although still regarded by many as pathogens of prosthetic rather than native valves, coagulase-​negative staphylococci also cause na- tive valve infection. This has become more common, or certainly more commonly recognized, in the last two decades. The infecting species is most often Staph. epidermidis, but in many reports the des- ignation ‘Staph. epidermidis’ tends to be used for any unspecified coagulase-​negative staphylococcus. As in community-​acquired Staph. aureus endocarditis, there is sometimes a presumptive predisposing skin lesion. Most patients have a pre-​existing cardiac abnormality. Many of these staphylococci (particularly Staph. lug- dunensis) can be as virulent as Staph. aureus and share some of the same virulence factors. Other organisms A wide variety of organisms account for the few cases of endocar- ditis that are not caused by streptococci, staphylococci, or entero- cocci: only a few warrant specific mention. HACEK group These are fastidious, slow-​growing species that are oropharyn- geal commensals and have a predilection for heart valves such that their presence in blood cultures is virtually synonymous with this infection. The group consists of Haemophilus parainfluenzae, Aggregatibacter spp., Cardiobacterium hominis, Eikenella corrodens, and Kingella spp. The large vegetations thought to be characteristic of HACEK organisms in native valve infection may be the result of diagnostic delay and prolonged illness rather than any inherent property of the microbes. Organisms that cannot be cultured by routine techniques Endocarditis is a rare (and late) sequel of acute Coxiella burnetii (Q fever) infection, mostly in middle-​aged men with pre-​existing valve disease. The reservoir of the organism is usually sheep or cattle, but the source and mode of transmission in many cases is unknown. The diagnosis is usually made serologically, although C. burnetii can be recovered from the blood and excised valves by special techniques. The disease is almost certainly underdiagnosed, with some cases labelled culture-​negative endocarditis. Bartonella infection is usually diagnosed by serology, although these bacteria can be recovered from the blood and excised valves by special culture techniques and their presence detected by poly- merase chain reaction. Fungi Fungal endocarditis is very rare and more likely to occur on pros- thetic than native valves, except in intravenous drug users. Most cases are hospital-​acquired and associated with infection at intra- vascular access sites and prior use of broad-​spectrum antibiotics. Candida species, usually Candida albicans, are the most common fungi, but aspergillus and more exotic genera have also been re- ported. Blood cultures are only likely to be positive with candida, and often only intermittently; for other fungi, the diagnosis must be made by serology and culture of the fungus from the excised valve or detection on valve histology. Culture-​negative endocarditis The possibility that an illness is not due to endocarditis should al- ways be entertained when blood cultures are repeatedly negative. However, the blood cultures will be negative in 5–​31% of definite cases of endocarditis. The most common explanation for this is pre- vious administration of antibiotics. In a few cases the pathogen will be recovered from another site, including the excised valve, excised emboli, or—​specifically in right-​sided endocarditis—​respiratory specimens. Other causes of negative blood cultures are infection 16.9.2  Endocarditis 3529 with organisms that cannot be grown by conventional blood cul- ture methods, and infections that are diagnosed by serology such as C. burnetii, bartonella, and chlamydia. Treatment Initial therapy The treatment of endocarditis should ideally be undertaken by a multidisciplinary team involving cardiologists, microbiologists, in- fectious disease specialists, and cardiac surgeons. Where possible, patients should be treated in cardiac centres that undertake cardiac surgery. Bactericidal antibiotics are the mainstay of treatment. The choice and duration of treatment depend on the type of micro- organism and its susceptibility profile, whether infection involves a native or prosthetic valve, and whether the patient is allergic to any antimicrobials. In those patients who have been ill for many weeks, antibiotic treatment can be deferred until the blood cultures are positive and the pathogen known. Antibiotic treatment should be started im- mediately after taking blood cultures in patients who are acutely ill, using a broad-​spectrum combination that can be adjusted when the pathogen is known. However, endocarditis is often not suspected initially in many patients who are acutely ill with native valve in- fection: there may be no obvious signs of this and antibiotics are started for ‘septicaemia’. When methicillin-​resistant staphylococci (whether Staph. aureus or coagulase-​negative staphylococci) are likely pathogens, vancomycin or teicoplanin is an essential com- ponent of any combination. If empirical therapy is indicated the choice of antimicrobial agent should be dictated by the type of presentation, whether or not there is an intracardiac prosthesis in place, and the likely causative organism as suggested by the clinical picture (Table 16.9.2.3). Definitive therapy There are various international guidelines for the treatment of spe- cific organisms. It is important to realize that these are based on con- sensus, because there are no randomized controlled trials to show the efficacy of any particular regimen. It is conventional to estimate the minimum inhibitory concentration (MIC) of the antibiotic for the pathogen, but in practice routine disc sensitivity tests are satis- factory in many cases. Although it is widely believed that prosthetic endocarditis requires a longer duration of antibiotic treatment than native valve infection, there are few data to support this. Recommendations for the treatment of the most common causative organisms are taken from guidelines published by the British Society for Antimicrobial Chemotherapy (Tables 16.9.2.4, 16.9.2.5, 16.9.2.6). HACEK endocarditis Treatment should be with a β-​lactamase-​stable cephalosporin, or with amoxicillin if the organism is sensitive, plus gentamicin 1 mg/​kg body weight according to renal function (for the first 2 weeks only) and with regular monitoring of drug levels. An alternative agent is ciprofloxacin. Other uncommon causes of endocarditis Treatments for uncommon causes of endocarditis are shown in Table 16.9.2.7. Table 16.9.2.3  Recommendations for empirical therapy of suspected endocarditis Antimicrobial Dose/​route Comment NVE—​indolent presentation Amoxicillina AND (optional) 2 g q4 h IV If patient is stable, ideally await blood cultures Better activity against enterococci and many HACEK microorganisms compared with benzylpenicillin Use regimen 2 if genuine penicillin allergy Gentamicina 1 mg/​kg ABW The role of gentamicin is controversial before culture results are available NVE, severe sepsis (no risk factors for Enterobacteriaceae, Pseudomonas) Vancomycina AND Dosed according to local guidelines In severe sepsis, staphylococci (including) need to be covered If allergic to vancomycin, replace with daptomycin 6 mg/​kg q24 h IV Gentamicina 1 mg/​kg IBW q12 h IV If there are concerns about nephrotoxicity/​acute kidney injury, use ciprofloxacin in place of gentamicina NVE, severe sepsis AND risk factors for multiresistant Enterobacteriaceae, Pseudomonas Vancomycina AND Dosed according to local guidelines, IV Will provide cover against staphylococci (including MRSA), streptococci, enterococci, HACEK, Enterobacteriaceae and P. aeruginosa Meropenema 2 g q8 h IV PVE pending blood cultures or with negative blood cultures Vancomycina AND 1 g q12 h IV Gentamicina AND 1 mg/​kg q12 h IV Rifampicina 300–​600 mg q12 h po/​IV Use lower dose of rifampicin in severe renal impairment ABW, actual body weight; IBW, ideal body weight; IV, intravenous; MRSA, methicillin-​resistant staphylococci; NVE, native valve endocarditis; PVE, prosthetic valve endocarditis; po, orally; q4 h, every 4 h; q8 h, every 8 h; q12 h, every 12 h. a Doses require adjustment according to renal function. From Gould FK, et al. (2012). Guidelines for the antibiotic treatment of endocarditis in adults: report of the Working Party of the British Society for Antimicrobial Chemotherapy. Antimicrob Chemother, 67, 269–​89. Reproduced with permission from the British Society for Antimicrobial Chemotherapy. section 16  Cardiovascular disorders 3530 Fungal endocarditis For Candida, echinocandins (e.g. caspofungin or anidulafungin) or lipid-​based amphotericin B preparations are first-​line therapies. For aspergillus, voriconazole is first-​line treatment. Expert advice on dosing should be sought. Monitoring of treatment Serum bactericidal titres against the infecting organism are no longer recommended. There was always great variation in the moni- toring methods used for these tests and in the interpretation of their results. At best, they could only predict bacteriological not clinical cure, and bacteriological failure is very rare. The most useful labora- tory test for monitoring the response to treatment (which is usually obvious clinically) is serial estimation of CRP; this is of greater use than the ESR, which is much slower to fall. If there is a relapse of endocarditis, this usually occurs within 2 months of cessation of treatment. The relapse rate is lowest for pa- tients with native valve endocarditis caused by penicillin-​sensitive viridans streptococci. Relapse rate in prosthetic valve endocarditis is 10–​15%. Prevention and prophylaxis Until recently, antibiotic prophylaxis in at-​risk patients, including those with native valve disease undergoing a wide variety of dental, medical, and surgical procedures, was accepted as reasonable. This was largely based on indirect data from in vitro studies, ex- perimental animal models, and studies of clinical bacteraemia, but there were many uncertainties about its value, and data confirming its clinical effectiveness were lacking. This lack of evidence has led international bodies to propose more restrictive guidelines in recent years. The most controversial area for the use of prophylactic antibiotics concerns dental treatment. Innovative French guidelines published in 2002 challenged conventional practice, suggesting prophylaxis only for those with the highest benefit to risk ratio, and empha- sizing the importance of oral hygiene. A working party of the British Society of Antimicrobial Chemotherapy recommended in 2006 that the practice of giving antibiotics to all patients with cardiac abnor- malities before dental treatment should be stopped, except for those with a history of previous endocarditis, prosthetic heart valves, or surgically constructed conduits. Many other groups vigorously op- posed this recommendation, not least because some cases of endo- carditis that involve dental procedures have resulted in litigation, and in most of these legal cases endocarditis was judged to be caused by dental manipulations on the basis of the dental procedure, cardiac pathology, infecting microorganism, and the temporal link between the onset of endocardial infection and the dental manipulation. In 2007 the American Heart Association (AHA) revised its guidelines limiting the use of antibiotic prophylaxis to the highest-​ risk patients who were undergoing the highest-​risk procedures Table 16.9.2.4  Summary of treatment options for streptococcal endocarditis Regimen Antimicrobial Dose and route Duration (weeks) Comment Treatment options for streptococci (penicillin MIC ≤0.125 mg/​litre) 1. Benzylpenicillina monotherapy 1.2 g q4 h IV 4–​6 Preferred narrow-​spectrum regimen, particularly for patients at risk of C. difficile or high risk of nephrotoxicity 2. Ceftriaxone monotherapy 2 g once a day IV/​IM 4–​6 Not advised for patients at risk of C. difficile infection; suitable for OPAT 3. Benzylpenicillina AND 1.2 g q4 h IV 2 Not advised for patients with PVE, extracardiac foci of infection, any indications for surgery, high risk of nephrotoxicity, or at risk of C. difficile Gentamicin 1 mg/​kg q12 h IV 2 4. Ceftriaxone AND 2 g once a day IV/​IM 2 Not advised for patients with PVE, extracardiac foci of infection, any indications for surgery, high risk of nephrotoxicity, or at risk of C. difficile Gentamicin 1 mg/​kg q12 h IV 2 Treatment of streptococci (penicillin MIC >0.125 to ≤0.5 mg/​litre) 5. Benzylpenicillina AND 2.4 g q4 h IV 4–​6 Preferred regimen, particularly for patients at risk of C. difficile Gentamicin 1 mg/​kg q12 h IV 2 Treatment of Abiotrophia and Granulicatella spp. (nutritionally variant streptococci) 6. Benzylpenicillina AND 2.4 g q4 h IV 4–​6 Preferred regimen, particularly for patients at risk of C. difficile Gentamicin 1 mg/​kg q12 h IV 4–​6 Treatment of streptococci penicillin MIC >0.5 mg/​litre Treatment of streptococci in patients with significant penicillin allergy 7. Vancomycin AND 1 g q12 h 4–​6 Or dosed according to local guidelines Gentamicin 1 mg/​kg q12 h IV ≥2 8. Teicoplanin AND 4–​6 Preferred option when high risk of nephrotoxicity Gentamicin 1 mg/​kg IV q12 h ≥2 IM, intramuscularly; IV, intravenously; OPAT, outpatient antimicrobial therapy; PVE, prosthetic valve endocarditis; q4 h, every 4 h; q12 h, every 12 h. All drug dosages to be adjusted in renal impairment; gentamicin, vancomycin, and teicoplanin levels to be monitored. a Amoxicillin 2 g every 4–​6 h may be used in place of benzylpenicillin 1.2–​2.4 g every 4 h. From Gould FK, et al. (2012). Guidelines for the antibiotic treatment of endocarditis in adults: report of the Working Party of the British Society for Antimicrobial Chemotherapy. Antimicrob Chemother, 67, 269–​289. Reproduced with permission from the British Society for Antimicrobial Chemotherapy. 16.9.2  Endocarditis 3531 Table 16.9.2.5  Recommended regimens for treatment of staphylococcal endocarditis Agent Dose/​route Duration (weeks) Comment NVE, methicillin-​susceptible Staphylococcus spp. Flucloxacillin 2 g every 4–​6 h IV 4 Use q4 h regimen if weight >85 kg NVE, methicillin-​resistant, vancomycin-​susceptible (MIC ≤2 mg/​litre) rifampicin-​susceptible Staphylococcus or penicillin allergy Vancomycin AND 1 g IV q12 h 4 Or dose according to local guidelines. Modify dose according to renal function and maintain predose level 15–​20 mg/​litre Rifampicin 300–​600 mg q12 h po 4 Use lower dose of rifampicin if creatinine clearance <30 ml/​min NVE, methicillin-​resistant, vancomycin-​resistant (MIC >2 mg/​litre), daptomycin-​susceptible (MIC ≤1 mg/​litre) Staphylococcus spp. or patient unable to tolerate vancomycin Daptomycin AND 6 mg/​kg q24 h IV 4 Monitor creatine phosphokinase weekly. Adjust dose according to renal function Rifampicin OR 300–​600 mg q12 h po 4 Use lower dose of rifampicin if creatinine clearance <30 ml/​min Gentamicin 1 mg/​kg IV, q12 h 4 PVE, methicillin, rifampicin-​susceptible Staphylococcus spp. Flucloxacillin AND 2 g every 4–​6 h IV 6 Use q4 h regimen if weight >85 kg Rifampicin AND 300–​600 mg q12 h po 6 Use lower dose of rifampicin if creatinine clearance <30 ml/​min Gentamicin 1 mg/​kg IV, q12 h 6 PVE, methicillin-​resistant, vancomycin-​susceptible (MIC ≤2 mg/​litre), Staphylococcus spp. or penicillin allergy Vancomycin AND 1 g IV q12 h 6 Or dose according to local guidelines. Modify dose according to renal function and maintain predose level 15–​20 mg/​litre Rifampicin AND 300–​600 mg q12 h po 6 Use lower dose of rifampicin if creatinine clearance <30 ml/​min Gentamicin 1 mg/​kg q12 h IV ≥2 Continue gentamicin for the full course if there are no signs or symptoms of toxicity PVE, methicillin-​resistant, vancomycin-​resistant (MIC >2 mg/​litre), daptomycin-​susceptible (MIC ≤1 mg/​litre) Staphylococcus spp. or patient unable to tolerate vancomycin Daptomycin AND 6 mg/​kg q24 h IV 6 Increase daptomycin dosing interval to 48 hourly if creatinine clearance <30 ml/​min Rifampicin AND 300–​600 mg q12 h po 6 Use lower dose of rifampicin if creatinine clearance <30 ml/​min Gentamicin 1 mg/​kg q12 h IV ≥2 Continue gentamicin for the full course if there are no signs or symptoms of toxicity IV, intravenously; NVE, native valve endocarditis; PVE, prosthetic valve endocarditis; po, orally; q12 h, every 12 h; q24 h, every 24 h. From Gould FK, et al. (2012). Guidelines for the antibiotic treatment of endocarditis in adults: report of the Working Party of the British Society for Antimicrobial Chemotherapy. Antimicrob Chemother, 67, 269–​289. Reproduced with permission from the British Society for Antimicrobial Chemotherapy. Table 16.9.2.6  Recommended regimens for treatment of enterococcal endocarditis Regimen Antimicrobial Dose and route Duration (weeks) Comment 1. Amoxicillin OR 2 g q4 h IV 4–​6 For amoxicillin-​susceptible (MIC ≤4 mg/​litre), penicillin MIC ≤4 mg/​litre AND gentamicin-​susceptible (MIC ≤128 mg/​litre) isolates Penicillin AND 2.4 g q4 h IV 4–​6 Duration 6 weeks for PVE Gentamicina 1 mg/​kg q12 h IV 4–​6 2. Vancomycina AND 1 g q12 h IV or dosed according to local guidelines 4–​6 For penicillin-​allergic patient or amoxicillin-​ or penicillin-​resistant isolate; ensure vancomycin MIC ≤4 mg/​litre Gentamicina 1 mg/​kg IBW q12 h IV 4–​6 Duration 6 weeks for PVE 3. Teicoplanina AND 10 mg/​kg q24 h IV 4–​6 Alternative to Regimen 2, see comments for Regimen 2; ensure teicoplanin MIC ≤2 mg/​litre Gentamicina 1 mg/​kg q12 h IV 4–​6 4. Amoxicillina, b 2 g q4 h IV ≥6 For amoxicillin-​susceptible (MIC ≤4 mg/​litre) AND high-​level gentamicin resistant (MIC >128 mg/​litre) isolates IBW, ideal body weight; IV, intravenously; PVE, prosthetic valve endocarditis; q4 h, every 4 h; q12 h, every 12 h; q24 h, every 24 h. a Amend dose according to renal function. b Streptomycin 7.5 mg/​kg every 12 h intramuscularly can be added if isolate is susceptible. From Gould FK, et al. (2012). Guidelines for the antibiotic treatment of endocarditis in adults: report of the Working Party of the British Society for Antimicrobial Chemotherapy. Antimicrob Chemother, 67, 269–​289. Reproduced with permission from the British Society for Antimicrobial Chemotherapy. section 16  Cardiovascular disorders 3532 (Tables 16.9.2.8 and 16.9.2.9). In the case of dental treatment these were manipulation of gingival tissue or the periapical re- gion of teeth, or perforation of the oral mucosa. More recently the American College of Cardiology (ACC)/​AHA Task Force on Practice Guidelines has downgraded the recommendation for antibiotic prophylaxis for high-​risk patients from Class 1 (manda- tory) to Class 2 (reasonable practice). The National Institute for Health and Care Excellence (NICE) developed guidelines in 2008 for adoption by the National Health Service in England, Wales, and Northern Ireland. Based on its findings that (1) there is no consistent association between having an interventional procedure and endocarditis, (2) the clinical ef- fectiveness of antibiotic prophylaxis is not proven, (3)  the risk of antibiotic-​associated adverse effects exceeds the benefits, and (4) prophylaxis is not cost-​effective, NICE concluded that antibiotic prophylaxis should not be given to any at-​risk patients undergoing an interventional procedure. NICE made one exception, namely in patients undergoing a gastrointestinal or genitourinary procedure where there is suspected pre-​existing infection, who should receive an antibiotic that covers endocarditis causative organisms. NICE have reiterated the same advice in guidelines published in 2015. In 2009 the European Society of Cardiology also suggested re- stricting prophylaxis to those with the highest risk of endocarditis undergoing the highest-​risk procedures and have reiterated the same advice in guidelines published in 2015. Dental procedures re- quiring prophylaxis mirror the AHA guidelines. Not surprisingly these departures from established practice have met with mixed reaction; the dental profession in the United Kingdom has welcomed the NICE proposals, but many British cardi- ologists and cardiovascular surgeons have opposed them. A sensible approach would appear to be to allow individual doctors to do what they feel is best for their patients and to be encouraged to discuss their reasons for taking a particular stance on antibiotic prophylaxis with them. Patients themselves should be taught the importance of good oral hygiene and to recognize symptoms that might indicate endocarditis and when to seek expert help. Suitable prophylactic antibiotic regimens are described in Table 16.9.2.9. Surgical treatment of endocarditis Surgery is required in about 50% of cases. Since surgery may be re- quired at any time during an episode of endocarditis, it is essential to involve a cardiac surgeon in the overall management from the outset, which in practice means transferring the patient to a centre with cardiac surgery whenever possible. Surgery for endocarditis carries a 10–​25% mortality risk, and up to 10% of patients develop a paravalvular leak requiring a further operation. The main predictive factors for mortality associated with surgery are prosthetic valve endocarditis, infections due to staphylococci or candida, periopera- tive shock, or late referral. Table 16.9.2.7  Management of uncommon causes of endocarditis Pathogen Proposed treatment Brucella spp. Doxycycline plus rifampicin plus cotrimoxazole (>3 months treatment) Coxiella burnetii Doxycycline plus hydroxychloroquine (>18 months treatment) Bartonella spp. Doxycycline (for 4–​6 weeks) plus aminoglycoside (for 2 weeks) Mycoplasma spp. Doxycycline or new fluoroquinolones (>12 weeks’ treatment) Legionella spp. Macrolides plus rifampicin or new fluoroquinolones (>6 months’ treatment) Tropheryma whipplei Doxycycline plus hydrochloroquine (≥18 months) Adapted from Heart, Prendergast BD, Vol 92, pp. 879–​85. The changing face of infective endocarditis. Copyright (2006) with permission from BMJ Publishing Group Ltd. Table 16.9.2.8  Guidelines for antibiotic prophylaxis in endocarditis American Heart Association, 2007 National Institute for Health and Clinical Excellence, 2008 and 2015 European Society of Cardiology, 2009 and 2015 High-​risk patients Previous IE Previous IE Previous IE Prosthetic valve Prosthetic valve Prosthetic valve or prosthetic material used for valve repair Unrepaired or incompletely repaired cyanotic congenital heart disease Acquired valvular heart disease with stenosis or regurgitation Cyanotic congenital heart disease (without surgical repair or with residual defects, palliative shunts, or conduits) Congenital heart disease repaired with prosthetic material (for 6 months after the procedure) Structural congenital heart disease, including surgically corrected, or palliated structural conditions; excluding isolated ASD, fully repaired VSD/​PDA, endothelialized closure devices Congenital heart disease repaired with prosthetic material (for 6 months if complete repair, indefinite if residual defect) Valve disease in cardiac transplant recipients Hypertrophic cardiomyopathy Procedures requiring prophylaxis Dental procedures involving manipulation of gingival tissue, the periapical region of teeth, or perforation of the oral mucosa Gastrointestinal and genitourinary procedures where there is suspected pre-​existing infection Dental procedures requiring manipulation of the gingival or periapical region of the teeth or perforation of the oral mucosa Invasive procedures of the respiratory tract needing incision or biopsy of the mucosa ASD, atrial septal defect; IE, infective endocarditis; PDA, patent arterial duct; VSD, ventricular septal defect. Adapted from Harrison JL, Prendergast BD, Habib G (2009). The European Society of Cardiology 2009 guidelines on the prevention, diagnosis, and treatment of infective endocarditis. Key messages for clinical practice. Pol Arch Med Wewn, 119, 773–​6. 16.9.2  Endocarditis 3533 The timing of surgery is all-​important and demands experience and clinical judgement. The main indications are haemodynamic in- stability, persistent infection, and annular or aortic abscesses. In such cases surgery should never be delayed, even if only hours or days of antibiotic treatment have been given. The primary goals of the surgeon are to remove all infected material and to reconstruct the heart and/​ or restore valvular function at the lowest operative risk. An under- standing of the surgical anatomy of endocarditis is a precondition for surgical success, which means the involvement of an experienced sur- gical team. Wherever possible, surgeons now strive to preserve the na- tive valve, either by removal of the vegetation(s) or by valve repair. In prosthetic valve endocarditis, removal of all foreign material is man- datory. Actuarial survival figures indicate a 75% survival at 5 years and a 61% survival at 10 years after cardiac surgery for endocarditis. There are several unresolved issues with regard to the surgical treatment of endocarditis. First, the use of surgery when embolism has already taken place remains controversial. Recurrent emboli, persistent vegetation after a major systemic embolus, and vegeta- tion size (>10 mm) have all been put forward as indications, but there are no controlled trials to support a firm recommendation. Secondly, the optimal timing of surgery in patients who have had a cerebrovascular accident, either as a result of an embolic stroke or from haemorrhage due to a ruptured mycotic aneurysm: as a general rule, delay of at least 4 weeks is suggested if haemorrhage is detected by CT scanning, but surgery can be undertaken within 72 h if no haemorrhage is present. Thirdly, the duration of anti- biotic treatment postoperatively: a short postoperative course is appropriate if the excised valve is sterile, whereas continuation for 4 to 6 weeks seems reasonable if the pathogen is isolated from the excised valve. FURTHER READING Baddour LM, et al. (2015). Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association. Circulation, 132, 1435–86. Cohen PS, Maguire JH, Weinstein L (1980). Infective endocarditis caused by gram negative bacteria:  a review of the literature 1945–​1977. Prog Cardiovasc Dis, 22, 205–​41. Gould FK, et al. (2012). Guidelines for the antibiotic treatment of endo- carditis in adults: report of the Working Party of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother, 67, 269–​89. Habib G, et al. (2015). ESC Guidelines for the management of infective endocarditis. Eur Heart J, 36, 3075–​128. Hoen B, et al. (1995). Infective endocarditis in patients with nega- tive blood cultures: analysis of 88 cases from a one year nationwide survey in France. Clin Infect Dis, 20, 501–​6. Kang DH, et al. (2012). Early surgery versus conventional treatment for infective endocarditis. N Engl J Med, 366, 2466–​73. Moreillon P, Que Y-​A (2004). Infective endocarditis. Lancet, 363, 139–​49. Mylonakis E, Calderwood SB (2001). Infective endocarditis in adults. N Engl J Med, 345, 1318–​29. NICE (2015). Prophylaxis against infective endocarditis. Clinical guide- line. https://​www.nice.org.uk/​guidance/​cg64 Prendergast BD (2006). The changing face of endocarditis. Heart, 92, 879–​85. Prendergast BD, Tornos P (2010). Surgery for infective endocar- ditis: who and when? Circulation, 121, 1141–​52. Rick A, et al. (2008). ACC/​AHA 2008 guideline update on valvular heart disease: focused update on infective endocarditis. Circulation, 118, 887–​96. Task Force on the Prevention, Diagnosis, and Treatment of Infective Endocarditis of the European Society of Cardiology (2009). Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009). Eur Heart J, 30, 2369–​413. Watkin R, et  al. (2003). The microbiological diagnosis of infective endocarditis. J Infect, 47, 1–​11. Wilson W, et al. (2007). Prevention of infective endocarditis. Guidelines from the American Heart Association. A guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation, 116, 1736–​54. Table 16.9.2.9  Prevention of endocarditis in patients with known cardiac risk Situation Antibiotic Adults Children Single dose 30–​60 min before procedure No allergy to penicillin or ampicillin Amoxicillin or ampicillina 2 g PO or IV 50 mg/​kg PO or IV Allergy to penicillin or ampicillin Clindamycin 600 mg PO or IV 20 mg/​kg PO or IV IV, intravenous; PO, by mouth. Cephalosporins should not be used in patients with anaphylaxis, angio-​oedema, or urticaria after intake of penicillin and ampicillin. a Alternatively cephalexin 2 g IV or 50 mg/​kg IV for children, cefazolin, or ceftriaxone 1 g IV for adults or 50 mg/​kg IV for children. From Habib G et al. (2015). 2015 ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC) Endorsed by: European Association for Cardio-​Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J, 36, 3075–​128. 16.9.3 Cardiac disease in HIV infection 3534 Peter 16.9.3 Cardiac disease in HIV infection 3534 Peter F. Currie section 16  Cardiovascular disorders 3534 16.9.3  Cardiac disease in HIV infection Peter F. Currie ESSENTIALS Symptomatic heart disease can affect up to 10% of HIV-​positive pa- tients and cause death in around 2%. Cardiovascular screening and risk factor management is recommended. In resource-​poor countries where access to antiretroviral drugs is limited the typical manifestations are (1) HIV heart muscle disease—​ this occurs in the late stages of HIV infection, with dilated cardiomy- opathy having a dismal prognosis, the median survival after diagnosis being about 100 days; standard therapy for heart failure should be considered; and (2)  pericardial effusion—​a common finding, but most are symptomless; significant effusions are often due to myco- bacterial infection or malignant infiltration, particularly with non-​ Hodgkin’s lymphoma. In the developed world, premature coronary artery disease is more common in patients with HIV than in controls. There is a two-​ to threefold increase in the incidence of acute coronary events in HIV patients treated with highly active antiretroviral therapy, which is thought to be related to HIV lipodystrophy, an ill-​defined syndrome that resembles the non-​HIV metabolic syndrome and is found in up to 35% of patients after 12 months of protease inhibitor therapy. Isolated pulmonary hypertension is a rare, non​infectious com­ plication of HIV infection and has a grave prognosis (50% survival at 1 year). Highly active antiretroviral therapy and specific pulmonary hypertension therapies may provide symptomatic relief. There are many important interactions between commonly used cardiac medications and components of highly active antiretroviral therapy. These should be carefully considered when managing car- diovascular conditions in this population. Introduction Cardiovascular manifestations of HIV infection are well recognized and have been reported in up to 40% of autopsies and about 25% of echocardiographic studies performed on patients with AIDS. While most of these lesions are minor, symptomatic heart disease can affect up to 10% of HIV-​positive patients and cause death in around 2%. Heart muscle disease was previously the dominant cardiac com- plication of HIV infection in the developed world until the advent of highly active antiretroviral therapy (HAART). This has signifi- cantly altered the course of HIV infection and most likely reduced the incidence of heart muscle disease and other forms of heart dis- ease in AIDS. However, HAART-​induced dyslipidaemia has become an important factor for the development of premature coronary ar- tery disease, which is becoming increasingly common. Despite sig- nificant progress in providing HAART to increasing numbers of patients in the developing world, HIV heart muscle disease, pericar- dial effusion, and pulmonary hypertension continue to predominate in resource-​poor countries where access to antiretroviral drugs is limited. The common cardiovascular manifestations of HIV infection are listed in Table 16.9.3.1. HIV/​AIDS and the pericardium Pericardial effusion and pericarditis were found frequently in early HIV autopsy studies and still remain a significant problem in Africa. Small effusions are common, but most are symptomless. Cardiac tamponade is rare, but the finding of unexplained breath- lessness, raised jugular venous pressure, or radiographic cardio- megaly should prompt early echocardiographic assessment (see Chapter 16.8). In Africa up to 72% of patients with serosanguinous effusions have been found to be HIV-​positive, and Mycobacterium tubercu- losis or M. avium-​intracellulare pericarditis is common. Appropriate antituberculous and antiviral therapies may be helpful, but it is not clear if corticosteroids are beneficial in this situation and they are generally avoided. Herpes simplex virus, cytomegalovirus, and other unusual organisms may clinically be implicated, but clinically significant pericardial effusions are often due to malignant infiltra- tion, particularly with non-​Hodgkin’s lymphoma. Pericardiocentesis and pericardiectomy can be used to treat tam- ponade in HIV infection, but surgical intervention may not be ap- propriate in patients with very advanced disease. Clearly, however, culture of pericardial biopsy or fluid from symptomatic effusions may be useful in identifying treatable opportunistic infections or malignancy. Table 16.9.3.1  Cardiovascular manifestations of HIV/​AIDS Pericardial effusion Idiopathic Infectious (viral, bacterial—​especially tuberculous, and fungal) Neoplastic (Kaposi’s sarcoma and non-​ Hodgkin’s lymphoma) Heart muscle disease Myocarditis (idiopathic/​lymphocytic, specific infections, toxins) Dilated cardiomyopathy Left ventricular dysfunction Isolated right ventricular dysfunction Endocarditis Marantic (non​bacterial thrombotic endocarditis) Infective Pulmonary hypertension Primary Secondary (recurrent bronchopulmonary infections, thromboembolism) Premature atherosclerosis and coronary artery disease Stroke Adverse drug effects Hyperlipidaemia Induction of arrhythmia Autonomic dysfunction Sudden death 16.9.3  Cardiac disease in HIV infection 3535 Cardiac tumours in HIV/​AIDS In AIDS patients, Kaposi’s sarcoma is a disseminated visceral dis- ease with cardiac involvement in up to 25% of cases. Isolated cardiac Kaposi’s sarcoma is rare. The tumour often invades the subpericardial fat around coronary arteries and may infiltrate the pericardium or myocardium. However, despite this, Kaposi’s sarcoma is not usually associated with cardiac symptoms and significant effusion is rare. The prevalence of cardiac Kaposi’s sarcoma in HIV/​AIDS appears to be falling. Primary cardiac lymphoma is extremely rare in HIV-​negative individuals, although disseminated lymphoma may involve the myocardium more frequently. Both patterns of malignant cardiac involvement occur in AIDS patients, and non-​Hodgkin’s lymphoma in particular, may involve the pericardium or myocardium. In con- trast to Kaposi’s sarcoma, cardiac lymphoma is commonly associ- ated with tamponade, symptomatic heart failure, and conduction abnormalities. This diagnosis should therefore be considered in AIDS patients with rapidly progressive cardiovascular symptoms, unexpected arrhythmias, or heart block. Endocardial disease in HIV/​AIDS Marantic or non​bacterial thrombotic endocarditis was a frequent finding in early AIDS post-​mortem series. Non​infectious systemic thromboembolism was a common sequel and hence the condition is associated with significant morbidity and mortality. It is now rarely described as a complication of AIDS. Although AIDS patients are susceptible to bacterial infections, in- fective endocarditis rarely occurs in HIV infection outwith the set- ting of injection drug use (see Chapter 16.9.2). Asymptomatic HIV infection per se appears to have little effect on the susceptibility to, or the mortality from, the condition, although bacterial endocar- ditis runs a more fulminant course in the late stages of AIDS. In par- ticular, a CD4 count of less than 200 cells/​μl is associated with a poor prognosis in these circumstances. As with infective endocarditis in patients who are HIV-​negative, in intravenous drug users the tri- cuspid valve is most commonly involved and Staphylococcus aureus or Streptococcus viridans are the most frequently isolated organisms. Aspergillus fumigatus, Pseudallescheria boydii, and other forms of bacterial and fungal endocarditis occur in end-​stage AIDS. Just as for patients without AIDS, adequate bacteriological in- vestigations are required when endocarditis is suspected in HIV-​ positive individuals, but initial ‘best guess’ antimicrobial treatment (see Chapter 16.9.2) may have to be widened, particularly if fungal endocarditis is suspected. Valvular heart surgery has been described in HIV-​positive intravenous drug users with endocarditis, but continued drug use often results in a poor prognosis, as in the non-​ HIV/​AIDS population. Heart muscle disease HIV heart muscle disease occurs in the late stages of HIV infection and is associated with low CD4 counts. Before HAART, symptomatic congestive cardiac failure was found in around 5% of HIV patients. However, the signs and symptoms of heart failure were frequently mistakenly attributed to anaemia or bronchopulmonary infection. Left ventricular systolic dysfunction—​either isolated or in the form of a dilated cardiomyopathy—​could be found echocardiographically in 10–​15% of patients with AIDS previously and currently in up to 3% of patients treated with HAART (Fig. 16.9.3.1). The cause or causes of HIV heart muscle disease remain un- known, but are almost certainly complex. It is likely that an auto- immune lymphocytic myocarditis plays a key pathogenic role, in line with current thinking on the pathogenesis of idiopathic dilated cardiomyopathy in HIV-​negative patients. Before HAART, some form of myocarditis was found by biopsy or at autopsy in up to 40% of patients with AIDS, and rarely specific organisms were identified (e.g. Toxoplasma gondii or cytomegalovirus), usually in the setting of disseminated infection. Some in situ hybridization studies have suggested that HIV-​1 may be present in the myocardium of patients with HIV heart muscle disease, although clear evidence for a pri- mary HIV myocarditis is still lacking. It is possible that the myo- carditis is secondary to an autoimmune reaction mediated through cytokines or circulating cardiac autoantibodies, but other potential cofactors include specific micronutrient deficiencies (especially selenium) or the cardiotoxic side effects of antiretroviral agents. An acute, lymphocytic myocarditis with intractable ventricular arrythmia has also recently been described as part of the immune reconstitution inflammatory syndrome. HIV-​related dilated cardiomyopathy has a dismal prognosis in the setting of advanced disease, with median survival after diag- nosis being about 100 days (Fig. 16.9.3.2). Conventional antiheart-​ failure treatment should be used, but vasodilating agents such as angiotensin-​converting enzyme (ACE) inhibitors are often poorly tolerated by end-​stage AIDS patients and β-​blockers may also pro- duce unacceptable side effects. Diuretics, digoxin, and aldosterone antagonists may be more useful in these circumstances. Successful cardiac transplantation, with or without a left ventricular assist de- vice as a bridging therapy, has been reported in two HIV-​positive patients, although the latest report relates to the diagnosis of cardio- myopathy in a subject with a normal CD4 count, undetectable viral Fig. 16.9.3.1  Four chamber dilatation and systolic dysfunction in HIV-​ positive man with undetectable viral load on HAART. section 16  Cardiovascular disorders 3536 load, and no history of opportunistic infection. Such treatment is applicable to only a very few HIV patients with heart muscle disease. Although still common in third world countries, the incidence of myocarditis, heart muscle disease, and symptomatic heart failure appears to have decreased in the HAART era, although reports of diastolic dysfunction possibly associated with hypertension and age are increasing. Right ventricular dysfunction and pulmonary hypertension in HIV/​AIDS Right ventricular dysfunction may occur as part of HIV heart muscle disease but can occur in isolation, without pulmonary hyperten- sion, and is of unknown significance. Bronchopulmonary infections should be treated aggressively, and intravenous drug use—​which may result in microvascular emboli—​should be discouraged. Isolated pulmonary hypertension is a rare, non​infective com­ plication of HIV infection and has a grave prognosis, with a 50% survival at 1  year (Fig. 16.9.3.3). It is prevalent in sub-​Saharan Africa and other developing countries. HAART has had no impact on the incidence of this devastating condition, which has little cor- relation with CD4 counts and may be related to the action of viral proteins or cytokines on the endothelial cell. Characteristic patho- logical lesions including intimal fibrosis and plexiform lesions con- firm its similarity to non-​HIV primary pulmonary hypertension. Right heart catheterization may be worthwhile to determine if pul- monary hypertension is reversible. Oxygen, calcium channel ant- agonists, vasodilators, phosphodiesterase V inhibitors, and nitric oxide therapy may be considered, but are unproven therapies in this circumstance and do not necessarily improve prognosis. Coronary artery disease in HIV infection HIV lipodystrophy is an ill-​defined syndrome that resembles the non-​HIV metabolic syndrome and includes dyslipidaemia and in- sulin resistance. Although it is dependent on the type and duration of antiretroviral therapy, and can be found in up to 35% of patients after 12 months of protease inhibitor therapy, it has also been sug- gested that HIV itself is a proatherogenic virus with specific effects on cellular cholesterol management. The significant changes in lipid metabolism noted in the recipi- ents of protease inhibitors make it likely that HIV/​AIDS patients are at risk of premature atherosclerosis, and observational studies sug- gest they have an almost twofold increase in the risk of coronary disease compared to non-​HIV controls. Acute myocardial infarction appears to be the commonest presentation of coronary heart disease in HIV populations and it is plausible that—​because acute coronary 1.00 0.75 0.50 Probability of survival 0.25 0 1.00 0.75 0.50 Probability of survival 0.25 0 0 200 400 600 800 1000 1200 1400 Days Normal Right ventricular dysfunction Left ventricular dysfunction Dilated cardiomyopathy Fig. 16.9.3.2  Top: Survival curves for 296 patients who were HIV-​positive with structurally normal hearts or cardiac dysfunction. Bottom: Survival time to death related to AIDS in 81 subjects with CD4 cell count less than 20 × 106/​litre. Reproduced from BMJ, Currie PF, et al., 309, 1605–​7. Copyright (1994) with permission from BMJ Publishing Group Ltd. (a) (b) Fig. 16.9.3.3  (a) Long-​axis and (b) short-​axis parasternal view of a two-​dimensional echocardiogram from an HIV-​positive intravenous drug user with idiopathic pulmonary hypertension illustrating dilatation of the right ventricle and flattening of the interventricular septum. LV, left ventricle; RV, right ventricle. 16.9.3  Cardiac disease in HIV infection 3537 syndromes involve low-​volume, lipid-​rich plaques—​HAART may promote development of vulnerable lesions or influence plaque rup- ture. Similarly, most HIV patients with coronary disease will have a long duration of HIV infection, which raises the possibility that op- portunistic infections may also be involved in this process. A case of coronary arteritis due to HIV has been described, but acute coronary events are not clearly related to HIV replication as one-​third of pa- tients have undetectable plasma HIV-​RNA at the time of symptoms. Coronary angiography can be carried out safely in patients with HIV and frequently reveals proximal vessel involvement and single vessel disease. Percutaneous coronary intervention is a reason- able therapy, with use of drug-​eluting stents advocated by some because of concerns over the possibility of aggressive restenosis. Fibrinolysis and coronary artery bypass have also been used with acceptable survival rates, hence it is reasonable that the clinical situ- ation should determine the use of coronary treatments in the same manner as for the non-​HIV population. However, care is required over the choice of antiplatelet agents in acute coronary syndromes. The non​nucleoside reverse transcriptase inhibitor etravirine inhibits CYP2C19 and can reduce the antiplatelet activity of clopidogrel and ticagrelor, the coprescription of these drugs is not recommended. Prasugrel may be a suitable alternative antiplatelet agent for use in these circumstances. It may be necessary to consider drug treatment for hyperlipid- aemia, particularly if antiretroviral treatment cannot be changed or interrupted. Like protease inhibitors, most HMG CoA reductase inhibitors (statins) are metabolized through the cytochrome P450 system. Coprescription of these drugs may therefore result in com- petitive inhibition, significantly increased plasma statin levels, and increased risk of myopathy and rhabdomyolysis (Table 16.9.3.2). Pravastatin is metabolized by a different pathway and for this reason it is recommended that hypercholesterolaemia in HIV patients re- ceiving protease inhibitors is initially treated with pravastatin 20 mg daily, with careful monitoring of virological parameters and creatine kinase levels. Rosuvastatin, a more powerful statin metabolized in a similar manner, may only be used in low dose. Fibrates are useful for the treatment of hypertriglycerides. Bile acid sequestrants, although attractive from the point of view of drug interactions, may have ad- verse effects on serum triglyceride levels or impair absorption of antiretrovirals and should be avoided. Ezetimibe may be considered for combination therapy or alone in cases of statin intolerance. Sudden death, cardiac arrhythmia, and stroke Sudden death due to cardiac rhythm abnormalities is well recognized in HIV infection and may be secondary to other cardiac pathology or be a consequence of some forms of treatment. Atrial fibrillation is becoming more common as the HIV population is now ageing. It can be found in 2.6% of patients and caution is required as there are important interactions between anticoagulants, antiarrhythmics, and HAART (see https://​www.hiv-​druginteractions.org/​). Stroke has also emerged as a relatively common event in young HIV patients treated with HAART, with both ischaemic stroke and intracranial haemorrhage being described. Apart from traditional risk factors, HIV-​RNA viral load may be an important predictor for ischaemic stroke, while the potential effect of HAART is less clear. Cardiovascular assessment of the patient with HIV/​AIDS Echocardiography Echocardiography can easily identify many cardiac conditions common in HIV-​positive patients, providing useful information on the appearance of the right ventricle, an indirect assessment of pulmonary pressures, and regional wall motion abnormalities sug- gestive of coronary artery disease. Any HIV-​positive patient at high risk of developing cardiovascular disease, or with any potential clin- ical manifestation of it, should therefore have an echocardiogram performed, with repeated imaging every 1 to 2 years. It may be jus- tifiable to perform a baseline study at the time of diagnosis of HIV in any patient, with further examination and closer monitoring on Table 16.9.3.2  Lipid-​lowering therapy in HIV infection Drug Indication Statin dose adjustment with HIV therapy PI NNRTI Statin Atorvastatin Pravastatin Rosuvastatin Simvastatin ↑↑LDL –​ first choice ↑LDL+↑TG –​ first choice Start with low dose Consider high dose Start with low dose Contraindicated May require high dose May require high dose Start with low dose May require high dose Fibrates ↑↑TG+↑LDL –​ first choice No reported interaction No reported interaction Ezetimibe Coprescription with statin Statin intolerance No reported interaction No reported interaction Fish oil ↑TG –​ second choice No reported interaction No reported interaction PCSK9 Inhibitors Evolocumab Alirocumab ↑↑LDL –​ under specialist advice No reported interaction No reported interaction ↑↑TG –​ Triglyceride >5.6 mmol/​litre ↑↑LDL –​ LDL >4.9 mmol/​litre ↑LDL –​ LDL >3.4 mmol/​litre NNRTI –​ non​nucleoside reverse transcriptase inhibitor; PI –​ protease inhibitor. section 16  Cardiovascular disorders 3538 discovery of cardiovascular abnormalities or in those with signifi- cant viral infection or unexplained pulmonary symptoms. Assessment of cardiovascular risk Traditional cardiovascular risk profiling has become more im- portant in the care of HIV-​positive patients. The prevalence of heavy cigarette smoking in HIV-​infected patients is as high as 40%. Diabetes mellitus requiring treatment is common, and HIV patients appear to be at higher risk of developing hypertension at a younger age than the general population, such that blood pressure screening is recommended. A careful history should also identify a family his- tory of premature vascular disease, recreational drug use, poor diet, and lack of physical exercise. A risk score may be calculated to help guide investigation and treatment (Fig. 16.9.3.4), but it may also be useful to consider HIV infection and HAART in themselves as spe- cific risk factors for premature atherosclerosis. FURTHER READING Balloca F, et al. (2017). Cardiovascular disease in patients with HIV. Trends Cardiovasc Med, 27, 558–​63. Calabrese LH, et al. (2003). Successful cardiac transplantation in an HIV-​1-​infected patient with advanced disease. N Engl J Med, 348, 2323–​8. Cecchia EJ, et al. (2007). Infective endocarditis in drug addicts: role of HIV infection and the diagnostic accuracy of Duke criteria. J Cardiovasc Med, 8, 169–​75. Cerrato E, et al. (2013). Cardiac dysfunction in pauci symptomatic human immunodeficiency virus patients:  a meta-​analysis in the highly active antiretroviral therapy era. Eur Heart J, 34, 1432–​6. Currie PF, et al. (1994). Heart muscle disease related to HIV infec- tion: prognostic implications. BMJ, 309, 1605–​7. D’Ascenzo F, et al. (2012). Acute coronary syndromes in human im- munodeficiency virus patients: a meta-​analysis investigating adverse event rates and the role of antiretroviral therapy. Eur Heart J, 33, 875–​80. D’Ascenzo F, et al. (2015). A meta-​analysis investigating incidence and features of stroke in HIV-​infected patients in the highly active anti- retroviral therapy era. J Cardiovasc Med, 16, 839–​43. DAD Study Group (2008). Use of nucleoside reverse transcriptase in- hibitors and risk of myocardial infarction in HIV-​infected patients enrolled in the DAD study. Lancet, 371, 1417–​26. Holloway CJ, Boccara F (2017). HIV-​related cardiovascular disease: closing the gap in mortality. Curr Opin HIV AIDS, 12, 509–​12. Hsue PY, Waters DD (2005). What a cardiologist needs to know about patients with human immunodeficiency virus infection. Circulation, 112, 3947–​57. Janda S, et al. (2010). HIV and pulmonary arterial hypertension: a sys- tematic review. HIV Med, 11, 620–​34. Jarrett H, Barnett C (2017). HIV-​associated pulmonary hypertension. Curr Opin HIV AIDS, 12, 566–​71. Knudsen A, et  al. (2013). Angiographic features and cardiovas- cular risk factors in human immunodeficiency virus-​infected patients with first-​time acute coronary syndrome. Am J Cardiol, 111, 63–​7. Krishan K, et al. (2012). Successful left ventricular assist device bridge to transplantation in a patient with end-​stage heart failure and human immunodeficiency virus. Artif Organs, 36, 759. Nahass RG, et al. (1990). Infective endocarditis in intravenous drug users:  a comparison of human immunodeficiency virus type 1–​ negative and positive patients. J Infect Dis, 162, 967–​70. Rogers JS, et  al. (2008). Immune reconstitution inflammatory syn- drome and human immunodeficiency virus-​associated myocarditis. Mayo Clin Proc, 83, 1275–​9. Sliwa K, et al. (2012). Contribution of the human immunodeficiency virus/​acquired immunodeficiency syndrome epidemic to de novo presentations of heart disease in the Heart of Soweto Study Cohort. Eur Heart J, 33, 866–​74. Stein JH, et al. (2014). Arterial disease in patients with human im- munodeficiency virus infection. J Am Coll Cardiol lmg, 7, 515–​25. Volberding PA, et al. (2003). The Pavia consensus statement. AIDS, 17 Suppl 1, S170–​9. LOW RISK: <50 yrs, normotensive, nonsmokers, no history of diabetes, dyslipidaemia or coronary heart disease. No family history of cardiovascular disease, normal BMI. MODERATE RISK: >50 yrs, history of lipodystrophy, impaired glucose tolerance, diabetes, hypertension, dyslipidaemia. Family history of cardiovascular disease, smokers, on HAART, increased BMI HIGH RISK: As above with history of coronary artery or other vascular disease Fasting lipid profile Fasting blood sugar As above, plus regular fasting lipid profile, standard oral glucose tolerance test. Consider cardiological involvement. Consider resting and exercise electrocardiography and echocardiography in individual cases As above, plus consider noninvasive or invasive assessment in each individual case PATIENT CHARACTERISTICS CARDIOVASCULAR INVESTIGATIONS Fig. 16.9.3.4  An approach to cardiovascular assessment in patients with HIV. 16.9.4 Cardiovascular syphilis 3539 Krishna Somers 16.9.4 Cardiovascular syphilis 3539 Krishna Somers 16.9.4  Cardiovascular syphilis 3539 16.9.4  Cardiovascular syphilis Krishna Somers ESSENTIALS Clinicians need to be aware of cardiovascular syphilis in patients at risk of infection, with the time taken from initial infection to clin- ical manifestation ranging from 10 to 25 years, although this is ac- celerated in patients with HIV infection. Inadequate or interrupted antibiotic therapy may confound the development of cardiovascular syphilis and make diagnosis difficult. Presentation may be with (1)  asymptomatic aortitis; (2)  aortic regurgitation—​the commonest manifestation resulting from annular dilatation of the aortic ring and eventually affecting 70% of patients with untreated syphilis; (3) coronary ostial stenosis; (4) aneurysm of the aorta; or (5) a combination of these. Syphilitic aortitis must be included in the differential diagnosis of aortic regurgitation in older people and those with predisposing factors. Diagnosis—​serological testing is the mainstay:  latent or inad- equately treated syphilis should be suspected with the finding of a positive non​specific treponemal serological test (e.g. rapid plasma reagin) and a positive specific treponemal antibody test (e.g. Treponema pallidum haemagglutination), but negative serology does not absolutely exclude infection with T. pallidum, particularly in an immunocompromised host. Management—​parenteral penicillin remains the treatment of choice for cardiovascular syphilis: the World Health Organization and European and United States guidelines recommend benzathine benzylpenicillin 2.4 × 106 units administered once weekly for 3 weeks by the intramuscular route. Modern imaging technology with MRI and three-​dimensional CT enables innovative surgical approaches in the repair of syphilitic aortitis. Introduction At the beginning of the 20th century cardiovascular syphilis ac- counted for 5–​10% of deaths due to cardiovascular disease. The in- stitution of public health measures—​early recognition of syphilis and treatment with penicillin since the 1940s—​produced a sharp decline in its incidence and hence in the tertiary manifestations and mortality from cardiovascular and neurosyphilis. The rarity of syphilitic aortitis in recent times has led to pub- lication of a succession of case reports describing challenges in diagnosis and management. With the re-​emergence of syph- ilis in both developed and developing countries, particularly in South East Asia and sub-​Saharan Africa, delayed cardiovascular complications of syphilis are likely to be seen with increasing frequency. Syphilis remains a major cause of ascending aortic aneurysm. An increased rate of infection with the causative organism, Treponema pallidum, prevails in sexually promiscuous individuals, intravenous drug abusers, men who have unsafe sex with men, sex workers trafficked from ‘east to west’, clients of sex workers, and so-​ called bridging populations, such as men who have both male and female sexual partners. Increase in syphilis infection rates among homosexual men is well documented in several cities in the United States of America and also in Europe, Canada, and Australia. As the syphilis epidemic continues to develop it is anticipated that increasing numbers of patients will present with cardiovascular or neurological tertiary syphilis in future decades. Clinicians need to be aware of cardiovascular syphilis in groups considered to have been at risk of infection. Inadequate or inter- rupted antibiotic therapy may confound the development of cardio- vascular syphilis and make diagnosis difficult. Pathogenesis and pathology of cardiovascular syphilis Syphilis is spread through body fluids and is usually acquired by sexual contact with an infected person. Men who have sex with men need to be aware that syphilis can be transmitted through oral sex. In the preantibiotic era, 50–​75% of partners of persons with primary or secondary syphilis were liable to become infected. Spontaneous healing of the early lesions of primary and secondary syphilis is fol- lowed by a long latent period, the time taken from initial infection to clinical manifestation of cardiovascular syphilis ranging from 10 to 25 years. The 2-​year mortality rate after diagnosis of untreated syphilitic aneurysm is about 80%. T. pallidum has a predilection for small vessels, especially in the aorta and the nervous system. In tertiary syphilis, obliterative end- arteritis of the vasa vasorum of the media and the adventitia of the aorta is characterized by the presence of an inflammatory cuff com- posed of lymphocytes and plasma cells around the affected vessels, causing ischaemic necrosis of collagen and elastic tissue in the aortic media. Syphilis classically involves the proximal ascending aorta, presumably because the vasa vasorum are more plentiful in that region. The pathological hallmark of syphilitic aortitis is ‘tree-​barking’, a description of longitudinal wrinkling of the aortic intima resulting from contraction of fibrous scars in the aortic media. Fibrosis of the media in the proximal ascending aorta results in dilatation of the aortic root and aneurysm formation, leading to aortic re- gurgitation, the most common complication of syphilitic aortitis afflicting 20 to 30% of patients. A  rarer form of cardiovascular syphilis is ‘gummatous’ myocarditis, which is usually diagnosed post-​mortem. Clinical presentation Cardiovascular syphilis may present in one of four forms, but the features may be mixed. • Asymptomatic aortitis—​the most prevalent form, and usually diagnosed at necropsy with the unexpected finding of character- istic ‘tree-​barking’ of the aortic intima. • Aortic regurgitation—​the commonest manifestation of cardio- vascular syphilis that results from annular dilatation of the aortic valve ring in syphilitic aortitis affecting the ascending aorta (the valve cusps remain normal); 70–​80% of patients with untreated syphilis eventually develop aortic regurgitation. section 16  Cardiovascular disorders 3540 • Coronary ostial stenosis—​occurs in up to 30% of cases of cardio- vascular syphilis, and frequently coexists with aortic regurgitation as a complication of aortitis affecting the proximal ascending aorta. • Syphilitic aneurysm of the aorta—​the least common manifest- ation of cardiovascular syphilis, occurring in 10–​15% of patients with untreated syphilis; usually saccular but may be fusiform, and can occur as solitary aneurysm anywhere along the aorta, with characteristic radiographic appearance of dilatation. Aortic regurgitation With typical location of syphilitic disease in the ascending aorta, the murmur of syphilitic aortic regurgitation may be more prominent along the right sternal edge, in contrast to the left side in rheumatic aortic regurgitation. Transthoracic echocardiography will demon- strate that the aortic regurgitation is a result of dilatation of the aortic root (Fig. 16.9.4.1). Patients with syphilitic aortitis of the ascending aorta die of heart failure resulting from aortic valve regurgitation. Coronary ostial stenosis Angina or acute myocardial infarction may be the first presentation of syphilitic heart disease, even in younger patients (Fig. 16.9.4.2), and may also result from associated coronary atherosclerosis. In the South African literature in the 1980s there were several reports of acute myocardial infarction and death due to syphilitic ostial sten- osis (see ‘Syphilis and HIV infection’, next); hence patients found at coronary angiography to have bilateral coronary ostial stenosis but no distal coronary disease should be screened for syphilis, especially if they have known risk factors. Syphilitic aneurysm Nearly one-​half of the cases of syphilitic aneurysm occur in the as- cending aorta, 30–​40% in the aortic arch, and the remainder in the descending aorta. Mural thrombus, often with calcification, may obliterate the lumen of an aneurysm. Aneurysm of the aortic arch may compress and erode contiguous structures, such as a bronchus, resulting in pulmonary atelectasis; great veins, with presentation of superior mediastinal obstruction; the left recurrent laryngeal nerve, causing cough and hoarseness; and the vertebral bodies or sternum, causing pain. Aneurysm of the aortic arch may also produce tracheal tug, stridor, and dysphagia. Sternal erosion may be an early mani- festation of syphilitic aortitis, as the junction between the ascending aorta and the aortic arch is near to the sternum, and massive aortic aneurysm may present as a pulsatile swelling in the right anterior thoracic cage. Rupture of an aortic aneurysm (70% of cases) into a bronchus—​resulting in massive and fatal haemoptysis—​or into the pleural space or pericardium may be the first clinical manifestation of syphilitic aneurysm. Although extremely rare, tertiary syphilis should be considered in the differential diagnosis of thoracic aneurysms, even in the setting of atherosclerotic disease in older subjects. Patients with syphilitic aneurysm of the thoracic aorta, if untreated, have a mean life expect- ancy of 6 to 9 months from the onset of symptoms. Aneurysm of the abdominal aorta due to syphilitic aetiology is rare and (if asymptomatic) of unknown prognosis, but it may pre- sent with lumbar or abdominal pain and—​extremely rarely—​as spontaneous aortocaval fistula. Diagnosis A high index of suspicion is required to make the diagnosis in a patient found to have aortic regurgitation or aortic aneurysm, but syphilitic disease should be considered, especially if the patient belongs to a group at high risk of syphilitic infection or is elderly with a suggestive background risk factor, such as birth in a country where diagnosis and treatment of syphilis are likely to have been inadequate. With appropriate questioning a history of syphilis and its treatment may be obtained, but patients will often not volunteer such information. The diagnosis of syphilitic aortitis is often over- looked because atherosclerosis has greatly surpassed it as a cause of aortic aneurysm (Fig. 16.9.4.3). Laboratory investigation Serological testing is the mainstay of diagnosis. Rapid plasma re- agin is currently the most widely available non​specific treponemal test: if positive in high titre, it may indicate latent or inadequately (b) (a) LV AoV LA Fig. 16.9.4.1  Transthoracic echocardiography of a 61-​year-​old woman with syphilitic aortitis. (a) Apical long-​axis view of the left ventricle in mid-​diastole. The aortic valve leaflets are closed. The diameter of the ascending aorta is 4.8 cm (normal <3 cm) with the dilatation extending to the arch. AoV, aortic valve; LA, left atrium LV, left ventricle. (b) Apical long-​axis colour Doppler study in mid-​diastole showing severe aortic regurgitation. 16.9.4  Cardiovascular syphilis 3541 treated disease and be used to gauge response to treatment, but false positives are not uncommon: it is always positive in patients with non​venereal treponematosis, and it may be negative in car- diovascular syphilis. Specific treponemal antibody tests such as T.  pallidum haemagglutination (TPHA) detect antibodies to T. pallidum-​specific antigen and are almost always positive in car- diovascular syphilis, indicating prior infection with this organism. However, negative serology does not absolutely exclude infection with T.  pallidum, particularly in an immunocompromised host. Latent syphilis, defined by the presence of positive serological tests in the absence of clinical evidence of syphilis, may progress to car- diovascular and gummatous manifestations of tertiary syphilis. Even when confirmatory tests are not readily available, treatment should be initiated on suspicion of diagnosis. The diagnostic gold standard remains direct identification of T. pallidum in clinical specimens obtained at surgery. Polymerase chain reaction assay can provide definite diagnosis of spirochaetal infection when biopsy material is available. Syphilitic aortitis is often diagnosed on histological examination of the aneurysmal wall in patients who undergo resection of an ascending aortic aneurysm. Between 10 and 20% of patients with cardiovascular syphilis have coexisting neurosyphilis, hence cerebrospinal fluid examination is recommended. Recent case-​based reports propose the usefulness of 18F-​fluorodeoxyglucose positron emission spectroscopy (FDG-​ PET)/​CT for the assessment of extent of disease and response to treatment in syphilitic aortitis. Syphilis and HIV infection Syphilis promotes the transmission of HIV infection, and these infections can interact with each other. Cardiovascular syph- ilis develops more quickly in patients who are HIV seropositive (40 months from the time of primary infection) compared to those who are HIV seronegative (102 months), suggesting that coinfection with HIV hastens progression to late syphilis, perhaps due to im- munosuppression. Even though new cases of cardiovascular syphilis remain rare, it has been suggested that the decline of tertiary syphilis (a) (b) Fig. 16.9.4.2  Coronary angiogram of a 40-​year-​old Indonesian man who presented with severe, central chest pain. Note tapering of the aortic root (a, thin arrows), left main coronary artery stump (a, large arrowhead), and 90% ostial lesion of the right coronary artery (b, arrow). Emergency coronary artery grafting was performed. Serology obtained afterwards proved positive for syphilis. From Tong SYC, et al. (2006). MJA, 184, 241–​3. © Copyright 2006. The Medical Journal of Australia. Fig. 16.9.4.3  Chest radiograph showing aneurysm of the ascending aorta in an elderly man with cardiovascular syphilis. Note the typical linear calcification in the wall of the dilated ascending aorta. Atherosclerotic aneurysm of the ascending aorta in diffuse atherosclerotic disease may present a similar picture, although calcification—​when present—​is usually limited to the aortic knuckle and descending aorta. section 16  Cardiovascular disorders 3542 in males in the 1990s could be attributed to mortality from AIDS. But at the same time, there has been an increase in the prevalence of infectious syphilis, with many cases undiagnosed. As a general principle, consideration of one sexually transmissible infection should lead to consideration of another. After appropriate consent, any person with syphilis should be studied for antibodies to HIV and hepatitis B virus, and vice versa, and contacts traced for evidence of infection. Medical treatment In spite of discrepancies in dosage regimens, international con- sensus supports the use of parenteral penicillin as first-​line treat- ment for all stages of syphilitic infection. T. pallidum has remained sensitive to penicillin despite more than 60 years of its use in the treatment of syphilis. A standard course cures most patients, al- though some authorities have recorded serological failure rates as high as 25%. It is thought that tertiary syphilis requires a longer course of treat- ment than early syphilis, since the treponemes may be dividing very slowly in the later stage of infection. The World Health Organization and European and United States guidelines recommend treatment of cardiovascular syphilis with benzathine benzylpenicillin 2.4 × 106 units administered once weekly for 3 weeks by the intramuscular route. United Kingdom guidelines propose 750 mg procaine benzyl penicillin once daily for 17 days by the intramuscular route. The Australian recommendation for the treatment of all forms of tertiary syphilis is benzylpenicillin 1.8 g intravenously 4-​hourly for 15 days. Doxycycline, 100 mg by mouth twice daily for 28 days, is recom- mended by the United States Centers for Disease Control in those with penicillin allergy; United Kingdom guidelines suggest that doxycycline 200 mg twice daily for 28 days is preferable. An unusual feature in the antibiotic treatment of syphilis is the Jarisch–​Herxheimer reaction. The mechanism of the reaction, which takes the form of malaise and fever within 24 h of penicillin treatment, is uncertain and may be due to release of endotoxins from the massive death of treponema. In patients with cardiovascular syphilis, the Jarisch–​Herxheimer reaction can be avoided by pred- nisolone 10–​20 mg three times daily for 3 days, starting 24 h before commencement of penicillin therapy. Established aortic aneurysm and aortic regurgitation cannot be reversed or halted by medical treatment. All patients with cardiovascular syphilis require clinical and sero- logical follow-​up 6 and 12 months after treatment. Syphilis serology is often difficult to interpret after treatment, as post-​treatment trepo- nemal tests usually remain positive even after completion of suc- cessful treatment. Treatment failure could be indicated by failure of non​specific treponema antibody titres to decline fourfold within 6 months of treatment. There is a higher rate of syphilis treatment failure in HIV-​positive patients. Surgical treatment Digital subtraction aortography, MRI, or three-​dimensional CT scanning enables visualization of the anatomy of syphilitic aortitis and can inform surgical strategy (Fig. 16.9.4.4). The aortic valve, if it is involved, may be replaced by a prosthetic valve if there is normal aortic tissue upstream. Alternatively, a Bentall procedure, which in- volves replacement of the ascending aortic arch, may be the surgical treatment of choice. Coronary ostial lesions have been convention- ally treated, with favourable results, using internal mammary grafts or in combination with saphenous vein grafting. Isolated aortic aneurysm may be treated with endovascular stent graft repair, especially in patients with comorbidities who may be at high risk for open surgery, provided the lesion is considered anatomically suitable with adequate proximal and distal vessels. Conventional surgery, combined with endovascular repair, may be tried in the patients with syphilitic aortic aneurysm involving the aortic arch and the descending thoracic aorta, with the 30-​day mor- tality of such intervention ranging from 5 to 10%. FURTHER READING Bodhey NK, et al. (2003). Early sternal erosion and luetic aneurysms of thoracic aorta. Eur J Cardiothorac Surg, 28, 499–​501. Cheng TO (2001). Syphilitic aortitis is dying but not yet dead. Catheter Cardiovasc Interv, 52, 240–​1. Feier H, et  al. (2012). Coronary ostial stenosis in a young patient. Circulation, 125, e367–​8. Goh BT (2005). Syphilis in adults. Sex Transm Infect, 81, 448–​52. Goldstein B, Carroccio A, Ellozy SH (2003). Combined open and endovascular repair of a syphilitic aortic aneurysm. J Vasc Surg, 38, 1422–​5. Hook EW 3rd (2017). Syphilis. Lancet, 389, 1550–​7. Jackman JD, Radolf JD (1989). Cardiovascular syphilis. Am J Med, 87, 425–​33. Kennedy JLW, Barnard JJ, Prahlow JA (2006). Syphilitic coronary ostial stenosis resulting in acute myocardial infarction and death. Cardiology, 105, 25–​9. Fig. 16.9.4.4  Three-​dimensional left-​profile reconstruction of the thoracic aorta and adjacent structures in a 51-​year-​old man with the finding, on routine chest radiography, of an aortic aneurysm that proved to be syphilitic. From de Cannière D, et al. (1999). 21st century imaging for a 19th-​century disease. Circulation, 100, 884–​5. 16.9.4  Cardiovascular syphilis 3543 Maharajan M, Sampath Kumaar G (2005). Cardiovascular syphilis in HIV infection: a case-​controlled study at the Institute of Sexually Transmitted Diseases, Chennai, India. Sex Transm Infect, 81, 361. Parkes R, et al. (2004). Review of current evidence and comparison of guidelines for effective syphilis treatment in Europe. Int J STD AIDS, 15, 73–​88. Roberts WC, et al. (2015). Syphilis as a cause of thoracic aortic an- eurysm. Am J Cardiol, 116, 1298–​303. Tomey MI, Murthy VL, Beckman JA (2011). Giant syphilitic an- eurysm:  a case report and review of the literature. Vasc Med, 16, 360–​4. Tong SYC, Haqqani H, Street AC (2006). A pox on the heart: five cases of cardiovascular syphilis. MJA, 184, 241–​3. Treglia G, et al. (2013). Usefulness of 18F-​FDG PET/​CT in disease ex- tent and treatment response assessment in a patient with syphilitic aortitis. Clin Nucl Med, 38, e185–​7. Adam D. Timmis 16.13.4 Management of acute coronar Adam D. Timmis 16.13.4 Management of acute coronary syndrome 3626 Rajesh K. Kharbanda and Keith A.A. Fox section 16  Cardiovascular disorders 3626 NICE (2011). Management of stable angina. Clinical guideline. https://​ www.nice.org.uk/​guidance/​cg126 NICE (2016). Chest pain of recent onset:  assessment and diagnosis. Clinical guideline. https://​www.nice.org.uk/​guidance/​cg95 Rapsomaniki E, et al. (2014). Prognostic models for stable coronary artery disease based on electronic health record cohort of 102,023 patients. Eur Heart J, 35, 844–​52. Sekhri N, et  al. (2007). How effective are rapid access chest pain clinics? Prognosis of incident angina and non-​cardiac chest pain in 8762 consecutive patients. Heart, 93, 458–​63. Sekhri N, et al. (2016). A 10-​year prognostic model for patients with suspected angina attending a chest pain clinic. Heart, 102, 869–​75. 16.13.4  Management of acute coronary syndrome Rajesh K. Kharbanda and Keith A.A. Fox ESSENTIALS Acute coronary syndrome (ACS) is precipitated by an abrupt change in an atheromatous plaque and/​or thrombotic occlusion. This re- sults in increased obstruction to perfusion and ischaemia or in- farction in the territory supplied by the affected vessel. The clinical consequences of plaque rupture can range from a clinically silent episode, through to unstable symptoms of ischaemia without in- farction, to profound ischaemia complicated by progressive infarc- tion, heart failure, arrhythmia, and risk of sudden death. Clinical presentation with an ACS identifies a patient at high risk of further cardiovascular events requiring a defined acute and long-​term management strategy. The choice and timing of acute management strategy is critic- ally dependent on the extent and severity of myocardial ischaemia, with the spectrum of ACS broken down into three elements:  (1) Unstable angina: typical ischaemic symptoms without ST elevation on ECG and without elevated biomarkers of necrosis. (2) Non-​ST-​ elevation myocardial infarction (NSTEMI): typical ischaemic symp- toms without ST elevation on ECG but with biomarkers of necrosis above the diagnostic threshold. (3) ST-​elevation myocardial infarc- tion (STEMI): typical ischaemic symptoms with ST elevation on ECG and with biomarkers of necrosis above the diagnostic threshold. An acute reperfusion strategy (primary percutaneous coronary intervention (PCI) or thrombolysis) is of proven benefit only in ST-​ segment elevation infarction (or MI with new bundle branch block). Prompt relief of pain is important, not only for humanitarian reasons, but also because pain is associated with sympathetic ac- tivation, vasoconstriction, and increased myocardial work. Effective analgesia is best achieved by the titration of intravenous opioids, with concurrent administration of an antiemetic. High-​flow oxygen is re- commended for symptom relief in those patients with evidence of desaturation, particularly in those who are breathless or who have features of heart failure or shock. The management of prehospital cardiac arrest requires special attention: at least as many lives can be saved by prompt resuscita- tion and defibrillation as by reperfusion. Patients may also require management of arrhythmic and haemodynamic complications, including heart failure. Acute coronary syndromes without ST elevation (unstable angina/​non-​ST elevation MI) Risk stratification and initial management Patients without ST elevation or left bundle branch block can be tri- aged into low, intermediate, and high-​risk categories. (1) High-​risk—​ patients with typical clinical features of ischaemia and ST-​segment depression or transient ST-​segment elevation, or with troponin eleva- tion and a high-​risk score (risk calculator downloadable from http://​ www.gracescore.org/​ or http://​www.timi.org/​). Patients are also at high risk when ischaemia provokes arrhythmias or haemodynamic compromise. (2) Intermediate or low risk—​patients with clinical fea- tures of ACS and non​specific ECG changes (e.g. T-​wave inversion, T-​wave flattening, minor conduction abnormalities). (3) Low risk or an alternative diagnosis—​patients with a normal ECG, normal bio- markers, normal cardiac examination, and normal echo. Patients at high risk—​(1) high-​risk patients with acute ischaemia at initial presentation, or those who develop such features after hospital admission, and especially those with haemodynamic compromise, re- quire emergency assessment for revascularization and dual antiplatelet therapy. (2) Those proceeding to emergency revascularization should receive (a) aspirin; (b) P2Y12 receptor inhibitor; (c) unfractionated or low molecular weight heparin (LMWH), or a direct thrombin inhibitor, and (d) if required for bail-​out, glycoprotein IIb/​IIIa inhibition. (3) In addition to anti-​ischaemic therapy, additional therapy may be re- quired: antiarrhythmic management, or haemodynamic support to reduce ischaemia and stabilize the patient for revascularization. Where the clinical features support a diagnosis of ACS, patients developing ST elevation require emergency assessment with cor- onary angiography and where appropriate reperfusion by primary PCI, or—​when a primary angioplasty service is not available—​by thrombolysis (see next). Patients at intermediate or low risk—​patients with non-​ST-​elevation ACS and an intermediate risk score require dual antiplatelet therapy (aspirin plus P2Y12 receptor inhibitor, e.g. ticagrelor or prasugrel; if neither available, clopidogrel) plus parenteral anticoagulation. They are candidates for an early elective revascularization strategy (within c.72 h). Clinically stable patients with minor or non​specific ECG abnor- malities and a low risk score (including negative repeat troponin) are at very low risk for in-​hospital, major cardiac events. Such patients may, nevertheless, have significant underlying coronary artery dis- ease. They require assessment of the cardiovascular risk and non-​ invasive ischaemia testing to identify the presence and extent of inducible ischaemia, ideally prior to discharge. Specific pharmacological therapies Anti-​ischaemic therapies—​(1) nitrates—​effective in reducing ischaemia in the in-​hospital management of non-​ST-​elevation ACS, but there is no evidence that they improve mortality; (2) β-​blockers—​patients with suspected acute coronary syndromes should be initiated on β-​blocker therapy unless contraindicated; (3) dihydropyridine cal- cium entry blockers—​should only be employed with β-​blockers in 16.13.4  Management of acute coronary syndrome 3627 ACS to avoid reflex tachycardia. In patients unable to tolerate β-​ blockers, a heart-​rate-​slowing calcium antagonist (e.g. diltiazem or verapamil) may be appropriate. Short-​acting dihydropyridines should not be used in isolation in ACS. Antiplatelet therapies—​(1) aspirin 75–​325 mg daily—​indicated in all patients with ACS unless there is good evidence of aspirin allergy or evidence of active bleeding; (2) P2Y12 receptor inhibitor—​patients with non-​ST-​elevation ACS should be given a loading dose of either ticagrelor 180 mg, prasugrel 60 mg (once anatomy is defined), or clopidogrel 300–​600 mg (if neither ticagrelor nor prasugrel are avail- able), followed by continued treatment, in combination with aspirin. Dual antiplatelet therapy should be maintained for 12 months, unless the risks of bleeding exceed potential benefits. Certain patients may benefit from more prolonged duration of dual antiplatelet therapy. (3) GPIIb/​IIIa inhibitors (e.g. abciximab, eptifibatide, tirofiban) can be used in patients requiring urgent percutaneous intervention for non-​ST-​segment elevation ACS and in those at intermediate to high risk. Current indications for treatment with GPIIb/​IIIa inhibitors are mainly as a bail-​out at PCI. Anticoagulation—​this is required in addition to antiplatelet therapy. Indirect thrombin inhibitors: low molecular weight heparin is better than unfractionated heparin and is most commonly used. In the ab- sence of an urgent/​early invasive strategy, fondaparinux (a synthetic pentasaccharide that selectively binds antithrombin and causes in- hibition of factor Xa) has the most favourable efficacy/​safety pro- file. Bilvalirudin is the only direct thrombin inhibitor currently used in ACS management. ST-​segment-​elevation myocardial infarction Patients with clear-​cut evidence of ST-​elevation infarction (STEMI) re- quire immediate triage to reperfusion therapy. ‘Fast-​track’ systems have been developed to minimize in-​hospital delay to reperfusion: these aim to achieve clinical assessment and electrocardiography within 15 min of arrival and rapid transfer for PCI or the institution of thrombolytic therapy within 30 min. Audit programmes and continuous training are necessary for centres to achieve this 30-​min median ‘door-​to-​needle’ time. PCI—​randomized clinical trials of primary PCI vs. thrombolysis have shown consistent findings:  primary PCI is better, providing more effective restoration of vessel patency, achieving better ven- tricular function, and improving important clinical outcomes with lower rates of death, reinfarction, stroke, major bleeding, and re- current ischaemia. Particular gains are seen in haemodynamically compromised patients. In consequence, primary PCI is the preferred therapeutic option in national and international guidelines. Thrombolysis—​prehospital thrombolysis is the next best option if a primary PCI programme is not available, or if transfer times are suffi- ciently prolonged that reperfusion may not be achieved within 120 min of patient call. The current reference standard for the comparison of fibrinolytic agents is the accelerated infusion regimen of alteplase (tPA), or—​for simplicity—​the single-​bolus administration of tenecteplase (TNK), which does not require an infusion pump or refrigeration and hence is particularly suited for prehospital administration. Internationally, streptokinase remains the most widely used fibrinolytic agent, prin- cipally because it is relatively inexpensive. If timely primary PCI is not available, a pharmaco-​invasive strategy (thrombolysis and subsequent revascularization) may provide similar benefit to primary PCI, but requires further testing. Antiplatelet agents and anticoagulants—​(1) aspirin 75–​325 mg daily—​indicated in all patients with ACS unless there is good evi- dence of aspirin allergy or evidence of active bleeding. (2)  P2Y12 receptor inhibitors should be given to all patients, continuing for at least 1 month in patients managed with fibrinolysis (or as deter- mined by the type of stents implanted). (3) Anticoagulants—​heparin or bivalirudin are indicated in patients managed with primary PCI. Patients treated with fibrinolytic therapy should receive low mo- lecular weight heparin or fondaparinux. (4) GPIIb/​IIIa inhibitors may be used in patients managed with primary PCI (mainly for bail-​out), but not in those managed with fibrinolysis. Secondary prevention measures in patients with ACS Patients require advice and help regarding cessation of smoking (including the avoidance of passive smoking), dietary modification, exercise, rehabilitation, and management of obesity. The following therapies have been shown to reduce the risk of subsequent cardiovascular events:  (1) antiplatelet therapy—​aspirin in a dose of 75 mg/​day, clopidogrel 75 mg/​day. Certain subgroups may benefit from prolonged dual antiplatelet therapy—​aspirin and ticagrelor 60 mg/​bd or aspirin and clopidogrel; (2)  β-​blockers in those without contraindications; (3) lipid lowering with 3-​hydroxy-​3-​ methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins); (4) angiotensin-​converting-​enzyme inhibitors/​angiotensin receptor blockers, especially in those with left ventricular dysfunction and heart failure, and benefit is also possible in other patients with vas- cular disease; (5) aldostrone blockade (e.g. eplerenone) in those with left ventricular ejection fraction (LVEF) less than 35% and diabetes or clinical features of heart failure. Introduction The term ‘acute coronary syndrome’ (ACS) describes the clinical manifestations of a heterogeneous spectrum of conditions that share key pathophysiological features:  disruption or erosion of coronary atheromatous plaque, changes in vascular tone, and a variable extent of thrombotic occlusion. The clinical presentation is determined by the extent of coronary obstruction, the volume of ischaemic myocardium, and timing of the atherothrombotic disease process. ACS occurs in patients with underlying symp- tomatic or occult coronary artery disease, and flow-​limiting or non-​flow-​limiting atheromatous plaques in the coronary arterial wall (Fig. 16.13.4.1). The ACS is precipitated by an abrupt change in an atheroma- tous plaque, resulting in increased obstruction to perfusion and ischaemia or infarction in the territory supplied by the affected (culprit) vessel. For discussion of the mechanisms involved, see Chapter 16.13.1. The pattern and severity of clinical manifestations are dependent not only on the degree of obstruction to perfusion, but also on the presence or absence of collateral perfusion, the ex- tent and distribution of fragmented microthrombi, and myocardial oxygen demand in the perfused territory. Thus, the clinical conse- quences of plaque rupture can range from an entirely silent episode, through to unstable symptoms of ischaemia without infarction, to profound ischaemia complicated by progressive infarction, heart failure, arrythmia, and risk of sudden death. section 16  Cardiovascular disorders 3628 The goals of early management of ACS are to relieve ischaemia (by reducing myocardial oxygen demand, inhibiting thrombotic occlu- sion, and reducing coronary obstruction), to prevent further throm- botic occlusion, and to prevent or manage complications. The choice and timing of management strategy, including pharmacological treat- ment and percutaneous or surgical revascularization, is critically de- pendent on the extent and severity of myocardial ischaemia. Despite sharing key pathophysiological mechanisms across the spectrum of ACS, ST-​segment-​elevation acute myocardial infarction (STEMI) and non-​ST-​elevation ACS (unstable angina and non-​STEMI) need to be considered separately because an acute reperfusion strategy (primary percutaneous coronary intervention (PCI) or thrombolysis) is of proven benefit in STEMI (or MI with new bundle branch block), but not in the remainder of the syndrome. Thus, although the manage- ment of STEMI differs, the remainder of the ACS should be managed as a continuous spectrum, but influenced by risk stratification. Clinical presentation and definition of ACS The ACS may present de novo (as new-​onset angina), with typ- ical ischaemic discomfort at rest (rest angina) or on minimal exer- tion. Alternatively, a previously stable pattern of angina may change, resulting in episodes of typical rest angina or angina provoked by minor exertion (crescendo angina). New-​onset exertional angina has not pre- viously been recognized as part of ‘acute coronary syndrome’, but the outcomes are similar—​c.7% develop non​fatal MI and 4% die, and a further 19% require revascularization within 15 months—​and such patients may fulfil the clinical and ECG/​biomarker characteristics of the syndrome (EuroHeart survey, GRACE, and CRUSADE registries). There are three components to the clinical diagnosis of ACS: the symptom description, the ECG, and biomarker evidence of myocyte necrosis. The symptoms must be distinguished from non​cardiac pain, and from stable angina. To improve the specificity of diagnosis, clinical trials use a more restricted definition, requiring at least 15 to 20 min of typical ischaemic discomfort or two 5-​min episodes at rest. The specificity is further improved when the definition requires objective evidence of ischaemia or evidence of underlying coronary artery disease. ST-​segment depression on the ECG, especially in as- sociation with typical pain, is highly predictive, whereas the less spe- cific ECG abnormalities, including T-​wave inversion, are less strong predictors. Markers of myocardial damage (troponins or cardiac en- zymes) are powerfully predictive, in the presence of a typical clinical syndrome. ST elevation or depression on the ECG and elevated bio- markers of necrosis are markers of higher risk and adverse outcome (Table 16.13.4.1). In the absence of such markers, documented Spectrum of acute coronary syndrome unstable angina ST elevation myocardial infarction Marker: Tn & CK-MB undetectable troponin elevated +/− CK-MB troponin elevated +/− CK-MB Non-ST elevation myocardial infarction myocardial infarction Fig. 16.13.4.1  The spectrum of acute coronary syndromes. Table 16.13.4.1  Prognostic value of admission ECG for early risk stratification in 12 142 patients with an acute coronary syndrome Outcome ST elevation + ST depression (n = 15) ST elevation (n = 28) ST depression (n = 35) T-​wave inversion (n = 23) p Acute infarction on admission (%) 87 81 47 31 <0.0001 Death (%) 6.8 5.0 5.0 1.8 <0.001 (Re) infarction (%) 6.9 5.1 6.7 4.3 <0.001 Death and reinfarction at 30 days follow-​up. Data from the GUSTO IIb trial. 16.13.4  Management of acute coronary syndrome 3629 evidence of underlying coronary artery disease (prior infarction or angiographically demonstrated coronary disease) helps to confirm the diagnosis. In brief, the three components of ACS are: • unstable angina—​typical ischaemic symptoms without ST eleva- tion on ECG and without elevated biomarkers of necrosis • non-​STEMI—​typical ischaemic symptoms without ST elevation on ECG but with biomarkers of necrosis above the diagnostic threshold • STEMI—​typical ischaemic symptoms with ST elevation on ECG and with biomarkers of necrosis above the diagnostic threshold. The definition of MI has been revised by a global task force of the European Society of Cardiology, the American College of Cardiology, the American Heart Association (AHA), and others and has identified five subtypes of MI (Box 16.13.4.1). Universal definition of acute myocardial infarction This requires a combination of criteria including an increase and/​or decrease of a cardiac biomarker (preferably high-​sensitivity troponin) and at least one of: Symptoms of ischaemia New significant ST-​T-​wave changes or LBBB Development of pathological Q waves Imaging evidence of new loss of viable myocardium or regional wall motion abnormality Intracoronary thrombus detected on angiography or autopsy Outcome of acute coronary syndrome Trial data and large-​scale observational registry studies Overall, based upon large-​scale registries with consistent dis- ease definitions, there are approximately two patients with non-​ STEMI ACS for each patient with STEMI. Previously, inclusion of patients with chest pain, but without diagnostic features of acute ischaemia, under the term ‘unstable angina’ may have masked the true hazards of the syndrome. Comparisons between studies may be confounded by different disease definitions and varying use of more sensitive markers of myocyte necrosis (troponins), but on the basis of data from randomized trials and prospective registry studies there is no doubt that patients with ACS (with or without persistent ST elevation) are at substantial risk of sub- sequent cardiac events despite current therapy. About 9 to 11% suffer death or MI in the first 6 months following presentation, and almost half of this risk is within the first 7 days (GUSTO IIb, OASIS registry, and GRACE registry). Whereas patients with STEMI are most at risk of death, especially in the first hours of symptom onset, those with non-​STEMI ACS are at higher risk after discharge (Fig. 16.13.4.2 and Table 16.13.4.2). These ob- servations highlight the need for treatment of both the acute and longer-​term phases of ACS. The clinical syndrome and outcome The Braunwald classification categorizes unstable angina according to the mode of onset and time course (Table 16.13.4.3). It was empir- ically based, but has been validated by prospective studies. Patients Box 16.13.4.1  Universal classification of myocardial infarction • Type 1—​spontaneous MI related to ischaemia due to a primary cor- onary event such as plaque fissuring, erosion or rupture, or dissection • Type 2—​MI secondary to oxygen demand and supply imbalance un- related to acute coronary athero-thrombosis (e.g. ­coronary spasm or embolism, anaemia, arrhythmias, hypertension, or hypotension) • Type 3—​sudden unexpected cardiac death, including cardiac arrest with symptoms suggestive of myocardial ischaemia, accompanied by new ST elevation, or new left bundle branch block, or definite new thrombus by coronary angiography (death before blood samples obtained) or in the lag phase of cardiac biomarkers • Type 4—​(a) MI associated with PCI; (b) MI related to stent thrombosis • Type 5—​MI associated with CABG ST elevation ACS ST depression ACS No ST shift Death rate 0.13 0.12 0.11 0.10 0.09 0.08 0.07 0.06 0.05 0.04 0.03 0.02 0.01 0.00 0 10 20 30 40 50 60 70 80 90 Days from presentation 100 110 120 130 140150 160 170 180 Fig. 16.13.4.2  Mortality over the first 180 days following presentation with ACS: patients stratified according to ST shift on presentation to hospital. Reproduced from Bassand J-​P, et al. (2007). Guidelines for the diagnosis and treatment of non-​ST-​segment elevation acute coronary syndromes. Eur Heart J, 28, 1598–​660, by permission of Oxford University Press. section 16  Cardiovascular disorders 3630 with unstable ischaemic pain at rest and those with ST depression have the highest risk of an adverse cardiac event. Similarly, those with unstable angina following acute myocardial infarction (MI) are at an increased risk. Although the classification is useful, many of the patients that present with ACS are in Braunwald class 3B and additional methods of risk characterization are required to optimize management. A diagnostic triage system can be developed for patients with sus- pected ACS (see ‘Emergency department—​triage and establishing a working diagnosis’). This is based on ECG changes, biomarker re- lease, and stress or perfusion testing. Patients with evolving STEMI are identified, and those with higher risk separated from those with lower risk. The respective categories of patients require different management strategies. The ECG and outcome The 12-​lead ECG (performed on admission) provides direct prognostic information (Table 16.13.4.1). The greatest risk of death and subsequent MI is seen in patients with simultaneous ST elevation and depression; the next highest risk is seen in those with transient ST-​segment elevation or ST-​segment depression (defined as being >0.5 mm in thrombolysis in mycocardial in- farction (TIMI) score); isolated T-​wave inversion carries a lower risk. The number of leads demonstrating ST deviation also yields prognostic information: among those with ST deviation in the anterior leads a rate of death or MI of 12.4% was seen at 1 year—​ higher than seen with similar changes in other locations (TIMI III trial). Patients with a left main and three-​vessel coronary artery disease may show a combination of ST-​segment elevation and depression. Ambulatory ST-​segment recording can identify patients with unstable angina and either silent or symptomatic myocardial is- chaemia with an increased risk for major subsequent cardiac events. However, conventional ambulatory monitoring usually requires offline analysis and is not suitable for the prediction of imminent events. Computer-​assisted, continuous, multilead, ECG monitoring techniques have become available for real-​time ECG and ST-​segment monitoring. The occurrence and extent of ischaemic territory identified by such continuous recordings can provide additional prognostic information over and above the ad- mission ECG. The information can be combined with biomarkers and, together, they provide additional prognostic information (FRISC study). Biochemical markers and outcome Markers of myocardial damage Biomarkers of necrosis are gradually released into the systemic cir- culation following complete or transient occlusion of the coronary artery, or fragmentation of a thrombus and embolization. Following total occlusion of the vessel, troponins and creatine kinase (or more specifically CK-​MB) are released and are detectable at clearly ab- normal levels about 6 to 8 h after the event unless there is extensive collateral perfusion. The cardiac isoforms of troponin I and troponin T are exclusively expressed in cardiac myocytes and provide specific evidence of myo- cardial damage. Following infarction, troponins are released from the cytosolic pool and first appear in the circulation in detectable concentrations between 3 and 4 h after the ischaemic event, reaching diagnostic concentrations at 6 to 8 h. Troponin release is evidence of myocardial injury and carries prognostic significance: the greater the troponin release, the greater the risk of subsequent MI and death. High-​sensitivity or ultrasensitive assays have a 10-​to 100-​fold lower limit of detection than current assays, allowing detection of MI more frequently and earlier (within 1 hour), but it is important to recognize that other causes of myocyte necrosis can give rise to detectable troponin concentrations in the circulation, hence the diagnosis of ACS requires an appropriate clinical context. A clinical assessment of the reasons for troponin detection in the circulation is vital for determination of the correct diagnosis (Fig. 16.13.4.3 and Table 16.13.4.4). When should the cardiac enzymes be measured? The time course of the release of troponins (or enzymes) from myocardium is such that diagnostic concentrations may not be achieved until some time after an ischaemic event, depending on Table 16.13.4.2  Mortality in hospital and at 6 months in low-​, intermediate-​, and high-​risk categories in registry populations according to the GRACE risk score Risk category (tertiles) GRACE risk score In-​hospital deaths (%) Low ≤108 <1 Intermediate 109–​140 1–​3 High 140 3 Risk category (tertiles) GRACE risk score Post-​discharge to 6 months deaths (%) Low ≤88 <3 Intermediate 89–​118 3–​8 High 118 8 The Global Registry of Acute Coronary Events (GRACE) risk score, assigns risk on the basis of the following patient characteristics on admission: age, heart rate, systolic blood pressure, serum creatinine, evidence of congestive heart failure, also the presence/​ absence of cardiac arrest, ST-​segment deviation, and elevated cardiac enzymes/​markers. For calculations, see http://​www. outcomes.org/​grace. Table 16.13.4.3  Classification of unstable angina (Braunwald) Class A: Secondary unstable angina (e.g. anaemia, hypoxia) B: Primary unstable angina C: Postinfarction (<2 weeks) unstable angina I New-​onset, severe or accelerated angina IA IB IC II Subacute rest angina (>48 h since last pain) IIA IIB IIC III Acute rest angina (<48 h since last pain) IIIA IIIB IIIC Braunwald E (1989). Unstable angina. A classification. Circulation, 80, 410–​14. 16.13.4  Management of acute coronary syndrome 3631 the assays employed. Thus, a normal value for a patient on arrival within a short duration of time after the event does not exclude infarction or unstable angina, but an elevated value is highly pre- dictive of subsequent infarction. Troponins should be measured on arrival depending upon the clinical presentation, and may re- quire a second sample. The timing of the second sample depends upon the troponin assay. The latest generation of high-​sensitive troponin assays increase diagnostic performance and improve the early diagnosis of MI regardless of the time of chest-​pain onset, and re-test within 3 hours maybe feasible. Implementation of a sensitive troponin assay, and lowering the diagnostic threshold for MI, reduces recurrent MI and death in patients with suspected ACS. Among those with persistently negative troponins and without significant ECG changes, there is a very low risk of subsequent infarction and death (provided that severe underlying cor- onary artery disease is excluded). Such patients should undergo predischarge risk assessment and stress testing. The best tests are myocardial perfusion scanning or stress echocardiography, but treadmill ECGs on exercise are more widely available. Rule-​in and rule-​out pathways The specific pathway depends upon the biomarker and assay system used. With the use of high-​sensitivity troponins a 0 h/​3 h pathway is suggested, although future refinements may endorse a 0 h/​1 h pathway. Current guidelines advocate a pathway as illus- trated in Fig. 16.13.4.4. Follow optimised pathways for acute coronary syndrome Presentation in the context of another acute illness SERIAL TROPONIN MEASUREMENT at least one value >99th centile INVESTIGATION RESULTS ACUTE CHRONIC CLINICAL ASSESSMENT CLINICAL ASSESSMENT SYMPTOMS OR SIGNS OF MYOCARDIAL ISCHAEMIA Significant change in troponin concentration Oxygen supply-demand imbalance? No Consider invasive coronary angiography Consider no further investigation Consider invasive or CT coronary angiography No further cardiac investigation Consider echocardiography or cardiac MRI scan No known CAD Known CAD Yes Coronary artery disease with plaque rupture Obstructive coronary artery disease No coronary artery disease eg sustained hypotension, tachycardia, hypoxaemia No significant change in troponin concentration Known structural heart disease or clear alternative pathology* Yes No No Yes 1 1 2 Injury Injury Fig. 16.13.4.3  Algorithm for the investigation of patients with elevated cardiac troponin concentration on serial measurements is used to identify patients with acute and chronic myocardial injury. The definition of significant change in cardiac troponin will be dependent on the particular assay used and should be consistent with the local pathway for the assessment of patients with an isolated presentation with acute coronary syndrome. CAD, coronary artery disease. * alternative pathologies that can lead to troponin elevation are shown in Table 16.13.4.4. Adapted from Chapman AR, Adamson PD, Mills NL (2017). Assessment and classification of patients with myocardial injury and infarction in clinical practice. Heart, 103, 10–​18. Table 16.13.4.4  Causes of elevation of serum troponins Cause Example Cardiac Cardiac contusion Cardiac failure Cardiac interventions/​surgery Cardiac toxins, e.g. cocaine, anthracyclines Cardiac tumour Cardiomyopathies Cardioversion Myocardial infarction Myocarditis (Myo)pericarditis Cardiovascular Aortic dissection Pulmonary embolism Neurological Stroke Subarachnoid haemorrhage Other Acute kidney injury Sepsis Chronic kidney disease section 16  Cardiovascular disorders 3632 Markers of left ventricular wall stress and inflammation Natriuretic peptides such as brain natriuretic peptide (BNP) or its N-​terminal prohormone fragment (NT-​proBNP) are associated with left ventricular dysfunction and elevated levels are associated with adverse prognosis; however, current management protocols are not determined by BNP levels. Inflammatory changes in the vessel wall promote plaque fis- suring or erosion, and inflammatory changes also follow episodes of minor myocardial damage. In ACS there is evidence that inflam- matory markers, such as C-​reactive protein (CRP) and interleukins IL-​6 and IL-​1, are independently associated with adverse outcome. After the acute phase, continuing inflammation (e.g. with elevated CRP) occurs in one-​half of those whose levels are acutely elevated and identifies a category of patients at increased risk. However, al- though inflammatory mechanisms are implicated in plaque growth and plaque destabilization, specific anti-​inflammatory therapies have not yet been demonstrated to improve outcome, and measure- ment of CRP or other inflammatory markers is not part of routine clinical practice. Non​invasive imaging and outcome Transthoracic echocardiography is useful to identify regional wall motion abnormality and assess LV function, in addition to detecting other important pathology associated with chest pain such as aortic dissection, pericardial effusion, valve disease, or right ventricular strain suggestive of pulmonary embolism for example. Non​invasive assessment of ischaemia can be performed in low risk patients using stress echo, cardiac magnetic resonance, or nuclear perfusion techniques. Multidetector computed tomography (MDCT) allows for visual- ization of the coronary arteries. It may be applied to assess certain ACS patients but requires a high level of expertise and is not yet rou- tinely available. Risk characterization in ACS The timing and the nature of key management decisions in ACS are dependent upon risk estimation. For example, the choice of reperfusion therapy in ST elevation may be influenced by the pres- ence of comorbidity, bleeding risk, and time delay from symptom onset. Similarly, in non-​STEMI ACS, ongoing ischaemia with ST depression or the presence of hypotension or a high-​risk score may initiate very early revascularization. Specific pharmacological (e.g. glycoprotein IIb/​IIIa inhibitors) or interventional therapies (PCI) have demonstrated benefit in high-​or moderate-​risk patients but not in low-​risk patients (5-​year outcome: RITA 3, FRISC-​II). In patients with ACS, risk can be separated into two compo- nents: ‘prior risk’ and ‘acute ischaemic risk’. Prior risk is determined by patient characteristics (age and gender), prior ischaemic heart disease (MI, heart failure, prior angina), and systemic factors that influence risk (hypertension, diabetes, renal dysfunction, and other life-​threatening systemic disorders). These can be considered as the background level of risk that the patients bring with them to the point of presentation. Although several of the individual risk com- ponents may not be modifiable, the combined impact of prior risk influences the balance between benefit and risk for each of the thera- peutic strategies in ACS. Thus, prior risk sets the baseline for risk–​ benefit decisions. By contrast, ‘acute ischaemic risk’ is potentially modifiable and determined by the severity of coronary obstruction and the extent of the territory affected. Collateral perfusion, embolization, myo- cardial oxygen demand, and cytoprotection mechanisms all influ- ence the extent of ischaemia. Patients with similar clinical features may have experienced transient complete occlusion, or severe sub- total occlusion complicated by distal embolization of fragments of a platelet-​rich thrombus, and altered vascular tone in the distal terri- tory. Clinical markers of acute ischaemic risk include ECG changes, Fig. 16.13.4.4  0 h/​3 h rule-​out algorithm of non-​ST elevation coronary syndromes using high-​sensitivity cardiac troponin assays. From Roffi M, et al. (2016). 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-​segment elevation. Eur Heart J, 37, 267–​315, by permission of Oxford University Press. 16.13.4  Management of acute coronary syndrome 3633 release of biomarkers of necrosis into the systemic circulation, and mechanical and arrhythmic complications of the ischaemic episode. Simplistically, prior risk can be regarded as the ‘baggage’ that the patient carries with them, and acute ischaemic risk as an ‘acquired hazard’ arising from the new ischaemic event. The distinction is im- portant because management strategies for prior risk aim to treat heart failure, underlying coronary and systemic disease, and risk factors. The management of acute ischaemic risk aims to reverse the impact of acute coronary obstruction and thrombosis and is the first priority in the management of patients with ACS. Assessment of the extent and impact of underlying coronary artery disease (e.g. with stress testing) and assessment of left ventricular function can take place later in the management of these patients (Box 16.13.4.2), and are important determinants of the longer-​term outcomes. In summary: (1) A diagnosis of ACS is a clinical diagnosis based on the suspicion that coronary ischaemia due to atherothrombosis is responsible for the patient’s presentation; (2) clinical examination and ECG provide early and rapid assessment tools; (3) patients with STEMI require consideration of emergency reperfusion therapy, and those without require further risk assessment to guide the ongoing management (Table 16.13.4.5). Management of ACS without ST elevation (unstable angina/​non-​STEMI) Anti-​ischaemic therapy Anti-​ischaemic therapy can decrease myocardial oxygen consump- tion by reducing heart rate, lowering blood pressure, or depressing left ventricular contractility, and may also act by inducing vaso- dilatation. In consequence, anti-​ischaemic therapy can limit the progression of occlusion and improve perfusion and improve the supply–​demand imbalance. Mechanical revascularization (PCI and coronary bypass surgery) also aims to relieve obstruction and re- duce a patient’s susceptibility to ischaemia and its complications—​ these interventions will be considered separately (see later section of this chapter and Chapter 16.13.5). Nitrates Nitrates act by venodilatation and—​in higher dose—​by arteri- olar dilatation, and hence reduce preload and afterload, thereby decreasing oxygen demand. In addition, nitrates can also induce coronary vasodilatation. They are effective in relieving symptoms of ischaemia. In the acute phase of the syndrome, where dose titra- tion is required, they are most conveniently administered intraven- ously. Once dose titration is no longer required, oral administration is feasible. However, continuous nitrate administration can induce tolerance, hence oral nitrates should be prescribed with appropriate nitrate-​free intervals when symptoms are controlled. An alternative is to use drugs with nitrate-​like properties but with­ out the same problems of tolerance, such as a potassium channel activator (see ‘Potassium channel activators and other antianginals’). Large outcome trials have been conducted with nitrates in acute STEMI but not in other ACS. However, patients without ST-​segment elevation or bundle branch block were randomized within the ISIS-​ 4 trial: their mortality was 5.3% for nitrate treatment and 5.5% for placebo treatment, a non​significant difference. Nitrates are effective Box 16.13.4.2  Practical steps to assess risk (in addition to clinical symptoms) • 12-​lead ECG—​obtained directly after first medical contact, repeated after recurrent symptoms • Troponin estimation (cTnT or cTnI)—​repeated if the initial test is negative • Apply a risk score (such as GRACE, TIMI—​see Table 16.13.4.2 and http://www.outcomes.org/grace) • An echocardiogram may be required to rule in/​out alternative diag- noses and assess left ventricular function • In patients with no recurrence of pain, normal ECG, and no troponin ­elevation, a non​invasive stress test or coronary imaging may be required Table 16.13.4.5  Recommendations for diagnosis and risk stratification in patients with suspected non-​ST-​segment elevation acute coronary syndromes Recommendations Class of recommendation Level of evidence Diagnosis and risk stratification It is recommended to base diagnosis and initial short-​term ischaemic and bleeding risk stratification on a combination of clinical history, symptoms, vital signs, other physical findings, ECG, and laboratory results. I A It is recommended to obtain a 12-​lead ECG within 10 min after first medical contact and to have it immediately interpreted by an experienced physician. It is recommended to obtain an additional 12-​lead ECG in case of recurrent symptoms or diagnostic uncertainty. I B Additional ECG leads (V3R, V4R, V7–​V9) are recommended if ongoing ischaemia is suspected when standard leads are inconclusive. I C It is recommended to measure cardiac troponins with sensitive or high-​sensitivity assays and obtain results within 60 min. I A A rapid rule-​out protocol at 0 h and 3 h is recommended if high-​sensitivity cardiac troponin tests are available. I B A rapid rule-​out and rule-​in protocol at 0 h and 1 h is recommended if a high-​sensitivity cardiac troponin test with a validated 0 h/​1 h algorithm is available. Additional testing after 3–​6 h is indicated if the first two troponin measurements are not conclusive and the clinical condition is still suggestive of ACS. I B It is recommended to use established risk scores for prognosis estimation. I B Modified from Roffi M, et al. (2016). 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-​segment elevation. Eur Heart J, 37, 267–​315, by permission of Oxford University Press. section 16  Cardiovascular disorders 3634 in reducing ischaemia in the in-​hospital management of non-​ST-​ elevation ACS, but there is no evidence that they improve mortality. β-​Blockers β-​Adrenoceptor antagonists reduce heart rate and blood pressure and myocardial contractility and hence decrease myocardial oxygen consumption. They are primarily employed to reduce ischaemia in ACS. Large-​scale trials have not been conducted in patients with non-​ ST-​elevation ACS. However, in the context of acute STEMI treated by thrombolysis, β-​blockers reduce mortality by approximately 10 to 15% (ISIS-​1 study). They may act by reducing ventricular arrhyth- mias, reinfarction, and myocardial rupture. However, this trial was conducted before the widespread use of reperfusion therapy and the findings may not be relevant to contemporary practice. More re- cently the large COMMIT/​CCS study demonstrated that immediate intravenous (metoprolol 5–​15 mg) followed by oral metoprolol 200 mg daily had no effect on mortality, with reductions in recurrent MI and cardiac arrest offset by increased cardiogenic shock. A meta-​ analysis of 27 trials showed a 13% relative risk reduction of mor- tality in the first week after MI. Patients with significantly impaired atrioventricular conduction or asthma or acute left ventricular dys- function should not receive β-​blockers. Although β-​blockers may exacerbate acute heart failure, extensive trials have produced strong evidence of a benefit for the gradual introduction of β-​blockers in ambulant patients with heart failure (see Chapter 16.5.3). In the absence of bradycardia or hypotension, patients with suspected ACS should be initiated on β-​blocker therapy unless contraindicated. Calcium entry blockers These agents inhibit the slow inward current induced by the entry of extracellular calcium through the cell membrane, especially in car- diac and arteriolar smooth muscle. They act by lowering myocardial oxygen demand, reducing arterial pressure, and reducing contract- ility. Calcium channel blockers can provide symptom relief in pa- tients already receiving nitrates and β-​blockers, and may be useful in patients with contraindications to β-​blockade. Some agents induce a reflex tachycardia (e.g. nifedipine, nicardipine, amlodipine) and are best administered in combination with a β-​adrenoceptor antagonist. By contrast, diltiazem and verapamil are suitable for patients who cannot tolerate a β-​blocker because they inhibit conduction through the atrioventricular node and tend to cause bradycardia. All calcium antagonists reduce myocardial contractility and may aggravate heart failure. Calcium entry blockers have been demonstrated to reduce the frequency of angina in patients with variant angina. A meta-​analysis of calcium entry blockers in ACS indicates a non-​ significant trend towards a higher mortality in treated vs. control pa- tients (5.9% vs. 5.2%, in 7551 patients). In individual trials, diltiazem has been compared with propranolol, and both agents produced a similar reduction in anginal episodes. Dihydropyridine calcium entry blockers should be employed with β-​blockers in ACS to avoid reflex tachycardia. In patients unable to tolerate β-​blockers, a heart-​ rate-​slowing calcium antagonist may be appropriate. Short-​acting dihydropyridines should not be used in isolation in ACS. Potassium channel activators and other antianginals These agents (e.g. nicorandil) have arterial and venous dilating prop- erties, but do not exhibit the tolerance seen with nitrates. They have been shown to be better than placebo in relieving the symptoms of angina. A randomized trial of nicorandil (a combined nitrate-​like and potassium channel activator) suggested benefit on a composite clinical endpoint (IONA study), and this drug may be considered as an alternative to nitrate administration. Ivabradine selectively inhibits the primary pacemaker current in the sinus node and maybe used in selective patients with contraindi- cations to β-​blockers. Ranolazine inhibits the late sodium current, and can reduce recurrent ischaemia in non-​ST-​elevation ACS. The recommendations in Box 16.13.4.3 are based on current clinical and trial evidence. Antiplatelet therapy Aspirin Exposure of the contents of atheromatous plaque to circulating blood triggers platelet activation by several different pathways. Aspirin is a potent and irreversible inhibitor of platelet cyclooxygenase, blocking the formation of thromboxane A2 and inhibiting platelet aggrega- tion. Although the effects of aspirin can be overcome in the presence of potent thrombogenic stimuli, nevertheless the benefits of aspirin treatment in unstable angina are clearly defined and substantial. The Antiplatelet Trialists Collaboration demonstrated a reduction of 36% in death or MI with antiplatelet treatment (predominantly as- pirin) vs. placebo in unstable angina trials. Aspirin treatment signifi- cantly reduces subsequent MI, stroke, and vascular death, with the largest reductions seen among patients at highest risk. In patients with unstable angina, four key studies have demonstrated that as- pirin significantly reduces the risk of cardiac death or non​fatal MI by approximately 50%. The efficacy of lower-​dose aspirin (75 mg/​day) therapy has been demonstrated in several studies, including those of Wallentin and colleagues where long-​term effects were evaluated in men under 70 years of age with unstable coronary artery disease. After 6 and 12 months of aspirin treatment, the risk of MI or death was reduced by 54% and 48%, respectively (risk ratio 0.52 with 95% confidence intervals 0.37–​0.72). The strength of evidence and magnitude of benefit demonstrated with aspirin treatment in non-​ST-​segment elevation ACS is such that aspirin is indicated in all patients with ACS, unless there is a clear contraindication. Nevertheless, pa- tients with ACS remain at significant risk despite aspirin therapy. In prospective registry studies of unstable angina/​non-​STEMI, and Box 16.13.4.3  Recommendations for anti-​ischaemic therapy • Anti-​ischaemic therapy should be administered in conjunction with antithrombotic and interventional therapy (see next), with the overall strategy guided by risk evaluation of the patient (see risk stratification) • Patients with suspected ACS should be initiated on nitrate and β-​blocker therapy, unless there are contraindications to the use of β-​blockers • In patients with contraindications to β-​blockers, heart-​rate slowing calcium antagonists should be employed • The combination of a calcium antagonist and β-​blocker is superior to either agent alone • Angiography and revascularization should be considered in patients with recurrent or persistent ischaemia, or patients with troponin ele- vation (including non-​STEMI). The timing of angiography should be guided by the risk status of the patient 16.13.4  Management of acute coronary syndrome 3635 in spite of aspirin treatment in more than 80% of patients, the risk of death or MI is approximately 10% at 6 months and the risk of death/​MI or refractory angina is approximately 22 to 33% over the same period (OASIS registry, PRAIS registry). Aspirin treatment (75–​325 mg daily) is indicated in all patients with ACS unless there is good evidence of aspirin allergy or evidence of active bleeding. P2Y12 receptor inhibitors Ticlopidine and clopidogrel are ADP receptor antagonists, and they block the ADP-​induced pathway of platelet activation by inhibiting the P2Y12 ADP receptor. Clopidogrel replaced ticlopidine on account of a superior safety profile and has been tested in a large-​scale trial of patients with un- stable angina/​non-​STEMI (n = 12 562, CURE trial). The agent was used on top of existing therapy, and in addition to aspirin. It reduced death, non​fatal MI, and stroke from 11.4 to 9.3% (95% confidence interval 0.72–​0.90, p <0.001). For every 1000 patients treated, there were 28 fewer major cardiovascular complications but six more transfusions. Importantly, benefits were seen across risk groups (dia- betics, hypertensives, biomarker elevation or not, revascularization or not). In a substudy (PCI-​CURE), clopidogrel also reduced death and MI in those undergoing percutaneous revascularization (2.9% clopidogrel vs. 4.4% for placebo). Thus, with the combination of clopidogrel and aspirin, there is evidence of early and sustained reductions in the risks of death and MI in patients that present with ACS. Several smaller studies have used higher loading doses of clopidogrel (usually 600 mg), and these show more rapid inhib- ition of platelet aggregation than that achieved with 300 mg. The CURRENT-​OASIS 7 trial assessed the effects of double-​dose (600 mg loading, 150 mg for 1 week, then 75 mg daily) vs. standard dose (300 mg loading, then 75 mg daily) clopidogrel in patients with ACS and intended early revascularization. The double-​dose clopidogrel regimen was associated with a reduction in cardiovas- cular events and stent thrombosis compared with the standard dose in patients who underwent PCI. Long-​term clopidogrel administration was tested in the CHARISMA study of 15 603 patients with documented vascular disease or risk factors for vascular disease. Overall, there was no difference in the primary endpoint of cardiovascular death, MI, or stroke. However, in the subgroup of patients with documented car- diovascular disease, the same endpoint was significantly reduced with dual antiplatelet therapy (DAPT), when compared with aspirin (6.9 vs. 7.9%, relative risk 0.88, 95% confidence interval 0.77–​0.99). Thus, longer-​term treatment with DAPT should only be considered in those in whom the risk of ischaemic events exceeds the risk of bleeding complications. Prasugrel is a more potent thienopyridine with faster onset than clopidogrel. Similar to clopidogrel, prasugrel is a prodrug that re- quires metabolism by enzymatic hydrolysis in the liver for activation. In moderate–​high-​risk patients with ACS scheduled to undergo PCI, prasugrel (60 mg loading dose, 10 mg maintenance) compared to clopidogrel (300 mg loading dose, 75 mg maintenance), reduced MI and stent thrombosis, particularly in diabetic patients, but with an increased risk of major bleeding, including fatal bleeding. Prasugrel should therefore be avoided in patients older than 75 years, with pre- vious intracerebral bleeding or transient ischaemic attack, or who weigh less than 60 kg. Prasugrel is approved for use in patients with ACS undergoing PCI. Ticagrelor is a reversible inhibitor of the platelet P2Y12 re- ceptor and belongs to a new class of antiplatelet agents, the cyclopentyltriazolopyrimidines. It does not require hepatic metab- olism to an active form and therefore has a rapid onset with more predictable platelet inhibition. The PLATO study demonstrated that ticagrelor (180 mg loading dose, 90 mg twice daily there- after) as compared to clopidogrel (300–​600 mg loading dose, 75 mg daily thereafter) reduced cardiovascular death, MI, and stent thrombosis without increasing the rate of major bleeding in pa- tients with ACS. This was the first study to demonstrate a mor- tality benefit with the addition of an antiplatelet agent to aspirin in patients with ACS. The PEGASUS study examined the role of extended aspirin and ticagrelor in a high-​risk group following MI and showed a reduction in CV death, MI, or stroke with extended dual antiplatelet therapy. The DAPT trial failed to show a benefit of extended dual antiplatelet therapy. ACS patients, however, rep- resent a higher-​risk group and current guidelines do suggest that prolonged therapy may be considered after assessment of the is- chaemic and bleeding risk. Cangrelor is an intravenous P2Y12 inhibitor with a short plasma half-​life. It may have a role in patients undergoing PCI, particularly where there are difficulties with prior antiplatelet loading. Guidelines for antiplatelet therapy are listed in Table 16.13.4.6. Glycoprotein IIb/​IIIa inhibitors Platelet adhesion is the initial step in haemostasis after disruption of an atheromatous plaque. It is triggered by damage to the vessel wall and exposure of the subendothelium and is followed by platelet acti- vation and aggregation. Regardless of the agonist, the final common pathway leading to the formation of a platelet aggregate is mediated by the glycoprotein (GP) IIb/​IIIa receptor. GPIIb/​IIIa receptor ant- agonists inhibit platelet aggregation irrespective of the agonist, and they prevent binding of fibrinogen to its receptor on the platelet surface. Three GPIIb/​IIIa receptor antagonists have been approved for clinical use: abciximab, eptifibatide, and tirofiban. They all require intravenous administration. Abciximab is a chimeric human–​ murine monoclonal antibody that binds with high affinity to the re- ceptor: it has a long biological half-​life of 6 to 12 h, and low levels of receptor occupancy are detected even 2 weeks after treatment. Eptifibatide is a synthetic cyclic heptapeptide with high affinity for the arginine–​glycine–​aspartic acid ligand-​adhesion site of the IIb/​ IIIa receptor. It inhibits platelet aggregation in a dose-​dependent manner and is readily reversible due to competitive binding and a short half-​life of approximately 2.5 h. Tirofiban is a non​peptide tyro- sine derivative which also binds to the arginine–​glycine–​aspartic acid site with high specificity. It inhibits platelet aggregation in a dose-​and concentration-​dependent manner and is rapidly revers- ible, with platelet function approaching normal levels in 90% of pa- tients within 4 to 8 h. Although it is convenient to group glycoprotein IIb/​IIIa receptor antagonists together, and undoubtedly there is evidence of a class effect, there are biological and pharmacological differences be- tween the agents. It is also important to note that there are limited data about the use of combination GPIIb/​IIIa and the newer P2Y12 receptor inhibitors. section 16  Cardiovascular disorders 3636 Trials of GPIIb/​IIIa inhibitors More than 32 000 patients have been randomized in clinical trials involving GPIIb/​IIIa inhibitors (16 trials). A  highly significant (p <0.001) benefit is observed for the combined endpoint of death or MI at 48 to 96 h, 30 days, and 6 months. At 30 days the odds ratio is 0.76, or 20 fewer events per 1000 patients treated, and a highly sig- nificant benefit is observed for the combined endpoint of death/​MI or revascularization at all time points. By contrast, mortality benefits are seen only at 48 to 96 h, with no significant benefit at 30 days or 6 months. A pooled analysis of abciximab trials has revealed a net mortality benefit, but there is no evidence of benefit for abciximab in medically treated patients (GUSTO-​4-​ACS). The impact of GPIIb/​IIa inhibitors is influenced by the risk status of the patient and whether administered in the context of percutaneous coronary intervention (PCI). In a meta-​analysis of 29 570 patients, there was a 9% reduction in relative risk overall, but with no significant benefit in those who were medically man- aged (death and MI at 30 days of 9.3% for IIb/​IIIa vs. 9.7% placebo, OR 0.95, 95% confidence interval 0.86–​1.04). Significant benefit was observed when GP IIb/​IIIa inhibitors were maintained during PCI (10.5 vs. 13.6%, OR 0.74, 95% confidence interval 0.57–​0.96). The EARLY-​ACS study demonstrated that the use of eptifibatide 12 h or more before coronary angiography was not superior to pro- visional use after angiography, and early use was associated with more non​fatal bleeding. Similarly, there is no convincing evi- dence of benefit in low-​risk patients, irrespective of interventional strategy. However, there are limited data on the use of GPIIb/​IIIa in the context of newer DAPT regimens, and the value of upstream GPIIb/​IIIa inhibition is uncertain. Current indications for treatment with GPIIb/​IIIa inhibitors are mainly as a bail-​out at PCI when there is large thrombus burden or evidence of no-​reflow. Anticoagulant therapy for non-​ST-​elevation ACS is summarized in Box 16.13.4.4. Anticoagulant therapy Unfractionated heparin Unfractionated heparin is widely used for the treatment of non-​ST-​ elevation ACS, but the evidence on which this is based is less ro- bust than for other widely adopted treatment strategies. In practice, unfractionated heparin is difficult to control because of its unpre- dictable levels of binding to plasma proteins, and this may be amp- lified by the acute-​phase response. In addition, heparin has reduced effectiveness against platelet-​rich and clot-​bound thrombin. Oler and colleagues conducted a meta-​analysis of the influence of adding heparin to aspirin in the treatment of patients with unstable angina. Only six randomized trials were available, with 1353 patients included: there were 55 deaths or MIs in the aspirin plus heparin arm and 68 in the aspirin-​alone arm, giving a risk reduction of 0.67 and a 95% confidence interval of 0.44 to 1.02. These results do not produce conclusive evidence of benefit from adding heparin to as- pirin, but it must be stressed that appropriately powered, larger-​scale trials have not been conducted. Nevertheless, clinical practice has Table 16.13.4.6  Recommendations for platelet inhibition in non-​ST-​segment elevation acute coronary syndromes Recommendation Class of recommendation Level of evidence Oral antiplatelet therapy Aspirin is recommended for all patients without contraindications at an initial oral loading dose of 150–​300 mg (in aspirin-​naïve patients) and a maintenance dose of 75–​100 mg/​day in long-​term regardless of treatment strategy. I A A P2Y12 inhibitor is recommended, in addition to aspirin, for 12 months unless there are contraindications such as excessive risk of bleeds. • Ticagrelor (180 mg loading dose, 90 mg twice daily) is recommended, in the absence of contraindications, for all patients at moderate-​to-​high risk of ischaemic events (e.g. elevated cardiac troponins), regardless of initial treatment strategy and including those pretreated with clopidogrel (which should be discontinued when ticagrelor is started). • Prasugrel (60 mg loading dose, 10 mg daily dose) is recommended in patients who are proceeding to PCI if no contraindication. • Clopidogrel (300–​600 mg loading dose, 75 mg daily dose) is recommended for patients who cannot receive ticagrelor or prasugrel or who require oral anticoagulation. I A I B I B I B P2Y12 inhibitor administration for a shorter duration of 3–​6 months after drug-eluting stent implantation may be considered in patients deemed at high bleeding risk. IIb A Long-​term P2Y12 inhibition P2Y12 inhibitor administration in addition to aspirin beyond 1 year may be considered after careful assessment of the ischaemic and bleeding risks of the patient. IIb A Modified from Roffi M, et al. (2016). 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-​segment elevation. Eur Heart J, 37, 267–​315, by permission of Oxford University Press. Box 16.13.4.4  Anticoagulation for non-​ST-​elevation ACS • Anticoagulation is required in addition to antiplatelet therapy • Anticoagulant options include unfractionated heparin, LMWH, fondaparinux, and bivalirudin, with choice dependent on the initial strategy (early invasive, or not) and the bleeding risk • With an urgent invasive strategy, unfractionated heparin, enoxaparin, or bivalirudin are treatment options • In the absence of an urgent/​early invasive strategy, fondaparinux (2.5 mg SC) has the most favourable efficacy/​safety profile • If fondaparinux is not available enoxaparin (1 mg/​kg twice daily) is recommended • Bivalirudin with bail-​out GPIIb/​IIIa are recommended as an alterna- tive to UFH/​GPIIb/​IIIa in patients with intended invasive manage- ment and high bleeding risk 16.13.4  Management of acute coronary syndrome 3637 adopted unfractionated heparin treatment with aspirin as a prag- matic extrapolation of the available evidence. Low molecular weight heparin Trials vs. placebo The FRISC trial tested dalteparin against placebo in aspirin-​ treated patients with unstable angina/​non-​STEMI. Some 1506 pa- tients were randomized to receive dalteparin (twice daily for the first 6 days and then once daily at a lower dose for approximately 6 weeks), and the trial showed a highly significant reduction in the frequency of death or new MI at 6 days (1.8% vs. 4.8%, with a risk ratio of 0.37). The effects were sustained to 42 days, but were attenuated at 6 months, the differences no longer maintaining sig- nificance. Nevertheless, this trial clearly showed the benefit of low molecular weight heparin (LMWH) over placebo in the presence of aspirin. Trials vs. unfractionated heparin LMWH possesses enhanced anti-​Xa activity in relation to anti-​IIa (antithrombin) activity, compared with unfractionated heparin. It also exhibits decreased sensitivity to platelet factor 4 (PF4), more predictable anticoagulant effect, and lower rates of thrombocyto- penia. In view of its enhanced bioavailability, it offers the substantial practical advantage of subcutaneous administration based on a dose per kilogram of body weight and without the need for laboratory monitoring. Acute-​phase treatment (c.2–​8 days) In the FRIC trial, dalteparin was tested against unfractionated hep- arin in 1400 patients with unstable angina: it had limited power to show a difference, and no significant difference was seen between unfractionated heparin and dalteparin. The ESSENCE trial was double-​blinded and placebo-​controlled and tested enoxaparin against unfractionated heparin. The treat- ments were given for 2 to 8 days (median 2.6 days) and the pri- mary endpoints were death, MI, or recurrent angina. Enoxaparin reduced the primary endpoint from 19.6% to 16.6% at 14 days (odds ratio 0.80 and confidence intervals 0.67–​0.98; see Fig. 16.13.4.5). A similar and significant odds ratio was maintained at 30 days and 1 year. At 1 year, there were 3.7 fewer events/​100 patients (p = 0.022). The study was not powered for death/​MI alone, but demonstrated corresponding trends for these endpoints. The TIMI 11b trial was also double-​blinded and tested enoxaparin vs. unfractionated heparin, but additionally it examined 72 h of treat- ment vs. 43 days of treatment. The results up to 14 days mirrored those seen in the ESSENCE trial: at 14 days the primary outcome occurred was 16.6% (heparin) vs. 14.2% (enoxaparin), risk ratio 0.85 (p = 0.03). A combined analysis of ESSENCE and TIMI 11b indi- cated an absolute reduction of 3.1 per 100 for death/​MI/​refractory angina, and showed a similar risk ratio of 0.79 (confidence interval 0.65–​0.96) for death and MI. Taken together, these findings indicate that short-​term treatment with enoxaparin results in about 3 per 100 fewer major cardiac endpoints compared to unfractionated heparin treatment, and this is achieved without additional major bleeding. Prolonged outpatient treatment The FRAXIS trial tested fraxiparin, for 6 or 14  days, against unfractionated heparin in 3468 patients; no difference was seen in efficacy, but there was a significant excess of major bleeds with longer-​term outpatient treatment. In TIMI 11b, the curves remained separated over the succeeding treatment interval: at 43 days there were 19.6% events (heparin) vs. 17.3% (enoxaparin) (p = 0.049), with no evidence of a further separation of the curves. There was 1.4% absolute excess in major bleeds over the chronic phase. ESSENCE ‘97 3171 s d e elb r oja M s y a d 0 3 ta I M r o h ta e D e ziS TIMI-11B ‘99 3910 A to Z ‘04 3620 INTERACT ‘03 746 ACUTE-II ‘02 525 SYNERGY ‘04 9974 All 21946 LMWH+ 0% 10% 0% 0.1 0.5 1 2 10 10% 5% 20% Incidence 10.1 vs. 11.0% Odds ratio and 95% CI 0.91 (0.83–0.99) NNT and 95% CI 113 (61–1438) Incidence 3.9 vs. 3.7% Odds ratio and 95% CI 1.1 (0.96–1.3) 0.5 1 2 1 1 10 10 102 102 ∞ LMWH+ + H F U + H F U + H F U LMWH+ Fig. 16.13.4.5  Death, MI, and major bleeds at 30 days in randomized trials of enoxaparin (filled bars) vs. unfractionated heparin (open bars). NNT, number of patients who needed to be treated to avoid one event. Reproduced from Bassand J-​P, et al. (2007). Guidelines for the diagnosis and treatment of non-​ST-​segment elevation acute coronary syndromes. Eur Heart J, 28, 1598–​660, by permission of Oxford University Press. section 16  Cardiovascular disorders 3638 Conclusions from the LMWH studies There is convincing evidence in aspirin-​treated patients (heparin or LMWH is not indicated in the absence of antiplatelet therapy) that LMWH is better than placebo (FRISC trial). The two trials using enoxaparin have provided consistent data in favour of LMWH over unfractionated heparin when administered as an acute regimen. The other trials have produced a similar outcome for the acute phase of treatment and it can be concluded that acute treatment is at least as effective as unfractionated heparin There is no convincing evidence to support longer-​term treatment with LMWH. The use of the Xa antagonist fondaparinux is now preferred to LMWH in high risk ACS (see next). Anti-​Xa inhibitors Fondaparinux is a synthetic pentasaccharide that selectively binds antithrombin and causes inhibition of factor Xa. In the OASIS-​5 study, 20 078 patients with non-​ST-​elevation ACS were randomized (double-​blind design) to receive 2.5 mg subcutaneous fondaparinux once daily vs. subcutaneous enoxaparin 1 mg/​kg twice daily for up to 8  days. Fondaparinux was non​inferior at 9  days (the primary endpoint), but subsequently those randomized to fondaparinux had reduced mortality and approximately half the rate of major bleeding. In those undergoing PCI, there was an excess of catheter-​ related thrombi, and administration of this agent requires additional antithrombin therapy (the excess thrombi were not seen when com- bined with unfractionated heparin and there was no evidence of ex- cess bleeding with this combination). Direct thrombin inhibitors Direct thrombin inhibitors (e.g. hirudin, bivalirudin) bind directly to thrombin (factor IIa) and inhibit thrombin-​induced conversion of fibrinogen to fibrin. They bind to and inactivate fibrin-​bound thrombin as well as thrombin in the circulation. They do not bind to plasma proteins or interact with PF4, and hence their anticoagulant effect is predictable. Hirudin has been tested in large-​scale trials (e.g. OASIS-​1, OASIS-​ 2, TIMI 9b, GUSTO IIb) against heparin and a combined analysis suggests a 22% relative risk reduction in cardiovascular death or MI at 72 h, 17% at 7 days, and 10% at 35 days. This combined analysis is significant at 72 h and 7 days but not beyond. Hirudin is licensed for heparin-​induced thrombocytopenia but not for ACS. Bivalirudin was tested in the open-​label randomized ACUITY trial in 13 819 patients with moderate-​to high-​risk non-​ST-​elevation ACS with a planned invasive strategy. The composite endpoints in- cluded death, MI, or unplanned revascularization for ischaemia, major bleeding (non​coronary artery bypass graft (CABG)-​related), and net clinical outcome (composite ischaemia or major bleeding). Bivalirudin plus GPIIb/​IIIa had similar outcomes (non​inferior) to heparin/​LMWH plus GPIIb/​IIIa and similar rates of bleeding. Bivalirudin alone had similar outcome (non​inferior composite) to heparin/​LMWH plus GPIIb/​IIIa, but had superior safety (less bleeding). An interaction with the effects of clopidogrel was evident; benefits were seen with clopidogrel but not without. The HORIZON-​ AMI trial tested a bilvalirudin strategy in PPCI for ST-​elevation ACS and showed superiority over GPIIb/​IIIa/​UFH (unfractionated hep- arin), primarily driven by a reduction in bleeding. A reduction in cardiovascular mortality was found at 30 days and 3 years. However, recent larger trials in contemporary practice have suggested that the major benefit of reduction in bleeding is related to use of the femoral access route. With increasing use of the radial access route, the bene- ficial effect of bivalirudin is attenuated. Oral antithrombotics Certain oral factor Xa inhibitors (e.g. rivaroxaban, apixaban, and otamixaban) have been assessed in dose-​ranging and safety phase II trials of patients with ACS. An efficacy study of apixaban in pa- tients with ACS (APPRAISE 2) was stopped due to excess bleeding. The ATLAS 2 study assessed the effect of rivaroxaban in addition to DAPT (aspirin and clopidogrel) and showed a significant re- duction in cardiovascular death at a dose of 2.5 mg/​bd. A recent metanalysis concluded that the addition of new oral anticoagulants to antiplatelet therapy was associated with a modest reduction in cardiovascular events but a substantial increase in bleeding. These agents may be considered in patients with a high ischaemic risk and low bleeding risk. Further studies using single agents or shorter dur- ation of therapy are underway. Oral platelet thrombin receptor ant- agonists (TRA) are currently under evaluation in a phase III clinical trial programme (TRA 2 degrees P-​TIMI 50). Vorapaxar selectively inhibits the cellular actions of thrombin via the protease-​activated receptor 1 (PAR-​1) on the surface of platelets. Given that the gen- eration of fibrin by thrombin is not affected by PAR-​1 inhibition, it is anticipated that this molecule will have potent antithrombotic effects with less bleeding than other antiplatelet agents. Antiplatelet and oral anticoagulant therapy In the setting of ACS, the evidence to guide the best approach in patients who require oral anticoagulation therapy is limited. If the indication for oral anticoagulation is strong, triple therapy with as- pirin, clopidogrel and oral anticoagulation may be considered for a short time (1–​6 months depending upon the bleeding risk) and dual therapy with an oral anticoagulant and aspirin or clopidogrel for 12 months, followed by monotherapy with anticoagulant long-​ term. The duration of therapy and choice of agent is a complex de- cision and should be personalized to the patient’s ischaemic and bleeding risk. Revascularization The aim of revascularization in non-​ST-​elevation ACS is to relieve angina, to alleviate myocardial ischaemia, and to prevent progres- sion to MI or death. The indications for myocardial revascularization are dependent on the risk status of the patients and the presence or absence of evidence of ongoing myocardial ischaemia and/​or evi- dence that the ischaemia has resulted in mechanical or electrical complications. Following angiography, the choice of PCI or cor- onary artery bypass grafting (CABG) is dependent on the extent and severity of angiographic stenoses and the comorbidity of the pa- tient. Angiographic analyses from the TIMI-​3B and FRISC-​2 studies demonstrate that about 30 to 38% of patients with non-​ST-​elevation ACS have single-​vessel disease and 44 to 60% have multivessel dis- ease (>50% diameter stenosis). Observational studies Large-​scale observational studies have demonstrated wide vari- ations between countries in the use of cardiac catheterization and 16.13.4  Management of acute coronary syndrome 3639 revascularization for patients with acute ischaemic syndromes, and a paradox whereby lower-​risk patients are less likely to re- ceive aggressive antithrombotic and interventional treatment than moderate-​or higher-​risk patients. Similar findings have been ob- served in the United States of America in the CRUSADE registry. Nevertheless, there is clear evidence over time of increasing use of guideline-​indicated therapies (especially class 1 indicated treat- ments) in non-​ST-​elevation ACS, including angiography and inter- ventional procedures. Overall, the changing pharmacological and interventional therapies have been associated with striking im- provements in outcome, including a halving of new heart failure and a reduced risk of death. Higher rates of revascularization have been associated with an increased frequency of procedural complications, including stroke and major bleeding. Definitive assessment of the impact of revascularization on outcomes requires randomized trials and longer-​term follow-​up. Randomized trial data Several smaller and older trials (including TIMI 3B and VANQWISH) tested the impact of a routine invasive strategy in ACS. These largely predated modern antithrombotic therapy, interventional tech- nology (including PCI and stents), and the use of radial access. The FRISC-​II trial compared an invasive strategy with a conser- vative strategy in patients who were initially stabilized with approxi- mately 6 days of treatment with LMWH. Coronary angiography was performed within the first 7 days and revascularization performed in 71% of those in the invasive arm and 9% of those in the non​invasive arm within 10 days. This was, therefore, the first trial to achieve sub- stantial separations in delivery of intended treatment and to include an appropriately powered population. After 6 months, death or MI occurred in 9.4% of the invasive group compared with 12.1% of the non​invasive group (a risk ratio of 0.78, p = 0.031) and the results remained significant at 1 year, but the mortality and the death or MI outcomes were no longer significant at 5 years. However, the re- sults at 5 years clearly demonstrate that most benefit was seen in higher-​risk patients, with no evidence of benefit in low-​risk patients. A  similar relationship between patient risk status and long-​term outcome had been demonstrated in the RITA-​3 trial. The FRISC-​II and the RITA-​3 trials demonstrated that invasive therapy was associated with an excess early (within 30 days) rate of death or MI due to periprocedural complications. Overall, there was a consistency of benefit (for the efficacy endpoints) across the FRISC-​II, TACTICS, and RITA-​3 trials. RITA-​3 demonstrated that most benefit in the first year was in preventing refractory angina, but over 5 years there was a significant benefit in death or MI, and in preventing cardiovascular death, in those randomized to interven- tion. The more recent ICTUS trial was smaller and had a high rate of intervention in the ‘selective invasive’ arm of the trial, about as high as the intervention arm in RITA-​3 and only modestly lower than in the intervention arm of FRISC-​II. ICTUS employed a high rate of adjunctive therapies (including GPIIb/​IIIa inhibitors), and the trial did not show an overall benefit for intervention. Differences in trial design, in the risk status of the trial populations, and in the defin- itions of MI in the respective trials must be taken into consideration. Nevertheless, a pooled analysis of all the trials is likely to represent the most reliable interpretation of all of the randomized trial data. Several meta-​analyses have been published recently. In a meta-​ analysis of eight trials, there was clear evidence for overall benefit on the outcomes of death, MI, or ACS in men and biomarker-​positive women for a routine invasive strategy. A meta-​analysis of FRISC-​ II, ICTUS, and RITA-​3 confirmed that a routine invasive strategy reduced 5-​year cardiovascular death and MI (17.9% vs. 14.7%, OR 0.83 (CI 0.710–​.93), p = 0.002), with most benefit in the highest risk group. Risk stratification of patients with non-​ST-​elevation ACS Risk stratification is required to guide management and therapeutic decisions in patients with non-​ST-​elevation ACS. Some patients are clearly at high risk at the time of initial presentation (e.g. those with typical ongoing ischaemic pain and ST depression on the ECG and elevated biomarkers). However, for the remainder it may not be possible to identify higher-​risk patients on the basis of biomarkers and ECG findings alone. Additional clinical criteria such as diabetes, renal insufficiency, impaired LV function, early post-​MI angina, recent PCI, prior CABG are important high-​risk factors. Several studies have demonstrated that simple risk scores can accurately pre- dict short-​and longer-​term outcome, not only in those with defined characteristics of ACS, but also in patients with suspected cardiac chest pain (GRACE and TIMI risk scores). Using a handheld device, a computer, or a scorecard, risk status can be calculated in less than a minute (risk calculator downloadable from http://​www.outcomes. org/​grace or http://​www.timi.org/​, Table 16.13.4.2). International comparisons have demonstrated superior predictive accuracy for the GRACE score and the European Society of Cardiology (ESC) guidelines for non-​ST-​elevation ACS recommend this score. The ESC guidelines also recommend that risk status be re-​evaluated, es- pecially if clinical or biochemical features change. Troponin (cTnT or cTnI) measurement should be performed at pres- entation (on the basis that those with elevated markers of necrosis on arrival are at increased risk) and repeated if the initial test is negative. Echocardiography may be required to demonstrate the presence or ab- sence of contractile dysfunction or to rule out alternative diagnoses. There is a substantial late mortality in non-​STEMI that is cur- rently underrecognized, with 5-​year death rates equivalent to pa- tients with STEMI. Although the GRACE risk score was derived and validated for in-​hospital and 6-​month outcomes, this analysis demonstrates that it has similarly high predictive accuracy for long-​ term outcomes. The late consequences of presentation with ACS, in terms of death, MI, and stroke, are substantially greater than those seen during the initial in-​hospital phase and novel approaches to di- minish long-​term risk are required. An integrated approach to the patient with non-​ST-​elevation ACS Patients with ACS may present to primary care physicians or dir- ectly to emergency hospital services. In addition, 15 to 20% of those presenting directly to chest pain clinics have ACS. Among patients presenting with an ACS, approximately 40% have evidence of prior coronary artery disease (e.g. MI, angiographically demonstrated disease, documented angina with a positive stress test). The evaluation of patients with suspected ACS needs to be con- sidered in a stepwise approach, proceeding from initial assessment and formulation of a working diagnosis (on the basis of clinical evaluation and the results of immediately available diagnostic tests) to confirmation of the diagnosis and stratification of the patients for emergency, urgent, and elective management. section 16  Cardiovascular disorders 3640 Emergency department—​triage and establishing a working diagnosis Acute chest pain is a common reason for presentation to the emer- gency room, and ACS is only one of several possible explanations. Other serious conditions such as aortic dissection, pulmonary em- bolus and bowel perforation must be considered in the differential diagnosis (see Chapter  16.2.1). Hence, for the patient with chest pain, two issues must be resolved urgently. First, is the chest pain/​ discomfort thought to be of cardiac origin? This is a clinical judge- ment and requires prompt and skilled assessment. Secondly, in those with suspected cardiac pain, is there evidence of evolving infarction? Patients with evolving infarction (ST-​segment elevation or bundle branch block and clinical features of infarction) require emergency reperfusion with primary angioplasty, or if unavailable, thromb- olysis (see next). Patients without ST elevation or left bundle branch block can be triaged into low, intermediate, high-​risk and very high risk categories (Box 16.13.4.5): • Very high-​risk ACS—​patients with haemodynamic instability, ongoing chest pain, arrhythmia, or cardiac arrest, acute heart failure, recurrent dynamic ECG changes, mechanical complica- tion of MI. These patients require early invasive assessment and management similar to that for those with STEMI. • High-​risk ACS—​patients with typical clinical features of ischaemia and ST-​segment depression or transient ST-​segment-​elevation, or with troponin elevation and a high-​risk score (e.g. GRACE >140 and/​or one high risk feature—​see Table 16.13.4.2). Patients are also at high risk when ischaemia provokes arrhythmias or haemo- dynamic compromise. These patients should have early invasive assessment (i.e. within 24 h). • Intermediate or low-​risk ACS—​patients with clinical features of ACS and non​specific ECG changes (e.g. T-​wave inversion, T-​ wave flattening, minor conduction abnormalities). • Patients with a normal ECG, normal biomarkers, normal cardiac examination, and normal echo are potentially low-​risk ACS; how- ever, an alternative diagnosis should be actively sought in this group. Management of patients with non-​ST-​elevation ACS and very high or high-​risk status Very high-​risk patients have been excluded from RCT. They have a poor short-​ and long-​term prognosis if left untreated, and very early invasive assessment and treatment is recommended, similar to reperfusion pathways for STEMI patients. High-​risk patients with acute ischaemia at initial presentation, and especially those with haemodynamic compromise, require emergency assessment for revascularization (Fig. 16.13.4.6). Those proceeding to emergency revascularization should receive (1) as- pirin, (2)  P2Y12 receptor inhibitors, (3)  Fondaparinux, LMWH, or bivalirudin, and (4) consideration of GPIIb/​IIIa inhibition, depending on the timing of planned invasive assessment. In add- ition, patients should receive anti-​ischaemic therapy (see earlier) and some patients require antiarrhythmic management or haemo- dynamic support (e.g. intra-​aortic balloon pump to reduce is- chaemia and stabilize the patient for revascularization). Management of patients with non-​ST-​elevation ACS at intermediate or low risk Patients without high-​risk features on initial presentation re- quire further assessment to guide management (Fig. 16.13.4.7). Application of a risk score will reveal that a significant propor- tion have unsuspected higher risk (approximately one-​third based on registry studies). Such patients require monitoring and repeat ECGs (ideally ST-​segment continuous analysis) and evaluation in a dedicated chest pain, cardiac, or combined assessment unit (while awaiting the results of biomarker and other investigations). • Patients who develop high-​risk features after initial presentation should be considered for urgent angiography and revascularization (within 24–​72 h). See Table 16.13.4.6. Those developing ST eleva- tion require emergency reperfusion (by primary PCI or—​if PCI not available—​by thrombolysis). • Patients with non-​ST-​elevation ACS and an intermediate risk score require DAPT plus anticoagulation (heparin, LMWH, fondaparinux, or bivalirudin). All patients at intermediate and high risk are candidates for an early elective revascularization strategy (within c.72 h). • Clinically stable patients without further chest pain, heart failure, no evolving ECG changes, and biomarker negative are at very low risk for in-​hospital major cardiac events. Such patients may, nevertheless, may have significant underlying coronary artery dis- ease. They require further assessment of cardiovascular risk and stress testing or perfusion scanning, ideally prior to discharge. Box 16.13.4.5  Risk criteria mandating an invasive strategy in non-​STEMI Very high risk criteria • Haemodynamic instability or cardiogenic shock • Recurrent or ongoing chest pain refractory to medical treatment • Life-​threatening arrhythmias or cardiac arrest • Mechanical complications of MU • Acute heart failure • Recurrent dynamic ST-​T-​wave changes, particularly with intermittent ST elevation High-​risk criteria • Rise or fall in cardiac troponin compatible with MI • Dynamic ST-​ or T-​wave changes (symptomatic or silent) • GRACE score >140 Intermediate-​risk criteria • Diabetes mellitus • Renal insufficiency (eGFR <60 ml/​min/​1.73 m2) • LVEF <40% or congestive heart failure • Early post-​infarction angina • Prior PCI • Prior CABG • GRACE risk score >109 and <140 Low-​risk criteria • Any characteristics not mentioned above CABG, coronary artery bypass graft; eGFR, estimated glomerular filtra- tion rate; GRACE, Global Registry of Acute Coronary Events; LVEF, left ventricular ejection fraction; PCI, percutaneous coronary intervention; MI, myocardial infarction. Modified from Roffi M, et al. (2016). 2015 ESC guidelines for the manage- ment of acute coronary syndromes in patients presenting without persistent ST-​segment elevation. Eur Heart J, 37, 267–​315, by permission of Oxford University Press. 16.13.4  Management of acute coronary syndrome 3641 Other considerations Coronary artery bypass surgery As demonstrated by the FRISC-​II study, those with three-​vessel or left main coronary artery disease and an ACS can be stabilized in the acute phase with antiplatelet and anticoagulant therapy and can proceed to coronary artery bypass surgery with a low perioperative and postoperative morbidity and mortality in experienced centres (c.2%, 30-​day mortality). Based on the findings of the CURE study, bleeding risk is minimized if the thienopyridine (clopidogrel) is stopped for 5 or more days prior to surgery. Patients at high risk for thrombotic events in the presurgery phase may require an Symptom onset PCI center Risk stratification Therapeutic strategy Immediate invasive (<2 hr) Early invasive (<24 hr> Invasive (<72 hr> Noninvasive testing if appropriate Very high High High Intermediate Intermediate Transfer Transfer optional EMS = emergency medical services; PCI = percutaneous coronary intervention. Low Low Very high Immediate transfer to PCI center Same-day transfer EMS or Non-PCI center First medical contact non-STEMI diagnosis Fig. 16.13.4.6  Treatment strategy and timing according to initial risk stratification in non-​STEMI. EMS, emergency medical service; PCI, percutaneous coronary intervention. Modified from Roffi M, et al. (2016). 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-​segment elevation. Eur Heart J, 37, 267–​315, by permission of Oxford University Press. High-risk non-ST elevation ACS Clinically stable and no evidence of continuing ischaemia Haemodynamically unstable or continuing ischaemia Elective in-patient angiography Emergency/urgent angiography PCI or CABG Secondary prevention Low or uncertain risk Non-ST elevation ACS Clinically stable • No ST shift • Troponin negative Haemodynamically unstable or continuing ischaemia or ST shift or Troponin elevation • Reconsider diagnosis • Pre-discharge stress test for underlying CAD • Elective angiography • Revascularization if indicated • Secondary prevention No stress induced ischaemia Non CAD diagnosis Stress induced ischaemia Manage as for high-risk non-ST elevation ACS Fig. 16.13.4.7  Flow chart to indicate the key management steps for patients with non-​ST elevation acute coronary syndromes. CABG, coronary artery bypass grafting; CAD, coronary artery disease; PCI, percutaneous coronary intervention. section 16  Cardiovascular disorders 3642 intravenous small molecule GP IIb/​IIIa inhibitor (to provide more potent but reversible platelet inhibition up until the time of surgery). See Chapter 16.13.6 for further discussion. Antiplatelet and LMWH therapy in patients on warfarin. There is continuing debate concerning the use of dual antiplatelet therapy in patients undergoing stent implantation for ACS who are on warfarin. Bleeding risk is increased in patients on triple therapy, and this has to be balanced against the risk of stent thrombosis with a single antiplatelet agent. Dual antiplatelet therapy is gener- ally recommended for at least 4 weeks for bare metal stents and for 6 months in patients with drug-​eluting stents. Where the indication for warfarin is atrial fibrillation alone, oral anticoagulation is often discontinued for this period if the embolic risk is low. There is in- sufficient evidence to provide firm recommendations regarding pa- tients on NOAC’s at present. A standard approach to antithrombotic strategy in patients with non​valvular atrial fibrillation is shown in Fig. 16.13.4.8. Secondary prevention All patients with ACS require cardiovascular secondary preven- tion measures (Table 16.13.4.7) including lifestyle modification (smoking cessation, diet, exercise), oral pharmacological therapy (antiplatelet, cholesterol-​lowering, ACE inhibitor/​ARB) and the Fig. 16.13.4.8  Antithrombotic strategies in patients with non-​STEMI and non​valvular atrial fibrillation. Modified from Roffi M, et al. (2016). 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-​segment elevation. Eur Heart J, 37, 267–​315, by permission of Oxford University Press. 16.13.4  Management of acute coronary syndrome 3643 management of established and newly detected comorbidities (e.g. diabetes, hypertension, renal dysfunction, heart failure). These are the same in patients with non-​ST-​elevation ACS as they are for those with STEMI. ST-​segment elevation myocardial infarction (STEMI) Outcome in STEMI is critically determined by the extent and severity of myocardial ischaemia, and the extent of prior disease including prior myocardial function. In addition, the eventual extent of irrevers- ibly injured myocardium is influenced by residual myocardial perfu- sion (via collaterals or subtotal coronary occlusion) and the duration of myocardial ischaemia. As a result, the clinical consequences of abrupt coronary occlusion can range from an entirely silent episode, to profound ischaemia with major cardiac rhythm disturbances (ven- tricular fibrillation or asystole), to acute mechanical decompensation with heart failure or cardiogenic shock. The outcome is influenced by the extent to which ischaemia is modified by prompt and effective reperfusion and the presence or absence of significant complications, especially arrhythmias (ventricular tachycardia, ventricular fibril- lation, and asystole) and acute heart failure. Prompt and successful reperfusion (e.g. within the first hour of symptom onset, may ‘abort’ or greatly attenuate the eventual extent of MI). Importantly, prompt and effective resuscitation for early ventricular arrhythmias (espe- cially ventricular fibrillation) may have a big impact on survival and freedom from cardiac complications. The priorities in the management of STEMI are to manage acute life-​threatening complications (resuscitation), relieve acute dis- tress, limit the extent of infarction, and treat complications. Beyond the acute phase, attention focuses on secondary prevention and rehabilitation. Outcome in STEMI Historically, community-​based studies in various populations dem- onstrated that the case fatality from acute MI, prior to the advent of resuscitation and reperfusion and other modern therapies, was approximately 50% by 1 month after the onset (MONICA studies). About one-​half of those deaths were within the first 2 h of symptom onset. However, the risk of death, prior to hospitalization, varies with age: 80% of those above 85 years die before reaching hospital but only 40% of those below 55 years. Before the introduction of cardiac care units in the 1960s, in-​patient mortality was in the range of 25 to 30%, and in the 1980s—​before the introduction of reperfusion—​in-​ patient mortality averaged about 18%. More recently, the MONICA study from five cities has indicated that the 28-​day mortality for pa- tients admitted to hospital with a MI ranged from 13 to 27%, and other studies have provided figures of 10 to 20%. There is a marked discrepancy between mortality figures from randomized clinical trials and those from observational studies. Publications reporting the outcome for individuals ineligible for in- clusion in trials have demonstrated substantially higher death rates than seen in those entered into contemporaneous trials in the same centres. Clinical trials can provide accurate information on what is possible in defined populations (often excluding patients with im- portant comorbidity), and carefully conducted registries can pro- vide an accurate reflection of ‘real-​world’ clinical practice. Both approaches are required. The multinational GRACE registry has demonstrated a decline in in-​hospital mortality from 8.4 to 4.6% and new heart failure from 19.5 to 11.0% between 1999 and 2006. The more widespread appli- cation of evidence-​based pharmacological and reperfusion therapy is closely linked with the improved outcome (with no change in the risk status of patients at presentation), highlighting the importance of ‘closing the gap’ between evidence from guidelines and clinical trials and application in clinical practice. International organiza- tions including the American College of Cardiology and the ESC have stressed this. Special attention needs to be drawn to the more comprehensive provision of acute resuscitation and defibrillation in the community and to the provision of early effective reperfusion. Prehospital care The priorities in prehospital care are to establish a prompt diagnosis of suspected acute infarction, to provide effective resuscitation (espe- cially for ventricular fibrillation), and to initiate prehospital thromb- olysis if primary PCI is not available. In addition, patients require effective analgesia and the management of acute complications. Where available, telemetry of the ECG can confirm the diagnosis, expedite emergency transfer for primary PCI, and prepare the car- diac team for receiving the patient in the cardiac catheter laboratory. The aim is to provide reperfusion within 90 min of symptom onset. Although this has been demonstrated to be feasible in many centres and various countries, there are major logistic challenges. ‘Door-​to-​ balloon’ times exclude the prehospital phase and, in many instances, ‘door-​to-​balloon’ times are longer than 90 min, just for this phase of Table 16.13.4.7  Recommendations for secondary prevention for patients with proven ACS Therapy Regime Aspirin Continue lifelong P2Y12 inhibitor Continue for 12 months (unless at high risk of bleeding) β-​Blocker If LV function depressed ACE inhibitor/​ARB If LV function depressed Consider for patients without depressed LV function Aldosterone antagonist/​eplerenone If depressed LV function (LVEF ≤35%) and either diabetes or heart failure, without significant renal dysfunction Statin Titrate to achieve target LDL-​C levels <1.8 mmol/​litre (<70 mg/​dl) Lifestyle Risk-​factor counselling, referral to cardiac rehabilitation/​secondary prevention programme ACE, angiotensin-​converting-​enzyme; ARB, angiotensin receptor blocker; LDL-​C, low-​density lipoprotein cholesterol; LV, left ventricular; LVEF, left ventricular ejection fraction. section 16  Cardiovascular disorders 3644 treatment. In rural and other communities with prolonged transfer times to a hospital with PCI facilities, or where such facilities are not routinely available, appropriate equipment and training needs to be established to allow prehospital or timely thrombolysis to be admin- istered safely and effectively. Making a diagnosis of suspected infarction and initiating treatment A working diagnosis of suspected infarction is based upon typical severe chest discomfort of more than 15 min duration which is un- responsive to glyceryl trinitrate. Characteristically, the pain may ra- diate to the neck, lower jaw, and arms, and is often accompanied by autonomic features including sweating and pallor. Unless compli- cations are present, physical examination may reveal no significant abnormalities, other than those associated with autonomic disturb- ance, but signs can include tachycardia or bradycardia, the presence of a third or fourth heart sound, and features of heart failure. The initial ECG is seldom normal, but may not show the classical features of ST-​segment elevation or evidence of Q waves (unless prior MI had occurred). Hyperacute T-​wave changes can be pre- sent within minutes of the onset of ischaemia due to coronary oc- clusion, and this may be followed by the evolution of characteristic ST-​segment elevation. However, minor or non​specific ECG abnor- malities in conjunction with a characteristic history may signal the early stages of infarction. The working diagnosis relies heavily on the clinical history, and when this suggests MI, repeat ECG within 30 to 60 min (or continuous ST analysis) will frequently reveal the evolution of recognizable ECG changes. It is critically important that infarction that evolves after initial presentation should be detected promptly. In the prehospital setting, a paramedic or primary care physician may have to rely on the clinical findings to establish the working diagnosis and to initiate immediate treatment. Prompt relief of pain is important, not only for humanitarian reasons, but because pain is associated with sympathetic activation, vasoconstriction, and in- creased myocardial work. Effective analgesia is best achieved by the titration of intravenous opioids, although some paramedic crews only have access to non​opioid analgesia. Side effects of analgesia include nausea and vomiting, hypotension, and respiratory depres- sion. Antiemetics can be administered concurrently; hypotension and bradycardia will usually respond to atropine and respiratory de- pression to naloxone. Oxygen should be administered to those with reduced oxygen saturations less than 90%, those who are breathless, or those with any features of heart failure or shock (see Chapter 17.2 for information on basic and advanced life support in the manage- ment of cardiac arrest or ventricular fibrillation). The logistics of providing acute care for patients with MI de- pend upon the locally available facilities. Guidelines recommend an integrated service involving prehospital emergency care (am- bulance and paramedic personnel, primary care physicians, and so on) and hospital-​based specialists, including cardiologists and emergency care physicians. Within an urban setting, with rela- tively short transfer times, the shortest delays and the most prompt initiation of reperfusion occurs when the patient seeks an emer- gency medical ambulance and achieves direct transfer to a hos- pital with available primary PCI facilities. Studies have shown that once the diagnosis is confirmed (e.g. by telemetry of the ECG) substantial time can be saved by direct transfer of the patient to the catheterization laboratory for PCI rather than transfer via an emergency department (Fig. 16.13.4.9). Prehospital thrombolysis If a primary PCI programme is not available, or if transfer times are sufficiently prolonged that reperfusion may not be achieved within 120 min of patient call, then prehospital thrombolysis is the best op- tion. The combined analysis of primary PCI vs. thrombolysis trials clearly shows superior outcome (deaths, recurrent MI, stroke, and so on) and less bleeding complications (especially intracerebral bleeds) for primary PCI. However, whether primary PCI—​with the inherent transfer delays—​is superior to very early thrombolysis (adminis- tered within the first hour of symptom onset) remains untested in trials of sufficient power. A review of eight trials comparing prehospital with in-​hospital administration of thrombolytic therapy showed that—depending upon the clinical setting—between 30 and 130 min are saved by prehospital thrombolysis (fibrinolytic drug plus aspirin). Overall, for the complete study population of 6607 patients, the 30-​day mortality was 10.7% for those receiving in-​hospital administra- tion of thrombolysis, and 9.1% for those where it was administered prior to hospital admission. This amounts to a 17% relative reduc- tion in early mortality with a p value of 0.02 (1.6% absolute reduc- tion). Complication rates were similar for community-​treated and hospital-​initiated thrombolysis, although ventricular fibrillation occurred more frequently with community administration and necessitated well-​trained staff and the availability of defibrillators. The greatest benefit is seen when prehospital treatment is applied in remote settings where transport delays are more than 1 h. Several studies have indicated that about 20 patients with chest pain require evaluation for each patient found to be eligible for thrombolytic therapy in the community. Nevertheless, with appropriate training and facilities, prehospital care can provide a gain of approximately 20 lives per 1000 treated among eligible patients. Prehospital cardiac arrest The management of prehospital cardiac arrest requires special con- sideration. At least as many lives can be saved by prompt resuscitation and defibrillation as by reperfusion. For these reasons, emergency assessment of the patient with suspected infarction necessitates that the clinician or paramedic has access to a defibrillator and the skills to manage cardiac arrest promptly and effectively. The provision of basic or advanced life support training to paramedic ambulance crews, together with semiautomatic defibrillators, has resulted in a substantial increase in the number of patients surviving out-​of-​ hospital cardiac arrest. Before the institution of such programmes, successful resuscitations were opportunistic and often relied on the availability of a bystander with medical or nursing training. Nationwide figures indicate that resuscitation now achieves survival in 7 to 10% of those patients found with cardiac arrest and in whom the initial rhythm is thought to be ventricular fibrillation. With effective integrated programmes, higher success rates have been achieved: for instance, in the south-​eastern region of Scotland, about 14% survive to reach hospital alive, and in Seattle, with a well-​ established community training and resuscitation programme, the figure exceeds 20%. About one-​half of those reaching hospital alive survive to be discharged home, but this is dependent on the pre- senting rhythm and duration of cardiac arrest. 16.13.4  Management of acute coronary syndrome 3645 Emergency Department triage and management Ideally, in those with typical clinical features and ST elevation on the ECG, a working diagnosis has been made in the prehospital setting (by paramedics with ECG telemetry or by a primary care physician) and early management initiated prior to hospital arrival. Where facilities are available, the patient should be transferred dir- ectly to the catheterization laboratory (with the team alerted while the patient is in transit), or if the decision is made for thrombolysis, then this is administered before arrival in hospital. In-​hospital evaluation is required in the remainder, where the symptoms are unclear, the ECG not diagnostic, or if significant comorbidity is present (e.g. bleeding risks). The priority imme- diately after arrival at the hospital is to identify those patients with ST elevation infarction for prompt reperfusion therapy (Fig. 16.13.4.10). Triage is usually performed in the emergency department, or, in some institutions, patients with a high prob- ability of infarction gain direct access to a cardiac care assessment area. An integrated strategy involving the paramedic or ambu- lance system, the emergency physicians, and the cardiologists is required. ‘Fast-​track’ systems have been developed to minimize in-​hospital delay to reperfusion: these are facilitated by specific- ally trained medical and nursing staff, with the aim of ensuring clinical assessment and ECG within 15 min of arrival and rapid transfer for PCI or the institution of thrombolytic therapy within 30 min. Audit programmes and continuous training are necessary for centres to achieve this 30-​min median ‘door-​to-​needle’ time. Definite vs. suspected infarction Rapid triage systems allow the identification of patients with clearly defined clinical and ECG features of infarction, i.e. characteristic symptoms of infarction which persist at rest and are not relieved by Fig. 16.13.4.9  Prehospital and in-​hospital management and reperfusion strategies for STEMI within 24 h of first medical contact. Cath, catheterization laboratory; EMS, emergency medical system; FMC, first medical contact; PCI, percutaneous coronary intervention; STEMI, ST-​segment elevation mycocardial infarction. Adapted from Wijns W, et al. (2010). Guidelines on myocardial revascularization. Eur Heart J, 31, 2501–​55, by permission of Oxford University Press. Acute ST elevation or BBB myocardial infarction Thrombolysis : aspirin and fibrinolytic (if primary PCI unavailable) Emergency Reperfusion Primary PCI: +/– llb/llla inhibitor Evidence of reperfusion (ST resolution) No evidence of reperfusion: Rescue PCI Risk stratification Routine predischarge coronary angiography Secondary prevention Rehabilitation Fig. 16.13.4.10  Management of ST elevation MI. BBB, bundle branch block; PCI, percutaneous coronary intervention. section 16  Cardiovascular disorders 3646 glyceryl trinitrate, in the presence of at least 1 mm ST-​segment eleva- tion in two or more contiguous leads, or the development of bundle branch block. Clinical trials have employed ECG criteria of 1 mm ST elevation for limb leads and 2 mm for chest leads, a definition that improves specificity, but is associated with reduced sensitivity. Among those without diagnostic ECG changes, a working diag- nosis of suspected MI or non-​ST-​elevation ACS can be established. Such patients require repeat clinical and ECG assessments or con- tinuous ST analysis to detect those with evolving infarction and separate them from those with unstable angina or non-​ST-​elevation infarction. The rationale for minimizing delays to reperfusion Experimental and clinical data demonstrate that the duration of is- chaemia prior to reperfusion is a critical determinant of the eventual extent of myocardial damage. These data are supported by the im- proved outcome seen with prehospital vs. in-​hospital thrombolysis, also observational data from large clinical trials in which survival gain diminishes with each additional hour of ischaemia. The Fibrinolytic Trials Overview suggests about 1.6 additional deaths per hour of delay per 1000 treated, and a more recent meta-​analysis suggests that early time delay is especially important. The relationship between the duration of ischaemia and the extent of infarction is nonlinear: the greatest potential for salvage occurs when reperfusion is initiated within 60 min of the onset of infarc- tion. Under such circumstances, some patients (5–​7%) will have the infarction aborted and will not develop Q waves or significant enzyme elevation despite characteristic ST elevation on the initial ECG. Minimizing the time delay is, therefore, critical in salvaging myocardium. Based on data from individual trials, and from the Fibrinolytic Trials Overview, most benefit occurs within the first 3 h of the onset of infarction, and highly significant benefits still occur at up to 6 h. Statistically significant gains are still present at 12 h, but beyond 12 h the benefits are marginal. However, some patients present with a stuttering pattern and in the presence of persistent or intermittent ST-​segment elevation and continuing symptoms of is- chaemia, reperfusion beyond 12 h may salvage significant ischaemic myocardium. Differential diagnosis Critically, thrombolytic therapy or angiography for anticipated primary angioplasty will be of no benefit to those who do not have MI and may convey significant hazards. Such patients suffer the dual hazards of thrombolysis or angiography in the acute phase of their illness and the delay in initiating appropriate treatment. Furthermore, those treated inappropriately with thrombolysis will experience the bleeding hazards of the drug (a net increase in intracerebral haemorrhage of c.0.5%) and the disrupted coagu- lation system will render other emergency surgery (e.g. for per- forated peptic ulceration) more hazardous. Alternative cardiac diagnoses include non-​ST-​segment-​elevation ACS, myocarditis, pericarditis, and aortic dissection. Non​cardiac diagnoses include gastrointestinal pain of oesophageal, peptic, or biliary origin; pancreatitis; pulmonary embolism; and respiratory and muscu- loskeletal disorders. When angiography has been performed in a patient with a suspected ACS and found to be normal, a careful review and investigation of alternative causes is essential prior to discharge. Aortic dissection presents a particular problem when it extends proximally to the origin of the right coronary artery and produces inferior infarction. CT or transoesophageal echocardiography may be required to establish the diagnosis (see Chapter 16.14.1). Transthoracic echocardiography can be valuable when infarction is suspected but characteristic ECG features are absent: normal left ventricular function excludes significant infarction, and conversely a regional contraction abnormality helps to confirm the diagnosis of ischaemia or possible infarction. However, in those with prior myo- cardial damage, the differentiation of new from old mechanical dys- function is complex and requires specialist assistance. Cardiac enzymes are helpful when abnormal, but most patients present within 3 h of the onset of symptoms and insufficient time has elapsed to produce a diagnostic release of biomarkers of necrosis—​ troponins, creatine kinase (CK), or CK-​MB. Patients with suspected infarction but normal ECGs require further clinical ECG and bio- marker estimations 4 to 6 h after the suspected event. Among elderly and very elderly patients (>90 years of age), the presentation of infarction is often atypical. They may not experience a typical pattern of symptoms and concomitant multisystem dis- orders may obscure the diagnosis. MI must be considered in the dif- ferential diagnosis of abrupt collapse, haemodynamic disturbance of sudden onset, or severe non​specific symptoms in elderly patients. Continuing management in the Cardiac Department Administration of analgesia, management of rhythm and haemo- dynamic compromise, and initiation of pharmacological therapy (heparin, LMWH, aspirin, P2Y12 receptor inhibitors, and so on) should have been initiated shortly after the diagnosis of ST-​elevation MI is made (in the emergency department or cardiac assessment area or prehospital). The first priority is for emergency reperfusion (primary PCI, or if unavailable thrombolysis). Patients may require management of heart failure and arrhythmias and pain relief while in transit to reperfusion therapy, but every effort should be made to avoid delays to reperfusion. Percutaneous coronary intervention Primary PCI Primary angioplasty is defined as PCI without concomitant fi- brinolytic therapy. It requires prompt availability of a highly skilled interventional cardiology team with substantial experience of the procedure. Randomized clinical trials of primary PCI vs. thrombolysis have shown consistent findings:  primary PCI has superior outcomes. In experienced centres it is more effective in restoring patency, achieves better ventricular function, and improves important clin- ical outcomes, with lower rates of death, reinfarction, stroke, major bleeding, and recurrent ischaemia (Table 16.13.4.8). Particular gains are seen in haemodynamically compromised patients and those with cardiogenic shock. In consequence, primary PCI is the preferred therapeutic option in national and international guide- lines (SIGN, ESC PCI Guidelines, American College of Cardiology, and AHA). Patients are transferred as an emergency to the cardiac catheter- ization laboratory and angiography undertaken (radial artery access preferred to femoral) to establish coronary anatomy and the nature of the vessel occlusion. A flexible guide wire is then passed across the 16.13.4  Management of acute coronary syndrome 3647 occluded lesion and balloon angioplasty (usually accompanied by stent implantation, with drug-eluting stent preferred to bare metal stent) performed (‘primary PCI’), thereby restoring patency to the previously occluded coronary artery. • Primary percutaneous coronary angioplasty (PCI) is the treat- ment of choice in patients with STEMI. • Primary PCI requires a highly experienced interventional team with 24-​h availability and an integrated approach to management to achieve reperfusion with the minimum of delay—​ideally within 120 min of symptom onset. • Where primary PCI is unavailable, the patient should undergo prompt thrombolytic therapy, provided no contraindications are present. • The limit in treating all potentially eligible patients with reperfusion therapy has not been reached. Internationally, at least one-​third of all MIs (without a major bleeding risk) receive neither thrombolysis nor primary PCI. Rescue PCI Thrombolytic therapy may fail to achieve effective reperfusion in 30% or more of those in whom it is administered for STEMI. Patients experience continuing symptoms of ischaemia and failure of resolution of ST elevation on the ECG (<50% resolution of the ST elevation within 1 h of administration). Rescue PCI is more effective than repeat thrombolysis or conservative treatment in improving outcome (REACT trial). Thus, in centres where primary PCI is not available, logistics need to be established for prompt transfer for rescue percutaneous coronary intervention of patients in whom thrombolysis does not result in signs of reperfusion. Facilitated PCI The combination of full-​dose or reduced-​dose fibrinolysis fol- lowed by emergency PCI has been tested in large-​scale trials and shown worse outcomes and greater bleeding risks (ASSENT 4 trial). Hence, planned emergency PCI after thrombolysis is not re- commended, although later PCI—​after the impact of thrombolysis has resolved—​may be of benefit (GRACIA 2 study). The latter ap- proach should also be considered as part of the strategy to deal with residual stenoses after PCI (prior to hospital discharge), ra- ther than as ‘facilitated’ PCI. Thrombolytic treatment Thrombolytic treatment refers to the combination of antiplatelet therapy (aspirin and clopidogrel) with fibrinolytic treatment. The fibrinolytic agent, directly or indirectly, converts plasminogen to plasmin and plasmin lyses fibrin in the clot. Cross-​linked fibrin is more resistant to fibrinolytic drugs than a newly formed fibrin clot. The combination of aspirin and a fibrinolytic agent has under- gone extensive clinical testing in trials involving more than 100 000 patients. Additional trials have been conducted comparing one fi- brinolytic agent with another. For patients presenting within 6 h of symptom onset, and with ST elevation or bundle branch block, ap- proximately 30 deaths are prevented per 1000 patients treated. For those presenting between 7 and 12 h, approximately 20 deaths are prevented per 1000 patients treated, and beyond 12 h the benefits are inconclusive. Thrombolysis is a very cost-​effective treatment for acute MI. A sustained benefit on survival has been demonstrated 14 years after thrombolysis. The ISIS-​2 trial demonstrated that the benefits of aspirin treatment were additional to those of fibrinolytic treatment, each achieving about 25 lives saved per 1000 patients treated (for the whole of the study population). Thus, in combination, about 50 lives are saved per 1000 patients treated, but the benefits are larger than this among those presenting within 3 h of infarction with ST-​segment elevation or bundle branch block. Overall, the largest absolute benefit is seen in patients at highest risk, although the proportional benefit may be similar for all. High-​ risk patients include those over 65 years of age, those with a systolic blood pressure below 100 mm Hg, and those with anterior infarction or more extensive ischaemia. The absolute benefit in lives saved per 1000 treated is 11 ± 3 for those under 55 years of age; 18 ± 4 for those between 55 and 64; 27 ± 5 for those 65 to 74; and 10 ± 13 for those over 75. However, for ST depression there is a net hazard of 14 lives lost per 1000 treated, and for those with a normal ECG seven lives lost per 1000 treated (Fibrinolytic Trials Overview). Thus, evidence supports thrombolysis treatment only for those patients with ST ele- vation or bundle branch block. Hazards of thrombolysis Thrombolytic therapy is associated with a significant excess of haemorrhagic complications, including cerebral haemorrhage. Overall, about two non​fatal strokes occur per 1000 patients treated, Table 16.13.4.8  Advantages of primary percutaneous coronary intervention over thrombolysis Clinical indices Event rate (%) Absolute risk benefit of PCI (%) Relative risk benefit of PCI (%) NNT Thrombolysis PCI Short-​term mortality (4–​6 weeks) 8 5 3 36 33 Long-​term mortality (6–​18 months) 8 5 3 38 33 Stroke 2 <1 2 64 50 Reinfarction 8 3 5 59 20 Recurrent ischaemia 18 7 11 59   9 Death or non​fatal reinfarction 12 7 5 44 20 Need for CABG 13 8 5 36 20 CABG, coronary artery bypass graft; NNT, number needed to treat; PCI, percutaneous coronary intervention. Data from Hartwell D, et al. (2005). Clinical effectiveness and cost-​effectiveness of immediate angioplasty for acute myocardial infarction: systematic review and economic evaluation. Health Technol Assess, 9(17). section 16  Cardiovascular disorders 3648 and of these, half are moderately or severely disabling. An add- itional two strokes per 1000 patients are fatal, and the net impact on mortality includes such patients. The risk of stroke increases with age, especially for those over 75 years of age, and for those with systolic hypertension. There is also an excess of non​cerebral bleeds of about 7 per 1000 treated. Bleeding occurs at arterial and venous puncture sites; hence blood sampling or cannulation of vessels should be limited to sites where external compression can achieve haemostasis. Streptokinase and other streptokinase-​containing agents can produce hypotension and, rarely, allergic reactions. Routine ad- ministration of hydrocortisone is not indicated. When hypotension occurs, it can be managed by interrupting the streptokinase infu- sion, lying the patient flat or head down, and by the administration of atropine or intravascular volume expansion. Comparison of thrombolytic agents The most widely used thrombolytic agents are streptokinase, alteplase (tissue plasminogen activator, tPA), tenecteplase (TNK), and reteplase (rPA). The GISSI International Trial and ISIS-​3 international trial both failed to find a difference in outcome between streptokinase and tPA. However, the GUSTO trial (Global Utilization of Streptokinase and Tissue plasminogen active for Occluded coronary arteries) employed an accelerated administration of alteplase over 90 min and intra- venous heparin adjusted using the activated partial thromboplastin time, finding 10 fewer deaths per 1000 patients treated with alteplase compared with the streptokinase group. Meta-​analysis confirms the superiority of clot-​specific agents (e.g. alteplase, tenecteplase) over streptokinase. The current reference standard for the comparison of fibrino- lytic agents is the accelerated infusion regimen of alteplase (tPA), or for simplicity the single-​bolus administration of tenecteplase (TNK). Tenecteplase does not require an infusion pump or re- frigeration and hence is particularly suited for prehospital ad- ministration, but internationally streptokinase remains the most widely used fibrinolytic agent, principally because it is relatively inexpensive. Invasive assessment after fibrinolysis Following lytic therapy, a strategy of routine early angiography (3–​24 h) is recommended. This approach reduces the risk of recur- rent infarction and ischaemia, without an increased risk of stroke or bleeding. Patients should have DAPT and antithrombin therapy as indicated in PPCI. Revascularization by PCI or CABG depends upon the extent and location of underlying coronary disease. Coronary artery bypass surgery (CABG) In the acute phase of MI, the role of CABG is limited to those pa- tients with acute mechanical complications, such as ventricular septal defect or mitral regurgitation due to papillary muscle rupture. Unless such mechanical complications are present, the hazards of acute bypass surgery are significantly increased compared to delayed revascularization in a stabilized patient. The Danish DANAMI study investigated the role of revascularization in those with ischaemia during the recovery phase of MI. It suggested that, following in- farction, individuals with symptomatic or electrocardiographic is- chaemia on stress testing experience significant long-​term benefit from surgical revascularization. Further in-​hospital management The period of hospitalization for reperfused and uncomplicated pa- tients following STEMI has progressively shortened, and is now in the range of 2 to 5 days. The main aims of further in-​hospital man- agement are the identification and treatment of acute complications of infarction, identification of patients at increased risk for subse- quent cardiac events, and initiation of secondary prevention and rehabilitation. There is time pressure to address these issues before hospital discharge in view of the risk that they will not be pursued afterwards. Major complications may be apparent at the time of presentation and haemodynamic, arrhythmic, or ischaemic complications may be evident shortly thereafter. Nevertheless, in the period beyond the first 12 to 24 h, it is appropriate to focus attention on the points just listed. Identification and treatment of complications of infarction Failure of reperfusion Electrocardiographic markers of failed thrombolysis reperfusion are the persistence of ST-​segment elevation together with clinical and haemodynamic features of continuing ischaemia. Continuous computed ST analysis allows the most accurate definition of ECG changes, but an approximation can be obtained with repeated 12-​ lead ECGs and measurement of ST-​segment elevation. In those with successful reperfusion, ST segments decrease to less than 50% of peak elevation within 60 min. In addition, some patients exhibit reperfusion arrhythmias (ventricular tachycardia, idioventricular rhythm, and—​rarely—​ ventricular fibrillation). Such arrhythmias are more common in the presence of marked ischaemia and prompt reperfusion within 60 to 90 min of occlusion. Rescue angioplasty is the appropriate management for failed reperfusion, and consists of mechanical recanalization of the oc- cluded vessel with percutaneous intervention, including stent im- plantation. This strategy achieves an ‘open artery’, and randomized trial data (REACT trial) shows superior outcome compared with re- peat thrombolysis or conservative management. Cardiogenic shock In cardiogenic shock, mechanical contractile abnormalities of the left ventricle or acute haemodynamic complications (papillary muscle rupture or ventricular septal defect) lead to reduced blood pressure and impaired tissue perfusion. Clinically, the condition is recognized by a systolic blood pressure of less than 90 mm Hg to- gether with impaired tissue flow, as reflected impaired cerebral func- tion, peripheral vasoconstriction and oliguria. Echocardiography is very helpful to help define the mechanism of cardiogenic shock and direct treatment. Between 5 and 20% of those patients admitted to hospital with acute MI demonstrate cardiogenic shock, although the frequency has been reduced by thrombolytic therapy and pri- mary PCI. The mortality rate when cardiogenic shock complicates an acute coronary event is in excess of 70% if acute revascularization is not possible. Time delay is critically important in the management of cardiogenic shock: mortality rises progressively if more than 2 h have elapsed since its onset. Treatment aims to improve the recovery of acutely is- chaemic myocardium (mechanical and surgical revascularization), 16.13.4  Management of acute coronary syndrome 3649 treat mechanical complications, and to support the circulation with a combination of inotropes, vasodilators, and loop diuretics. Evidence suggests that the most important treatment may be to reopen the infarct-​related artery. In addition to achieving reperfusion, management of the patient with cardiogenic shock after MI may require inotropic support. Dopamine is commonly used, initially at a low ‘renal dose’ (1–​5 micrograms/​kg per min) that activates dopaminergic receptors (but also has an effect on the circulation), but if necessary at higher doses of 5 to 20 micrograms/​kg per min that have positive inotropic and chronotropic effects. In doses above 20 micrograms/​kg per min, there is activation of α-​adrenoceptors with undesirable peripheral vasoconstriction and a decline in renal perfusion. Dobutamine acts mainly as a β1-​adrenoceptor agonist and is used in the range of 2 to 40 micrograms/​kg per min. Phosphodiesterase inhibitors have both inotropic and vasodilator effects and, although they have produced favourable haemodynamic responses, the studies conducted have not shown an improvement in outcome. The management of pulmonary oedema consists of opiates (to relieve distress and to reduce vascular resistance), oxygen, vasodilators, and diuretics. If it is severe, patients may require positive end-​expiratory ventilation or even full mechanical venti- lation. Vasodilators (including nitrates, salbutamol, and sodium nitroprusside) reduce venous and pulmonary arterial pressure, but tachycardia may be a limiting feature and their use is limited in those who are profoundly hypotensive. Loop diuretics are employed in bolus intravenous doses or by infusion. In all instances, decisions to proceed to mechanical external support of the circulation or mechanical ventilation need to take account of the extent to which the cardiac dysfunction may be re- versible, the presence of comorbidity, and the wishes of the patient and their family. Left ventricular dysfunction and heart failure Large-​scale trials of angiotensin-​converting-​enzyme (ACE) in- hibitors and angiotensin receptor blockers (ARBs) have been con- ducted in patients with left ventricular dysfunction and those with clinical and radiological features of heart failure. Clear evidence demonstrates improved short-​and long-​term outcome with ACE in- hibitors/​ARBs in patients with heart failure and those with asymp- tomatic left ventricular dysfunction. Caution must be exercised with the introduction of ACE inhibi- tors in patients with intravascular volume depletion, when they can cause hypotension, and in patients with low arterial pressure or renal impairment. ACE inhibition should commence with a very small dose (e.g. 6.25 mg of captopril), with dosages increased progressively in conjunction with clinical monitoring. They can provoke deteri- oration in renal function in patients with renal artery stenosis and in those with significant pre-​existing renal impairment, hence it is important to check serum electrolytes and creatinine during early treatment and follow-​up. Arrhythmias Many arrhythmias can be seen in the context of acute MI and its treatment. The most serious, including ventricular fibrillation, ventricular tachycardia, and heart block, can lead to cardiac ar- rest. However, routine administration of antiarrhythmic agents is not indicated. They are almost invariably negatively inotropic, and they may also be proarrhythmic in the context of acute cor- onary ischaemia. An overview of randomized trials into the use of prophylactic lidocaine (lignocaine) showed that it increased mortality. Ventricular fibrillation should be treated with direct current (DC) cardioversion, and recurrent ventricular arrhyth- mias require antiarrhythmics (e.g. amiodarone). Importantly, at- tention should be paid to electrolyte imbalance and the correction of reversible ischaemia or other factors provoking arrhythmias. (see Chapter 16.4 for details of the diagnosis and treatment of arrhythmias). Heart block of any degree can occur after acute MI. It is more common with inferior than anterior infarction because the right coronary artery supplies the atrioventricular node, and also be- cause vagal reflexes are more likely from this area. It is often transient, and does not necessarily imply a large infarct, except when it occurs with anterior infarction, in which case the prog- nosis is grave. Temporary transvenous pacing is justified when bradycardia compromises the circulation, but is not advocated ‘prophylactically’. Ventricular septal defect, papillary muscle rupture, and myocardial rupture Rupture of the interventricular septum occurs in up to 3% of acute infarctions and is responsible for about 5% of deaths due to MI. Rupture in the apical area may complicate anterior infarction and in the basal inferior area may complicate inferior infarction. Clinically, the condition is associated with the development of a new pansystolic murmur and clinical features of a left-​to-​right shunt with increased pulmonary congestion. The findings are confirmed on echocardiog- raphy or cardiac catheterization. Surgery should be undertaken as soon as possible: the outlook for those who are not operated upon is very bleak, with few surviving. However, some patients with small shunts survive the acute phase, in which case they may suffer the later consequences of the shunt. Papillary muscle rupture occurs as a result of acute ischaemic damage due to obstruction of either the left anterior descending or circumflex coronary arteries. It causes the abrupt onset of severe mi- tral regurgitation and accounts for 5% of deaths after acute MI. The complication generally occurs within the first week after infarction, and may be recognized as the abrupt onset of acute pulmonary oe- dema. It is often accompanied by a new systolic murmur, but when the left atrial pressure rises acutely the murmur may be insignifi- cant. The findings are confirmed with echocardiography. The man- agement is acute surgical repair with or without revascularization. In the patient who deteriorates haemodynamically after MI—​ with hypotension, pulmonary oedema, or both—​it is important to consider the possibility of a ventricular septal defect or acute mi- tral regurgitation. However, it can be impossible to distinguish be- tween the two on clinical grounds. Both classically produce a new pansystolic murmur, and although differences between the mur- murs have been described, these are not robust enough to discrim- inate with certainty in the individual case. Acute mitral regurgitation is best diagnosed by echocardiography, but transthoracic echocar- diography may be unable to detect a ventricular septal defect in a reliable manner. Transoesophageal echocardiography is better, as is the use of a contrast-​enhanced technique. If this is unavailable, an al- ternative approach is to pass a flow-​directed pulmonary catheter and take blood samples from the pulmonary artery, right ventricle, and section 16  Cardiovascular disorders 3650 right atrium. A step-​up in oxygen tension between the right atrium and the pulmonary artery indicates the presence of a left-​to-​right shunt and confirms the diagnosis of a ventricular septal defect. Myocardial rupture may follow acute infarction, usually involving the free wall of the left ventricle. It is responsible for approximately 10% of all deaths in acute MI. Half of the ruptures occur within the first week, and 90% within 2 weeks. The location of rupture is usually within the infarcted area, but may be at the junction with adjacent normal myocardium. In most cases, death is immediate and due to electromechanical dissociation. The patient is unresponsive to re- suscitation measures but rarely—​with subacute rupture—​patients can be supported until surgical repair is performed. The diagnosis is made on clinical and echocardiographic criteria with assessment for possible cardiac tamponade (see Chapter 16.8). In some patients, partial rupture of the free wall can result in the late development of a false aneurysm. Left ventricular thrombus A left ventricular thrombus can be detected using echocardiog- raphy in up to 40% of patients with acute anterior MI. The thrombus is usually located at the apex in association with a dyskinetic or aneurysmal section of myocardium with impaired contractile function. The thrombus may be large and is associated with risks of embolization (in 15–​20% of cases). Anticoagulation with hep- arin followed by warfarin is advised in patients with extensive in- farction and those in whom apical aneurysms or mural thrombi are detected for up to 6 months. Both thrombolysis and surgical removal have been successfully conducted. However, there is no clear evidence that either strategy is superior (provided there is no evidence of embolization). Combining oral anticoagulation with DAPT increases bleeding risk. The duration of therapy is unknown but should reflect the relative risk of bleeding and stent throm- bosis. Repeat imaging may help to confirm thrombus resolution and/​or improvement of LV function to guide a decision about long-​term therapy. Right ventricular infarction Right ventricular infarction may occur in isolation, or associated with inferior STEMI. The triad of hypotension, clear lung fields, and raised central venous pressure should prompt its diagnosis. ECG may show ST elevation in V1 and V4R. The chest radio-​graph is char- acteristically clear despite the presence of shock. Echocardiography conforms right ventricular (RV) dilatation, low pulmonary artery (PA) pressure, dilated hepatic veins. Fluid loading to maintain RV filling is the key therapeutic intervention, and PA catheter inser- tion maybe necessary for accurate monitoring. Maintaining sinus rhythm and atrioventricular synchrony is important. Pericarditis Pericarditis may complicate an extensive MI, and may be manifest clinically as a pericardial friction rub accompanied by pleuritic chest pain. A small pericardial effusion may be detected using echocar- diography. Dressler’s syndrome is a rare late complication and is associated with pericarditis between 2 weeks and 3 months after acute infarction. It has an autoimmune basis, often accompanied by pleural and pericardial effusions. It is managed with salicylates, paracetamol, or colchicine. The frequency of both pericarditis and Dressler’s syndrome is reduced with acute reperfusion. An integrated approach to the management of STEMI Prehospital management In a patient with suspected acute infarction, the priorities are to establish whether typical clinical features and ST elevation (or left bundle branch block) are present, and if so to initiate reperfusion with the absolute minimum of delay. Where possible, the diag- nosis is confirmed and the transfer of the patient arranged by tel- emetry of the ECG. The phrase ‘time is muscle’ has been coined for acute STEMI. Acute resuscitation may be required for cardiac ar- rest or major arrhythmic complications, especially ventricular fib- rillation. Additional priorities are to provide analgesia and oxygen. Prehospital thrombolysis may be given by appropriately trained paramedic crews when transfer times to a PCI hospital are such that more than 120 min will elapse from diagnosis to PCI. In-​hospital management Initial triage and management Initial assessment involves the identification of those with clear-​cut evidence of STEMI (based on clinical and diagnostic ECG criteria). Such patients require immediate triage to reperfusion therapy (pri- mary PCI, or if unavailable thrombolysis with a fibrinolytic agent plus an antiplatelet agents). In transit to primary PCI or while preparing pharmacological reperfusion, patients may require fur- ther analgesia and management of arrhythmic and haemodynamic complications, including heart failure. Patients in whom the diagnosis of MI is suspected, but the ECG criteria are not diagnostic, should be managed in an intensive care setting (in the emergency department or cardiac care unit) with re- peat ECG evaluation at 30-​min intervals (or ST-​segment analysis). Cardiac biomarkers (troponins) may be elevated at presentation, if sufficient time has lapsed from onset of ischaemia (4–​6 h), or they may become elevated following arrival (repeat measurement at 8–​12 h). Such patients may be divided into those with evidence of non-​STEMI (ECG abnormalities and troponin elevation) and those with unstable angina (T-​wave inversion, ST-​segment depression, or transient ST-​ segment elevation, without elevated cardiac troponins). Among those with minor or non​specific ECG changes and no enzyme elevation, re-​evaluation should take place for alternative diagnoses, and stress testing performed subsequently to detect underlying coronary ar- tery disease (Fig. 16.13.4.7). A key component of initial evaluation of those without ST elevation or left bundle branch block involves risk stratification (see Table 16.13.4.2). Echocardiography may be valu- able to detect signs of ischaemia/​infarction or to demonstrate normal contractile function in those with an alternative diagnosis. Later in-​hospital management During this phase the management of complications, initiation of secondary prevention, and early cardiac rehabilitation should take place. In high-​risk patients (those with recurrent acute ischaemia or those with failure of ST-​segment resolution and continuing pain), emergency PCI or surgical revascularization can be performed in appropriately equipped centres (Fig. 16.13.4.9). 16.13.4  Management of acute coronary syndrome 3651 Regular clinical and electrocardiographic assessments are required during the recovery phase to detect acute mechanical and arrhythmic complications, and to identify impaired contractile function in pa- tients who will benefit from ACE inhibitor/​ARB treatment. This treatment is indicated in those with overt heart failure in the acute phase and also indicated for secondary prevention in patients with established vascular disease (HOPE trial). Thus, ACE inhibitors or ARBs are indicated for those with vascular disease, irrespective of whether there is evidence of overt heart failure or impaired left ven- tricular function in acute phase. Patients also require lipid-​lowering therapy: robust evidence demonstrates that all patients with MI or non-​ST-​elevation ACS will benefit (MRC/​BHF Heart Protection Study). There is evidence to support management of diabetes with glu- cose and insulin during the in-​hospital and early posthospital phase. All patients will benefit from smoking cessation, the management of hypertension (systolic pressure to <140 mm Hg), and dietary and lifestyle modification, including exercise. After STEMI, patients benefit from participation in a rehabilitation programme, with im- proved quality of life, symptom relief, and return to an active lifestyle or occupation. Secondary prevention measures in those with STEMI or non-​STEMI ACS Following an ACS, patients require dietary and lifestyle advice including the support necessary to discontinue smoking with the introduction of nicotine replacement therapy. (SIGN Guideline 2007). Lipids should be measured within the first 24 h of admis- sion, with evidence supporting the use of lipid-​lowering therapy. Individuals with documented coronary artery disease, and espe- cially those with left ventricular contractile dysfunction or heart failure, have reduced long-​term risks of death and MI if main- tained on an ACE inhibitor or ARB. In addition, patients may re- quire antianginal therapy if revascularization is incomplete, and all should receive long-​term, low-​dose aspirin. DAPT should be given for at least 1 month in STEMI (the limits of the evidence) and a year for non-​ST-​elevation ACS (or as determined by the type of stents implanted). Non​pharmacological interventions Evidence supports the following non​pharmacological interven- tions in secondary prevention: cessation of smoking (including the avoidance of passive smoking), dietary modification, exer- cise, rehabilitation, and management of obesity. Patients with impaired LV function and or later symptomatic heart failure may need to be considered for defibrillator or resynchronization therapy. Pharmacological interventions Trial evidence supports therapeutic interventions to modify the fol- lowing conditions:  hyperlipidaemia, left ventricular dysfunction, and heart failure, diabetes mellitus, and hypertension. Reduction of cardiovascular risk Evidence (summarized in Tables 16.13.4.9 and 16.13.4.10) supports the following therapies to reduce the risk of subsequent cardiovas- cular events: antiplatelet therapy (aspirin in a dose of 75 mg/​day, clopidogrel 75 mg day); β-​blockers in those without contraindica- tions; lipid lowering with 3-​hydroxy-​3-​methylglutaryl coenzyme A  (HMG CoA) reductase inhibitors (statins); ACE inhibitor or ARB, especially in those with left ventricular dysfunction and heart failure, although benefit is also possible in other patients with vas- cular disease (Table 16.13.4.10). Anticoagulants These are indicated in those with high risks of embolism due to left ventricular or atrial thrombus. There is evidence to support the use of anticoagulants in post-​MI patients but no definitive evidence that such treatment is superior to aspirin therapy. Current trials are evaluating the role or oral antithrombins and oral anti-​Xa inhibitors following ACS. Table 16.13.4.9  Estimated benefits of long-​term secondary prophylactic treatment/​intervention after MI Treatment/​intervention Problems prevented per 1000 patient-​ years of treatment All post-​MI patients (unless specific contraindications exist) Aspirin (meta-​analysis) 7 vascular deaths 9 non​fatal reinfarctions 3 non​fatal strokes Oral β-​blocker 21 deaths 21 reinfarctions Statin (hyperlipidaemia, post-​MI) 7 deaths 11 revascularizations 12 nonfatal MIs 3 strokes 4 congestive heart failure 13 angina Statin (average cholesterol, post-​MI) 2 deaths 9 re-​vascularizations 4 non​fatal MIs 2 strokes 4 unstable angina Smoking cessation (observational studies) 15 deaths 46 reinfarctions Post-​MI patients with LVD or heart failure (additional treatment unless specific contraindications exist) ACE inhibitor (left ventricular ejection fraction ≤ 40%) 12 deaths 9 MIs 10 congestive heart failure (requiring hospital admission) ACE inhibitor (heart failure) 45 deaths 26 congestive heart failure (severe) LVD, left ventricular dysfunction. Sivers, F (1999). Evidence-​based strategies for secondary prevention of coronary heart disease, 2nd edn. A&M Publishing, Guildford, Surrey. section 16  Cardiovascular disorders 3652 Hormone replacement therapy (HRT) HRT is not indicated for risk reduction after ACS. When used to relieve menopausal symptoms, HRT is associated with a small ­increased risk of thrombotic events. Calcium channel blockers An overview of data from 19 000 patients, based on all randomized trials of acute infarction and unstable angina, suggests that calcium channel blockers are unlikely to reduce the rate of subsequent in- farct development, infarct size, or subsequent infarction. They may, however, have indications for the relief of angina (especially heart-​ rate-​lowering calcium antagonists). Antiarrhythmic agents A review of the effects of antiarrhythmic agents (with the excep- tion of β-​blockers) does not demonstrate a beneficial impact on mortality. Many have significant proarrhythmic complications and negative inotropic effects. FURTHER READING Antithrombotic Trialists Collaboration (2002). Collaborative meta-​ analysis of randomised trials of antiplatelet therapy for prevention of death, mycocardial infarction, and stroke in high risk patients. BMJ, 324, 71–​86. Antman EM, et al. (1996). Cardiac-​specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med, 335, 1342–​9. Antman EM, et al. (1999). Abciximab facilitates the rate and extent of thrombolysis: results of the thrombolysis in mycocardial infarction (TIMI) 14 trial. Circulation, 99, 2720–​32. Antman EM, et  al. (1999). Assessment of the treatment effect of enoxaparin for unstable angina/​non-​Q-​wave mycocardial in- farction. TIMI IIB–​ESSENCE meta-​analysis. Circulation, 100, 1602–​8. Antman EM, et al. (2006). Enoxaparin versus unfractionated heparin with fibrinolysis for ST elevation mycocardial infarction. 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Table 16.13.4.10  Comparison of the treatment benefits from interventions to prevent cardiovascular events Problems/​therapy Events prevented NNT* Severe hypertension (DBP 115–​129 mm Hg) Death or stroke or MI 3 Coronary artery bypass surgery for left main stem stenosis Death 6 Aspirin for transient ischaemic attack Death or stroke 6 Statin for hyperlipidaemia, post-​MI/​angina Death or non​fatal MI or CABG/​PTCA or cerebrovascular event 6 Warfarin for atrial fibrillation Stroke 7 ACE inhibitor for LV dysfunction post-​MI CV death or hospitalization for CHF 10 Statin for average cholesterol post-​MI (CARE trial) or stroke Death or non​fatal MI or CABG/​PTCA 11 Aspirin post-​MI CV death or stroke or MI 12 Statin for average/​elevated cholesterol, post-​MI/​unstable angina (LIPID trial) Death or non​fatal MI or CABG/​PTCA or stroke 15 B-​blocker post-​MI Death 20 ACE inhibitor for LV dysfunction CV death or hospitalization for CHF 21 ACE inhibitor for vascular disease (HOPE trial) Deaths 50 MI 42 Stroke 67 Statin for hypercholesterolaemia in primary prevention Death or non​fatal MI or CABG/​PTCA or stroke 26 Mild hypertension (DBP 90–​109 mm Hg) Death or stroke or MI 141 ACE, angiotensin-​converting-​enzyme; CABG, coronary artery bypass grafting; CARE, Cholesterol and Recurrent Events Trial; CHF, congestive heart failure; CV, cardiovascular; DBP, diastolic blood pressure; HOPE, Heart Outcomes Prevention Evaluation Trial; LIPID, Long-​term Intervention with Pravastatin in Ischaemic Disease Trial; LV, left ventricle; MI, myocardial infarction; NNT, estimated number of patients that need to be treated for 5 years to prevent one event; PTCA, percutaneous transluminal coronary angioplasty. 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(2004). Prognostic value of the admission electro- cardiograph in patients with unstable angina/​ST segment elevation myocardial infarction treated with very early revascularisation. Am J Med, 117, 145–​50. National Institute of Health Care Excellence (2016). Chest pain of recent onset. Clinical guideline. https://​www.nice.org.uk/​ guidance/​cg95 Rautaharju PM, et  al. (2009). AHA/​ACCF/​HRS recommendations for the standardization and interpretation of the electrocardio- gram: part IV: the ST segment, T and U waves, and the QT interval. J Am Coll Cardiol, 53, 982–​91. Savonitto S, et al. (1999). Prognostic value of the admission electrocar- diogram in acute coronary syndromes. JAMA, 281, 707–​13. Sharma S, et al. (2017). International recommendations for elec- trocardiographic interpretation in athletes. J Am Coll Cardiol, 69, 1057–75. Surawicz B, et al. (2009). AHA/​ACCF/​HRS recommendations for the standardization and interpretation of the electrocardiogram: part III: intraventricular conduction disturbances. J Am Coll Cardiol, 53, 976–​81. Wagner GS, et al. (2009). AHA/​ACCF/​HRS recommendations for the standardization and interpretation of the electrocardiogram: part VI: acute ischemia/​infarction. J Am Coll Cardiol, 53, 1003–​11. Waller AD (1887). A demonstration on man of electromotive changes accompanying the heart’s beat. J Physiol (Lond), 8, 229–​34. 16.3.2  Echocardiography James D. Newton, Adrian P. Banning, and Andrew R.J. Mitchell ESSENTIALS Ease of use, rapid data provision, portability, and safety mean that echocardiography has become the principal investigation for almost all cardiac conditions. A  modern transthoracic echocardiography examination combines real-​time two-​dimensional imaging of the myocardium and valves with information about velocity and direc- tion of blood flow obtained by Doppler and colour-​flow mapping. A complete examination can be performed in most patients in less than 30 min. Valvular heart disease—​echocardiography has revolutionized the diagnosis and follow-​up of patients with these conditions. Serial cardiac catheterization to assess severity and progress of valvular stenosis has been completely superseded by Doppler echocardi- ography, and the role of invasive investigation is increasingly limited to the assessment of the coronary arteries prior to revascularization. Transoesophageal echocardiography—​this is now a routine inves- tigation in many centres. Under sedation, an ultrasound probe is passed into the oesophagus to a position behind the heart, produ- cing excellent resolution of cardiac structures. It is used diagnostically in many emergency situations, including aortic dissection and sus- pected prosthetic mechanical valve dysfunction, and as an additional method of monitoring cardiac performance during cardiac and noncardiac surgery. Other technological developments—​these include (1)  stress echocardiography—​used to detect occult coronary disease and pre- dict cardiac risk; (2) use of contrast agents—​these improve visualiza- tion of the endocardium in patients with poor acoustic windows and allow some estimation of myocardial perfusion; and (3) real-​time three-​dimensional imaging—​this is available on modern platforms and allows detailed assessment of myocardial and valve func- tion. Recent developments in assessing myocardial mechanics by quantifying strain offer new insights into early pathological changes, and progressive miniaturization of platforms including fully portable systems have further increased the utility of echocardiography in the assessment of cardiac structure and function. 16.3.2  Echocardiography 3315 History of echocardiography The timeline of key discoveries and inventions is as follows: • 1842—​Christian Doppler observed that the pitch of a sound varies if the source is moving. • 1880—​first piezoelectric crystals developed. • 1912—​Richardson develops sonar technique using sound waves to detect underwater objects. • 1929—​Sokolov uses ultrasound to identify flaws in metal components. • 1954—​heart visualized with ultrasound by Carl Herz and Inge Edler. • 1960s—​multielement scanners lead to development of two-​ dimensional (2D) echocardiography. • 1970s—​Doppler colour-​flow mapping used to evaluate valve disease. • 1970s—​transoesophageal and stress echocardiography developed. • 1980s—​ultrasound contrast agents developed. • 1990s—​intracardiac and intracoronary ultrasound in wider use. • 2000s—​development and refinement of three-​dimensional (3D) echocardiography and advances in myocardial deformation imaging. Principles of echocardiography The transducer used for most echocardiographic examinations contains piezoelectric crystals that emit ultrasound frequencies of 2.5–​5 MHz. Most of the sound energy is scattered or absorbed, but reflection occurs at interfaces between tissues of different acoustic impedance (e.g. between blood and muscle). The transducer collects these reflections and the time delay between emission and reception is calculated. This allows the depth of the reflection to be derived and its position to be displayed on a screen as a dot (pixel). The bright- ness of the dot is related to the magnitude of the reflected signal. In general, higher-​frequency transducers allow better discrimination between structures, but the increased attenuation leads to reduced penetration. There are three main echocardiographic techniques:  two-​ dimensional (cross-​sectional), M-​mode, and Doppler. Two-​dimensional echocardiography (cross-​sectional) Cross-​sectional images are constructed as the ultrasound beam sweeps across the heart in a sector (Fig. 16.3.2.1). Between 50 and 100 cross-​sections are presented each second, giving the impression of a moving picture. These images are readily interpretable by an ob- server with knowledge of cardiac anatomy, and this technique is the cornerstone of modern echocardiography. M-​mode echocardiography M-​mode echocardiography preceded modern 2D imaging. Unlike 2D imaging, which uses a series of sweeps across the heart, M-​mode uses a single static beam of ultrasound pulses at a very high fre- quency. The narrow beam is analogous to a vertical mineshaft passing through various layers of rock. Displayed in real time, this results in reflections from cardiac structures being displayed as horizontal lines, with superficial structures at the top of the screen and the deeper structures at the bottom (Fig. 16.3.2.2). These data are interpretable when one knows which structure each line represents. The technique has excellent spatial resolution and temporal resolution; hence, with the advent of 2D echocardiography and Doppler, M-​mode is now principally used for measurement of cardiac chamber dimensions and observation of the relative movement of cardiac structures to each other; for example, the relationship of the anterior leaflet of the mitral valve to the septum in hypertrophic cardiomyopathy. Doppler echocardiography The Doppler principle allows the velocity and direction of move- ment of an object (blood or myocardium in the case of cardiac ultrasonography) to be calculated from the shift in the frequency of a reflected waveform relative to the observer. Cardiac imaging employs pulsed-​wave, continuous-​wave, and colour Doppler techniques. Pulsed-​wave Doppler allows information about flow to be obtained from a defined point within the heart. The range of detectable velocities is limited, and the technique is used for sampling normal and low velocities (e.g. mitral valve flow). Fig. 16.3.2.1  Parasternal long-​axis view of the heart using 2D echocardiography. The sector images through the right ventricle (RV) to the left ventricle (LV). In this view, 2D echocardiography provides useful data on the structure and function of the aortic valve (AV) and mitral valve (MV). Fig. 16.3.2.2  M-​Mode view of the left ventricle. The high imaging frequency of M-​mode allows accurate measurements of structures to be made, in this case the diastolic (D) and systolic (S) cavity size. section 16  Cardiovascular disorders 3316 Continuous-​wave Doppler identifies the peak velocity encoun- tered along the whole of the ultrasound beam and is particularly valuable for measuring high-​velocity jets such as those in aortic valve disease (Fig. 16.3.2.3). It is important to remember, however, that failure to align the transducer exactly parallel to flow results in measurement of artefactual low velocities and potentially an underestimation of valvular stenosis. Colour Doppler allows a dynamic representation of the direction and velocity of flow to be superimposed on to a 2D image of the heart. Velocities towards the transducer are usually coded in red and velocities away in blue (Fig. 16.3.2.4). Turbulent and high-​velocity flow produces variable velocities and results in a mosaic pattern that is ideal for characterization of regurgitant lesions. This technique is now so sensitive that it can detect trivial regurgitation during the closure of many normal heart valves. Tissue Doppler echocardiography uses the same principles but by changing the settings the direction and velocity of the myocardium is encoded rather than the blood pool. Pulse-​wave Doppler can then be used to interrogate a specific part of the myocardium and provide detailed information on myocardial mechanics in both systole and diastole (Fig. 16.3.2.5). Transthoracic echocardiography Imaging is performed using dedicated echocardiography equip- ment with the patient lying on their left hip in the left lateral position and with their left arm behind their head to open the rib spaces. Ultrasound cannot travel through bone and thus cardiac imaging is performed via intercostal spaces to the left of the sternum and at the apex of the heart in the axillary line. These ‘echo windows’ pro- vide standard views described as the parasternal short and long axis and apical two-​, four-​, and five-​chamber views. Useful additional views can also be obtained from the subcostal and suprasternal ap- proach in some patients. A standard echocardiography examination involves 2D imaging from the parasternal, apical, and subcostal ap- proaches supported by M-​mode measurements, continuous, pulsed, and colour Doppler and tissue Doppler imaging. Valvular heart disease Transthoracic echocardiography is the investigation of choice for pa- tients with suspected valvular heart disease. All four cardiac valves can be visualized and interrogated by Doppler and 2D echocardiog- raphy. Concomitant abnormalities in ventricular performance can be assessed simultaneously. Aortic stenosis Two-​dimensional echocardiography can usually image the aortic valve cusps; if they are thin and freely mobile, it is unlikely that there is significant aortic stenosis. However, if the valve cusps are thickened and calcified, interrogation by continuous-​wave Doppler is mandatory. The severity of aortic stenosis is usually expressed as the peak pressure difference (or gradient) across the valve, and is calculated from the maximum flow velocity (V) using the modi- fied Bernoulli equation (pressure gradient = 4 V2). In patients with normal left ventricular systolic function, a peak gradient measured by Doppler of over 65 mm Hg or a mean gradient of over 40 mm Hg suggests significant aortic stenosis. The aortic valve area can be estimated using the continuity equation which requires measure- ment of the left ventricular outflow tract diameter on 2D echo and Fig. 16.3.2.3  Continuous-​wave Doppler of the aortic valve showing aortic regurgitation (flow towards the probe above the line). Calculations can be performed using on-​machine software to instantly provide useful haemodynamic data. Fig. 16.3.2.4  Colour-​flow mapping of mitral regurgitation. There is high-​velocity flow in systole from the left ventricle into the left atrium through the mitral valve. Fig. 16.3.2.5  Tissue Doppler of the basal interventricular septum allowing measurement of the systolic contraction (S) and early passive relaxation (E′) phase. 16.3.2  Echocardiography 3317 the velocity at this point using pulse-​wave Doppler (Fig. 16.3.2.6). Severe stenosis usually equates to a valve area of less than 1.0 cm2 but should be indexed to the patient’s body surface area. When chronic critical outflow obstruction results in declining left ventricular function and reduced cardiac output, the gradient produced by any degree of valve obstruction also falls. Doubt about the severity of the stenosis can usually be resolved by enhancing left ventricular function by administering intravenous dobutamine and evaluating the gradient during increased flow. Aortic regurgitation Assessment of the mechanism and severity of aortic regurgitation requires a combination of all three echocardiography modalities. M-​mode may demonstrate fluttering of the anterior leaflet of the mitral valve and, in the setting of acute severe aortic regurgitation, may reveal premature closure of the mitral valve. Two-​dimensional echocardiography will occasionally demonstrate prolapse of one more of the aortic cusps, but even severe aortic regurgitation can occur through an aortic valve that appears to be structurally normal. The severity of aortic regurgitation can be estimated using continuous-​wave and colour Doppler (see Chapter  16.6, Figs. 16.14.1.3 and 16.14.1.4), although assessment can be difficult as it is influenced by left ventricular function and blood pressure. Doppler-​ derived pressure half-​time and measurement of regurgitant fraction and/​or flow convergence zone are valuable when there is uncertainty over lesion severity. M-​mode and colour Doppler can be combined and, when the regurgitant jet fills more than 50% of the left ven- tricular outflow tract, the regurgitation is classified as severe. Flow within the descending thoracic aorta can be measured using pulse-​ wave Doppler and in severe aortic regurgitation there is typically holodiastolic flow reversal—​analogous to the collapsing pulse. In patients with severe asymptomatic aortic regurgitation, serial in- crease in left ventricular dimensions or a progressive fall in ejection frac- tion are indications for surgery. However, any increase in ventricular dimension should be at least 0.5 cm before it is regarded as significant, given the limited reproducibility of echocardiographic parameters. Mitral stenosis Mitral valve stenosis is well visualized using either M-​mode or cross-​sectional echocardiography. Its severity can be determined by estimating the area of the valve orifice either by direct planimetry on a 2D short-​axis image or from the Doppler pressure half-​time (mitral valve area = 220/​pressure half-​time). A valve area of less than 1.0 cm2 usually indicates severe mitral stenosis (Fig. 16.3.2.7). The mean gradient across the valve can also be measured by Doppler and is typically more than 10 mm Hg in severe stenosis. Transthoracic echocardiography is also used to assess the suitability of the mitral valve for balloon dilation, although transoesophageal imaging is ne- cessary to exclude left atrial thrombus. Mitral regurgitation Transthoracic echocardiography will usually demonstrate the mechanism and severity of mitral regurgitation. Two-​dimensional imaging identifies abnormalities of the valve leaflets and colour-​ flow shows jet direction and area (Fig. 16.3.2.8). Severe mitral re- gurgitation is suggested by increased left ventricular end-​diastolic dimension and hyperdynamic function due to volume overload. Fig. 16.3.2.6  Continuous-​wave Doppler through the aortic valve. The peak velocity is 503 cm/​s. This equates to a peak pressure gradient (A0 max PG) of 101 mm Hg. Previous measurements of the left ventricular outflow tract diameter and velocity allow a calculated aortic valve area to be derived, in this case 0.57 cm2. Fig. 16.3.2.7  Pulse-​wave Doppler at the mitral valve leaflet tips in a patient with severe mitral valve stenosis. The pressure half-​time is calculated as 368 ms, giving an estimated valve area of 0.6 cm2. Fig. 16.3.2.8  Apical four-​chamber view with colour-​flow demonstrating an eccentric jet of mitral regurgitation from the left ventricle (LV) to the left atrium (LA). In this case, the leak is due to prolapse of the posterior mitral valve leaflet. section 16  Cardiovascular disorders 3318 Precise quantification of the amount of regurgitation is demanding as it is influenced by left ventricular function, the direction of the jet, and left atrial size. Various algorithms have been de- vised to improve quantification of mitral regurgitation, including measurement of the flow convergence zone and the proximal isovelocity surface area (PISA) method, but most centres simply classify the extent of regurgitation as mild, moderate, or severe (Table 16.3.2.1). Pulmonary and tricuspid valve disease In adults, 2D imaging of the pulmonary valve may be difficult, par- ticularly if there is lung disease. Despite this, accurate Doppler infor- mation is usually obtainable. Tricuspid stenosis is very uncommon, but some degree of tricuspid regurgitation is detectable even in healthy individuals. Measurement of the peak velocity of tricuspid regurgitation (V) is valuable as, in the absence of pulmonary valve disease, it can be used to estimate pulmonary artery (PA) systolic pressure: PA systolic pressure (mm Hg) = 4V2 + right atrial pressure       (usually 5−10 mm Hg). Prosthetic valves Transthoracic echocardiography is commonly performed as part of the routine follow-​up of prosthetic valves. It is usually able to assess biological valves accurately, but for mechanical mitral valve prostheses, attenuation artefact produced by the metal may be problematic. Transoesophageal imaging is recommended when transthoracic imaging is suboptimal or if improved resolution is required, for example, in patients with suspected prosthetic valve endocarditis. Haemodynamic assessment Using Doppler to evaluate flow across all four cardiac valves and the great vessels, the pressure within each cardiac chamber can be estimated and a comprehensive description of the current haemo- dynamic status provided (Fig. 16.3.2.9). This can be extremely helpful in the setting of intensive cardiorespiratory support, although obtaining clear and accurate images in critically ill patients can be very challenging. Abnormal left ventricular function In most patients, a full transthoracic echocardiography study will confirm or refute a clinical suspicion of left ventricular dysfunction and identify the likely aetiology of any abnormality. Systolic and diastolic left ventricular function can be assessed, and a variety of methods can be used to derive an estimate of left ventricular ejec- tion fraction. The most accurate methods use imaging in two or- thogonal planes or a 3D technique to model the whole left ventricle (Fig. 16.3.2.10). The normal ejection fraction (calculated from the end-​diastolic and end-​systolic volumes) is greater than 55%. An ejection fraction of 45–​54% equates to mild left ventricular dysfunction, 30–​44% to moderate dysfunction, and less than 30% to severe dysfunction. However, ejection fraction as a single measure of systolic function can be misleading as it is influenced by both preload and afterload, and can be preserved even with significant myocardial pathology. Advances in image processing have facilitated the advent of speckle tracking, whereby unique patterns of ultrasound reflections within the myocardium are tracked frame by frame and used to derive measures of myocardial deformation. The most robust of these is global longitudinal strain, with a value of –​20% being considered normal and abnormal values being closer to 0%. There is emerging evidence that this parameter changes before ejection fraction and is more reproducible. In patients with ischaemic heart disease, assessment of re- gional wall motion is valuable. Segments may be described as normokinetic, hypokinetic, akinetic, dyskinetic, or aneurysmal. Detection of a regional wall motion abnormality in patients pre- senting with left ventricular systolic dysfunction supports an is- chaemic aetiology. The echocardiographic assessment of diastolic dysfunction is complex, but increasingly important in the assessment of pa- tients with heart failure presenting with a normal ejection fraction. Impaired diastolic filling is indicated by a combination of echocar- diographic findings routinely measured. Measurements of early Table 16.3.2.1  Classification of mitral regurgitation Mild Severe Specific signs of severity Vena contracta <0.3 cm 0.7 cm Jet size <4 cm2 or <20% left atrium 40% left atrium Small and central Large and central or wall-​impinging and swirling PISA radius None/​minimal (<0.4 cm) Large (>1 cm) Pulmonary vein flow Systolic reversal Valve structure Flail or rupture Supportive signs of severity Pulmonary vein flow Systolic dominant Mitral inflow A-​wave dominant E-​wave dominant (>1.2 m/​s) CW trace Soft and parabolic Dense and triangular LV and LA Normal size LV if chronic MR Enlarged LV and LA if no other cause CW, continuous wave; LA, left atrium; LV, left ventricle; PISA, proximal isovelocity surface area. 16.3.2  Echocardiography 3319 Fig. 16.3.2.9  An example of the haemodynamic parameters that can be estimated with a standard transthoracic echocardiography data set. Fig. 16.3.2.10  Apical four-​chamber and two-​chamber views in end diastole and end systole with an overall ejection fraction derived from the change in volume. section 16  Cardiovascular disorders 3320 diastolic filling E (the peak early diastolic flow velocity) compared to that associated with atrial filling (A) giving an E/​A ratio greater than 1.0 are often used as an indicator of diastolic dysfunction but rely on the patient being in sinus rhythm and can be misleading in severe diastolic dysfunction where pseudo normalization may occur. The ratio of tissue Doppler measurement of peak early dia- stolic mitral annular tissue velocities (e′) in combination with peak early diastolic filling (E) providing a ratio (E/​e′) is also used as an indicator of diastolic dysfunction. A ratio greater than 15 is strongly supportive of diastolic dysfunction. The presence of an enlarged left atrium is an important discriminator as left atrial size is rarely normal in the presence of significant diastolic dysfunction. These parameters are often abnormal in older people and only support a diagnosis of diastolic heart failure in conjunction with appropriate clinical features. Pulmonary artery pressure Estimation of pulmonary artery pressure from a tricuspid regurgitant jet is possible in most echocardiographic examinations (see earlier). Causes of an elevated pulmonary artery systolic pressure (>35 mm Hg) include left heart failure, valvular disease (particularly mitral valve disease), pulmonary embolic disease, chronic obstructive air- ways disease, and pulmonary vascular disease. Left ventricular hypertrophy Left ventricular hypertrophy is detected by echocardiography and a measurement of left ventricular mass can also be derived. Transthoracic echocardiography may also detect intracardiac thrombus, particularly in patients with impaired systolic ventricular function (Fig. 16.3.2.11). Minor concentric left ventricular hypertrophy is common in patients with hypertension. In hypertrophic cardiomyopathy, 2D imaging may demonstrate asymmetrical septal hypertrophy with disproportionate thickening of the interventricular septum com- pared with the left ventricular free wall, or dramatic concentric hypertrophy with left ventricular cavity obliteration. Other char- acteristic features of hypertrophic cardiomyopathy include systolic anterior motion of the mitral valve and partial midsystolic closure of the aortic valve, which usually correlates with the presence of outflow tract obstruction. In the absence of conditions that may in- duce ventricular hypertrophy (e.g. aortic stenosis), these findings are diagnostic of hypertrophic cardiomyopathy. Colour Doppler can demonstrate turbulence in the outflow tract and continuous-​ wave Doppler may detect characteristic ‘dynamic’ gradients that increase in severity as systole progresses. Other associated echocar- diographic abnormalities in hypertrophic cardiomyopathy include mitral regurgitation and severe diastolic dysfunction. Atrial fibrillation Most patients with atrial fibrillation should undergo echocar- diography as it excludes a structural cause for atrial fibrillation (e.g. mitral stenosis) and facilitates thromboembolic risk stratifi- cation. It also allows measurement of left atrial dimensions, which can guide treatment as the success of cardioversion falls as the left atrium enlarges. Identification of left ventricular hypertrophy can guide the choice of antiarrhythmic drug therapy. Transoesophageal echocardiography can be useful to facilitate cardioversion in patients with atrial fibrillation of unknown duration by excluding intracardiac thrombus, particularly in the left atrial appendage (Fig. 16.3.2.12). Following an embolic event or stroke Echocardiography is the investigation of choice when a cardiac source of an embolus is suspected. It should be considered in all patients presenting with embolic occlusion of a peripheral artery, or thromboembolic episodes in more than one vascular territory. Echocardiography should not, however, be performed in circum- stances when the result is unlikely to influence patient manage- ment. In patients with ischaemic stroke and a low likelihood of atheromatous arterial disease, an echocardiogram can be con- sidered as, occasionally, it will detect occult abnormalities such as a cardiac thrombus or atrial myxoma (Fig. 16.3.2.13). Enhancement of the right heart with non​transpulmonary contrast such as agi- tated saline should be considered to exclude paradoxical em- bolism through a cardiac shunt, and include Valsalva manoeuvres Fig. 16.3.2.11  Apical four-​chamber view showing the left ventricle (LV), left atrium (LA), right ventricle (RV), and right atrium (RA). There is a large thrombus attached to the left ventricular apical septum. Fig. 16.3.2.12  Transoesophageal echocardiography of a patient with atrial fibrillation. There is a large thrombus filling (and extending from) the left atrial appendage (LAA). LA, left atrium; LV, left ventricle. 16.3.2  Echocardiography 3321 to augment any right to left shunt. In patients with a high clinical suspicion of a cardiac source of embolus, in whom transthoracic echocardiography is normal, transoesophageal echocardiography is recommended. Pericardial disease Echocardiography is not routinely indicated in patients with uncom- plicated pericarditis. It can, however, diagnose the presence of peri- cardial fluid and is useful when a pericardial effusion is suspected and percutaneous drainage is being considered. Echocardiographic signs of pericardial tamponade include exaggerated respiratory variation in the mitral valve Doppler, presystolic closure of the aortic valve, and (particularly) right atrial and right ventricular diastolic collapse (Fig. 16.3.2.14). Constrictive pericarditis is a dif- ficult diagnosis to make using standard echocardiographic tech- niques. Patients may complain of episodic breathlessness and fluid retention, have characteristic abnormalities of the venous pressure, and have subtle abnormalities on mitral and tricuspid valve inflow Doppler patterns. Pulmonary embolism Echocardiography can be useful in patients with pulmonary em- bolism as it can demonstrate right ventricular dilation and/​or im- paired right ventricular systolic function. Tricuspid regurgitant velocity can be used to estimate pulmonary artery systolic pressure, although it is unusual for this to be more than 70 mm Hg acutely. Exceptionally, 2D imaging may show a thrombus within the right heart or the proximal pulmonary arteries. Although echocardiog- raphy is diagnostically useful when it demonstrates features con- sistent with pulmonary embolism, it cannot exclude the diagnosis. Infective endocarditis Echocardiography cannot be used to exclude endocarditis but is valuable when endocarditis is suspected clinically while there is insufficient data to make a formal diagnosis. Under these circum- stances, a typical vegetation (Fig. 16.3.2.15) detected by an ex- perienced observer is regarded as a major criterion in the Duke diagnostic classification, and this may facilitate appropriate man- agement. Transoesophageal echocardiography should be performed when there is a suspicion of aortic root abscess, if prosthetic endo- carditis is suspected, or occasionally, in cases where there is per- sistent diagnostic doubt and the additional sensitivity and spatial resolution of transoesophageal echocardiography might be valuable. Congenital heart disease Echocardiography is the diagnostic modality of choice for patients with suspected congenital heart disease. Detailed transthoracic car- diac imaging is possible in cooperative infants and children, but occasionally sedation or a short anaesthetic may be required. Rates of cardiac catheterization have been reduced by miniaturization of transoesophageal probes that facilitate diagnosis and follow-​up of complex congenital heart disease. Fetal echocardiography is performed when surveillance obstetric ultrasound is abnormal, or in cases where previous history suggests a possible cardiac problem. Fig. 16.3.2.13  Transoesophageal echocardiography revealing a large myxoma in the left atrium (LA) and close to the mitral valve. Fig. 16.3.2.14  Apical four-​chamber view demonstrating a large pericardial effusion. There is collapse of the right ventricle, suggesting cardiac tamponade. Fig. 16.3.2.15  Apical four-​chamber view demonstrating a large vegetation involving the mitral valve. section 16  Cardiovascular disorders 3322 Transoesophageal echocardiography Transoesophageal echocardiography is now available in many centres (Fig. 16.3.2.16). The ultrasound probe is like an endoscope used for upper gastrointestinal investigation, except that there are no optical fibres. Transoesophageal echocardiography is an invasive procedure for which the patient’s written consent is (usually) re- quired. After fasting for a minimum of 4 h, a local anaesthetic spray (10% lidocaine) is applied to the upper pharynx and the patient is usually sedated, typically with a short-​acting intravenous benzodi- azepine (e.g. midazolam 2 mg). The probe is manipulated into the oesophagus where its position behind the heart produces excel- lent resolution, particularly of posterior cardiac structures. Blood pressure and oxygen saturation are monitored throughout, and both resuscitation equipment and the benzodiazepine antagonist flumazenil should be readily available. Even though transoesophageal echocardiography is commonly performed in high-​risk, haemodynamically unstable patients, the rate of serious complications (aspiration and oesophageal rupture/​ tears) is less than 1%. Absolute contraindications to transoesophageal echocardiography include oesophageal tumours, strictures, diver- ticula, and varices. Who should have a transoesophageal echocardiogram? The indications for transoesophageal echocardiography are listed in Box 16.3.2.1. The principal advantages over transthoracic imaging are improved spatial resolution and the ability to image posterior structures such as the left atrium and descending aorta. It is valuable in many emergency situations, including suspected aortic dissection, prosthetic mechanical valve failure, and possible endocarditis. Transoesophageal echocardiography may be used to image the heart in patients in whom data from transthoracic imaging is unsatisfactory due to obesity, lung dis- ease, or chest deformity. Other indications include screening for left atrial thrombus before cardioversion of atrial fibrillation, and monitoring cardiac performance during cardiac and some non-​ cardiac surgery. Valve disease Patients with mitral stenosis are at increased risk of thrombo- embolism, and transthoracic echocardiography has limited sen- sitivity for the detection of left atrial thrombus. Transoesophageal echocardiography is recommended in those patients with mitral stenosis if embolic events occur despite therapeutic anticoagulation, and may demonstrate spontaneous echocardiography contrast (smoke-​like echoes produced by the interaction of erythrocytes and plasma proteins under conditions of stasis). This is an independent predictor of left atrial thrombus and cardiac thromboembolic events. Transoesophageal echocardiography is also used to assess anatomy and exclude left atrial thrombus before balloon valvuloplasty in patients with mitral stenosis and to assess anatomy, severity, and suitability for surgical repair in patients with mitral regurgitation. In patients with mitral prostheses, reverberation artefact overlying the left atrium limits the ability of transthoracic imaging to detect paraprosthetic regurgitation. Transoesophageal imaging provides excellent visualization of the left atrium and is particularly recom- mended under these circumstances. Endocarditis Characteristic vegetations or evidence of abscess formation iden- tified by echocardiography are increasingly used as diagnostic criteria in patients with possible endocarditis. The excellent spa- tial resolution (<1  mm) of transoesophageal echocardiography Fig. 16.3.2.16  Transoesophageal echocardiography. Box 16.3.2.1  Principal indications for transoesophageal echocardiography Valve disease • Mitral stenosis—​to assess suitability for percutaneous balloon commisurotomy and exclude left atrial thrombus • Mitral regurgitation—​to assess anatomy, severity, and suitability for surgical repair • Prosthetic valves—​particularly to assess prosthetic mitral regurgitation Infective endocarditis • Possible aortic root abscess • Failure to respond to antibiotics, or recurrent fever in a patient with endocarditis • High clinical suspicion of endocarditis with no diagnostic abnormality on transthoracic imaging • Possible prosthetic valve endocarditis Aortic disease • Possible acute aortic dissection • Follow-​up of patients with known aortic pathology • Imaging aortic atheroma before surgery or patients with possible chol- esterol embolization Potential cardiac source of embolism • Before elective cardioversion of atrial fibrillation • Patients with valvular heart disease and a definite embolic episode despite anticoagulation • Patients with a definite embolic episode and a ‘normal heart’ on transthoracic imaging Incomplete or impractical transthoracic imaging • Chest deformity or pulmonary disease • Patients undergoing mechanical ventilation • Congenital heart disease • Perioperative imaging of cardiac function and surgical procedures 16.3.2  Echocardiography 3323 makes it superior to transthoracic imaging for the detection of vegetations and its sensitivity may exceed 90% (Fig. 16.3.2.17). Transoesophageal echocardiography should be considered when there is a high clinical suspicion of endocarditis but blood cultures are sterile and transthoracic imaging is not diagnostic, or under cir- cumstances when the sensitivity of transthoracic imaging is particu- larly poor, for example, prosthetic valves or calcific valvular disease. Transoesophageal echocardiography is also recommended if there is a possibility of aortic root abscess formation, as this complication is not easily identified using transthoracic imaging and surgery may be required. Aortic disease Transthoracic imaging of the aorta is limited to the proximal aortic root and the arch in most patients. Using transoesophageal imaging, most of the ascending and the entire descending thor- acic aorta can be visualized and image quality is improved. This is particularly useful in patients with suspected acute aortic dis- section and, in many cases, it is the only imaging necessary be- fore emergency surgery (see Chapter 16.14.1, Figs. 16.14.1.8 and 16.14.1.9). Large, mobile, or pedunculated aortic atheromas in the descending aorta which can be associated with ischaemic stroke may be detected by transoesophageal echocardiography (Fig. 16.3.2.18). Transoesophageal imaging of the aorta has also been recommended in suspected cases of cholesterol embolization and to assess thromboembolic risk prior to cardiac intervention or surgery. Thromboembolism In patients with thromboembolism, there has been extensive debate over the value of imaging with transoesophageal echocardiography. Clinical examination, electrocardiography, and transthoracic echo- cardiography provide sufficient information to determine optimal management in the majority. However, transoesophageal echocar- diography is indicated when embolic events occur in anticoagulated patients with native or prosthetic valvular heart disease, especially if endocarditis is suspected, or when transthoracic images are in- conclusive. In patients with unexplained or cryptogenic ischaemic stroke, wider use of transoesophageal echocardiography has been advocated. Transthoracic echocardiography and exclusion of al- ternative pathologies such as thrombophilia and carotid stenosis should precede the transoesophageal examination, but under these circumstances minor cardiac structural abnormalities are more likely to be clinically relevant. Transoesophageal echocardiography is superior to the transthoracic approach for imaging the interatrial septum for atrial septal aneurysm (a redundant bulge in the fossa ovale, with respiratory movement >10 mm) and assessing patency of the for- amen ovale (Fig. 16.3.2.19). However, the clinical relevance of such atrial septal abnormalities can be questionable as the relationship to the thromboembolic event is commonly speculative. Currently, anticoagulation is the usual management following an otherwise unexplained, single, embolic event, but occasionally percutaneous or surgical correction of the defect is recommended. Fig. 16.3.2.17  Transoesophageal echocardiography demonstrating a large vegetation attached to the mitral valve. LA, left atrium; LV, left ventricle. Fig. 16.3.2.18  Transoesophageal echocardiography of the descending aorta (AO). There is a prominent, eccentric, and mobile atherosclerotic plaque. Fig. 16.3.2.19  Transoesophageal echocardiography of the interatrial septum. The flap of the patent foramen ovale can be seen where the septum primum is overlapped by the septum secundum. There is colour-​flow through it (arrowed) from the left atrium (LA) to the right atrium (RA). section 16  Cardiovascular disorders 3324 Stress echocardiography Diagnosis of reversible ischaemic myocardial dysfunction is now possible using echocardiography. Imaging can be performed ei- ther during or immediately after exercise, but more commonly an intravenous infusion of dobutamine is used to mimic the cardiac re- sponse to exercise. Development of reversible systolic regional wall motion abnormalities suggests coronary artery disease. Stress echo- cardiography also has an increasing role in risk stratification before general surgical procedures and in assessing myocardial viability before revascularization. The use of transpulmonary contrast agents to opacify the left ventricle and enhance endocardial definition greatly reduces the number of inconclusive scans, allowing more ac- curate assessment of left ventricular function and some measure of myocardial perfusion (Fig. 16.3.2.20). Intracardiac echocardiography Miniaturization of echocardiography probes has led to the devel- opment of echocardiography from within the heart. Small, flex- ible catheters with ultrasound transducers (Fig. 16.3.2.21) can be manoeuvred within the heart to provide very high-​resolution im- ages of intracardiac structures. This has been particularly useful during percutaneous closure of atrial septal defects and during radiofrequency ablation procedures (Fig. 16.3.2.22). Three-​dimensional echocardiography Real-​time, 3D image acquisitions with both transthoracic and trans­ oesophageal echocardiography are now available on most high-​end echocardiography machines. Some systems acquire a series of gated images to reconstruct the entire heart during a cardiac cycle. This image can then be manoeuvred and slices cut away to visualize the area of interest (Fig. 16.3.2.23). Regional wall tracking can also allow a 3D model of left ventricular function to be acquired and provides Fig. 16.3.2.20  A sequence of apical two-​chamber images during a stress echo. At peak stress a wall motion abnormality in the inferior apex is evident, which persists into the recovery phase. Fig. 16.3.2.21  Comparison of an intracardiac echocardiography probe with a standard transoesophageal echocardiography probe with a close-​up view of the tip of the probes. The intracardiac probes are for single use only; the transoesophageal probes are sterilized after each procedure. Fig. 16.3.2.22  Intracardiac echocardiography from the right atrium (RA). An atrial septal defect is being closed using a percutaneous approach. The disc in the left atrium (LA) has been deployed and is about to be pulled tight to the interatrial septum. Fig. 16.3.2.23  3D transoesophageal echocardiography of the mitral valve. The images show prolapse of the central portion of the posterior leaflet with three ruptured chordae. The whole of the mitral valve is in view and oriented to mimic the view of the cardiac surgeon at the time of mitral valve repair. 16.3.2  Echocardiography 3325 an accurate assessment of left ventricular function (Fig. 16.3.2.24) as well as identifying areas of left ventricular dys-​synchrony. Transthoracic 3D acquisition is limited by frame rate and image quality in the same way as 2D echocardiography. Transoesophageal 3D echocardiography usually produces clear 3D images, particularly of the mitral valve and is excellent for examination of prosthetic mi- tral valves (Fig 16.3.2.25). It is particularly helpful in displaying and communicating pathology, as views familiar to cardiac surgeons can be recreated and displayed. Echocardiography in the emergency setting Echocardiography equipment increases in sophistication but also continues to miniaturize, and now several small portable ultrasound devices are available (Fig. 16.3.2.26). These are increasingly avail- able in emergency and intensive care departments. A hand-​held ‘screening ultrasound’ can be performed in a matter of seconds to exclude pericardial effusion, recognize left ventricular dysfunction Fig. 16.3.2.24  3D transthoracic echocardiography of the left ventricle. The whole of the left ventricle is captured over four cardiac cycles and stitched together to create a single volume of data. Corrections for foreshortening can be made, the volume traced over time, and a 3D ‘model’ of the left ventricle created with each segment shaded a different colour. Fig. 16.3.2.25  3D transthoracic echocardiography of a mechanical prosthetic mitral valve. The sutures placed by the surgeon are visible as a row of dots around the sewing ring. Fig. 16.3.2.26  Hand-​carried ultrasound allows rapid assessment of cardiac function and can exclude a pericardial effusion. Andrew R.J. Mitchell 16.3.3 Cardiac investigations Andrew R.J. Mitchell 16.3.3 Cardiac investigations: Nuclear, MRI, and CT 3326 Nikant Sabharwal, Andrew Kelion, Theodoros Karamitos, and Stefan Neubauer section 16  Cardiovascular disorders 3326 or pulmonary embolism, and to diagnose most valvular abnormal- ities. This is proving extremely useful in the management of critic- ally ill patients. Transducers compatible with smartphones further increase the availability of immediate ultrasound assessment; a rechargeable and fully wireless platform linked to a smartphone app by Bluetooth or Wi-​Fi has recently been released. It is important to recognize that these devices cannot perform a full echocardiogram and a more detailed study is needed if the screening scan is abnormal or inconclusive. In critically ill patients with sepsis or severe metabolic derangement, left ventricular func- tion is often abnormal; however, this does not always imply that left ventricular dysfunction is the cause of the presentation. Repeat examination following treatment of the underlying illness often re- veals that this finding is transient and is not always an indication of primary cardiac disease. The advent of portable ultrasound has prompted the development of several types of emergency ultrasound including: • FAST scan—​focused assessment with sonography for trauma • FEEL scan—​focused echocardiography in emergency life support • FICE scan—​focused intensive care echocardiography • FATE scan—​focused transthoracic echocardiography Each of these require specific training, mentoring, and accredit- ation to become proficient. Full training in transthoracic echocar- diography typically requires 2 years and over 500 scans performed and reported. Limitations of echocardiography Despite the rapid and substantial advances in ultrasound tech- nology and the widespread use of echocardiography, it is important to recognize and understand the limitations of the technique. These include reliance on acoustic windows (clear images are impossible in some patients), evaluation at rest (most echo studies are per- formed with the patient resting, so dynamic lesions such as out- flow tract gradients of mitral regurgitation can be underestimated), subjective assessments (precise quantification of cardiac function and valve disease can be challenging and often a more subjective opinion is required, which depends critically on the operator’s ex- perience and training), evaluation of complex structures such as the right ventricle remains a major challenge (3D techniques are showing promise but are not in mainstream use), and the fact that the scope of an ‘echo’ is broad (to measure every parameter possible would take more than 60 min). Like any other test, echocardi- ography is most powerful when the pretest probability has been considered and a specific question asked; for example, ‘Is there im- portant aortic stenosis to explain symptoms and signs?’ FURTHER READING Cheitlin MD, et  al. (2003). ACC/​AHA/​ASE guideline update for the clinical application of echocardiography:  summary article. Circulation, 108, 1146. Douglas PS, et al. (2011). ACCF/​ASE/​AHA/​ASNC/​HFSA/​HRS/​SCAI/​ SCCM/​SCCT/​SCMR 2011 appropriate use criteria for echocardiog- raphy. J Am Soc Echo, 24, 229. Feigenbaum H (2004). Feigenbaum’s echocardiography. Lea & Febiger, Philadelphia, PA. Flachskampf FA, et  al. (2001). Recommendations for performing transesophageal echocardiography. Euro J Echocardiol, 2, 8. King A, et  al. (2016). Global longitudinal strain:  a useful everyday measurement? Echo Research and Practice, 3, 85–​93. Leeson P, Augustine D, Mitchell ARJ, Becher H (2012). Echocardiography, 2nd edition. Oxford University Press, Oxford. Rimington H, Chambers J (2016). Echocardiography: a practical guide for reporting and interpretation, 3rd edition. CRC Press, Florida, US. Zoghbi WA, et al. (2003). Recommendations for evaluation of the severity of native valvular regurgitation with two-​dimensional and Doppler echocardiography. J Am Soc Echo, 16, 777. 16.3.3  Cardiac investigations: Nuclear, MRI, and CT Nikant Sabharwal, Andrew Kelion, Theodoros Karamitos, and Stefan Neubauer ESSENTIALS Myocardial perfusion scintigraphy Myocardial perfusion scintigraphy provides physiological informa- tion about the coronary circulation, in contrast to the anatomical information provided by angiography. Three radionuclide-​labelled perfusion tracers are routinely used in single photon emission computed tomography (SPECT) imaging: thallium-​201 and the technetium-​99m-​labelled complexes sestamibi and tetrofosmin. Imaging is performed following tracer injection during stress (exercise or pharmacological) and at rest; comparison allows determination of whether regional perfusion is normal, or if there is inducible hypoperfusion or infarction/​scar. Myocardial perfusion imaging is minimally invasive, and—​in con- trast to other methods of investigation—​can be performed regardless of overall exercise capacity, abnormalities of the resting electrocar- diogram (ECG), pacemakers, obesity, claustrophobia, renal dysfunc- tion, iodine allergy, or acoustic windows. In the investigation of a patient with possible coronary artery dis- ease, a normal SPECT study is very reassuring, predicting a very low chance of cardiac death or non​fatal myocardial infarction over the following few years (<1% per year). High-​risk markers on SPECT pro- vide additional prognostic value to clinical, exercise test, and even angiographic variables, and decisions about revascularization can be usefully informed by SPECT imaging. ECG-​gated SPECT allows images to be taken throughout the cardiac cycle, when comparison of end-​systolic and end-​diastolic images then allows volumetric analysis and calculation of left ven- tricular ejection fraction. Positron emission tomography (PET) Using PET, myocardial perfusion imaging can be performed with nitrogen-​13 ammonia or rubidium-​82, and metabolic imaging with 16.3.3  Cardiac investigations 3327 fluorine-​18 fluorodeoxyglucose (FDG). Cardiac PET is expensive, but image quality is superior to SPECT and absolute flow quantification is possible. PET is gaining a significant foothold in the developed world, largely driven by the roll-​out of scanners for oncological imaging and the availability of generator-​supplied rubidium-​82 as a perfu- sion tracer. Imaging using oxygen-​15-​water is considered the gold standard for absolute quantification of myocardial perfusion (though static perfusion images cannot be obtained), and metabolic imaging with FDG occupies the same position in the assessment of myocar- dial viability. Cardiac MRI MRI uses the magnetic properties of the hydrogen nucleus, radio waves, and powerful magnets, to provide high-​quality still and cine images of the cardiovascular system with and without the use of exogenous contrast (gadolinium). Cardiovascular MRI is the gold standard method for the three-​dimensional analysis of cardiothor- acic anatomy, the assessment of global and regional myocardial function, and viability imaging (late gadolinium enhancement tech- nique). Using first-​pass perfusion imaging under vasodilator stress, cardiovascular MRI has high diagnostic accuracy for the identifica- tion of myocardial ischaemia. Oedema imaging using T2-​weighted techniques is useful for the identification of acute coronary syn- dromes and myocardial inflammation. Coronary MRI is feasible, and particularly indicated for anomalous coronaries. Its spatial and temporal resolution is inferior to CT or conventional angiography, and the identification and grading of stenoses remains challenging. Molecular imaging may in future allow visualization of unstable plaque. Parametric mapping techniques such as T1 and T2 map- ping offer a quantitative measure of tissue characteristics further improving the ability to detect oedema and diffuse fibrosis. Abnormal signal can be distinguished either without contrast (native T1 or T2), or post-​contrast (extracellular volume measurement). Cardiovascular MRI also provides important prognostic data for many cardiovas- cular diseases and is now an essential component of an advanced cardiovascular imaging service, and it is anticipated that its role will continue to grow. Cardiac CT Multidetector computed tomography is a fast and non​invasive method for the visualization of the coronary arteries. In comparison to CT imaging of other organs, it requires a scanner with at least 64 detectors and ECG gating. CT can be used to assess the overall burden of coronary atheroma in terms of calcification, and angio- graphic images can be obtained following power injection of iodin- ated X-​ray contrast. The spatial and temporal resolution of cardiac CT remains in- ferior to invasive angiography. Its positive predictive value is limited by artefacts, particularly in relation to calcified plaques, though in experienced hands this may be less of a problem than the litera- ture suggests. However, the great strength of the technique lies in its extremely high negative predictive value, which exceeds 99% in most studies. Hence cardiac CT is an excellent test to rule out cor- onary stenoses in patients with low to intermediate likelihood of dis- ease. With further technical developments it is likely that coronary CT will replace invasive coronary angiography for many diagnostic purposes. Nuclear imaging Introduction to myocardial perfusion scintigraphy Myocardial perfusion scintigraphy (MPS) can provide information on (1) viable vs. infarcted myocardium on the resting scan; (2) in- ducible hypoperfusion on the stress scan (in comparison with rest); and (3) regional and global left ventricular function, both at rest and post-​stress. The procedure is versatile and minimally invasive, and is not limited by overall exercise capacity, abnormalities of the resting ECG, pacemakers, obesity, claustrophobia, renal dysfunction, iodine allergy, or acoustic windows. Indeed, it is very difficult to identify any patient who is not suitable for nuclear perfusion imaging, and as a result the technique has matured into a first-​line procedure for the assessment of coronary artery disease in many countries. Over 5  million nuclear cardiology procedures were undertaken in the United States of America in 2001. Basic principles of MPS An intravenous injection of a radiopharmaceutical tracer is admin- istered, which enters intact myocardial cells and is retained within them to allow time for subsequent imaging. Usually, the comparison of stress and rest images determines whether regional myocardial perfusion is uniform, or if there are in- ducible or reversible perfusion defects (corresponding to inducible ischaemia) or fixed perfusion defects (corresponding to infarction; Fig. 16.3.3.1). There are currently three radiopharmaceutical perfusion tracers used in single photon emission computed tomography (SPECT) imaging:  thallium-​201, and two technetium-​99m-​labelled agents, sestamibi and tetrofosmin. All are monovalent cations, roughly the same size as a hydrated potassium ion. Following injection, they are delivered to the myocardium in proportion to blood supply and enter the cells down the electrochemical gradient. Thallous-​201 chloride has been in use since the mid-​1970s. It is produced in a commercial cyclotron, and has a half-​life of 73 h. It emits photons of varying energies (predominantly 68–​80 keV). Following myocardial uptake, thallium-​201 gradually re-​equilibrates with the extracellular space (redistribution). Therefore, following injection of 80 MBq during stress (exercise or pharmacological), imaging must be performed immediately (within 10 min). A redis- tribution scan 3–​4 h later reflects resting viability/​perfusion without the need for a second injection. Nevertheless, a second injection of thallium (40 MBq) may be administered at rest to optimize the as- sessment of myocardial viability. Sestamibi and tetrofosmin are organic complexes with technetium-​99m. Technetium-​99m is widely available in nuclear medicine departments from a generator and is used to label a freeze-​dried product in a vial. Technetium-​99m emits γ-​rays at 140 keV and has a half-​life of 6 h. Sestamibi and tetrofosmin bind to intracellular components, and hence their distribution at the time of imaging (typically 30–​60 min after injection) reflects myocardial perfusion at the time of injection. Separate injections are required for stress and rest imaging, either on separate days (typically 400 MBq on each day) or on the same day (with a larger second dose—​ 750 MBq after 250 MBq—​to swamp residual activity). Sublingual section 16  Cardiovascular disorders 3328 glyceryl trinitrate can be given before the resting injection of sestamibi or tetrofosmin to maximize the detection of myocardial viability. Photons emitted from the patient are imaged by a gamma camera, the head of which is essentially a large crystal of sodium iodide. Absorption of a γ-photon produces a burst of photons within the visible range (scintillation), which is detected by underlying photo- multiplier tubes. The gamma camera rotates around the patient over a 180° arc from right anterior oblique to left posterior oblique. A planar image is acquired at each of a series of 32–​64 steps, and these can be gated to the patient’s ECG to provide functional in- formation on the processed scan. Acquisition usually takes 15–​20 min. The planar projections are reconstructed and reoriented to give sets of vertical long-​axis, horizontal long-​axis, and short-​axis slices. Stress and rest slices are viewed side by side to facilitate comparison. A new design of cardiac gamma camera is now available, which uses cadmium zinc telluride (CZT) in columns of solid-​state de- tectors, rather than the traditional single sodium iodide crystal. These cameras have far higher sensitivity and spatial resolution, offering the potential for substantially reduced acquisition times (2–​5 min) and/​or tracer dose reductions. Principles of stress testing for MPS The wide variety of stress modalities available to nuclear cardiology is one of its major advantages. Exercise (or physiological) stress can be achieved with a treadmill or bicycle following a specified protocol, such as the Bruce protocol. This is the preferred method, mimicking ‘real world’ stress and providing valuable physiological data. The in- crease in myocardial oxygen demand provokes secondary coronary arteriolar dilatation. The radiopharmaceutical is injected at peak stress, and the patient maintains exercise for a further 1–​2 min while it is being taken up by the myocardium. Patients unable to exercise can undergo pharmacological stress. Vasodilators such as dipyridamole, adenosine, or regadenoson can be injected or infused intravenously to induce maximal coronary ar- teriolar dilatation, provoking flow heterogeneity between coronary vascular beds. Dipyridamole and adenosine are contraindicated in patients with significant airways disease and those with unpaced second-​or third-​degree atrioventricular block because of their non-​ selective actions on adenosine receptors. However, regadenoson is a selective adenosine A2A receptor agonist which can safely be used in mild-​moderate reversible airways disease. Vasodilator drugs can also be utilized to augment dynamic stress in patients unable to ex- ercise to target heart rate. In patients who are unable to exercise and in whom there is a contraindication to a vasodilator drug, ino- tropic stress with escalating doses of dobutamine (± atropine) can be employed. Some practical considerations for MPS The overall radiation exposure of a patient undergoing a stress-​rest technetium study is 6–​10 mSv, which is comparable to that of a diag- nostic coronary angiogram, but without the invasive and vascular complications. Much lower doses have been recorded with modern CZT cameras. Cost-​effectiveness studies have been performed with SPECT in both Europe and the United States of America. In general, diag- nostic strategies that utilize MPS are more cost-​effective than those that do not. This has helped to drive a significant increase in the number of SPECT procedures performed worldwide. Clinical value of MPS in the investigation of known or suspected coronary artery disease In a large meta-​analysis of 33 studies the sensitivity and specificity of myocardial perfusion imaging were 87% and 73%, respectively. The Fig. 16.3.3.1  Myocardial perfusion imaging—​an example of inducible hypoperfusion in the anterior wall and apex. Panels from left to right show representative vertical long axis (VLA), horizontal long axis (HLA), and mid short-​axis (SAX) slices, with stress above rest. The white arrows show a perfusion defect on the stress slices which resolves at rest. 16.3.3  Cardiac investigations 3329 normalcy rate, which removes the referral bias of false-​positive pa- tients being referred on for coronary angiography, was 91%. Similar results are available for vasodilator and dobutamine stress. More importantly, a wealth of prognostic data is available. The value of a normal SPECT study is beyond doubt, with a meta-​analysis including just under 21 000 patients followed up for 2.3 years demonstrating a risk of cardiac death or non​fatal myocardial infarction of 0.7% per year. Follow-​up studies extending up to 7 years have demonstrated similar low event rates. High-​risk markers on SPECT have incremental prognostic value over electrocardiographic and clinical variables. They include multivessel disease patterns, a large burden of ischaemia (>10% of myocardium), transient ischaemic left ventricular dilatation, left ventricular ejection fraction (LVEF) less than 0.4 (see ‘Assessment of left ventricular volume and function’), and lung uptake (only with thallium-​201). SPECT is also able to add prognostic data when risk scores such as the Duke treadmill score are applied to exercise ECG variables (Fig. 16.3.3.2), and can stratify risk in specific populations such as patients after myocardial infarction or with diabetes mellitus, women, and patients with an abnormal ECG (e.g. left bundle branch block). More recent data have emphasized the value of MPS even in pa- tients with proven coronary artery disease. In a large retrospective study from Cedars-​Sinai Hospital (Los Angeles, California), patients managed conservatively had higher event rates than those managed with revascularization if they had inducible hypoperfusion that was more extensive than 10% of the left ven- tricular myocardium (see Fig. 16.3.3.3). The COURAGE trial failed to show any prognostic benefit of percutaneous coronary intervention (PCI) plus optimal medical therapy (OMT) over OMT alone. However, a nuclear substudy suggested that PCI was better at reducing inducible hypoperfusion than OMT alone, and that event rates were lower for patients with greater decreases in inducible hypoperfusion. Further research is ongoing to identify if MPS could be used to identify a subgroup of patients in whom, despite OMT, the prognosis could be improved by PCI. Nuclear techniques are well suited to the identification of myo- cardial viability, which predicts functional recovery (identified by echocardiography) in approximately 80% of dysfunctional seg- ments after revascularization. Comparative studies with low-​dose dobutamine echocardiography (see Chapter 16.3.2), positron emis- sion tomography (PET), and cardiovascular magnetic resonance (CMR) have been performed. Each test is broadly similar in its ability to predict functional recovery. SPECT has also been used to assess success of revascularization procedures. In the acute setting, resting SPECT may be performed in patients attending the emergency department with chest pain and a non-​ diagnostic initial ECG. A normal perfusion scan is associated with a low risk of future events, lower likelihood of requiring cardiac cath- eterization, and lower costs owing to the shorter hospital stay and fewer subsequent investigations. Non​perfusion uses of SPECT techniques Myocardial perfusion imaging for the investigation of suspected or known coronary disease is by far the most commonly performed nuclear cardiology investigation. However, scintigraphic imaging using other radiopharmaceuticals is increasingly performed to answer specific physiological questions in several other cardiac diseases. It has been recognized for almost 40 years that some patients with cardiac amyloidosis exhibit myocardial uptake of phosphate bone tracers. More recently, it has become apparent that this phenom- enon tends to be limited to those with transthyretin-​type (ATTR) cardiac amyloidosis, as opposed to those with the light-​chain-​type (AL). Cardiac planar and SPECT imaging using bone tracers such as technetium-​99m-​3,3-​diphosphono-​1,2-​propanodicarboxylic acid (DPD—​Europe) or technetium-​99m-​pyrophosphate (PYP—​USA) can therefore be used to confirm a diagnosis of ATTR-​amyloid with very high positive predictive value, thereby obviating the need for cardiac biopsy. Iodine-​131-​meta-​iodobenzylguanidine (mIBG) is a false-​ transmitter analogue of norepinephrine and can be used to image the state of cardiac sympathetic innervation, which can become abnormal in patients with heart failure. Reduced cardiac uptake and increased washout of mIBG is associated with increased mor- tality, heart failure progression, and re-​admission, independent of 0 1 2 3 4 5 6 7 8 9 low intermediate high risk normal mild-abnormal mild abnormal Result of exercise ECG (Duke treadmill score) SPECT result hard events/year (%) Fig. 16.3.3.2  Incremental value of myocardial perfusion imaging over exercise ECG: hard event rates per year as a function of exercise SPECT in patients initially stratified by low, intermediate, and high Duke treadmill scores. Fig. 16.3.3.3  Annualized cardiac death rate according to ischaemic burden and treatment strategy. Increasing ischaemia appears to be better treated with revascularization in this retrospective study. From Hachamovitch, R. et al. (2003). Comparison of the short-​term survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation, 107, 2900–​7. section 16  Cardiovascular disorders 3330 left ventricular (LV) ejection fraction and brain natriuretic peptide (BNP) level. There is interest in using mIBG scintigraphy to stratify the risk of sudden arrhythmic death to help gauge the likely benefit of an implantable cardioverter-​defibrillator (ICD). The increasing use of implantable cardiac devices (pacemakers, ICDs, prosthetic valves) has led to a rise in the number of pa- tients presenting with suspected device-​related infection. Echo imaging, even transoesophageally, is not always diagnostic, and scintigraphic imaging using the patient’s own labelled white cells may have a role. This technique is less sensitive but more specific than fluorine-​18-​fluorodeoxyglucose (FDG), and can be particu- larly useful within three months of valve replacement when false-​ positive FDG scans are common due to non​infective post-​surgical inflammation. Assessment of left ventricular volumes and function using nuclear techniques Nuclear cardiology techniques have been used for the non​invasive assessment of left ventricular function since the early 1970s. Three radionuclide techniques are available for assessing left ventricular function:  first-​pass radionuclide ventriculography, equilibrium radionuclide ventriculography, and gated myocardial perfusion SPECT. The first is rarely performed nowadays and will not be con- sidered further. Equilibrium radionuclide ventriculography This investigation, also affectionately (but inaccurately) known as multigated acquisition (MUGA), is performed following label- ling of red blood cells with technetium-​99m-​pertechnetate. This is usually performed in vivo following a preceding injection of stan- nous pyrophosphate. For a simple assessment of LVEF, gated planar imaging of the blood pool is performed in a LAO 45° projection to optimize separation of the left and right ventricular cavities. This method is independent of left ventricular geometry, and hence very accurate and reproducible. The wide availability of echo (with its lack of radiation exposure) has led to a substantial decrease in the number of equilibrium radionuclide ventriculography studies performed. However, the radionuclide method can still be valuable when a quick and repro- ducible assessment of LVEF is required, for example in the moni- toring of patients undergoing chemotherapy with anthracyclines or trastuzumab. ECG-​gated myocardial perfusion SPECT SPECT acquisition during MPS can be gated at no extra incon- venience, cost, or risk to the patient. Tomographic slices are re- constructed for each of 8 or 16 frames and can be played as a cine for visual assessment. Left ventricular volumes and LVEF can be derived following endomyocardial border definition. Gated SPECT (Fig. 16.3.3.4) can be very useful in identifying at- tenuation artefacts (which appear as fixed perfusion defects but demonstrate normal wall motion). Indices of left ventricular func- tion (ejection fraction and end-​systolic volume) provide inde- pendent prognostic information and are powerful predictors of cardiac death. Importantly, changes in regional and global func- tion from post-​stress to rest imaging can help unmask multivessel ischaemia which has been underestimated by the visible regional perfusion defects. Positron emission tomography PET scanners employ coincidence detection of 511-​keV photons travelling 180° apart following annihilation of a positron with an electron. Cardiac PET studies are no longer confined to research centres, mainly due to the rapid increase in availability of combined PET/​CT scanners driven by developments in oncological practice. Myocardial perfusion can be assessed with nitrogen-​13-​ammonia (requiring an on-​site cyclotron) or rubidium-​82 (from a generator), but is best done with oxygen-​15-​water (though this tracer requires a cyclotron and does not permit myocardial imaging). Myocardial viability in terms of metabolic integrity is assessed with fluorine-​18-​ fluorodeoxyglucose (FDG), which has become widely commercially available with the growth of oncological PET. FDG-​PET is increas- ingly used to image intracardiac infection and inflammation as it is avidly taken up by metabolically active white cells. For this in- dication, careful patient preparation is essential to suppress myo- cardial FDG uptake using a carbohydrate-​restricted diet followed by fasting. FDG-​PET has a high sensitivity for identifying cardiac device-​related infection, though white cell scintigraphy is more reli- able within three months of valve surgery. Its role in cardiac sarcoid- osis is also well-​established, especially for disease monitoring. Sodium fluoride-​18 (NaF) PET is an interesting research tool for imaging microcalcification in coronary atheromatous plaques, which may identify those most likely to become unstable causing an acute coronary syndrome. Fig. 16.3.3.4  Gated SPECT to assess left ventricular systolic function at rest in a patient with an extensive anteroapical and septal infarct and poor left ventricular systolic function. Left column: end-​diastolic frame showing (from top to bottom) apical, mid, and basal short-​axis slices, horizontal, and vertical long-​axis slices. Right column: end-​systolic frame showing corresponding slices. Right column: calculated volumes and ejection fraction (middle panel), with time-​volume curve (bottom panel). 16.3.3  Cardiac investigations 3331 Comparison of nuclear techniques with other imaging modalities For physiological assessment of known or suspected coronary artery disease, the alternatives to SPECT and PET are exercise electrocar- diography, stress (exercise or dobutamine) echocardiography, and stress CMR (with vasodilator stress for perfusion or dobutamine for wall motion). The exercise ECG is inferior, mainly due to its depend- ence on exercise ability and the poor sensitivity and specificity of ECG changes. Stress echocardiography is a good alternative technique, with a slightly lower sensitivity but higher specificity in comparative studies. It is physician-​intensive and operator-​dependent, but har- monic imaging and microbubble contrast agents have greatly im- proved image quality. An important advantage over the radionuclide techniques is the avoidance of ionizing radiation, which makes it particularly attractive for younger patients. Cardiac MRI can assess regional and global left ventricular sys- tolic function during a dobutamine infusion, similar to stress echo- cardiography. Alternatively, gadolinium can be used as a first-​pass myocardial perfusion tracer during vasodilator stress, with late-​ enhancement used to identify infarction. A large multicentre com- parative study has suggested that CMR is an equivalent alternative to SPECT. In practice, the different modalities should be regarded as largely interchangeable, with local clinical expertise being more important than any marginal differences in technical performance between them. Functional imaging, however performed, is recommended in the latest National Institute for Health and Care Excellence (NICE) guidelines for the assessment of patients with chest pain of recent onset. Cardiac MRI Introduction Cardiovascular MRI (CMR) has undergone significant advancement in terms of imaging capabilities, ease of use, and speed of acquisition over the past 20 years. A study of cardiovascular anatomy, left and right ventricular function, and viability/​fibrosis (late gadolinium en- hancement) with a modern CMR scanner can be performed in less than 30 min by an experienced operator. These improvements have led to the widespread adoption of CMR in clinical practice. How CMR works MRI is typically based on the magnetic properties of the hydrogen nucleus, though other nuclei can also be used. Hydrogen nuclei (protons), which are abundant in the human body, behave like small spinning magnets that have an alignment (magnetic moment) par- allel to the direction of the external magnetic field and a rotation (precession) frequency proportional to the strength of the field. Radio waves in the form of a radiofrequency pulse transmitted into the patient cause the alignment of the protons to change, that is, the magnetic moments in that region are flipped out at an angle (flip angle) to the magnetic field (excitation). When this radiofrequency pulse is turned off, the protons in the patient’s body return to their neutral position (relaxation), emitting their own weak radio-​wave signals, which are detected by receiver coils and used to produce an image. The contrast between tissues (e.g. heart muscle and fat) depends on the tissue density of hydrogen atoms (proton density), and on two distinct MR relaxation processes that affect the net mag- netization: the longitudinal relaxation time (T1), and transverse re- laxation time (T2). The differences in these parameters in distinct tissues are used to generate contrast in MR images. Image contrast can also be modified by modulating the way the radiofrequency pulses are played out (the MR sequence): for example, in so-​called T1-​weighted images, myocardial tissue is dark whereas fat is bright. On the other hand, T2-​weighted images highlight unbound water in the myocardium and are used to demonstrate myocardial oedema due to inflammation or acute ischaemia. CMR requires advanced technology, including a high-​field super- conducting magnet which produces a homogeneous and stable magnetic field (1.5 or 3.0 Tesla), gradient coils within the bore of the magnet which generate the gradient fields, a radiofrequency amplifier to excite the spins with radiofrequency pulses, and a radiofrequency antenna (coil), which receives the radio signals coming from the patient. A computer and specific software are also needed to control the scanner and generate (reconstruct) the im- ages. To prevent artefacts from cardiac motion, most CMR images are generated with ultrafast sequences gated to the R wave of the ECG. Respiratory motion, which is another factor that can pro- duce artefacts, is eliminated by acquiring most CMR images in end-​ expiratory breath-​hold. When acquisition is long and cannot be completed within one breath-​hold, special free-​breathing sequences that track the diaphragm’s position (navigators) are used. CMR safety MRI scan subjects and operators are not exposed to ionizing radi- ation and there are no proven detrimental biological side effects of MRI, if safety guidelines are followed. Ferromagnetic objects can be attracted by the scanner, becoming projectiles that could lead to significant patient or operator injury and also damage the scanner. The presence of certain medical implants and devices (e.g. most pacemakers and defibrillators, cochlear implants, cerebrovascular clips) is a contraindication for routine MR scanning, but nearly all prosthetic cardiac valves, coronary and vascular stents, and ortho- paedic implants are safe in a 3-​T (or less) MR environment. MRI conditional pacemakers and defibrillators (generator and leads) are now available. Whenever there is uncertainty regarding a particular device or implant, the CMR operator should consult a more detailed source of information, such as reference manuals, dedicated web- sites (e.g. http://​www.mrisafety.com), or the manufacturer’s product information. Claustrophobia may be a problem for a few patients, and mild sedation usually helps to overcome this. Gadolinium contrast agents are safe for most patients (safer than iodine-​based contrast), but gadolinium-​containing contrast agents have been linked with the development of a rare systemic disorder called nephrogenic systemic fibrosis. The patients at risk for developing this disease are those with acute kidney injury or chronic kidney disease (glomerular filtration rate <30 ml/​min/​1.73 m2), or acute renal dysfunction of any severity due to the hepatorenal syndrome, or in the perioperative liver trans- plantation period. To date, there is no evidence that other patient groups are at risk. The risk of nephrogenic systemic fibrosis also de- pends on the nature of the gadolinium-​containing agent employed, and most MR centres now use gadolinium agents that are tightly section 16  Cardiovascular disorders 3332 bound to a cyclic chelate, for which the incidence of nephrogenic systemic fibrosis is near zero. However, it seems prudent to avoid use of gadolinium-​based contrast media in high-​risk patients unless the diagnostic information is essential and not available with non-​ contrast-​enhanced CMR or other imaging modalities. Whether im- mediate post-​imaging haemodialysis protects against nephrogenic systemic fibrosis is not known. Applications of CMR Normal and pathological anatomy Historically, the first widespread application of CMR was the three-​ dimensional analysis of cardiovascular anatomy. By providing ex- cellent soft tissue contrast, cardiovascular anatomy can be assessed in virtually any imaging plane (coronal, transverse, sagittal), or indi- vidualized double-​angulated planes. The latter is particularly valu- able in complex congenital heart disease. Myocardial function and mass CMR is the accepted gold standard for quantification of left and right ventricular function. Using steady-​state free precession tech- niques that provide excellent delineation of the blood-​myocardium interface, long-​axis, and short-​axis cine views (Fig. 16.3.3.5) can be obtained during all phases of the cardiac cycle (cine-​CMR). Planimetry of each short-​axis slice and summation of slice vol- umes allow precise determination of systolic and diastolic left and right ventricular volumes, stroke volumes, and ejection fraction with high reproducibility. Ventricular mass can also be determined by multiplication of the myocardial volume by its specific weight of 1.05 g/​cm3. The excellent interstudy reproducibility of volume and mass measurements by CMR has allowed reductions of sample sizes of 80–​97% to achieve the same statistical power for demonstrating a given change in left ventricular volumes, ejection fraction, or cardiac mass. Analysis of regional myocardial function is feasible both at rest and during pharmacological stress, typically using dobutamine. Dobutamine stress CMR has high sensitivity and specificity for detecting ischaemic heart disease and is particularly useful in pa- tients with difficult acoustic windows. Blood flow Phase contrast mapping of velocities through planes transecting blood flow in the main pulmonary artery and the ascending aorta can provide accurate measurements of cardiac output, shunt flow, aortic or pulmonary regurgitation and, indirectly, of mitral and tricuspid regurgitation. For stenotic jets, the peak velocity can be measured on through-​plane velocity-​encoded images. Peak pres- sure gradients can be estimated according to the modified Bernoulli equation. Valve morphology can be assessed with the use of steady-​ state free precession (SSFP) cine images and valve area can be as- sessed with accuracy by direct planimetry using cross-​sectional cine images, although valve structure is generally better assessed by echocardiography. Bicuspid aortic valves or fused valve leaflets can be readily identified. CMR is an excellent technique for the quan- titative assessment of regurgitation. If a single valve is affected, the regurgitant volume can be measured from the difference in left and right ventricular stroke volumes. If both the mitral and tricuspid valves are affected, the regurgitant volumes can be calculated by sub- tracting the flow in main pulmonary artery and the ascending aorta, measured by CMR velocity mapping, from the left and right stroke volumes (measured by the volumetric method), respectively. This technique compares favourably with measurements from catheter- ization and Doppler echocardiography techniques. For pulmonary and aortic regurgitation, direct measurement of regurgitant volume is also possible using CMR velocity mapping. These CMR tech- niques have high interstudy reproducibility and can be used for the longitudinal follow-​up of patients with valve disease over time. Apart from the evaluation of patients with valve pathologies, flow imaging by CMR is regularly used in assessing patients with congenital heart disease. By measuring flow in the ascending aorta and main pulmonary artery with velocity-​encoding CMR, the pulmonary-​to-​systemic flow ratio (Qp/​Qs) can be determined. These CMR measurements show excellent correlation with calculations obtained from oximetry during haemodynamic catheterization. Fig. 16.3.3.5  End-​diastolic still images from multiple contiguous short-​axis SSFP cines that encompass the left ventricle, from base to apex. Note the position of the short-​axis (SA) slices marked on the still frames of end-​diastolic horizontal long axis (HLA) cine image and the excellent delineation of the myocardium from the blood and the surrounding tissue. 16.3.3  Cardiac investigations 3333 Myocardial viability The assessment of myocardial viability using gadolinium-​based contrast agents (late gadolinium enhancement (LGE) technique) has revolutionized the use of CMR in cardiology. Gadolinium che- lates are extracellular tracers that cannot cross cell membranes. In normal myocardium the myocytes are densely packed, and the extracellular space and vascular volume represents less than 15% of the myocardial volume; hence after injection of gadolinium there are only few gadolinium molecules in a myocardial sample volume. By contrast, when the membranes of myocytes rupture, gadolinium molecules can penetrate into the myocytes and stay there, even late after gadolinium injection, such that in scar tissue the interstitial space is expanded and increased gadolinium concentration is found (Fig. 16.3.3.6). In practice, on inversion-​recovery T1-​weighted sequences obtained 5–​10 min after gadolinium administration, non​viable myocardium (scarred or irreversibly injured) shows high signal intensity, whereas normal and viable (stunned, hibernating) myocardium shows low signal intensity. Myocardial infarction (acute or chronic) has a characteristic LGE pattern due to the wavefront of myocardial necrosis that always involves the subendocardium at the core of the infarct (Fig. 16.3.3.7). The LGE technique has undergone extensive histo- pathological validation. The superb spatial resolution of LGE-​CMR allows the detection of even small subendocardial infarcts that might otherwise be missed by lower spatial resolution techniques such as SPECT. Several studies have demonstrated an inverse re- lationship between the transmural extent of myocardial infarction and segmental functional recovery after revascularization. In prac- tice, segments which show more than 50% scarring are considered non​viable, whereas segments with only subendocardial enhance- ment (<50%) have a high likelihood of functional recovery. CMR can also assess myocardial viability using a low-​dose dobutamine protocol in a way analogous to echocardiography, but in practice, this is rarely required. Several CMR techniques, including LGE, can also identify areas of microvascular obstruction (no-​reflow phenomenon) after revascularization in patients with acute myo- cardial infarction. LGE-​CMR in non​ischaemic cardiomyopathies Specific patterns of regional fibrosis and scarring have also been described for many non​ischaemic cardiomyopathic processes (Fig. 16.3.3.8). For example, the majority of patients with hypertrophic cardiomyopathy show patchy fibrosis in the hypertrophied septum involving left/​right ventricular junctions, whereas about a third of patients with dilated cardiomyopathy show a midwall band of septal fibrosis. Furthermore, most patients with myocarditis have subepicardial LGE in the lateral left ventricular wall. Several other patterns of LGE exist for other rarer cardiomyopathies such as cardiac amyloidosis or sarcoidosis. The LGE technique is a major part of nearly every scanning protocol and provides valuable diag- nostic and pathophysiological insights in both ischaemic and non​ischaemic cardiomyopathies. normal myocytes acute cell injury myocardial scar Gadolinium collagen matrix Fig. 16.3.3.6  Mechanism for late gadolinium enhancement (LGE) in acute and chronic myocardial damage. (a) Densely packed myocytes with intact cell membrane—​gadolinium chelates only in the vessels and extracellular space. (b) Acute myocardial damage with ruptured cell membranes of myocytes—​intracellular accumulation of gadolinium chelates. (c) Chronic myocardial damage with loss of myocytes and replacement by scar tissue—​mostly collagen fibres that are filled with gadolinium chelates. Fig. 16.3.3.7  Short-​axis LGE image at the midventricular level in a patient with near transmural anteroseptal myocardial infarction (white arrows). Fig. 16.3.3.8  Short-​axis LGE image at the midventricular level in a patient with hypertrophic cardiomyopathy. Note the patchy LGE due to fibrosis in the hypertrophied septum (white arrows), including both left-​ right ventricular junctions. section 16  Cardiovascular disorders 3334 Myocardial perfusion Regional myocardial perfusion can be measured during the first pass of a gadolinium-​based contrast agent. Using sequential multislice fast gradient-​echo CMR, passage of the contrast agent through the heart chambers and the myocardial tissue can be followed. From a series of such images, regional time–​signal intensity curves can be derived. Pharmacological vasodilatation (with adenosine, dipyrid- amole, or regadenoson) induces a three-​to fivefold increase of blood flow in myocardial areas subtended by normal coronary arteries, whereas no (or only minimal) change is found in areas subtended by stenotic coronary arteries. Contrast arrival in these areas is delayed, hence they appear hypointense (dark) compared to adjacent normal myocardium (Fig. 16.3.3.9). Many clinical trials have assessed the feasibility, safety, and diag- nostic accuracy of stress perfusion CMR. A meta-​analysis showed that first-​pass perfusion CMR under vasodilator stress has excel- lent sensitivity (89%) and very good specificity (76%) to diagnose coronary artery disease, with quantitative coronary angiography (≥50% diameter stenosis) as the gold standard. The CE-​MARC study compared the diagnostic accuracy of stress perfusion CMR with SPECT and showed that both techniques have similar speci- ficity, but CMR is more sensitive to detect ischaemia compared to scintigraphy. It should be noted that CMR perfusion techniques have higher spatial resolution than nuclear techniques (by at least an order of magnitude) and can be used to study the transmural aspect of myocardial perfusion. Non​invasive magnetic resonance perfusion imaging can guide patient management with stable cor- onary disease as safely as the currently used invasive coronary angi- ography supported by fractional flow reserve in a population at high risk for cardiovascular events. Myocardial oedema Various technical improvements have enabled the wide clinical use of T2-​weighted CMR for the qualitative or semi-​quantitative detec- tion of myocardial oedema and inflammation, primarily in acute coronary syndromes and myocarditis. Despite these improvements, a few well-​recognized limitations of conventional T2-​weighted tech- niques remain, including the need for a ‘normal’ reference region of interest in either remote myocardium or skeletal muscle. This can lead to false-​negative results when these reference areas are also af- fected in systemic processes. Quantitative parametric T1 and T2 mapping techniques have been developed to overcome these limi- tations. Myocardial haemorrhage in patients with acute myocardial infarction can also be assessed using T2-​weighted or T2*-​ CMR. Coronary arteries CMR of the coronary arteries remains a technical challenge because of their small size (up to 4 mm) and continuous, complex movement. Fast, flow-​sensitive gradient-​echo sequences allow imaging of prox- imal coronary arteries using breath-​hold or navigator techniques, with a maximum in-​plane resolution of about 700 µm2. However, the sensitivity for coronary stenosis is only 60–​90% because of the inferior spatial resolution compared to CT or invasive coronary angiography. Further developments (parallel acquisition, gradient performance, intravascular contrast agents, higher-​field magnets) might in the future allow the development of high-​resolution MR coronary angiography with CT-​like quality. At present, MR cor- onary angiography can be used for diagnosis of anomalous coronary arteries or coronary aneurysms. Iron overload The most common cause of iron overload cardiomyopathy is re- peated blood transfusions in patients with transfusion-​dependent anaemias (e.g. β-​thalassaemia major) and in primary hemochroma- tosis. The cardiomyopathy is reversible if chelation is commenced early, but diagnosis is often delayed because of the late onset of symptoms and patients often die from heart failure. T2* MRI allows the accurate quantification of cardiac and liver iron levels. This al- lows identification of patients who are at risk of developing heart failure (i.e. those with myocardial T2* <10 ms), allowing more ag- gressive iron chelation therapy to be administered. T1 and T2 parametric mapping T1 and T2 mapping refers to parametric maps that are generated from a series of images acquired with different T1 or T2 weighting so that each pixel can be assigned a T1 or T2 value. These maps are usually displayed using colour or thresholded scales to enable quantitative visual interpretation. Each tissue type exhibits a char- acteristic range of normal T1 and T2 relaxation times at a particular field strength, deviation from which may be indicative of disease. Myocardial T1-​mapping methods are used for native (i.e. without the use of gadolinium-​based contrast agents) and also for post-​ contrast T1 measurements. In combination with haematocrit, these T1 measurements enable the quantification of extracellular volume fraction (ECV). Elevated native T1 times and ECV in the myocardium have been reported in several commonly encountered cardiac conditions including myocardial infarction, myocarditis, hypertrophic and Fig. 16.3.3.9  Example of a stress perfusion scan. Short-​axis stress perfusion at the midventricular level showing an extensive perfusion defect (black arrows) in the anterior wall, septum, and the inferior wall. The lateral wall (white arrow) has relatively normal perfusion. 16.3.3  Cardiac investigations 3335 dilated cardiomyopathy, cardiac amyloidosis (Fig. 16.3.3.10), car- diac involvement in systemic diseases, and diffuse fibrosis in patients with aortic stenosis. Native myocardial T1 values may be lowered by water–​protein interactions, fat or iron content, and thus can also serve as a diagnostic tool in characterizing Anderson–​Fabry disease, fat in cardiac masses, and myocardial siderosis. Native T1 mapping is particularly useful in the differential diagnosis of patients with acute chest pain including acute coronary syndromes, myocarditis, and takotsubo cardiomyopathy. T2 mapping can detect oedematous myocardial territories in a variety of cardiac pathologies, including acute myocardial infarc- tion, myocarditis, takotsubo cardiomyopathy, and heart transplant rejection. Patients with poor renal function (or on dialysis), where gadolinium-​based contrast agents are relatively contraindicated, may benefit from using native T1 mapping instead of LGE imaging. CMR and prognosis The evolving prognostic evidence base of CMR is rapidly expanding for both ischaemic and non​ischaemic cardiomyopathies. The com- pletion of ongoing multicentre trials and registries (e.g. HCMR study) is expected to provide more outcome and cost-​effectiveness data, which will further strengthen the clinical role of CMR. Cardiac CT Multidetector computed tomography can be used to produce high-​ quality anatomical images in a variety of cardiac pathologies (e.g. complex congenital heart disease). However, its most widespread use is in the non​invasive anatomical assessment of the coronary ar- teries. The entire coronary tree is imaged during a single breath-​hold over a few cardiac cycles (or even a single cycle if the scanner has sufficient detectors). A stack of transaxial slices is acquired, covering the thorax be- tween the carina and the diaphragmatic border of the heart. This is achieved over a few cardiac cycles, depending on the number of detectors. Coronary calcification is assessed from a non​contrasted scan. For angiographic imaging (to assess for luminal stenoses), an intravenous power injection of an iodinated X-​ray contrast agent is given, typically 40–​80 ml at 4–​6 ml/​s, followed by a saline flush. Following a breath-​hold, the scan is triggered once the left side of the circulation is sufficiently opacified. The timing can be judged either by using an initial test bolus, or by a bolus tracking method where a test slice is monitored until the Hounsfield value in the ascending or descending aorta exceeds a certain threshold. ECG gating is required to image the coronary arteries free of motion. Prospective gating is now the preferred method, with the Fig. 16.3.3.10  Cardiac magnetic resonance (CMR) end-​diastolic frame from cine (left panel), ShMOLLI non​contrast T1 map (middle panel), and late gadolinium enhancement (LGE) images (right panel) in normal volunteer, aortic stenosis patient, and cardiac amyloid patient. Note the markedly elevated myocardial T1 time in the cardiac amyloid patient (1170 ms, into the red range of the colour scale) compared to the normal control (955 ms) and the patient with aortic stenosis and left ventricular hypertrophy (998 ms). ED, end-​diastolic. Reprinted from the Journal of the American College of Cardiology, Vol 6, Issue 4, Karamitsos TD, et al., Noncontrast T1 mapping for the diagnosis of cardiac amyloidosis, pp. 488–​97, Copyright (2013) with permission from Elsevier. section 16  Cardiovascular disorders 3336 patient being imaged (and irradiated) for only a brief period of the cardiac cycle, typically at 75% of the R-​R interval. This usually repre- sents end-​diastole, when the coronary arteries (particularly the right coronary) are at their stillest. Retrospective gating offers imaging throughout the cardiac cycle, which can be valuable when heart-​rate control is poor or information about cardiac function is required. However, radiation exposure is relatively high, and the prospective method is routinely preferred. High-​quality angiographic images also depend on the patient having a relatively slow heart rate (<65 and preferably <60 bpm), which is achieved by giving a β-​blocker, either orally or intraven- ously. Many centres also give sublingual glyceryl trinitrate prior to the study to achieve coronary vasodilatation. Once the scan has been acquired and reconstructed, it must be carefully examined. The thin transaxial slices must be reviewed, and several tools are available to help reorientate the images to display the coronary arteries and other cardiac structures. Some of the technical limitations of cardiac CT are shown in Box 16.3.3.1. Clinical uses of cardiac CT CT coronary calcium scoring The ability of CT to detect and quantify calcified structures is un- rivalled by other imaging techniques. Pathological studies indicate that coronary calcification is an integral part of the atherosclerotic process, and unique to it (with the possible exception of patients with renal failure). Specifically, the square root of the extent of calci- fication is directly proportional to the square root of the overall ex- tent of atheromatous plaque. On a non​contrast-​enhanced CT scan, the Agatston score is used to quantify the total amount of coronary calcium, and assesses the area and density of plaques in all arteries. The coronary calcium score is a good measure of the overall coronary atheroma burden and predicts the likelihood of luminal coronary stenoses, as well as the risk of cardiac events over at least 10 years of follow-​up. In particular, a score of zero predicts an ex- tremely low risk. Stand-​alone coronary calcium scoring may be valuable in the risk stratification of asymptomatic patients or those with atypical chest pain. However, its value in patients with possible angina is less Box 16.3.3.1  Limitations of coronary CT • Radiation exposure, which is highly dependent on the scanner being used and the mode of gating: calcium scoring alone delivers approxi- mately 1 mSv. Angiography with retrospective gating on a 64-​slice scanner could deliver as much as 15 mSv, while prospective gating may routinely deliver less than 1 mSv. • Iodinated X-​ray contrast required. This can problematic for patients with renal dysfunction or hypersensitivity. • β-​blockade required to achieve low heart rate (preferably <60 bpm) to minimize motion artefacts in angiography. • Calcium and stents can cause blooming and beam-​hardening arte- facts, obscuring the lumen. Fig. 16.3.3.11  CT coronary angiography of the left anterior descending coronary artery. Note how the heavy calcification makes it difficult to exclude or confirm significant luminal stenosis at several locations. Image courtesy of Dr N. Sabharwal, Oxford Heart Centre. 16.3.3  Cardiac investigations 3337 straightforward: a few patients with no coronary calcification will nevertheless have a significant coronary stenosis due to soft plaque. Moreover, the location of calcification is a poor guide to the exact location of luminal stenoses, which are typically caused by non-​ calcified soft plaques. Therefore, in patients with possible angina, most authorities would regard coronary calcium scoring as comple- mentary to angiography rather than an alternative. CT coronary angiography Multidetector CT is unique among the non​invasive imaging modalities in providing anatomical (rather than physiological) information about the coronary arteries. Invasive coronary angi- ography remains the gold standard as CT does not yet approach its spatial or temporal resolution. However, CT is extremely reliable for the exclusion of coronary stenoses, with a negative predictive value that approaches 99% in the literature. Positive predictive values are less robust, largely due to artefacts, particu- larly in relation to calcified plaques (Fig. 16.3.3.11). These ob- servations make CT coronary angiography (CTCA) particularly suitable for the diagnostic investigation of patients with low to intermediate probability of obstructive coronary disease (Fig. 16.3.3.12). As well as its role in patients with stable chest pain, cardiac CT is increasingly used in low-​risk patients admitted with acute chest pain, where it is cost-​effective compared with alternative strategies. CT can also be useful in certain groups of patients with estab- lished coronary disease. It offers a very straightforward way of as- sessing graft patency after coronary artery bypass surgery and can also be valuable in the exclusion of stent obstruction (though arte- fact can make this difficult for smaller stents). Two large randomized studies (SCOT-​HEART and PROMISE) have compared CTCA with more traditional functional assessment in the investigation of patients with suspected coronary disease. In the short-​term, the two investigational approaches are equivalent in terms of patient events and symptom outcomes. However, CTCA leads to higher rates of coronary angiography and revascularization, with higher usage of preventative medication such as aspirin and statins. Whether the resultant increase in expense will be justified by better long-​term outcomes remains to be seen. Other uses of cardiac CT Although CT coronary angiography is essentially an anatomical imaging technique, it can be used to provide physiological informa- tion in patients with coronary disease. Using sophisticated compu- tational fluid dynamics, a virtual fractional flow reserve (FFR) can be calculated throughout the coronary tree, analogous to the FFR that can be obtained with a pressure wire during invasive coronary angiography. This can be particularly valuable in the assessment of moderate coronary stenosis, although further large-​scale clinical val- idation is necessary to fully establish this technique. An alternative Fig. 16.3.3.12  CT coronary angiography showing a critical soft plaque stenosis in the left anterior descending coronary artery also involving the first diagonal. No coronary calcification is present. Image courtesy of Dr N. Sabharwal, Oxford Heart Centre. section 16  Cardiovascular disorders 3338 approach is to perform first-​pass CT myocardial perfusion imaging during vasodilator stress. However, this requires a second injection of iodinated contrast and image acquisition following the initial CT coronary angiogram, and is not widely performed in clinical practice. For routine CT coronary angiography, prospective gating is now- adays preferred over retrospective gating because of the signifi- cant reduction in radiation exposure. However, when retrospective gating is performed for technical or clinical reasons, it is possible to reconstruct sets of slices throughout the cardiac cycle (typically 10). This makes it possible to quantify left ventricular function (or even right ventricular function if an appropriate contrast infusion protocol is used) using automated software. Cardiac CT offers an excellent anatomical assessment of the heart from a single standardized image acquisition. It can therefore be of great value in complex congenital heart disease, particularly when the exact anatomy is unclear or echocardiography and cardiac MRI have proven inconclusive. Contrast injection and imaging protocols can be modified according to the information required. Cardiovascular CT has become an essential ‘one stop shop’ in the investigation of patients with severe aortic stenosis who are being con- sidered for transcatheter aortic valve implantation. From a single injec- tion of contrast it is possible to assess the dimensions and shape of the aortic annulus, the optimal imaging angle for valve deployment in the catheterization laboratory, the heights of the coronary ostia above the an- nulus, the presence of important coronary disease, the state of the aorta throughout its length, the suitability of the iliac and femoral arteries for a transfemoral approach, and the presence of comorbidity (e.g. unex- pected malignancy) that might influence decision-​making. Acknowledgements The authors of the CMR section acknowledge support from the National Institute for Health Research Oxford Biomedical Research Centre Programme. Professor Stefan Neubauer also acknowledges support from the Oxford British Heart Foundation Centre of Research Excellence. FURTHER READING Nuclear imaging Anagnostopoulos D, et  al. (2012). Myocardial perfusion scintig- raphy:  technical innovations and evolving clinical applications. Heart, 98, 353–​9. Berman DS, et al. (2006). Roles of nuclear cardiology, cardiac com- puted tomography, and cardiac magnetic resonance:  noninvasive risk stratification and a conceptual framework for the selection of noninvasive imaging tests in patients with known or suspected coronary artery disease. J Nuclear Med, 47, 1107–​18. Cardiac Radionuclide Imaging Writing Group (2009). 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Cardiac failure 3390 16.5.1 Epidemiology and gener Cardiac failure 3390 16.5.1 Epidemiology and general pathophysiological classification of heart failure 3390 Theresa A. McDonagh and Kaushik Guha 16.5 Cardiac failure CONTENTS 16.5.1 Epidemiology and general pathophysiological classification of heart failure  3390 Theresa A. McDonagh and Kaushik Guha 16.5.2 Acute cardiac failure: Definitions, investigation, and management  3397 Andrew L. Clark and John G.F. Cleland 16.5.3 Chronic heart failure: Definitions, investigation, and management  3407 John G.F. Cleland and Andrew L. Clark 16.5.4 Cardiorenal syndrome  3421 Darren Green and Philip A. Kalra 16.5.5 Cardiac transplantation and mechanical circulatory support  3428 Jayan Parameshwar and Steven Tsui 16.5.1  Epidemiology and general pathophysiological classification of heart failure Theresa A. McDonagh and Kaushik Guha ESSENTIALS Definition and classification Heart failure is a clinical syndrome caused by cardiac dysfunction, most commonly left ventricular systolic dysfunction. Patients with heart failure symptoms or signs and normal or near normal left ven- tricular function are often classified as having heart failure with pre- served ejection fraction (HF-​PEF), but there is no clear and generally accepted definition of this condition. Epidemiology Estimates of incidence and prevalence are heavily influenced by definition. An echocardiographic study of a random sample of the general population estimated a prevalence of heart failure of 1.5%, with a further 1.4% having asymptomatic left ventricular systolic dys- function. Prevalence rises significantly with age, with a median age of first presentation in the mid-​seventies. Longitudinal data suggests that the incidence of heart failure has remained fairly stable over the last few decades, but prevalence is increasing as more people survive cardiovascular disease earlier in life. Aetiology Determining the aetiology of heart failure in epidemiological studies is difficult: the commonest cause in the developed world is coronary artery disease, followed by hypertension, which predominates in those with a diagnosis of HF-​PEF. Prognosis and morbidity Data from the United States of America and the United Kingdom show that those admitted to hospital with a diagnosis of heart failure have a mortality of over 30% at one year. The outcome has improved in recent years, perhaps linked to the increased usage of angiotensin inhibitors and β-​blockers. Heart failure accounts for around 5% of all adult general medical admissions, and in de- veloped countries the condition consumes 1–​2% of healthcare budgets. Introduction Over the last 30 years we have gone from famine to feast for heart failure epidemiological data. The first seminal publication on the natural history of heart failure was from the Framingham Heart Study in 1971, showing a prevalence of heart failure of 0.8% in those aged between 50 and 59, rising to 9.1% in those over 80 years, with incidence rates of 0.2% at age 54 and 0.4% at age 85 (Fig. 16.5.1.1). This was followed by a large European study, ‘The Men Born in 1913’, which gave similar figures of a prevalence of 2.1% at age 50 and 13% at age 67 and incidence rates of 0.15% and 1%, respectively, at ages 50 and 67. These landmark studies relied on a clinical diagnosis of heart failure, based on symptoms, signs and scoring systems to identify cases. More modern epidemiological studies have used ­definitions of heart failure which include objective measures of ­cardiac function, and in keeping with the ever-​changing definitions of heart failure we have developed more insight into its pathophysi- ology and treatment. Initially studies focused on systolic dysfunction as they reported at much the same time as the heart failure treat- ment trials which also enrolled patients with systolic heart failure. 16.5.1  Epidemiology and classification of heart failure 3391 More recently attention has turned to describing the epidemiology of heart failure with preserved systolic function. This chapter out- lines the contemporary epidemiology of heart failure by describing its prevalence, incidence, aetiology, mortality, and trends. Pathophysiological description of heart failure Most clinical practice guidelines produced by the major inter- national cardiology and heart failure societies have very similar definitions of heart failure. All agree that it is not a diagnosis, per se, but a clinical syndrome: a constellation of symptoms and signs that are ultimately due to cardiac dysfunction. That car- diac dysfunction can be epicardial, myocardial, or endocardial in origin. Most commonly heart failure is attributable to myo- cardial dysfunction. Of particular importance, due to its main causes being coronary artery disease and hypertension, is the occurrence of left ventricular systolic dysfunction (LVSD). This has added significance because the main heart failure treatment trials, which sealed the place of the neurohormonal antagon- ists in the therapeutics of heart failure, were conducted in those with left ventricular ejection fractions (LVEF) of less than 40%. 35 30 25 20 15 10 5 45–54 n = 1 n = 2 n = 3 n = 5 n = 6 n = 9 n = 13 Average annual incidence/1000 people Females Males n = 17 n = 28 n = 31 55–64 65–74 Age (years) 75–84 85–94 0 Fig. 16.5.1.1  Incidence of heart failure within the Framingham cohort. From McKee PA, Castelli WP, McNamara PM, Kannel WB (1971). The natural history of congestive heart failure: the Framingham study. N Engl J Med, 285, 1441–​6. Copyright © 1971, Massachusetts Medical Society. Table 16.5.1.1  Prevalence of symptomatic and asymptomatic LVSD in populations with a calculated prevalence of manifest heart failure, where applicable Authors Name of study Number of patients (no. of cases of heart failure) Location Age range Percentage of symptomatic left ventricular systolic dysfunction (LVSD) Percentage of asymptomatic left ventricular systolic dysfunction (ASLVD) Prevalence of heart failure <65 yrs of age Prevalence of heart failure 65 yrs of age Parameshwar et al., 1992 Prevalence of heart failure in 3 GP practices 30 204 (117) Northwest London, UK 5–​99 28% had echoes 0.6 per 1000 27.7 per 1000 Murphy et al., 2004 National survey of heart failure 307 741 (2186) Scotland, UK 0–​>85 —​ 7.1 per 1000 (though not <65) 85–​90.1 per 1000 Rutten et al., 2003 A questionnaire-​ based survey of heart failure (202) Utrecht, Netherlands 40–​95 53% had echoes 97%-​LVSD McDonagh et al., 1997 MONICA 1640 (43) North Glasgow, UK 25–​74 2.9% LVSD 1.4% ALVSD 15 per 1000 Davies et al., 2001 ECHOES 3960 (72) West Midlands, UK 1.8% LVSD 3.5% Preserved EF 0.9% ALVSD 31 per 1000 (>45 yrs of age) Kupari et al., 1997 Helsinki Ageing Study 501 (41) Helsinki, Finland 75–​86 4.1 % HEFPEF 3.9 % LVSD 9% ASLVD (75–​86) –​82 per 1000 Mosterd et al., 1999 Rotterdam Heart Study 2267 (88) Rotterdam, Netherlands 55–​94 3.7% LSVD 1.4% ASLVD Men 7 per 1000 (55–​64) Women 6 per 1000 (55–​64) Men 37 per 1000 (65–​74) 144 per 1000 (75–​84) 59 per 1000 (85–​94) Women 16 per 1000 (65–​74) 121 per 1000 (75–​84) 140 per 1000 (85–​94) Morgan et al., 1999 Poole Heart Study 817 (61) Poole, Dorset, UK 70–​84 7.5 % LVSD 3.9 % ASLVD section 16  Cardiovascular disorders 3392 Many epidemiology studies therefore focused on character- izing the incidence and prevalence of LVSD, using varying cut points of the normally distributed variable, LVEF, ranging from less than 30% to 50%. This difference in the cut points chosen affects the incidence and prevalence rates which are quoted (see Tables 16.5.1.1 and 16.5.1.2). Often studies have classified those with heart failure symptoms and signs with a normal or only mildly reduced left ventricular function to have heart failure with preserved ejec- tion fraction (HF-​PEF). In the absence of any convincingly posi- tive drugs trials for this end of the spectrum of heart failure, no unifying definition of HF-​PEF has emerged and been applied to community-​based studies. The latest definitions of HF-​PEF, in addition to symptoms and or signs of heart failure and a relatively preserved ejection fraction, also require evidence of structural heart disease (usually left ventricular hypertrophy, increased left atrial size/​volume and Doppler or tissue Doppler evidence of dia- stolic dysfunction). Rigorous population-​based studies with these more modern definitions have yet to appear. Prevalence studies Community-​based studies Many studies have been conducted in primary care or across geo- graphical healthcare communities. One of the first was in northwest London where 30 204 case records were reviewed, yielding a crude prevalence of 3.8/​100 cases in the general population with a marked rise from those under 65 to those above 65 years of age, where the rate rose from 0.6 per 1000 to 28.0 per 1000. More recent data is available from the Scottish Continuous Morbidity scheme, which covers 57 general practices in Scotland and uses GP Read codes for heart failure in 307 741 patients. This results in a calculated prevalence of heart failure within the general population in Scotland of 7.1 per 1000, increasing to 90.1 per 1000 in the population above 85 years old. The population identified in the primary care setting were more elderly and had more comorbidities than in population-​based studies or clinical trial populations. These findings have been corroborated in a European study based in Utrecht, Netherlands, where patients with heart failure who were under the supervision of a cardiologist were more likely to be male, in their sixties, and have an ischaemic aetiology. When considering such data, it should be remembered that the signs and symptoms of heart failure are neither sensitive nor specific. Studies evaluating referrals from primary care, when compared to expert cardiology assessment, have revealed only approximately 30% of such patients actually have heart failure. Population-​based studies using echocardiography Systolic dysfunction The North Glasgow MONICA study was the first to report on the prevalence of left ventricular dysfunction in a random sample of the general population of 2000 men and women aged 25–​74 years. In Table 16.5.1.2  Studies demonstrating incident rates of heart failure within different populations Study Name of study Number of patients Location Age range Mean/​ Median age of diagnosis Incidence of heart failure <65 yrs of age Incidence of heart failure 65 yrs of age McKee et al., 1971 Framingham Framingham, US 45–​94 2 per 1000 (45–​54 years) 40 per 1000 (85–​94 years) Erikkson et al., 1989 The men born in 1913 973 Gothenburg, Sweden 67 10 per 1000 Cowie et al., 1999 Hillingdon Heart Study 151 000 Hillingdon, northwest London, UK 29–​95 76 years 0.02 per 1000 (25–​34 years) 0.2 per 1000 (35–​44 years) 0.2 per 1000 (45–​54 years) 1.2 per 1000 (55–​64 years) 3 per 1000 (65–​74 years) 7.4 per 1000 (75–​84 years) 11.6 per 1000 (85–​94 years) Murphy et al., 2004 GP database, Continuous morbidity recording scheme 307 741 (2186 cases) Scotland, UK 45–​85 —​ 1.3 per 1000 (45–​64 years) 6.1 per 1000 (65–​74) 16 per 1000 (75–​84 years) De Giuli et al., 2005 GP research database 696 884 (6478 cases) United Kingdom 45–​101 77 years 3.4 per 1000 (55–​64 years) 25.5 per 1000 (75–​84 years) Kalogeropoulos et al., 2009 ABC study 2934 (258) Pittsburgh, and Memphis, Tennessee US 70–​79 73.6 years 13.6 per 1000 Bibbins-​ Domingo et al. CARDIA study 5115 (27) Birmingham, Alabama, Chicago, Illinois, Minneapolis, Oakland, California, US 18–​30 39.1 years African-​American male (cumulative incidence)—​0.9% African-​American Female (cumulative incidence)—​1.1% White male (cumulative incidence)—​0% White female (cumulative incidence)—​0.08% —​ 16.5.1  Epidemiology and classification of heart failure 3393 this cohort 2.9% had significant systolic dysfunction, and of these just over half had symptoms of breathlessness or were taking a loop diuretic. The estimated prevalence of heart failure in this population was therefore 1.5%, with 1.4% having the important precursor of heart failure, asymptomatic LVSD. The prevalence rose with age and was higher in men than in women (Fig. 16.5.1.2). Many studies have reported since, both in Europe and in the United States of America. Data from these cohorts is fairly consistent for the general population. Prevalence rates for LVSD were 1.8–​ 3.5% in the Echocardiographic Heart of England Screening Study (ECHOES) study from the English Midlands, with 50% of the left ventricular dysfunction being asymptomatic, and in the US Olmsted county study 2.2% had heart failure validated using the Framingham criteria, and of these 56% had systolic dysfunction. When we look at population-​based studies which have included much older subjects, the prevalence rates increase markedly. In the Helsinki Ageing Study of 501 subjects aged 75–​86 years, the overall prevalence of clinical heart failure was found to be 8.2%, with 2.3% having systolic dysfunction, and 9% with asymptomatic LVSD. In the Rotterdam Study of 2267 men and women aged 55–​ 95, 3.7% had fractional shortening of 25% or less (5.5% men and 2.2% women) and 2.2% had asymptomatic left ventricular dysfunc- tion (Fig. 16.5.1.3). Similar findings were reported in a UK study of 817 subjects aged 70–​84 years from Poole (southern England) which demonstrated that 7.5% had LVSD (12.2% of men and 2.9% of women) and 52% were undiagnosed. Analysis of a cohort of 585 participants within a Dutch primary care system corroborated the lack of diagnosis within elderly patients. Using panel of history, examination, brain natriuretic peptide (BNP), electrocardiograms (ECG), and echocardiography (in those with a raised BNP or ab- normal ECG), 92 further cases of heart failure were identified. Most of these had HF-​PEF, with only 17 individuals suffering from LVSD using a LVEF cut point of 45%. Heart failure with preserved systolic function Many of the population-​based studies have also—​by default or design—​been able to comment on the prevalence of HF-​PEF. Hogg et al. reviewed the epidemiological data for HF-​PEF and found that the prevalence ranged from 1.5% to 4.8% depending on the study. There was a definite increase in the proportion of heart failure due to this in cohorts which studied more elderly subjects. In the ECHOES study of the general population, 1.1% had definite heart failure and a LVEF greater than 50%, whereas in the Helsinki Ageing Study, 72% of all the heart failure identified occurred with a normal LVEF. In the United States of America, the Rochester Epidemiology Project in a random sample of 2042 subjects over 45 years of age reported similar findings, with 44% of subjects having heart failure with a LVEF greater than 50%. Even higher prevalence rates have been found in a recent large cross-​sectional study from Portugal: 16.1% in the population above 80 years old had heart failure. The prevalence was split roughly equally between preserved and reduced ejection fraction. These studies all confirm one thing, namely that heart failure is common and in- creases exponentially with age (Fig. 16.5.1.3). It is unsurprising, therefore, that heart failure affects 25 million Europeans and more than 10 million Americans. Incidence Contemporary studies of incidence are far fewer than those for prevalence. In the west London district of Hillingdon, all incident cases of heart failure were identified via either a specialist referral clinic or emergency hospital admission (Fig. 16.5.1.4). The popu- lation served was 151 000, and 220 new cases were identified. Participants had a full clinical assessment, standard investigations including a chest radiograph, electrocardiogram, and echocardi- ography; 99% of the study population had an echocardiogram. The gold standard diagnosis was made by a panel of three cardiologists. The incidence rose from 0.02/​1000 per year in the 25–​34 age group to 11.6/​1000 in those aged over 85. Most had LVSD. This study con- firmed that heart failure is predominantly a disease of older people with a median age of first presentation of 76 years. Incidence data for the United States of America are also reported from the Cardiovascular Health Study, showing a rate of 19.3/​1000 person-​years in 5.5  years of follow-​up. In the United Kingdom data are also available for incidence from general practice from the General Practice Research Database (GPRD):  696 884 potential patients aged above 45 years old were identified. The records were interrogated and categorized on the basis of clinical data and medi- cation prescription patterns. Using this approach, 6478 patients had 15 25–34 35–44 45–54 55–64 65–74 Age (years) Glasgow 10 Prevalence (%) 5 0 Fig. 16.5.1.2  Prevalence of left ventricular systolic dysfunction in the North Glasgow MONICA cohort. Reprinted from The Lancet, Vol. 350, McDonagh TA et al., Symptomatic and asymptomatic left ventricular systolic dysfunction in an urban population, pp. 829–​ 33, Copyright 1997, with permission from Elsevier. 15 10 5 0 55–64 65–74 75–84 Age (years) Rotterdam Prevalence (%) 85–94 Fig. 16.5.1.3  Prevalence of left ventricular systolic dysfunction within the Rotterdam Study. From Mosterd A, et al. (1999). Prevalence of heart failure and left ventricular dysfunction in the general population; the Rotterdam study. Eur Heart J, 20(6), 447–​55, by permission of Oxford University Press. section 16  Cardiovascular disorders 3394 definite heart failure, 14 050 possible heart failure, and 6076 were treated with diuretics but a non​heart-​failure diagnosis was assigned. The overall incidence of definite heart failure was 9.3/​1000 per year, but when possible heart failure was included the figure increased to 20.2/​1000 per year. The mean age of the definite heart failure popu- lation was 77 years. More recently data from the Scottish Continuous Morbidity Recording data set showed an overall incidence of 2/​1000 popula- tion per year; it was 25/​1000 per year in men over the age of 85 years. Trends in incidence and prevalence Data from the Framingham Heart Study have not shown any in- crease in incidence since the 1970s, dispelling the theory that we are experiencing an epidemic of heart failure. Similarly, data from Medicare records show a slight reduction in incidence from 57.5/​ 1000 to 48.4/​1000 person-​years in the 80–​84-​year age group in the period 1994–​2003. However, despite the slight reduction in inci- dence, the prevalence rate rose markedly from 90/​1000 to 120/​1000. The latest data from the Olmsted county gives similar findings: the annualized incidence rate of heart failure within the cohort declined by 4.6%, despite an ongoing raised level of mortality. These trends will continue with the changing demography of most Western popu- lations, with more elderly people and a greater number of survivors from cardiovascular disease earlier in life. Aetiology Determining the exact aetiology of patients with heart failure in epi- demiological studies is difficult. The commonest cause within the Western world is coronary artery disease. This represents a change in aetiology over time. When the Framingham study first reported, the main factor was hypertension. Over time in this study the in- fluence of coronary heart disease has increased by 40% in men and 20% in women. In the North Glasgow MONICA study over 95% of patients with symptomatic LVSD had some evidence of prior ischaemic heart disease (IHD), although hypertension was also prevalent in this group, occurring in 68%. Other data from prevalence studies show similar results. In the ECHOES study, 53% of those with systolic dysfunction had evidence of IHD and 42% had hypertension, and in the Helsinki Ageing Study it was 54% for hypertension and for IHD. In the United States of America data from the Cardiovascular Health Study confirm similar results, with the population attribut- able risk for heart failure for coronary heart disease being 13.1% and for hypertension 12.8%. Both are clearly important aetio- logical factors. In the original Hillingdon study of incident heart failure, 41% of the heart failure cohort was due to coronary artery disease and a much smaller number, 6%, had hypertension. A subsequent study carried out in Bromley (south London) looked into putative is- chaemic aetiologies in more depth. All incident cases of heart failure were identified and referred to a specialist dedicated clinic or iden- tified by tracking the patient during their hospitalization. Using the diagnostic criteria, 332 patients had been identified and 99 of the 136 cases under 75 years of age also underwent coronary angiog- raphy. An ischaemic aetiology was eventually attributed to 52% of the 136 cases. Hypertension as a cause of heart failure still seems to predominate in those HF-​PEF patients in whom ischaemic heart disease seems less prominent. These patients tend to be older and there is a higher proportion of women than men. Both diseases are still common: a recent study by Zile showed a prevalence rate of 82% for hyperten- sion and 45% for coronary heart disease in patients with HF-​PEF. 18 16 14 12 10 8 6 4 2 0 25–34 0.00 0.04 0.16 0.18 0.26 0.07 1.70 0.67 3.88 2.31 9.82 5.92 9.62 16.76 Incidence (cases per 1000 population per year) 35–44 45–54 55–64 65–74 75–84 85+ Age (years) Fig. 16.5.1.4  Incidence of heart failure by sex and age group in Hillingdon Heart Failure Study. From Cowie MR, et al. (1999). Incidence and aetiology of heart failure; a population-​based study. Eur Heart J, 20(6), 421–​8, by permission of Oxford University Press. 16.5.1  Epidemiology and classification of heart failure 3395 Comorbidities Heart failure is predominantly a disease of elderly people and is therefore associated with multiple comorbidities, which include renal impairment, anaemia, diabetes mellitus, obstructive sleep ap- noea, and chronic obstructive pulmonary disease. These all have an adverse impact on survival when associated with heart failure. Anaemia was present in 51% of patients with heart failure in the Rochester Epidemiology Project. Severely impaired renal function was present in 10%. These rates are increased in patients presenting with acute heart failure syndromes:  renal dysfunction occurred in 20% of those admitted with decompensated heart failure in the EuroHeart Failure Survey II. Prognosis Mortality The 32-​year follow-​up of the Framingham study highlighted the substantial mortality rate of heart failure: 62% for men and 42% for women at 5 years of follow-​up from incident diagnosis. However, data from the Framingham study have shown consistent improvements in survival over time for both men and women. In Europe, the mor- tality of incident heart failure also seems to be falling. In the initial Hillingdon study, 25% of patients were dead at 6 months, but in the more recent cohort of this study from 2004 to 2005 this figure had dropped to 14%. This was independent of confounding variables and linked to the increased usage of angiotensin inhibitors and β-​blockers. Although mortality is higher in studies of incident heart failure, it is also poor in prevalent cases (Fig. 16.5.1.5). In the ECHOES study, the 5-​year survival rate was 53% for those with heart failure due to systolic dysfunction. Survival for those with HF-​PEF was a little better, at 62%. This is in contrast to the Mayo Clinic data which showed that survival in the community with heart failure was similar for those with LVSD or HF-​PEF. However, more recently the Mayo Clinic group reported on 4596 patients, of whom 47% had preserved left ventricular function between 1987 and 2001. The survival rate was slightly better within the population with preserved systolic function. However, rates of mortality declined in the population with systolic dysfunction over the study period, whereas patients with normal ventricular function had no change in mortality rates throughout the study period. This was supported further by the MAGGIC group (Meta-​ Analysis Global Group in Chronic Heart Failure) who reviewed the data on 50 000 previous trial participants. Patients with LVSD had higher rates of mortality, but the absolute level of mortality within patients with HF-​PEF remained high. The mortality rates for left ventricular dysfunction in the popu- lation are also high—​21% dead at 4 years in the North Glasgow MONICA cohort—​with no significant difference between those with symptoms of heart failure and those with asymptomatic left ventricular dysfunction. This underscores the need for early detec- tion and treatment of this precursor phase of heart failure. Data from hospitalized patients in Scotland also show a trend to- wards improved survival (Fig. 16.5.1.6). Between 1986 and 2003 median survival after a first admission to hospital with heart failure improved in men from 1.3 to 2.3 years and in women from 1.3 to 1.8 years. Overall survival remains poor, with 50% of men dead at 2.3 years and 50% of women dead at 1.7 years after a first admission for heart failure. This poorer survival between those with acute heart failure syn- dromes requiring admission, compared to population-​based sur- veys of prevalence, is now well described. Data from large European and US registries show consistent findings. Initial European data from the EUROHEART II study demonstrated an in-​hospital mor- tality rate of 6.6%, but this has declined to 3.8% by the time of the ESC-​HF Pilot. American data from the OPTIMISE registry suggests an in-​hospital mortality of 4%. However, the picture is probably bleaker when we look to data sources that try to capture consecutive admissions to hospital with heart failure. One of the world’s largest single-​country audits of acute hospital admissions is the national heart failure audit from England and Wales. Inpatient case fatality rates for those admitted to hospital with a primary diagnosis of heart failure remain high, with a mortality of 9.6% (2015–​2016), and the 1-​year mortality following a solitary admis- sion is 30%. Indeed, the mortality of the heart failure syndrome remains unfavourable compared to patients with commonly en- countered solid organ malignancies, despite the recent thera- peutic and technological advances in management for ­systolic dysfunction. Morbidity and hospitalizations Part of the enormous morbidity incurred by heart failure patients relates to frequent hospitalizations. In advanced heart failure, pa- tients who have been hospitalized experience rehospitalization rates at 6  months of 36–​45%. In the 1990s studies in the Netherlands, Scotland, the United States of America, and Sweden documented increasing trends of admissions relating to heart failure. The rise in hospital admissions was accompanied with increasing expenditure. In Scotland, 0.2% of the population were hospitalized per annum and heart-​failure-​related admissions accounted for more than 5% of all adult general medical admissions. Some evidence has now emerged that heart failure admissions may have peaked in some European countries during the mid-​1990s. Data from Scotland on 116 556 100 75 50 25 0 0 2 4 6 8 10 HF, LVSD HF, no LVSD No HF, LVSD No HF, no LVSD Years since screening % Surviving Fig. 16.5.1.5  Mortality after screening in the Echocardiographic Heart of England Screening Study (ECHOES). HF, heart failure; LVSD, left ventricular systolic dysfunction. Reproduced from Hobbs FD, et al. (2007). Prognosis of all-​cause heart failure and borderline left ventricular systolic dysfunction: 5 year mortality follow-​up of the Echocardiographic Heart of England Screening Study (ECHOES). Eur Heart J, 28(9), 1128–​34. With permission from Oxford University Press. section 16  Cardiovascular disorders 3396 patients identified from hospital discharge records during the period 1986–​2003 showed that rates of admission rose and peaked in the mid-​1990s and subsequently fell by 2003. This is also the case in the Netherlands (Fig. 16.5.1.7). The latest data from the United States now concurs with the picture described in Europe. Using the national inpatient sample, covering the period between 2001 and 2009, there was a decrease in the number of primary heart failure admissions with an as- sociated rise of secondary heart failure hospitalizations, most commonly due to intercurrent illness, renal dysfunction, and pul- monary disease. Health economics The high prevalence and frequent and recurrent hospitalizations place a large economic burden on healthcare budgets. In the United States of America, total expenditure on heart failure in 2007 was more than $33 billion (£21 billion, €24 billion). The statistics are mirrored in European settings. Within the United Kingdom heart failure consumes 1–​2% of the National Health Service budget, which is approximately £1.2 billion (€1.3 billion, $1.8 million). It is the leading cause of hospitalization within the elderly population in the United Kingdom. Approximately 60% of the total expenditure on heart failure in the United Kingdom is spent on hospital admis- sions. Figures are similar in continental Europe, with heart failure consuming approximately 1% of healthcare budgets. The length of stay also contributes to the expense, with median stay in Europe of 9 days. These estimates of cost are likely to be underestimates as the true costs should include all primary care consultations, secondary care referrals, diagnostics, prescribing further ther- apies including devices and care networks, and surgical intervention including transplantation. Conclusions Despite the advances which have been made in its treatment over the course of the last 20 years, which have seen mortality rates for those in clinical trials of heart failure therapies fall to less than 10% per annum, epidemiological studies still indicate that heart failure remains a common, lethal, disabling, and expensive condition. This is hardly surprising as most of the reduction in mortality is due to advances in treatment for a subset of heart failure patients, those with chronic heart failure due to LVSD. We still have much to do. The increasing prevalence of heart failure, and the lack of 3 2.5 1.5 1 0.5 0 1986 1987 1988 Median survival (years) 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 Year 2 Men Women Fig. 16.5.1.6  Trends in median survival in Scotland from 1986 until 2003. Reprinted from Jhund PS, et al. (2009). Long term trends in first hospitalization for heart failure and subsequent survival between 1986 and 2003: A study of 5.1 million people. Circulation, 119, 515–​23. 190 170 150 Men Women 130 110 90 70 81 84 87 90 93 96 99 Year Per 100 000 per year Fig. 16.5.1.7  Heart failure hospitalization rate in the Netherlands from 1980 to 1999. Reproduced from Heart, Mosterd A and Hoes AW, vol. 93, pp. 1137–​46, copyright © 2007 with permission from BMJ Publishing Group Ltd. Chronic peripheral oedema and lymphoedema 3811 Pet Chronic peripheral oedema and lymphoedema 3811 Peter S. Mortimer ESSENTIALS Lymph transport, not venous reabsorption, is the main process re- sponsible for interstitial fluid drainage. Oedema develops when the microvascular filtration rate exceeds lymph drainage for a suffi- cient period, and any chronic oedema represents a failure of lymph drainage. In practice, any chronic oedema should be managed in the same way as lymphoedema. Causes of lymphoedema Lymph drainage may fail either because of a defect intrinsic to the lymph conducting pathways (primary lymphoedema), or because of irreversible damage from some factor(s) originating from out- side the lymphatic system (secondary lymphoedema). Primary lymphoedema is caused by genetic faults in lymphatic development (e.g. germline mutations in the vascular endothelial growth factor receptor-​3 gene which causes Milroy’s disease), but in most cases the genetic cause is unknown. Filariasis is by far the most common cause of secondary lymphoedema worldwide. Most cases in the developed world are secondary to cancer treatment, obesity, and poor mobility. Clinical features and management Lymphoedema causes persistent swelling often associated with recur- rent cellulitis. It should be managed clinically by considering reasons for impaired lymph drainage and reasons for high lymph load (e.g. high venous pressures including heart failure, hypoproteinaemia, and inflammation). The investigation of choice for confirmation of diagnosis is lymphoscintigraphy. No drug is known to improve lymph drainage. Diuretics should only be considered for high lymph loads. Current best practice aims to (1) improve lymph drainage through physiological principles known to stimulate lymph flow (i.e. exercise and movement combined with compression); and (2) control any high lymph load. Recurrent cellulitis is common, with each attack causing fur- ther decline in lymph drainage and worse swelling. Prevention and prompt treatment are crucial to the control of lymphoedema. Introduction The primary function of the lymphatic vessels is to drain the plasma filtrate within body tissues and return it to the blood circu- lation. Lymphatic vessels also have an important immune surveil- lance function, as they are the main drainage route from the tissues for immune active cells such as dendritic cells, lymphocytes, and macrophages. Intestinal lymphatics are responsible for fat absorp- tion. Impaired lymphatic function leads to disturbed fluid homeo- stasis (swelling), dampened immune responses (infection), and disturbed fat homeostasis (increased peripheral fat deposition), all features of lymphoedema. Lymphatic vessels are also the preferen- tial route for cancer spread. Oedema Oedema is an excess of interstitial fluid and is an important sign of ill health in clinical medicine. The usual clinical approach to peripheral oedema is to consider a single diagnosis such as heart failure, nephrotic syndrome, venous obstruction, or lymphoedema. This viewpoint fails to appreciate the many dynamic physiological forces contributing to oedema development and in particular the central role of the lymphatic drainage system in tissue fluid (and consequently plasma volume) homeostasis. Hence the clinician’s ap- proach to peripheral oedema is often misguided and the necessary medical intervention inappropriate (e.g. empirical use of diuretics). Management of peripheral oedema is better based on physiological principles that can then guide treatment. Pathophysiology Lymph transport, not venous reabsorption, is the main process re- sponsible for interstitial fluid drainage. Oedema develops when the microvascular (from capillaries and venules) filtration rate exceeds lymph drainage for a sufficient period, either because the filtration rate is high (high lymph load) or because lymph flow is weak, or a combination of the two. Filtration rate is governed by the Starling 16.18 Chronic peripheral oedema and lymphoedema Peter S. Mortimer section 16  Cardiovascular disorders 3812 principle of fluid exchange, which is described succinctly and quan- titatively by the Starling equation for flow across a semipermeable membrane (Fig. 16.18.1). In simple terms, filtration of fluid from capillary into interstitium is driven by the hydraulic (water) pressure gradient across the wall (Pc − Pi) and is opposed by the osmotic pressure gradient (πp − πi), which is the ‘suction’ force keeping fluid in the circulation. The Starling equation provides a logical approach for classifying oedema that is due to increased filtration (Box 16.18.1) Traditionally it has been taught that the arterial end of capillaries filters fluid while the venous end reabsorbs the bulk of fluid filtered. This view is not supported by modern evidence, which demonstrates that in most vascular beds there is a net but dwindling filtration along the entire length of well-​perfused capillaries. The sum of all Starling forces is not an absorptive force in venous capillaries but a slight fil- tration force (except following haemorrhage, for example, when ca- pillary pressure drops sufficiently for transient absorption to occur). Even under such circumstances Starling forces soon re-​equilibrate and slight filtration is restored. Sustained reabsorption of fluid is a normal feature of some microcirculatory beds, namely intestinal mucosa, renal peritubular, and lymph node capillaries, but not per- ipheral tissues. Since the old concept of sustained fluid absorption by venous capillaries is no longer tenable, the major responsibility for drainage of interstitial fluid is through the lymphatic system. Restraining factors against oedema include (1) elevation of inter- stitial fluid pressure, (2) fall in interstitial colloid osmotic pressure (COP), and (3)  increased lymph flow. Stiffness in tissues resists swelling. A small increase in interstitial fluid in a stiff tissue (low compliance) will cause a relatively large increase in interstitial pres- sure (Pi), which then opposes filtration. Placing a bandage or rigid stocking around a leg will reduce compliance by effectively increasing stiffness. Consequently, Pi will increase more steeply for a given inter- stitial volume increase and the increased Pi will oppose filtration. Relating to interstitial COP, an increase in filtration rate will dilute the interstitial protein concentration and consequently reduce the osmotic pressure (π immediately outside the semipermeable mem- brane). The resulting increase in the osmotic pressure gradient will raise the suction force keeping fluid within the blood compartment. Increases in interstitial fluid pressure and volume stimulate lymph flow. Lymph drainage is a complex process involving absorption of protein and fluid (as well as other macromolecules, microorgan- isms, immune cells, and cancer cells) from the interstitium into initial lymphatic vessels (also known as lymphatics) and then down- stream through vessels of ever-​enlarging diameter until reaching the main collecting lymphatics that pump lymph to the sentinel lymph nodes. Valves ensure unidirectional flow. Transport of interstitial fluid into and along initial lymphatics is largely a passive process L dv dt V – J J L (net capillary filtration rate) (rate of swelling) (Lymph flow) JV = S σ } ( p– i) Starling force Mechanism Starling equation (Pc – Pi) { Interstitial osmotic pressure Raised with increased permeability i.e. water follows protein-altered in inflammation Plasma osmotic pressure Reduced in hypoproteinaemia- protein losing states e.g. nephrotic syndrome, malnutrition, or a failure of hepatic protein synthesis e.g. cirrhosis Ability of capillary to ‘reflect’ or hold protein in circula- tion-altered in inflammation Osmotic reflection coefficient Interstitial pressure Raised in oedema, lowered if compliance of tissues increases e.g. lax skin Capillary pressure Raised predominantly by venous pressure- altered in heart failure, venous obstruction, fluid retention e.g. secondary hyperaldo- steronism Surface area of capillary Influenced by capillary density and length of capillaries such as in angiogenesis, and vasodilatation e.g. inflammation Hydraulic conductance Ease of passage of fluid across capillary wall- altered in inflammation π π Fig. 16.18.1  Physiology of oedema. Box 16.18.1  Starling forces in the classification of oedema 1    Raised capillary pressure Capillary pressure is more susceptible to changes in venous pressure than systemic (arterial) blood pressure because postcapillary resistance is much lower than precapillary resistance. Peripheral venous pressure is raised in: • right ventricular failure • salt and water overload (e.g. overtransfusion) • venous obstruction • venous reflux (chronic venous disease), e.g. following deep vein thrombosis, primary varicose veins • dependency (the effect of gravity) 2    Reduced plasma osmotic pressure (COP) • This essentially means hypoalbuminaemia, which can arise from: • malnutrition • intestinal disease (malabsorption or protein loss) • nephrotic syndrome • hepatic failure to synthesize albumin—​due to liver disease or chronic inflammatory states 3    Increased capillary permeability Inflammation can cause a breakdown in the endothelial barrier, facilitating the passage of both plasma proteins and water across the ca- pillary wall. In addition, vasodilatation causes a rise in capillary pressure (and blood flow). 16.18  Chronic peripheral oedema and lymphoedema 3813 dependent upon changes in tissue (interstitial) pressure from move- ment (active and passive exercise), massage, and local arterial pulsa- tion and—​in more central tissues—​breathing. The larger collecting lymphatics contract and are mainly responsible for pumping lymph against gravity. Successive segments of collecting lymphatics be- have like ‘mini hearts’ in series, and their contractile cycle bears striking similarities to the cardiac cycle. Sympathetic input influ- ences the pumping rate, while the diastolic filling (preload or supply from upstream lymphatics) controls the force of contraction. Flow in collecting lymphatics is only as good as the supply from initial (non​contractile) lymphatics. Influx of calcium ions is important for smooth muscle contraction in the walls of the collecting lymphatics, hence calcium channel antagonists may cause oedema by paralysing lymphatic pumping. The lymph vessels return the capillary filtrate back to the blood- stream via the lymph nodes and eventually the thoracic duct. This completes the extravascular circulation of fluid and protein and maintains tissue volume homeostasis. Lymph flow should respond to increases in capillary filtration and so prevent oedema. By failing to compensate for increased capillary filtration and so permit swelling, the lymphatic is to some extent failing in its duty to preventing all types of oedema. Differences in lymph drainage capacity could be the explanation for differing levels of leg oedema seen in patients with right-​sided heart failure despite no difference in ejection frac- tion. Similarly, peripheral oedema that persists after heart failure has been successfully treated is likely to be lymphatic in origin. True lymphoedema is strictly oedema arising from reduced lymph transport that is unable to cope with normal levels of capil- lary filtration. Most oedema arises from increased capillary filtra- tion (high lymph load) overwhelming lymph transport capacity for a sustained period of time. Once high lymph flow cannot be sus- tained and transport capacity fails, ‘true’ lymphoedema ensues. This pathophysiology is comparable with that occurring in high-​output cardiac failure. Aetiology Lymph drainage may fail either because of a defect intrinsic to the lymph conducting pathways (primary lymphoedema, Figs. 16.18.2a and 16.18.2b) or because of irreversible damage from some factor(s) originating from outside the lymphatic system (secondary lymphoedema, Fig. 16.18.2c). Physiologically there are only a limited number of ways that lymphatics can fail. They may be reduced in number (aplasia/​ hypoplasia), obliterated or damaged without repair (failed lymphangiogenesis), or obstructed; they may lose contractility (pump failure), or become incompetent (valvular reflux). A lack of sensitive methods for investigation makes it difficult to dis- tinguish between these mechanisms. Primary lymphoedema Primary lymphoedema arises from an inborn, or intrinsic, fault in lymphatic vessel architecture, function, or both, and by implica- tion is genetic in origin. Lymphoedema is seen in many syndromes, including Turner and Noonan syndromes, but as an associated fea- ture and not the main manifestation. A defining moment in lymphatic research came with the dis- covery of the receptor vascular endothelial growth factor receptor-​ 3 (VEGFR-​3) and its ligands VEGF-​C and VEGF-​D as the main signalling mechanism for lymphangiogenesis. Historically, all cases of congenital lymphoedema were classified as Milroy disease, but Fig. 16.18.2  (a) Causes of primary lymphoedema. (b) Classification and diagnostic algorithm for primary lymphatic dysplasia. (c) Causes of secondary lymphoedema. Part (b) is adapted from Connell F, et al. (2013). The classification and diagnostic algorithm for primary lymphatic dysplasia: an update from 2010 to include molecular findings. Clin Genet, 84, 3031–​4, Copyright © 2013, John Wiley and Sons. section 16  Cardiovascular disorders 3814 Multiple segments No Yes Disturbed growth/ cutaneous manifestations/ vascular anomalies Unknown syndrome Known syndrome SOX18, e.g. Noonan and Turner Yes Start No No Syndromic Systemic/visceral involvement pre- or postnatal onset Generalized lymphatic dysplasia (GLD)/ Hennekam syndrome Consider CCBE1, FAT4, PIEZO1 Lymphatic-related hydrops fetalis (LRHF) Consider PIEZO1, EPHB4 Multisegmental lymphatic dysplasia with systemic involvement (MLDSI) Yes Some segments All segments Bilateral One limb No No No Lower limbs only Distichiasis Lymphoedema-distichiasis syndrome FOXC2 Late-onset unilateral leg lymphoedema Meige-like Meige Consider GJC2 Late-onset unisegmental lymphoedema Late-onset multisegmental lymphoedema Late-onset lower limbs ± genitalia Consider GATA2 4-limb Consider GJC2, Turner Bilateral Unilateral FH +ve FH –ve Yes Yes Congenital onset (<1 y) Late onset (>1 y) Unilateral FH –ve Lower limb + genitalia Much of the improved knowledge about lymphatic science has come from investigating mouse models, but knowledge of genetic causes has come from human studies. Identification of genes underlying primary lymphoedema has also led to greatly enhanced knowledge of lymphangiogenesis as a result of investigating previously unrecognised pathways (e.g. SOX18, FOXC2, CCBE1 and VEGFR3). We also believe that the discovery of genes important for lymphatic development may help in the understanding of diseases where lymphatic dysfunction is known to play a part, e.g. Crohn’s disease. Lower limb FH +ve Proteus syndrome AKT1 (b) PIK3CA-related overgrowth spectrum (PROS) • CLOVES • Fibroadipose hyperplasia • KTS / KT-like • Lymphatic malformation • Combined vascular malformation PIK3CA Parkes-Weber syndrome RASA1 Progressive lymphangiomastosis Gorham syndrome Generalized lymphatic anomaly WILD syndrome Congenital multisegmental oedema without systemic involvement Congenital unisegmental oedema Congenital lower limb oedema with reflux and rerouting Milroy disease FLT4 (VEGFR3) Milroy-like Consider KIF11, VEGFC Congenital lower limb genital oedema Consider PIEZO1 Fig. 16.18.2  Continued 16.18  Chronic peripheral oedema and lymphoedema 3815 several different types of congenital lower limb primary lymphoedema are now recognized. They may all look clinically similar at birth, and only with genetic testing can they be distinguished from one another. For example, mutations in VEGFR3, VEGFC, and KIF11 can all present with exactly the same type of lymphoedema at birth. Mutations in the gene VEGFR-​3 are the cause of congenital fa- milial lymphoedema (Milroy disease). The phenotype manifests with inheritable lymphoedema at or soon after birth, with swelling confined to one or both feet and ankles due to impaired function of initial lymphatics. A phenotype similar to Milroy and also occurring from birth or within the first year is microcephaly lymphoedema syndrome, for which the mutation is in KIF11, hence it is important to measure head circumference in congenital lymphoedema con- fined to the feet and legs. A widespread developmental abnormality of the lymphatic system leads to systemic/​visceral involvement and swelling that may not be confined to the limbs (generalized lymphatic dysplasia). Lymphatic dysfunction may present prenatally with hydrothoraces, ascites, or hydrops fetalis. The development of in-​utero oedema may cause dysmorphic facial features such as epicanthic folds, a broad nasal bridge, and neck webbing with low-​set ears. Primary lymphoedema may be sporadic and involve several limbs, genitalia, or even the face (multisegmental). A failure in lymphatic development may also manifest with internal lymphatic abnormalities such as pleural/​peri- cardial effusions, and pulmonary or intestinal lymphangiectasia. Intestinal lymphangiectasia, or disturbances in mesenteric lymph drainage, may result in chylous reflux, with chyle rerouting to various parts of the body (e.g. chylous effusion or ascites). The fat as well as protein content of such fluids should be measured for diag- nosis. Intestinal lymphangiectasia will cause a protein losing enter- opathy which will result in hypoalbuminaemia, which will make any existing lymphoedema worse by increasing microvascular fluid filtration. Four genes are currently known to cause lymphoedema with sys- temic lymphatic abnormalities: CCBE1, FAT4, PIEZO1, and EPHB4. Generalized lymphatic dysplasia due to CCBE1 or FAT4 (Hennekam syndrome) is autosomal recessive and presents with lymphoedema of all four limbs, intestinal, and/​or pulmonary lymphatic dys- plasia, a variable degree of learning difficulties, and characteristic facies. Mutations in PIEZO1 result in a high incidence of non-​ immune hydrops fetalis and childhood onset of facial and four limb lymphoedema. The term late‐onset lymphoedema is used to describe a primary lymphoedema that develops after the first year of life (i.e. non-​ congenital lymphoedema). Some of these forms of lymphoedema have life‐threatening-​associated diseases, but they all share the common finding of non‐congenital limb swelling. Emberger’s syn- drome, caused by mutations in the transcription factor GATA2, manifests with myelodysplasia which predisposes to acute mye- loid leukaemia. Systemic immunodeficiency is another associated feature, indicating the close relationship between the lymphatic system and immune competence. Mutations in FOXC2 cause lymphoedema–​distichiasis, a dominantly inherited late-​onset (postpubertal) lymphoedema associated with a double row of (ingrowing) eyelashes (distichiasis) and varicose veins. A defect in lymphatic valves results in lymph reflux. Swelling may not mani- fest until the fifth decade, indicating how genetic abnormalities can cause late-​onset lymphoedema. The phenotype can also cause congenital heart disease, emphasizing the close relationship be- tween cardiovascular and lymphatic development. For most forms of primary lymphoedema the genetic cause re- mains unknown. Familial forms with a reduction in size and number of superficial lymphatic collecting vessels but no other phenotypic features are called Meige’s disease. Lymphoedema of the proximal obstructive type with unilateral whole-​limb swelling is sporadic in type, with lymphangiograms demonstrating obstruction at the inguinal nodes, so called ilio-​inguinal nodal sclerosis, with no ap- parent cause. In cases of proximal obstruction, it is of the utmost importance to exclude tumour or iliac vein thrombosis. Asymmetrical primary lymphoedema associated with tissue overgrowth with, or without, a vascular birthmark is often caused by a somatic mutation. These mosaic disorders develop mutations during embryonic development after fertilization, and so are gener- ally not inherited. Cases of unilateral limb swelling associated with overgrowth and a port wine stain and/​or varicose veins are often caused by somatic mutations in the PI3K-​AKT-​MTOR pathway and as such are known as PIK3CA-​related overgrowth spectrum or PROS. Certain lymphatic malformations and Klippel–​Trenaunay syndrome develop through this mechanism. Proteus syndrome caused by mutations in the AKT pathway is related. The yellow nail syndrome, although given an OMIM number, rarely has a family history and is of unknown cause. It is diagnosed when at least two out of three associated clinical features are pre- sent, namely discoloured yellow, thickened, and slow-​growing nails; lymphoedema; and respiratory disease such as bronchiectasis, pleural effusions, or chronic sinusitis. Secondary lymphoedema Filariasis is by far the most common cause of lymphoedema world- wide (filarial elephantiasis). It is endemic in eastern Asia, the Indian subcontinent, west and east Africa, Brazil, and the Caribbean. Microfilaria introduced into the skin by mosquitoes migrate to- wards and enter initial lymphatics. Adult worms develop within the main collector vessels close to the nodes, resulting in lymphatic dila- tation and lymphadenitis. Podoconiosis (endemic elephantiasis) is a form of endemic non-​ filarial lymphoedema caused by microparticles of silica that pene- trate the feet during barefoot walking in soil containing silica and aluminosilicates in tropical west and east Africa, certain volcanic islands, and Central America (see Chapter 10.5). The skin changes are often gross with minimal pitting oedema. There may be a genetic predisposition. In developed countries, surgical removal or irradiation (or both) of lymph nodes for cancer treatment results in lymphoedema. In breast-​cancer-​related lymphoedema the exact mechanisms for de- velopment are unclear, but evidence suggests a simple ‘stopcock’ obstruction from scarring in the axilla is unlikely. Lymphoedema can develop in some patients after removal of one (sentinel) node, but not in others who have had a complete axillary clearance. The incidence of arm lymphoedema remains stubbornly high at over 1 in 5 despite developments such as breast-​conserving surgery and sentinel lymph node biopsy. Obesity is a strong risk factor for the condition, as it is for all types of lymphoedema, and weight loss has been shown to improve existing lymphoedema significantly. The use of taxanes in chemotherapy appears to be contributing to breast-​cancer-​related lymphoedema. Cancer rarely presents with section 16  Cardiovascular disorders 3816 lymphoedema, except in advanced disease, but relapsed tumour fre- quently results in lymphoedema due to obstruction or infiltration of collateral lymphatic routes that have hitherto permitted escape of lymph. Kaposi’s sarcoma is thought to arise from human herpesvirus-​ 8-​induced reprogramming of lymphatic endothelial cells. Vascular plaques in skin and lymphoedema characterize Kaposi’s sarcoma. Lymphangiosarcoma is a highly malignant tumour of endothelial cells which usually arises in long-​standing lymphoedema. Sustained periods of high lymph load (increased micro- vascular filtration) from venous hypertension due to heart failure or venous disease will overwhelm and then eventually exhaust lymph drainage capacity so that permanent impairment of lymph drainage results. A  good example is right-​sided heart failure. Peripheral oedema results from a high lymph load overwhelming lymph drainage. If the oedema does not resolve when the heart failure is controlled (and lymph load normalized), an exhausted and permanently weakened lymph drainage (i.e. lymphoedema), is one likely explanation. Obesity is increasingly recognized as a risk factor for lymphoedema. It impairs lymph drainage, which in turn causes deposition of per- ipheral subcutaneous fat, excess fat (as well as fluid) being one of the main tissue components contributing to the swelling in a breast-​ cancer-​related lymphoedema arm. Morbidly obese patients will often have other comorbidities contributing to leg lymphoedema, including poor movement and a lack of exercise. Long periods sit- ting with legs dependent increase lymph load. Lymphangitis or cellulitis probably only causes lymphoedema when the lymphatics are perilously vulnerable. Any patient suffering recurrent lymphangitis/​cellulitis in the same region is likely to have pre-​existing impaired lymphatic function. Recurrent attacks of cel- lulitis frequently lead to a stepwise deterioration in swelling. Functional leg lymphoedema may develop as a result of immo- bility and dependency due to infirmity following stroke, severe arth- ritis, or respiratory disease, with long periods spent in a chair. It is the lack of exercise which results in no stimulation of lymph drainage. Lymphoedema is a common consequence of post-​thrombotic syndrome (following deep vein thrombosis) and severe long-​ standing venous reflux due to varicose veins. High filtration rates from the ambulatory venous hypertension slowly exhaust lymph drainage. Irreversibly impaired lymph drainage eventually results. Lymphoedema can also result from long-​term inflammatory states such as rheumatoid arthritis and chronic hand or foot dermatitis (with or without infection). Drug treatment can cause or contribute to lower limb lymphoedema. The most common culprits are calcium channel ant- agonists, which are known to paralyse lymphatic vessel pumping, but an increase in lymph load may also be a factor. The incidence and severity of oedema varies between agents, with amlodipine being one of the worst. Other drugs reported to cause oedema include steroids, taxanes, pramipexole, cabergoline, NSAIDs, pregabalin, olanzapine, thiazolidinediones, quetiapine and pemetrexed (eyelid oedema). Epidemiology An estimated 15 million people suffer from leg lymphoedema in filariasis-​endemic areas of the world. Other lymphatic manifest- ations such as genital lymphoedema and hydrocoele are equally common. Lymphoedema due to podoconiosis is estimated to af- fect approximately 4 million people, with the greatest numbers in Ethiopia. In the United Kingdom, secondary forms of lymphoedema, par- ticularly cancer-​related lymphoedema, are most frequent. More than one in five women who survive breast cancer will develop arm lymphoedema. Other cancers such as cervix, uterus, vulva, prostate, penis, head and neck, melanoma, and sarcoma are commonly asso- ciated with lymphoedema as a result of treatment or through pro- gressive disease. Attempts to determine the prevalence of lymphoedema in the general population are sparse, and most previous studies have re- lied on information that has been obtained from specific patient groups such as those with breast cancer. A recent epidemiological study of community patients revealed a point prevalence that was much higher among women than men (5.37 vs. 248/​1000 popula- tion). It was also more prevalent among the obese, and there was a clear rise in prevalence with increasing age. The prevalence among hospital inpatients was a staggering 28.5%, which was not the reason for admission but highlights that lymphoedema frequently coexists with other morbidities. Prevention Identification of patients at risk of lymphoedema relies on awareness of its causes. In breast cancer the strongest risk factors are obesity, stage of cancer, extent of surgery, and postoperative infection. In fil- ariasis and podoconiosis avoidance of infection through good skin and foot care seems the most important aspect of care for preventing elephantiasis changes. Clinical features Painless swelling that develops in the wake of cancer treatment is likely to be lymphoedema. Primary lymphoedema is rarely con- sidered at presentation and consequently diagnosis is usually de- layed while other possible causes of swelling are investigated and excluded. Lymphoedema most commonly affects the extremities, particu- larly the leg, although midline swelling affecting head and neck or genitalia can be an isolated finding. Truncal oedema is often observed in the adjoining quadrant of the trunk to an affected limb because of the shared lymph routes within the same lymph drainage basin. Oedema that is symmetrical (equal between right and left legs) is more likely to have systemic origins (e.g. right-​ sided heart failure or hypoproteinaemia). Oedema that is asym- metrical (more in one leg than the other) implies a local cause (e.g. impaired venous or lymph drainage, but both systemic and local causes can coexist). In a patient with advanced cancer leg oedema may result from a combination of hypoproteinaemia (liver metas- tases), impaired lymph drainage (original lymphadenectomy and/​ or lymphatic infiltration by tumour), venous obstruction (deep vein thrombosis or vein compression by tumour), immobility, and dependency. History Leg swelling frequently develops rapidly—​within a day—​but may be mild and intermittent at first. Pain may feature initially, prompting diagnoses such as deep vein thrombosis, soft tissue injury, or infec- tion (although cellulitis often triggers lymphoedema). 16.18  Chronic peripheral oedema and lymphoedema 3817 No oedema is normal. Foot or ankle swelling that regularly occurs on long haul flights, with prolonged standing or in heat, suggests that lymph drainage is not robust. Indeed, it is not unusual for a patient with primary lymphoedema to experience such symptoms for some years before, eventually, more permanent swelling ensues. Discomfort, aching, and heaviness are common symptoms. Functional impairment is slight until swelling becomes more se- vere (Fig. 16.18.3). Lymphoedema does not respond much to elevation or diuretics, except in the early stages or when it is compounded by increased capillary filtration (high lymph load). Chronic oedema that does not reduce significantly overnight is likely to be lymphatic in origin. Clinical signs It is often said that lymphoedema does not pit, but this is not true unless the advanced stages of fibrosis (elephantiasis) have been established. To demonstrate pitting in lymphoedema sustained pressure for some 20 s may be necessary, owing to the firmer (and thicker) nature of the skin and subcutaneous tissues. The skin may double in thickness in lymphoedema, particularly at the base of the second toe, where it may become impossible to pinch up a fold of skin. An inability to pinch and lift a fold of skin at the base of the second toe is referred to as the (Kaposi–​) Stemmer sign and is pathognomonic of lymphoedema (Fig. 16.18.4, Table 16.18.1). As the skin thickens so creases become enhanced and a warty texture (hyperkeratosis) develops. Accumulation of lymph under pressure in dermal lymphatics can result in lymph blisters that bulge on the surface (lymphangiectasia) and weep lymph. When associated with dermal fibrosis the surface bulges are firmer and resemble cobblestones (papillomatosis). The resemblance of the skin texture to elephant hide explains the term elephantiasis (as well as having a leg the size of an elephant’s leg). Intestinal lymph that is rerouted or refluxes into more dependent re- gions of the body will appear milky (chyle) due to its high fat con- tent. Chyle may reflux into the lower limbs, genitalia, peritoneal cavity, urinary and genital tracts, pleural cavity, and other cavities such as synovial joints and pericardium. Chyle will only appear if the lymphatic incompetence extends up to the preaortic lymphatics and cisterna chyli. Cellulitis (erysipelas) In addition to swelling, impaired lymph drainage also predis- poses to infection because of the role the lymphatic system plays in immunosurveillance. Episodes of cellulitis or erysipelas can often be recurrent and frequent. Such events occur irrespective of the cause of the lymphoedema, and covert lymphoedema should be con- sidered as a possible cause in patients presenting with acute cellu- litis, particularly if attacks are recurrent. In filarial lymphoedema, where the episodes of infection are called acute dermato-​lymphangio-​adenitis, these secondary bacterial Fig. 16.18.3  Lymphoedema exhibiting characteristic skin changes (thickened skin with warty surface change and in more advanced cases ‘cobblestone’ papillomatosis) together with loss of shape and folds developing around the ankles. Fig. 16.18.4  Kaposi–​Stemmer sign: the inability to pinch and pick up a fold of skin at the base of the second toe (due to thickened skin). Table 16.18.1  Criteria for diagnosis of lymphoedema Symptoms Persistent swelling (can be intermittent at first) Oedema does not resolve with overnight elevation Poor response to diuretics Associated with cellulitis Signs Pitting oedema (but difficult to pit) Thickened, warty skin Kaposi–​Stemmer sign Investigation Abnormal lymph drainage routes or impaired transport on lymphoscintigraphy section 16  Cardiovascular disorders 3818 infections appear to be important for the progression of the ele- phantiasis. They manifest with increased oedema, pain, fever, or flu-​like symptoms, and can be prevented with long-​term penicillin and improvements in skin hygiene. In primary and cancer-​related lymphoedema recurrent cellulitis can be as common as in filariasis, suggesting that disturbed immune cell trafficking associated with the lymphoedema is the fundamental cause. Differential diagnosis of the swollen limb Both excessive capillary filtration and compromised lymph drainage frequently coexist (Fig. 16.18.5). ‘Venous’ oedema Most cases of chronic venous disease giving rise to venous hyper- tension do not manifest with oedema because of increased lymph flow in response to increased capillary filtration. This suggests that the development of oedema in post-​thrombotic syndrome and venous ulceration is as much a failure of lymph drainage as it is due solely to overwhelming microvascular fluid filtration (high lymph load). Correction of the superficial vein incompetence by surgery may not resolve the oedema because of coexistent and permanent lymphatic insufficiency. Lipodermatosclerosis Chronic ‘congestion’ in the lower leg resulting from both in- creased capillary filtration and impaired lymph drainage will often result in lipodermatosclerosis. This manifests with skin red- ness, induration of underlying subcutaneous tissues, tenderness, and oedema. It is usually seen just above the medial malleolus or anterior gaiter region (Fig. 16.18.6). Lipodermatosclerosis is reported to occur with venous disease but it can frequently be seen with lymphoedema in the absence of venous disease. It is frequently mistaken for cellulitis but antibiotics have little effect. Only ‘decongestion’ through compression or elevation improves the condition. ‘Armchair’ legs (dependency syndrome) This syndrome refers to those patients who sit in a chair day and night with their legs dependent. Immobility results in minimal lymph drainage and ‘functional lymphoedema’ ensues (i.e. there is no stimulation of lymph drainage from movement). The asso- ciated increased capillary filtration from gravitational forces leads to profound lower limb oedema. Patients predisposed are those suffering cardiac or respiratory failure who cannot lie flat, those paralysed from stroke or spinal damage including spina bifida, and those with crippling arthritis, particularly rheumatoid. Becoming more common with this scenario are excessively obese individuals with or without obstructive sleep apnoea. Lipoedema (lipodystrophy, lipohypertrophy, lipidosis) Frequently misdiagnosed as lymphoedema, lipoedema is almost exclusive to females with onset at or after puberty. Lipoedema (lip  =  fat, oedema  =  swelling) results in excessive fat deposition below the waist (and sometimes upper arms), but not affecting the Fig. 16.18.5  Causes of a chronically swollen limb. Fig. 16.18.6  Lipodermatosclerosis, a consequence of chronic congestion, manifests with fixed plum-​red discolouration of skin, subcutaneous induration, and oedema—​and is often mistaken for cellulitis. 16.18  Chronic peripheral oedema and lymphoedema 3819 feet. This gives rise to a disproportionate, large, pear-​shaped lower half with thick, heavy, chunky legs (Fig. 16.18.7). The skin is soft, tender, and bruises easily. Pain may be a striking feature. Distinction from a gynoid-​distributed obesity or a ‘fatty’ lymphoedema may be difficult, but lipoedema is not influenced by dieting and is there- fore distinct from morbid obesity. Lipoedema is probably a genetic condition with either X-​linked dominant inheritance or, more likely, autosomal dominant inheritance with sex limitation. Clinical investigation The investigation of choice for confirming that oedema is primarily of lymphatic origin is lymphoscintigraphy (isotope lymphography). Traditional direct-​contrast radiographic lymphography is now rarely undertaken to investigate lymphoedema. MRI or CT is of value in identifying a cause for lymphatic obstruction (e.g. cancer). Indocyanine Green lymphography has recently been developed to facilitate imaging of superficial lymphatic collecting vessels. Lymphoscintigraphy A radiolabelled protein or colloid is administered via a subcuta- neous or intradermal injection, and its absorption and transport through lymphatic vessels to lymph nodes is imaged by gamma camera. Theoretically, lymphoscintigraphy permits examination of lymph drainage from any site to which radiolabelled tracer can be administered, as has happened with sentinel node mapping for melanoma, breast, and genital cancer management. For the investigation of a swollen limb, tracer is administered bilaterally into feet or hands. Lymph drainage routes can be crudely imaged and abnormalities identified (Fig. 16.18.8). Offline calculation of time–​activity curves over regions of interest permit quantitative analysis of lymph drainage. Lymphoscintigraphy is very specific (i.e. there are few false positives), but it can be normal in the pres- ence of lymphoedema. Quantification (i.e. calculation of lymph transport) is important as imaging alone can miss lymphoedema where anatomy is normal but function is reduced. Indocyanine green lymphography Indocyanine green lymphography involves the intradermal injec- tion of indocyanine green, which is taken up by local lymphatics and transported to the sentinel lymph node. The use of a near infrared camera images the lymphatic vessels, as well as their active contrac- tions, and indicates the direction of lymph drainage. The technique is used for sentinel lymph node mapping prior to node biopsy in cancer management, particularly breast cancer and melanoma. It is also used in supermicrosurgery to identify subcutaneous lymph ves- sels suitable for anastomosis with small veins, so-​called lymphatico-​ venular anastomosis, as treatment for lymphoedema. MRI MRI (or CT) demonstrates a thicker skin and a ‘honeycomb’ pat- tern in the swollen subcutaneous compartment of lymphoedema. Following deep vein thrombosis of the leg the subfascial muscle Fig. 16.18.7  Lipoedema—​a condition almost exclusive to women resulting in excess subcutaneous fat on hips, buttocks, thighs, or legs giving rise to disproportionately large lower limbs and often mistaken for lymphoedema. Fig. 16.18.8  Lymphoscintigraphy is the investigation of choice for determining if limb swelling is due to lymphoedema. Following a web space injection (hand or foot) of a radiolabelled colloid (99mTc–​antimony sulphide colloid) the transport of radioactivity is imaged by gamma camera. Image abnormalities or a quantitative reduction in radioactivity in a region of interest within draining lymph nodes indicates lymphoedema. (a) Normal lymphoscintigraphy. (b) A patient with Milroy’s disease and identified mutation in the VEGFR3 gene giving rise to dysfunctional initial (absorbing) lymphatics in the feet. (c) A patient with lymphoedema–​distichiasis due to mutation in the FOXC2 gene that results in lymph reflux due to lymphatic valve failure. section 16  Cardiovascular disorders 3820 compartment is enlarged, but not so in lymphoedema. MRI and CT are more objective than ultrasonography for identifying enlarged lymph nodes or pathology responsible for lymphatic obstruction such as pelvic tumour. MRI can be helpful to differentiate fat from fluid in cases of lipoedema/​lipodystrophy and where there is tissue overgrowth of fat or muscle (e.g. Proteus syndrome). MR Lymphangiography utilizes a contrast agent that enters the lymphatic vessels to highlight them and the lymph nodes. Long examination times and discrimination of lymph vessels from veins limit this type of investigation. Colour Doppler duplex ultrasound Venous disease (primary varicose veins or post-​thrombotic syn- drome) may cause or contribute to lower limb swelling. Venous du- plex ultrasonography is helpful for identifying venous reflux. Iliac vein thrombosis or compression can be a cause of whole-​leg swelling. Gene testing Gene testing is now the definitive means of diagnosing several lymphoedema genotypes, one example being Milroy disease (mu- tations in VEGFR3). With at least 12 causal genes now known for primary lymphoedema the use of a gene panel for clinical testing is becoming more commonplace. Treatment Physical therapy to stimulate lymph drainage No drug therapy is known to improve lymph drainage. The treat- ment of lymphoedema relies on improving lymph drainage through the application of simple physiological principles known to stimu- late lymph flow, while at the same time restoring any excessive ca- pillary filtration to as near normal as possible. The principles of treatment are generic, but obviously vary according to individual circumstances dependent on site (e.g. facial vs. leg lymphoedema), and cause (e.g. genetic lymphoedema in a child vs. lymphoedema in advanced cancer). Unlike blood flow, which is predominantly driven by the heart, lymph flow falls to low levels unless stimulated by movement and in particular exercise. Alternating changes in interstitial fluid pressure (by active or passive exercise or massage) increase ini- tial lymphatic filling and flow within initial lymphatics. Increases in lymph load (from higher microvascular fluid filtration) to col- lecting lymphatics will stimulate greater contractility within these main pumping vessels. Patients with leg lymphoedema often notice that walking re- duces swelling. The addition of a bandage or stocking will enhance the effect of movement. The idea of compression is not to squeeze fluid out of the limb with force, like squeezing toothpaste out of a tube, but to create an outer envelope to the leg that resists expan- sion of the calf muscle during contraction. This generates a high interstitial pressure during muscle contractions to drive lymph drainage. Low pressures during skeletal muscle relaxation permit lymphatic vessel refilling before further muscle contraction repeats the cycle. Compression without movement (active or passive exer- cises) does not improve lymph drainage. Isotonic muscle exercise and compression is particularly helpful in circumstances where lymphatic collector contractility is impaired (normally once lymph has entered a lymphatic collecting vessel, smooth muscle contrac- tions drive lymph forwards and valves ensure unidirectional flow). Compression has the added benefit of lowering venous pressure in the leg, so reducing microvascular fluid filtration and therefore lymph load. Manual lymphatic drainage therapy, a specific form of lymphatic massage, operates on the same principle of stimulating alternating rises and falls in interstitial pressure and is used to decongest more proximal regions of the body (e.g. the adjoining quadrant of the trunk to a swollen limb, through which lymph from the limb needs to pass before being directed to a normally functioning lymphatic basin). In right-​arm lymphoedema, manual lymphatic drainage would serve to direct collateral lymph drainage to normally draining lymph routes in the contralateral left axilla and so complement the effect of any compression and exercise to the right arm. In moderate to severe lymphoedema, treatment with an inten- sive course of manual lymphatic drainage, multilayer lymphoedema bandaging, and exercise (decongestive lymphatic therapy/​combined decongestive therapy) can reverse more or less all the comorbidity from swelling, including ‘elephantiasis’ skin changes. Once swelling has been reduced and limb shape improved, control is maintained through exercise while wearing appropriately fitted compres- sion garments. In elderly and infirm individuals, the application and removal of hosiery can be problematic, but most patients will manage if good technique is taught and aids to application provided. Compression wraps with Velcro attachments (e.g. Farrow wraps) provide easily applied graduated support. Elevation of the legs is often wrongly chosen over exercise as treat- ment for lymphoedema. Elevation helps oedema by lowering venous pressure and consequently reducing capillary pressure. This reduces lymph load but does not improve lymph drainage. Nevertheless, it allows base line levels of lymph drainage to ‘catch up’ with demand. While exercise is preferred to elevation as treatment, elevation is re- commended during periods of rest. Intermittent pneumatic compression pumps probably displace fluid as much as improve lymph flow. Nevertheless, they can simu- late the massaging effects of movement and reduce high venous pres- sures, and thereby prove helpful for patients spending considerable time in chairs, or those with venous hypertension for other reasons. Prevention of infection The main risk factors for cellulitis (erysipelas) or Acute Dermato-​ Lymphangio-​Adenitis are lymphatic insufficiency and loss of skin integrity (wounds, interdigital skin breaks, and leg ul- cers). Good skin care is the first consideration when treating lymphoedema. This has been well demonstrated in elephantiasis and podoconiosis. Avoidance of skin damage (including sterile needle puncture), good hygiene, regular emollients, treatment of any dermatitis or fungal infection, and antisepsis following minor wounds are im- portant. Consensus recommendations for the treatment of cellulitis with lymphoedema are found in Table 16.18.2 and at http://​www. thebls.com/​cellulitis. Recurrent cellulitis can be a particular problem. Prophylactic phenoxymethylpenicillin 250 mg twice daily for 12 months halves rates of infection compared to placebo. Obesity, multiple previous 16.18  Chronic peripheral oedema and lymphoedema 3821 attacks, and lymphoedema are associated with increased failure of prophylaxis. Drug therapy Too often diuretics are prescribed for oedema on an empirical basis, without due thought for the underlying pathophysiology. They have very little effect in established lymphoedema because their main action is in the kidneys to excrete body salt and water, and so in turn reduce microvascular fluid filtration and lymph load. They should really only be prescribed in circumstances of salt and water retention, whereupon spironolactone may be pre- ferred. Rutoside (a glycoside) and flavonoids have been advocated, but clinical effect is minimal. Calcium channel antagonists should be avoided in lymphoedema because they encourage oedema. The mechanism is unclear, but lymphatic pumping is paralysed by this class of drug in animal studies. Surgery Surgery can involve removal of excess tissue (reducing/​debulking operations or liposuction) or bypassing of local lymphatic defects, but traditional debulking or reducing surgical operations are now rarely performed. Because excess fat can make up a considerable component of the swelling, suction lipectomy (liposuction) is now an accepted treatment for severe lymphoedema or lymphoedema where fat is the dominant tissue component. However, surgery can be effective in selected patients. Supermicrosugical lymphatico-​ venular anastomoses join obstructed lymphatics to small veins to enhance lymph drainage and can succeed in reducing swelling and frequency of cellulitis. Vascularized lymph node transfer seeks to transplant an autologous lymph node from one normally draining lymph node basin to a compromised basin in order to reconstitute lymph drainage through stimulating lymphangiogenesis in the re- cipient site. Surgery often does not obviate the need for long-​term compression garments. Lymphoedema in other sites Genital Genital lymphoedema may arise from a genetic fault in lymph- atic development, in which case internal lymph problems (e.g. intestinal lymphangiectasia), and leg lymphoedema may coexist. Acquired forms may result from filariasis, cancer treatment, in- fection (cellulitis), anogenital granulomatosis/​Crohn’s disease, and hidradenitis suppurativa. Control of any inflammation is essential for control of oedema. Facial Impaired lymph drainage within skin and subcutaneous local lymphatics is likely to be a factor in cases of facial swelling, par- ticularly periorbital oedema associated with rosacea, dermato- myositis, and thyroid disease. Head and neck lymphoedema has become a greater burden with the increased incidence of head and neck cancer treatment. FURTHER READING Aspelund A, et  al. (2016). Lymphatic system in cardiovascular medicine. Circ Res, 118, 515–​30. British Lymphology Society (2005). Consensus document on the management of cellulitis in lymphoedema. http://​www.thebls.com/​ concensus. php Table 16.18.2  Antibacterials for cellulitisa,b Situation First-​line antibacterials If allergic to penicillin Second-​line antibacterials Comments Acute cellulitis septicaemia (inpatient admission) Flucloxacillin 1–​2 g IV q6 hc,6 or amoxicillin 2 g IV q8 hc (see main text) Clindamycin 600 mg IV q6 h13 Clindamycin 600 mg IV q6 h (if poor or no response by 48 h) Switch to PO flucloxacillin 500 mg q.d.s. or amoxicillin 500 mg t.d.s. or clindamycin 300 mg q.d.s. when: no fever for 48 h and inflammation much resolved and falling CRP. Then continue as below. Acute cellulitis (home care) or emergency back-​up supply of antibacterials Flucloxacillin 500 mg q.d.s. or amoxicillin 500 mg t.d.s.d Erythromycine 500 mg q.d.s. or clarithromycine 500 mg b.d. Clindamycin 300 mg q.d.s. If fails to resolve, convert to first-​line IV regimen above Give for a minimum of 2 weeks. Continue antibacterials until the acute inflammation has completely resolved; in severe cases this may take 1–​2 months. (Note: residual ‘staining’ may persist beyond this.) Prophylaxis if 2+ episodes of cellulitis per year Phenoxymethylpenicillin 250 mg b.d. (500 mg b.d. if BMI ≥33)14 Erythromycine 250 mg once daily or clarithromycine 250 mg once daily Clindamycin 150 mg once daily or doxycycline 50 mg once dailyf Continue for 2 years, after 1 year, halve the dose of phenoxymethylpenicillin; if acute cellulitis develops after dose reduction/​discontinuation, treat the acute cellulitis, and then commence life-​long prophylaxis a but follow local guidelines, particularly for IV antibacterials b PO unless stated otherwise c add gentamicin 5 mg/​kg IV daily for 1 week if anogenital region involved, adjust dose according to renal function and gentamicin plasma concentration d if Staph. aureus infection suspected (folliculitis, pus formation, crusted dermatitis), flucloxacillin 500 mg q.d.s. should definitely be used e for patients taking astemizole, tolterodine, or statins, do not prescribe macrolide antibacterials (clarithromycin, erythromycin) f in these circumstances, review by local specialist lymphoedema services and advice from a microbiologist is recommended. There is a need to balance the use of certain antibiotics (e.g. clindamycin, cefalexin) as prophylaxis against the risk of predisposing to C. difficile infection. section 16  Cardiovascular disorders 3822 Brorson H (2016). Liposuction in lymphedema treatment. J Reconstr Microsurg, 32, 56–​65. Browse NL, Burnand KG, Mortimer PS (2003). Diseases of the lym- phatics. Arnold, London. Burnier P, et  al. (2017). Indocyanine green applications in plastic surgery: a review of the literature. J Plast Reconstr Aesthet Surg, 70, 814–​27. Carl HM, et al. (2017). Systematic review of the surgical treatment of extremity lymphedema. J Reconstr Microsurg, 33, 412–​25. Child AH, et al. (2010). Lipedema: an inherited condition. Am J Med Genet A, 152A, 970–​6. Connell FC, et al. (2013). The classification and diagnostic algorithm for primary lymphatic dysplasia: an update from 2010 to include molecular findings. Clin Genet, 84, 3031–​4. DiSipio T, et al. (2013). Incidence of unilateral arm lymphoedema after breast cancer: a systematic review and meta-​analysis. Lancet Oncol, 14, 5001–​5. Foldi M, Foldi E, Kubik S (2003). Textbook of lymphology for physicians and lymphoedema therapists. Urban & Fischer, San Francisco, CA. International Society of Lymphology (2013). The diagnosis and treat- ment of peripheral lymphedema: 2013 consensus document of the International Society of Lymphology. Lymphology, 46, 1–​11. Keppler-​Noreuil KM, et  al. (2015). PIK3CA-​related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, dif- ferential diagnosis, and evaluation. Am J Med Genet A, 167A, 287–​95. Keramida G, et al. (2017). Importance of accurate ilio-​inguinal quanti- fication in lower extremity lymphoscintigraphy. Nucl Med Commun, 38, 209–​14. Lee BB, et al. (2013) Diagnosis and treatment of primary lymphedema. Consensus document of the International Union of Phlebology (IUP)-​2013. Int Angiol, 32, 541–​74. Levick JR (2009). An introduction to cardiovascular physiology, 5th edi- tion. CRC Press, London. Levick JR, Michel CC (2010). Microvascular fluid exchange and the revised Starling principle. Cardiovasc Res, 87, 1982–​10. Lymphoedema Framework Project (2006). Best practice for the manage- ment of lymphoedema, international consensus. Medical Education Partnership, London. http://​www.lympho.org/​mod_​turbolead/​up- load/​file/​Lympho/​Best_​practice_​20_​July.pdf Moffatt C, et  al. (2003). Lymphoedema:  an underestimated health problem. Q J Med, 96, 731–​8. Moffatt CJ, et  al. (2017). Chronic oedema:  a prevalent health care problem for UK health services. Int Wound J, 14, 772–​81. Mortimer PS, Levick JR (2004). Chronic peripheral oedema: the crit- ical role of the lymphatic system. Clin Med, 4, 4448–​53. NICE Interventional procedures guidance; liposuction for chronic lymphoedema. Nutman TB (ed) (2000). Lymphatic filariasis. Imperial College Press, London. Tekola Ayele F, et al. (2012). HLA class II locus and susceptibility to podoconiosis. N Engl J Med, 366, 1200–​8. Thomas KS, et al.; UK Dermatology Clinical Trials Network’s PATCH I Trial Team (2013). Penicillin to prevent recurrent leg cellulitis. N Engl J Med, 368, 1695–​703. Twycross RG, Wilcock A, Howard P (2014). Palliative care formulary, 5th edition. http://​www.palliativedrugs.com Zuther JE, Norton S (2013). Lymphedema management, 3rd edition. Thieme, New York. Edward D. Folland 16.13.6 Coronary artery bypass a Edward D. Folland 16.13.6 Coronary artery bypass and valve surgery 3666 Rana Sayeed and David Taggart section 16  Cardiovascular disorders 3666 for long-​term anticoagulation, although it must be kept in mind that patients treated with this procedure require at least 45 days of anticoagulation to allow endothelialization of the device. FURTHER READING De Bruyne B, et al. (2012). Fractional flow reserve guided-​PCI versus medical therapy in stable coronary disease. N Engl J Med, 367, 991–​1001. Dowson A, et  al. (2008). Migraine Intervention with STARFlex Technology (MIST) Trial. A  prospective, multicenter, double-​ blind, sham-​controlled trial to evaluate the effectiveness of patent foramen ovale closure with STARFlex septal repair im- plant to resolve refractory migraine headache. Circulation, 117, 1397–​404. Du Z-​D, et al. (2002). Comparison between transcatheter and sur- gical closure of secundum atrial septal defect in children and adults. J Am Coll Cardiol, 39, 1836–​44. Holmes DR Jr, et al. (2014). Prospective randomized evaluation of the Watchman Left Atrial Appendage Closure device in patients with atrial fibrillation versus long-​term warfarin therapy: the PREVAIL trial. J Am Coll Cardiol, 64, 1–​12. Kent DM, et al. (2016). Device closure of patent foramen oval after stroke: pooled analysis of completed randomized trials. J Am Coll Cardiol, 67, 907–​17. Leon MB, et al. (2010). Transcatheter aortic-​valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med, 363, 1597–​607. Leon MB, et  al. (2016). Transcatheter or surgical aortic valve replacement in intermediate risk patients. N Engl J Med, 374, 1609–​20. Mas JL, et al. (2017). Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. J Engl J Med, 377, 1011–21. Sharma SK, Chen V (2006). Coronary interventional devices: balloon, atherectomy, thrombectomy and distal protection devices. Cardiol Clin, 24, 201–​15. Smith CR, et al. (2011). Transcatheter versus surgical aortic-​valve replacement in high-​risk patients. N Engl J Med, 364, 2187–​98. Sondergaard L, et al. (2017). Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N Engl J Med, 377, 1033–42. Stefanini GG, Holmes DR (2013). Drug-​eluting coronary-​artery stents. N Engl J Med, 368, 254–​65. Stettler C, et al. (2007). Outcomes associated with drug-​eluting and bare-​metal stents:  a collaborative network meta-​analysis. Lancet, 370, 937–​48. The Task Force on the management of ST-​segment elevation acute myocardial infarction of the European Society of Cardiology (ESC) (2012). ESC guidelines for the management of acute myocardial in- farction in patients presenting with ST-​segment elevation. Eur Heart J, 33, 2569–​619. Thourani VH, et  al. (2016). Transcatheter aortic valve replacement versus surgical valve replacement in intermediate risk patients: a propensity score analysis. Lancet, 387, 2218–​25. Tonino PA, et al. (2009). Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med, 360, 213–​24. Topol EJ, Teirstein PS (eds) (2016). Textbook of interventional cardi- ology, 7th edition. Elsevier, Philadelphia, PA. Tuzcu EM, Kapadia S (2017). Bioresorbable scaffold: balancing risks to promissory benefits. J Am Coll Cardiol Intv, 10, 1016. Webb JG, Wood MD (2012). Current status of transcatheter aortic valve replacement. J Am Coll Cardiol, 60, 483–​92. Wiebe J, et al. (2017). Long-​term clinical outcomes of patients treated with everolimus-​eluting bioasorbable stents in routine practice: 2-​year results of the ISAR-​ABSORB registry. J Am Coll Cardiol Intv, 10, 1222–​9. Wijeysundera HC, et al. (2013). Coronary artery bypass graft surgery vs percutaneous interventions in coronary revascularization: a sys- tematic review. JAMA, 310, 2086–​95. 16.13.6  Coronary artery bypass and valve surgery Rana Sayeed and David Taggart ESSENTIALS Coronary artery bypass grafting (CABG)—​the two main indications are relief of symptoms, usually angina and/​or breathlessness, that persist even with optimal medical therapy, and/​or prognosis. There is a prognostic benefit for CABG in patients with large volumes of ischaemia (i.e. affecting >12% of the ventricular myocardium), and the benefit of revascularization increases with increasing volumes of ischaemia. The overall mortality for elective CABG in the United Kingdom is around 1% and has fallen steadily over the last decade despite an increasingly adverse risk profile of patients undergoing surgery. In randomized trials and large propensity-​matched cohort registries, CABG—​in comparison to percutaneous coronary inter- vention, even with drug-​eluting stents—​has been shown to improve survival and to reduce the subsequent risk of myocardial infarction and recurrent angina. Approximately 80% of patients are alive a decade after surgery, of whom around 70% are still free from angina. Valve surgery—​this is primarily performed for patients with severe valvular disease and symptoms. Indications also include deteriorating ventricular function and the requirement for coronary artery sur- gery in patients with coexistent valve disease. Mitral valve repair is a highly successful procedure in patients with non​rheumatic valvular regurgitation and is associated with an excellent long-​term survival. Aortic valve disease is usually treated with aortic valve replacement. A range of biological and mechanical valves are available for valve surgery, with no difference in outcomes between mechanical and biological valves with respect to mortality, prosthetic valve endocar- ditis, or thromboembolism, but biological valves have a higher rate of reoperation, and the haemodynamic profiles of biological and newer mechanical valves are similar. Biological valves are particularly attractive for elderly patients in whom anticoagulation is deemed high risk, and are now the commonest type of valve implanted worldwide. Patients with aortic stenosis may also be considered for transcatheter valve implantation when the risks of conventional sur- gery are high or prohibitive. The indications for transcatheter valve implantation for aortic stenosis, and for mitral regurgitation, are likely to expand significantly as these techniques develops. 16.13.6  Coronary artery bypass and valve surgery 3667 Introduction Valve surgery was developed in the 1920s for the treatment of con- genital heart disease and mitral stenosis. The development of durable valve prostheses in the 1950s allowed surgery for a wider range of ac- quired valvular heart disease. Currently, degenerative disease–​causing aortic stenosis, aortic regurgitation, and mitral regurgitation is preva- lent in North America and Europe; rheumatic heart disease remains a significant cause of valvular stenosis and/​or regurgitation elsewhere. Every year, over 13 000 valve procedures are performed in the United Kingdom and almost 100 000 in the United States of America. Coronary artery bypass grafting (CABG) has now been per- formed for over half a century and it is estimated that approxi- mately three-​quarters of a million such operations are performed worldwide annually. Over the last decade the numbers of CABG operations have fallen in most developed countries because of im- proved medical therapy and advances in percutaneous coronary intervention (PCI), while the numbers of CABG operations con- tinue to increase in the developing world. Attempts to improve the blood supply to the heart through in- direct means were first attempted over a century ago. However, it was technological advances in the 1960s that allowed direct suturing of either the internal thoracic artery or saphenous vein grafts to the native coronary artery that led to dramatic improvements in the relief of angina and the explosive growth in CABG surgery. The publica- tion of randomized trials comparing CABG to medical therapy in the 1970s demonstrated the superior efficacy of CABG in relieving an- gina, and a subsequent meta-​analysis of these trials also reported that CABG resulted in a survival benefit over a 10-​year follow-​up period. This led to further dramatic increases in the number of CABG oper- ations in developed countries over the following two decades. Initially, most CABG operations were performed using saphe- nous vein graft conduits, but the demonstration of superior patency and clinical outcomes with an internal thoracic artery graft eventu- ally resulted in most patients receiving an internal thoracic artery graft to the anatomically and functionally most important coronary artery, the left anterior descending artery. The superior angiographic patency of the internal thoracic artery in comparison to vein grafts is largely explained by the tendency to develop intimal hyperplasia and atherosclerosis in vein grafts, a pathological process from which the internal thoracic artery remains largely immune. Over the last decade there have been attempts to promote the use of more arterial grafts during multivessel CABG surgery, and particularly the use of both internal thoracic arteries. Although earlier meta-​analyses suggested an improved survival benefit for bilateral versus single internal thoracic artery use, the Arterial Revascularization Trial (ART) found no significant difference be- tween CABG patients receiving single internal thoracic artery grafts and those receiving bilateral grafts with regard to mortality or the rates of cardiovascular events at ten years of follow-​up on an inten- tion to treat analysis. However, interpretation of ART is complicated by the fact that 40% of patients received a different treatment from that initially proposed. In an as-treated analysis of patients receiving at least two arterial grafts there was a strong survival advantage and marked reduction in cardiovascular events at 10 years. A separate post hoc analysis of the ART cohort showed that an additional ra- dial artery graft was associated with lower risk for mid-​term major adverse cardiac events in both single and bilateral internal thoracic artery groups. The use of a third arterial conduit in CABG surgery is associated with superior long-​term survival, irrespective of gender and diabetic mellitus status. Over the last two decades there has also been considerable enthu- siasm for the use of off-​pump CABG to avoid the deleterious effects of cardiopulmonary bypass, but recent large trials have shown no difference in clinical outcome for most patients whether CABG sur- gery is performed on or off pump. General considerations in assessing patients for cardiac surgery The decision to proceed to cardiac surgery involves a careful assess- ment of the operative risk. In an ageing population with multiple comorbidities these considerations become increasingly important and significantly influence the decision to intervene and the choice between surgery and percutaneous or transcatheter intervention. The presence of significant comorbidity has more importance when surgery is being performed for prognostic rather than symptom- atic grounds. In some patients, long-​term prognosis is determined to a greater degree by their comorbidity than by their coronary or valvular disease, and in those who have asymptomatic disease the benefits of intervention have to be carefully weighed against the risks. All patients will have routine haematological and biochemical assessment, coronary angiography, and echocardiography. Patients undergoing valve surgery should have a dental assessment including a panoramic radiograph. Angiographic assessment can be refined by the use of pressure wire studies, particularly in those cases where the presence of a given coronary stenosis will determine the choice be- tween PCI and surgery. In patients in whom coronary bypass surgery is being performed for prognostic benefit, in particular those with significant left ventricular impairment, assessment with myocardial perfusion imaging or MRI will guide the decision to revascularize based on the extent of viable myocardium and reversible ischaemia. Right heart catheterization may be required in the assessment of mi- tral valve disease or where significant pulmonary hypertension has been identified on echocardiography. Antiplatelet therapy with the exception of aspirin should be with- drawn in patients undergoing elective surgery (see Box 16.13.6.1). Box 16.13.6.1  Management of antiplatelet therapy before coronary artery bypass grafting surgery • Assessment of the risk of bleeding and ischaemia is recommended when making the decision for CABG surgery • Low-​dose aspirin (75–​160 mg daily) should be maintained in patients undergoing CABG surgery • In patients with increased bleeding risk and in those who refuse blood transfusion, cessation of aspirin 3–​5 days before surgery is re- commended based on individualized assessment of ischaemic and bleeding risks • In patients on P2Y12 inhibitors it is recommended to postpone surgery for 5 days after interruption of ticagrelor or clopidogrel, and 7 days for prasugrel, unless the patient is at high risk of ischaemic events Adapted from Sousa-​Uva M, et  al., on behalf of ESC Working Group on Cardiovascular Surgery and ESC Working Group on Thrombosis (2013). Expert position paper on the management of antiplatelet therapy in patients undergoing coronary artery bypass graft surgery. Eur Heart J, 10, 1093. section 16  Cardiovascular disorders 3668 Several scoring systems have been developed to estimate the risks of cardiac surgery. Meanwhile, in the EuroSCORE II, a number of parameters have been identified on univariate analysis to influence the outcome of surgery as shown in Table 16.13.6.1. The operative mortality in elderly patients has fallen substantially over the past 30 years and it is no longer unusual to consider sur- gery in patients over the age of 80 if their overall risk is acceptable. The risk of coronary artery bypass surgery in patients over the age of 85 is approximately 9% compared to less than 1% in those aged 60 or under; the corresponding figures for isolated valve surgery are 7% and 2.6% respectively. The risks are substantially affected by comorbidities such as chronic obstructive airways disease, cerebro- vascular disease, and renal disease, which are more common in this age group. Frailty, though increasingly important, is difficult to de- fine and is probably best assessed by an experienced physician re- viewing the patient, although attempts have been made to develop a frailty index to assist in decision-​making. Moderate to severe chronic obstructive airways disease (i.e. FEV1/​ FVC <0.7 and FEV1 <80% predicted) increases surgical mortality threefold and if combined with a DLCO of less than 50% the mor- tality increases tenfold. Many patients with chronic obstructive pulmonary disease (COPD) are wrongly classified prior to cardiac surgery and routine pulmonary function testing in patients with a smoking history or history of COPD is advised. Carotid artery disease is associated with an increased risk of stroke during cardiac surgery; however, there is no evidence that routine screening of all patients is required. Screening of patients aged over 70 with an additional risk factor (carotid bruit, history of cerebro- vascular disease, diabetes mellitus, or peripheral vascular disease) is probably justified. Intervention for carotid disease should be con- sidered at or before surgery in patients with a history of cerebrovas- cular disease and a carotid stenosis (50–​99% in men and 70–​99% in women). The role of carotid surgery in asymptomatic patients is controversial but it should be considered in men with bilateral se- vere carotid stenosis or contralateral occlusion if the operative com- plication rate for carotid surgery is low and life expectancy is good. The 30-​day mortality of patients with acute renal failure in the postoperative period approaches 60% in some series. The risk is largely dependent on the baseline creatinine clearance (see Fig. 16.13.6.1). Cardiac surgery in patients on dialysis carries a threefold greater mortality and patients are more likely to suffer a stroke, pneumonia, or sepsis in the postoperative period. There is some evidence that off-​pump bypass surgery reduces the risks of surgery in this group of patients. The decision to proceed to cardiac surgery involves a multidis- ciplinary team of cardiologists, surgeons, and physicians, and de- tailed preoperative assessment is required for an informed decision to be made. Coronary artery bypass surgery Indications Indications for revascularization by either PCI or CABG are shown in Table 16.13.6.2. The major indications for CABG are the relief of angina or breathlessness in patients who remain symptomatic despite optimal medical therapy and for prognosis in patients with Table 16.13.6.1  Variables associated with mortality for cardiac surgery (EuroSCORE II) Patient-​related factors Cardiac-​related factors Operation-​related factors Age NYHA class Operative urgency (elective, urgent, emergency, or salvage) Female CCS class 4 angina Weight of intervention (isolated CABG, single non-​CABG, two procedures, >2 procedures) Renal impairment Left ventricular function Surgery on the thoracic aorta Extracardiac arteriopathy Recent myocardial infarction Poor mobility Pulmonary hypertension Previous cardiac surgery Chronic lung disease Active endocarditis Critical preoperative statea Diabetes on insulin a Critical preoperative state is defined as ventricular tachycardia or fibrillation, aborted sudden death or cardiac massage, ventilation prior to surgery, inotropic support, ventricular assist device/​balloon pump preoperatively or acute renal failure (anuria or oliguria <10 ml/​h). Adapted from Nashef SAM, et al. (2012). EuroSCORE II. Eur J Cardiothorac Surg, 41, 734–​45. 5 0 100 <40 40–60 60–80 Creatinine clearance 80–100 1 2 3 Risk of acute rental failure (%) 4 Fig. 16.13.6.1  Risk of acute renal failure according to baseline creatinine clearance. From Chertow GM, Lazarus JM, Christiansen CL, Cook EF, Hammermeister KE, Grover F, Daley J (1997). Preoperative renal risk stratification. Circulation, 95(4), 878–​84. 16.13.6  Coronary artery bypass and valve surgery 3669 substantial volumes of ischaemia (classified as involving >12% of the ventricular myocardium). Recent guidelines published in Europe and North America broadly agree that there is a prognostic advantage of CABG in pa- tients with the most severe coronary artery disease and particularly in the presence of complex three-​vessel disease and/​or left main dis- ease. Revascularization is also indicated in patients with impaired left ventricular function and severe coronary artery disease and es- pecially with the demonstration of significant ischaemia and viable myocardium. Non-​ST-​elevation myocardial infarction Patients with non-​ST-​elevation myocardial infarction often require urgent revascularization by either PCI or CABG. For isolated one-​ or two-​vessel disease, and particularly where the culprit lesions are not complex, PCI is an appropriate strategy. In contrast, for those patients with complex multivessel coronary artery disease CABG is still the preferred treatment option soon after medical stabilization of the patient using optimal medical therapy. ST-​elevation myocardial infarction There is universal agreement that the primary treatment of ST-​ elevation myocardial infarction is immediate PCI, preferably within 90 min. There is a prohibitively high risk for CABG surgery in patients with acute myocardial infarction. CABG is therefore reserved for patients who exhibit persistent symptoms or evidence of ischaemia despite PCI or who become haemodynamically un- stable, and those who develop mechanical complications of myo- cardial infarction such as papillary muscle rupture or ventricular septal defect. The CABG operation Most CABG operations are performed through a median sterno­ tomy, which allows excellent access to all anatomical regions of the heart. In certain situations, CABG can be performed through a minithoracotomy, with or without the aid of robotic instruments. After median sternotomy one or both internal thoracic arteries are harvested, while the saphenous vein from the lower limb and/​ or the radial artery from the forearm may also be harvested sim- ultaneously as additional conduits. The left internal thoracic artery remains attached proximally to the subclavian artery, and the right internal thoracic artery can either remain in situ or be anastomosed as a composite graft to the left internal thoracic artery. Around 80% of all CABG operations are completed using cardio- pulmonary bypass by draining venous blood from the right atrium into the extracorporeal perfusion circuit, where it is oxygenated and cooled, and then returning it to the ascending aorta so that the heart and lungs are effectively bypassed. A large clamp is then placed across the ascending aorta and a cardioplegia solution—​ usually either crystalloid or blood containing a high concentration of potassium—​is used to arrest the heart to provide the surgeon with a motionless, bloodless operating field. After completion of the distal anastomoses the aortic clamp is removed so that the heart is reperfused while the proximal end of the radial artery or vein graft is sewn to the ascending aorta after isolating part of the as- cending aorta with a side-​biting clamp. If the operation is performed off pump (without the use of car- diopulmonary bypass) a stabilizing device is used to immobilize a small area of the heart to allow the anastomosis to be performed to the coronary artery. Outcomes The 10-​year survival for a patient following a standard CABG operation using internal thoracic artery and saphenous vein grafts is expected to be in the region of 80%. Half of late deaths are due to vein graft failure, which has been a driving force for increasing the use of two internal thoracic arteries. At 10 years the patency of the internal thoracic artery is around 95% in comparison to about 50% for vein grafts. Recent studies have shown that the patency of the internal thoracic artery remains at over 90% two decades after follow-​up. In younger patients there is general agreement to try to maximize the use of internal thoracic arteries and radial arteries because of their improved patency over the longer term. There is evidence that use of two internal thoracic arteries improves survival and freedom from further interventions in comparison to a single internal thor- acic artery. Similarly, there is increasing evidence that the more frequent use of arterial grafts also reduces rates of myocardial in- farction and recurrent angina. Secondary prevention The use of secondary prevention is mandatory in patients who have undergone any revascularization whether by PCI or CABG. Minimum therapy should be at least one antiplatelet medication, β-​blockers, statins, and angiotensin-​converting enzyme inhibitors in the presence of impaired left ventricular function. The choice between CABG and PCI There is strong evidence from randomized trials such as SYNTAX and FREEDOM (in diabetic patients), and from several large-​scale Table 16.13.6.2  Indications for revascularization in stable angina or silent ischaemia Subset of coronary disease by anatomy Evidence class For prognosis Left main stem stenosis >50% IA Any proximal LAD stenosis >50% IA Two-vessel or three-vessel disease with stenosis >50% with impaired LV function (LVEF ≤35%) IA Large area of ischaemia (>10% LV or abnormal fractional flow reserve) IB Single remaining patent coronary artery with >50% stenosis IC For symptoms Any stenosis >50% with limiting angina or angina equivalent unresponsive to optimal medical treatment IA CHF, chronic heart failure; LAD, left anterior descending artery; LV, left ventricle. The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) (2014). Guidelines on myocardial revascularization. Eur Heart J, 35, 2541–619. section 16  Cardiovascular disorders 3670 propensity-​matched registries with tens of thousands of patients, of a persistent survival advantage of CABG by around 5%, 3 to 5 years after intervention. In patients with the most severe dis- ease the difference in survival in favour of CABG is around 10%. These survival curves continue to diverge with further duration of follow-​up, suggesting that over the longer term the benefits of CABG may be even greater. This difference between CABG and PCI has persisted despite advances in PCI technology from bal- loon angioplasty to bare metal stents to drug-​eluting stents and to the newer generation of drug-​eluting stents. The likely reason for the persistent survival advantage of CABG is that placing bypass grafts to the mid-​coronary vessels makes the complexity of prox- imal coronary artery disease irrelevant and protects against the development of new proximal disease, which is still common des- pite optimal medical therapy. In contrast, PCI can only deal with localized proximal culprit lesions and has no prophylactic benefit against the development of new disease. Heart valve surgery Indications The indications for valve surgery are covered in more detail else- where (see Chapter 16.6). In brief, surgery is indicated for symp- tomatic (breathlessness, angina, syncope) severe valvular disease or for asymptomatic severe valvular disease with evidence of patho- physiological changes (e.g. abnormal exercise test for asymptom- atic severe aortic stenosis, left ventricular dysfunction, pulmonary hypertension, or atrial fibrillation for asymptomatic severe mitral regurgitation). Repair or replacement The suitability and success of valve repair rather than replace- ment depends on valve pathology, the pathophysiological conse- quences, and surgical expertise. The advantages of valve repair are the avoidance of anticoagulation, prosthetic valve dysfunction, and paravalvular leak, with lower procedural risks and better long-​term outcome. Techniques for mitral valve repair for degenerative disease are well established with excellent long-​term outcomes with respect to reoperation. More than 90% of degenerative mitral valves are suit- able for repair using a combination of techniques: resection or pli- cation of prolapsing or redundant leaflet tissue; chordal replacement with expanded polytetrafluoroethylene neochords; or annuloplasty, usually with implantation of a prosthetic ring or band to support the repair and prevent further annular dilatation. The cumulative reoperation rate is less than 1%/​year, better for isolated posterior leaflet repair (0.5%), and worse for bileaflet (0.9%) or anterior leaflet (1.6%) repairs. Current guidelines support early mitral valve re- pair for asymptomatic severe mitral regurgitation when there is a high expectation of successful durable repair and low procedural mortality. Surgical repair for rheumatic mitral valve disease is more limited, depending on the extent and chronicity of rheumatic changes: closed and open commissurotomy may be performed to palliate mitral stenosis. Several techniques for aortic valve repair for aortic regur- gitation in bicuspid and trileaflet valves have been described to treat cusp, commissural, and annular pathology in selected cases, but long-​term outcomes are uncertain. Surgical approaches Most valve procedures are performed through a median sternotomy on cardiopulmonary bypass, as described for CABG. Several minimal-​ access approaches have been described that allow better cosmesis compared with median sternotomy. Aortic valve replacement may be undertaken through a partial upper sternotomy with a J-​shaped or in- verted T sternal incision through the third or fourth intercostal space, or through a right anterior thoracotomy. The mitral valve may be ap- proached through a lower partial sternotomy, right thoracotomy, or a port access approach through the right chest using a thoracoscopic camera for guidance and specialized instruments; robotic mitral valve surgical techniques have also been developed, but these are limited to specialized centres owing to the high costs of a surgical robot. Depending on the exposure, these minimal-​access approaches may require peripheral cannulation for cardiopulmonary bypass, with specialized surgical equipment for venting and arresting the heart, and clamping the aorta. There is a recognized learning curve for these newer surgical approaches, and, although a shorter in-​hospital stay and faster early recovery have been reported, the medium-​term out- comes remain equivalent to standard open approaches. Transcatheter valve implantation Percutaneous valve intervention techniques have been developed that have replaced surgery in cases with prohibitive surgical risk. Transcatheter aortic valve implantation (TAVI) for aortic stenosis uses standard pericardial bioprosthetic valves mounted in balloon-​ expandable or self-​expanding alloy frames, implanted through the femoral or subclavian artery, ascending aorta, or left ventricular apex, depending on the type of device, presence of vascular disease, and institutional expertise. The procedural success rate is 95% with a 90% or lower 30-​day mortality and lower than 2% stroke rate. TAVI is re- commended for inoperable patients (logistic EuroSCORE ≥ 20, STS PROM ≥ 8) following the PARTNER B study that found a significant reduction in 2-​year all-​cause mortality with TAVI compared with optimal medical therapy in inoperable severe aortic stenosis (43.3% vs. 68%). The PARTNER A study found TAVI to be non-​inferior to surgical aortic valve replacement with respect to 2-​year all-​cause mortality (33.9% vs. 35%) in a high-​risk surgical cohort (STS pre- dicted mortality ≥10). TAVI devices for aortic regurgitation have not yet been widely introduced. Further improved devices are under development to facilitate intraprocedural positioning and to reduce the risks of acute coronary ostial occlusion and paravalvular leak. Transcatheter mitral valve devices are also coming into clinical prac- tice. The MitraClip (Abbott Vascular) has an established role for edge-to-edge mitral valve repair in symptomatic mitral regurgitation patients at prohibitive or high surgical risk, and novel percutaneous mitral valve replacement devices are under development. Types of valve prosthesis Biological valves Biological or bioprosthetic valves may be xenografts, homo- grafts (allografts), or autografts. Xenograft valves are made from glutaraldehyde-​fixed animal leaflet tissue with a proprietary anticalcification treatment, most commonly bovine pericardium or 16.13.6  Coronary artery bypass and valve surgery 3671 porcine aortic valve mounted in an alloy frame for a stented valve, or a whole porcine aortic root for a stentless prosthesis. The advan- tages of stented xenograft valves are the ease of implantation, the avoidance of long-​term anticoagulation, and the ease of reoperation; the development of transcatheter valve-​in-​valve implantation offers an additional less invasive option. Porcine stentless valves became popular in the 1990s because of their excellent haemodynamics and avoidance of long-​term anticoagulation; however, these valves are more challenging to implant reliably, either as a subcoronary im- plant or as a mini-​root replacement, and the rate of structural valve deterioration is higher than for stented valves. Homografts (allografts) are antibiotic-​treated cryopreserved cadav- eric grafts including the aortic root and valve. Homografts are resistant to infection and are used for aortic root replacement, particularly for aortic valve endocarditis, in younger patients to avoid the need for anticoagulation, and where there is extensive periannular infection and tissue destruction to allow left ventricular outflow tract reconstruction. However, although the durability at 10 years is similar to pericardial bioprosthetic valves, the reoperation rate for structural valve deterior- ation at 15 years is as high as 20% in patients aged 41–​60 years, and reoperation is challenging owing to homograft calcification. Finally, the Ross procedure, described in 1962, uses a pulmonary autograft for aortic root replacement with the pulmonary outflow tract replaced with an aortic homograft. The pulmonary autograft is viable tissue and is able to grow in young patients, has excellent haemodynamics with a low thromboembolic risk, and is resistant to infection. The complexity of the Ross procedure limits its use to specialist centres for selected cases (e.g. women of childbearing age keen to avoid anticoagulation). The Ross procedure is complicated by homograft stenosis in 10 to 20% and aneurysmal dilatation of the autograft causing aortic regurgitation; the 10-​year structural valve deterioration rate is up to 30%. ‘Sutureless’ or rapid-​deployment valves are bioprosthetic aortic valves incorporating many features of transcatheter valves, to allow faster implantation in the debrided aortic annulus after open sur- gical resection of the diseased valve. Cardiopulmonary bypass and cardioplegic arrest are still required, but these valves facilitate min- imally invasive approaches and allow shorter procedural times, al- though the longer-​term benefits have yet to be confirmed. Mechanical valves Mechanical valves offer the advantage of excellent durability but the disadvantages of long-​term anticoagulation and the risks of bleeding; modern low-​profile valves have better haemodynamic properties and lower thromboembolic risk than earlier gener- ations. The PROACT study is comparing standard anticoagulation against lower intensity anticoagulation for high thromboembolic risk cases and dual antiplatelet therapy for low-​risk cases with the On-​X bileaflet valve: early results are encouraging, with a 0.6%/​year thromboembolic event rate and 0.4%/​year significant bleeding rate. Meta-​analyses of the randomized studies comparing mechanical with biological valves have found no difference in outcomes between mechanical and biological valves with respect to mortality, pros- thetic valve endocarditis, or thromboembolism; biological valves have a higher rate of reoperation, mechanical valves a higher risk of significant bleeding complications. The Veterans Administration study found a better 15-​year survival for mechanical valves, but the Edinburgh Heart Valve trial found no difference in survival at 20 years. The choice of valve prosthesis for an individual patient de- pends on several factors including, most importantly, the wishes of the patient, age and life expectancy, metabolic factors predisposing to calcification and early structural valve deterioration (e.g. chronic kidney disease), any contraindication to anticoagulation, expect- ation of pregnancy, previous infection, and risk of reoperation. There has been a steady increase in the proportion of biological valves im- planted over the last decade with these valves now making up more than 80% of valves implanted. Anticoagulation Anticoagulation for prosthetic valves Anticoagulation is required for all currently available mechanical valves. The intensity of anticoagulation depends on valve char- acteristics and its position, and patient factors such as a history of thromboembolism, atrial fibrillation, left atrial enlargement, and left ventricular dysfunction. Current recommendations for anticoagulation are summarized in Box 16.13.6.2. Management of anticoagulation for non​cardiac surgery Anticoagulation is usually stopped for non​cardiac surgery depending on the prosthesis type and bleeding risk of sur- gery. Patients with modern bileaflet or tilting disc mechanical aortic valves at low risk of thromboembolism and with no risk Box 16.13.6.2  Guidelines for choice of prosthetic heart valve Guidelines favouring bioprosthetic valves ECS/EACTS 2017 guidelines Anticoagulation contraindicated, unavailable, or unable to be managed appropriately Class IC Patient preference Class IC Reoperation for mechanical valve thrombosis despite good long-term anticoagulation Class IC Women of childbearing age contemplating pregnancy Class IIaC Low risk for future redo valve replacement Class IIaC A bioprosthesis should be considered in those aged >70 years (>65 years for aortic valve replacement in European guidelines) Class IIaC Guidelines favouring mechanical valves ECS/EACTS 2017 guidelines Informed patient preference Class IC Accelerated risk of structural valve deterioration (age <40 years, hyperparathyroidism) Class IC Patient already on anticoagulation for a mechanical valve in another position Class IIaC Reasonable life expectancy (>10 years) and high risk for future repeat valve replacement Class IIaC A mechanical prosthesis is reasonable for those aged <60 years (<65 years for mitral valve replacement in European guidelines) Class IIaC Patient already on anticoagulation due to high risk of thromboembolism (atrial fibrillation, venous thromboembolism, thrombophilia, severe left ventricle dysfunction) Class IIbC section 16  Cardiovascular disorders 3672 factors such as atrial fibrillation, history of thromboembolism or hypercoagulability, or left ventricular dysfunction, may stop war- farin 3 to 5 days before surgery, with no need for bridging therapy with low molecular weight or unfractionated heparin. In all other cases, bridging therapy is indicated before and after surgery for an INR of 2.0 or less; heparin should be resumed after surgery as soon as the immediate risk of bleeding has passed. Excessive anticoagulation Anticoagulation may need to be reversed because of an excessive INR, for bleeding, or for emergency surgery. Prothrombin com- plex concentrate is recommended for rapid reversal for bleeding. A mildly elevated INR with no signs of bleeding may be managed by the omission and/​or adjustment of warfarin doses. Oral vitamin K and omission of warfarin are recommended for the correction of a higher INR with no bleeding. Complications of cardiac surgery Operative mortality The overall mortality for all CABG in the United Kingdom is around 1.8%, being just under 1% for elective CABG and approximately 2% for all urgent CABG. Overall mortality has remained low des- pite an increasing risk profile in patients who are ever more elderly with significant comorbidities. Valve surgery caries a slightly higher risk: the mortality rates for uncomplicated mitral valve repair and aortic valve replacement are approximately 2%. A consistently low mortality almost certainly reflects improvements in medical man- agement of patients as well improvements in anaesthetic, surgical, and perfusion techniques. Neurological injury Significant neurological injury is arguably the most feared compli- cation of cardiac surgery and occurs with an incidence of around 1 to 2% during surgery or in the perioperative period. Of patients with neurological injury approximately one-​third will die, one-​third will remain severely disabled, and one-​third will make a good recovery. The incidence of stroke is statistically higher in patients with left main disease than those with isolated three-​vessel disease and this may reflect a concomitant higher burden of carotid artery disease in patients with left main disease. The major risk factors for stroke are advanced age, significant disease of the ascending aorta, carotid artery disease, previous neurological injury, and the development of postoperative atrial fibrillation. There is strong evidence that CABG performed off pump using a no-​touch aortic technique is the best surgical methodology for reducing incidence of stroke. Sternal wound complications Sternal wound dehiscence is another particularly troublesome complication of median sternotomy. The overall incidence is around 0.6% and the main risk factor is insulin-​dependent dia- betes, especially in combination with obesity. In such patients the use of two internal thoracic arteries leads to a small but significant increase in this risk of sternal dehiscence, and is therefore gen- erally avoided. The treatment of sternal dehiscence is prolonged, complex, and miserable for all parties, usually requiring a period of vacuum-​assisted dressings followed by plastic surgical reconstruc- tion with muscle flaps. Pleural effusion Pleural effusions are usually small and self-​limiting and easily treated by chest drainage. They may also develop after patient dis- charge as a late event. Pericardial effusion All patients develop pericardial effusions after cardiac surgery and in the vast majority these are self-​limiting and require no specific therapy. A small percentage of patients may develop significant peri- cardial effusions which can usually be drained by a small incision under the xiphisternum or by using a thoracoscope through the pleural cavity and the pericardium. Pericardial effusions can also appear after patient discharge and can usually be drained without having to reopen the full sternotomy. Atrial fibrillation Atrial fibrillation occurs temporarily in around 30% of patients after CABG and the incidence may be reduced by peri-​and postoperative β-​blockade. It is now standard practice to anticoagulate these pa- tients as well as treat with amiodarone for 6 weeks. If the patient remains in atrial fibrillation after this period, then cardioversion is indicated. Conduction defects Cardiac conduction defects are common after valve surgery, par- ticularly aortic valve replacement owing to the proximity of the atrioventricular node and bundle of His to the right coronary–​ non​coronary commissure: conduction pathways may be damaged during valve debridement, by direct injury from a suture, or by postoperative oedema. First-​degree or higher degrees of heart block are common after aortic valve surgery and most surgeons routinely place epicardial atrial and ventricular pacing wires for temporary postoperative pacing. Complete heart block requiring implantation of a permanent pacemaker is needed in 3 to 8% of aortic valve re- placement cases, being more common in older people, with pre-​ existing conduction defects, and in valve surgery. Structural valve deterioration Acute primary valve failure is rare in current mechanical or bio- logical valves, but emergent or urgent reoperation is indicated. Structural valve deterioration is a complication of biological valves owing to leaflet fibrosis and calcification causing progressive valvular stenosis, and perforation and leaflet tearing leading to re- gurgitation. Structural valve deterioration develops at a predictable rate related to younger patient age, valve position, mitral more af- fected than aortic, altered calcium metabolism (e.g. chronic kidney disease), and pregnancy. Pericardial valves deteriorate more slowly than porcine bioprostheses. The indications for reoperation for structural valve deterioration are the same as for native valve dis- ease, based on symptoms, ventricular size and function, and pul- monary hypertension. Thromboembolism The incidence of clinical thromboembolic events is up to 2.3 cases per 100 patient-​years. The risk is similar for biological and 16.13.6  Coronary artery bypass and valve surgery 3673 anticoagulated mechanical valves. Risk factors for thrombo- embolism include prosthesis type and position, a history of thromboembolism or hypercoagulability, atrial fibrillation and left atrial size, and left ventricular dysfunction. Thromboembolism with a mechanical valve is managed by ensuring that the INR is in the therapeutic range, or if the INR is already therapeutic, by increasing the target INR or adding low-​dose aspirin. Prosthetic valve thrombosis Thrombosis of a mechanical valve may be a life-​threatening com- plication. The diagnosis is suggested by heart failure, signs of a low cardiac output, or thromboembolism with reduced or absent pros- thetic valve sounds, new murmurs, or documented inadequate anticoagulation. Mitral and tricuspid valves are more commonly in- volved. Echocardiography or fluoroscopy usually confirm reduced leaflet or disc motion caused by an occluding thrombus. Emergency reoperation is recommended for left-​sided valve thrombosis with shock or New York Heart Association (NYHA) III or IV symptoms or cases with large thrombi (>0.8 cm2 on transoesophageal echocardi- ography (TOE)) but the operative mortality is up to 30%. Fibrinolysis with tPA or streptokinase may be used for left-​sided valves with less severe symptoms (NYHA I and II) or smaller thrombus burdens and for patients unsuitable for reoperation; fibrinolysis is recommended for right-​sided valve thrombosis. Fibrinolysis for left-​sided valve thrombosis is associated with a 15–​20% risk of systemic embolism or death. Prosthetic valve endocarditis Prosthetic valve endocarditis (PVE) is more common early after surgery, with an incidence up to 3% at 1 year. Mechanical valves are more commonly involved over the first year, but the incidence for mechanical and biological valves is similar thereafter. Early PVE (within 1 year) in most commonly due to nosocomial coagulase-​ negative staphylococci; late PVE (after 1  year) is caused by a similar range of organisms as native valve endocarditis. PVE fol- lows a more aggressive course than native valve endocarditis with early perivalvular tissue destruction and abscess formation. TOE is important to establish the diagnosis and identify complications indicating early surgery. Medical therapy is usually ineffective in PVE. Early surgery is recommended for heart failure, abscess for- mation, valve dehiscence or other dysfunction, or infection with a resistant organism; surgery is also indicated for a persistent bacter- aemia despite adequate antibiotic therapy or recurrent embolism from vegetations. The operative mortality for early surgery for PVE is up to 35%. Paravalvular leak A paravalvular leak may develop because of poor surgical technique, suture dehiscence, poor native tissue strength, and infection: PVE must always be excluded in the setting of a new paravalvular leak. A small leak may cause a haemolytic anaemia due to mechanical red cell damage; iron and folic acid supplements may be beneficial. Reoperation is indicated for heart failure, a persistent need for trans- fusion, or an impaired quality of life. Large leaks, particularly mitral, may cause volume overload: the development of intractable heart failure is an indication for reoperation. Catheter-​based approaches may be helpful to avoid redo surgery. FURTHER READING Bonow RO, et al. (2016). Management strategies and future challenges for aortic valve disease. Lancet, 387, 1312–​23. Falk V, et al. (2017). 2017 ESC/EACTS Guidelines for the manage- ment of valvular heart disease. European Journal of Cardio-thoracic Surgery, 52, 616–64. Gaudoni M, et al. (2017). Three arterial grafts improve late survival: a meta-​analysis of propensity-​matched studies. Circulation, 135, 1036–​44. Head SJ, et al. (2017). Current practice of state-​of-​the-​art coronary revascularisation. Circulation, 136, 1331–​45. Iqbal J, et al. (2013). Optimal revascularization for complex coronary artery disease. Nat Rev Cardiol, 10, 635–​47. Mohr FW, et al. (2013). Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-​vessel disease and left main coronary disease: 5-​year follow-​up of the ran- domised, clinical SYNTAX trial. Lancet, 381, 629–​38. Neumann F-J, et al. (2019). 2018 ESC/EACTS Guidelines on myocar- dial revascularization. Eur Heart J, 40, 87–165. Nishimura RA, et al. (2016). Mitral valve disease—​current manage- ment and future challenges. Lancet, 387, 1324–​34. Partridge JS, et al. (2012). Frailty in the older surgical patient: a review. Age Ageing, 41, 142–​7. Stone GW, et al. (2016). Everolimus-​eluting stents or bypass surgery for left main coronary artery disease. N Engl J Med, 375, 2223–​35. Taggart DP, et al. (2019). Bilateral versus Single Internal-Thoracic- Artery Grafts at 10 Years. N Engl J Med, 380, 437–46. Taggart DP, et al. (2017). Associations between adding a radial artery graft to single and bilateral internal thoracic artery grafts and out- comes: insights from the Arterial Revascularization Trial. Circulation, 136, 454–​63. Vohra HA, et al. (2013). Outcomes following cardiac surgery in pa- tients with preoperative renal dialysis. Interact Cardiovasc Thorac Surg, 18, 103–​11. Jay W. Mason and Heinz- Peter Schultheiss 16.7.2 T Jay W. Mason and Heinz- Peter Schultheiss 16.7.2 The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular 3468 Oliver P. Guttmann and Perry Elliott section 16  Cardiovascular disorders 3468 Wojinicz R, et al. (2001). Randomized, placebo-​controlled study for immunosuppressive treatment of inflammatory dilated cardiomy- opathy: two-​year follow-​up results. Circulation, 104, 39–​45. Yajima T, Knowlton KU (2009). Viral myocarditis from the perspective of the virus. Circulation, 119, 2615–​24. 16.7.2  The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular Oliver P. Guttmann and Perry Elliott ESSENTIALS The term cardiomyopathy is used to describe heart muscle disease unexplained by abnormal loading conditions (hypertension, valve disease, and others), congenital cardiac abnormalities, and ischaemic heart disease. The current classification is based on the predominant phenotype, that is, hypertrophic, dilated, arrhythmogenic right ven- tricular, restrictive, and unclassifiable (including left ventricular non-​ compaction), and—​ where possible—​ incorporating inheritance and genotype. Cardiomyopathies associated with systemic diseases are described in Chapter 16.7.3. Hypertrophic cardiomyopathy The diagnosis of hypertrophic cardiomyopathy is based on the dem- onstration of unexplained myocardial hypertrophy, defined as a wall thickness measurement exceeding two standard deviations above normal for gender and age. In practice, in an adult of normal size, the presence of a left ventricular myocardial segment of 1.5 cm or greater in thickness is diagnostic. Less stringent criteria should be applied to first-​degree relatives of an unequivocally affected individual. Ninety per cent of patients have familial disease, usually with autosomal dominant inheritance. Mutations in genes encoding proteins of the cardiac sarcomere are most common (60% of cases). Symptomatic presentation may be at any age, with breathlessness on exertion, chest pain, palpitation, syncope, or sudden death. In children and adolescents, the diagnosis is most often made during screening of siblings and offspring of affected family members. In most patients, the physical examination is unremarkable, but char- acteristic features include a rapid upstroke arterial pulse, a forceful left ventricular cardiac impulse with palpable atrial beat, an ejection systolic murmur, and a fourth heart sound. Investigation and diagnosis—​the 12-​lead ECG is the most sen- sitive diagnostic test, with ST-​segment depression and T-​wave changes being the most common abnormalities, usually associated with voltage changes of left ventricular hypertrophy and/​or deep S waves in the anterior chest leads V1 to V3. Echocardiography reveals left ventricular hypertrophy that may be symmetric or asymmetric and localized to the septum or the free wall, but most commonly to both the septum and free wall with relative sparing of the posterior wall. Management—​β-​adrenoceptor blockers and calcium antagonists (verapamil, diltiazem) are the mainstay of symptomatic pharmaco- logical therapy. Surgery is considered for patients with left ventricular outflow tract obstruction (typically, resting left ventricular outflow tract gradient >50 mm Hg) and/​or mitral valve abnormalities, the commonest operation being removal of a segment of the upper an- terior septum (myectomy) via a transaortic approach. Injection of alcohol into the septal artery that supplies the septal muscle is an alternative percutaneous technique that can be used in patients with suitable cardiac and coronary anatomy. Prognosis—​overall annual cardiovascular mortality is 1–​2%/​ year, with sudden cardiac death (c.1%), heart failure (c.0.5%), and thromboembolism (c.0.1%) the main causes. The risk of death and other disease-​related complications varies between individuals. Prevention of sudden death relies on risk factor stratification to identify high-​risk individuals and targeted therapy with implantable cardioverter–​defibrillators. Dilated cardiomyopathy Dilated cardiomyopathy is defined by dilatation and impaired sys- tolic function of the left or both ventricles not attributable to cor- onary artery disease, valvular abnormalities, or pericardial disease. Up to 50% of cases are familial, with many disease-​causing gene mu- tations described. Initial presentation is usually with symptoms of cardiac failure, but other presentations include arrhythmia, systemic thromboembolism, or the incidental finding of an electrocardiographic or radiographic abnormality. Physical examination may reveal cardiac enlargement and signs of congestive heart failure. Investigation and diagnosis—​on echocardiography, the presence of ventricular end-​diastolic dimensions greater than two standard devi- ations above the mean and ejection fraction less than 50% is gener- ally sufficient to make the diagnosis. Management—​symptomatic therapy involves the treatment of heart failure with diuretics, mineralocorticoid receptor antagon- ists, angiotensin-​converting enzyme inhibitors, and β-​blockers. Anticoagulation with warfarin is advised in patients in whom an intracardiac thrombus is identified echocardiographically, or those with a history of thromboembolism. Implantable cardioverter–​ defibrillators are warranted if sustained or symptomatic ventricular arrhythmias are documented and for primary prophylaxis in selected high-​risk patients. Cardiac resynchronization therapy can improve symptoms and prognosis in selected patients with broad QRS dur- ation, and cardiac transplantation may be appropriate for those with progressive deterioration. Restrictive cardiomyopathy Restrictive cardiomyopathies are defined by restrictive ventricular physiology in the presence of normal or reduced diastolic volumes of one or both ventricles, normal or reduced systolic volumes, and normal ventricular wall thickness. In developed countries amyloid- osis is the commonest cause; in the tropics it is endomyocardial fibrosis. Familial restrictive cardiomyopathy is usually caused by sarcomere protein gene mutations, with the full spectrum of re- strictive cardiomyopathy and hypertrophic cardiomyopathy some- times seen within individual families. Presentation is usually insidious. Left-​sided disease may present with symptoms of pulmonary congestion and/​or mitral regurgitation; 16.7.2  The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular 3469 right-​sided disease presents with raised jugular venous pressure, hepatomegaly, ascites, and tricuspid regurgitation. Atrial fibrillation is common. Echocardiography confirms the diagnosis, typically showing that ventricular dimensions and wall thickness are normal, but the atria are grossly enlarged. Congestive symptoms from raised right atrial pressure can be im- proved with diuretics, though too great a reduction in ventricular filling pressure will lead to a reduction in cardiac output. Prognosis of advanced disease is poor. Arrhythmogenic right ventricular cardiomyopathy Arrhythmogenic right ventricular cardiomyopathy is a heart muscle disease characterized by progressive fibro-​fatty replacement of right ventricular myocardium, associated with ventricular arrhythmia, heart failure, and sudden cardiac death. It is inherited and caused by mutations in desmosomal genes in at least 50% of cases. Symptomatic presentation is usually with palpitation and/​or syn- cope from sustained ventricular arrhythmia, but the first presenta- tion of the disease may be with sudden cardiac death. There is no single diagnostic test, and the diagnosis is based on the presence of criteria encompassing structural, histological, electrocardiographic, arrhythmic, and genetic parameters. The most common electrocar- diographic abnormality is T-​wave inversion in leads V1 to V3 in the absence of right bundle branch block. Typical echocardiographic findings include right ventricular dilatation, regional hypokinesia or dyskinesia, and aneurysms. Management—​patients with symptomatic, non-​life-​threatening ventricular arrhythmias are treated empirically with β-​blockers, amiodarone, or sotalol. Those with a history of sustained, haemo- dynamically compromising ventricular arrhythmia should be offered an implantable cardioverter–​defibrillator. Introduction Cardiomyopathies are defined as heart muscle disorders unex- plained by abnormal loading conditions (hypertension, valve dis- ease, and others), congenital cardiac abnormalities, and ischaemic heart disease. The current classification is based on the predominant clinical phenotype and, when feasible, assessment of the familial and genetic basis. Heart muscle disease associated with systemic or extracardiac diseases are described in more detail in Chapter 16.7.3. Hypertrophic cardiomyopathy Definition Hypertrophic cardiomyopathy (HCM) is defined by the presence of increased myocardial thickness in the absence of loading con- ditions (hypertension, valve disease, and others) sufficient to cause the observed degree of hypertrophy. Historically, ventricular thick- ening caused by systemic diseases such as amyloidosis and glycogen storage disease has been excluded from the definition in order to separate conditions in which there is myocyte hypertrophy from those in which left ventricular mass and wall thickness are increased by interstitial infiltration or intracellular accumulation of metabolic substrates. In everyday clinical practice, however, it is frequently impossible to differentiate these two entities using non​invasive imaging, and hence metabolic and infiltrative disease should be con- sidered in the differential diagnosis of hypertrophic cardiomyopathy. Causes Pedigree analysis reveals familial disease in 40–​50% of patients, but when cardiovascular evaluation of first-​degree relatives using elec- trocardiography (ECG) and echocardiography is performed, up to 90% of patients are found to have familial disease. In most cases, the inheritance is autosomal dominant. Approximately 60% of patients with familial hypertrophic car- diomyopathy have mutations in genes encoding proteins of the cardiac sarcomere: specifically, cardiac β-​myosin heavy chain, car- diac myosin-​binding protein C, essential and regulatory myosin light chain, α-​tropomyosin, cardiac troponin T and I, cardiac actin, and α-​myosin. Most mutations involve a single base-​pair change in exons encoding highly conserved regions that result in amino acid substitutions. De novo mutations occur but appear to account for less than 10% of cases. Some 5–​10% of patients carry multiple sarcomeric mutations, with compound heterozygotes presenting with more severe disease at an earlier age. Several genes related to the sarcomere Z-​disc and calcium handling have been associated with hypertrophic cardiomyopathy, but are relatively uncommon. Variable clinical expression and incomplete penetrance is common, even within families bearing the same gene defect, but some phenotypes do seem to associate with particular mutations. β-​ Myosin heavy chain mutations that are fully penetrant are associated with worse prognosis (such as Arg403Glu or Arg453Cys), while dis- ease complications are uncommon in patients with mutations that cause mild or no clinical expression (such as Leu908Val). This con- trasts with troponin T disease, which although associated with mild hypertrophy and few symptoms can still cause premature sudden death. Mutations in myosin-​binding protein C cause 20–​30% of dis- ease; most are major deletions rather than single base-​pair changes. Disease expression can occur later in life, sometimes associated with mild hypertension, but once disease expression occurs (abnormal ECG and/​or echocardiogram), patients are at the same risk from symptoms and disease-​related complications as patients with dis- ease onset in early life. The expression of disease in patients with troponin I mutations is variable and mutations in this gene may also cause restrictive cardiomyopathy. Many inborn errors of metabolism and congenital syndromes are associated with HCM. Most are inherited as autosomal reces- sive traits, but a few are X-​linked. The most common metabolic dis- orders in adults with HCM are Anderson–​Fabry disease (0.5–​1% of patients older than 35–​40 years), and disease caused by mutations in the gene encoding the γ2 subunit of the adenosine monophosphate activated protein kinase (PRKAG2) (1%). LAMP-​2 mutations that cause Danon disease occur in 0.7% to 2.7%. Although still rare, metabolic disorders account for a greater proportion of disease in children and adolescents (Table 16.7.2.1). Pathology Hypertrophic cardiomyopathy may involve the left or both vent- ricles (Fig. 16.7.2.1). Hypertrophy in the left ventricle is usually asymmetric, involving the anterior and posterior septum and the free wall to a greater extent than the posterior wall. Right ven- tricular hypertrophy is seen in up to 30% of patients but isolated section 16  Cardiovascular disorders 3470 right ventricular hypertrophy (in the absence of pulmonary hyper- tension or right ventricular outflow obstruction) rarely if ever oc- curs. Many patients have structural abnormalities of the mitral valve, including increased leaflet area and length, and malposition or anomalous insertion of the papillary muscles. A  common macroscopic finding is a patch of endocardial thickening just below the aortic valve, which results from contact of the septum with the anterior mitral leaflet in patients with dynamic left ventricular out- flow tract obstruction. The histological findings in hypertrophic cardiomyopathy are distinctive and provide the basis for the pathological diag- nosis. Affected myocardium shows interstitial fibrosis with gross disorganization of the muscle bundles resulting in a character- istic whorled pattern. The cell-​to-​cell orientation of muscle cells is lost (disarray) and there is disorganization of the myofibrillar architecture within cells. Myocardial cells are broad, short, and often bizarre in shape. Foci of disorganized cells are often interspersed among areas of hypertrophied muscle cells that are otherwise normal in appearance. Such changes are not com- pletely specific: small amounts of myofibre disarray may be seen in congenitally abnormal hearts and in secondary left ventricular hypertrophy; disarray is also present at the junction of the septum with the anterior and posterior walls of the left ventricle in normal subjects. However, the extent of myocyte disarray in normal subjects rarely exceeds 5%, while in hypertrophic cardiomyop- athy up to 40% of the myocardium may be involved. As well as contributing to diastolic and systolic dysfunction, the disorgan- ized myocardial architecture provides a substrate for electrical instability. Pathophysiology Diastolic dysfunction Diastolic abnormalities caused by myocardial hypertrophy, myo- cardial ischaemia, myocyte disarray, and fibrosis are common but variable in severity. Typically, left ventricular end-​diastolic pressure and atrial pressures are elevated as a consequence of ab- normal left ventricular diastolic filling and reduced compliance. The isovolumic relaxation time is prolonged, left ventricular filling is slow, and the proportion of filling volume that results from atrial systolic contraction (while still preserved) may be increased. Occasionally, there is rapid early filling with restrictive physiology similar to that seen in constrictive pericarditis or endocardial fi- brosis (see Chapter 16.8). Systolic function and dynamic outflow tract obstruction Most patients with hypertrophic cardiomyopathy have rapid and near-​complete ventricular emptying resulting in a high ejection frac- tion but the stroke volume, particularly during exercise is frequently reduced. ‘End-​stage’ hypertrophic cardiomyopathy—​characterized by severe impairment of contractile performance, restrictive left ventricular physiology, and heart failure symptoms—​is uncommon (>5%), but can develop at any age including childhood and adoles- cence. In most, the time from onset of symptoms to diagnosis of severe systolic impairment is long (a mean of 14 years). Approximately 30% of patients have a gradient between the body and outflow tract of the left ventricle at rest; an additional 20–​25% have latent gradients that develop following manoeuvres that in- crease myocardial contractility or that reduce ventricular afterload or venous return. The presence and magnitude of a gradient is de- termined by the size and geometry of the left ventricular outflow tract, which are in turn a function of the severity of septal hyper- trophy, mitral leaflet morphology, and papillary muscle size and position. The conventionally accepted mechanism of the gradient is that Venturi forces from increased ejection velocity in the nar- rowed outflow tract draw the anterior and/​or posterior mitral leaf- lets towards the septum, but other data suggest that the abnormally positioned mitral valve leaflets are ‘driven’ rather than sucked into the septum. By convention, left ventricular outflow tract obstruc- tion is defined as an instantaneous peak Doppler LV outflow tract pressure gradient of 30 mm Hg or more at rest, or during physio- logical provocation such as Valsalva manoeuvre, standing, and ex- ercise. A gradient of 50 mm Hg or more is usually considered to be the threshold at which LV outflow tract obstruction is haemo- dynamically important. Table 16.7.2.1  Non​sarcomeric causes of left ventricular hypertrophy, including mitochondrial cardiomyopathies, neuromuscular diseases, and malformation syndromes Metabolic Glycogen storage disease (GSD): Pompe disease (GSD II), Forbes’ disease (GSD III), Danon Total lipodystrophy Hurler’s syndrome Carnitine disorders​ AMP kinase (PRKAG2) Lysosomal storage disease: Anderson–​Fabry disease Infant of a diabetic mother Hypertrophic cardiomyopathy with associated syndromes Noonan’s syndrome LEOPARD syndrome Beckwith–​Wiedemann syndrome Mitochondrial myopathy MELAS MERFF NADH–​coenzyme Q reductase deficiency Neuromuscular diseases Cytochrome b deficiency Friedreich’s ataxia, FHL1 Amyloidosis Familial ATTR Wild type ATTR (senile) AL amyloidosis​ Drug-​induced Tacrolimus Hydroxychloroquine Steroids Miscellaneous causes Hypertension In utero ritodrine HCl exposure Swyer’s syndrome (46, XY pure gonadal dysgenesis) AL, amyloid light chain; ATTR, amyloid transthyretin; FHL1, four and a half LIM domains 1; GSD, glycogen storage disorder; MELAS, myopathy, encephalopathy, lactic acidosis, stroke-​like episodes; MERFF, myoclonic epilepsy and ragged red fibres. 16.7.2  The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular 3471 Myocardial ischaemia Patients with hypertrophic cardiomyopathy have reduced coronary flow reserve and evidence for myocardial ischaemia during rapid atrial pacing and pharmacological stress. Myocardial ischaemia is almost certainly a major cause of exertional symptoms and may be a trigger for ventricular arrhythmia. However, detection of ischaemia in everyday clinical practice is challenging because conventional markers of ischaemia such as ST-​segment change and reversible per- fusion abnormalities on single photon emission computed tomog- raphy (SPECT) imaging correlate poorly with objective biochemical markers of ischaemia. Diagnosis Left ventricular hypertrophy in the absence of moderate to severe hypertension and valve disease occurs in about 1 in 500 adults. The prevalence of HCM in children is unknown, but population-​based studies report an annual incidence of 0.3–​0.5 per 100 000 (range 0.005–​0.07%). The diagnosis of HCM is based on the demonstra- tion of unexplained myocardial hypertrophy, defined as a wall thick- ness measurement exceeding two standard deviations for gender and age. In practice, in an adult of normal size the presence of a left ventricular myocardial segment of 1.5 cm or greater in thickness is diagnostic. Less stringent criteria should be applied to first-​degree relatives of an unequivocally affected individual, where the prob- ability of carrying the disease gene is 1 in 2 (Table 16.7.2.2). Problems in diagnosis may arise in patients with moderate to se- vere hypertension. The determinants of the hypertrophic response in a patient with hypertension are unknown, but are partly influ- enced by racial origin, with a greater increase in left ventricular mass in African-​Caribbean individuals. In general, however, hyper- trophic cardiomyopathy should be suspected in any individual with hypertension and a wall thickness in excess of 1.5 cm, particularly if the ECG shows widespread repolarization abnormalities or there is evidence of good blood pressure control. The physiological changes of athletic training can rarely mimic hypertrophic cardiomyopathy. Athletes who participate in events that combine both isometric and isotonic activities (e.g. rowing and cycling) have the greatest increases in left ventricular wall thick- ness. Pure strength training is associated with an increase in left ventricular mass and wall thickness relative to the left ventricular cavity size, but is rarely associated with an increase in absolute wall thickness (unless the athlete also uses anabolic steroids). A diag- nosis of hypertrophic cardiomyopathy in an elite athlete is likely when left ventricular wall thickness exceeds 1.6 cm in males and 1.4 cm in females and when they are symptomatic or have a family history of HCM. In athletes, the ECG frequently displays voltage criteria for left ventricular hypertrophy, sinus bradycardia, and sinus arrhythmia. Abnormal Q waves or marked repolarization ab- normalities are rare in elite athletes and should raise suspicion of myocardial disease. Echocardiographic features favouring hyper- trophic cardiomyopathy include small left ventricular cavity di- mensions, left atrial enlargement, left ventricular outflow gradients, and diastolic impairment. The absence of fibrosis on cardiac MRI may be helpful in differentiating HCM from physiological adapta- tion in athletes. Fig. 16.7.2.1  Transverse short-​axis section through the ventricles from patients with cardiomyopathy. Upper left shows symmetrical left ventricular hypertrophy in hypertrophic cardiomyopathy. Upper right shows dense white fibrous tissue obliterating the apex of both ventricles in endomyocardial fibrosis. Lower left shows a globular, dilated left ventricle in a child with dilated cardiomyopathy. Lower right shows a grossly dilated right ventricle with adipose infiltration of the right ventricular free wall in arrhythmogenic right ventricular dysplasia. Reproduced from Davies MJ, 1986, Colour Atlas of Cardiovascular Pathology, with permission from Oxford University Press. section 16  Cardiovascular disorders 3472 Clinical features History Symptomatic presentation may be at any age with breathlessness on exertion, chest pain, palpitation, syncope, or sudden cardiac death. HCM is occasionally found at autopsy in a stillborn baby or pre- sents during infancy with cardiac failure, which is usually fatal. In children and adolescents, the diagnosis is most often made during screening of siblings and offspring of affected family members. Paroxysmal symptoms or mild impairment of exercise tolerance are often present, but in the absence of a murmur, may not prompt car- diac evaluation. About 50% of adults present with symptoms; in the remainder the diagnosis is made during family screening or following the de- tection of an unsuspected abnormality on physical, electrocardio- graphic, or echocardiographic examination. Dyspnoea is common (>50%) as a consequence of elevated left atrial and pulmonary ca- pillary wedge pressures resulting from impaired left ventricular re- laxation and filling, and about 50% complain of chest pain, which is exertional, atypical, or both in similar proportions of patients. Atypical pain may have no obvious precipitant; more commonly it follows exercise-​or anxiety-​related tachycardia, when it persists for up to several hours after the stress has been removed without en- zymatic evidence of myocardial damage. Syncopal episodes occur in 15 to 25%, but in only a few are there findings suggestive of an ar- rhythmia or evidence of overt conduction disease: in most patients, the mechanism cannot be determined. Patients rarely present with paroxysmal nocturnal dyspnoea, ascites, or peripheral oedema. Physical examination In most patients with hypertrophic cardiomyopathy the physical examination is unremarkable. There may be a rapid upstroke ar- terial pulse reflecting dynamic left ventricular emptying. In about one-​third, the jugular venous pulse may demonstrate a prominent ‘a’ wave, reflecting diminished right ventricular compliance secondary to right ventricular hypertrophy. Many patients have a forceful left ventricular cardiac impulse, best appreciated on full-​held expiration in the left lateral position, when there may be a palpable atrial beat reflecting forceful atrial systolic contraction that may or may not be associated with significant forward flow of blood. The first and second heart sounds are usually normal, and—​unless the patient is in atrial fibrillation—​there is likely to be a loud fourth heart sound, reflecting increased atrial systolic flow into a non-​ compliant ventricle. However, in those patients (20–​30%) who have a resting left ventricular outflow tract gradient, the most obvious physical sign is an ejection systolic murmur. This murmur starts well after the first heart sound and ends before the second. It is best heard at the left sternal border, radiating towards the aortic and mi- tral areas, but not into the neck or the axilla. The intensity varies with changes in ventricular volume; it can be increased by physiological and pharmacological manoeuvres that decrease afterload or venous return (amyl nitrate, standing, Valsalva, and others), and decreased by manoeuvres that increase afterload and venous return (squatting, phenylephrine, and others). Occasionally there is an ejection sound at the onset of the systolic murmur. Most patients with a left ventricular outflow tract gradient also have mitral regurgitation. Doppler examination reveals that mitral regurgitation usually begins just before (30–​40 ms) the onset of the gradient and continues for the duration of systole. Radiation of the systolic murmur to the axilla is often the best auscultatory clue to the presence of coexistent mitral regurgitation, which may be mod- erate to severe, either alone or in association with a left ventricular outflow tract gradient. A mid-​diastolic rumble may sometimes re- sult from increased transmitral flow in patients with severe mitral regurgitation. Early diastolic murmurs of aortic incompetence may develop fol- lowing surgical myectomy or infective endocarditis involving the aortic valve. Although such murmurs are rare in the absence of such complications, they appear to occur more commonly than would be expected by chance and may reflect traction on the non​coronary Table 16.7.2.2  Major and minor criteria for the diagnosis of hypertrophic cardiomyopathy in adult members of affected families. Criteria are fulfilled if (1) one major echocardiographic, or (2) two minor echocardiographic, or (3) one minor echocardiographic plus two minor electrocardiographic abnormalities are seen Major criteria Minor criteria Echocardiography Left ventricular wall thickness ≥13 mm in the anterior septum or posterior wall or ≥15 mm in the posterior septum or free wall Left ventricular wall thickness of 12 mm in the anterior septum or posterior wall or of 14 mm in the posterior septum or free wall Severe SAM (septal–​leaflet contact) Moderate SAM (no septal–​leaflet contact) Redundant mitral valve leaflets Electrocardiography Left ventricular hypertrophy + repolarization changes (Romhilt and Estes) Complete bundle branch block or (minor) interventricular conduction defect (in LV leads) T-​wave inversion in leads I and aVL (≥3 mm) (with QRS–​T-​wave axis difference ≥30°), V3–​V6 (≥3 mm), or II and III and aVF (≥5 mm) Minor repolarization changes in LV leads Abnormal Q (>40 ms or >25% R wave) in at least two leads from II, III, aVF (in absence of left anterior hemiblock), V1–​V4; or I, aVL, V5–​V6 Deep S in V2 (>25 mm) Clinical There are no clinical major criteria Unexplained chest pain, dyspnoea, or syncope LV, left ventricular; SAM, systolic anterior motion of the mitral valve. Reproduced from Heart, McKenna WJ, et al., 77, 130–​2. Copyright 1997 with permission from the BMJ Publishing Group Ltd. 16.7.2  The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular 3473 cusp of the aortic valve by the septum. An ejection systolic murmur in the pulmonary area, reflecting right ventricular outflow tract ob- struction, is also rare; when present, it is usually associated with severe biventricular hypertrophy in the young or in those with co- existent Noonan’s syndrome and a dysplastic pulmonary valve (see Chapter 16.12). Prognosis Patients with hypertrophic cardiomyopathy experience slow pro- gression of symptoms and gradual deterioration of left ventricular function, and are at risk of sudden cardiac death throughout life. Annual mortality rates are in the range of 1–​2%, but the risk of death and other disease-​related complications varies between individuals and within individuals during the course of the disease. Severe heart failure symptoms may develop in association with progressive myocardial wall thinning caused by myocardial fibrosis and severe reduction in left ventricular systolic performance and/​ or diastolic filling. The development of systolic failure is associated with a poor prognosis, with rapid progression from onset to death or transplantation, and an overall mortality rate of up to 11% per year. Left atrial size provides important prognostic information on the risk of sudden cardiac death and atrial fibrillation/​flutter. Atrial arrhythmias are important in the clinical course, leading to a risk of acute deterioration and thromboembolic stroke. Onset of atrial fibrillation is part of the evolution of patients with diastolic dys- function, and with appropriate management need not represent a major cause of morbidity or mortality. A few patients who experi- ence such deterioration present with a clinical picture resembling restrictive cardiomyopathy, with grossly enlarged atria, signs of right heart failure, and relative preservation of left ventricular systolic performance. Left ventricular hypertrophy develops during childhood and ado- lescence, but is rarely progressive in adults. The trigger and other de- terminants of disease expression in late-​onset disease are uncertain. Investigations Cardiological evaluation of patients with hypertrophic cardiomyop- athy is performed to confirm the diagnosis, to guide symptomatic therapy, and to assess the risk of complications, particularly that of sudden death. Electrocardiography The 12-​lead ECG is the most sensitive diagnostic test, although oc- casionally normal (c.5%), particularly in the young. At the time of diagnosis, 5–​10% of patients are in atrial fibrillation. Many have an intraventricular conduction delay and 20% have left-​axis devi- ation, but complete right bundle or left bundle branch block is un- common (c.5%). The latter may develop following surgery and is occasionally seen in elderly patients. ST-​segment depression and T-​wave changes are the most common abnormalities and are usu- ally associated with voltage changes of left ventricular hypertrophy and/​or deep S waves in the anterior chest leads V1 to V3. Isolated repolarization changes or giant negative T waves are occasionally seen. Voltage criteria for left ventricular hypertrophy are rare in the absence of repolarization changes. About 20% of patients have ab- normal Q waves, either inferiorly (II, III, and aVF), or less com- monly in leads V1 to V3. P-​wave abnormalities of left and/​or right atrial overload are common. The distribution of the PR interval is similar to that in the normal population, but occasionally a short PR interval may be associated with a slurred upstroke to the QRS com- plex. This is not usually associated with evidence of pre-​excitation, although patients with hypertrophic cardiomyopathy and acces- sory pathways have been described. Despite the many electrocar- diographic abnormalities, there is no ECG that is typical of HCM; a useful rule is to consider the diagnosis whenever the ECG is bizarre, particularly in younger patients. The incidence of arrhythmias during 48-​h ambulatory elec- trocardiographic monitoring increases with age. Non​sustained ventricular tachycardia is detected in 20–​25% of adults and, al- though usually asymptomatic, is associated with an increased risk of sudden cardiac death. Supraventricular arrhythmias are also common in adults and can be poorly tolerated if sustained (>30 s) unless the ventricular response is controlled. Atrial fibrillation or flutter carry an increased risk of thromboembolism. By con- trast, most children and adolescents are in sinus rhythm, and ar- rhythmias during ambulatory electrocardiographic monitoring are uncommon. The increased incidence of supraventricular ar- rhythmias with age is related to increased left atrial dimensions and increased left ventricular diastolic pressure. The aetiology of ven- tricular arrhythmias is not known, but may relate to myocyte loss and myocardial fibrosis. Documented sustained ventricular tachy- cardia is uncommon, but is a recognized complication in patients with an apical aneurysm, which may develop as a consequence of midventricular obstruction. Chest radiography The chest radiograph may be normal or show evidence of left and/​or right atrial or left ventricular enlargement; if left atrial pressure has been chronically elevated, there may be evidence of redistribution of blood flow to upper lung zones. Mitral valve annular calcification is seen, particularly in elderly patients. Echocardiography Left ventricular hypertrophy may be symmetric or asymmetric and localized to the septum or the free wall, but most commonly to both the septum and free wall with relative sparing of the posterior wall (Fig. 16.7.2.2). Isolated apical hypertrophic cardiomyopathy oc- curs in about 10% of patients. Approximately one-​third of patients also have hypertrophy of the right ventricular free wall, the pres- ence and severity of which is strongly related to the severity of left ventricular hypertrophy. Typically, left ventricular end-​systolic and end-​diastolic dimensions are reduced, and the left atrial dimension is increased. Indices of systolic function such as ejection fraction may be increased, but systolic function is often impaired, which may be best appreciated by measurement of long-​axis rather than short-​ axis function. Colour Doppler provides a sensitive method of detecting left ventricular outflow tract turbulence (Fig. 16.7.2.3), and when combined with continuous wave Doppler the peak velocity (Vmax) of left ventricular blood flow can be measured and left ventricular outflow tract gradients calculated. Doppler gradients (pressure gradient (mm Hg) = 4 Vmax2) are seen in 20–​30% of patients and correlate well with those measured invasively. Systolic anterior motion of the mitral valve is usually present when the calculated outflow tract gradient is more than 30 mm Hg, and early closure or fluttering of the aortic valve leaflets is often seen in association section 16  Cardiovascular disorders 3474 with such motion. A posteriorly directed mitral regurgitant jet is seen in association with and related to the magnitude of the out- flow tract gradient (Fig. 16.7.2.3). An anterior regurgitant jet or mitral regurgitation in the absence of obstruction suggests the coexistence of structural mitral valve abnormalities. Other imaging techniques Good-​quality echocardiography suffices for diagnostic and thera- peutic purposes in most patients with hypertrophic cardiomy- opathy, but cardiac MRI is useful in selected cases to assess right ventricular, apical, and lateral left ventricular involvement. Gadolinium-​enhanced cardiac MRI permits detection of myo- cardial fibrosis, the extent of which may predict evolution to the burnt-​out phase. Cardiac catheterization Two-​dimensional echo/​Doppler evaluation has replaced invasive haemodynamic measurements and angiography as the method of assessing left ventricular structure and function in hypertrophic car- diomyopathy. Cardiac catheterization is not necessary for diagnosis and is rarely indicated unless symptoms are refractory and direct measurement of cardiac pressures is potentially informative, particu- larly in assessing the severity of mitral regurgitation. Coronary ar- teriography may be necessary to exclude coexistent coronary artery disease in older patients who have significant angina or ST-​segment changes during exercise. The left coronary arteries are usually large in calibre. The left anterior descending and septal perforator ar- teries may demonstrate narrowing during systole in the absence of fixed obstructive lesions, but such changes do not appear to relate to symptoms. Left ventricular angiography is rarely indicated, but rec- ognition of the abnormally shaped ventricle, which typically ejects at least 75% of its contents in association with mild mitral regurgi- tation, may provide a valuable diagnostic clue when hypertrophic cardiomyopathy was not suspected before catheterization. Exercise testing Maximal exercise testing in association with respiratory gas analysis provides useful functional and prognostic information, which can be monitored serially. Oxygen consumption at peak exercise (peak Vo2) is usually moderately reduced, even in patients who do not complain of exertional symptoms. Continuous measurement of the blood pres- sure during upright treadmill or bicycle exercise reveals that about one-​ third of younger patients (<40 years) have an abnormal blood pressure response, with either a drop of more than 10 mm Hg from peak record- ings or a failure to rise by 20 mm Hg or more despite an appropriate increase in cardiac output. Such changes are usually asymptomatic but are associated with an increased risk of sudden death. The mechanism of the hypotensive response during exercise in hypertrophic cardio- myopathy varies, but may relate to myocardial mechanoreceptor ac- tivation and altered baroreflex control causing inappropriate drops in systemic vasculature resistance, to a poor cardiac output response, or to exercise-​induced left ventricular outflow tract obstruction. ST-​segment depression of up to 2 mm from baseline is documented in 25% of patients, but appears not to be of prognostic significance. Electrophysiological studies Electrophysiological studies may occasionally be necessary in pa- tients with sustained, rapid palpitation to identify associated ac- cessory pathways or aid management of sustained monomorphic ventricular tachycardia. Conventional, programmed ventricular stimulation does not aid the identification of high-​risk patients (see ‘Risk stratification’). Tests for specific causes of hypertrophic cardiomyopathy Several clinical features that suggest particular causes of hypertrophic cardiomyopathy are listed in Table 16.7.2.3; the presence of such clues should trigger appropriate biochemical and genetic testing. Management Pharmacological The goal of therapy is to improve symptoms and prevent com- plications, in particular sudden cardiac death. β-​Adrenoreceptor Fig. 16.7.2.2  An echocardiogram (parasternal long-​axis view) of a patient with hypertrophic obstructive cardiomyopathy demonstrating hypertrophy of the interventricular septum (IVS), enlargement of the left atrium (LA), and systolic anterior motion of the mitral valve, bringing it into contact with the septum (arrow). Fig. 16.7.2.3  Colour-​flow Doppler image (parasternal long-​axis view) of the same patient as shown in Fig. 16.7.2.2, demonstrating left ventricular outflow tract (LVOT) turbulence and mitral regurgitation (MR) with a posteriorly directed jet. 16.7.2  The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular 3475 blockers and calcium antagonists, especially verapamil, are the mainstay of symptomatic pharmacological therapy. Both drugs have several potentially beneficial actions, including a decrease in myo- cardial oxygen consumption and blunting of the heart rate response during exercise, thereby increasing time for filling. Both agents exert a negative inotropic effect, thereby reducing hyperdynamic systolic function and left ventricular gradients, and they may improve dia- stolic function, verapamil by improving relaxation and β-​blockers by increasing compliance. The side effects of propranolol are rarely serious, but the suppressant effect of verapamil on atrioventricular nodal conduction may cause problems in patients with unsuspected pre-​existing conduction disease, and its vasodilatory and negative inotropic effects can result in acute pulmonary oedema and death in symptomatic patients with severe obstruction and pulmonary hypertension. Disopyramide may be added if β-​adrenoreceptor blockers and cal- cium antagonists are ineffective in patients with LV outflow tract obstruction. This Class IA antiarrhythmic drug can abolish LV out- flow pressure gradients and improve exercise tolerance and func- tional capacity without proarrhythmic effects. Anticholinergic side effects including dry eyes and mouth, urinary hesitancy or reten- tion, and constipation are dose-​limiting. Endocarditis is a rare complication of hypertrophic cardiomy- opathy, occurring predominantly in patients with left ventricular outflow tract turbulence and/​or mitral regurgitation. Current guide- lines no longer support the previous recommendation of antibiotic prophylaxis in patients with outflow tract obstruction or intrinsic valve disease. Surgical Surgery is a therapeutic option in patients with LV outflow tract ob- struction. The conventional indication for surgery is a resting left ventricular outflow tract gradient of more than 50 mm Hg in patients refractory to medical therapy, and the commonest operation is the removal of a segment of the upper anterior septum (myectomy) via a transaortic approach. Transventricular approaches have been used, but these are associated with a higher incidence of late complica- tions, particularly of cardiac failure. Mitral valve repair and papillary muscle remodelling may be required, and mitral valve replacement has also been advocated; excellent results can be achieved in patients with severe mitral regurgitation, but operative mortality and mor- bidity are higher. Specialist hypertrophic cardiomyopathy centres re- port perioperative mortality of 1% or less for septal myectomy, with 70–​80% success in abolishing gradients and improving symptoms. Alcohol septal ablation Injection of alcohol into the septal artery that supplies the septal muscle has been developed as a percutaneous approach to gra- dient reduction. Most experienced centres have reported symp- tomatic improvement in 70% of patients. As for surgery and dual-​chamber (DDD) pacing (see next), patient selection—​in par- ticular, regarding the mechanism of the gradient—​and technical considerations are important determinants of outcome. The major complication has been the need for a pacemaker in up to 20%. At present, alcohol septal ablation offers a therapeutic option that is especially used in older patients with suitable anatomy who are refractory to drugs. Pacing Alteration of the ventricular activation sequence by pacing the right ventricular apex may result in reduction of gradients and filling pressures and improved symptoms in selected patients. The role of atrioventricular synchronous pacing (DDD pacing) in symptom- atic management of obstruction has been evaluated in two random- ized multicentre trials, demonstrating symptomatic improvement and gradient reduction (50%), but no change in exercise capacity. Table 16.7.2.3  Clinical features suggesting the aetiology of hypertrophic cardiomyopathy Clinical feature Examples Symptoms Acroparaesthesiae, tinnitus, deafness (Anderson–​Fabry disease) Skeletal muscle weakness (desminopathy, mitochondrial cytopathy, and others) Physical examination Retinitis pigmentosa (mitochondrial, Danon disease, and others) Postural hypotension (amyloidosis) Cutaneous angiokeratoma (Anderson–​Fabry disease) Lentigines (LEOPARD syndrome) Facial morphology (Noonan, Anderson–​Fabry disease, and others) Electrocardiogram Glycogen storage disease: short PR interval, left ventricular hypertrophy Anderson–​Fabry disease: short PR interval, left ventricular hypertrophy, repolarization abnormalities, bundle branch block, AV conduction delay Amyloidosis: low voltage QRS, pseudoinfarct pattern, atrial arrhythmias Mitochondrial disease: conduction defects, accessory pathways Danon: pre-​excitation, left ventricular hypertrophy AMP kinase: pre-​excitation/​premature conduction disease Echocardiography Concentric/​biventricular hypertrophy (infiltrative and storage disorders and others) Valve thickening (Anderson–​Fabry disease, amyloidosis, and others) Family history X-​linked inheritance (Anderson–​Fabry disease, Danon, and others) Diabetes, epilepsy, and deafness (mitochondrial) Biochemistry Creatine kinase (glycogen storage disease, mitochondrial, and others) Lactate (mitochondrial) Renal dysfunction (Anderson–​Fabry disease, mitochondrial, and others) Paraproteinaemia (amyloid) Exercise testing Severe premature acidosis (mitochondrial) section 16  Cardiovascular disorders 3476 However, the placebo effect of the procedure was considerable. Nevertheless, pacing offers a therapeutic option in patients with obstruction that is refractory to drug treatment, and in whom sur- gery is either not acceptable or inappropriate. It appears that elderly patients with localized septal hypertrophy and without significant free wall involvement or mitral regurgitation may be the most likely to respond. Clinical approach to individual symptoms Dyspnoea Dyspnoea most often occurs in patients who also experience chest pain or discomfort. Treatment depends on the predominant mechanism. In patients with dyspnoea who have slow filling that continues throughout diastole, β-​blockers and verapamil are appro- priate. Conversely, those with rapid, early filling may benefit from a relative tachycardia and do better without negative chronotropic agents. When dyspnoea is associated with significant obstruction, β-​blockers, disopyramide, and (failing these) myectomy or the other non​pharmacological options may be beneficial. Disopyramide should be used in the maximum tolerated dose (anticholinergic side effects may limit higher doses) in conjunction with a conven- tional β-​blocker. Occasionally, dyspnoea is associated with severe mitral regurgitation and responds well to mitral valve repair or replacement. Chest pain Exertional chest pain often responds to therapy with β-​adrenoreceptor blockers and calcium antagonists, and when refractory can respond to very high doses of these agents (propranolol 480 mg daily, bisoprolol 10 mg daily, and verapamil 480 mg daily). Short-​acting nitrates, di- uretics, and high-​dose verapamil may be useful in selected patients, perhaps by reducing filling pressures and improving coronary flow to subendocardial layers. Atypical chest pain may persist long after the initial stimulus has been removed. Arrhythmia Arrhythmias are a common complication of hypertrophic cardio- myopathy. The overall prevalence and annual incidence of atrial fibrillation are around 23% and 3%, respectively. Treatment with anticoagulants and verapamil or β-​blockers is appropriate once atrial fibrillation is established, the aims being to control the ven- tricular response and prevent emboli. Most patients who develop atrial fibrillation during electrocardiographic monitoring are un- aware of changes from sinus rhythm to atrial fibrillation as long as the ventricular response is well controlled. However, in a few cases the loss of atrial systolic contribution to filling volume is important, when electrical cardioversion can be facilitated by prior therapy (4–​6 weeks) with amiodarone (300 mg daily) if pharmacological cardioversion does not occur first. Sustained (>30 s) episodes of paroxysmal atrial fibrillation or supraventricular tachycardia can cause haemodynamic collapse and systemic emboli. Low-​dose amiodarone (1000–​1400 mg weekly) is effective in suppressing such episodes and also provides control of the ventricular response should breakthrough occur. All patients with atrial fibrillation or flutter should be considered for anticoagulation (unless contraindicated) as embolic complications are common, even when atrial dimensions are only moderately increased. Non​sustained episodes of supraventricular arrhythmia are common, and although often asymptomatic, they are a marker (al- beit of low positive predictive accuracy) for the subsequent devel- opment of established atrial fibrillation. The threshold to introduce amiodarone or β-​adrenoreceptor blockers and calcium antagonists, with or without anticoagulation, should be low if they occur in the presence of atrial enlargement. Episodes of non​sustained ventricular tachycardia are common but are rarely symptomatic: therapy is war- ranted only if it can be shown to improve prognosis (see prevention of sudden cardiac death). Prevention of sudden cardiac death Sudden cardiac death is a consequence of multiple interacting mech- anisms. The histological abnormalities—​particularly myocyte dis- array, small-​vessel disease, and replacement scarring—​contribute to the underlying anatomical substrate. Events may be triggered by haemodynamic alterations, myocardial ischaemia, and arrhythmias, including ventricular tachycardia, atrial fibrillation, atrioventricular block, and rapid conduction of a supraventricular arrhythmia via an accessory pathway. Intense physical exertion may also contribute to the aforementioned triggers. The interaction of triggers and sub- strate may be modified by inappropriate peripheral vascular re- sponses and the development of myocardial ischaemia. Risk stratification Prevention of sudden death relies on risk factor stratification to identify a high-​risk cohort who will benefit from an implantable cardioverter–​defibrillator (ICD). Several adverse features that can be elicited from the clinical history and non​invasive evaluation have been identified (Box 16.7.2.1). Their relative importance varies with age; for example, the finding of non​sustained ventricular tachy- cardia on 24-​h electrocardiographic monitoring in children and adolescents is uncommon (<5%), but is associated with an eightfold increased risk of sudden death, whereas in adults this arrhythmia is common (20–​25%), but in isolation confers only a twofold increased risk. In young people (<25  years) the finding of non​sustained ven- tricular tachycardia, severe and extensive left ventricular hyper- trophy, unexplained syncope (particularly if recurrent or exertional), or a family history where a high proportion of affected individuals experienced premature (<40 years) sudden death warrants prophy- lactic treatment. Such patients usually also exhibit abnormal blood pressure responses to exercise; indeed, the finding of a normal ex- ercise blood pressure response appears to identify the low-​risk younger (<40 years) patient (negative predictive accuracy 97%), al- lowing appropriate reassurance that is also clinically important. In Box 16.7.2.1  Risk factors for sudden death • Family history of sudden death (≥1 premature (<40 years) sudden death) • Unexplained syncope within previous year • Abnormal exercise blood pressure • Non​sustained ventricular tachycardia (≥3 beats at ≥120 beats/​min) • Severe left ventricular hypertrophy (>3 cm) • Severe left ventricular outflow tract obstruction (>90 mm Hg) • Cardiac arrest (or sustained ventricular tachycardia) 16.7.2  The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular 3477 adults aged 25 to 60 years, the positive predictive accuracy for each of the risk factors is much lower (15–​20%): conventionally, prophy- lactic treatment was advised for those with two or more risk factors who would have a predicted risk of sudden death of at least 3% per year. Those with a single risk factor have an annual sudden death risk of 1%, but the confidence limits range from 0.2 to 2%, indicating that some but not all single risk factor patients may benefit from an ICD. Recently, a large multicentre longitudinal cohort study of 3675 patients (HCM-​RISK SCD) developed and validated a statistical sudden cardiac death risk prediction model, which provides indi- vidualized risk estimates. This model uses left atrial diameter, peak left ventricular outflow tract gradient, and patient age, together with the same major risk factors recommended in previous guidelines (with the exception of abnormal blood pressure response) to esti- mate the risk of sudden cardiac death at 5 years. It is important to consider risk in all patients, even those who are asymptomatic or who have mild echocardiographic features of hypertrophic cardio- myopathy. Although children and adolescents with severe congestive symptoms may be at greater risk, the data reveals that the severity of chest pain, dyspnoea, and exercise limitation are not reliable pre- dictors of the risk of sudden death in adults. In addition, it is recog- nized that most patients who die suddenly have mild (1.5–​2.0 cm) or moderate (2.0–​2.5 cm) left ventricular hypertrophy, while some genetic defects (e.g. cardiac troponin T) may cause sudden death in the absence of symptoms or hypertrophy. The presence of a left ventricular outflow tract gradient is also as- sociated with sudden death. The management of symptomatic pa- tients should be focused on gradient reduction; in asymptomatic patients, severe left ventricular outflow tract obstruction should be considered in the overall risk profile of the patient. Diastolic impair- ment with abnormal Doppler filling patterns associated with symp- tomatic limitation and poor prognosis, and atrial enlargement is associated with premature sudden cardiac death. Some investigators have suggested that the induction of sus- tained ventricular arrhythmias during programmed electrophysio- logical stimulation is associated with a higher risk of sudden death. However, the predictive accuracy is low, and as most high-​risk patients can be identified using non​invasive clinical markers, the inherent risks and inconvenience associated with programmed stimulation dictate that it should not be used routinely to assess risk in hypertrophic cardiomyopathy. Dilated cardiomyopathy Definition Dilated cardiomyopathy (DCM) is a heart muscle disorder defined by dilatation and impaired systolic function of the left ventricle or both ventricles in the absence of coronary artery disease, valvular abnor- malities, or pericardial disease. Systolic dysfunction is defined by an abnormal LV ejection fraction, preferably demonstrated by echocar- diography or MR imaging. LV dilatation is defined by LV end-​diastolic volumes or diameters greater than 2SD from normal according to standard nomograms. Many different cardiac and systemic diseases are associated with left ventricular dilatation and impaired contract- ility (see Chapter 16.7.3). When no identifiable cause is found, the condition is referred to as idiopathic dilated cardiomyopathy. Dilated cardiomyopathy has been described in Western, African, and Asian populations, affecting both genders and all ages. In North America and Europe, symptomatic dilated cardiomyopathy has an incidence and prevalence of 20 and 38 per 100 000, respectively, and is the commonest indication for cardiac transplantation. A recent position statement from the European Society of Cardiology (ESC) working group on myocardial and pericardial diseases proposed a revised definition of DCM (Fig. 16.7.2.4) to Preclinical or early phase (Relative of patients with DCM or hypokinetic non dilated CM) DCM clinical spectrum No cardiac expression Isolated ventricular dilation Arrhythmic CM Hypokinetic nondilated CM Dilated CM Clinical phase (Mutation carrier and/or AHA positive) (Dilation/no hypokinesia)* ∧ (Arrhythmias or conduction defect) (Hypokinesia/no dilation) Progressive expression of the phenotype *Shown by two independent imaging modalities, ∧mutation carrier or not, anti-heart autoantibody (AHA) positive or negative (LV dilation + hypokinesia) (HNDC or DCMND-H) (DCMD-H) (DCMD-NH, with or without Mut+AHA+) (DCMND-NH-A/CD, with or without Mut+AHA+) (DCMND-NH-Mut+AHA+) ∧ ∧ (no LV abn, no arrhythmia) Fig. 16.7.2.4  Description of the clinical spectrum of DCM. LV abn, left ventricle abnormality. DCM can be further classified as ND or D (non​dilation/​dilation) or NH or H (non​hypokinetic/​hypokinetic) or mut + (mutation carrier) or AHA + (antiheart autoantibody positive) or A/​CD (arrhythmia/​conduction defect). Reprinted from Pinto YM, et al. (2016). Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non​dilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases. Eur Heart J, 37(23), 1850–​8, by permission of Oxford University Press. section 16  Cardiovascular disorders 3478 encompass both preclinical or early phase and the clinical phase of the disease. The DCM clinical spectrum includes isolated ven- tricular dilatation or arrhythmic DCM in the preclinical or early phase, hypokinetic non​dilated cardiomyopathy, and dilated cardio- myopathy. The definition of hypokinetic non​dilated cardiomyop- athy requires LV ejection fraction less than 45% that is not explained by abnormal loading conditions or coronary artery disease. Causes Syndromic diseases (e.g. mitochondrial diseases), drug toxicity, toxins, nutritional deficiency, electrolyte disturbances, endocrine abnormalities, infection, and auto-​immune disease are important causes of DCM and need to be considered in the differential diag- nosis (see Chapter 16.7.3). Pedigree analysis of patients with ‘idiopathic’ DCM reveals fa- milial disease in at least 25% of cases; a further 20–​30% of relatives have mild abnormalities of left ventricular performance that evolve into dilated cardiomyopathy in about one-​third. Inheritance is usu- ally autosomal dominant with incomplete penetrance, with a smaller number of families having X-​linked transmission. Penetrance is age dependent and has been estimated to be 10% in those aged less than 20 years, 34% in young adults aged 20 to 30 years, 60% in adults aged 30 to 40 years, and 90% in those over 40 years. Guidelines for the diagnosis of familial disease based on the iden- tification of major and minor criteria are shown in Box 16.7.2.2 and Fig. 16.7.2.5. If a relative satisfies the criteria for DCM or hypokinetic non​dilated cardiomyopathy just described, then they have definite disease. They have probable disease if they have one major plus at least one minor criterion, or have one major criterion and are carrying the proband’s causative mutation. They have possible disease if they have two minor criteria, one minor criterion, and are carrying the proband’s causative mutation, or have one major criterion but without any minor criterion and without genetic information from the family. Disease-​causing mutations are reported in numerous genes, most of which are important in maintaining cardiomyocyte cytoskeletal integrity, including dystrophin, metavinculin, cardiac actin (auto- somal dominant), lamin A/​C (associated with premature conduc- tion disease and sudden death), desmin, myosin-​binding protein C, troponin T and C, β-​myosin heavy chain, and Z-​line associated pro- tein (ZASP). Lamin A/​C mutations also cause Emery–​Dreifuss and limb-​girdle muscular dystrophy and familial partial lipodystrophy; desmin may cause conduction disease with restrictive cardiomyop- athy; dystrophin mutations cause childhood (Duchenne) and adult (Becker) forms of muscular dystrophy. Myotonic dystrophy—​type I (DM1) due to mutations in DMPK and type II (DM2) due to mu- tations in CNBP—​can be associated with AV block. A further gene mutation implicated in the development of dilated cardiomyopathy (DCM) is titin (TTN), which is a connectin linking the Z-​line to the M-​line in the sarcomere. The frequency of TTN mutations is high in subjects with dilated cardiomyopathy (27%), but they are also found in some normal individuals. Other genes implicated include RNA-​binding Motif-​20 (RBM 20), myopalladin (MYPN), sodium channel α-unit (SCN5A), BaCl2-​associated athanogene 3 (BAG3), and phospholamban (PLN). Different patterns of disease expression are recognized. Disease progression appears to be slow (over decades) in most cases, and conduction disturbance is a late complication related to disease se- verity. However, in some families (<10%), particularly those with mutations in the lamin A/​C gene, the early stages are character- ized by progressive conduction disease, and left ventricular dilata- tion and impairment are later manifestations, in the fourth to sixth decade. Sudden death in the absence of severe left ventricular im- pairment is seen in disease caused by mutations in lamin A/​C or desmosomal genes. Pathology and pathophysiology Macroscopic examination of hearts with dilated cardiomyopathy re- veals dilated cardiac chambers (see Fig. 16.7.2.1), mural thrombi, and platelet aggregates with normal extra-​and intramural coronary Index case DCM (dilated LV & reduced EF) Familial Nonfamilial yes yes yes Probable disease Definitive disease (DCM/HNDC) Possible disease Possible disease No disease +≥1 minor criterion? OR mutation carrier? ≥2 minor without mutation carrier? OR 1 minor criterion + mutation carrier? yes no no no no Relative Criteria as for index cases? Major criteria for relatives? (dilated LV OR LV EF 45–50%) HNDC (EF <45% & no dilation) Fig. 16.7.2.5  Diagnostic criteria for DCM in probands (index cases) and relatives. Reprinted from Pinto YM, et al. (2016). Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non​dilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases. Eur Heart J, 37(23), 1850–​8, by permission of Oxford University Press. Box 16.7.2.2  Diagnostic criteria for relatives of an index case of dilated cardiomyopathy Major criteria • Unexplained decrease of LV ejection fraction to <50% (but >45%) • Unexplained LV end-​diastolic dilatation (>2SD + 5%) according to standard nomograms Minor criteria • ECG showing complete left bundle branch block or atrioventricular block • Unexplained ventricular arrhythmia • Left ventricular segmental wall motion abnormalities in the absence of intraventricular conduction defect • Late enhancement of non​ischaemic origin on cardiac MR imaging • Evidence of non​ischaemic myocardial abnormalities (inflammation, necrosis and/​or fibrosis) on endomyocardial biopsies • Presence of serum organ-​specific and disease-​specific antiheart anti- bodies by one or more autoantibody tests Adapted from Pinto YM, et al. (2016). Proposal for a revised definition of di- lated cardiomyopathy, hypokinetic non-​dilated cardiomyopathy, and its im- plications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases. Eur Heart J, 37(23),1850–​8. 16.7.2  The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular 3479 arteries. Myocardial mass is increased, but ventricular wall thick- ness is normal or reduced. Histology is non​specific with patchy perimyocyte and interstitial fibrosis, various stages of myocyte death, as well as myocyte hypertrophy and often extensive myofibrillary loss, resulting in a vacuolated appearance of the myocytes. An inter- stitial T-​lymphocyte infiltrate and focal accumulations of macro- phages associated with individual myocyte death are common. The identification of disease-​causing mutations in genes encoding various components of the cardiac myocyte cytoskeletal and sarcomeric contractile apparatus shows that the pathogenesis of di- lated cardiomyopathy is heterogeneous. Two models have been pro- posed to explain ventricular remodelling in dilated cardiomyopathy. In the ‘final common pathway’ hypothesis, dilated cardiomyopathy reflects a non​specific degenerative state, which may result from a variety of stimuli, including genetic mutations, viral infections, toxins, and volume overload. The alternative hypothesis suggests that several distinct, independent pathways can remodel the heart and cause dilated cardiomyopathy—​in other words, the different causes of dilated cardiomyopathy share a common histopathology, but their molecular biology is distinct. The final common pathways resulting in dilated cardiomyopathy include altered myocyte ener- getics and calcium handling. Clinical features History Initial presentation is usually with symptoms of cardiac failure (fa- tigue, breathlessness, decreased exercise tolerance, and others), but arrhythmia (atrial fibrillation, ventricular tachycardia, atrioven- tricular block), systemic embolism, or the incidental finding of an ECG or radiographic abnormality during routine screening may prompt earlier diagnosis. Physical examination Physical examination may be entirely normal or may reveal evi- dence of myocardial dysfunction with cardiac enlargement and signs of congestive heart failure. Systolic blood pressure is often low, with a narrow pulse pressure and a low-​volume arterial pulse. Pulsus alternans may be present in patients with severe left ven- tricular failure, and the jugular veins may be distended, with a prom- inent V wave reflecting tricuspid regurgitation. In such patients, the liver may be engorged and pulsatile, and there is usually peripheral oedema and ascites. The precordium often reveals a diffuse and dyskinetic left (and occasionally right) ventricular impulse. The apex is usually displaced laterally, reflecting ventricular dilatation. The second heart sound is usually normally split, but paradoxical split- ting may be present when there is left bundle branch block, which occurs in about 15% of patients. With severe disease and the de- velopment of pulmonary hypertension, the pulmonary component of the second heart sound may be accentuated. Characteristically, a presystolic gallop or fourth heart sound is present before the de- velopment of overt cardiac failure. However, once cardiac decom- pensation has occurred, ventricular gallop or third heart sound is often present. When there is significant ventricular dilatation, sys- tolic murmurs are common, reflecting mitral and (less commonly) tricuspid regurgitation. The development of unexplained cardiac failure in the last month of pregnancy or 5  months post-​partum is termed peripartum cardiomyopathy. There is sometimes uncertainty whether the car- diac failure is acute or chronic and exacerbated by the haemo- dynamic stress of pregnancy and labour. When the heart failure is acute and there is persistence of left ventricular chamber dilatation or impaired systolic performance, the diagnosis of peripartum car- diomyopathy can legitimately be made. An abnormally cleaved pro- lactin producing a raised 16 kDa prolactin level (normal prolactin is 23 kDa) has been identified in some patients with peripartum cardiomyopathy and, in a pilot study, treatment with the prolactin inhibitor bromocriptine improved left ventricular function and outcome. The diagnostic utility of urinary 16 kDa prolactin, its potential genetic basis, and the spectrum of therapeutic utility of bromocriptine remain to be determined. Genetic predisposition to peripartum cardiomyopathy includes mutations in titin (TTN) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which alters oxidative stress and has been reported to be involved in the pathogenesis. For further discussion of cardiac disease in preg- nancy, see Chapter 14.6. Prognosis The natural history of dilated cardiomyopathy is uncertain because the diagnosis is usually not made until clinical features, which are late manifestations of the disease, become obvious. Follow-​up of asymptomatic first-​degree relatives suggests that disease progres- sion is insidious over decades. An upper respiratory tract infection or a salt or fluid load can precipitate clinical presentation. Symptoms develop when filling pressures rise or when stroke volume dimin- ishes sufficiently to cause salt and water retention and oedema. Once clinical symptoms and signs of impaired ventricular performance are apparent, prognosis is related to the degree of left ventricular dilatation and impaired contractile performance, but survival has been substantially improved by modern management with angio- tensin converting enzyme (ACE) inhibitors, β-​blockade, mineralo- corticoid antagonists, aggressive treatment of arrhythmias, and cardiac transplantation. Arrhythmia Atrial arrhythmias, particularly atrial fibrillation, are common and associated with the severity of symptoms, left ventricular dys- function, and poor prognosis, but atrial fibrillation is not an inde- pendent predictor of disease progression or sudden cardiac death. Occasionally, however, persistent atrial tachycardia or atrial fibril- lation may cause gradual deterioration in left ventricular function, resembling dilated cardiomyopathy (‘tachycardia induced cardio- myopathy’). In this situation, systolic function usually returns to normal with control of the arrhythmia. Ventricular arrhythmias are common and like supraventricular arrhythmias are markers of disease severity. Non​sustained ven- tricular tachycardia during ECG monitoring is seen in about 20% of asymptomatic or mildly symptomatic patients and in up to 70% of those who are severely symptomatic. The prognostic sig- nificance of this arrhythmia is controversial: its presence early in the course of disease, when left ventricular function is relatively preserved, is probably an independent marker of sudden death risk, whereas in general markers of haemodynamic severity (such as ejection fraction, left ventricular end-​diastolic dimension, or filling pressures) are more predictive of disease-​related mortality section 16  Cardiovascular disorders 3480 and sudden death. Risk of sudden death in patients with severe disease (New York Heart Association, NYHA class III or IV) in- creases approximately threefold when syncope is present. Investigation Electrocardiography The electrocardiographic features of dilated cardiomyopathy are non​specific and highly variable. Sinus tachycardia is common ­(particularly in children and infants); non​specific ST-​segment and T-​wave changes may be seen, most commonly in the inferior and lateral leads; and pathological Q waves may be present in the septal leads in patients with extensive left ventricular fibrosis. Atrial en- largement is common, and in advanced disease may be associated with bundle branch block. All degrees of atrioventricular block may also be seen and should raise the possibility of mutations in specific genes such as lamin A/​C and DES (which encodes desmin) if associ- ated with relatively mild impairment of left ventricular function, or when present in a young patient. Chest radiography The chest radiograph is usually abnormal in patients with dilated cardiomyopathy, except in a rare subset of patients with acute viral myocarditis associated with left ventricular systolic impairment and preserved cavity dimensions. An increased cardiothoracic ratio (>0.5) is typically seen, reflecting left ventricular and left atrial dila- tation. Increased pulmonary vascular markings and pleural effu- sions may be present in patients with elevated left ventricular filling pressures. Echocardiography Echocardiography is used to identify the presence of left ventricular cavity dilatation and systolic impairment, which are the typical fea- tures of the condition. In general, the presence of ventricular end-​ diastolic dimensions more than two standard deviations above body surface area-​corrected mean values and fractional shortening less than 25% are sufficient to make the diagnosis (Fig. 16.7.2.6). Two-​dimensional echocardiography is also used to determine whether intracavitary thrombus is present in the ventricles. Colour-​flow Doppler may be used to determine the presence and quantify the severity of functional mitral and tricuspid regurgitation (Fig. 16.7.2.7). Pulsed wave and-​continuous wave Doppler can be used to estimate pulmonary artery pressures. Patients with dilated cardiomyopathy usually have abnormalities of diastolic left ven- tricular function in addition to systolic impairment: these can be assessed using mitral inflow, pulmonary vein, and tissue Doppler parameters. Cardiac biomarkers Serum creatine kinase should be measured in all patients with di- lated cardiomyopathy because this simple test may provide an important clue to the aetiology of the condition (e.g. muscular dys- trophy, lamin A/​C defect, and others). Other cardiac biomarkers (e.g. troponin I and troponin T), may also be elevated in dilated cardiomyopathy, particularly in association with an inflammatory cause. Plasma natriuretic peptide levels are elevated in chronic heart failure and predict mortality. Many of the systemic diseases that are associated with heart muscle disorders have typical clinical, immunological, and biochemical features (see Chapter 16.7.3), and in the absence of clinical clues to (a) (b) Fig. 16.7.2.6  Echocardiographic appearances of two patients with familial dilated cardiomyopathy. (a) Parasternal long-​axis view showing significant left atrial (LA) and biventricular dilatation with a thin intraventricular septum (IVS). (b) Apical four-​chamber view demonstrating a globular dilated left ventricle. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. Fig. 16.7.2.7  Colour-​flow Doppler image of the same patient as shown in Fig. 16.7.2.6a demonstrating a regurgitant tricuspid jet (TR). 16.7.2  The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular 3481 suggest a systemic disease an exhaustive ‘routine screen’ is probably not cost-​effective. There are, however, several potential reversible secondary causes of heart muscle disorder that may simulate dilated cardiomyopathy, and basic screening tests should include serum phosphorus (hypophosphataemia), serum calcium (hypocalcaemia), serum creatinine and urea (uraemia), thyroid function tests (hyper- thyroidism), and serum iron and ferritin (haemochromatosis). Exercise testing Symptom-​limited exercise testing (treadmill or bicycle) combined with respiratory gas analysis is a useful technique to assess func- tional limitation in patients with dilated cardiomyopathy and pro- vides a means of objectively evaluating disease progression. The detection of respiratory markers of severe lactic acidaemia during metabolic exercise testing may suggest a mitochondrial or other metabolic cause for dilated cardiomyopathy. Assessment of exercise capacity is essential in the assessment of patients prior to cardiac transplantation. Cardiac catheterization Cardiac catheterization is performed to exclude coronary artery disease as a cause of impaired systolic function. Haemodynamic assessment of left ventricular end-​diastolic and pulmonary ar- tery pressures is performed as part of cardiac transplant work-​up. Endomyocardial biopsy may be diagnostic and is recommended in patients with clinically suspected myocarditis (i.e. acute chest pain in the absence of coronary artery disease), new-​onset (days up to 3 months) or worsening of dyspnoea at rest or exercise with or without left and/​or right heart failure signs, unexplained arrhythmia and/​or aborted sudden cardiac death or unexplained cardiogenic shock, in the presence of biochemical markers of cardiac damage or compatible cardiac imaging features. See Chapter 16.7.1 for fur- ther discussion. Endomyocardial biopsy should also be considered when there is a clinical suspicion of storage or metabolic disease that cannot be confirmed by other means. Cardiac MRI Cardiac MRI may be a useful alternative imaging technique in patients with poor echocardiographic windows. In addition, the de­tection of fibrosis with gadolinium contrast enhancement may provide additional prognostic and diagnostic information. Cardiac MRI is also helpful in suspected myocarditis. In ischaemic car- diomyopathy, cardiac MRI shows segmental wall motion abnor­ malities or wall thinning in a particular coronary territory in addition to subendocardial or transmural late gadolinium en- hancement, whereas in non​ischaemic cardiomyopathy this en- hancement is located mostly in the mid-​wall to subepicardial layer. A non​transmural, patchy or epi/​mid-​myocardial distribution may therefore help exclude myocardial infarction as the cause of left ventricular dysfunction. Inflammatory cell injury leads to in- creased cell permeability and tissue oedema, which cardiac MRI can detect by T2-​weighted imaging. Electrophysiological testing Programmed electrical stimulation is of limited clinical value in the identification of high-​risk patients. Polymorphic ventricular tachy- cardia is inducible in up to 30% of cases, but this is a non​specific finding. Approximately 10% of patients have inducible sustained monomorphic ventricular tachycardia; about one-​third of these die suddenly, but most (75%) who die in this way do not have indu- cible ventricular tachycardia during programmed stimulation. In some patients, ventricular tachycardia arises as the consequence of bundle branch re-​entry. This tachycardia is typically rapid (mean cycle length 280 ms) and uses a macro re-​entrant circuit that in- volves the His–​Purkinje system, usually with right bundle branch anterograde conduction and left bundle branch retrograde con- duction. Differentiation from myocardial ventricular tachycardia is confirmed by the presence of a His or right bundle branch potential preceding each QRS: diagnosis is important since catheter ablation of either the left or right bundle branch is usually curative. Management Management in dilated cardiomyopathy aims to improve symptoms, to attenuate disease progression, and prevent arrhythmia, stroke, and sudden death. Pharmacological treatment Symptomatic therapy is the treatment of heart failure with reliance on diuretics, ACE inhibitors, and β-​blockers (see Chapters 16.5.2 and 16.5.3). Diuretics Loop and/​or thiazide diuretics should be used in all patients with fluid retention to achieve a euvolaemic state, but they should never be used as monotherapy as they exacerbate neurohormonal activa- tion, thereby worsening disease progression. The aldosterone antag- onist, spironolactone, reduces the overall risk of death by 30% in adults with severe heart failure (NYHA class IV and ejection frac- tion <35%): side effects include hyperkalaemia (infrequent in the presence of normal renal function) and painful gynaecomastia. Eplerenone is similar to spironolactone but more selective for the mineralocorticoid receptor, thus avoiding oestrogenic problems such as gynaecomastia. ACE inhibitors and angiotensin receptor blockers Activation of the renin–​angiotensin–​aldosterone system is central to the pathophysiology of heart failure, regardless of the underlying aetiology, and ACE inhibitors should be considered in all patients with dilated cardiomyopathy. Many clinical trials have shown that ACE inhibitors improve symptoms, reduce hospitalizations, and reduce cardiovascular mortality in adults with symptomatic heart failure, and reduce the rate of disease progression in asymptomatic patients. ACE inhibitors are usually well tolerated, the most common side effects being cough and symptomatic hypotension. The angiotensin receptor blockers (ARBs) have similar haemo- dynamic effects to ACE inhibitors. Clinical trials in adults with heart failure have shown similar efficacy, and safety to ACE inhibitors, such that ARBs are currently recommended in adults who are in- tolerant of ACE inhibitors. Combination treatment with ACE in- hibitors and ARBs may be more beneficial at preventing ventricular remodelling than either drug alone, but with little additional benefit on overall survival. Combination therapy of sacubitril (a neprilysin inhibitor) and valsartan (ARB) has shown significant symptomatic and prog- nostic benefit in patients treated for heart failure. Neprilysin is a neutral endopeptidase that degrades vasoactive peptides including section 16  Cardiovascular disorders 3482 natriuretic peptides, hence its inhibition leads to vasodilatation and reduction of extracellular fluid volume via increased sodium excretion. β-​Blockers Excess sympathetic activity contributes to heart failure and nu- merous multicentre placebo-​controlled trials—​using carvedilol, metoprolol, and bisoprolol—​have shown substantial reductions in mortality (both sudden death and death from progressive heart failure) in adults with NYHA class II and III heart failure symp- toms. β-​Blockers are usually well tolerated, but side effects include bradycardia, hypotension, and fluid retention, and they are generally contraindicated in asthma. β-​Blockers should be started at low doses and slowly up-​titrated; they should not be started in patients with decompensated heart failure. Digoxin Digoxin improves symptoms in patients with heart failure, but no survival benefit has been demonstrated in large study cohorts. High serum digoxin levels may be associated with increased mortality in some patients. Digoxin should be used only in patients who remain symptomatic in spite of treatment with diuretics, ACE inhibitors, and β-​blockers, or to control heart rate in patients with permanent atrial fibrillation. Anticoagulation The prevalence of intramural thrombi and systemic thrombo- embolism ranges between 3% and 50%, with an incidence between 1.5% and 3.5% per year. Anticoagulation with warfarin or novel oral anticoagulants is therefore advised in patients in whom an intracardiac thrombus is identified echocardiographically, or those with a history of thromboembolism. There are no trial data to guide prophylactic anticoagulation in dilated cardiomyopathy, but pa- tients with severe ventricular dilatation and moderate to severe sys- tolic impairment may also benefit from anticoagulation. Treatment of arrhythmia in dilated cardiomyopathy If sustained or symptomatic arrhythmias are documented during 24-​h ECG monitoring or exercise testing, conventional treat- ment is warranted (see Chapter 16.4). Many commonly prescribed antiarrhythmic agents should be avoided or used with caution be- cause of their negative inotropic and proarrhythmic effects. Data on amiodarone are contradictory, but the Sudden Cardiac Death in Heart Failure Trial (SCD-​HeFT) showed that amiodarone had no beneficial effect on survival when compared with implantable cardioverter–​defibrillators. It can, however, be used safely to prevent or treat atrial arrhythmias. Non​pharmacological treatment Permanent pacing can correct two important intracardiac con- duction abnormalities. First, a small subset of patients who have marked PR interval prolongation (>220 ms), usually secondary to atrioventricular nodal disease, experience deleterious effects on left ventricular haemodynamics with reduction in diastolic ventricular filling time and the development of end-​diastolic tricuspid and mi- tral regurgitation. Correction of PR interval prolongation with short atrioventricular delay dual-​chamber pacing may increase stroke volume and blood pressure, thus decreasing mitral regurgitation with dramatic clinical improvement. Second, patients with marked intraventricular conduction delay (left bundle branch block >150 ms) have dyssynchronous contraction of the left ventricular free wall and interventricular septum (which may decrease ejection fraction) and late activation of the anterolateral papillary muscle (which may increase functional mitral regurgitation). Biventricular or left ven- tricular pacing with specialized leads via the coronary sinus can cor- rect both problems and has been shown to improve symptoms and prognosis in randomized trials. In addition, the resultant increase in blood pressure and pacemaker maintenance of the desired min- imum heart rate permits use of higher doses of β-​blockade and ACE inhibition with potential secondary benefit. Implantation of an implantable cardioverter–​defibrillator (ICD) is recommended for patients with heart failure and reduced ejec- tion fraction. Evidence for this on prognostic grounds is strong for heart failure due to coronary artery disease. Subgroup analyses have primarily been used as evidence for patients with systolic heart failure that is not due to coronary artery disease. A large prospective study (DANISH trial) did not show a significant prognostic benefit of prophylactic ICD implantation in patients with non​ischaemic cardiomyopathy. Cardiac transplantation may be appropriate in patients with pro- gressive deterioration. In addition, improvements in left ventricular assist devices and artificial heart technology provide alternatives that are now reasonably seen as viable future treatment options. These issues are discussed in Chapter 16.5.5. Restrictive cardiomyopathy Definition Restrictive left ventricular physiology is characterized by a pattern of ventricular filling in which increased stiffness of the myocardium causes ventricular pressure to rise precipitously with only small in- creases in volume. The definition of restrictive cardiomyopathy has been confusing because this pattern can occur with a wide range of different pathologies. For the purposes of this chapter, restrictive cardiomyopathies are defined by restrictive ventricular physiology in the presence of normal or reduced diastolic volumes of one or both ventricles, normal or reduced systolic volumes, and normal ventricular wall thickness. Historically, systolic function was said to be preserved in restrictive cardiomyopathy, but it is rare for con- tractility to be truly normal. Causes Though restrictive physiology is often seen in hypertrophic cardio- myopathy and dilated cardiomyopathy, restrictive cardiomyopathy, as defined earlier, is uncommon. There are many causes including infiltrative and storage disorders, and endomyocardial disease including Loeffler’s endocarditis with hypereosinophilia. In the Western world amyloidosis is the commonest cause in adults, with some familial cases caused by mutations in the transthyretin gene. In the tropics, endomyocardial fibrosis is the commonest cause in adults, and probably also in children. Rare reports of familial restrictive cardiomyopathy associated with autosomal dominant skeletal myopathy, autosomal recessive musculoskeletal abnormalities, and Noonan’s syndrome have been described in children. Mutations in the gene encoding desmin (an intermediate filament protein) cause restrictive cardiomyopathy as- sociated with skeletal myopathy and, in some cases, abnormalities of 16.7.2  The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular 3483 the cardiac conduction system. Familial restrictive cardiomyopathy is increasingly recognized as a specific phenotype within the spec- trum of hypertrophic cardiomyopathy caused by sarcomere muta- tions, particularly troponin I and β-​myosin heavy chain. Families are described in which restrictive cardiomyopathy and asymmetric hypertrophy are seen alone and in combination in carriers of affected genes. Pathology Restrictive cardiomyopathy is best regarded as a heterogeneous group of conditions with different aetiologies rather than a single disease entity. Macroscopically, restrictive cardiomyopathy is char- acterized by marked biatrial dilatation in the presence of normal heart weight, a small ventricular cavity, and no left ventricular hypertrophy. The histological features of idiopathic restrictive car- diomyopathy are usually non​specific, with patchy interstitial fibrosis that may range in extent from very mild to severe. There may also be fibrosis of the sinoatrial and atrioventricular nodes. Myocyte dis- array is not uncommon in patients with pure restrictive cardiomy- opathy, even in the absence of macroscopic ventricular hypertrophy, consistent with restrictive cardiomyopathy being a clinically unrec- ognized manifestation of hypertrophic cardiomyopathy caused by sarcomere protein gene mutations. When restrictive cardiomyopathy is caused by endomyocardial fi- brosis the cardiac pathology is distinctive, with endocardial fibrosis and overlying thrombosis involving the inflow tracts and the apices, but sparing the outflow tracts of one or both ventricles. Necrotic, thrombotic, and fibrotic stages have been defined in patients with endomyocardial fibrosis and hypereosinophilia. In the necrotic stage, there is an acute inflammatory reaction characterized by eo- sinophilic abscesses in the myocardium, with associated necrosis and arteritis. The endocardium is often thickened and mural thrombi may develop. The thrombotic stage is characterized by endocardial thrombus formation that may be severe, with massive intracavitary thrombosis causing restriction to ventricular filling and a low-​ output state with high filling pressures. There is a risk of systemic emboli. During the necrotic and thrombotic stages the disease may mimic a hyperacute rheumatic carditis (see Chapter 16.9.1). If the patient survives, healing by fibrosis with hyaline fibrous tissue oc- curs. There is no further evidence of inflammation and the impact of the disease is caused by the effect of the dense fibrous tissue on ven- tricular filling volume and atrioventricular valve function. Clinical features and investigation Disease onset is usually insidious. Left-​sided disease may present with symptoms of pulmonary congestion and/​or mitral regurgita- tion; right-​sided disease with raised jugular venous pressure, hep- atomegaly, ascites, and tricuspid regurgitation. Radiographic and electrocardiographic appearances are non​specific, showing evi- dence of raised left and/​or right atrial pressure and cardiomegaly with left ventricular hypertrophy. Pulmonary infiltrates, non-​ specific repolarization changes, and fascicular blocks may be seen. Two-​dimensional echocardiography confirms the diagnosis, al- lowing visualization of the structural abnormalities involving the endocardium and atrioventricular valves as well as demonstration of the abnormal physiology with restriction to filling (Fig. 16.7.2.8). There may be intracavitary thrombus with apical cavity obliteration, or bright echoes from the endocardium of the right or left ventricle with tethering of the chordae and reduced excursion of the posterior mitral valve leaflet. Typically, ventricular dimensions and wall thick- ness are normal, whereas the atria are grossly enlarged. Left ven- tricular filling terminates early and is followed by a plateau phase coincident with the third heart sound. Diagnosis and management Idiopathic restrictive cardiomyopathy Demonstration of diagnostic features requires detailed imaging and may involve haemodynamic measurements at cardiac catheteriza- tion. Endomyocardial biopsy may be required to exclude storage and infiltrative diseases. It is particularly important to differentiate idiopathic restrictive cardiomyopathy from constrictive pericarditis, where surgical therapy may be curative (see Chapter 16.8). The clin- ical course of idiopathic restrictive cardiomyopathy is protracted (one to two decades), but once congestive symptoms develop, time to transplant or death is typically less than 5 years. Endomyocardial fibrosis The principal haemodynamic consequence of endomyocardial scarring is a restriction to normal filling. Early diastolic pressures are normal, but there is a rapid mid-​diastolic rise which plateaus (square root sign) and is not associated with impairment of systolic performance. A similar functional haemodynamic abnormality is seen in pericardial constriction (see Chapter 16.8), but in the latter condition end-​diastolic pressures are usually similar within the two ventricles, whereas in endomyocardial fibrosis there is usually in- equality of the end-​diastolic pressures. Mitral and tricuspid regurgi- tation may be severe and both ventricles appear abnormal in shape on angiography due to obliteration of the apices. This may be par- ticularly marked in the right ventricle in which the infundibulum is hypertrophied and hypocontractile. In addition, the fibrotic process results in smoothing of the internal architecture of the ventricle with loss of the normal trabeculae. The presence of intracavitary thrombi in the left ventricle may give rise to the erroneous diagnosis of a car- diac tumour. The structural and physiological abnormalities that can be dem- onstrated with two-​dimensional echocardiography or during car- diac catheterization result from the thrombotic and fibrotic stages of the disease. Diagnosis may be difficult during the early acute phase, RA LA Fig. 16.7.2.8  Two-​dimensional echocardiogram (apical four-​chamber view) showing normal-​sized ventricles with massive dilatation of left (LA) and right (RA) atria. section 16  Cardiovascular disorders 3484 when the appearances of the left and right ventricle are far less ab- normal, and may require confirmation by endomyocardial biopsy. In later stages, however, the diagnosis should be readily apparent, and the risk of biopsy is excessive. There is no good medical treatment for advanced disease and the prognosis is poor, with 35–​50% 2-​year mortality. Congestive symp- toms from raised right atrial pressure can be improved with diuretics, though too great a reduction in ventricular filling pressure will lead to a reduction in cardiac output. Arrhythmias are common, but their prognostic significance is uncertain, and they should not be treated un- less they are sustained or associated with symptoms. Antiarrhythmic drugs that significantly slow the heart rate may be deleterious because of the small stroke volume. Digoxin may be helpful to control the ventricular response in atrial fibrillation, but cannot be expected to improve congestive symptoms as systolic function is usually well pre- served. Anticoagulants may help to prevent venous thrombosis and systemic emboli; both warfarin and antiplatelet drugs are advised. Surgery with either mitral and/​or tricuspid valve replacement, with or without decortication of the endocardium, has been carried out in some patients with endomyocardial fibrosis. Good long-​term results have been obtained, but there is significant perioperative mortality (15–​20%). Arrhythmogenic right ventricular cardiomyopathy Definition Arrhythmogenic right ventricular cardiomyopathy (ARVC, which replaces the older term ‘arrhythmogenic right ventricular dysplasia’) is a heart muscle disease characterized by progressive fibro-​fatty re- placement of right ventricular myocardium, initially with regional and later with global right and left ventricular involvement, associated with ventricular arrhythmia, heart failure, and sudden cardiac death, with as many as 20% of such deaths in young individuals and athletes attributable to the condition. Arrhythmogenic right ventricular car- diomyopathy occurs worldwide in all ethnic groups. The prevalence is unknown, but is conservatively estimated to be between 1 in 1000 and 1 in 5000. Causes Systematic family studies have shown that arrhythmogenic right ventricular cardiomyopathy is inherited in at least 50% of cases. The mode of transmission is usually autosomal dominant with variable penetrance, but rare autosomal recessive forms provided the first in- sights into the genetic basis of the condition. Two autosomal reces- sive syndromes characterized by arrhythmogenic right ventricular cardiomyopathy, woolly hair, and palmoplantar keratoderma (Naxos disease, Carvajal–​Huerta syndrome) are caused by muta- tions in the genes encoding plakoglobin and desmoplakin, respect- ively. These proteins are important components of the desmosome, with key roles in cell-​to-​cell adhesion and transduction of mech- anical stress. Analysis of these and similar proteins in families with the more common autosomal dominant form of disease have re- vealed mutations in desmoplakin, plakophilin, desmoglein, and desmocollin. There are isolated reports of non​desmosomal gene mutations in arrhythmogenic right ventricular cardiomyopathy involving the ryanodine-​2 receptor (more typically associated with catecholaminergic polymorphic ventricular tachycardia) trans- forming growth factor β, and lamin AC. Overlap with dilated cardiomyopathy While right ventricular disease defines ARVC, there are several characteristics that can overlap with DCM. Specifically, involvement of the left ventricle ranging from scars on cardiac MR imaging to severe LV dilation and systolic impairment is reported in many pa- tients. There is also overlap in the cause of disease (e.g. desmosomal gene mutations are common in patients with a clinical diagnosis of DCM). Even though the degree to which both DCM and ARVC coexist within families is poorly characterized, the presence of right ventricular abnormalities such as dilatation and ventricular ectopy of right ventricular origin in relatives of patients with DCM may be a diagnostic red flag for the presence of familial disease. Likewise, the presence of LV dysfunction in a relative of a patient with un- equivocal ARVC does not necessarily imply a different disease. Pathology and pathophysiology Segmental disease is usual in arrhythmogenic right ventricular car- diomyopathy, with involvement of the diaphragmatic, apical, and infundibular regions of the right ventricular free wall (the ‘triangle of dysplasia’). Evolution to more diffuse right ventricular involve- ment and left ventricular abnormalities with heart failure is more common than previously suspected. Macroscopic examination of the heart may show diffuse thinning of the right ventricular wall, with aneurysms present in up to 50% of cases. The fibro-​fatty re- placement of the myocardium may be focal or widespread, usually involves the subepicardial layer of the right ventricular free wall and, when severe, may appear transmural. Isolated and predominantly left ventricular disease caused by desmosomal mutations is not un- common. Histologically, arrhythmogenic right ventricular cardio- myopathy is characterized by replacement myocardial fibrosis with thinning and discrete bulges of the ventricular apices and of the right ventricular free wall, often in association with lymphocytic infil- trates surrounding degenerating or necrotic myocytes. Suggested arrhythmic mechanisms include re-​entry circuits arising from fibro-​fatty myocardial replacement and heterogeneous conduction resulting from destabilization of cell adhesion com- plexes and gap junctions. Clinical features Symptomatic presentation is usually with palpitation and/​or syn- cope from sustained ventricular arrhythmia, but the first presen- tation of the disease—​especially in young people—​may be with sudden cardiac death in an individual who was previously asymp- tomatic. Occasionally, the victim will have experienced syncope in the months preceding their death (particularly during exercise). Other symptoms are presyncope and chest pain. Features of right and later biventricular failure may be present, including dyspnoea on exertion, as the disease progresses. ‘Hot phases’ are recognized, during which previously stable patients may suffer repeated epi- sodes of ventricular arrhythmia and be prone to sudden death. Investigation There is no single diagnostic test for arrhythmogenic right ventricular cardiomyopathy, and the diagnosis is based on the presence of major and minor criteria encompassing structural, histological, electro- cardiographic, arrhythmic, and genetic factors (Table 16.7.2.4). 16.7.2  The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular 3485 Table 16.7.2.4  Revised Task Force criteria I. Global or regional dysfunction and structural alterationsa Major By 2D echo: Regional RV akinesia, dyskinesia, or aneurysm and 1 of the following (end diastole): • PLAX RVOT ≥32 mm (corrected for body size [PLAX/​BSA] ≥19 mm/​m2) • PSAX RVOT ≥36 mm (corrected for body size [PSAX/​BSA] ≥21 mm/​m2) • or fractional area change ≤33% By MRI: Regional RV akinesia or dyskinesia or dyssynchronous RV contraction and 1 of the following: • Ratio of RV end-​diastolic volume to BSA ≥110 ml/​m2 (male) or ≥100 ml/​m2 (female) • or RV ejection fraction ≤40% By RV angiography: • Regional RV akinesia, dyskinesia, or aneurysm Minor By 2D echo: Regional RV akinesia or dyskinesia and 1 of the following (end diastole): • PLAX RVOT ≥29 to <32 mm (corrected for body size [PLAX/​BSA] ≥16 to <19 mm/​m2) • PSAX RVOT ≥32 to <36 mm (corrected for body size [PSAX/​BSA] ≥18 to <21 mm/​m2)v • or fractional area change >33% to ≤40% By MRI: Regional RV akinesia or dyskinesia or dyssynchronous RV contraction and 1 of the following: • Ratio of RV end-​diastolic volume to BSA ≥100 to <110 ml/​m2 (male) or ≥90 to <100 ml/​m2 (female) • or RV ejection fraction >40% to ≤45% II. Tissue characterization of wall Major Residual myocytes<60% by morphometric analysis (or <50% if estimated), with fibrous replacement of the RV free wall myocardium in ≥1 sample, with or without fatty replacement of tissue on endomyocardial biopsy Minor Residual myocytes 60–​75% by morphometric analysis (or 50% to 65% if estimated), with fibrous replacement of the RV free wall myocardium in ≥1 sample, with or without fatty replacement of tissue on endomyocardial biopsy III. Repolarization abnormalities Major Inverted T waves in right precordial leads (V1, V2, and V3) or beyond in individuals >14 years of age (in the absence of complete RBBB QRS ≥120 ms) Minor Inverted T waves in leads V1 and V2 in individuals >14 years of age (in the absence of complete RBBB) or in V4, V5, or V6 Inverted T waves in leads V1, V2, V3, and V4 in individuals >14 years of age in the presence of complete RBBB IV. Depolarization/​conduction abnormalities Major Epsilon wave (reproducible low-​amplitude signals between end of QRS complex to onset of the T-​wave) in the right precordial leads (V1–​V3) Minor Late potentials by SAECG in ≥1 of 3 parameters in the absence of a QRS duration of ≥110 ms on the standard ECG Filtered QRS duration (fQRS) ≥114 ms Duration of terminal QRS <40 µV (low-​amplitude signal duration) ≥38 ms Root-​mean-​square voltage of terminal 40 ms ≤20 µV Terminal activation duration of QRS ≥55 ms measured from the nadir of the S wave to the end of the QRS, including R′, in V1, V2, or V3, in the absence of complete RBBB V. Arrhythmias Major Non​sustained or sustained ventricular tachycardia of left bundle branch morphology with superior axis (negative or indeterminate QRS in leads II, III, and aVF and positive in lead aVL) Minor Non​sustained or sustained ventricular tachycardia of RV outflow configuration, LBBB morphology with inferior axis (positive QRS in leads II, III, and aVF and negative in lead aVL) or of unknown axis 500 ventricular extrasystoles per 24 h (Holter) VI. Family history Major ARVC confirmed in a first-​degree relative who meets current Task Force criteria ARVC confirmed pathologically at autopsy or surgery in a first-​degree relative Identification of a pathogenic mutationb categorized as associated or probably associated with ARVC in the patient under evaluation Minor History of ARVC in a first-​degree relative in whom it is not possible or practical to determine whether the family member meets current Task Force criteria Premature sudden death (<35 years of age) due to suspected ARVC/​D in a first-​degree relative ARVC confirmed pathologically or by current Task Force criteria in second-​degree relative a VF, augmented voltage unipolar left foot lead; aVL, augmented voltage unipolar left arm lead; BSA, body surface area; LBBB, left bundle branch block; PLAX, parasternal long-​axis view; PSAX, parasternal short-​axis view; RBBB, right bundle branch block; RVOT, RV outflow tract. Diagnostic terminology for revised criteria: definite diagnosis: 2 major or 1 major and 2 minor criteria, or 4 minor from different categories; borderline: 1 major and 1 minor or 3 minor criteria from different categories; possible: 1 major or 2 minor criteria from different categories. b A pathogenic mutation is a DNA alteration associated with ARVC that alters or is expected to alter the encoded protein, is unobserved or rare in a large non-​ARVC control population, and either alters or is predicted to alter the structure or function of the protein or has demonstrated linkage to the disease phenotype in a conclusive pedigree. From Marcus FI, et al. (2010). Diagnosis of arrhythmogenic right ventricular cardiomyopathy/​dysplasia: proposed modification of the Task Force Criteria. Eur Heart J, 31, 806–​14. section 16  Cardiovascular disorders 3486 The diagnosis of arrhythmogenic right ventricular cardiomyopathy is fulfilled in the presence of two major criteria, or one major plus two minor criteria, or four minor criteria from different categories. The recently revised criteria reflect family studies which (1)  show that at least 30% of patients have left ventricular involvement in the form of regional or global left ventricular dysfunction, and many have subclinical left ventricular fibrosis (evident on magnetic resonance) affecting particularly the posterolateral segments, and (2) show that first-​degree relatives of affected individuals may have minor car- diac abnormalities, which—​although not fulfilling these diagnostic criteria—​are likely to represent disease expression in the context of an autosomal dominant disease. Electrocardiography The most common electrocardiographic abnormality is T-​wave in- version in leads V1 to V3 in the absence of right bundle branch block (but note that this is a normal finding in children and there- fore cannot be used as a diagnostic criterion) (Fig. 16.7.2.9). Other electrocardiographic features include QRS dispersion (localized prolongation of the QRS complex in the right ventricular leads, with a difference in QRS duration of at least 40 ms between right and left precordial leads), right intraventricular conduction delay (progressing to right bundle branch block in some patients) and the presence of an epsilon wave (a terminal notch in the QRS com- plex), typically seen in lead V1. Ventricular tachycardia is of left bundle branch block morphology, suggesting a right ventricular origin. The signal-​averaged ECG is used to detect late potentials which predict susceptibility to ventricular arrhythmia and disease progression. Exercise testing The role of exercise testing in arrhythmogenic right ventricular car- diomyopathy is primarily to detect ventricular arrhythmias induced by physical activity. Ventricular ectopy and non​sustained ven- tricular tachycardia of right ventricular origin have been described in young patients. Cardiopulmonary exercise testing may be useful as an objective measure of functional capacity in patients with ad- vanced disease. Echocardiography Echocardiography is used to confirm the diagnosis and to ex- clude congenital heart disease, which may present as a differential diagnosis for arrhythmogenic right ventricular cardiomyopathy. Typical echocardiographic findings include right ventricular dilatation, regional hypokinesia or dyskinesia, free wall aneur- ysms, increased echogenicity of the moderator band, and right ventricular apical hypertrabeculation. Left ventricular involve- ment with posterior wall hypokinesia or ventricular dilatation may be seen in up to 30% of cases. In patients in whom the right ventricle is difficult to visualize adequately using standard two-​ dimensional echocardiography, injection of echocardiographic contrast may provide improved definition of the right ventricular endocardial border. Cardiac MRI Assessment of the right ventricle using echocardiography is chal- lenging, even in experienced hands. Cardiovascular MRI has the advantage that it is a three-​dimensional technique with no limi- tations imposed by acoustic windows (Fig. 16.7.2.10). When per- formed with a dedicated protocol by experienced operators, in both children and adults, the technique has a high sensitivity for detecting right ventricular abnormalities in individuals who fulfil conventional diagnostic criteria. Assessment of right ventricular fat, gadolinium late enhancement, and wall thinning on MRI are not considered to be adequately robust measures for inclusion in the revised diagnostic criteria. Left ventricular late enhancement, which often involves the epi-​and mid-​myocardial segments of the posterolateral wall, may provide the earliest non​electrical mani- festation of desmosomal disease and be observed with otherwise normal left ventricular structure and function. Fig. 16.7.2.9  A 12-​lead ECG from a young woman showing the most common electrocardiographic abnormalities found in arrhythmogenic right ventricular cardiomyopathy with low voltage and T-​wave inversion in the precordial leads V1–​V4. 16.7.2  The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular 3487 Endomyocardial biopsy Although a histological diagnosis of arrhythmogenic right ven- tricular cardiomyopathy may be definitive, the sensitivity of endomyocardial biopsies is low because (1) the disease is segmental in nature; (2) the amount of tissue usually obtained is insufficient to differentiate fibro-​fatty replacement from islands of adipose tissue that are not infrequently seen between myocytes in the right ven- tricle of normal subjects; and (3) samples are usually taken from the septum, a region that is less frequently involved. The complication rate—​which includes cardiac perforation and tamponade because of thinning of the right ventricular wall—​is also relatively high, hence endomyocardial biopsies are no longer considered part of the rou- tine diagnostic work-​up for the condition. Management Treatment in arrhythmogenic right ventricular cardiomyopathy is individualized according to the presence of symptoms, arrhythmia, and perceived risk of sudden death. Patients with symptomatic, non-​life-​threatening ventricular arrhythmias are treated empirically with β-​adrenoreceptor blockers, amiodarone, or sotalol. β-​blockers are particularly effective at treating symptoms related to exercise-​ induced arrhythmia, and sotalol suppresses ventricular arrhythmia in most patients. Those with a history of sustained, haemodynam- ically compromising ventricular arrhythmia should be offered an implantable cardioverter–​defibrillator (ICD). Studies in such pa- tients have shown a high rate of appropriate device discharges, ran- ging from 15% to 22% per year. More problematic is the prevention of sudden death in patients without such a history. Some markers of increased risk have been proposed, including unexplained syncope, symptomatic ventricular tachycardia, family history of sudden death, young age, left ventricular involvement, and diffuse right ven- tricular dilatation. However, population-​based survival studies are needed to evaluate the significance of these and other factors (such as asymptomatic non​sustained ventricular tachycardia). Patients with severe right ventricular or biventricular involve- ment should be treated according to current heart failure treat- ment guidelines, including the use of diuretics, ACE inhibitors, and anticoagulation. Patients with advanced disease are candidates for cardiac transplantation (see Chapter 16.5.5). Evaluation, genetic testing, and follow-​up of asymptomatic patients with cardiomyopathy It is now possible to offer genetic testing to individuals with un- equivocal cardiomyopathy, particularly with highly penetrant dis- ease in large families and in families affected by a sudden cardiac death. If a disease-​causing mutation is identified, relatives can be offered predictive genetic testing, but this should only be done after appropriate genetic counselling and informed consent obtained by a trained healthcare professional working within a multidisciplinary team. This is to ensure understanding of the psychological, social, professional, ethical, and legal implications of a genetic disease. In children and adolescents with a sarcomeric protein gene mu- tation, ECG and echocardiographic manifestations of myocar- dial hypertrophy often develop during growth. For this reason, young people should be assessed annually during adolescence. The earliest clinical manifestations of hypertrophic cardiomyopathy Fig. 16.7.2.10  Arrhythmogenic right ventricular cardiomyopathy. On the cine images (top) the right ventricle (RV) is globally dilated with multiple RV wall motion abnormalities. There are two areas of LV involvement with wall thinning (free wall, apex). On T1-​weighted imaging, fat can be seen in the septum and RV trabeculae (arrows). After contrast, late enhancement representing fibrosis is also seen (arrows). section 16  Cardiovascular disorders 3488 are electrocardiographic, while diastolic dysfunction and altered biomarkers of collagen synthesis may precede the development of left ventricular hypertrophy and also provide early markers of dis- ease. In adults, de novo development of unexplained left ventricular hypertrophy is uncommon, but it does occur, particularly in patients with myosin-​binding protein C gene mutations. In dilated cardio- myopathy follow-​up of asymptomatic first-​degree relatives suggests that disease progression is slow (over decades). The same applies to arrhythmogenic right ventricular cardiomyopathy. Asymptomatic normal adults with a family history of cardiomy- opathy but no identifiable mutation should be offered rescreening every 5 years, or sooner should they develop symptoms. This includes a clinical evaluation with ECG and echocardiography. Rescreening should be guided by the age of onset and severity of cardiomyopathy within the family. Individuals with non​diagnostic clinical features that could represent early disease should be seen more frequently. Athletes, sports, and cardiomyopathy Differentiation between pathological changes of HCM and physio- logical hypertrophy in athletes is required by many governing bodies prior to participation in competitive exercise. Careful assess- ment is needed and often a detraining period of 3 months is recom- mended. Presence of a family history of HCM or sudden cardiac death, symptoms (palpitations, syncope), and ECG changes such as Q waves, ST depression, deep T-​wave inversions in inferolateral leads, all favour a diagnosis of HCM rather than athlete’s heart. Other important clues to a diagnosis of HCM include low aerobic capacity, a maximal wall thickness of more than 13 mm, and dia- stolic dysfunction (Box 16.7.2.3). The upper limits of left ventricular wall thickness used to discrim- inate physiological left ventricular hypertrophy from HCM are es- tablished in white athletes. Left ventricular hypertrophy with a wall thickness of more than 15 mm can be physiological in black athletes. The most extreme increase in left ventricular wall thickness have been observed in isotonic or endurance exercise such as rowing, cycling, or swimming. Female athletes have smaller left ventricular diastolic cavity dimension and smaller wall thickness than males. International guidelines advise against competitive exercise in HCM in view of a potential increased risk of sudden cardiac death. Some evidence implicates physical exercise in increased disease progression and risk of sudden death in arrhythmogenic right ven- tricular cardiomyopathy. Data on exercise in dilated cardiomyop- athy is very limited and controversial. FURTHER READING Hypertrophic cardiomyopathy Davies MJ, McKenna WJ (1995). Hypertrophic cardiomyopathy: path- ology and pathogenesis. Histopathology, 26, 493–​500. Elliott P, McKenna WJ (2004). Hypertrophic cardiomyopathy. Lancet, 363, 1881–​91. Elliott P, et al. (2008). Classification of the cardiomyopathies: a position statement from the European Society of Cardiology Working Group on myocardial and pericardial diseases. Eur Heart J, 29, 270–​6. Elliott P, et al. (2014). ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the diagnosis and management of hypertrophic cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J, 35, 2733–​79. Jacoby D, McKenna WJ (2012). Genetics of cardiomyopathy. Eur Heart J, 33, 296–​304. Maron BJ (2002). Hypertrophic cardiomyopathy. A systematic review. JAMA, 287, 1308–​20. Maron BJ, et al. (2003). American College of Cardiology Foundation Task Force on clinical expert consensus documents; European Society of Cardiology Committee for practice guidelines. American College of Cardiology/​European Society of Cardiology clinical expert con- sensus document on hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on clinical expert consensus documents and the European Society of Cardiology Committee for practice guidelines. Eur Heart J, 24, 1965–​91. O’Mahony C, et al. (2014). A novel clinical risk prediction model for sudden cardiac death in hypertrophic cardiomyopathy (HCM Risk-​ SCD). Eur Heart J, 35, 2010–​20. Priori SG, et al. (2015). ESC guidelines for the management of pa- tients with ventricular arrhythmias and the prevention of sudden cardiac death: the Task Force for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death of the European Society of Cardiology (ESC). Eur Heart J, 36, 2793–​867. Rapezzi C, et  al. (2013). Diagnostic work-​up in cardiomyopathies: bridging the gap between clinical phenotypes and final diagnosis. A position statement from the ESC Working Group on myocardial and pericardial diseases. Eur Heart J, 34, 1448–​58. Richard P, et al. (2003). Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a mo- lecular diagnosis strategy. Circulation, 107, 2227–​32. Wang L, Seidman JG, Seidman CE (2010). Narrative review: harnessing molecular genetics for the diagnosis and management of hyper- trophic cardiomyopathy. Ann Intern Med, 152, 513–​20, W181. Dilated cardiomyopathy Caforio AL, et al. (2007). Prospective familial assessment in dilated cardiomyopathy:  cardiac autoantibodies predict disease develop- ment in asymptomatic relatives. Circulation, 115, 76–​83. Box 16.7.2.3  Features favouring a diagnosis of pathological versus physiological hypertrophy in athletes with mild left ventricular hypertrophy (≥12 mm) • Family history of HCM or sudden cardiac death in first-​degree relative(s) ≤40 years • Female gender • Palpitations, syncope • ECG: Abnormal Q waves in at least two leads, ST depression, deep T-​wave inversion in inferolateral leads • Peak VO2 <100% of predicted • MWT ≥14 mm • Small left ventricle cavity size (left ventricular end-​diastolic diameter <45 mm) • Diastolic dysfunction • Reduced longitudinal left ventricular function • No response to detraining for 3 months • Left atrial enlargement >50 mm • Myocardial fibrosis on cardiac MRI Adapted from Elliott PM, Lambiase PD, Kumar D (2011). Inherited cardiac disease. Oxford University Press, Oxford. Nikant Sabharwal, Andrew Kelion, Theodoros Karamit Nikant Sabharwal, Andrew Kelion, Theodoros Karamitos, and Stefan Neubauer 16.3.4 Cardiac catheterization and angiography 3339 Edward D. Folland 16.3.4  Cardiac catheterization and angiography 3339 Takx RA, et  al. (2015). Diagnostic accuracy of stress myocar- dial perfusion imaging compared to invasive coronary angiog- raphy with fractional flow reserve meta-​analysis. Circ Cardiovasc Imaging, 8, e002666. 16.3.4  Cardiac catheterization and angiography Edward D. Folland ESSENTIALS Cardiac catheterization/​angiography is indicated for evaluation of patients with coronary, valvular, and congenital heart disease in whom diagnostic or therapeutic decisions cannot be made on the basis of non​invasive tests. Most patients presenting for cardiac cath- eterization have coronary artery disease:  catheterization and cor- onary angiography are integral parts of interventional treatments for patients experiencing ischaemic coronary syndromes. Technique and diagnostic utility—​vascular access is usually obtained percutaneously from the femoral, radial, or brachial artery (for the left heart), or the femoral, internal jugular, or brachial/​antecubital vein (for the right heart). Key information that can be obtained by cardiac catheterization/​angiography include (1) pressures within car- diac chambers; (2) cardiac output; (3) quantitative estimation of left ventricular function; (4) diagnosis and quantitation of intracardiac shunts; (5) calculation of systemic and pulmonary vascular resist- ances; (6) assessment of cardiac valves; and (7) details of coronary arterial anatomy and function. Therapeutic utility—​cardiac catheterization/​angiography permits interventions, particularly coronary angioplasty/​stenting that are of great and increasing therapeutic importance. Introduction Invasive cardiac diagnosis by means of catheterization and angiog- raphy developed hand in hand with cardiac surgery throughout the 20th century. It answered the need for precise information about cardiac physiology and anatomy, which arose in the 1940s when surgical techniques for the treatment of congenital and rheumatic heart disease first became available. A few years earlier, in 1929, Werner Forsman of Germany successfully and safely passed a fili- form urinary catheter from a median basilic vein into the right atrium of his own heart and documented it on X-​ray film. Although this feat cost him his own job, it enabled Andre Cournand and Dickenson Richards a decade later to use catheters for sampling blood, measuring pressure and flow, and injecting radiopaque contrast medium (angiography) into the intact, beating human heart, ushering in the era of invasive cardiac diagnosis. Cournand, Richards, and Forsman later won the Nobel Prize for their important work. This chapter reviews the diagnostic applications of cardiac catheterization and angiography. Indications for cardiac catheterization and angiography Catheterization entails some degree of risk and discomfort, and is expensive, hence patients should be carefully selected. In broadest terms, it is indicated for detailed evaluation of those with coronary, valvular, and congenital heart disease, once they have been identi- fied as candidates for surgery or other forms of intervention. It may also be indicated for patients whose diagnosis is uncertain from noninvasive evaluation. Coronary artery disease Most patients presenting for cardiac catheterization have coronary artery disease. Angiography of the coronary arteries performed during cardiac catheterization is essential for patients in whom revascularization is indicated. In spite of the limitations discussed later in this chapter, no other imaging modality, including MRI and CT (see Chapter 16.3.3), can as yet provide the detailed anatomy of the entire coronary circulation that is needed for planning revascularization procedures such as coronary artery bypass surgery and percutaneous intervention. Coronary angiography is indicated for patients with chronic stable angina that persists in spite of reasonable efforts at pharma- cological therapy. It is also indicated for patients whose survival would be improved by revascularization, regardless of symptoms. Such patients are those with severe stenosis of the main left cor- onary artery and those with severe two-​and three-​vessel coronary artery disease in combination with impaired left ventricular func- tion. These patients may be identified by the following features of stress testing: ischaemia at low workload (especially in stage 1 of the Bruce protocol); marked depression of the electrocardiographic ST segment (>2 mm); failure to augment systolic blood pressure during exercise; and large exercise-​induced defects or increased lung up- take during radionuclide perfusion imaging (see Chapters  16.3.1 and 16.3.3). In addition, patients with high-​risk clinical presenta- tions such as acute myocardial infarction, unstable angina, and post-​myocardial infarction ischaemia are candidates for angiog- raphy. Patients having acute myocardial infarction are best served by immediate percutaneous coronary intervention if this is avail- able in a timely manner (see Chapter 16.13.5). Finally, catheteriza- tion is sometimes indicated to obtain a definitive diagnosis when non​invasive testing has yielded equivocal or inconsistent results. Valvular disease Catheterization was once considered essential prior to the surgical treatment of valvular heart disease. This is no longer the case because of advances in non​invasive testing using ultrasound and Doppler techniques. Nevertheless, catheterization is often helpful for gath- ering the information needed to properly select patients for surgical therapy, and to guide the surgeon in providing optimum treatment, the most common issue being to assess the need for coronary ar- tery revascularization, particularly among those with aortic sten- osis, who commonly have coronary artery disease. Haemodynamic section 16  Cardiovascular disorders 3340 studies may also be necessary in cases where non​invasive diagnostic data are limited or equivocal. By contrast, it is often possible to avoid catheterization in young patients in whom non​invasive studies yield unequivocal conclusions and there is no evidence of coronary artery disease. Congenital disease Most patients with congenital heart defects can be definitively diag- nosed by transthoracic or transoesophageal ultrasound, CT, or MRI (see Chapters 16.3.2 and 16.3.3). As in valvular disease, catheteriza- tion is most useful in cases where the abnormality is unusually com- plex, the non​invasive data are incomplete, or the patient is suspected of having coronary artery disease. Catheterization is particularly useful in quantifying shunt flow and pulmonary vascular resist- ance, both of which are important considerations in the treatment of intracardiac defects. The physical passage of a systemic venous catheter across the atrial septum into a pulmonary vein or the left ventricle is diagnostic of an atrial septal defect. Pericardial disease Pericardial tamponade and constriction lend themselves particu- larly well to diagnosis by catheterization. Although ultrasonography has superseded catheterization as a rapidly available method of con- firming the clinical diagnosis of tamponade, it is usually inconclu- sive for patients with pericardial constriction. At catheterization, patients with both conditions usually demonstrate equalization of all intracardiac diastolic pressures, with unique pressure waveforms ex- hibited in the right atrium and right ventricle usually distinguishing the two diagnoses (Fig. 16.3.4.1). Congestive heart failure The aetiology and pathophysiology of congestive heart failure are readily elucidated by catheterization. States of pressure and volume overload as well as systolic and diastolic dysfunction of the ventricles can be easily identified, as explained in detail later in this chapter. Furthermore, catheterization is uniquely suited for identifying transient or reversible causes of left ventricular dysfunction caused by ischaemia or myocardial hibernation due to underlying cor- onary artery disease. Sometimes exercise or other interventions are performed during a catheter study to elicit transient abnormal haemodynamic function. Myocardial biopsy performed during catheterization can sometimes identify the aetiology of primary myocardial dysfunction. Pulmonary vascular disease Patients with primary pulmonary hypertension (see Chapter 16.15.2) should undergo catheterization to measure pulmonary vascular pressure and resistance. Certain vasodilating drugs may or may not benefit the patient, depending upon their effect on pressure and re- sistance during acute administration. Pulmonary angiography per- formed during right heart catheterization is traditionally regarded as the most definitive test for pulmonary embolism, although in most cases the diagnosis can be secured by CT angiography or radioiso- tope lung scanning. Practicalities of cardiac catheterization Preparing the patient Precatheterization evaluation should consist of a careful history and examination, particularly aimed at eliciting details of prior cardiac procedures, reactions to contrast medium, renal function, periph- eral vascular status, and haemostatic function. The patient should be carefully advised of the indications, alternatives, risks, discom- forts, and expected benefits of the procedure. The skilled clinician does this while building the patient’s confidence and avoids creating undue alarm. Following an uncomplicated diagnostic catheteriza- tion, the patient should usually expect to go home the same day and to resume customary physical activities within a day or two. Vascular access The traditional approach to vascular access is via a cut-​down near the antecubital fossa, with isolation and mobilization of the bra- chial or antecubital vein and the brachial artery for right and left heart catheterization, thereby allowing arterial and venous access. After the procedure, the arterial entry site is repaired by suture and the vein is usually tied off. However, although this approach has the advantage of enabling early post-​procedure ambulation and the security of direct arterial closure in anticoagulated patients, it has the disadvantage of being time-​consuming for most physicians and less cosmetic for the patient. Hence the cut-​down approach is now seldom used, with percutaneous arterial catheterization becoming increasingly popular. Percutaneous vascular access is achieved by direct puncture with a needle, through which a flexible spring guide wire is passed into the vessel. Catheters may then be passed into the vessel over the guide wire. Following the procedure haemostasis is achieved by applying pressure over the puncture site until bleeding stops. Percutaneous access is frequently employed at the femoral site, al- though it may also be used at brachial, axillary, internal jugular, and radial locations. It has the advantage of speed, simplicity, and—​ when performed from the femoral vessels—​frees the upper body 150 100 50 RV LV 1 s Fig. 16.3.4.1  Pericardial constriction. This is a tracing of simultaneous left ventricular (LV) and right ventricular (RV) pressure in a patient with pericardial constriction. Generally, the diastolic pressure of the left ventricle is higher than that of the right ventricle. For patients with a constriction, the pericardium determines the diastolic compliance of both chambers, causing the diastolic pressures to be equal. Note also the typical ‘dip–​plateau’ pattern or ‘square-​root sign’ of both chambers in diastole. Although diastolic ventricular pressures are also equal for patients having tamponade, the dip–​plateau pattern is usually absent. 16.3.4  Cardiac catheterization and angiography 3341 and arms during angiographic filming. However, it has the disad- vantage of sometimes requiring several hours’ immobilization of the catheterization site following the procedure. Nevertheless, the femoral approach remains popular, especially when smaller cath- eters (4 and 5 French) and arterial closure devices enable earlier ambulation. In recent years, the percutaneous approach to the ra- dial artery has become the preferred choice of many physicians because it is associated with fewer bleeding complications and shortens hospital time. Right heart catheterization Right heart catheterization can be performed from any of the ap- proaches described earlier. Although traditionally performed with a stiff, woven Dacron, end-​hole catheter, it is often done with a flexible, balloon-​tip, flow-​directed catheter (Swan–​Ganz) because this is safer and enables the measurement of cardiac output by thermodilution. Catheterization of the right heart is indicated by itself for the study of pulmonary vascular disease and haemodynamic response to exercise or drug administration. It is indicated in combination with left heart catheterization for patients requiring haemodynamic study of valvular, congenital, or myocardial disease, and for patients being studied primarily for coronary artery disease who also have heart failure, valvular, or pulmonary disease. Left atrial pressure can be measured indirectly via right heart catheterization by wedging the tip of the catheter in a pulmonary ar- teriole, or by occluding a pulmonary artery branch with the inflated balloon at the tip of a Swan–​Ganz catheter. In either case, this creates a static column of blood from the tip of the catheter, through the pul- monary capillary bed, to the left atrium. This static column of blood has the effect of extending the tip of the catheter to the left atrium for pressure-​measuring purposes. The resulting pressure is iden- tical to the directly measured left atrial pressure, except that it is de- layed temporally by approximately 80 ms. This pressure, commonly known as the pulmonary (artery) capillary wedge (PCW) pressure, is very useful in the management of left heart failure and shock, and for estimating the diastolic gradient across the mitral valve in pa- tients with mitral stenosis. Left heart catheterization Left heart catheterization is generally performed in conjunction with coronary angiography but is specifically required for the assessment of left ventricular function and assessment of stenosis or regurgita- tion of the left-​sided valves (mitral and aortic). It is most often ac- complished by femoral, radial, or brachial arterial access, and by retrograde crossing of the aortic valve to enter the left ventricle. Left heart catheterization may also be achieved by controlled puncture of the interatrial septum with a catheter originating from the right femoral vein (trans-​septal left heart catheterization): this can then be used to measure left atrial pressure directly and be passed antegradely through the mitral valve to measure pressure and perform angiog- raphy of the left ventricle. Retrograde access of the left atrium from the left ventricle is technically difficult and seldom done. The left ventricle may also be entered via transthoracic needle puncture. This approach, known as direct left ventricular puncture, is occasionally necessary for studying patients who have both mitral and aortic mechanical prosthetic valves. The passage of the needle into the left ventricle from the cardiac apex is facilitated by echocar- diographic guidance. Information obtained from cardiac catheterization and angiography Intracardiac pressures Methodology Pressure at the tip of the catheter is transmitted through the fluid inside the catheter (usually saline) to a transducer, which converts the pressure signal to an electrical signal that can then be ampli- fied, displayed on a screen, and stored as a digital time recording. Once calibrated, the pressure at the tip of the catheter can be read graphically from the recording screen and analysed electronically. The fidelity of recording depends upon the physical characteristics of the fluid-​filled catheter, stopcocks, connecting tubing, and the pressure transducer itself. A fluid-​filled system is usually capable of responding to transient pressure changes up to 20 Hz or occasion- ally 30 Hz, which is of sufficient fidelity to reproduce diagnostically useful pressure waveforms from the heart. However, it is not respon- sive enough to accurately reproduce the rate of rise of left ventricular pressure during the isovolumic phase of systole (dP/​dt). This re- quires responsiveness to transient pressure changes of at least 60 Hz, of which fluid-​filled catheter systems are not capable. For such ap- plications catheter-​tip manometers are available (Millar catheters), in which the transducer is placed at the catheter tip, eliminating the need for an intervening column of fluid. These devices are expensive and are used only when such fidelity is required, usually in research applications. Normal intracardiac pressures The upper limits of all normal intracardiac pressures measurable from a right heart catheter are approximate multiples of six, hence they are easily remembered by the ‘rule of sixes’ (Table 16.3.4.1). For example, the mean right atrial pressure is 6 mm Hg or less, mean left Table 16.3.4.1  Normal intracardiac pressuresa Location Phasic pressure (mm Hg) Mean pressure (mm Hg) Right atrium 3 ± 2 Right ventricle Systole 24 ± 4 Diastole 5 ± 3 Pulmonary artery 13 ± 5 Systole 24 ± 6 Diastole 13 ± 5 Pulmonary capillary Wedge 9 ± 3 Left atrium 9 ± 3 Left ventricle Systole 120 ± 18 Diastole 10 ± 5 a These values are derived from 100 consecutive catheterization studies of patients proven to have no evidence of heart disease at the West Roxbury Veterans Administration Hospital from 1955 to 1980. An easy way to remember the upper limits of normal values (≤2 standard deviations above mean) is that they are generally multiples of the number 6. section 16  Cardiovascular disorders 3342 atrial pressure is 12 mm Hg or less. A further aid to remembering normal pressures is the ‘corollary of continuity’, which means that contiguous chambers have a common pressure when the intervening valve is open. For example, the right ventricle and right atrium are essentially a common chamber when the tricuspid valve is open in diastole, therefore the upper limit of right ventricular end-​diastolic pressure is the same as the upper limit of the normal right atrial pres- sure, or 6 mm Hg. This assumes there is no significant stenosis or re- gurgitation across the tricuspid valve, and that the right ventricle has normal compliance. The same condition applies to the mitral valve in diastole and the pulmonic and aortic valves in systole. Another practical rule is that the pulmonary artery diastolic and pulmonary artery capillary pressures approximate each other in the absence of severe pulmonary vascular disease. Once this has been established for any given patient, the pulmonary artery diastolic pressure can be followed as a surrogate for pulmonary capillary wedge pressure in situations where a pulmonary artery catheter is used for intensive-​ care monitoring. All intracardiac pressures rise and fall phasically with breathing due to transmission of shifting intrapleural pressure during respira- tory effort. Usually this variation is no more than a few mm Hg from inspiration to expiration, but it can be quite marked in patients with obstructive lung disease. Standards of normal pressure are based upon measurements taken during resting respiration, averaging sev- eral respiratory cycles. Pressures in the catheterization laboratory should be similarly measured: asking a patient to hold their breath may generate misleading data. Waveforms The shape of intracardiac pressure waveforms carries useful diag- nostic information. Atria and ventricles have characteristic wave- forms, the left-​sided chambers normally demonstrating similar patterns at relatively higher pressures than right-​sided chambers. The state of volume loading and the relative compliance or ‘stiffness’ of the respective ventricles during diastolic filling determines pres- sures in the right and left atria. The left ventricle is generally thicker, stiffer, and less compliant to the stretch of increasing volume than the right ventricle; hence the left atrial and left ventricular diastolic pressures are higher than the respective pressures in the right heart. Conditions such as pericardial constriction and tamponade alter this normal relationship (see Fig. 16.3.4.1). Cardiac flow and output Measurement of cardiac output was one of the earliest applications of catheterization. Most methods entail application of the indicator dilution theory (the Fick principle), summarized graphically in Fig. 16.3.4.2, which can be stated simply as follows: the rate of flow can be measured if an indicator substance is added to the moving vehicle (e.g. blood) at a known rate, and the concentration of the indicator is also known proximal and distal to the point where the indicator is added. The indicator can be any readily meas- ured substance such as oxygen, indocyanine green dye, or saline, the temperature of which is known and different from that of the bloodstream. Cardiac output by oximetry In this method, commonly called the Fick method, the indicator is oxygen that is carried physiologically by the blood. The method requires that the subject be in a metabolic steady state where the use of oxygen is constant. Such a steady state exists at rest and also during exercise, provided that the workload is constant for at least 3 min. As seen in Fig. 16.3.4.3, the pulmonary blood flow can be calculated when the oxygen consumption rate is known and the oxygen contents of blood in systemic and pulmonary arteries are q/min Incomplete mixing Complete mixing conc. q/l F (l/min) F = q/min conc. (q/l) = Litre/min q = indicator q/min = injection rate conc. (q/l) = indicator concentration after complete mixing Fig. 16.3.4.2  The Fick principle. The flow rate (F) through a vessel (cardiac output, in this case) can be measured if an indicator is added to the flowing liquid at a known rate (q/​min) and the concentration (q/​litre) of the indicator is measured after complete mixing has occurred. CO = QO2 SAO2 – PAO2 ccO2/min ccO2/l – ccO2/l = Litre/min O2 Tissue SAO2 (ccO2/litres of blood) F (l/min) LV O2 Lungs QO2 (ccO2/min) PAO2 (ccO2/litres of blood) RV VC A O PA PV Fig. 16.3.4.3  Cardiac output measured by oximetry. This is an application of the Fick principle in which oxygen is the indicator carried by flowing blood. The patient’s metabolism must be at steady state, a condition where oxygen consumption and utilization are matched. It requires three measurements: oxygen consumption rate (Qo2), systemic arterial oxygen content (SAo2), and pulmonary arterial oxygen content (PAo2). Ao, aorta; cc, volume in ml; CO, cardiac output; LV, left ventricle; PV, pulmonary vein; RV, right ventricle; VC, vena cava. 16.3.4  Cardiac catheterization and angiography 3343 known. In the absence of intracardiac shunts the pulmonary blood flow equals the systemic blood flow, or cardiac output. Dye dilution This method entails the rapid injection of a known quantity of indocyanine dye into the pulmonary artery. Blood is then sampled by withdrawal at a constant rate from a systemic artery. The sam- pled blood passes through a spectrophotometer, which is calibrated to measure the concentration of dye. A concentration curve is in- scribed when the injected bolus of dye passes the sampling point (Fig. 16.3.4.4). Dividing the quantity of dye injected by the area of the time–​concentration curve (corrected for recirculation as indi- cated by the dashed line in Fig. 16.3.4.4) yields the cardiac output. This method is now seldom used. Thermodilution Measurement of cardiac output by thermodilution uses the same principle as dye dilution, with the indicator being ‘negative calories’ (the difference between the caloric content of the injected bolus of cool saline and the caloric content of the same quantity of the subject’s blood). The downstream ‘concentration’ of injected nega- tive calories is measured as a transient drop in temperature by a thermistor at the tip of the injection catheter several centimetres from the point of injection. Dividing the negative calories injected by the area of the distal time–​temperature curve yields cardiac output. The advantages of speed, automaticity, and repeatability of this method make it particularly suitable for serial measurements during different haemodynamic states. Angiographic output This is the only commonly used method that does not employ the indicator dilution or Fick principle. The left ventricular stroke volume calculated from quantitative angiography is multiplied by the heart rate to yield the left ventricular output. In the absence of valvular regurgitation, this is the same as cardiac output. As ex- plained in greater detail later in the chapter, this method is particu- larly useful in assessing mitral and aortic valvular regurgitation. Quantitative angiography Quantitative left ventricular angiography enables the measure- ment of left ventricular volume at instants throughout the car- diac cycle. Radiographic contrast medium is injected rapidly into the left ventricle and the shadow image of the opacified ventricle captured electronically at a particular frame rate in any chosen projection. The most common projection is 30° right anterior ob- lique at a framing rate of 30 images/​s. In this view the image of the left ventricle is parallel to its long axis, resembling an ellipse. Arvidsson and Greene first suggested that the volume of the left ventricle could be calculated from the volume formula for an el- lipsoid, the three-​dimensional structure created by rotating an ellipse on its long axis. Dodge and Sandler improved upon this concept by deriving the minor hemi-​axes from an idealized el- lipse of the same length and area as the projected image of the ventricle. This method is still commonly used and is often re- ferred to as the area–​length method. Images captured at end diastole and end systole are analysed and corrected for magni- fication to yield end-​diastolic and end-​systolic volumes, the dif- ference between these volumes being the stroke volume and the product of the stroke volume and heart rate, the angiographic left ventricular output. These indices are useful in the assessment of left ventricular function and valvular regurgitation as discussed later in this chapter. Intracardiac shunts The same methods of oximetry and indicator dilution used in measuring cardiac output can be employed for the detection and quantitation of intracardiac shunts. Under normal resting con- ditions, blood is approximately 75% saturated as it returns from the body to the right heart and pulmonary artery. As it leaves the lungs in the pulmonary veins, blood is 99% saturated. Intracardiac shunts can be detected, localized, and quantified by measuring the oxygen saturation in various locations. Left-​to-​right shunts will cause a step-​up in the saturation of the blood at the location of the shunt; for example, in a patient with an atrial septal defect the saturation will rise in the right atrium, whereas with a ventricular septal defect the saturation will rise in the right ventricle. A pa- tient with Eisenmenger’s syndrome (pulmonary hypertension and right-​to-​left shunting) will exhibit a drop in saturation at the loca- tion of the shunt, namely at the left atrium or ventricle in the case of atrial and ventricular septal defects, respectively. The degree of the change in saturation is proportional to the size of the shunt and enables calculation of the shunt flow in either direction in litres/​ min. Fig. 16.3.4.5 presents a scheme and formulae for calculating shunt volume. Vascular resistance Blood flow through the pulmonary and systemic circulations can be compared to the flow of an electric current through a circuit. Pressure is the driving force analogous to voltage, flow rate is analo- gous to current, and the impediment to flow through the vascular Q (g) Sampling point O conc. (g/l) conc.∫o t conc.∫o t Inject 0 Q F = = l/s g g-s/l Time (s) F (litre/s) Fig. 16.3.4.4  Cardiac output measured by dye curve. The concentration curve of indocyanine green dye generated by sampling distal to an injection point can be analysed to yield cardiac output. See text for more details. Thermodilution cardiac output employs the same principle, except that temperature is the measured indicator. F, flow or cardiac output; Q, quantity of indicator injected. section 16  Cardiovascular disorders 3344 bed is resistance. Pressure, flow, and resistance relate to each other in a fashion analogous to Ohm’s law: resistance = pressure/​flow. In this formula, ‘pressure’ is the difference in mean pressure across the systemic vascular bed (systemic arterial pressure − right atrial pressure) or the pulmonary vascular bed (pulmonary artery pres- sure − left atrial pressure). In the absence of intracardiac shunts ‘flow’ is the same for both circulations and is measured as cardiac output by methods already described. In cases of intracardiac shunting the systemic and pulmonary flows will differ according to the degree of shunting, and can be calculated as described under the section on cardiac shunts and in Fig. 16.3.4.5. Normal values for pulmonary vascular and systemic vascular resistance are expressed either in dyne s cm–​5 or Wood units as shown in Table 16.3.4.2. Total pul- monary resistance is a useful concept for expressing the total resist- ance against which the right ventricle must work, and includes not only the pulmonary vascular resistance but also the resistance en- gendered by the static pressure in the left atrium. Hence, pulmonary vascular disease, left heart failure, or both, can increase the total pul- monary resistance. Measurement of resistance is useful for assessing the state of the pulmonary circulation in congenital heart disease with intracardiac shunting: high pulmonary vascular resistance may preclude the safe correction of an intracardiac shunt, particularly if the shunt is from right to left. It is also useful in diagnosing the relative contribution of left heart failure and pulmonary vascular disease in patients with pulmonary hypertension, and is the best indicator of the effective- ness of vasodilating drugs for patients with pulmonary hypertension. Valvular stenosis Valvular stenosis is assessed by measuring the transvalvular pressure gradient and by calculating the valvular orifice area using a formula introduced in the late 1940s by cardiologist Richard Gorlin and his father, an engineer. The Gorlin formula for valve area was initially de- veloped for patients with rheumatic mitral stenosis. It is based upon a study which utilized data from right heart catheterization alone, validated by relatively crude intraoperative estimates of valve area using the index finger of surgeon Dwight Harken during closed mi- tral commissurotomy operations at the Peter Bent Brigham Hospital in Boston, Massachusetts, or by autopsy in some cases. Although its validation was relatively crude, the formula has stood the test of time and remains the standard for the haemodynamic assessment of valvular stenosis. In its generalized form it is expressed as follows: Value area TFR ( ) / , K m where K is a constant unique to mitral or aortic valve analysis (38 and 44.5, respectively), TFR is the transvalvular flow rate, and m is the mean pressure gradient in mm Hg during the time when the valve is open. In aortic valve applications TFR (i.e. cardiac output normalized for the time that the valve is actually open) is the cardiac output div- ided by the product of heart rate and systolic ejection period. In mi- tral valve applications it is the cardiac output divided by the product of heart rate and diastolic filling period. Cardiac output is the ef- fective systemic blood flow as determined by Fick, thermodilution, or dye dilution methods, unless there is associated valvular regur- gitation, in which case it is the total left ventricular output as deter- mined by quantitative left ventricular angiography. Fig. 16.3.4.6 shows tracings that demonstrate typical gradients from patients with aortic and mitral stenosis. The ranges of the cal- culated valve area associated with various levels of stenosis for both aortic and mitral valves are displayed in Table 16.3.4.3. In general, procedures performed for the relief of anatomical stenosis are ex- pected to be beneficial in symptomatic patients with severe valvular obstruction. However, many factors enter into such a decision and Resistance = pressure/flow PBF EPBF SA Mixed venous return EPBF R L R L EPBF (l/min) = O2 consumption (ml/min) (PVO2– mixed VO2) × 10 PBF (l/min) = O2 consumption (ml/min) (PVO2– PAO2) × 10 SBF (l/min) = O2 consumption (ml/min) (SAO2– mixed VO2) × 10 Shunt flow (l/min): PV PA SBF L R = PBF – EPBF R L = SBF – EPBF Fig. 16.3.4.5  Quantitation of intracardiac shunts. Shunts between the left and right sides of the heart due to septal defects can be quantified by oximetry using this scheme. Oxygen content is measured in units of cc oxygen per decilitre of blood. EPBF, effective pulmonary blood flow (i.e. that part of the systemic venous return that actually passes through the lungs and is oxygenated); PBF, pulmonary blood flow; mixed Vo2, mixed systemic venous oxygen content; PAo2, pulmonary artery oxygen content; PVo2, pulmonary vein oxygen content; SAo2, systemic artery oxygen content; SBF, systemic blood flow. Table 16.3.4.2  Normal vascular resistancea Location Resistance (dynes s cm–​5)b Wood units Total systemic resistance 1276 ± 371 16 ± 4.6 Total pulmonary resistance   185 ± 57 2.3 ± 0.7 Pulmonary vascular resistance     55 ± 18 0.7 ± 0.2 a These values are derived from 100 consecutive catheterization studies of patients proven to have no evidence of cardiac disease at the West Roxbury Veterans Administration Hospital during the years 1955–​1980. b Divide these values by 10 to obtain values in MPa s m−3. 16.3.4  Cardiac catheterization and angiography 3345 individual clinical judgement is required. Although patients with large transvalvular gradients generally experience the best result from intervention, the gradient by itself can be misleading due to its exponential relationship to cardiac output. Valvular regurgitation Qualitative assessment Regurgitation of all four cardiac valves can be qualitatively assessed by angiography. The downstream side of the valve in question is opacified by a rapid injection of radiographic contrast me- dium. Regurgitation is visualized as upstream leakage of contrast across the closed valve. In the case of mitral regurgitation systolic opacification of the left atrium occurs during injection of the left ventricle. In aortic regurgitation diastolic opacification of the left ventricle occurs during supravalvular injection of the aorta. The de- gree of regurgitation is graded on an arbitrary scale from mild (1 +) to severe (4 +). Quantitative assessment Aortic and mitral regurgitation can be quantified in terms of regurgitant flow in litres/​min or regurgitant fraction as a percentage of left ventricular output. Regurgitant flow is the difference obtained by subtracting the effective forward flow (Fick method described earlier) from the total left ventricular output (angiographically de- rived). It is the best method for measuring the severity of regurgita- tion, provided that the left ventricular angiogram, which itself may change cardiac output, is performed soon after the Fick measure- ment. Furthermore, both measurements must be made with consid- erable care to ensure accuracy. Regurgitation is considered clinically severe when 50% or more of the total left ventricular output is simply shuttling or regurgitating across the defective valve. The ability to quantify regurgitation across either valve is lost when both mitral and aortic valves are leaky. Left ventricular function Global function Global function of the left ventricle is broadly described by its ability to generate pressure and flow under particular conditions of preload and afterload. Plotting the pressure and volume of the left ventricle at instants in time for a single cardiac cycle generates a pressure–​ volume loop displayed in Fig. 16.3.4.7. Most of the commonly used indices of left ventricular function can be derived from such a loop, including end-​diastolic volume, end-​systolic volume, stroke volume, ejection fraction, end-​diastolic pressure, and dP/​dt. Of these, the Mitral stenosis Aortic stenosis (b) (a) 200 100 0 mm Hg LV Ao 1 s 40 20 0 mm Hg 1 s PCW LV Fig. 16.3.4.6  Pressure gradients associated with valvular stenosis. The upper panel shows simultaneous tracings of left ventricular (LV) and ascending aortic (Ao) pressure in a patient with severe aortic stenosis. The mean systolic gradient across the aortic valve is 60 mm Hg. The lower panel shows simultaneous tracings of left ventricular (LV) and pulmonary capillary wedge (PCW) pressure in a patient with severe mitral stenosis. The mean diastolic pressure gradient across the valve is 16 mm Hg. The respective valvular gradients are cross-​hatched. Table 16.3.4.3  Calculated valve areas associated with various degrees of mitral and aortic stenosis Severity Valve area (cm2) Aortic Mitral Mild 1.2 2.0 Moderate 0.8–​1.2 1.1–​2.0 Severea <0.8 ≤1.0 a Severe stenosis is generally considered to be sufficient to warrant surgical or percutaneous intervention. 0 250 150 250 350 LV volume (ml) A B D C 200 150 100 50 LV pressure (mm Hg) 50 Normal Pressure load Volume load Cardiomyopathy Fig. 16.3.4.7  Pressure–​volume loops. Simultaneously plotting the instantaneous pressure and volume of the left ventricle throughout a single cardiac cycle produces these loops. The loop is a synthesis of most information relevant to left ventricular function. In this figure a loop from a normal patient is contrasted with those from patients with pressure load (hypertension or aortic stenosis), volume load (aortic or mitral regurgitation), and cardiomyopathy. Point A represents mitral valve closure; segment A–​B, isovolumic contraction; point B, aortic valve opening; segment B–​C, systolic ejection; point C, aortic valve closure; segment C–​D, isovolumic relaxation; point D, mitral valve opening; and segment D–​A, diastolic filling. section 16  Cardiovascular disorders 3346 ejection fraction is most useful because it correlates with prognosis in a variety of cardiac diseases. Grading angiographic wall motion in various segments of the left ventricle as normal, hypokinetic, akinetic, or dyskinetic assesses the regional function of the left ventricle. Regions of abnormal func- tion generally correspond to locations of infarcted or ischaemic myocardium. Contractility This parameter is difficult to assess in the intact heart because all pressure and volume indices are dependent upon preload and afterload. Although ejection fraction is clinically useful it can be misleading in situations of high afterload (e.g. severe aortic sten- osis) and low afterload (e.g. severe mitral regurgitation). The con- cept of ‘elastance’ has gained favour as a useful index of intrinsic contractility because it is relatively independent of loading condi- tions. Elastance is the slope of the line generated by plotting the end-​ systolic left ventricular pressure from a series of pressure–​volume loops generated at differing afterloads created by the infusion of pressor or vasodilator drugs. The method is laborious and generally reserved for research applications. Diastolic function Diastolic function of the left ventricle is best appreciated from the slope of the pressure–​volume loop during the period from mitral valve opening to its closure at the onset of systole. The curve be- comes steeper as the left ventricle becomes less compliant due to the effects of hypertrophy, ischaemia, or infiltrative disease. In general, left ventricular end-​diastolic pressure rises as diastolic compliance falls, accounting for the high left atrial pressure and heart failure seen in diastolic left ventricular dysfunction. Assessment of coronary arterial anatomy and function Disease of the coronary arteries can be characterized at catheteriza- tion by both anatomical and functional assessment. Coronary angi- ography images the lumen of the vessel, which has been rendered radiopaque by injection of radiographic contrast medium. It is a shadowing technique that displays the impact of the lesion on the arterial lumen but does not image the plaque per se. Intracoronary ultrasonography provides a tomographic image of the vessel wall and is capable of demonstrating the thickness and sonic density of the vessel wall and any associated plaque, hence angiography and intravascular ultrasonography are complementary methods of (a) (b) (c) (d) Fig. 16.3.4.8  Normal coronary anatomy. Left coronary angiogram showing main stem, left anterior descending, and left circumflex arteries from right anterior oblique view (a) and left anterior oblique view (b). Right coronary angiogram showing right coronary and posterior descending arteries from right anterior oblique view (c) and left anterior oblique view (d). 16.3.4  Cardiac catheterization and angiography 3347 assessing vascular anatomy. To learn the haemodynamic import- ance of a coronary lesion, it may be necessary to analyse its effect on function by measuring pressure and flow in the affected vessel. All these anatomical and functional modalities may be accomplished by catheterization. Coronary arteriography or angiography Coronary arteriography or angiography is presently the single most essential application of cardiac catheterization. The anatomy of coronary arteries in living, conscious humans was first dem- onstrated by non​selective injection of the aortic root. In the early 1960s David Littmann developed a loop catheter that enabled the injection of contrast medium preferentially in the outer circum- ference of the aortic root, opacifying the left and right coronary arteries simultaneously. At the time it was commonly believed that selective injection of contrast material into a coronary artery would have fatal consequences. This changed when Mason Sones accidentally performed the first selective coronary angiogram without harm. He was intending to inject the left ventricle, but the catheter recoiled across the aortic valve and into the right coronary artery. Sones, a cardiologist by training, went on to develop a safe method of selective coronary angiography from the brachial ar- tery cut-​down approach using the flexible-​tip catheter bearing his name. At the same time Melvin Judkins, a radiologist by training, was perfecting his own method of selective coronary angiography, using preshaped catheters, from a percutaneous femoral artery ap- proach. Both methods have continued to be practised, although the percutaneous femoral, or Judkins’ approach, has become most popular because of its speed and simplicity. However—​as stated previously—​in recent years there has been a return to the arm approach using percutaneous catheterization of the radial ar- tery, which enables more rapid patient ambulation, and the radial artery approach is also associated with fewer serious access site complications. Normal coronary anatomy is demonstrated in Fig. 16.3.4.8. A patient’s anatomy is considered to be right (80%)—​or left (20%)—​ dominant, depending upon whether the posterior descending artery arises from the right or left coronary artery, respectively. Atherosclerotic disease is manifest by lesions that encroach upon the opacified lumen of the coronary artery (Fig. 16.3.4.9). Various approaches are used to grade the severity of these lesions. Most commonly a visual estimate of the percentage of the stenotic reduction in luminal diameter is given to each lesion, with severity quantified by comparing the minimal lumen diameter within a lesion to the diameter of the nearest normal segment of artery. This can be done manually using callipers or automatically using computer-​based systems for edge detection and contrast densi- tometry. Quantitative coronary angiography is a complex subject because it requires attention to many variables, such as selection of view and frame, and choice made from among several analytical techniques. Early work by Lance Gould determined that a lesion must impair coronary blood flow to be clinically important. Although flow at rest is not usually reduced until stenosis reduces vessel diameter by 90%, flow under stress may be impaired when the diameter is reduced by 70%. The clinical impact of a stenosis of any given severity is also dependent upon the degree of collateral flow into the vascular bed distal to the stenosis. Coronary physiological measurements (pressure and flow) Flow and pressure may be directly measured in the coronary artery by means of special guide wires that have pressure transducers or Doppler flow transducers mounted near their tips. As just men- tioned, the flow at rest may be normal across a particular coronary artery stenosis. Coronary flow normally increases after maximal vasodilatation induced by local vasodilators. The quotient of the vasodilated flow divided by the resting flow, which is called the cor- onary flow reserve, is normally greater than 2. If not, the lesion in question is considered to be haemodynamically important. Pressure can be measured in the coronary artery at a location distal to a le- sion using a guide wire with a transducer at its tip. The quotient of pressure distal to a lesion compared to the proximal pressure during maximal vasodilatation is called the fractional flow reserve. A quotient less than 0.75 is considered to be clinically important. The measurement of fractional flow reserve has proven useful in selecting vessels in need of revascularization. Intravascular ultrasonography Intravascular ultrasonography (IVUS; see Fig. 16.3.4.10) is ac- complished by advancing a catheter over a guide wire previously placed into a coronary artery. The catheter has a miniature ultra- sound transducer near its tip, which enables rotational Doppler imaging of the vessel wall in a plane perpendicular to its axis. IVUS is particularly useful for assessing the nature of angio- graphically questionable lesions, determining the true size of the vessel prior to stent deployment, and assessing the complete- ness of stent deployment. It is also probably the best method for Fig. 16.3.4.9  Atherosclerotic coronary artery disease. The constrictions and blunt terminations seen in this patient’s coronary angiogram represent atherosclerotic lesions. section 16  Cardiovascular disorders 3348 serial studies of coronary anatomy during drug treatment trials because it images the plaque itself and is therefore more sensitive than angiography. Complications of cardiac catheterization Although cardiac catheterization is a relatively safe procedure, it is nevertheless important for both the patient and the referring physician to recognize the nature and likelihood of potential com- plications. Table 16.3.4.4 lists the complications of bilateral heart catheterization, including coronary, left ventricular, and aortic angiography, in a prospective study of valvular heart disease from the United States Veterans Administration. Even though these data were collected over 30 years ago from a particularly high-​ risk group of patients, the frequency of complication is a realistic estimate of what should currently be expected. The rate of each particular complication will vary with the age and general health of the patient. For example, the risk of vascular complication is considerably increased by the presence of vascular disease, and the risk of renal failure due to contrast medium is particularly high in diabetic patients with pre-​existing renal dysfunction. Access site complications (bleeding, haematoma, arteriovenous fistula, pseudoaneurysm, and occlusion) have received particular atten- tion in recent years because of the use of aggressive anticoagulation and antiplatelet treatments during percutaneous coronary inter- vention. The use of smaller gauge catheters and careful location of the arterial puncture site are important. Vascular closure devices enable earlier ambulation of patients having femoral procedures. In counselling the patient regarding the likelihood of untoward events, it is important to give individualized advice based on the patient’s particular circumstances. The decision to recommend catheterization must be based on the anticipation that its benefits justify its risk and cost. Fig. 16.3.4.10  Intravascular ultrasound images. The dark central circles represent the ultrasound catheter. Measurement markers are spaced by 1 mm. The top two panels demonstrate the appearance of a cross-​ section of a normal coronary artery. The arrows in magnified image on the right point to the intimal layer. The three lower panels demonstrate coronary arteries with soft, mixed fibrous/​calcified and hard calcified plaque. Reprinted from Nissen SE, Yock P (2001). Intravascular ultrasound: Novel pathophysiological insights and current clinical applications. Circulation, 103, 604–​16. 16.3.4  Cardiac catheterization and angiography 3349 FURTHER READING De Bruyne B, et al. (2012). Fractional flow reserve guided-​PCI versus med- ical therapy in stable coronary disease. N Engl J Med, 367, 991–​1001. Moscucci M (2014). Grossman and Baim’s cardiac catheterization, an- giography and intervention, 8th edition. Lippincott Williams and Wilkins, Baltimore, MD. Nissen SE, York P (2001). Intravascular ultrasound:  novel patho- physiological insights and current clinical applications. Circulation, 103, 604–​16. Sorajja P, Lim M, Kern M (2019). Kern’s cardiac catheterization hand- book, 7th edition. Elsevier, Philadelphia, PA. Tonino PA, et al. (2009). Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med, 360, 213–​24. Table 16.3.4.4  Complications of cardiac catheterization from a prospective study of 1559 procedures performed on 1483 United States veterans having valvular heart disease during the years 1977–​1982a Type of complication Frequency (%) Death within 24 h 0.1 Death between 24 h and 30 days 0.1 Stroke 0.3 Transient cerebral ischaemia 0.1 Myocardial infarction 0.2 Peripheral arterial embolism 0.1 Access site complications 1.7 Cardiac tamponade 0.3 Ventricular fibrillation 0.5 Arrhythmia other than ventricular fibrillation 1.5 Primary hypotension 0.5 Reaction to contrast medium (allergic and renal) 1.8 Arterial perforation or dissection 0.3 Miscellaneous complications 1.4 Patients having one or more of the above complications 6.9 a Although this is a high-​risk group of patients undergoing extensive study, the rates are very comparable to what should be expected today. In fact, some complications, especially bleeding, are now more frequent because of aggressive anticoagulation and antiplatelet treatments given to many patients undergoing percutaneous intervention. Recent data from national registries in the United States indicate frequency of vascular access site injury to be less than 1% for diagnostic procedures. Oliver P. Guttmann and Perry Elliott 16.7.3 Specif Oliver P. Guttmann and Perry Elliott 16.7.3 Specifific heart muscle disorders 3489 Oliver P. Guttmann and Perry Elliott 16.7.3  Specific heart muscle disorders 3489 Caforio AL, et al. (2013). Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis:  a position statement of the European Society of Cardiology working group on myocardial and pericardial diseases. Eur Heart J, 34, 2636–​48. Herman DS, et al. (2012). Truncations of titin causing dilated cardio- myopathy. N Engl J Med, 366, 619–​28. Hershberger RE, Morales A, Siegfried JD (2010). Clinical and genetic issues in dilated cardiomyopathy: a review for genetics professionals. Genet Med, 12, 655–​71. Jefferies JL, Towbin JA (2010). Dilated cardiomyopathy. Lancet, 375, 752–​62. McNally EM, Mestroni L (2017). Dilated cardiomyopathy: genetic de- terminants and mechanisms. Circ Res, 121, 731–​48. Pinto YM, et al. (2016). Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non-​dilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases. Eur Heart J, 37(23),1850–​8. Sliwa K, et al. (2010). Evaluation of bromocriptine in the treatment of acute severe peripartum cardiomyopathy: a proof-​of-​concept pilot study. Circulation, 121, 1465–​73. Restrictive cardiomyopathy Muchtar E, Blauwet LA, Gertz MA (2017). Restrictive cardiomyop- athy: genetics, pathogenesis, clinical manifestations, diagnosis, and therapy. Circ Res, 121, 819–​37. Arrhythmogenic right ventricular cardiomyopathy Corrado D, et  al. (2015). Treatment of arrhythmogenic right ven- tricular cardiomyopathy/​dysplasia: an international task force con- sensus statement. Eur Heart J, 36, 3227–​37. Corrado D, Link MS, Calkins H (2017). Arrhythmogenic right ven- tricular cardiomyopathy. N Engl J Med, 376, 61–​72. Marcus FI, et al. (2010). Diagnosis of arrhythmogenic right ventricular cardiomyopathy/​dysplasia: proposed modification of the Task Force criteria. Eur Heart J, 31, 806–​14. Quarta G, et al. (2011). Familial evaluation in arrhythmogenic right ventricular cardiomyopathy:  impact of genetics and revised Task Force criteria. Circulation, 123, 2701–​9. 16.7.3  Specific heart muscle disorders Oliver P. Guttmann and Perry Elliott ESSENTIALS Systemic immune-​mediated diseases Cardiovascular involvement is very common, but may be occult and often goes undetected. Any anatomical structure in the heart can be involved, hence patients may present with pericarditis, myocarditis, endocarditis, or coronary vasculitis. There is often no correlation between the extent of systemic disease and cardiac involvement. Systemic lupus erythematosus—​more than 50% have cardiovascular involvement at some time; 30% have clinical pericarditis; myocarditis can occasionally present with heart failure or arrhythmias; marantic endocarditis can be identified in at least 30% at autopsy, but is rarely clinically significant; neonates born to mothers with systemic lupus erythematosus who have anti-​Ro/​anti-​La antibodies frequently de- velop complete heart block; atherosclerosis is the leading cause of late death in systemic lupus erythematosus. Systemic sclerosis—​symptomatic cardiac involvement is un- common (10%); pulmonary hypertension, usually secondary to lung involvement, has a very poor prognosis. Rheumatoid arthritis—​10–​15% have clinical cardiac involvement; echocardiography is abnormal in 60%, typically demonstrating pericarditis and/​or pericardial effusion; vasculitis affecting epicar- dial arteries, non​specific valvitis, and conduction disturbances are reported. Seronegative arthropathies—​associated with pancarditis, proximal aortitis, aortic incompetence, and varying degrees of conduction abnormalities. Takayasu arteritis—​proximal coronary arteries are involved in 15–​20%; dilatation of the aortic root may cause aortic regurgitation; pulmonary artery aneurysms and stenoses are common; involve- ment of the renal arteries can cause malignant hypertension; aortic, coronary, pulmonary, and bronchial arterial fistulae are reported. Kawasaki disease—​myocarditis is frequent (35%) in the acute stage, often in association with a pericardial effusion; coronary ar- tery involvement occurs in 20%, resulting in aneurysm formation and thrombotic occlusion, such that—​in the longer term—​patients can present with myocardial ischaemia. Other conditions Amyloidosis—​in systemic AL (primary) amyloidosis up to 50% have cardiac involvement. The heart is frequently involved in familial amyloid polyneuropathy caused by mutations in the transthyretin gene in transthyretin and is the main organ involved in senile (wild-​ type) transthyretin amyloidosis. The typical clinical presentation mimics hypertrophic cardiomyopathy, with restrictive physiology. The ECG may show diminished voltages, loss of R waves in precor- dial leads with a pseudoinfarction pattern. Echocardiography may show a characteristic ‘sparkling’ appearance to the myocardium, thickening of the heart valves and the interatrial septum, and pericar- dial effusions. Symptomatic heart disease typically occurs late in the course of amyloidosis and carries a poor prognosis. Sarcoidosis—​cardiac involvement is clinically apparent in less than 10% of cases, but sudden (presumed arrhythmic) death is not in- frequent among these. Isolated cardiac sarcoidosis can present with ventricular arrhythmia, AV block, or myocarditis. Endocrine disorders—​diabetes is associated with an increased risk of developing heart failure; hyperthyroidism can cause a high-​output state with heart failure with dilated cardiomyopathy and systolic dysfunction; hypothyroidism frequently causes pericardial effusion; phaeochromocytoma and acromegaly can cause cardiomyopathy. Neuromuscular disorders—​myocardial dysfunction is common in the muscular dystrophies. In Duchenne and Becker muscular dys- trophy (dystrophin gene mutations) the commonest abnormality is dilated cardiomyopathy; in laminopathies (lamin AC gene mu- tations) atrial arrhythmia, heart block, dilated cardiomyopathy, and sudden cardiac death are frequent. section 16  Cardiovascular disorders 3490 Inherited metabolic disorders—​hereditary haemochromatosis causes thickening of the ventricular walls, dilatation of the ven- tricular chambers, and heart failure; cardiac disease is par- ticularly important in lysosomal and glycogen storage diseases, including hypertrophic and dilated cardiomyopathy, arrhythmia, and valvular disease. Cardiomyopathy can also be caused by drugs, toxins, nutri- tional deficiency, and electrolyte disorders. Systemic immune-​mediated diseases Systemic immune-​mediated diseases are autoimmune and auto­ inflammatory diseases affecting at least two-​organ systems, and can be classified as shown in Fig. 16.7.3.1. Autoinflammatory diseases are a family of conditions characterized by episodes of unprovoked inflammation in the absence of high autoantibody titres or auto re- active T lymphocytes, reflecting a primary dysfunction of the in- nate immune system. Autoimmune diseases are characterized by aberrant B, T, and dendritic cell responses with predominantly cell-​ mediated or autoantibody-​mediated responses to self-​antigens in genetically susceptible individuals. Cardiovascular involvement in systemic immune-​mediated dis- eases may be occult and often goes undetected, but is associated with a poor prognosis. As any anatomical structure in the heart may be involved, patients can present with one or more features consistent with pericarditis, myocarditis, endocarditis, and vasculitis. There is often no correlation between the extent of systemic disease and cardiac involvement. For details of the cardiac manifestations of specific autoimmune rheumatic diseases and the vasculitides, see Tables 16.7.3.1 and 16.7.3.2. General approach to diagnosis of cardiac involvement The pattern of myocardial involvement varies in different systemic immune-​mediated diseases, but there are some general consider- ations when assessing cardiac involvement. Symptoms suggesting myocarditis include dyspnoea, palpitations, chest pain, syncope, arrhythmia, and acute or chronic heart failure. As many systemic immune-​mediated diseases are associated with accelerated coronary artery disease, myocardial ischaemia should also be ruled out when- ever there are cardiac symptoms. A strategy for diagnostic cardiac work up and management is shown in Fig. 16.7.3.2. An increase in serum cardiac troponin or NT-​pro B-​natriuretic peptide (BNP) supports a diagnosis of myocardial involvement, but myocarditis can occur in the absence of troponin release. Any unexplained abnormality on standard 12-​lead electrocardiography (ECG) or 24-​h-​ECG Holter monitoring should raise suspicion of cardiac involvement. Standard echocardiography with Doppler and deformation imaging can detect subclinical myocardial, Rare monogenic autoimmune diseases Autoimmune Autoinflammatory Classic polygenic autoimmune diseases (organ nonspecific) Mixed pattern diseases with aquired component (MHC class 1 associations) and autoinflammatory components ALPS IPEX APECED Rheumatoid arthritis Coeliac disease Primary biliary cirrhosis Pemphigus, pemphigoid, Myasthenia gravis Dermatomyositis, polymyositis, Scleroderma Goodpasture syndrome ANCA associated vasculitis Sjogren syndrome Systemic lupus erythematosus Ankylosing spondylitis Reactive arthritis Psoriasis/psoriatic arthritis Behcet syndrome HLA-B.27 associated uveitis Crohn’s disease, ulcerative colitis AOSD and juvenile idiopathic arthritis (JIA) Gout/pseudogout/other crystal arthropathies Some categories of reactive arthritis and Psoriasis arthritis (no MHC associations) Nonantibody associated vasculitis including giant cell and Takayasu arteritis Idiopathic uveitis Acne and acneiform associated diseases Erythema nodosum associated disease, including sarcoidosis FMF, TRAPS, HIDS, PAPA DIRA DITRA FCAS NLRP 12 associated Autoinflammatory Disorders (NLRP12AD) PFAPA CANDLE Majeed syndrome Blau syndrome NOMID MAS CRMO FCAS 2 (Guadalupe type fever syndrome) Interferonopathies Mutant adenosine Deaminase 2 (organ nonspecific) Polygenic autoinflammatory diseases Rare monogenic autoinflammatory diseases Fig. 16.7.3.1  Classification of systemic inflammatory diseases. ALPS, autoimmune lymphoproliferative syndrome; AOSD, adult-​onset Still’s disease; APECED, autoimmune polyendocrinopathy-​candidiasis-​ectodermal dystrophy syndrome; CANDLE, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature; CMRO, chronic multifocal recurrent osteomyelitis; DIRA, deficiency of interleukin-​1 receptor antagonist; DITRA, deficiency of the interleukin-​36-​receptor antagonist; FCAS, familial cold autoinflammatory syndrome; FMF, familial Mediterranean fever; HIDS, hyperimmunoglobulinaemia D with periodic fever syndrome; HLA, human leukocyte antigen; IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X-​linked; MAS, macrophage activation syndrome; MHC, major histocompatibility complex; NOMID (also known as CINCA), neonatal onset multisystem inflammatory disease; PAPA, pyogenic arthritis, pyoderma gangrenosum, and severe cystic acne; PFAPA, periodic fever, aphthous stomatitis, pharyngitis, and adenitis; TRAPS, tumour necrosis factor receptor-​associated periodic fever syndrome. From Caforio ALP, et al. (2017). Diagnosis and management of myocardial involvement in systemic immune-​mediated diseases: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Disease. Eur Heart J, 38(35), 2649–​62, by permission of Oxford University Press. 16.7.3  Specific heart muscle disorders 3491 pericardial, and valvular involvement. Tricuspid and pulmonary Doppler are important methods of assessment for the non​invasive diagnosis of pulmonary hypertension. Cardiac magnetic resonance imaging with tissue characterization sequences provide supportive evidence for cardiac involvement. Specifically, a subepicardial or mid-​myocardial late gadolinium enhancement pattern correlates with disease activity in rheumatoid arthritis and systemic scler- osis, and such imaging can also identify early disease in these con- ditions. Computed tomography (CT) is used for the diagnosis of aortic disease, coronary atheroma, and pericardial disease. Positron emission tomography (PET) is useful for detection of myocardial inflammation in sarcoidosis. Autoimmune rheumatic disorders Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a multisystem immune dis- order characterized by the formation of autoantibodies to various cell antigens. The pathogenesis of SLE myocarditis is thought to be immune-​complex mediated. Immunoglobulin deposits and granular complement are evident at autopsy and on endomyocardial biopsy. The prevalence of cardiovascular involvement at some point in the illness is more than 50%. The pericardium is most commonly affected, with as many as 30% of patients having clinical pericarditis at some stage, and up to 80% affected at autopsy. Progression to con- strictive pericarditis or tamponade is extremely rare. Clinically evident myocardial involvement occurs less fre- quently, but is reported in 40–​50% of patients at autopsy: signs and symptoms are uncommon, but patients may occasionally pre- sent with heart failure or arrhythmias. Unexplained increases in troponin I and/​or NT-​pro BNP, global or segmental hypokinesis on transthoracic echocardiography, and a non​ischaemic pat- tern of myocardial late gadolinium enhancement and/​or oedema on cardiac magnetic resonance imaging, support the diagnosis of myocarditis. SLE myocarditis may be associated with muta- tions in the gene encoding the 3′-​5′ DNA exonuclease TREX1. Other factors that may contribute to ventricular dysfunction in Table 16.7.3.1  Cardiac manifestations of systemic immune-​ mediated diseases and the vasculitides Disease Cardiac manifestation Systemic lupus erythematosus Accelerated atherosclerosis Non​infective endocarditis (Libman–​Sacks) Myocarditis Pericarditis Rheumatoid arthritis Coronary arteritis Aortic and mitral regurgitation Seronegative arthropathies—​ ankylosing spondylitis, Reiter’s syndrome, psoriatic arthritis, ulcerative colitis, Crohn’s disease Pancarditis Proximal aortitis Conduction disease Systemic sclerosis Myocarditis Pericarditis Arrhythmias Granulomatosis with polyangiitis (GPA; formerly Wegener’s granulomatosis) Constrictive pericarditis Atrioventricular block Eosinophilic granulomatosis with polyangiitis (EGPA; also known as Churg–​Strauss syndrome) Congestive cardiac failure Pericarditis Coronary arteritis/​myocardial infarction Arrhythmias Polyarteritis nodosa Hypertension Congestive heart failure Partial or complete coronary artery occlusion Pericarditis Arrhythmias Takayasu’s syndrome Pericarditis Aortic arch vasculitis Heart failure Table 16.7.3.2  Cardiac involvement in the more common autoimmune rheumatic disorders Pericardial involvement Myocardial involvement Valvular involvement Coronary/​arteritis Conduction system involvement Rheumatoid arthritis 16–​40% at autopsy 10–​15% clinical pericarditis 4–​20% at autopsy Symptomatic in <5% 50% valvulitis at autopsy Symptoms rare 11–​20% involvement of coronary vessels at autopsy Vasculitis affecting the aorta rare Any part of conduction system involved Varying degrees of heart block in 0.1% SLE 45–​66% at autopsy 20–​30% clinical pericarditis 30% at autopsy Symptomatic in <10% Libman–​Sacks lesions in 30% at autopsy Coronary vessels involved in <10% Vasculitis affecting the aorta rare Any part of conduction system involved Varying degrees of heart block in <1% Systemic sclerosis and variants 70% at autopsy 7–​15% clinical pericarditis Up to 60% at autopsy Symptoms rare Rare, AR, and MVP described Symptoms in <10% Reversible perfusion defects in up to 40% Vasculitis demonstrated rarely Any part of conduction system involved; Abnormal ECG in 50% Polymyositis/​ dermatomyositis Clinical involvement rare (usually in children with dermatomyositis) Up to 25% at autopsy Symptoms in 13–​26% MVP common Other lesions rare Any part of conduction system involved Symptoms extremely rare Seronegative spondyloarthropathies <1% incidence of pericarditis in AS and Reiter’s Myocardial involvement/​ dysfunction common on echo in AS Symptoms rare Aortic incompetence most common: 1–​10% in AS, 1–​15% in Reiter’s MR very rare Aortitis: 1–​10% in AS, 1–​15% in Reiter’s Heart block: 8% in AS, 8% in Reiter’s, rare in other forms of spondyloarthropathy AR, aortic regurgitation; AS, ankylosing spondylitis; MR, mitral regurgitation; MVP, mitral valve prolapse; SLE, systemic lupus erythematosus. section 16  Cardiovascular disorders 3492 SLE include atherosclerosis, hypertension, and drug therapy, in particular chloroquine. The latter can be distinguished using endomyocardial biopsy. As many as one-​third of patients with SLE have systolic murmurs, which are usually caused by hyperdynamic flow. The classic verru- cous vegetations adherent to the endocardium described by Libman and Sacks in 1924 (marantic endocarditis) can be identified in 30% or more at autopsy. These lesions most commonly affect the mitral valve but are rarely clinically significant. Neonates born to mothers with SLE who have anti-​Ro/​anti-​ La antibodies frequently develop complete heart block (see Chapter 14.14). Various degrees of heart block and bundle branch block can be seen in adults, but complete heart block is rare. Arrhythmias such as atrial fibrillation and flutter may also occur, particularly in association with pericarditis. Myocardial infarction is uncommon in patients with SLE, but ac- celerated or premature atherosclerosis is the leading cause of late death in SLE. Its cause is unknown, but suggested contributory fac- tors include chronic inflammation, immune complex deposition, antiphospholipid antibodies, hypertension, dyslipidaemia, and hyperglycaemia (caused by chronic steroid administration). Death from the cardiac complications of lupus is rare. Mild peri- cardial disease may respond to non​steroidal anti-​inflammatory drugs, heart failure is treated conventionally, and conduction defects may require pacing. Coronary vasculitis and/​or lupus myocarditis are usually treated with steroids and other immunosuppressants such as azathioprine, cyclophosphamide, or intravenous immuno- globulin (IVIg), but there are no trials to guide therapeutic decision-​ making in these rare conditions. Antiphospholipid syndrome The antiphospholipid syndrome is recognized both in patients without SLE (primary) and with SLE. It is a thrombophilic dis- order characterized by arterial and venous occlusions, recurrent fetal loss, thrombocytopenia, and increased maternal compli- cations of pregnancy, and is associated with persistently raised titres of anticardiolipin antibodies. Anticoagulation is indicated in patients with thrombotic symptoms and prevents miscar- riage in pregnant women. In refractory cases plasmapheresis can be used. Systemic sclerosis Systemic sclerosis is characterized by abnormal collagen deposition in various organ systems and cardiac involvement may be primary or secondary to concomitant kidney and/​or pulmonary vascular/​ interstitial disease. Symptomatic heart disease is uncommon (10%), but cardiac involvement is frequently detected at autopsy (60%), when the most common features are chronic pericarditis (70%) and myocardial fibrosis (37%). Clinically these cause heart failure, ventricular arrhythmia, and conduction disease. A high arrhythmic burden has been reported, with a 5% sudden death rate in patients with both skeletal and cardiac muscle disease. Rare cases of cardiac tamponade have been described. Valve involvement is uncommon, except for tricuspid regurgitation, which occurs in 40% of patients and is usually associated with pulmonary hypertension. Pulmonary hypertension is present in 47% of patients, usually secondary to lung involvement, and is associated with a 1-​year survival of only 50%. Involvement of the large epicardial blood vessels is not a feature Cardiac red flags (one or more) in a patient with known SIDs: unexplained dyspnoea, palpitations, chest pain with or without troponin increase, syncope, arrhythmia, acute or chronic heart failure, aborted sudden cardiac death, fulminant unexplained cardiogenic shock Cardiological evaluation History, Examination, ECG, Echo, Troponin, BNP/pro-BNP, CMR, PET, CT, complete heart catheterisation; if available, serum cardiac autoantibodies Exclude: pericardial, valvular and coronary artery disease, extra-cardiac causes (e.g. pulmonary embolism) Specific work-up tailored to the individual case and clinically oriented No coronary artery disease, no known causes for cardiac red flags Clinically suspected myocardial involvement in SIDs (e.g. myocarditis) Consider EMB (histology, immunohistology, special stains, search for infectious agents Multidisciplinary management at baseline and follow-up including a cardiologist Disease-specific therapies: personalised and targeted to lowest level of disease activity, e.g. treat-to-target strategy Fig. 16.7.3.2  Myocardial involvement in systemic immune-​mediated diseases: diagnostic workup and management. CMR, cardiac magnetic resonance; CT, computed tomography; EMB, endomyocardial biopsy; SIDs, systemic immune-​mediated diseases. From Caforio ALP, et al. (2017). Diagnosis and management of myocardial involvement in systemic immune-​mediated diseases: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Disease. Eur Heart J, 38(35), 2649–​62, by permission of Oxford University Press. 16.7.3  Specific heart muscle disorders 3493 of systemic sclerosis, but microvascular dysfunction is common and may contribute to myocardial ischaemia and patchy myocar- dial fibrosis. In the limited form of systemic sclerosis (formerly known as CREST syndrome) the overall prognosis is more favour- able: pulmonary hypertension without severe lung disease occurs in 10–​15%, and subclinical left ventricular dysfunction is reported. Autoimmune myocarditis should be managed by immunosuppres- sive treatment. Rheumatoid arthritis Cardiac involvement is found in up to 60% of patients on echo- cardiography, but in only 10–​15% clinically. The presence of car- diac disease correlates with the severity of joint disease and the presence of rheumatoid nodules, male gender, age, high titres of rheumatoid factor, and other systemic markers of disease activity. Histological changes consist of a non​specific inflammatory infil- trate, myocyte necrosis, and fibrosis affecting any part of the heart. Focal lymphocytic, diffuse necrotizing or granulomatous myocar- ditis may cause cardiomyopathy in 3–​30% of patients. Rheumatoid nodules may accompany this, and the heart may be affected rarely 5% by secondary amyloidosis. Myocarditis is reported in up to 40% at autopsy, but symptoms are uncommon. Pericarditis oc- curs more frequently, and up to 40% of patients have an effusion on echocardiography, but progression to constrictive pericarditis or tamponade is rare. Acute vasculitis involving the larger epi- cardial arteries has been reported but is uncommon. Accelerated atherosclerosis is considered a complication, resulting from com- bination of chronic systemic inflammation and oxidative stress in addition to classic cardiovascular risk factors. Non​specific valvitis may affect the mitral and particularly the aortic valve: this may eventually lead to scarred, hyalinized, and even incompetent valves. Rheumatoid nodules may occasionally deform the mitral valve and lead to valvular incompetence. Conduction disturb- ances may be secondary to infiltration by rheumatoid nodules: the commonest ECG abnormality is first-​degree heart block, but left bundle branch block and complete heart block are also described. Although pericarditis is usually responsive to steroids, it is unclear whether steroids or disease-​modifying drugs alter the other car- diac manifestations. Seronegative arthropathies This group of disorders is characterized by the absence of rheuma- toid factor and includes ankylosing spondylitis, Reiter’s syndrome, and psoriatic and gastrointestinal arthropathies. These may all be associated with cardiac involvement, in particular pancarditis, prox- imal aortitis, aortic incompetence, and varying degrees of conduc- tion abnormalities. They may also result in amyloid deposition. On occasion cardiac disease may present before joint disease. Treatment is empirical and based on symptomatology. Polymyositis and dermatomyositis Cardiac symptoms in polymyositis or dermatomyositis are rare, but post-​mortem and clinical studies suggest that left ventricular diastolic dysfunction and conduction disturbances are present in 40–​50% of cases. When cardiac symptoms are present they are as- sociated with a poor prognosis. Rare cases of cardiac tamponade are reported. Interstitial lung disease, found in 5–​30% of cases, may lead to right heart failure. Treatment is symptomatic. Vasculitides Takayasu’s arteritis Takayasu’s arteritis is a rare inflammatory arteritis that predomin- antly affects the thoracic aorta and the proximal portions of its major branches, the pulmonary arteries, and the coronary vessels. Asians are thought to be affected more than other ethnic groups with a 10:1 female to male ratio. The disease typically evolves from an early in- flammatory stage to a fibrotic obliterative phase with arterial aneur- ysms, stenoses, and occlusions. The proximal coronary arteries are involved in 15–​20% of cases. Dilatation of the aortic root may cause aortic regurgitation. Pulmonary artery aneurysms and stenoses are common and can cause pulmonary hypertension, right heart failure, and pulmonary haemorrhage. Involvement of the renal arteries can cause malignant hypertension. Compared with healthy controls, higher rates of hypertension, low birth rate, and increased perinatal mortality occur in women with a diagnosis of Takayasu’s arteritis. Aortic, coronary, pulmonary, and bronchial arterial fistulae are reported. Subclinical myocardial involvement, in the absence of cor- onary lesions, is reported in up to 50% of patients. Pericarditis is rare. Assessment of disease activity in Takayasu arteritis is challen- ging as there are no gold standard clinical signs or laboratory measures. Computerized tomography and magnetic resonance angiography show vascular stenosis, occlusions, and aneurysms. Fluorodeoxyglucose positron emission tomography-​computerized tomography (FDG-​PET/​CT) often shows vascular inflammation before any structural changes. There are no randomized controlled trials of immunosuppressive therapy, but corticosteroids with adjunctive immunosuppressive agents are standard care. Biological agents such as antitumour ne- crosis factor (TNF) agents, tocilizumab, and rituximab have been used in refractory cases. Patients with ischaemic vascular lesions are treated with endovascular intervention or vascular surgery, but re- currence is frequent. Polyarteritis nodosa Classic polyarteritis nodosa (PAN) is a rare, ANCA-​negative, non-​ granulomatous, necrotizing arteritis of small and medium-​sized vessels without microscopic angiitis or glomerulonephritis. The most typical cardiovascular complication is malignant hypertension caused by renal artery vasculitis. Coronary vasculitis causing an- eurysms, myocardial infarction, and cardiomyopathy are reported, but they are rare. Pericarditis and clinically important conduction system involvement is uncommon. Valve disease is not seen. Giant cell (temporal) arteritis Giant cell arteritis is a granulomatous arteritis of the aorta and its major branches, in particular the carotid artery. It usually affects people older than 50 years of age. Around 5–​10% of patients have cardiac involvement, the most common lesions being thoracic aortic aneurysms and aortic regurgitation. 18F-​FDG-​PET scan may show tracer uptake in the aorta and large arteries in the absence of clinical activity and may be associated with aortic dilatation. Coronary ar- terial involvement is rare. Kawasaki’s disease Kawasaki’s disease (or mucocutaneous lymph node syndrome) is an acute vasculitis of small and medium-​sized vessels that typically section 16  Cardiovascular disorders 3494 presents in children aged less than 5 years, with a peak at 1 year and a small male predominance (1.5:1). Diagnosis is based on the presence of persistent fever in combination with a polymorphous exanthema, cervical lymphadenopathy, non​purulent conjunctival injection, changes of the lips and oral cavity (strawberry tongue, cracked lips, redness of the mucosae), and changes in extremities (swelling, redness, and desquamation of the palms). desquamation in the subacute phase). In the acute stage, myocarditis is frequent (35%), often in associ- ation with pericardial effusions, treatment being with aspirin and high-​dose γ-globulin. Coronary artery involvement occurs in 20%, resulting in aneurysm formation and thrombotic occlusion, such that in the longer-​term patients can present with acute coronary syndromes and myocardial ischaemia, which are managed conven- tionally. See Chapter 19.11.12 for further discussion. Antineutrophil cytoplasm antibody (ANCA)-​associated vasculitides Antineutrophil cytoplasm antibody (ANCA)-​associated vasculit- ides are small-​vessel vasculitides that include granulomatosis with polyangiitis (GPA; formerly Wegener’s granulomatosis), micro- scopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA; also known as Churg–​Strauss syndrome). ANCA-​associated vasculitides affect both genders equally and the average age at diagnosis is in the fifth decade. Microscopic polyangiitis Microscopic polyangiitis is a necrotizing vasculitis of capillaries, venules, and arterioles with occasional involvement of medium-​ sized vessels. Cardiac involvement is rare, but described in the forms of pericarditis, heart failure, and myocardial infarction. Granulomatosis with polyangiitis (formerly Wegener’s granulomatosis) Granulomatosis with polyangiitis is a necrotizing vasculitis of me- dium and small vessels associated with granulomatous lesions in the upper and lower respiratory tract, but any other organ can be affected. Pericarditis (35% of cases), coronary arteritis (12%), and cardiomyopathy (30%) are the most frequently reported cardiac ab- normalities. Valvulitis and arrhythmias have also been described, but their frequency varies substantially between series. Coronary arteritis is relatively common at post-​mortem, but rarely causes myocardial infarction. Myocarditis and complete heart block are rare (2%). Treatment is with combinations of immunosuppressant drugs, including biologic agents such as rituximab. Eosinophilic granulomatosis with polyangiitis (formerly Churg–​ Strauss syndrome) and other hypereosinophilic syndromes Hypereosinophilic syndromes are defined by a persistent blood eo- sinophilia (>1.5 × 109/​litre) lasting for more than six consecutive months, associated with evidence of eosinophil-​induced organ damage in the absence of other causes of hypereosinophilia, such as allergy, parasitic infection, or malignancy. Hypereosinophilia is a fea- ture of some vasculitides, in particular eosinophilic granulomatosis with polyangiitis (formerly Churg–​Strauss syndrome). Some cases of hypereosinophilia are caused by stem cell mutations that lead to expression of fusion genes (mainly FIP1L1-​PDGFRA) with constitutive tyrosine kinase activity that cause overproduction of interleukin-​5 by activated T-​cell subsets. Clinically, hypereosinophilia syndromes can be classified into chronic eosinophilic leukaemia, lymphocytic hypereosinophilic syndrome, myeloproliferative hypereosinophilic syndrome, and idiopathic hypereosinophilic syndrome. The term organ-​restricted eosinophilic disease is used when disease is confined to a specific organ or tissue. Löeffler’s fibroplastic endocarditis with eosinophilia refers to cardiac disease caused by direct toxicity of circulating eosinophils. Hypereosinophilic heart disease includes endomyocarditis, endo­ myocardial fibrosis, or cardiomyopathy. It is characterized by endocar- dial thickening and apical obliteration caused by large mural thrombi. A  restrictive left ventricular filling pattern is typical. Gadolinium delayed-​enhanced cardiac magnetic resonance imaging identifies regions of myocardial fibrosis and thrombosis. Diffuse myocardial involvement may lead to heart failure, ventricular remodelling, and dilated cardiomyopathy. Involvement of the atrioventricular valves can lead to severe mitral and tricuspid regurgitation. General therapy includes anticoagulation and heart failure therapy. Patients with the FIP1L1-​PDGFRA fusion gene chromo- somal rearrangement are treated with the tyrosine kinase inhibitor imatinib, often following pretreatment with corticosteroids. For patients without the FIP1L1-​PDGFRA fusion gene, corticosteroids are the usual first-​line therapy; steroid-​sparing and second-​line drugs include hydroxycarbamide, interferon alfa, cyclophospha- mide, and imatinib. The prognosis is generally poor, even if the hypereosinophilia is resolved, due to high mortality from heart failure, sudden death, or thromboembolism, depending on the underlying cause and end-​organ damage. Behçet’s disease Behçet’s disease is a relapsing inflammatory disorder character- ized by oral and genital ulceration, uveitis, and arterial and venous thrombosis. The disease is common in the eastern Mediterranean and eastern Asia. Cardiac disease, including myocarditis, atrio- ventricular block, pericarditis, and valve disease, is present in less than 5% of patients. Coronary artery disease is very rare (<1%) but poses challenges for revascularization because of tissue fragility and pseudoaneurysm formation. Aneurysms may also be seen in the pul- monary (Hugues–​Stovin syndrome), coronary, and other arteries. Amyloidosis Amyloidosis describes a group of diverse diseases (see Chapter 12.12.3) that is characterized by extracellular insoluble fi- brils derived from the aggregation of various misfolded proteins that deposit with a range of chaperone proteins in organs such as the heart, kidneys, liver, gastrointestinal tract, lungs, and soft tis- sues. There are more than 30 proteins that can form amyloid fi- brils, five of which frequently infiltrate the heart and cause cardiac amyloidosis: immunoglobulin light chain (AL or primary amyloid- osis), immunoglobulin heavy chain (AH), transthyretin (ATTR), serum amyloid A  (AA), and apolipoprotein A  I (AApoA1). The overwhelming majority of patients with cardiac amyloidosis are af- fected by either AL or ATTR amyloidosis. 16.7.3  Specific heart muscle disorders 3495 AL cardiac amyloidosis is a rare condition with an estimated preva- lence of 8 to 12 per million. The population prevalence of TTR-​ cardiac amyloidosis is less certain, but recent data suggest that is relatively common in older people with heart failure with preserved ejection fraction, low-​flow aortic stenosis, and atrial fibrillation. AL amyloidosis occurs equally between the genders and as many as 50% of patients have cardiac involvement, which will mani- fest clinically in up to one-​half of these. Multiorgan involvement causing neuropathy and nephropathy is typical. Some ‘benign’ gammopathies are implicated in the pathogenesis, but any B-​cell dyscrasia can be the cause. The heart is frequently involved in familial amyloid polyneurop- athy. This is the most common type of hereditary amyloidosis and is caused by one of more than 70 mutations in the transthyretin (TTR) gene. Senile TTR amyloidosis caused by deposition of wild-​type TTR is extremely common; indeed, almost all individuals over the age of 80 years will have scattered deposits of amyloid, particularly affecting the aorta: clinical involvement is variable, depending on the extent of deposition. In patients with severe cardiac involve- ment, there is a large male predominance, and the condition is al- most exclusive to individuals older than 65 years of age. The disease is slowly progressive with a median survival of about 75 months. The extracellular deposition of amyloid results in a firm, thick- ened, non​compliant myocardium. Deposition occurs throughout the atrial and ventricular muscle and in the specialized conduction tissue: fibrosis of these structures may occur. Valvular function is rarely affected, although thickening of cardiac valves is common. Intramural coronary arteries and veins frequently contain deposits, which can occasionally compromise the lumina of these vessels. Amyloid heart disease most frequently mimics hypertrophic car- diomyopathy with restrictive physiology. The reduced compliance of the myocardium produces the characteristic diastolic dip and plateau (square root sign) in the ventricular pressure waveform. An impaired rate of early diastolic filling is characteristic and systolic dysfunction may also occur, leading to congestive heart failure. Arrhythmias are common, in particular ventricular premature beats and atrial fibrillation. Complex ventricular arrhythmias may be harbingers of sudden death. Progressive atrioventricular con- duction delay is common and infiltration of the autonomic nervous system results in orthostatic hypotension in 10% of cases. The chest radiograph may show cardiomegaly in patients with systolic dysfunction but is often normal in those with restrictive cardiomyopathy, although pulmonary congestion may be prom- inent. Electrocardiography (CG) shows diminished voltages in about 50% of patients, and loss of R waves in precordial leads; the presence of Q waves in the inferior leads may simulate myocar- dial infarction. Echocardiography reveals an increased thickness of the ventricular walls with small ventricular chambers, dilated atria, intra-​atrial septal thickening, left ventricular dysfunction, and a characteristic ‘sparkling’ appearance to the myocardium. The pattern of hypertrophy is usually concentric but may be asymmet- rical septal. 99mTc-​phosphate derivatives (99mTc-​PYP and 99mTc-​ 3,3-​diphosphono-​1,2-​propanodicarboxylic (DPD)) are useful in diagnosing ATTR-​cardiac amyloidosis, which is particularly avid for bone tracers, and radionuclide imaging with these ligands may better estimate amyloid load than cardiac magnetic resonance imaging. Serum amyloid protein scintigraphy is useful to assess extracardiac but not cardiac involvement in AL amyloidosis. Cardiac magnetic resonance imaging with gadolinium contrast agents has a charac- teristic pattern of late enhancement once there is left ventricular hypertrophy and/​or systolic impairment. Myocardial T1 mapping by cardiac magnetic resonance is also useful in the diagnosis of car- diac amyloidosis. In AL cardiac amyloidosis, troponin T, and BNP plasma concentrations are usually elevated and relate to prognosis. Diagnosis can be confirmed histologically from rectal, salivary gland, subcutaneous fat, or (if necessary) cardiac biopsy; all forms of amyloid show an amorphous proteinaceous substance that demon- strates apple green birefringence under polarized light when stained with Congo Red. Genetic testing can be used to confirm hereditary TTR amyloidosis. Symptomatic heart disease typically presents late in the course of amyloidosis and the presence of clinical signs is an ominous feature, with mortality approaching 100% at 2 years for AL amyl- oidosis. Treatment is supportive in combination with measures to suppress the underlying amyloidogenic condition. Chemotherapy or peripheral autologous stem cell therapy may be appropriate in some cases of AL amyloidosis. Orthotopic liver transplantation or combined heart and liver transplantation have shown promising results, particularly in selected cases of TTR-​related familial amyl- oidosis. Anticoagulation is important in patients with atrial ar- rhythmia due to the high incidence of thromboembolism. Digoxin and calcium channel antagonists should be avoided as they select- ively bind to amyloid fibrils, enhancing their effect. Patients with symptomatic conduction system disease require a pacemaker. Diuretics and vasodilators should be used cautiously as they may aggravate hypotension. Cardiac transplantation is feasible in selected cases, but is a palliative procedure without treatment of the underlying process. Sarcoidosis Sarcoid is a multisystem granulomatous disorder of unknown aeti- ology. The overall prevalence is about 20 per 100 000 population. Myocardial involvement is seen in 20–​30% of patients at autopsy but is clinically apparent in less than 10% of cases. Primary cardiac in- volvement is extremely rare. Non​caseating granulomas may involve any region of the heart, although the left ventricular free wall and interventricular septum are the most commonly affected sites. The granulomas can be lo- calized or widespread, and healing may result in the formation of scars. The ventricular muscle eventually becomes increasingly non-​ compliant, leading to defects in contractile function as well as wall motion. Replacement of large portions of the ventricle by sarcoid tissue may lead to aneurysm formation. Granulomas and fibrosis may also extend to involve nodal or conducting tissue. Isolated peri- cardial involvement is rare, although pericardial effusions are com- monly seen on echo. Valvular dysfunction occurs in less than 5% of patients and may be the result of infiltration of papillary muscles or direct valvular involvement, which is less common. Clinical manifestations of myocardial sarcoidosis are shown in Table 16.7.3.3. Chest pain has been described in up to 28% of pa- tients, and since about one-​half of these will have abnormal thallium section 16  Cardiovascular disorders 3496 perfusion scans despite arteriographically normal coronary arteries, this is thought to be secondary to microvascular dysfunction. Sudden death secondary to ventricular tachycardia and fibrilla- tion occurs in some cases. The presence of a ventricular aneurysm may be associated with resistant ventricular arrhythmias and neces- sitate its resection. Conduction disturbances such as complete heart block are a frequent occurrence, particularly in the acute phase of the disease. The electrocardiogram is frequently abnormal, with T-​wave abnormalities and varying degrees of intraventricular or atrioventricular block. Pathological Q waves may simulate myo- cardial infarction when myocardial involvement becomes exten- sive. Echocardiography shows features which may mimic dilated, restrictive or arrhythmogenic cardiomyopathy with systolic and/​or diastolic dysfunction, regional wall motion abnormalities, and an- eurysms. Gallium or fluorodeoxyglucose (FDG) PET, single photon emission computed tomography (SPECT), and magnetic resonance imaging with gadolinium late enhancement have all been used to detect affected areas of myocardium. Endomyocardial biopsy can be diagnostic, but may be negative due to the patchy nature of the disease. Steroids can improve symptoms as well as electrocardiographic and echocardiographic features and myocardial perfusion de- fects, but there is a lack of randomized trial data. Steroid-​sparing agents such as methotrexate and azathioprine may be used in re- lapsing or refractory disease. Amiodarone may be of benefit in re- sistant arrhythmia, and the insertion of an implantable defibrillator (ICD) may protect against sudden death in susceptible patients. Transplantation may improve prognosis and quality of life in pa- tients who remain symptomatic despite these measures, although recurrence in the graft has been documented. Cardiac disease in endocrine disorders Diabetes A man with diabetes has a relative risk of developing heart failure that is 2.4 times higher than that of a man without diabetes, and the equivalent relative risk for a woman is 5:1. The risk has been shown to be independent of age, systolic blood pressure, serum cholesterol, and weight. People with diabetes have elevated end-​ diastolic pressures, reduced ejection fractions, left ventricular dila- tation, and hypertrophy, even in the absence of coronary artery disease. Diastolic dysfunction as well as a diffuse hypokinesis of the myocardium has also been demonstrated. Implicated mechanisms include small-​vessel disease and autonomic neuropathy. The most prominent histopathological finding is myocardial fi- brosis. Occasionally a picture resembling restrictive heart disease is seen, with a small left ventricular chamber and reduced compliance of the left ventricle. The treatment of heart failure is the same as in patients without diabetes, although β-​blockers with intrinsic sympathomimetic ac- tivity are preferred. Preload and afterload reducing agents should be used cautiously because of autonomic dysfunction. It is unclear whether tight glucose control affects the progression of diabetic car- diomyopathy, but it is clearly prudent for other reasons to optimize control as well as to reduce obesity and control hypertension. Hyperthyroidism In general, excess thyroid hormone results in a high-​output state with tachycardia, increased cardiac contractility, and peripheral vasodilatation. In the long term this can result in ventricular hyper- trophy and an increase in ejection fraction. However, some patients may develop a low-​output state with symptoms of heart failure and echocardiographic demonstration of dilated cardiomyopathy and systolic dysfunction. These changes may be a result of long-​standing tachycardia and increased cardiac work, but thyroxine (T4) itself may directly alter the expression of cardiac proteins involved in cardiac function, and there is also some evidence that direct auto- immune myocardial damage may occur in Graves’ disease. Typical cardiac symptoms of hyperthyroidism include angina-​like chest pain, fatigue, palpitations, and exertional dyspnoea. Cardiac findings include sinus tachycardia and atrial flutter or fibrillation in 17–​20%. These may be complicated by thromboembolism in up to 40%; also by congestive heart failure. Mitral valve prolapse has been reported in patients with Graves’ disease. Control of the ventricular rate in atrial fibrillation should be achieved with digoxin, β-​blockers, or calcium channel antagonists. The increased metabolic clearance of digoxin may necessitate a higher maintenance dose. Attempts at cardioversion should gener- ally be deferred until the patient is euthyroid, at which time they may have spontaneously reverted to sinus rhythm. The presence of an al- ready dilated vascular bed means that diuretics should be used with caution and vasodilators are generally contraindicated. Hypothyroidism Patients suffering from hypothyroidism, whether in its mild form or myxoedema, present a wide variety of symptoms. Complaints of fa- tigue, lethargy, mental slowness, and cold intolerance usually dom- inate. Less frequently, symptoms suggestive of cardiac dysfunction such as dyspnoea on exertion, syncope, or angina-​like chest pain may be prominent. The most common cardiac abnormality is pericardial effusion, which is usually asymptomatic but reported in at least 30% of untreated patients. Heart failure generally represents exacerbation of pre-​existing cardiac disease by the superimposed haemodynamic consequences of thyroid deficiency—​bradycardia, diminished myo- cardial contractility, and increased peripheral vascular resistance. Rarely, hypothyroidism alone can closely resemble cardiomyopathy and be severe enough to cause heart failure. Echocardiographic evi- dence of asymmetric thickening of the interventricular septum as well as reduced dimensions of the left ventricular outflow tract has Table 16.7.3.3  Clinical manifestations in myocardial sarcoidosis Abnormality Reported percentage of patients affected Atrioventricular block 41–​52 Ventricular ectopics 31–​47 Congestive heart failure 12–​19 Sudden death 21–​38 Bundle branch block 26–​34 Supraventricular tachycardia 11–​25 Ventricular tachycardia 12–​23 Simulating myocardial infarction on ECG 14–​18 Pericarditis/​pulmonary embolism 4–​8 16.7.3  Specific heart muscle disorders 3497 been reported. The characteristic ECG findings are sinus brady- cardia, prolongation of the QT interval, and a reduction in voltages if there is an associated pericardial effusion. The management of heart failure involves the identification of any coexisting cardiac disease and thyroid hormone replacement. Levothyroxine significantly enhances myocardial performance within 1 week but in patients with known or suspected coronary ar- tery disease it should be initiated at a lower dose than usual, typically 25 micrograms/​day, and increased slowly at 4-​to 6-​week intervals until the thyroid-​stimulating hormone is within the normal range. Tri-​iodothyronine (T3) may be preferable in severe cases as clinical improvement occurs sooner. β-​blockade can be used prophylac- tically or added if treatment with thyroxine exacerbates ischaemic heart disease. Adrenal disorders An acute takotsubo-​like (see later) catecholamine cardiomyopathy has been described in 3–​11% of cases in large series of patients with phaeochromocytoma or paraganglioma. Cardiac function improves following effective treatment of the tumour. Acromegaly In a large series of patients presenting with acromegaly, 10% had overt high-​output heart failure with a dilated left ventricle, increased ventricular mass, and modest decline in ejection fraction. Effective treatment of the acromegaly, with control of growth hormone secre- tion, can produce stabilization or improvement in cardiac function, but prognosis is poor if this cannot be achieved. Cardiac disease in neuromuscular disorders Myocardial dysfunction is particularly common in the muscular dystrophies, a group of disorders characterized by progressive skel- etal and cardiac muscle involvement (Table 16.7.3.4). Dystrophic effects on skeletal muscle result in fibre necrosis, followed by fi- brosis and fatty replacement. These structural and functional changes, which occur in the ventricles, can lead to the development of cardiomyopathy, in particular dilated cardiomyopathy and heart failure. The effect on the specialized conducting tissue may lead to bradyarrhythmias, conduction defects, malignant arrhythmias, and sudden death. Duchenne and Becker muscular dystrophy are progressive dis- orders arising from abnormalities (deletion, duplication, or point mutation) in the genes coding for the extrasarcomeric cytoskeletal protein dystrophin. In addition to defects in dystrophin, other de- fects that cause muscular dystrophy and dilated cardiomyopathy in- clude those affecting the genes for the intracellular proteins emerin (a transmembrane protein that is embedded in the inner nuclear cell membrane) and lamin A/​C (filament-​like proteins that form a proteinaceous mesh underlying and attached to the inner nuclear membrane). Mutations in desmin, a type III intermediate filament protein, cause dilated cardiomyopathy, restrictive cardiomyopathy, and progressive distal myopathy. By the age of 13 years more than 50% of boys with Duchenne mus- cular dystrophy have an abnormal echocardiogram (hypertrophic or dilated cardiomyopathy). ECG abnormalities (poor R wave ampli- tude, axis deviation, and Q waves) are found in more than 90% from an early age. There is some evidence that angiotensin-​converting enzyme (ACE) inhibitors delay progression of dilated cardiomyop- athies in Duchenne muscular dystrophy. Cardiac death occurs in up to 50% of patients with Becker mus- cular dystrophy. ECG and echocardiography are abnormal in most patients, and it is noteworthy that the severity of cardiomyopathy is not related to the degree of skeletal muscle involvement. Autosomal dominant Emery–​Dreifuss muscular dystrophy and limb girdle muscular dystrophy type 1B are caused by mutation in lamin A/​C. Heart block is common and patients require pacing at a mean age of 32 years. About 35% of patients will have early-​onset di- lated cardiomyopathy (age 19–​55 years). ICD implantation is often indicated as pacemakers do not prevent sudden cardiac death. Myotonic dystrophy type I is an autosomal dominant disease caused by expanding CTG repeats in the DMPK gene. Cardiomyopathy is rare, but cardiac involvement in the form of distal atrioventricular conduction disturbance is very common (90%). Bradycardia, PR interval prolongation, atrioventricular block, bundle branch block, and atrial arrhythmias are described. Sudden cardiac death occurs in 10–​33% of patients. An electrophysiology study should be con- sidered in patients with first-​degree atrioventricular block or with evidence of arrhythmia and syncope/​near syncope. Implantation of a permanent pacemaker is indicated if the HV interval is greater than 70 ms. Therapy with ICD can be considered in patients with symptomatic ventricular arrhythmia. Myotonic dystrophy type II is similar to type I, but less severe, with cardiac involvement in about 20% of patients. Cardiac disease in inherited metabolic disorders Haemochromatosis Hereditary haemochromatosis is the most common single-​gene dis- order in people of northern European origin, where approximately 3 to 5 persons per 1000 are homozygous for the condition. It results in excessive and inappropriate mucosal absorption of iron, which is then deposited predominantly in the heart, liver, gonads, and pan- creas. Clinical involvement of the heart is uncommon, but thickening of the ventricular walls together with dilatation of the ventricular chambers and heart failure is described. Histopathologically, myo- cardial degeneration and fibrosis occur over time and may extend to involve the conducting system of the heart. The ECG most commonly reveals changes in ST and T waves. Supraventricular arrhythmias are characteristic, with atrioven- tricular conduction defects and ventricular arrhythmias being less common. Echocardiography typically shows a mixed dilated and restrictive cardiomyopathy with thickened ventricular walls, ven- tricular chamber enlargement, systolic and/​or diastolic dysfunction. Endomyocardial biopsy may be useful to confirm the diagnosis. Treatment involves repeated phlebotomy and/​or iron chelators. Lysosomal diseases Cardiac disease is particularly important in lysosomal storage disorders. They are categorized into mucopolysaccharidoses, mucolipidoses, glycoproteinoses, and glycosphingolipidoses (Anderson–​Fabry disease). The prevalence of lysosomal storage dis- orders is about 1 in 7000. With the exception of Anderson–​Fabry, section 16  Cardiovascular disorders 3498 Danon’s, and Hunter’s syndrome, which are X-​linked, all are auto- somal recessively inherited. Cardiac involvement is character- ized by substrate accumulation within the myocardium and heart valves. This results in structural abnormalities and arrhythmias. Management requires a multidisciplinary approach in view of the chronic and progressive nature of these diseases. Treatment options (depending on the particular disorder) include substrate inhib- ition therapy, surgical intervention, bone marrow transplantation Table 16.7.3.4  Cardiovascular abnormalities in neuromuscular disorders Condition Inheritance Cardiac disease Non​cardiac manifestations Genetic defects Duchenne X-​linked 1:3500 male births HCM and DCM reported Symptoms uncommon Begins in first decade, 62% have ECG changes by age 10 years: short PQ, prolonged QT, tall R in V1 Conduction system anomalies/​dependency by age 12 Death in adolescence Severe muscle weakness, proximal-​ girdle distribution at 2–​5 years in males Calf pseudohypertrophy, mild cognitive impairment, high CPK Wheelchair Xp21; dystrophin gene mutations Becker X-​linked 1:15 000 male births High incidence of clinical cardiac involvement, heart failure is the most common cause of death DCM seen ECG usually abnormal: reduced R wave or prominent Q in 1, AVL, and V6 Arrhythmias and heart block in <10% Mild to moderate muscle weakness, proximal-​girdle distribution from childhood, and ambulation preserved at least until late teens Calf pseudohypertrophy, high CPK Lifespan usually dependent on severity of cardiac involvement Xp21; dystrophin gene mutations X-​linked dilated cardiomyopathy X-​linked (rare) 2nd or 3rd decade onset of CM and heart failure, rapid cardiac progression Milder variants possible Heart block not reported, arrhythmias in <10% No muscular weakness. Muscle cramps, myalgias CPK usually elevated Xp21; altered or selective loss of cardiac dystrophin Limb girdle AD Variable degrees of AV block, AF, with high degree block, bradycardia, palpitations, and syncope Mild to moderate muscle weakness, proximal limb girdle distribution. CPK elevated Lamin A/​C gene, 1q11–​21 1B AD DCM in 35% 19–​55 yrs, 90% conduction anomalies by 30 yrs, SCD in 50% (despite pacing) Childhood onset of contractures, mild muscle weakness in humeroperoneal distribution Lower extremities affected first CPK elevated moderately May be little evidence of skeletal myopathy Allelic to AD-​EDMD and isolated cardiomyopathy with conduction system disease mapped to 1q 2A AR Cardiac involvement rare Muscle weakness, proximal-​girdle distribution CPK elevated 15q15 Calpain-​3 (calcium activated neutral protease) With sarcoglycan deficiency AR DCM reported Arrhythmias uncommon Proximal-​girdle distribution of muscle weakness Calf pseudohypertrophy. CPK elevated Severity varies from Duchenne to Becker-​like α-​Sarcoglycan, 17q12 β-​Sarcoglycan, 4q12 γ-​Sarcoglycan, 13q12 δ-​Sarcoglycan, 5q3 Myotonic (1:8000) AD Conduction defects and arrhythmias common yet most remain asymptomatic ECG changes in 23–​80%: prolonged PR and QRS intervals Left and right bundle branch block, AF, a flutter, and bradycardias MVP common DCM and HCM detected rarely Muscle weakness, may be associated with frontal balding, cataracts, hypogonadism, and myotonia 19q13.3 Myotonin-​protein kinase gene mutations (unstable CTG trinucleotide repeats) Emery–​Dreifuss X-​linked AV block is the most common feature, high incidence of sudden death (pacemaker advised) Sinus node disease as well as tachyarrhythmias are common DCM is rare Childhood onset of contractures, mild muscle weakness in humeroperoneal distribution Lower extremities affected first CPK elevated moderately No calf pseudohypertrophy Xq28 defect of nuclear transmembrane protein emerin Desminopathies AD (actually more common than X-​linked) AD, AR DCM associated with conduction system disease commonly seen Ventricular fibrillation reported despite pacing Restrictive cardiomyopathy Cardiac conduction blocks Arrhythmias Echo/​MRI changes of DCM Same as X-​linked form May be little evidence of skeletal myopathy Progressive distal myopathy CPK elevated 1.q11–​21 Lamin A/​C mutation (allelic to LGMD1B) DES 2q35 AD, autosomal dominant; AR, autosomal recessive; AF, atrial fibrillation; AV, atrioventricular; CM, cardiomyopathy; CPK, creatinine phosphokinase; DCM, dilated cardiomyopathy; EDMD, Emery–​Dreifuss muscular dystrophy; HCM, hypertrophic cardiomyopathy; MVP, mitral valve prolapse. Adapted from Cox GF, Kunkel LM (1997). Dystrophies and heart disease. Current Opinion in Cardiology, 12, 329–​42. 16.7.3  Specific heart muscle disorders 3499 to replace enzyme deficiencies, and enzyme replacement therapy (available at very considerable cost for mucopolysaccharidoses I, II, and VI, Pompe’s, Gaucher’s, and Anderson–​Fabry disease). Mucopolysaccharidoses Mucopolysaccharidosis type I  (Hurler’s syndrome, Hurler–​Scheie syndrome, and Scheie’s syndrome) is a progressive childhood disorder with skeletal and cardiopulmonary involvement. Cardiac involvement consists of systolic and diastolic dysfunction and progressive aortic and mitral valve disease. Mucopolysaccharidosis type II (Hunter’s syndrome) is characterized by later onset, similar cardiomyopathy and valvular involvement as in mucopolysaccharidosis type I. Sudden cardiac death due to atrioventricular block has been described. Anderson–​Fabry disease (angiokeratoma corporis diffusum universale) Anderson–​Fabry disease is an X-​linked condition with a population prevalence of 1 in 40 000–​117 000 live births. It is caused by mutations in the gene encoding the lysosomal enzyme α-​galactosidase A, which leads to intralysosomal accumulation of neutral glycosphingolipids, mainly globotriaosylceramide (Gb3), in various organ systems. The disease is characterized by progressive clinical manifestations and pre- mature death from renal disease, stroke, and cardiac disease. The ECG often shows left ventricular hypertrophy, a short PR interval, conduction defects, and arrhythmias. Echocardiography usually demonstrates in- creased thickness of the left ventricle, which may simulate hypertrophic cardiomyopathy. Differentiation from other hypertrophic or restrictive processes may require magnetic resonance imaging or endomyocardial biopsy. A low leucocyte α-​galactosidase activity is diagnostic in males. Enzyme replacement therapy is available for these patients. Gaucher’s disease Gaucher’s disease is the most common sphingolipidosis, caused by a deficiency in β-​glucocerebrosidase that leads to lysosomal accumu- lation of glucocerebroside within macrophages. Lipid-​laden macro- phages (Gaucher cells) accumulate within the reticuloendothelial system resulting in hepatosplenomegaly, bone marrow replacement, anaemia, and thrombocytopenia. Valvular and aortic calcification, heart failure, and pericarditis are reported, but the heart is not in- volved in most patients. Pulmonary hypertension occurs in up to 30% of untreated patients, with enzyme replacement treatment re- ducing the prevalence to 7.4%. Glycogen storage diseases Glycogen storage diseases affect the storage, synthesis, and break- down of glycogen. Glycogen storage disease types II (Pompe’s dis- ease), IIb (Danon’s disease), III, IV, and VI, IX, and 0 affect the heart, causing left ventricular hypertrophy, restrictive cardiomyopathy, di- lated cardiomyopathy, and conduction disease. Pompe’s disease presents in neonates and infants with short PR interval, QT dispersion, and extreme left ventricular hypertrophy on ECG. On echocardiography severe concentric biventricular hyper- trophy, small left ventricular cavity, left ventricular outflow tract obstruction, and diastolic dysfunction are evident. The adult-​onset form presents with few cardiac features. Conduction abnormalities are common. Danon’s disease presents in boys with hypertrophic cardiomyop- athy, conduction disease, and skeletal muscle weakness; female car- riers present later in adulthood with dilated cardiomyopathy. Disease caused by mutations in the PRKAG2 (AMP kinase) gene is characterized by biventricular hypertrophy, impaired systolic function, high-​grade atrioventricular conduction system disease, and ventricular pre-​excitation. Mitochondrial diseases Defects affecting mitochondrial DNA are maternally inherited. Prevalence studies suggest that mitochondrial DNA defects affect 9.2 in 100 000 adults aged less than 65 years. Neurological sequelae usually present before cardiac manifestations. Conduction defects (Kearns–​Sayre syndrome), left ventricular hypertrophy, and dilated cardiomyopathy are presenting features. Ocular myopathy with large mitochondrial DNA deletions can be associated with ECG abnormalities. Arrhythmias, in particular ventricular tachycardia, may occur in about 10% of patients. Second-​or third-​degree atrioventricular block necessitates cardiac pacing, and sudden death can occur. The serum creatine kinase may be mildly elevated and the blood lactate high. Management consists of supportive care and surveillance in addition to genetic counselling and pharmacological therapies for mitochondrial disease. Takotsubo (stress-​induced) cardiomyopathy Transient left ventricular apical ballooning syndrome, takotsubo cardiomyopathy, is a cardiac syndrome characterized by transient left ventricular dysfunction. It is associated with ECG changes that can mimic acute myocardial infarction. The left ventricular angio- gram usually reveals a hyperkinetic base and a hypokinetic apex, mimicking the shape of a round-​bottomed, narrow-​necked pot used to catch octopus in Japan (tako-​tsubo). Coronary spasm, microvascular dysfunction, or cardiotoxicity due to catecholamines have been postulated as causes. Most cases (up to 88%) occur in postmenopausal women (mean age 58–​77 years). The onset of symptoms is frequently preceded by physical or emotional stress. The most common presentation is with chest pain and dyspnoea, but cardiogenic shock and ventricular ar- rhythmias are reported in 4.2% and 1.5% of patients, respectively. Between 21% and 49% of patients will have ST-​segment eleva- tion at the time of presentation, typically in the precordial leads. Reciprocal inferior ST depression is less likely when compared to patients with anterior ST elevation myocardial infarction. Most patients recover fully, and the left ventricular impairment usually improves swiftly in a period of days to weeks. The prognosis is gen- erally very good, with a recurrence in few patients (3–​5%) and a mortality of about 1%. There are no randomized controlled studies on therapy of takotsubo cardiomyopathy. Empirical supportive treatment is ad- vised with use of diuretics and vasodilators. In view of the potential role of catecholamines and sympathetic activation, β-​blockers have been recommended as well. Patients with haemodynamic instability may require mechanical support. Other conditions Other conditions that can cause DCM are shown in Table 16.7.3.5. section 16  Cardiovascular disorders 3500 FURTHER READING Bargout R (2004). Sarcoid heart disease: clinical course and treatment. Int J Cardiol, 97, 173–​82. Benson MD, Dasgupta NR (2016). Amyloid cardiomyopathy. J Am Coll Cardiol, 68, 25–​8. Caforio ALP, et al. (2017). Diagnosis and management of myocar- dial involvement in systemic immune-​mediated diseases: a pos- ition statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Disease. Eur Heart J, 38, 2649–​62. Dawson DK (2017). Acute stress-​induced (takotsubo) cardiomyop- athy. Heart, 104, 96–​102. Dubrey SW, Falk RH (2010). Diagnosis and management of cardiac sarcoidosis. Prog Cardiovasc Dis, 52, 336–​46. Dubrey SW, Comenzo RL (2012). Amyloid diseases of the heart: cur- rent and future therapies. Q J Med, 105, 617–​31. Gianni M (2006). Apical ballooning syndrome or takotsubo cardiomy- opathy: a systematic review. Eur Heart J, 27, 1523–​9. Gotlib J (2014). World Health Organization-​defined eosinophilic dis- orders: 2014 update on diagnosis, risk stratification, and manage- ment. Am J Hematol, 89, 325–​37. Guertl B, Noehammer C, Hoefler G (2000). Metabolic cardiomyop- athies. Int J Exp Pathol, 81, 349–​72. Hermans MC, et al. (2010). Hereditary muscular dystrophies and the heart. Neuromusc Disord, 20, 479–​92. Jabbar A, et al. (2017). Thyroid hormones and cardiovascular disease. Nat Rev Cardiol, 14, 39–​55. Lofiego C (2005). Ventricular remodeling in Löeffler endocarditis: im- plications for therapeutic decision making. Eur J Heart Fail, 7, 1023–​6. McGeoch L (2015). Vasculitis Clinical Research Consortium. Cardiac involvement in granulomatosis with polyangiitis. J Rheumatol, 42, 1209–​12. Pinto YM, et al. (2016). Proposal for a revised definition of dilated cardio- myopathy, hypokinetic non-​dilated cardiomyopathy, and its implica- tions for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases. Eur Heart J, 37(23), 1850–​8. Shabina H, Isenberg DA (1999). Autoimmune rheumatic diseases and the heart. Hospl Med, 60, 95–​9. Wicks E, Elliott P (2012). Genetics and metabolic cardiomyopathies. Herz, 37, 598–​610. Zhang R, Gupta D, Albert SG (2017). Phaeochromocytoma as a revers- ible cause of cardiomyopathy: analysis and review of the literature. Int J Cardiol, 249, 319–​23. Zipes DP, et al. (eds) (2018). Braunwald’s heart disease: a textbook of cardiovascular medicine, 11th edition, pp. 1580–​616. W. B. Saunders, Philadelphia, PA. Table 16.7.3.5  Miscellaneous conditions that can cause dilated cardiomyopathy Transient Cause Example Comments Drugs Antineoplastic drugs Anthracyclines, cyclophosphamide, trastuzumab Psychiatric drugs Clozapine, phenothiazines Other drugs Chloroquine, antiretroviral agents (zidovudine, didanosine, zalcitabine), methysergide Toxic Ethanol Risk related to mean daily intake and duration of alcohol intake; good response to withdrawal Cocaine, amphetamines, ecstasy Chronic users Other toxic Cobalt (Quebec beer drinkers’ cardiomyopathy; possible following degeneration of metal-​on-​ metal hip replacements), lead, lithium, mercury, beryllium, anabolic/​androgenic steroids Nutritional deficiency Thiamine (Beri-​Beri) High-​output cardiac failure associated with malnutrition and alcohol abuse Selenium Affects children and women of childbearing age in some areas of China where local diets contain almost no selenium (Keshan disease) Zinc and copper Possible causes of DCM Carnitine Inherited cases in children; possible role in cardiomyopathy of dialysis patients Electrolyte disturbance Hypocalcaemia Chronic severe vitamin D deficiency in adults; rickets in children Hypophosphataemia Uraemia Peter S. Mortimer 16.19 Idiopathic oedema of women Peter S. Mortimer 16.19 Idiopathic oedema of women 3823 John D. Firth ESSENTIALS Idiopathic oedema is an unsatisfactory label that is applied to women who complain of swelling, typically variable, with diag- nosis requiring exclusion of known causes of oedema and (most authors would agree) demonstration of weight gain, from morning to evening, of more than 1.4 kg. The cause of idiopathic oedema is (by definition) unknown: hypotheses include abnormal capillary permeability/​leakage, re-​ feeding oedema, and diuretic-​induced oedema. There is no clear relationship to the menstrual cycle. Even if not a primary cause, the use and abuse of diuretics can complicate and exacerbate the problem. Management is difficult, but patients can be helped by a sympa- thetic approach from the physician and (1) encouragement to lose weight if they are obese; (2) avoidance of excess dietary salt; and (3) weaning from consumption of high doses of diuretics that can cause or exacerbate the tiredness, lethargy, weakness, and dizziness that are suffered by many. Definition and diagnosis In some women fluid retention occurs in the absence of any clear explanation and is termed idiopathic oedema. Since the condi- tion typically fluctuates in severity from one time to another it is sometimes called cyclical or periodic oedema, but these terms mis- lead; first, because there is rarely any recognizable periodicity, and second, because the condition is not related to menstrual periods. Most women retain fluid just before the menses and lose this fluid immediately afterwards. Idiopathic oedema occurs most com- monly in women aged 20 to 40 years, but has no clear relationship with the menstrual cycle and can persist after the menopause or oophorectomy. The diagnosis of idiopathic oedema depends on the exclusion of other causes of oedema, including cardiac, hepatic, renal, allergic, or hypoproteinaemic disease, venous or lymphatic obstruction, and use of some medications. The role of diuretics, causally or in treatment, is contentious, as discussed next. However, it is always unsatisfactory when a diagnosis is made by exclusion of other con- ditions rather than on the basis of ‘positive’ criteria. Such criteria for the diagnosis of idiopathic oedema have not been universally agreed, although both Thorn and McKendry (see Kay et al. for discussion) have made proposals that (1) require evidence of substantial weight gain during the course of the day from morning to evening, with a figure of more than 1.4 kg often quoted, although this does not provide a clear-​cut separation from normal, and (2) demand the presence of (loosely specified) emotional or psychological factors. Many authors comment on the aggravation of swelling by prolonged sitting or standing, but this does not feature in the diagnostic criteria mentioned. Clinical features The patient’s complaint is of swelling, which usually waxes and wanes but can be constant. In the morning the face and eyelids feel swollen and heavy. By the end of the day the areas worst affected are the hands, breasts, trunk, abdomen, thighs, ankles, and feet. Rings no longer fit swollen fingers, and undergarments and clothes can feel so uncomfortably tight that they have to be removed or replaced with something larger. The feet and ankles may be relatively spared, hence the disposition of oedema tends to be different from that in most other oedematous states, where it begins distally in the feet and ankles and progresses proximally. Episodes or exacerbations of fluid retention often occur unpre- dictably, but obesity, emotional stress, and consumption of high-​ carbohydrate food are thought to be triggers in some. Sufferers are often mentally and physically lethargic during periods of fluid re- tention, frequently expressing the view that they feel bloated and ugly, even though this may not be apparent to the observer. Many appear to be emotionally labile or anxious and some are depressed, invariably (and perhaps correctly) claiming that this is secondary to the fluid retention. Other common symptoms include carpal tunnel syndrome, non​articular rheumatism, palpitations, non​ulcer dys- pepsia, and headaches, and idiopathic oedema may be a factor in women troubled by severe cellulite. Women with idiopathic oedema are often very concerned about their weight. One study showed an association between symptoms 16.19 Idiopathic oedema of women John D. Firth section 16  Cardiovascular disorders 3824 of this condition and abnormal attitudes to eating. Some patients will report that they episodically severely reduce their food intake, perhaps making them susceptible to the phenomenon of re-​feeding oedema when they start eating again. Aside from oedema, which may or may not be present at the time of medical assessment, examination is unremarkable, as are routine in- vestigations for the cause of oedema. Those patients that have used di- uretics may have a hypokalaemic hypochloraemic metabolic alkalosis. Idiopathic oedema has been reported to be associated with a range of conditions including obesity, diabetes, and psychiatric disorders. Apart from depression, the latter may include purging behaviours (self-​induced vomiting, laxative abuse, diuretic abuse). Making the diagnosis of an additional ‘idiopathic’ condition in such circum- stances is fraught with difficulties. Pathophysiology The cause of idiopathic oedema is not known (by definition). Because of pooling of extracellular fluid in the legs when standing, normal weight gain during the day is typically around 1 kg, and di- urnal weight fluctuation of more than 1.4 kg is required for diag- nosis, but weight may fluctuate from day to day by up to 4 or 5 kg. During periods of weight gain the patient may be oliguric, passing low volumes of urine in which there is little sodium (<20 mmol/​ litre). There are three main pathophysiological hypotheses. Abnormal capillary permeability The blood vessels of women with idiopathic oedema are more perme- able to albumin, the fractional catabolic rate of albumin is increased, both intravascular and total body albumin pools are smaller, and the plasma volume decreases by more on standing than in normal controls. Activation of the sympathetic nervous system, renin–​ angiotensin–​aldosterone system, and high levels of antidiuretic hor- mone in the plasma that are consistent with intravascular volume depletion have all been reported, and these changes provide a plaus- ible explanation for why the kidney retains salt and water in idiopathic oedema. They also form the background to postural water-​loading or sodium-​loading tests that have been advocated as diagnostic tools, al- though these are not used routinely in clinical practice. After similar loading on two separate occasions, patients with idiopathic oedema who remain upright throughout the test excrete less water or sodium than they do if they remain supine. However, the prime mover re- mains uncertain: decreased release of dopamine has been reported, as has generalized impairment of hypothalamic function. Re-​feeding oedema If women concerned about their weight engage in ‘crash dieting’ followed by binge eating, then they may induce re-​feeding oedema. This has led some authors to the conclusion that idiopathic oedema may be a presentation of eating disorder. Why re-​feeding should pre- cipitate oedema is not clear, but in a study of malnourished patients with anorexia nervosa, those re-​fed with a low-​sodium diet were less susceptible to oedema than those re-​fed with a normal-​sodium diet. Diuretic-​induced oedema Many patients seen in hospital practice will already be taking diur- etics or have taken them in the past, and some will be consuming large doses of loop agents every day. One influential study re- ported 10 such patients who started to take diuretics because of concern about swelling or their body weight and who continued to take them because cessation provoked rapid weight gain, facial bloating, and abdominal distension. When prevailed upon to stop diuretics they each gained weight (up to 5 kg), reaching a max- imum in 4 to 10 days, but by 20 days 7 of the 10 had fallen to below their previous weight, and 9 of the 10 remained free of oedema over a long period of follow-​up without taking diuretics. This led the authors to suggest that diuretic abuse might be the cause of all cases of idiopathic oedema. This view is not held by most with ex- perience in the field, but rebound oedema on diuretic withdrawal can undoubtedly be an exacerbating feature, and it is appropriate to look for evidence of diuretic abuse if the patient denies taking such drugs and yet routine biochemical testing of blood and urine suggests the possibility. Management Women with idiopathic oedema frequently complain that doc- tors have not taken their condition seriously, and there is no doubt that it is a frustrating disorder for both patients and their phys- icians. Sympathetic explanation of the nature of the problem helps management. A patient who is obese should be given advice as to how to lose weight, and—​independent of any effect on weight—​some find that reducing dietary sodium and carbohydrate intake helps. They should be advised to avoid long periods of standing or sitting and to wear loose-​fitting clothing, although most will have discovered these things for themselves. Avoidance of an excessive dietary intake of so- dium is a sensible recommendation. On theoretical grounds the use of elastic stockings would also seem appropriate, since these might reduce the postural reduction in plasma volume seen in idiopathic oedema. However, few find that the benefits of elastic stockings out- weigh their disadvantages and it is difficult to get most patients to persist with them for long enough to see whether or not they really would be of help. Diuretics are a real problem. It seems intuitively obvious to most patients and to many doctors that someone who is retaining fluid would benefit from a diuretic, hence many patients with idiopathic oedema end up on very large doses of loop agents, often combined with amiloride or spironolactone. Rather than helping, these may worsen symptoms of tiredness, lethargy, weakness, and dizziness by exacerbating intravascular volume depletion, and attempts to stop typically lead to rebound oedema. Long-​term use of high doses of furosemide can also cause medullary nephrocalcinosis and variable degrees of renal insufficiency. Explanation is the key here, in that if patients recognize rebound oedema for what it is and relieve oedema with supine rest rather than renewed consumption of high doses of diuretics, then there is a reasonable chance that they can be weaned off diuretics with benefit. A range of agents including levodopa, carbidopa, bromocrip- tine, captopril, metformin, calcium dobesilate, and ephedrine have been tried in idiopathic oedema. None is of widely proven benefit. There is a single report that aminaphtone (aminophenazone) pro- duced improvement in 70% of cases in a small series, but this drug (formerly used as an antipyretic and analgesic, but which can cause 16.19  Idiopathic oedema of women 3825 leucocytopenia) is not widely available. A controlled study suggested that non-​surgical periodontal therapy led to improvement in idio- pathic oedema and hypothesized that this might be by reducing a source of systemic inflammation. However, the duration of follow-​ up was very short (4 weeks), and further studies of adequate dur- ation are needed to know whether or not such treatment should be recommended for this chronic condition. FURTHER READING Bihun JA, McSherry J, Marciano D (1993). Idiopathic oedema and eating disorders: evidence for an association. Int J Eat Disord, 14, 197–​201. Dunningan MG, et  al. (2004). Unexplained swelling symptoms in women (idiopathic oedema) comprise one component of a common polysymptomatic syndrome. QJM, 97, 755–​64. Joseph R, et al. (2011). Non-​surgical periodontal therapy improves serum levels of C-​reactive protein and edematous states in female patients with idiopathic oedema. J Periodontol, 82, 201–​9. Kay A, Davis CL (1999). Idiopathic edema. Am J Kidney Dis, 34, 405–​23. MacGregor GA, et  al. (1979). Is ‘idiopathic’ oedema idiopathic? Lancet, i, 397–​400. Marks AD (1983). Intermittent fluid retention in women. Is it idio- pathic edema? Postgrad Med, 73, 75–​83. Pereira de Godoy JM (2008). Aminaphtone in idiopathic cyclic oedema syndrome. Phlebology, 23, 118–​19. Pereira de Godoy JM, Pereira de Godoy HJ, Pereira de Godoy LM, Godoy G (2017). Prevalence of idiopathic cyclic edema in women with lower limb lymphedema. J Clin Med, 7, 2. Sabatini S (2001). Hormonal insights into the pathogenesis of cyclic idiopathic edema. Semin Nephrol, 21, 244–​50. Soudet S, et  al. (2017). Long term use of metformin in idiopathic cyclic edema, report of thirteen cases and review of the literature. Pharmacol Res, 119, 237–​9. Streeten DH (1995). Idiopathic edema. Pathogenesis, clinical fea- tures, and treatment. Endocrinol Metabol Clin North Am, 24, 531–​47. SECTION 17 Critical care medicine Section editor: Simon Finfer 17.1 The seriously ill or deteriorating patient  3829 Carole Foot and Liz Hickson 17.2 Cardiac arrest  3839 Gavin D. Perkins, Jasmeet Soar, Jerry P. Nolan, and David A. Gabbott 17.3 Anaphylaxis  3849 Anthony F.T. Brown 17.4 Assessing and preparing patients with medical conditions for major surgery  3860 Tom Abbott and Rupert Pearse 17.5 Acute respiratory failure  3867 Susannah Leaver, Jeremy Cordingley, Simon Finney, and Mark Griffiths 17.6 Circulation and circulatory support in the critically ill  3881 Michael R. Pinsky 17.7 Management of raised intracranial pressure  3892 David K. Menon 17.8 Sedation and analgesia in the ICU  3898 Michael C. Reade 17.9 Metabolic and endocrine changes in acute and chronic critical illness  3906 Eva Boonen and Greet Van den Berghe 17.10 Palliative and end-​of-​life care in the ICU  3914 Phillip D. Levin and Charles L. Sprung 17.11 Diagnosis of death and organ donation  3918 Paul Murphy 17.12 Persistent problems and recovery after critical illness  3925 Mark E. Mikkelsen and Theodore J. Iwashyna Thomas A. Traill 16.11 Cardiac involvement in gene Thomas A. Traill 16.11 Cardiac involvement in genetic disease 3551 Thomas A. Traill ESSENTIALS Many clinicians find themselves faced, from time to time, with a pa- tient who has a family history of a known disorder, such as Marfan syndrome, or who has non​cardiac features that suggest a syndrome. Syndromic congenital heart disease Down’s syndrome—​25–​50% have congenital heart disease, most char- acteristically atrioventricular canal defect. Turner’s syndrome—​causes coarctation of the aorta and congenital abnormalities of the aortic valve (usually bicuspid). Noonan’s syndrome—​the most common heritable syndrome that characteristically causes congenital heart disease. Mutations in an intracellular signalling molecule protein tyrosine phosphatase SHP-​ 2 account for 40% of cases. Characteristics include short stature, with a facies that is variously described as elfin or triangular, ocular hypertelorism, ears that are set low and rotated forwards, and web- bing of the neck (the most obvious of the features that may lead to confusion with Turner’s syndrome). The most typical cardiac lesion is pulmonary stenosis. Williams’ syndrome—​caused by macrodeletions of chromosome 7 that include the elastin gene; includes the cardiovascular features of familial supravalvar aortic stenosis along with a characteristic facial appearance, with round, blue eyes, a distinctive stellate pattern of the irises, depression of the nasal bridge, outwards tilting of the nostrils, abnormal dentition, and big lips. Other conditions—​many other genetic syndromes have significant cardiac and vascular manifestations. Connective tissue disorders Marfan syndrome—​caused by mutations of the fibrillin-​1 gene (FBN1); characteristic cardiovascular findings are aneurysmal dilatation of the aorta, and occasionally other large arteries, and floppy mitral valve. Diagnosis is based on the presence of particular major or minor criteria, the major criteria being (1) aortic aneurysm, (2) lens subluxation, (3) characteristic skeletal abnormalities, and (4) dural ectasia. Aortic dissection and rupture are the commonest causes of death in untreated cases. β-​Blockers are commonly given to slow the progression to aneurysm, but the benefit is probably modest; recent work suggests that angiotensin-​II receptor blockers may be equally more effective. Surgical replacement of the aortic root is generally recommended when the maximum measurement across the aorta reaches 5 cm. Other conditions—​the Ehlers–​Danlos syndromes and many other genetic disorders have significant cardiac and vascular manifestations. Introduction The online catalogue of heritable disorders and their causes, Mendelian Inheritance in Man (OMIM), is expanding week by week, and with it the long list of candidates for inclusion in a chapter such as this. The following pages deal only with a few of the more commonly seen heritable syndromes that affect the heart and blood vessels, and which are seen in adult patients. Mendelian conditions that affect only the heart, that are ‘non​syndromic’, are considered in the chapters of this textbook dealing with their pathologic effects (e.g. cardiomyopathies in Chapter 16.7.2, familial hypercholester- olemia in Chapter 12.6). Other heritable conditions whose main pathologic significance lies outside of the heart are also discussed elsewhere (e.g. metabolic and neuromuscular disorders). Left to be considered here are conditions which many clinicians face from time to time, in the form of a patient who has a family history of a known disorder, such as Marfan’s syndrome, or who has non-​ cardiac features that suggest a syndrome, perhaps Noonan’s. They may wonder how to make the diagnosis, what else to look for, and how to screen family members. It is no longer given that there is a clean distinction between men- delian, single-​gene disorders on the one hand and, on the other, polygenic disease such as high blood pressure and atherosclerosis. Increasingly we recognize the role of epigenetic factors in mono- genic disorders, and of likely oligogenic inheritance in conditions with suggestive family patterns. Familial aortic aneurysm disease and its relationship to bicuspid aortic valve seem to be an important example of an oligogenic pattern, as is pulmonary arterial hyper- tension. Both of these influences—​oligogenic inheritance and epigenetics—​contribute to phenotypic variation and to our impres- sion of penetrance. They also contribute to an important phenom- enon that affects our assessment of severity and prognosis. When a 16.11 Cardiac involvement in genetic disease Thomas A. Traill section 16  Cardiovascular disorders 3552 syndrome is first identified as an inherited condition, it is usually in people whose phenotype is quite extreme. As a genetic condition or syndrome becomes easier to detect and more widely diagnosed, including in people whose findings are less egregious than in the ori- ginal description, so the expanding denominator of less severe cases makes for a smaller percentage risk that any given complication will occur, which means that our perception of the danger posed by a particular diagnosis generally evolves over the years in a favourable direction. The first part of this chapter deals with developmental syn- dromes that include congenital cardiac defects, with coverage re- stricted to a few relatively common disorders that are seen in adult patients. The second part describes the two common connective tissue disorders—​Marfan’s and Ehlers–​Danlos syndromes—​and the more recently described Loeys–​Dietz syndrome that shares some pathogenetic mechanisms with Marfan’s. Some other her- itable diseases that affect the heart are listed in a table, without discussion in the text: though they are important to other organ systems, they offer little opportunity to the cardiologist for diag- nosis or management. Syndromic congenital heart disease Aneuploidy disorders The two commonest chromosomal disorders in adult patients are Down’s and Turner’s syndromes, and each includes characteristic cardiac abnormalities. A third, Klinefelter’s syndrome, does not. Some 25–​50% of patients with Down’s syndrome (OMIM 190685) have congenital heart disease. The characteristic lesion, present in about one-​half of the affected hearts, is atrioventricular canal defect. This ranges from the relatively simple primum atrial septal defect to the complete type, in which the defect involves both the atrial and ventricular septa, between which there lies a single atrioventricular valve ring. In other patients, ventricular septal defect, tetralogy of Fallot, and persistent ductus arteriosus are seen in roughly equal numbers. Patients with Down’s syndrome undergo heart surgery most easily when they are infants, and the tendency has shifted from the nihilistic approach of past years to correcting serious cardiac malformations early in life. Turner’s syndrome causes coarctation of the aorta, and congenital abnormalities of the aortic valve, usually a bicuspid valve. These are lesions that commonly accompany one another, even in the absence of an identifiable genetic cause. Patients with either lesion frequently have aortic ectasia. In some patients with Turner’s syndrome, the whole aorta is abnormal—​either hypoplastic or weakened by the presence of cystic medial necrosis. Aortic dissection may occur, and aortic surgery (e.g. to repair coarctation), can sometimes be very dif- ficult, owing to the fragile nature of the aortic wall. Other congenital heart abnormalities are not common in Turner’s syndrome, except for anomalies of pulmonary venous return. Mendelian syndromes that include congenital heart disease Noonan’s syndrome Noonan’s syndrome (OMIM 163950) is the most common heritable syndrome that characteristically causes congenital heart disease. The syndrome shares some features with the Turner phenotype, and the two were confused between 1930 and the 1960s. In 1963, Noonan described a small series of patients with pulmonary stenosis who shared a characteristic facial appearance. Since then, the expanded phenotype has been well described and shown to be associated with a normal karyotype and autosomal dominant inheritance. The con- dition is genetically heterogeneous, with causative mutations shown in eight proteins, all members of the RAS-​MAPK growth-​regulating pathway that links extracellular signalling proteins to gene tran- scription factors. Mutations in the intracellular signalling molecule protein tyrosine phosphatase SHP-​2 (the gene is called PTPN11) are the most common, and account for 50% of cases. The pathogenetics are complicated by both clinical and genetic overlap. Another syndrome—​LEOPARD syndrome (OMIM 151100)—​ is also caused by PTPN11 mutations, and the Noonan phenotype is closely related to disorders caused by mutations affecting other members of the RAS-​ERK intracellular signalling cascade. Within Noonan’s syndrome there is some suggestion that mutations of par- ticular proteins within the signalling cascade may predict particular phenotypic features. Patients with Noonan’s syndrome are of short stature, with a facies that is variously described as elfin or triangular (Fig. 16.11.1), em- phasized by ocular hypertelorism. The palpebral fissure may slope (a) (b) (c) Fig. 16.11.1  Two patients with Noonan’s syndrome: (a, b) patient 1 aged 18 and 40; (c) patient 2—​note scars at site of plastic surgery for pterygium colli. 16.11  Cardiac involvement in genetic disease 3553 downwards and outwards, and display ptosis and an epicanthal fold. The ears are set low and rotated forwards so that the lobes are prominent, and there is characteristic webbing of the neck—​ the most obvious of the features that may lead to confusion with Turner’s syndrome. Pectus deformities are common, as are other miscellaneous skeletal abnormalities, including cubitus valgus. Patients with Noonan’s syndrome are prone to develop keloid scars. Cryptorchidism is common, as is delayed sexual maturation, but not infantilism as in Turner’s syndrome. Unlike Turner’s syndrome, many patients with Noonan’s syndrome have a degree of mental handicap, but this is quite variable. Among the author’s patients with Noonan’s syndrome are a physician, an architect, a certified ac- countant, and a high-​school mathematics teacher. The frequency of cardiac involvement in Noonan’s syndrome is high, estimated as more than 80%, but because the diagnosis is so easily missed in the absence of congenital heart disease the true fre- quency may be less. The most characteristic lesion is pulmonary stenosis, but in contrast to the almost stereotypical cardiovascular findings in Turner’s syndrome, the range in Noonan’s syndrome is broad. In many patients, the stenotic pulmonary valve leaflets are not simply fused, as in non​syndromic pulmonary stenosis, but may be dysplastic, thickened, and immobile—​unsuitable for simple balloon or surgical valvotomy. Other congenital lesions found in Noonan’s syndrome are ventricular and atrial septal defects, tricuspid atresia, single ventricle, and abnormalities of the left ventricle, including congenital mitral stenosis, subaortic stenosis, and a combination of these two lesions. The electrocardiogram often shows a superior axis (left-​axis deviation), even when there is pulmonary stenosis and right ventricular hypertrophy. The most ominous complication of Noonan’s syndrome is cardio- myopathy, taking the form of myocardial hypertrophy complicated by progressive fibrosis. This leads, over the course of 5–​15 years, to low cardiac output with very high ventricular diastolic pressures—​ the pathophysiology of restrictive cardiomyopathy. Since the valvular abnormalities are for the most part correctable, this hyper- trophic restrictive cardiomyopathy is the main factor limiting life expectancy. Familial supravalvar aortic stenosis and Williams’ syndrome Familial supravalvar aortic stenosis is caused by loss-​of-​function mutation or deletion affecting the gene for elastin located on chromosome 7. Affected patients develop a tight, fleshy constric- tion of the aorta, or sometimes the pulmonary artery, at the level of the sinotubular junction above the semilunar valve (Fig. 16.11.2). In some patients, both great arteries are affected. Supravalvar aortic stenosis can lead to severe left ventricular outflow obstruction, with left ventricular failure or even sudden death. This is not a setting for balloon dilation or stenting, but the results of surgery are good, for either lesion or for both. Williams’ syndrome (OMIM 194050) is one of the best-​documented examples of a contiguous gene phenomenon seen in adult medicine. It is caused by macrodeletions of chromosome 7 that include the elastin gene. Hence, Williams’ syndrome includes the cardiovas- cular features of familial supravalvar aortic stenosis described in the previous paragraph. In addition, more far-​reaching effects caused by deletion of contiguous genes accompany these vascular abnor- malities. The full syndrome includes a characteristic facial appear- ance, with round, blue eyes, a distinctive stellate pattern of the irises, (a) (b) (c) Fig. 16.11.2  Supravalvar aortic stenosis: (a) contrast angiogram of the thoracic aorta showing normal sinuses of Valsalva (broad arrow) with constriction at the sino–​tubular junction (narrow arrow). (b) Operative photograph. The patient’s head is to the right. Arrows as in panel (a). (c) Fluorescence in situ hybridization (FISH) showing two markers for chromosome 7 (bright fluorescence), but only one for the elastin gene (orange fluorescence). section 16  Cardiovascular disorders 3554 depression of the nasal bridge, outwards tilting of the nostrils, ab- normal dentition, and big lips, together with small stature, mental retardation, and a history of infantile hypercalcaemia. Mental re- tardation in Williams’ syndrome takes on very individual forms, the patients often being articulate and socially adept: several purported idiot savants have had Williams’ syndrome. As in the purely cardiac syndrome, surgery may be required to relieve severe left (or right) ventricular outflow obstruction. DiGeorge and velocardiofacial syndromes (chromosome 22 deletion syndrome) DiGeorge syndrome (OMIM 188400), described in 1965, comprises abnormalities of the parathyroid glands, absence or hypoplasia of the thymus, and conotruncal abnormalities of the heart such as pul- monary atresia and severe forms of tetralogy of Fallot. Some affected patients have learning disabilities or schizophrenia. It was recog- nized soon after the original description that the syndrome is gener- ally caused by deletions in a region of chromosome 22. Velocardiofacial syndrome (OMIM 192430), or Shprintzen’s syn- drome, described in 1981, comprises similar cardiac abnormalities along with cleft palate, a characteristic facies, and learning difficulty. It has since proved to be caused by deletions in the same region of chromosome 22, now often referred to as the DiGeorge critical re- gion (DGCR). A third syndrome, known as ‘conotruncal anomalies face’, is also linked to this site. With a broad spectrum of phenotypic variation, and deletions that are often quite large, it was suspected for some time that these syndromes are related manifestations of a contiguous gene phenom- enon, just as in Williams’ syndrome. However, it has emerged that the size of the deletion does not predict the extent of the pheno- type, and that within a family the same (presumably stable) dele- tion can be the cause of a wide range of phenotypes. Two candidate genes lie within the DGCR—​TBX1 and UFDIL; it remains to be seen whether either can be implicated as the cause of the entire group of phenotypes. Heart–​hand syndromes The two commonly recognized heart–​hand syndromes are Holt–​ Oram syndrome and Ellis–​van Creveld syndrome. Holt–​Oram syndrome Holt–​Oram syndrome (OMIM 142900), inherited as an autosomal dominant trait, was described in 1960. It includes a secundum atrial septal defect and skeletal abnormalities, principally affecting the upper limbs and shoulder girdle, never the legs, and usually more pronounced in the left arm (Fig. 16.11.3). Within a family, affected individuals may have skeletal abnormalities, congenital heart dis- ease, or both. The limb abnormalities cover a wide spectrum from just a triphalangeal thumb to phocomelia. Abnormalities of the hand and forearm always involve the radial side and thumb (in con- trast to Ellis–​van Creveld syndrome). The characteristic cardiac ab- normality is fossa ovalis (secundum) atrial septal defect, but affected patients may have other relatively simple lesions (e.g. ventricular septal defect or pulmonary stenosis). Holt–​Oram syndrome is caused by mutation in a transcription factor, TBX5, a close homologue of a transcription factor seen as phylogenetically far away as the fruit fly, where mutations produce abnormalities of the wing. Ellis–​van Creveld syndrome Ellis–​van Creveld syndrome (OMIM 225500) is inherited as a re- cessive trait, hence the more complete clinical descriptions have come from studies in genetically circumscribed communities, notably the Old Order Amish of Pennsylvania where, thanks to a founder effect, the gene is common and homozygotes abound. The syndrome, described in 1940, includes dwarfism, caused mainly by shortening of the forearms and lower legs, and symmetrical polydactyly affecting the ulnar side with accessory sixth and even seventh digits attached to or beyond the little finger. Cardiac in- volvement is very common, present probably in three-​quarters of homozygotes. The characteristic lesion is common atrium—​a lesion that has the appearance, on echocardiography and to the surgeon, of a very large primum atrial septal defect. A  few pa- tients have more complete forms of atrioventricular canal defect, and—​at least among the Amish—​there is a high perinatal mor- tality rate among affected infants, suggesting the possibility of still more extensive cardiac involvement. The gene has been mapped to chromosome 4, sequenced, and named EVC. The protein has been identified as playing a role in the hedgehog signal transduc- tion pathway. Connective tissue disorders Marfan’s syndrome Thanks principally to the work of McKusick and his collabor- ators, beginning in 1955, Marfan’s syndrome (OMIM 154700) has become the paradigm for the clinical, genetic, and molecular investigation of the heritable disorders of connective tissue. The importance of the syndrome is heightened by the fact that its recognition and treatment have had a dramatic impact on survival among those affected. Untreated, patients had a median survival into the fourth decade before death from aortic dissec- tion and rupture (Fig. 16.11.4). Today, affected patients have a near-​normal lifespan, and there are reasons to hope that recent Fig. 16.11.3  Holt–​Oram syndrome. 16.11  Cardiac involvement in genetic disease 3555 advances in understanding the molecular pathogenesis may yet offer treatments of this genetic disease that can forestall its complications. In 1896, Marfan described a weak, generally hypotonic child, with what he termed arachnodactyly. In the ensuing 100 years it was appreciated that the syndrome is mendelian and pleiotropic, involving several apparently unrelated organs whose common feature seemed initially to be just the importance of elastic tissue to their structural integrity. Ocular involvement, with the lens subluxed because of failure of its suspensory ligament, was rec- ognized early in the 20th century. Cardiovascular involvement was noted incidentally in the 1940s, and studied systematically from the 1950s onwards. Skeletal involvement includes—​besides long limbs and arachnodactyly—​scoliosis and other abnormal- ities of the thoracic cage. The sternum may be pushed outwards or inwards by the abnormally long ribs, hence pectus carinatum and/​or excavatum, often asymmetrical. Skin involvement is iden- tified by light-​coloured striae, which should be looked for over the deltopectoral groove and the flanks. Less common findings are dural ectasia, which can sometimes be so marked as to cause ra- dicular symptoms, and pulmonary involvement with emphysema, spontaneous pneumothorax, or apical blebs. In severely affected children, like the one Marfan described, there may be generalized weakness and hypotonia. These last findings are hard to account for just on the basis of abnormal elastic tissue, and recognizing this led to an appreciation that the pathogenesis of Marfan involves ab- normal growth regulation, not simply a fixed physical abnormality of ground substance scaffolding. The characteristic cardiovascular findings in Marfan’s syndrome are aneurysmal dilatation of the aorta, and occasionally other large arteries, and floppy mitral valve. The former was recognized in the 1920s, but not really addressed until McKusick showed that it was the principal cause of early death in the disease. Shortly afterwards, echocardiography became available to identify and follow these ab- normalities, and surgical techniques were developed by Bentall and Gott to repair the aneurysms. Until then, median life expectancy for men with Marfan’s syndrome had been 45 years, for women a year or two longer. Fibrillin-​1 mutations The syndrome (OMIM 134797)  is caused by mutations of the fibrillin-​1 gene (FBN1) on chromosome 15. It has recently emerged that besides a purely structural role, one that could hardly be re- placed by any form of treatment, fibrillin-​1 acts to modulate cell-​to-​ cell signalling during development and, at least in a mouse model, after birth. The dominant negative hypothesis, in which the mutated fibrillin protein was believed to have its effect by interfering with polymerization of the product of the non​mutated allele, thus proves to have been an oversimplification. Rather, the pleiotropic effects of FBN1 mutations prove to be mediated through upregulation of the signalling pathway transforming growth factor-​β1 (TGFβ1), which is modulated by fibrillin-​1. Such findings have led to the like- lihood of pharmacological treatment for the disease. Losartan, an angiotensin-​II receptor blocker, which like other members of its class also blocks TGFβ1 signalling, has been shown dramatically to prevent aortic dilation in a mouse model, also in a small clin- ical cohort study. However, a larger randomized study in a group of children and young adults did not show benefit from losartan compared to traditional treatment with a β-​blocking agent directed, not towards the molecular mechanism of disease, but just to redu- cing cardiac ejection rate and hence the rate of stress on the aortic wall. Only further experiment will reveal whether this unexpected result reflects differences between mice and humans with respect to signalling pathways, or whether it was related to some particular de- tail of the conduct of the trial. Diagnostic criteria The fibrillin molecule is large and some disease-​causing mutations have yet to be described, hence genetic diagnosis by screening for known mutations is often not possible and diagnosis usually de- pends on clinical assessment. There are generally accepted major and minor criteria. In an index case, involvement of three organ systems is required, with major criteria in two. Major criteria are aortic aneurysm, lens subluxation, characteristic and severe skel- etal abnormalities, and dural ectasia. Minor criteria can be skin striae, mitral valve prolapse, joint laxity, the facies, or moderate pectus excavatum. Characteristic skeletal abnormalities can be Fig. 16.11.4  Aortic ectasia and dissection in a patient with Marfan’s syndrome. Note that the aortic root enlargement, to 7 cm, is not apparent from the chest radiograph. section 16  Cardiovascular disorders 3556 arachnodactyly (encircling the wrist with the thumb and little finger, the ‘wrist sign’, and making a fist with a protruding thumb, the ‘thumb sign’), marked pectus deformity, wingspan increased to 5% more than the height, and scoliosis. In the relative of an index case, the positive family history becomes another major criterion. In clinical practice, determining whether a patient satisfies these criteria may be fairly subjective and requires experience with the syndrome. Often, it is enough to know whether or not there is car- diovascular involvement, and there are numerous families with aortic aneurysms or ectasia who do not satisfy clinical criteria for Marfan syndrome, yet whose long-​term management is identical. Indeed, in a busy cardiac surgery practice with expertise in aortic root replacement, such ‘non​syndromic’ familial aortopathy repre- sents a significant proportion of patients treated, and some of these families have yielded other loci as sites for the cause of their disease. On the other hand, a lanky patient who has a normal aorta needs only infrequent follow-​up, even though there may be a suspicion that he or she has a mild case of the syndrome. Clinical management Patients with Marfan syndrome should be followed up with annual or 6-​monthly echocardiograms to examine the aortic root. If there is reason to suspect that the aorta may be dilated above the echo plane, then CT scanning or MRI is required at least once to validate the echo measurement. When the maximum measurement across the aorta reaches 5 cm, we generally recommend surgical replacement of the aortic root, to prevent aortic dissection (see Chapter 16.14.1), which becomes a real risk once the dimension reaches 6 cm. The traditional and very successful approach is with the composite graft, whereby a mechanical aortic valve prosthesis—​to which is indissol- ubly attached a tubular vascular prosthesis—​is used to replace the entire aortic root and annulus. The coronary artery ostia are excised from the native aorta and reattached to the prosthetic root. Recently, to avoid anticoagulation in certain patients, there has been interest in a valve-​sparing technique of root replacement in which a vascular prosthesis is fitted snugly over the aortic valve commissures, with the native leaflets suspended in their normal anatomical arrange- ment. Long-​term success with this approach will depend on the de- gree to which the valve leaflets themselves degenerate because of the connective tissue abnormality. The Ross (pulmonary autograft) pro- cedure is not appropriate in Marfan syndrome. After surgery, and especially in patients whose surgery was done as an emergency for dissection, follow-​up is with periodic imaging by CT or MRI to keep the remaining aorta under surveillance. Management of mitral pro- lapse and regurgitation in Marfan syndrome is the same as in other patients. Surgery is required for severe or symptomatic regurgita- tion; mitral valve repair has proved surprisingly successful. It is usual to treat patients who have aortic involvement with β-​ adrenergic blockers to slow the progression to aneurysm, but the benefit is probably modest. In mice with fibrillin-​1 mutations in which the Marfan phenotype is well reproduced, β-​adrenergic blockade had only slight effect on aortic ectasia. This was in contrast to the dramatic effect of losartan, alluded to in a previous paragraph, and many clinicians now recommend use of this drug. We generally advise against excessively demanding sports, particularly competi- tive basketball, but in all affected children it is important to balance the risks of aortic disease against the importance of normal psycho- logical development. Pregnancy is not contraindicated in all women with Marfan syndrome, but genetic counselling should be offered, and it is advised that women not become pregnant if the aorta is en- larged to over 4 cm. Indeed, aortic dissection has been reported in a very few affected patients during pregnancy, even when they did not previously have aortic enlargement. In this autosomal dominant condition with high penetrance, the risk for the offspring of affected mothers or fathers is 50%. This can be mitigated, when the disease-​ causing mutation has been identified, by preimplantation genetic diagnosis. Loeys–​Dietz syndrome If the pathogenesis of Marfan syndrome lies with abnormal TGFβ signalling, then it should not come as a surprise that mutations in the TGFβ receptors also cause abnormalities of vascular and other tissues. Recently, this was confirmed in the description of Loeys–​ Dietz syndrome (OMIM 609192, 610380, 610168, 608967), a disease that shares some aspects of the Marfan phenotype and is associated with mutations of either of the two TGFβ receptors. Patients with Loeys–​Dietz syndrome have more diffuse vascular involvement than those with Marfan, and may have dissection even in vessels that are only mildly dilated. In this, they resemble patients affected by the vascular form of Ehlers–​Danlos syndrome, and the pheno- types may be very difficult to distinguish. Prominent non​vascular features include ocular hypertelorism with malar hypoplasia, bifid or broad uvula (Fig. 16.11.5), cleft palate, arachnodactyly, scoliosis, and pectus excavatum, yet excessive height is uncommon. Ehlers–​Danlos syndromes In the early part of the 20th century, Ehlers and Danlos independ- ently described an association between hyperextensibility of the skin, atrophic scarring, and hypermobility of the large joints. In the Fig. 16.11.5  Loeys–​Dietz syndrome, illustrating the characteristic bifid uvula. 16.11  Cardiac involvement in genetic disease 3557 following 75 years, numerous accounts were published of what we now recognize to be a group of related conditions, so that by 1988 a new classification of the Ehlers–​Danlos syndrome included 10 sep- arate phenotypes in an unwieldy classification. For practical pur- poses, clinicians distinguish ‘classical’ Ehlers–​Danlos, formerly types I and II, from the potentially fatal ‘vascular’ form, previously type IV. Classical Ehlers–​Danlos The classical Ehlers–​Danlos syndrome (OMIM 130000, 130010) is characterized by skin elasticity, abnormal scars, and joint hypermobility, and is inherited as a dominant trait. Skin hypere­ xtensibility is obvious (e.g. on tugging at the side of the neck or face. Joint laxity is much more marked than in Marfan syndrome, and allows for tricks like placing the feet behind the head or other con- tortionist performances, besides permitting a remarkable span on the piano or violin. It also leads eventually to severe degenerative arthritis, often with considerable deformity of the hands. Ability to touch the nose with the tip of the tongue may also provide a clue to the diagnosis. The third aspect of the phenotype, atrophic scarring, if not immediately apparent, may be sought by inspecting the knees for the results of minor childhood injuries: there one may find char- acteristic wide, atrophic (‘cigarette paper’) scars still obvious from bygone years. Cardiovascular findings in classical Ehlers–​Danlos are for the most part benign. Affected patients frequently have mitral valve prolapse, as do many people with joint laxity who do not have diagnosable Ehlers–​Danlos syndrome. Relatively few progress to develop severe mitral reflux or to the point of requiring surgery. Enlargement of the aortic sinuses of Valsalva may occur, but only rarely is this severe or progressive. Surgical replacement of the aortic root, as is performed in Marfan syndrome, is unusual in Ehlers–​Danlos syndrome. Vascular Ehlers–​Danlos Unlike classical Ehlers–​Danlos, vascular Ehlers–​Danlos syndrome (OMIM 130050) is a potentially fatal condition, with a natural his- tory worse than Marfan syndrome. It is genetically and biochem- ically well characterized: patients have mutations in the COL3A1 gene which encodes for type III procollagen, with inheritance as a dominant trait. The collagen defect leads to excessive fragility of blood vessels, bowel, and uterus, and the natural history of the con- dition is to present with spontaneous rupture of one of these three (in the case of the uterus, during pregnancy). Because of the intrinsic weakness of the affected tissues, surgical repair is challenging and these complications frequently prove fatal. Furthermore, in patients who have once undergone vascular or bowel rupture, the likelihood of a second event is high. Table 16.11.1  Rare mendelian disorders affecting the cardiovascular system Biochemical abnormality Non​cardiac features Cardiovascular features Osteogenesis imperfecta (OMIM 166200, and others) Heterogeneous, abnormalities of type 1 procollagen Bony fractures and deformity, blue scleras (four types described) Mitral valve prolapse and regurgitation Aortic root enlargement and aortic regurgitation Pseudoxanthoma elasticum (OMIM 264800) Areas of thickened skin and pseudoxanthomas Vascular fragility and haemorrhage Fundus: angioid streaks Extensive vascular narrowing and calcification with angina, claudication, and limb ischaemia Hunter’s syndrome (MPS II) (OMIM 309900) Iduronate sulphate sulfatase X-​linked usually severe with dwarfing, mental retardation, gargoylism Cardiomyopathy, coronary narrowing, valve lesions Scheie’s syndrome (MPS IS) (OMIM 607016) α-​Iduronidase (as in the much more severe, allelic, Hurler’s syndrome, MPS IH) Arthropathy, hepatosplenomegaly, corneal clouding Aortic regurgitation Abnormal valve leaflets Morquio’s syndrome (MPS IV) (OMIM 253000 and others) Galactosamine-​6-​sulphate sulfatase or α-​galactosidase Dwarfism, deafness, spinal cord compression, and injury Aortic regurgitation and stenosis Homocystinuria (OMIM 236200) Cystathionine-​α-​synthase Osteoporosis, sternal deformity, lens subluxation, mental retardation Vascular thrombosis, precocious coronary atherosclerosis Fabry’s disease (OMIM 301500) α-​Galactosidase A Painful neuropathy, CNS disease, renal failure, corneal opacity Coronary artery disease, myocardial infarction, mitral valve dysfunction Friedreich’s ataxia (OMIM 229300) Frataxin Spinocerebellar degeneration Cardiomyopathy with increased wall thickness and restrictive physiology Ventricular arrhythmias Duchenne’s muscular dystrophy (OMIM 310200) Dystrophin X-​linked muscular dystrophy with rapid progression during childhood and adolescence Dilated cardiomyopathy, characteristic ECG Becker’s muscular dystrophy (OMIM 300376) Dystrophin X-​linked muscular dystrophy, less severe than Duchenne’s Dilated cardiomyopathy, variable severity Dystrophia myotonica (OMIM 160900) Myotonin protein kinase Weakness and myotonia, ptosis, cataracts, frontal balding, intellectual slowing Bundle branch block, bradyarrhythmias, less frequently VT Haemochromatosis (OMIM 235200 and others) HFE protein Diabetes, liver disease, pigmentation, arthritis, pituitary dysfunction Dilated or restrictive cardiomyopathy Arrhythmogenic right ventricular dysplasia (OMIM 107970 and others) Desmosomes, Transforming growth factor-​β-​3 (and others) None Palpitations, syncope, sudden death CNS, central nervous system; MPS, mucopolysaccharidosis; VT, ventricular tachycardia. section 16  Cardiovascular disorders 3558 The joint and skin features of the vascular phenotype are less ob- vious than those of the classical form. Joint hypermobility is not seen, nor the resulting arthropathy. However, the skin feels soft and thin, and is abnormally translucent such that the veins are easily seen through it as one examines the shoulders and upper chest. The face is often thin and bony, and the nose pinched. Vascular complications are hard to anticipate. Aortic ectasia and aneurysm occur only in a few patients. Moreover, arterial rupture—​ as common as dissection—​may occur in medium-​sized vessels of the brain, thorax, or abdomen just as often as the aorta. In these regards, the vascular complications of this disease are comparable to those of the Loeys–​Dietz syndrome. In affected patients and their families, detailed genetic evaluation is important and should in- clude screening of COL3A1 and biochemical analysis of type III col- lagen obtained from skin biopsy and cultured fibroblasts as well as screening the TGFβ receptor genes. Other heart-​related connective tissue and metabolic disorders Osteogenesis imperfecta causes aortic and mitral regurgitation, as do several of the mucopolysaccharidoses (Table 16.11.1). It is striking, particularly in the case of osteogenesis imperfecta, how healing is almost non​existent where there is foreign material. If the opportunity arises, even years later, to inspect the operative result in a patient who has undergone valve replacement, the sutures look as though they had only just been placed, with minimal endothelial reaction and scar-​tissue formation. FURTHER READING Brooke BS, et al. (2008). Angiotensin II blockade and aortic-​root dila- tion in Marfan’s syndrome. N Engl J Med, 358, 2787–​95. D’Asdia MC, et al. (2013). Novel and recurrent EVC and EVC2 mu- tations in Ellis-​van Creveld syndrome and Weyers acrofacial dysostosis. Eur J Med Genet, 56, 80–​7. Groenink M, et al. (2013). Losartan reduces aortic dilatation rate in adults with Marfan syndrome: a randomized controlled trial. Eur Heart J, 34, 34913–​500. Habashi JP, et al. (2006). Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science, 312, 117–​21. Judge DP, Dietz HC (2005). Marfan’s syndrome. Lancet, 366, 1965–​76. Lacro RV, et al. (2014). Atenolol versus losartan in children and young adults with Marfan’s syndrome. N Engl J Med, 371, 2061–​71. Lowery MC, et al. (1995). Strong correlation of elastin deletions, de- tected by FISH, with Williams syndrome: evaluation of 235 patients. Am J Hum Genet, 57, 49–​53. McKusick VA (2000). Ellis–​van Creveld syndrome and the Amish. Nat Genet, 24, 203–​4. Oderich GS, et al. (2005). The spectrum, management and clinical outcome of Ehlers–​Danlos syndrome type IV: a 30-​year experience. J Vasc Surg, 42, 98–​106. Prendiville TW, et al. (2014). Cardiovascular disease in Noonan syn- drome. Arch Dis Child, 99, 629–​34. Pyeritz RE (1983). Cardiovascular manifestations of heritable dis- orders of connective tissue. Progr Med Genet, 5, 191–​302. Roberts AE, et al. (2013). Noonan syndrome. Lancet, 381, 333–​42. disease 3509 16.9.1 Acute rheumatic fever 3509 Jon disease 3509 16.9.1 Acute rheumatic fever 3509 Jonathan R. Carapetis 16.9 Cardiac involvement in infectious disease CONTENTS 16.9.1 Acute rheumatic fever  3509 Jonathan R. Carapetis 16.9.2 Endocarditis  3519 James L. Harrison, John L. Klein, William A. Littler, and Bernard D. Prendergast 16.9.3 Cardiac disease in HIV infection  3534 Peter F. Currie 16.9.4 Cardiovascular syphilis  3539 Krishna Somers 16.9.1  Acute rheumatic fever Jonathan R. Carapetis ESSENTIALS Acute rheumatic fever is an immunologically mediated multisystem disease induced by recent infection with group A  streptococcus. About 5% of people have the potential to develop acute rheum- atic fever after infection by a strain of streptococcus with propen- sity to cause the condition. Most cases (97%) occur in low-​income and some middle-​income countries, with indigenous populations in some affluent countries also affected. Children aged 5–​15 years are most commonly affected, and rheumatic heart disease remains the most common acquired heart disease of childhood in the world. Presentation—​after a latent period (1–​5 weeks in most cases, but up to 6 months for presentation with chorea) the disease presents with one or more of the following major criteria: (1) carditis—​most typ- ically manifest as an apical pansystolic murmur of mitral regurgita- tion, but subclinical disease (evident only on echocardiogram) is also now recognized; (2) polyarthritis—​severe, large-​joint, and migratory; (3)  chorea; (4)  subcutaneous nodules; (5)  erythema marginatum. Other minor criteria that can support the diagnosis include fever, polyarthralgia, or monoarthritis, elevated C-​reactive protein or erythrocyte sedimentation rate, prolongation of the PR interval on the ECG. Diagnosis—​in addition to the criteria just described, evidence of preceding group A streptococcal infection is required: (1) positive throat culture, or (2) elevated or rising antistreptolysin O or other streptococcal antibody, or (3) rapid antigen test for group A strepto- coccus. The most recent revision of the Jones criteria for diagnosis of acute rheumatic fever allows subclinical carditis as a major mani- festation and more sensitive criteria in populations at moderate or high risk of disease, with monoarthritis and polyarthralgia acceptable as major manifestations and lower grade fever (≥38°C compared to ≥38.5°C) and less-​elevated ESR (≥30 mm/​h compared to ≥60 mm/​h) as minor manifestations in those groups. Prognosis and management—​untreated acute rheumatic fever lasts for about 3 months. All patients with acute disease should be given penicillin to eradicate the group A streptococcus that precipi- tated the attack. Children with arthritis or severe arthralgia should be treated with non​steroidal anti-​inflammatory medication (usually salicylates). For severe carditis, many clinicians use oral prednisone or prednisolone at a dose of 40–​60 mg/​day (1–​2 mg/​kg per day in children), tapering after 2 or 3 weeks, but benefit is not proven. Important prognostic factors are the severity of the acute carditis and the number of recurrences: 30–​60% of patients with a first episode of acute rheumatic fever will develop chronic rheumatic heart disease, but more than 70% of those with severe carditis at the first episode, or with recurrent episodes. Recent evidence suggests a benefit of cor- ticosteroids for severe or refractory chorea. Secondary prophylaxis—​every patient with acute rheumatic fever should immediately commence intramuscular benzathine benzy­ lpenicillin every 3 or 4 weeks (preferable), or twice daily oral phenoxy­methylpenicillin. In patients without carditis, this should continue for 5  years or until age 21, whichever comes later (al- though some organizations recommend a minimum of 10 years from last episode); with mild or healed carditis, for 10 years or until age 21, whichever is longer; those with more severe valvular disease or after valve surgery should have secondary prophylaxis until age 40 or sometimes for life. Primary prophylaxis—​a full course of penicillin treatment com- mencing within 9 days of the onset of symptomatic group A strepto- coccal pharyngitis will prevent the subsequent development of acute rheumatic fever in most cases and should be advocated. section 16  Cardiovascular disorders 3510 Introduction Acute rheumatic fever is an immunologically mediated multisystem disease induced by recent infection with group A  streptococcus. Most medical practitioners in industrialized countries will rarely, if ever, see a case. However, the dramatic decline in incidence of acute rheumatic fever in industrialized countries during the second half of the 20th century was not replicated in many developing countries, or among some indigenous and other populations living in poverty in industrialized countries. Acute rheumatic fever continues largely unabated in many low-​income countries, and rheumatic heart dis- ease remains the most common acquired heart disease of childhood in the world. Epidemiology It is estimated that 33.4 million people are affected by rheumatic heart disease, with more than 10.5 million disability adjusted life years lost and 319 000 deaths occurring each year as a result. Ninety-​ seven per cent of acute rheumatic fever cases and deaths occur in developing countries. Although acute rheumatic fever and rheum- atic heart disease are relatively common in all developing countries, they occur at particularly high rates in sub-​Saharan Africa, Pacific nations, Australasia, the Indian subcontinent, and Central Asia. There have been dramatic declines in incidence in recent decades in many Latin American and Asian countries with improving eco- nomic and living conditions, although many of these countries have subpopulations living in poverty that continue to suffer high rates. In most populations with high incidence, the predisposing condi- tions are those that promote endemicity and high levels of transmis- sion of group A streptococci: these include overcrowded housing, poor personal and community hygiene, poor access to medical services, and, in some circumstances, widespread skin infection, and scabies infestation. Outbreaks of acute rheumatic fever occurred in middle-​class areas of the United States during the 1980s and 1990s. These out- breaks arose because of the emergence of virulent strains of group A streptococci, particularly belonging to M serotypes 1, 3, and 18. By contrast, outbreaks of acute rheumatic fever have rarely, if ever, been described from developing countries; most cases appear to arise from the ongoing circulation of pathogenic group A streptococcal strains in the population. Recurrent episodes are almost as common as primary episodes in many populations with high incidence rates of acute rheumatic fever. These may lead to accumulated cardiac valvular damage and are therefore responsible for many cases of rheumatic heart disease, yet they are almost entirely preventable using secondary prophylaxis. In many developing countries, females are affected more than males, although this gender association is stronger for rheumatic heart disease (especially mitral stenosis) than for acute rheumatic fever; this may reflect a greater tendency to recurrences among fe- males. Any female preponderance may relate to inherited charac- teristics, to greater exposure to group A streptococci because of the increased involvement of girls and young women in child-​rearing in most cultures, or to reduced access by females to primary and sec- ondary prophylaxis. The maximum incidence of acute rheumatic fever is between the ages of 5 and 15 years in all populations. Approximately 5% of cases occur in children younger than 5 years, but very rarely are children younger than 3 years affected. This age distribution par- allels that of group A streptococcal pharyngitis, and supports the hypothesis that all cases of acute rheumatic fever follow this condi- tion. However, it may be that cases do not occur in infants or very young children because of the need for maturity of the immune system (particularly of cellular immunity), or sensitization of the immune response by prior streptococcal infections. New cases occur occasionally up to age 30, but rarely beyond. Hypotheses to explain the reduced incidence in adulthood include development of non-​type-​specific immunity to primary group A streptococcal infections, further maturation of immune responses, or reduced sensitization by recurrent streptococcal infections. Pathogenesis Despite a century of research, the pathogenesis of acute rheumatic fever remains incompletely understood. The presumed pathogenetic pathway relies on development of cross-​reactive immune responses between epitopes of group A streptococcus and human tissue, sum- marized in Fig. 16.9.1.1. Host factors Epidemiological evidence suggests that less than 5–​6% of people have the potential to develop acute rheumatic fever after relevant streptococcal exposure, and that this proportion does not vary substantially between populations. Attack rates of acute rheum- atic fever after untreated group A streptococcal pharyngitis vary from less than 1% to 3%. Genetic susceptibility to acute rheum- atic fever is suggested by a 44% concordance in monozygotic twins compared to 12% in dizygotic twins, and heritability more recently estimated at 60%. Older studies have associated genetic susceptibility with human leukocyte antigen (HLA) class  II alleles, particularly HLA-​DR7 and DR4, polymorphisms at the tumour necrosis factor-​α locus (TNF​α-​308 and TNF​α-​238), high levels of circulating mannose binding lectin, and Toll-​like receptors. Recent genome-​wide asso- ciation studies are providing further insights: in New Caledonian and Fijian populations an association with the Immunoglobulin Heavy Chain locus on chromosome 14 was reported, and a study in Aboriginal Australians found an association at the HLA DQA1 locus on chromosome 6, both of which support the hypothesis of molecular mimicry leading to the aberrant immune response of acute rheumatic fever. Organism factors The observation that outbreaks of pharyngitis due to certain sero- types of group A streptococcus resulted in high attack rates of acute rheumatic fever, whereas no cases occurred after infection with other serotypes, led to the concept of ‘rheumatogenicity’—​that only some strains of group A streptococcus have the potential to cause acute rheumatic fever. M serotypes 1, 3, 5, 6, 14, 18, 19, 24, 27, and 29 were most frequently implicated in studies predominantly from the United States of America. However, recent studies from regions 16.9.1  Acute rheumatic fever 3511 with high endemicity of group A streptococcal infections have not found consistent M serotype, or emm genotype, associations with acute rheumatic fever. There may be substantial genetic diversity among strains belonging to a particular emm type, and not all strains of ‘rheumatogenic serotypes’ appear to cause acute rheumatic fever. Therefore, rheumatogenicity may be strain specific rather than sero- type specific (i.e. any group A streptococcus may acquire the poten- tial to cause acute rheumatic fever). The pathogenic factor(s) are not known. Parts of the organism have immunological cross-​reactivity with human tissue; there is close homology between regions of the M protein and human myosin, tropomyosin, keratin, actin, laminin, vimentin, and N-​ acetylglucosamine. Other components of group A  streptococci, including the hyaluronic acid capsule, the cell-​wall associated group-​specific carbohydrate, and the cell membrane, cross-​react with a variety of human tissues damaged in acute rheumatic fever, including components of heart muscle and valves, joints, and brain. Acute rheumatic fever-​associated strains of group A streptococcus also tend to be heavily encapsulated with hyaluronic acid, and not to express opacity factor. Group A  streptococci possess compo- nents which act as superantigens, selectively stimulating subsets of T cells without the need for antigen presentation. Their role in acute rheumatic fever pathogenesis is not yet clear. Site of infection Although it is widely accepted that acute rheumatic fever may result from group A streptococcal infection of the upper respira- tory tract, but not of the skin, there is increasing evidence that this may not always be the case. Upper respiratory tract infection certainly accounts for most, if not all, episodes of acute rheumatic fever in populations with low rates of streptococcal skin infections. However, in populations where streptococcal impetigo is highly endemic, it may be that skin infection accounts for many cases of acute rheumatic fever, either de novo or after subsequent throat in- fection. Determining whether group A streptococcal skin infection may have a role in pathogenesis of acute rheumatic fever would have enormous public health implications, as it may redirect pre- sent approaches to primary prevention. The immune response Molecular mimicry between group A streptococcal epitopes and human tissue is thought to be the basis for the autoimmune re- sponse that leads to rheumatic fever. Some models suggest that binding of cross-​reactive antibodies to heart valve endothelium leads to activation of the adhesion molecule VCAM-​1 and sub- sequent recruitment of inflammatory cells. The ensuing tissue damage results in the release of peptides such as laminin, keratin, and tropomyosin, which lead to further damage from activation of cross-​reactive T cells. Recently, an alternative hypothesis has been suggested proposing that streptococcal invasion of epithe- lial surfaces leads to binding of streptococcal M protein to type IV collagen through a mechanism not involving molecular mimicry. Overall, it is not entirely clear if the initial damage in rheumatic fever is primarily due to cellular or humoral immunity, but it does appear that ongoing damage is mainly due to T-​cell and macro- phage infiltration. GAS adhesion and invasion GAS antigen processing and presentation to B and T cells BCR B cell Macrophage TCR T cell MHC class II Activated cross- reactive T cell Activated cross- reactive B cell Generarion of cross-reactive B and T cells Tissue and organ- specific manifestations Heart Brain (chorea) Joints (arthritis) Skin (erythema marginatum and subcutaneous nodules) Cross-reactive antibody GAS Pharyngeal epithelium Fig. 16.9.1.1  Generation of cross-​reactive immune response in acute rheumatic fever. GAS, group A streptococcus. Reprinted from Carapetis JR, et al. (2016). Acute rheumatic fever and rheumatic heart disease. Nat Rev Dis Primers, 14(2), 15084. section 16  Cardiovascular disorders 3512 Clinical manifestations There is always a latent period between group A streptococcal infec- tion and the development of acute rheumatic fever. This varies from 1 to 5 weeks in most cases (usually c.3 weeks), but may be shorter in recurrences. Chorea may occur up to 6 months after the precipitating streptococcal infection. The preceding infection is asymptomatic in about two-​thirds of cases. The tissues most commonly affected are the heart, joints, and brain. Although the symptoms due to each can be disabling in the short term, only cardiac damage may be permanent and progressive. Therefore, the focus in controlling or treating acute rheumatic fever is always to prevent the development of rheumatic heart disease. The frequency with which the various clinical manifestations have occurred in recent descriptions of acute rheumatic fever is listed in Table 16.9.1.1. Carditis Although inflammation in acute rheumatic fever may affect the pericardium (causing pericardial rubs and occasionally pleuritic chest pain) or the myocardium (sometimes causing cardiac failure, and evident on biopsy with pathognomonic Aschoff bodies), endo- cardial inflammation is the most important cause of cardiac damage. If either acute cardiac failure or chronic cardiac disease occurs, it is almost always due to damage to the cardiac valves. A murmur is the most common evidence of acute valvular dis- ease, usually the apical pansystolic murmur of mitral regurgita- tion, with or without a low-​pitched mid-​diastolic (Carey–​Coombs) murmur. Occasionally an aortic regurgitant murmur may be heard, mainly in older adolescents or young adults. Murmurs of tricuspid or pulmonary regurgitation are rare and are usually secondary to increased pulmonary venous pressures resulting from mitral regur- gitation or stenosis. Sinus tachycardia or gallop rhythms may also be present in acute carditis. Valves affected by rheumatic carditis may have a characteristic appearance or pattern of regurgitation on Doppler echocardiog- raphy (when interpreted by experienced technicians), which may be found even in the absence of a cardiac murmur (subclinical dis- ease). Recent efforts to standardize the echocardiographic diagnosis of rheumatic heart disease have led to publication of an evidence-​ based guideline by the World Heart Federation, which focuses on features of mitral and aortic regurgitation and valvular morphology that can be considered pathological, and combines these features into criteria for ‘definite’ and ‘borderline’ rheumatic heart disease. Although these criteria were devised for rheumatic heart disease ra- ther than acute rheumatic fever, there is accumulating evidence that many similar features are useful in diagnosing acute rheumatic card- itis on echocardiography. The recent revision of the Jones criteria identifies the features of regurgitant jets and valvular morphology that can be used to make a diagnosis of acute rheumatic carditis, even in the absence of a significant cardiac murmur (Table 16.9.1.2). Mitral or aortic stenosis may develop as later complications of se- vere and/​or recurrent acute carditis due to scarring and contraction following the acute inflammatory process. Rarely, mitral stenosis may occur in young children with acute rheumatic fever—​so-​called ‘juvenile mitral stenosis’—​the reasons for the development of this condition are not clear. Damage to the electrical conduction pathways may result in prolongation of the PR interval on electrocardiography (ECG). Although a subset of healthy people may have this finding, the pres- ence of a prolonged PR interval that resolves over the ensuing few days to weeks may be a useful diagnostic feature in cases where the clinical manifestations are not clear. Occasionally, in the acute phase, second-​or third-​degree heart block or a nodal rhythm may be present (Fig. 16.9.1.2). Arthritis The characteristic joint manifestation of acute rheumatic fever is severe, large-​joint, migratory polyarthritis. The knees, ankles, wrists, and elbows are most commonly involved; only rarely, and usually only when the patient is untreated for several days, are the hips or small joints of the hands or feet inflamed. One joint char- acteristically becomes exquisitely painful and inflamed as another is waning. Most patients have only one or two joints affected at any one time, and each joint may be involved for just a few hours or up to 1 or 2 days. The arthritis is so responsive to non​steroidal anti-​ inflammatory medication (NSAIDs) that its persistence more than 1 or 2 days after commencing high-​dose aspirin should lead one to consider alternative diagnoses. Arthritis of a single large joint, and polyarthralgia in the absence of clear arthritis, are increasingly described in acute rheumatic fever from regions with high rates of disease. This is sometimes, but not always, due to early administration of anti-​inflammatory medica- tion, before the typical migratory pattern has emerged. Other causes of monoarthritis, including septic arthritis, should first be excluded before a diagnosis of acute rheumatic fever is entertained. Arthralgia (joint pain without objective evidence of inflammation) is usually migratory and affects large joints, and like the arthritis of acute rheumatic fever is very responsive to NSAIDs. Sydenham’s chorea In 1686 the English physician Thomas Sydenham described rheum- atic chorea, initially naming it ‘St Vitus’ dance’. It is the most intriguing manifestation of acute rheumatic fever, particularly as it commonly occurs in the absence of other manifestations, usually follows a pro- longed latent period (up to 6 months) after the precipitating group A streptococcal infection, and occurs most commonly in females Table 16.9.1.1  Frequency of clinical manifestations in acute rheumatic fever Manifestation Proportion of patients with manifestation (%) Choreaa absent Choreaa present Carditis 40–​60 20–​30 Polyarthritis 50–​75 <10 Erythema marginatum 1–​10 0–​1 Subcutaneous nodules 1–​10 0–​1 Fever >37.5°C 90 10–​25 Arthralgia <10–​20 <5 Elevated acute-​phase reactants 90 10–​25 Prolonged PR interval 30–​50 5–​10 a Chorea is present in <10% to >30% of patients with acute rheumatic fever, depending on the population. 16.9.1  Acute rheumatic fever 3513 (and almost never in postpubertal males). The rapid, jerky, invol- untary movements affect predominantly the upper limbs and face, may be asymmetrical, and may be sufficiently severe to render the patient unable to eat, drink, walk, or perform other activities of daily living. Mild chorea can sometimes be detected by having the patient join palms above the head to reveal occasional twitches of the arms or the head. Typical signs include the ‘milkmaid’s grip’ (rhythmic squeezing when the patient grasps the examiner’s fingers), spooning of extended hands (caused by flexion of the wrists and extension of the fingers), darting of the protruded tongue, and the ‘pronator sign’ (the arms and palms turn outwards when held above the head). As with other forms of chorea, the disorder usually becomes more evident with anxiety or purposeful movements (such as drinking or writing). Movements may appear semi-​purposeful, and symptoms subside during sleep. Sydenham’s chorea is often associated with ex- cessive emotional lability or personality changes, which may pre- cede the abnormal movements. Most patients can be reassured that Sydenham’s chorea will re- solve completely and leave no long-​lasting effects, usually within 6 weeks and almost always within 6 months, but rarely lasting up to 3 years. Subcutaneous nodules and erythema marginatum Both of these manifestations are found in less than 2% of patients with acute rheumatic fever, although they were described in up to 10–​20% of patients in earlier studies from the United States of America and the United Kingdom. Subcutaneous nodules are firm, painless lumps, usually between 0.5 and 2 cm in diameter, commonly found in crops of three or more, and usually appear 2 to 3 weeks after the onset of acute rheumatic fever. They occur mainly over extensor surfaces or bony protuberances, particularly the hands, feet, occiput, and back. The nodules are similar to those found in rheumatoid arthritis, though often smaller, and are most likely to be associated with severe carditis. Nodules usually last from a few days to 2 or 3 weeks. The characteristic rash, erythema marginatum, appears as a light pink macule that spreads outwards with a serpiginous, well-​ demarcated edge, while the central portion clears. It appears, disap- pears, or moves before the observer’s eyes. Multiple areas are often involved, usually over the trunk, occasionally over the proximal por- tions of the limbs, but rarely, if ever, the face. It usually appears to- gether with the other initial symptoms of acute rheumatic fever but may recur intermittently for weeks or even months. This does not indicate ongoing rheumatic inflammation, and patients can be re- assured that the rash will eventually disappear without complications. Fever With the exception of those with pure chorea, 90% of patients will have a temperature at presentation higher than 37.5°C. Although it has been reported that the temperature usually exceeds 39°C, others have found only 25% of confirmed cases with fever to that level. The recent revision of the Jones criteria specifies that a temperature of 38.5°C or more is sufficient to be a minor manifestation in low-​risk populations while a temperature of 38.0°C or more is sufficient in moderate-​to high-​risk populations. As with arthritis, fever is very sensitive to NSAIDs, usually resolving completely within 1 or 2 days of commencing high-​dose salicylates. Table 16.9.1.2  Findings on echocardiography in rheumatic valvulitis Valve Doppler findings Morphological findings Mitral valve Pathological mitral regurgitation (all 4 met) Acute mitral valve changes Seen in at least 2 views Annular dilation Jet length ≥2 cm in at least one view Chordal elongation Peak velocity >3 m/​s Chordal rupture resulting in flail leaflet with severe mitral regurgitation Pansystolic jet in at least one envelope Anterior (or less commonly posterior) leaflet tip prolapse Beading/​nodularity of leaflet tips Chronic mitral valve changes: not seen in acute carditis Leaflet thickening Chordal thickening and fusion Restricted leaflet motion Calcification Aortic valve Pathological aortic regurgitation (all 4 met) Aortic valve changes in either acute or chronic carditis Seen in at least 2 views Irregular or focal leaflet thickening Jet length ≥1 cm in at least one view Coaptation defect Peak velocity >3 m/​s Restricted leaflet motion Pan diastolic jet in at least one envelope Leaflet prolapse Reproduced with permission from Gewitz MH, et al. (2015). Revision of the Jones criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: a scientific statement from the American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council of Cardiovascular Disease in the Young Endorsed by the World Heart Federation. Circulation, 131, 1806–​18. section 16  Cardiovascular disorders 3514 Elevated acute-​phase reactants Almost all patients, except those with pure chorea, have a dra- matically elevated erythrocyte sedimentation rate (ESR) or serum C-​reactive protein (CRP). There appears little difference between these measurements in their diagnostic usefulness. The CRP may return to normal more rapidly than the ESR when rheumatic activity subsides. Mild to moderate peripheral leucocytosis is common, al- though this is a less sensitive marker of rheumatic inflammation and has therefore been removed as a minor manifestation from the most recent revision of the Jones criteria. Other features Severe central abdominal pain is found at presentation in a small proportion of patients. It may be associated with other features of acute rheumatic fever; if not, these features usually appear within 1 or 2 days. The pain responds quickly to NSAIDs. Epistaxis was reported frequently in historical accounts of acute rheumatic fever, but does not feature prominently in recent descriptions. Pulmonary infiltrates may be found in patients with acute carditis; this has been labelled ‘rheumatic pneumonia’ although it is not clear whether the infiltrates represent rheumatic inflammation or another process. There may be microscopic haematuria, pyuria, or proteinuria; also mild elevations of liver transaminases—​these are non​specific and not usually severe. Associated poststreptococcal syndromes Poststreptococcal reactive arthritis has been differentiated from rheumatic fever by some authors because it has a shorter incubation period after streptococcal infection, sometimes follows non​group-​ A β-​haemolytic streptococcal infection, may have a different pattern of arthritis (including small joint involvement), and is less responsive to NSAIDs. Because of the lack of cardiac involvement, these patients are said not to require secondary prophylaxis. However, descriptions of patients who have subsequently developed carditis have led other authors to question the distinction between poststreptococcal re- active arthritis and rheumatic fever. If poststreptococcal reactive arthritis is diagnosed, secondary prophylaxis should be prescribed for at least 1 year and discontinued if there is no evidence of carditis. In populations with high incidence rates of acute rheumatic fever, it may be prudent to treat all cases of possible poststreptococcal re- active arthritis as acute rheumatic fever. The frequent finding of emotional lability, motor hyperactivity, and occasional obsessive–​compulsive symptoms in patients with Sydenham’s chorea led to the observation that group A  strepto- coccal infections may precipitate or exacerbate other disorders of the basal ganglia. These include tic disorders, Tourette’s syndrome, and obsessive–​compulsive disorder, and the term PANDAS (paedi- atric autoimmune neuropsychiatric disorders associated with streptococcal infections) has been coined. A recent follow-​up study that failed to find any exacerbations of symptoms associated with streptococcal infections in PANDAS patients has raised questions about the existence of PANDAS as a distinct disease entity. Diagnosis Because of the diversity of symptoms and signs, and the non​specific nature of most of them, in 1944 Dr T. Duckett Jones developed a set of criteria to aid in the diagnosis of acute rheumatic fever. The Jones criteria have subsequently been revised and updated several times to improve their specificity in an era of declining acute rheumatic fever incidence in high-​income countries. Because the Jones cri- teria were perceived to be overly specific for populations with high incidence of disease, other bodies have recently published their own diagnostic criteria, including the World Health Organization (WHO) and expert groups in Australia and New Zealand. The American Heart Association has responded to these concerns in its latest revision of the Jones criteria, presenting more sensitive cri- teria for populations at moderate or high risk of acute rheumatic fever (Table 16.9.1.3). The manifestations are divided into major, those which are most predictive of acute rheumatic fever, and minor, those which are commonly found in acute rheumatic fever but are less specific. The diagnosis of an initial episode requires the presence of either two major, or one major and two minor criteria, plus the demonstration of a current or recent group A streptococcal infection. Evidence of group A streptococcal infection is not required for chorea, where the Day 1 Complete heart block Day 3 Second-degree heart block Day 4 First-degree heart block Day 18 Normal sinus rhythm Fig. 16.9.1.2  ECG changes in a young adult with acute rheumatic fever, showing evolution over 18 days from complete heart block, to second-​ degree (Wenckebach) block, to first-​degree block, and then to normal sinus rhythm. Reprinted from Bishop W, et al. (1996). A subtle presentation of acute rheumatic fever in remote Northern Australia. Australian and New Zealand Journal of Medicine, Vol 26, Issue 2, © 1996 John Wiley & Sons Inc. 16.9.1  Acute rheumatic fever 3515 onset may be delayed up to 6 months after streptococcal infection, and late-​onset carditis, when low-​grade inflammation may persist for prolonged periods after the precipitating infection. Recurrences can be diagnosed with less stringent criteria. Proof of a recent group A  streptococcal infection can include demonstrating the organism in the upper respiratory tract, either by culture or rapid antigen techniques. However, most children with acute rheumatic fever no longer have a group A streptococcus Table 16.9.1.3  Revised Jones criteria (2015 revision) A. For all patient populations with evidence of preceding group A streptococcal infection: Diagnosis—​initial ARF 2 major manifestations or 1 major plus 2 minor manifestations Diagnosis—​recurrent ARF 2 major or 1 major and 2 minor or 3 minor B. Major criteria Low-​risk populationsa Moderate/​high-​risk populations Carditisb Carditis Clinical and/​or subclinical Clinical and/​or subclinical Arthritis Arthritis Polyarthritis only Monoarthritis or polyarthritis Polyarthralgia Chorea Chorea Erythema marginatum Erythema marginatum Subcutaneous nodules Subcutaneous nodules C. Minor criteria Low-​risk populationsa Moderate/​high-​risk populations Polyarthralgia Monoarthralgia Fever (≥38.5°C) Fever (≥38°C) ESR ≥60 mm/​in the first hour and/​or CRP ≥3.0 mg/​dlc ESR ≥ 30 mm/​Hr and/​or CRP ≥3.0 mg/​dlc Prolonged PR interval (unless carditis is a major criterion) Prolonged PR interval (unless carditis is a major criterion) ARF, acute rheumatic fever; CRP, C-​reactive protein; ESR, erythrocyte sedimentation rate; RHD, rheumatic heart disease. a Low-​risk populations = ARF incidence ≤2 per 100 000 school-​aged children or all age RHD prevalence of ≤1 per 1000 population per year. b Subclinical carditis = echocardiographic valvulitis as defined in Table 16.9.1.2. Erythema marginatum and subcutaneous nodules are rarely ‘standalone’ major criteria. Additionally, joint manifestations can only be considered in either the major or minor categories but not both in the same patient. c CRP value must be greater than upper limit of normal for laboratory. Reproduced with permission from Gewitz MH, et al. (2015) Revision of the Jones criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: a scientific statement from the American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council of Cardiovascular Disease in the Young Endorsed by the World Heart Federation. Circulation, 131, 1806–​18. Table 16.9.1.4  Differential diagnoses of common major presentations of acute rheumatic fever Presentation Polyarthritis and fever Carditis Chorea Differential diagnoses Septic arthritis (including gonococcal) Innocent murmur SLE Connective tissue and other autoimmune diseasea Mitral valve prolapse Drug intoxication Viral arthropathyb Congenital heart disease Wilson’s disease Reactive arthropathyb Infective endocarditis Tic disorderc Lyme disease Hypertrophic cardiomyopathy Choreoathetoid cerebral palsy Sickle cell anaemia Myocarditis—​viral or idiopathic Encephalitis Infective endocarditis Pericarditis—​viral or idiopathic Familial chorea (including Huntington’s) Leukaemia or lymphoma Intracranial tumour Gout and pseudogout Lyme disease Hormonald SLE, systemic lupus erythematosus. a Includes rheumatoid arthritis, juvenile chronic arthritis, inflammatory bowel disease, systemic lupus erythematosus, systemic vasculitis, sarcoidosis, among others. b Mycoplasma, cytomegalovirus, Epstein–​Barr virus, parvovirus, hepatitis, rubella vaccination, Yersinia, and other gastrointestinal pathogens. c Possibly including PANDAS. d Includes oral contraceptives, pregnancy (chorea gravidarum), hyperthyroidism, hypoparathyroidism. Reprinted from The Lancet, Vol. 366, Carapetis JR, McDonald M, Wilson NJ, Acute rheumatic fever, pp. 155–​68. Copyright (2005), with permission from Elsevier. section 16  Cardiovascular disorders 3516 detectable by these methods, and up to 15–​25% of normal children in temperate climate countries may carry the organism in their throat. Serological techniques are therefore most commonly used, par- ticularly the antistreptolysin O, anti-​DNase B, or antihyaluronidase titres. One of any two of these tests will be positive in well over 90% of recent streptococcal infections. Their usefulness is increased by per- forming more than one serological test, or by demonstrating rising titres in paired sera. Serology is of limited value in regions with high prevalence rates of streptococcal impetigo, where children may have positive antistreptococcal titres most of the time. There is therefore a need for a better diagnostic test of recent streptococcal infection, or an objective diagnostic test for acute rheumatic fever itself. The most common clinical presentation, that of a child with fever and polyarthritis, raises multiple differential diagnoses that will vary by region. Table 16.9.1.4 lists some alternative diagnostic possibil- ities for the three most common major manifestations. Treatment If untreated, acute rheumatic fever lasts on average for 3 months. Except in the case of life-​threatening acute carditis, there is no evi- dence that presently available treatments alter the outcome. Most treatments are designed to provide symptomatic relief or are based on theoretical (but unproven) approaches to attenuating the long-​ term damage. If practical, all patients with acute rheumatic fever should be ad- mitted to hospital to confirm the diagnosis, perform baseline in- vestigations to ascertain the status of the heart, provide adequate treatment for the acute phase, commence secondary prophylaxis, allow communication of details to personnel responsible for long-​ term follow-​up of the patient, and begin education of the patient and family. The mainstays of treatment are bed rest, penicillin, and salicylates. Bed rest Previous recommendations that children with acute rheumatic fever be rested in bed until all signs of active inflammation abated were probably more extreme than is necessary. Once symptoms of arth- ritis have subsided and any cardiac failure is controlled, the child may begin gentle mobilization, which may be increased as tolerated. There is no evidence that bed rest beyond the period where mobil- ization leads to exacerbation of pain or cardiac failure has any long-​ term benefit. Penicillin All patients with acute rheumatic fever should be given penicillin to eradicate the group A streptococcus that precipitated the attack. This is based on an early finding that, in some cases, prolonged group A streptococcal infection led to more severe acute rheumatic fever. Although in most cases the precipitating organism cannot be cul- tured, a treatment course of penicillin is prudent in case the strain remains present in low numbers, and to prevent its transmission to other contacts. As the aim is eradication of group A streptococcal in- fection, penicillin may be administered either as a single intramus- cular injection of benzathine benzylpenicillin at a dose of 1.2 million units (600 000 U for patients <27 kg) into the gluteal or quadriceps muscles, or as a 10-​day course of oral phenoxymethylpenicillin (V) at a dose of 500 mg (adolescents and adults) or 250 mg (children) given two times daily or amoxicillin 50 mg/​kg (max 1 g) daily. In the case of penicillin allergy, the present recommendation is to use oral erythromycin at 20–​40 mg/​kg per day given two to four times daily for 10 days, although in some regions levels of erythromycin resist- ance among group A streptococci are increasing. Anti-inflammatory treatment Children with arthritis or severe arthralgia should be treated with NSAIDs; salicylates have been most widely used, although the increasing experience with other non-steroidal anti-inflammatory medications and the relatively narrow safety profile of salicylates mean that naproxen or ibuprofen are preferred agents. If aspirin is to be used, it should be administered at a dose of 50–​60 mg/​kg per day up to a maximum of 80–​100 mg/​kg per day (4–​8 g/​day in adults), given in 4–​5 divided doses, usually results in defervescence and resolution of arthritis and arthralgia within 1–​2 days. Sometimes higher doses lead to nausea or vomiting, which can be minimized by increasing from lower starting doses. After a few days or up to 2 weeks, when the initial symptoms are abating, patients on higher doses can have the dose re- duced to 50–​60 mg/​kg per day for the remaining 2–​4 weeks. Arthritis or arthralgia may return up to 2 to 3 weeks after discontinuation of therapy; this is usually a brief and mild recrudescence, often associ- ated with increased ESR or CRP, and can be managed either with rest and reassurance or a short course of lower-​dose NSAIDs. When the diagnosis is uncertain, NSAIDs should be withheld for a day or two to look for the development of characteristic migratory polyarthritis. In such cases, paracetamol or codeine can be used to control pain until the diagnosis is confirmed. There is no evidence that salicylates reduce the severity of acute carditis or the risk of chronic cardiac valve damage. Corticosteroids For many years, corticosteroids have been used in acute rheumatic fever, particularly for patients with severe carditis. Two meta-​analyses have found no evidence that they reduce the risk of long-​term valve damage. However, the studies included in these meta-​analyses were all conducted more than 40 years ago and used corticosteroid medi- cations not in common usage today. Many clinicians continue to use oral prednisone or prednisolone at a dose of 40–​60 mg/​day (1–​2 mg/​ kg per day in children), tapering after 2 or 3 weeks, in the belief that this might reduce the severity of acute carditis. The role of cortico- steroids in chorea is discussed separately. Treatment of cardiac failure There is no doubting the need to treat cardiac failure. Diuretics, angiotensin-​converting enzyme (ACE) inhibitors (especially in aortic regurgitation), and fluid restriction are most commonly em- ployed. Digoxin is usually restricted to cases where atrial fibrillation coexists with cardiac failure, often found in older patients with es- tablished mitral stenosis. If medical therapy fails, cardiac surgery should be considered, even during the acute phase. In populations where fulminant acute carditis is relatively common (e.g. South Africa), mitral valve repair or replacement can be life-​saving and surgeons have developed tech- niques for undertaking these procedures despite friable, acutely in- flamed valvular and perivalvular tissues. In recent years, there has been a greater tendency to undertake valve repair rather than re- placement, or to use homografts or xenografts rather than mech- anical prostheses. This is to avoid high rates of thromboembolic 16.9.1  Acute rheumatic fever 3517 complications associated with mechanical prostheses, particularly in populations where compliance with anticoagulation chemo- therapy is suboptimal and there are difficulties in monitoring co- agulation indices. Treatment of chorea Sydenham’s chorea always resolves, and in most cases there is no need for medical treatment. However, medications may reduce ab- normal movements in moderate or severe chorea. Carbamazepine or sodium valproate are recommended as first line treatment, halo- peridol less commonly because of its side effect profile. Other medi- cations sometimes employed include pimozide, chlorpromazine, or benzodiazepines. All of these medications should be used sparingly and only for limited periods, and the tendency to try multiple medi- cations should be avoided. Recent evidence suggests that corticosteroids lead to more rapid symptom reduction in chorea, so oral prednisone or prednisolone may be considered for severe or refractory cases (0.5 mg/​kg daily, weaning as early as possible, preferably after 1 week if symptoms reduce). Psychotherapeutic interventions have little role in the short to medium term, and may increase the stigma of this self-​limited or- ganic disease. However, behavioural therapy should be considered if longer-​term behavioural abnormalities persist (e.g. emotional la- bility, obsessive–​compulsive traits). Newer therapies Because of the autoimmune nature of acute rheumatic fever, immunomodulatory therapies have been tried. Intravenous im- mune globulin (IVIG) has been given in some small trials. One study showed no apparent benefit on rate of improvement of clin- ical, laboratory, or echocardiographic parameters of acute carditis, but another suggested that it may accelerate recovery from chorea. Other therapies have yet to be formally assessed. Prognosis and follow-​up The most important prognostic factors are the severity of the acute carditis and the number of recurrences. Overall, approximately 30–​ 50% of patients with a first episode of acute rheumatic fever will de- velop chronic rheumatic heart disease. This increases to more than 70% in patients with severe carditis at the first episode, or in those who have had at least one recurrence. Any patient with acute rheumatic fever requires long-​term follow-​ up. Follow-​up assessments should focus on cardiac status, adherence to secondary prophylaxis, early treatment of group A streptococcal pharyngitis, and prevention of streptococcal pyoderma (including hygiene and treatment or prevention of scabies infestation). Patients with evidence of cardiac valve damage should be assessed regularly by specialist physicians and considered for cardiac surgery before substantial left ventricular dysfunction occurs. Vasoactive drugs, particularly ACE inhibitors, may delay the need for operation in asymptomatic patients with chronic aortic regurgitation. Regular echocardiography may be useful to follow the progress of rheum- atic heart disease, especially in populations where follow-​up may be irregular or in whom communication or cultural differences make clinical assessment difficult. For reasons that are not clear, presentations of acute rheumatic fever are uncommon in many low-​income countries where rheumatic heart disease is highly prevalent. In these settings, rheumatic heart disease often presents at an advanced stage, and the prognosis is poor; the recent REMEDY study followed nearly 3000 individuals with rheumatic heart disease and found that 21% of those in low-​ income countries had died within the first two years of presentation. Recurrences About 75% of all recurrences occur within 2 years of an episode of acute rheumatic fever. The reasons for this are not known, but are thought to relate to a time-​dependent sensitization of the im- mune response. The clinical features of recurrences tend to mimic those present at the initial episode, particularly in the case of chorea. However, this rule is not absolute, and the risk of developing other manifestations, particularly carditis, increases with each recurrence. The practical implication of this is that the absence of carditis at the first episode does not help to identify patients who may not need secondary prophylaxis. Prevention of acute rheumatic fever Secondary prophylaxis Every patient with acute rheumatic fever should immediately com- mence secondary prophylaxis:  long-​term, regular antibiotics to prevent primary group A  streptococcal infections. This strategy is proven to reduce the incidence of recurrences and the risk of developing chronic rheumatic heart disease. The optimal regimen is 1.2 million units (900 mg) of intramus- cular benzathine benzylpenicillin every 3 or 4 weeks, and this is com- monly given in populations with high incidences of acute rheumatic fever and programmes in place to support the regimen. An alterna- tive strategy is to use oral phenoxymethylpenicillin at a dose of 250 mg twice daily; this is less effective than benzathine benzylpenicillin, and adherence is usually less reliable. For patients proven to be allergic to penicillin, the present rec- ommendation is to use oral erythromycin at a dose of 250 mg twice daily. Recent trials have shown newer oral cephalosporins to be effective at eliminating upper respiratory tract carriage of group A streptococci. However, none of these antibiotics has been evalu- ated for the ability to prevent acute rheumatic fever. The duration of secondary prophylaxis is dictated by the redu- cing risk of recurrence with increasing age, with time since the last episode, and the possible consequences of recurrences. In pa- tients without carditis, secondary prophylaxis should continue for 5 years following the most recent episode or until age 21 years, whichever comes later. In patients with mild or healed carditis, prophylaxis should be continued for 10 years following the most recent episode or until age 21 years, whichever is longer. Patients with more severe valvular disease or those who have undergone valve surgery should have secondary prophylaxis until age 40 or sometimes for life. Primary prophylaxis A full course of penicillin treatment commencing within 9  days of the onset of symptomatic group A  streptococcal pharyngitis will prevent the subsequent development of acute rheumatic fever in most cases. After the diagnosis has been confirmed by a throat culture or rapid antigen diagnostic test, the treatment of choice is penicillin, administered either as a single intramuscular injection section 16  Cardiovascular disorders 3518 of benzathine benzylpenicillin (600 000 U for children who weigh <27 kg, or 1.2 million U for larger children and adults) or as a full 10 days of oral phenoxymethylpenicillin (250 mg for children or 500 mg for adults given two times daily) or amoxicillin (50 mg/​kg to a maximum of 1 g as a daily dose). The importance completing the 10-​day course, even if symptoms abate quickly, should be stressed to patients and parents. Shorter courses of oral penicillin treatment are associated with higher risks of acute rheumatic fever. There has never been a clinical isolate of group A streptococcus that is re- sistant to penicillin; therefore, the use of other antibiotics for pri- mary prophylaxis should be restricted to patients who are allergic to penicillin. In the case of penicillin allergy, a 10-​day course of erythro- mycin or clarithromycin is recommended. First-​generation oral cephalosporins may also be considered, as may a 5-​day course of azithromycin. However, these agents have not been evaluated in populations with high incidences of acute rheumatic fever. It is not possible to predict which episodes of group A strepto- coccal pharyngitis will precipitate acute rheumatic fever, so this treat- ment must be offered in all cases to be effective. Unlike prevention of recurrent episodes, which is virtually complete using secondary prophylaxis, penicillin treatment of streptococcal pharyngitis will at best prevent only the one-​third or so of cases of acute rheumatic fever that follow a sore throat. However, this important intervention may also arrest the spread of pathogenic group A streptococci in the community. Penicillin treatment of group A streptococcal pharyn- gitis should begin as early as possible in patients with a history of acute rheumatic fever, should they not be taking secondary prophy- laxis, but even then may not prevent a recurrence, hence the need for secondary prophylaxis. In recent years, the use of primary prophylaxis has been ques- tioned in some industrialized countries where acute rheumatic fever is now rare. It is argued that the strategy prevents few cases of acute rheumatic fever but contributes to overuse of antibiotics. Similar arguments were raised in the United States of America during the 1970s, but faded somewhat with the resurgence of acute rheumatic fever in that country during the 1980s. Any country considering abandoning primary prophylaxis should first have in place effective surveillance to detect changes in the epidemiology of primary group A  streptococcal infections and the appearance of cases of acute rheumatic fever. Primary prophylaxis is unsuccessful in most developing coun- tries. It requires trained health workers, microbiology laboratories, transportation, and communication infrastructure, the availability of penicillin, and a population likely to seek and adhere to treat- ment for sore throats. Approaches based on diagnosis using clinical algorithms, or an approach of treating all sore throats with intra- muscular benzathine benzylpenicillin without further attempts at diagnosis, are being increasingly recommended in resource-​poor settings. If primary prophylaxis were to be instituted effectively in developing countries, there would be a substantial impact on acute rheumatic fever incidence, but it would not disappear because most cases do not follow a sore throat. Other methods of primary prevention are clearly needed in developing countries. Improved living standards, particularly less-​crowded housing, and access to primary healthcare, are pri- orities. Although streptococcal skin infections may be linked to acute rheumatic fever pathogenesis, there are no trials of impetigo control programmes to prevent acute rheumatic fever. There is a current focus on attempts to develop a group A streptococcal vac- cine. Clinical trials of prospective vaccines have begun, but the pro- cess will take many years, and recent experience suggests that new vaccines are often beyond the financial reach of most developing countries. For the foreseeable future at least, acute rheumatic fever prevention in many developing countries will depend on improving adherence to secondary prophylaxis and developing new strategies for primary prevention. FURTHER READING Anonymous (1995). Strategy for controlling rheumatic fever/​rheum- atic heart disease, with emphasis on primary prevention: memo- randum from a joint WHO/​ISFC meeting. Bull World Health Org, 73, 583–​7. Bisno AL (1991). Group A streptococcal infections and acute rheum- atic fever. 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