13 - PART 6 Disorders of the Cardiovascular System

01 - SECTION 1 Introduction to Cardiovascular Disorders

SECTION 1 Introduction to Cardiovascular Disorders

Disorders of the Cardiovascular System PART 6 Section 1 Introduction to Cardiovascular Disorders Joseph Loscalzo

Approach to the

Patient with Possible Cardiovascular Disease ■ ■THE MAGNITUDE OF THE PROBLEM Cardiovascular diseases comprise the most prevalent serious disor­ ders in industrialized nations and are a rapidly increasing problem in developing nations (Chap. 245). Age-adjusted death rates for coronary heart disease have declined by two-thirds in the past four decades in the United States, reflecting the identification and reduction of risk factors as well as improved treatments and interventions for the management of coronary artery disease, arrhythmias, and heart failure. Nonetheless, car­ diovascular diseases remain the most common causes of death, respon­ sible for nearly 700,000 deaths each year. Approximately one-third of these deaths are sudden. In addition, cardiovascular diseases are highly prevalent, diagnosed in nearly half of the adult population. The growing prevalence of obesity (Chap. 414), type 2 diabetes mellitus (Chap. 415), and metabolic syndrome (Chap. 420), which are important risk factors for atherosclerosis, now threatens to reverse the progress that has been made in the age-adjusted reduction in the mortality rate of coronary heart disease. Globally, the impact of cardiovascular diseases is steadily mounting, with an estimated 19 million deaths worldwide. For many years, cardiovascular disease was considered to be more common in men than in women. In fact, cardiovascular disease is the leading cause of all deaths among women and men (Chap. 410). In addition, although the absolute number of deaths secondary to cardio­ vascular disease has declined over the past decades in men, this num­ ber has actually risen in women. Inflammation, obesity, type 2 diabetes mellitus, and the metabolic syndrome appear to play more prominent roles in the development of coronary atherosclerosis in women than in men. Coronary artery disease (CAD) is more frequently associated with dysfunction of the coronary microcirculation in women than in men. Exercise electrocardiography has a lower diagnostic accuracy in the prediction of epicardial obstruction in women than in men. ■ ■NATURAL HISTORY Cardiovascular disorders often present acutely, as in a previously asymp­ tomatic person who develops an acute myocardial infarction (Chap. 286), or a previously asymptomatic patient with hypertrophic cardiomyopathy (Chaps. 266–270) or with a prolonged QT interval (Chap. 259) whose first clinical manifestation is syncope or even sudden death. However, the alert physician may recognize the patient at risk for these complications long before they occur and often can take measures to prevent them. For example, a patient with acute myocardial infarction will often have had risk factors for atherosclerosis for many years. Had these risk factors been recognized, their elimination or reduction might have delayed or even prevented the infarction. Similarly, a patient with hypertrophic cardio­ myopathy may have had a heart murmur for years and a family history of this disorder. These findings could have led to an echocardiographic examination, recognition of the condition, and appropriate therapy long before the occurrence of a serious acute manifestation. Patients with valvular heart disease or idiopathic dilated cardiomy­ opathy, by contrast, may have a prolonged course of gradually increas­ ing dyspnea and other manifestations of chronic heart failure that is punctuated by episodes of acute deterioration only late in the course of

the disease. Understanding the natural history of various cardiac dis­ orders is essential for applying appropriate diagnostic and therapeutic measures to each stage of the condition, as well as for providing the patient and family with the likely prognosis. ■ ■CARDIAC SYMPTOMS The symptoms caused by heart disease result most commonly from myocardial ischemia, disturbance of the contraction and/or relaxation of the myocardium, obstruction to blood flow, or an abnormal cardiac rhythm or rate. Ischemia, which is caused by an imbalance between the heart’s oxygen supply and demand, is manifest most frequently as chest discomfort (Chap. 15), whereas reduction of the pumping ability of the heart commonly leads to fatigue and elevated intravascular pressure upstream of the failing ventricle. The latter results in abnormal fluid accumulation, with peripheral edema (Chap. 43) or pulmonary con­ gestion and dyspnea (Chap. 39). Obstruction to blood flow, as occurs in valvular stenosis, can cause symptoms resembling those of myocar­ dial failure (Chap. 264). Cardiac arrhythmias often develop suddenly, and the resulting symptoms and signs—palpitations (Chap. 45), dys­ pnea, hypotension, and syncope (Chap. 23)—generally occur abruptly and may disappear as rapidly as they develop. Although dyspnea, chest discomfort, edema, and syncope are cardinal manifestations of cardiac disease, they occur in other conditions, as well. Thus, dyspnea is observed in disorders as diverse as pulmonary disease, marked obesity, and anxiety (Chap. 39). Similarly, chest discomfort may result from a variety of noncardiac and cardiac causes other than myo­ cardial ischemia (Chap. 15). Edema, an important finding in untreated or inadequately treated heart failure, also may occur with primary renal disease and in hepatic cirrhosis (Chap. 43). Syncope occurs not only with serious cardiac arrhythmias but in a number of neurologic condi­ tions as well (Chap. 23). Whether heart disease is responsible for these symptoms frequently can be determined by carrying out a careful clinical examination (Chap. 246), supplemented by noninvasive testing using electrocardiography at rest and during exercise (Chap. 247), echocar­ diography, and cardiopulmonary imaging (Chap. 248). Myocardial or coronary function that may be adequate at rest may be insufficient during exertion. Thus, dyspnea and/or chest discom­ fort that appear during activity are characteristic of patients with heart disease, whereas the opposite pattern, that is, the appearance of these symptoms at rest and their remission during exertion, is rarely observed in such patients. It is important, therefore, to question the patient carefully about the relation of symptoms to exertion. Many patients with cardiovascular disease may be asymptomatic both at rest and during exertion but may present with an abnormal physical finding such as a heart murmur, elevated arterial pressure, or an abnormality of the electrocardiogram (ECG) or imaging test. It is important to assess the global risk of CAD in asymptomatic indi­ viduals, using a combination of clinical assessment and measurement of cholesterol and its fractions, as well as other biomarkers, such as C-reactive protein, in some patients. Since the first clinical manifesta­ tion of CAD may be catastrophic—sudden cardiac death, acute myo­ cardial infarction, or stroke in previous asymptomatic persons—it is mandatory to identify those at high risk for such events and institute further testing and preventive measures. ■ ■DIAGNOSIS As outlined by the New York Heart Association (NYHA), the elements of a complete cardiac diagnosis include the systematic consideration of the following:

  1. The underlying etiology. Is the disease congenital, hypertensive, isch­ emic, or inflammatory in origin?
  2. The anatomic abnormalities. Which chambers are involved? Are they hypertrophied, dilated, or both? Which valves are affected? Are they regurgitant and/or stenotic? Is there pericardial involvement? Has there been a myocardial infarction?

03 - 244 Basic Biology of the Cardiovascular System

244 Basic Biology of the Cardiovascular System

By contrast, two-dimensional and Doppler echocardiography (Chap. 248) are indicated in patients with loud systolic murmurs (grades ≥III/ VI), especially those that are holosystolic or late systolic, and in most patients with diastolic or continuous murmurs. ■ ■PITFALLS IN CARDIOVASCULAR MEDICINE Increasing subspecialization in internal medicine and the perfection of advanced diagnostic techniques in cardiology can lead to several undesirable consequences. Examples include the following:

  1. Failure by the noncardiologist to recognize important cardiac mani­ festations of systemic illnesses. For example, the presence of mitral stenosis, patent foramen ovale, and/or transient atrial arrhythmia should be considered in a patient with stroke, or the presence of pulmonary hypertension and cor pulmonale should be considered in a patient with scleroderma or Raynaud’s syndrome. A cardiovas­ cular examination should be carried out to identify and estimate the severity of the cardiovascular involvement that accompanies many noncardiac disorders.
  2. Failure by the cardiologist to recognize underlying systemic disor­ ders in patients with heart disease. For example, hyperthyroidism should be considered in an elderly patient with atrial fibrillation and unexplained heart failure, and Lyme disease should be considered in a patient with unexplained (fluctuating) atrioventricular block. A cardiovascular abnormality may provide the clue critical to the rec­ ognition of some systemic disorders. For example, an unexplained pericardial effusion may provide an early clue to the diagnosis of tuberculosis or a neoplasm.
  3. Overreliance on and overutilization of laboratory tests, particularly invasive techniques, for the evaluation of the cardiovascular sys­ tem. Cardiac catheterization and coronary arteriography (Chap. 249) provide precise diagnostic information that may be crucial in developing a therapeutic plan in patients with known or suspected CAD. Although a great deal of attention has been directed to these examinations, it is important to recognize that they serve to supple­ ment, not supplant, a careful examination carried out with clinical and noninvasive techniques. A coronary arteriogram should not be performed in lieu of a careful history in patients with chest pain sus­ pected of having ischemic heart disease. Although coronary arteri­ ography may establish whether the coronary arteries are obstructed and to what extent, the results of the procedure by themselves often do not provide a definitive answer to the question of whether a patient’s symptom of chest discomfort is attributable to coronary atherosclerosis and whether or not revascularization is indicated. Despite the value of invasive tests in certain circumstances, they entail some small risk to the patient, involve discomfort and substantial cost, and place a strain on medical facilities. Therefore, they should be carried out only if the results can be expected to modify the patient’s management. ■ ■DISEASE PREVENTION AND MANAGEMENT The prevention of heart disease, especially of CAD, is one of the most important tasks of primary health care givers as well as cardiologists. Prevention begins with risk assessment, followed by attention to life­ style, such as achieving optimal weight, physical activity, and smoking cessation, and then aggressive treatment of all abnormal risk factors, such as hypertension, hyperlipidemia, and diabetes mellitus (Chap. 415). After a complete diagnosis has been established in patients with known heart disease, a number of management options are usually available. Several examples may be used to demonstrate some of the principles of cardiovascular therapeutics:
  4. In the absence of evidence of heart disease, the patient should be clearly informed of this assessment and not be asked to return at intervals for repeated examinations. If there is no evidence of dis­ ease, such continued attention may lead to the patient’s developing inappropriate concern about the possibility of heart disease.
  5. If there is no evidence of cardiovascular disease but the patient has one or more risk factors for the development of ischemic heart

disease (Chap. 284), a plan for their reduction should be developed and the patient should be retested at intervals to assess compliance and efficacy in risk reduction. 3. Asymptomatic or mildly symptomatic patients with valvular heart

disease that is anatomically severe should be evaluated periodically, every 6–12 months, by clinical and noninvasive examinations. Early signs of deterioration of ventricular function may signify the need for surgical treatment before the development of disabling symp­ toms, irreversible myocardial damage, and excessive surgical risk (Chap. 272). 4. In patients with CAD (Chap. 284), available practice guidelines CHAPTER 244 Basic Biology of the Cardiovascular System should be considered in the decision on the form of treatment (medical, percutaneous coronary intervention, or surgical revas­ cularization). Mechanical revascularization may be employed too frequently in the United States and too infrequently in Eastern Europe and developing nations. The mere presence of angina pectoris and/or the demonstration of critical coronary arterial nar­ rowing at angiography should not reflexively evoke a decision to treat the patient by revascularization. Instead, these interventions should be limited to patients with CAD in whom revasculariza­ tion has been shown to improve the natural history (e.g., acute coronary syndrome or multivessel CAD with left ventricular dysfunction). ■ ■FURTHER READING Tsao CW et al: Heart disease and stroke statistics—2023 update: A report from the American Heart Association. Circulation 147:e93, 2023. Joseph Loscalzo, John F. Keaney, Jr.,

Calum A. MacRae

Basic Biology of the Cardiovascular System DEVELOPMENTAL BIOLOGY OF THE CARDIOVASCULAR SYSTEM The heart forms early during embryogenesis (Fig. 244-1), circulating blood, nutrients, molecular signals, and oxygen to the other developing organs while continuing to grow and undergo complex morphoge­ netic changes. Early cardiac progenitors arise within crescent-shaped fields of lateral splanchnic mesoderm under the influence of mul­ tiple cues and migrate to the midline to form the linear heart tube: a single layer of endocardium and a single layer of spontaneously beating cardiomyocytes. The simple linear heart tube undergoes chamber specification and asymmetric looping, coordinated with longitudinal and concentric growth of different regions of the heart tube, to produce the presump­ tive atria and ventricles. Cells continue to migrate into the heart at both ends from additional heart fields in pharyngeal mesoderm as looping and growth occur. These cells exhibit distinctive gene expression (e.g., Islet-1) and distinctive physiology (e.g., calcium handling), contribut­ ing to discrete areas of the adult heart, including the right atrium and the right ventricle. These different embryonic origins of cells within the right and left ventricles correlate with distinctive single-cell RNA sequencing profiles decades later and help explain why some forms of congenital and adult cardiac diseases affect different regions of the heart. After looping and chamber formation, a series of morphogenetic events divide the left side from the right side of the heart, separate the

Neural folds Early heart-forming regions Pericardial coelom Foregut Forming heart PART 6 Disorders of the Cardiovascular System A B First heart field Second heart field LV RV C D E F FIGURE 244-1  A. Schematic depiction of a transverse section through an early embryo depicts the bilateral regions where early heart tubes form. B. The bilateral heart tubes subsequently migrate to the midline and fuse to form the linear heart tube. C. At the early cardiac crescent stage of embryonic development, cardiac precursors include a primary heart field fated to form the linear heart tube and a second heart field fated to add myocardium to the inflow and outflow poles of the heart. D. Second heart field cells populate the pharyngeal region before subsequently migrating to the maturing heart. E. Large portions of the right ventricle and outflow tract and some cells within the atria derive from the second heart field. F. The aortic arch arteries form as symmetric sets of vessels that then remodel under the influence of the neural crest to form the asymmetric mature vasculature. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. atria from the ventricles, and fashion the aorta and pulmonary artery from the truncus arteriosus. Cardiac valves form between the atria and the ventricles and between the ventricles and the outflow vessels. Early in development, myocardial cells secrete an extracellular matrix rich in hyaluronic acid, or “cardiac jelly,” which accumulates within the endocardial cushions, precursors of the valves. Signals from overlying myocardial cells trigger migration, invasion, and phenotypic changes in underlying endocardial cells, an epithelial-mesenchymal transfor­ mation, that then invade and populate the endocardial cushion matrix. Mesenchymal cells then proliferate and form the mature valve leaflets. The great vessels form as a series of symmetric bilateral aortic arch arteries that remodel asymmetrically to define the mature central vasculature. Migrating neural crest cells from the dorsal neural tube orchestrate this process and are necessary for aortic arch remodeling and septation of the truncus arteriosus. Smooth-muscle cells within the tunica media of the aortic arch, the ductus arteriosus, and the carotid arteries all derive from neural crest. By contrast, smooth muscle within the descending aorta arises from lateral plate mesoderm, and smooth muscle of the proximal outflow tract arises from the second heart field. Neural crest cells are sensitive to both vitamin A and folic acid, and congenital heart diseases involving abnormal remodeling of the aortic arch arteries are observed with maternal deficiencies of these vitamins. Shared embryonic origins of different cardiovascular cell types lead to

syndromic associations between various congenital heart diseases and a range of extracardiac abnormalities. Coronary artery formation requires the addition of yet another cell popula­ tion to the embryonic heart. Epicardial cells arise in the proepicardial organ, a derivative of the septum transversum, which also contributes to the fibrous portion of the diaphragm and to the liver. Proepicardial cells contribute smooth muscle to the coronary arteries and are required for proper coronary patterning. Other cell types within the heart (e.g., fibroblasts) also can arise from the proepicardium. The cardiac conduction system, which generates and propagates electri­ cal impulses, differentiates from car­ diomyocyte precursors. The conduction system is composed of slow-conducting (proximal) components, such as the sinoatrial (SA) and atrioventricular (AV) nodes, as well as fast-conducting (distal) components, including the His bundle, bundle branches, and Purkinje fibers. Precursors within the sinus venosus give rise to the SA node, whereas those within the AV canal mature into hetero­ geneous cell types that compose the AV node. Decremental conduction through the AV node delays electrical impulses between atria and ventricles, enabling sequential antegrade contraction. The AV node also reduces the transmission of higher impulse rates to the vulner­ able ventricle, whereas the distal con­ duction system rapidly propagates each impulse throughout the ventricles. The conduction system is composed of com­ plex and heterogeneous cell populations with distinct gap junction proteins and ion channels that define the particular local electrical properties. Developmen­ tal defects in the conduction system can lead to clinical electrophysiologic disorders, such as congenital heart block or pre-excitation (WolffParkinson-White syndrome) (Chap. 256). RA LA RV LV ■ ■ORIGIN OF VASCULAR CELLS Smooth-muscle cells are of varied origin. Some upper-body arterial smooth-muscle cells derive from the neural crest, whereas lower-body arteries develop smooth-muscle cells from neighboring mesodermal structures. Embryonic endothelial progenitor cells are derived from mesoderm. In adults, resident vascular or bone marrow–derived endothelial progenitors may aid repair of damaged or aging arteries. Bone marrow clonality, increasingly prevalent in aging, may impart significant clonality to endothelial cell populations. Vascular stem cells resident in the vessel wall may give rise to some smooth-muscle cells in injured or atheromatous arteries. THE BLOOD VESSEL ■ ■VASCULAR ULTRASTRUCTURE Blood vessels participate in disease biology as well as physiologic function in virtually every organ system. The smallest blood vessels— capillaries—consist of a monolayer of endothelial cells on a basement membrane adjacent to a discontinuous layer of smooth-musclelike cells known as pericytes (Fig. 244-2A). Arteries typically have

A. Capillary B. Vein C. Small muscular artery Pericyte Endothelial cell D. Large muscular artery Internal elastic lamina External elastic lamina Adventitia FIGURE 244-2  Schematics of the structures of various types of blood vessels. A. Capillaries consist of an endothelial tube in contact with a discontinuous population of pericytes. B. Veins typically have thin medias and thicker adventitias. C. A small muscular artery features a prominent tunica media. D. Larger muscular arteries have a prominent media with smooth-muscle cells embedded in a complex extracellular matrix. E. Larger elastic arteries have cylindrical layers of elastic tissue alternating with concentric rings of smooth-muscle cells as well as vasa vasorum to facilitate tissue blood supply. a trilaminar structure (Fig. 244-2B–E). The intima consists of a monolayer of endothelial cells continuous with those of the capil­ laries. The middle layer, or tunica media, consists of a syncytium of smooth-muscle cells that in veins are much sparser than in arteries (Fig. 244-2B). The outer layer, or adventitia, consists of extracellular matrix with fibroblasts, mast cells, and nerve terminals. Larger arteries require nourishment of the tunica media that is accomplished via their own vasculature, the vasa vasorum (Fig. 244-2E). Arterioles are small muscular arteries (Fig. 244-2C) that regulate blood pressure and flow through arterial beds. Medium-size muscular arteries also contain prominent smooth-muscle layers (Fig. 244-2D) that participate in atherogenesis. Larger elastic arteries have a highly structured tunica media with concentric bands of smooth-muscle cells, interspersed with strata of elastin-rich extracellular matrix (Fig. 244-2E). Larger arteries form an internal elastic lamina between intima and media while an external elastic lamina partitions the media from sur­ rounding adventitia. ■ ■VASCULAR CELL BIOLOGY Endothelial Cell  The endothelium forms the interface between tissues and the blood compartment, regulating the passage of mol­ ecules and cells. This function of endothelial cells as a selectively permeable barrier fails in vascular diseases, including atherosclerosis, hypertension, and renal disease, as well as in pulmonary edema, sepsis, and other situations exhibiting “capillary leak.” The endothelium also participates in the local regulation of vascular tone and blood flow. Endogenous endothelium-derived substances, such as prostacyclin, endothelium-derived hyperpolarizing factor, nitric oxide (NO), and hydrogen peroxide (H2O2), provide tonic stimu­ lation of endothelial homeostatic properties under physiologic condi­ tions in vivo (Table 244-1). Impaired production or excess catabolism of these substances can mediate dysfunctional properties of the endo­ thelium. A major homeostatic influence on the endothelium is laminar blood flow, and the measurement of flow-mediated dilatation directly assesses endothelial vasodilator function in humans (Fig. 244-3).

Endothelial cells also produce potent vasoconstrictor substances such as endothelin. Excessive production of reactive oxygen species, such as super­ oxide anion (O2

CHAPTER 244 –), by endothelial or smooth-muscle cells under pathologic conditions (e.g., excessive exposure to angiotensin II) can promote local oxi­ dative stress and inactivate NO. Vascular smooth-muscle cell Endothelial cells also regulate cel­ lular traffic through tissues. Normal endothelium exhibits limited interac­ tion with circulating leukocytes, but bacterial products such as endotoxin or proinflammatory cytokines can induce endothelial cells to express an array of adhesion molecules that selectively bind various classes of leukocytes in different pathologic conditions. The adhesion molecules and chemokines generated during acute bacterial infec­ tion tend to recruit granulocytes, while in chronic inflammatory diseases such as tuberculosis or atherosclerosis, the adhesion molecules expressed favor monocyte recruitment. Endothelial cell injury participates in the patho­ physiology of many immune-mediated diseases. For example, complementmediated lysis of endothelial cells con­ tributes to tissue injury. The foreign histocompatibility complex antigens on endothelial cells in solid-organ allografts can promote allograft arte­ riopathy, while immune-mediated endothelial injury also plays a role in thrombotic thrombocytopenic purpura or hemolytic-uremic syndrome. Basic Biology of the Cardiovascular System E. Large elastic artery The endothelium also regulates the balance between thrombosis and hemostasis through a highly tuned set of regulatory pathways. For example, inflammatory cytokines, bacterial endotoxin, or angiotensin II can activate endothelial cells to produce substantial quantities of plasminogen activator inhibitor 1 (PAI-1), the major inhibitor of fibri­ nolysis. Inflammatory stimuli also induce endothelial expression of the potent procoagulant tissue factor, a contributor to disseminated intra­ vascular coagulation in sepsis; similar effects are observed in hyper­ glycemia. Thus, in pathologic circumstances, endothelial dysfunction tends to promote local thrombus accumulation rather than combat it. Endothelial cells regulate the growth of subjacent smooth-muscle cells by elaborating heparan sulfate glycosaminoglycans that inhibit smooth-muscle proliferation. In the setting of vascular injury, endo­ thelium-derived growth factors and chemoattractants (e.g., plateletderived growth factor) induce the migration and proliferation of vascular smooth-muscle cells. Dysregulation of these growth-stimula­ tory molecules may promote smooth-muscle accumulation in athero­ sclerotic lesions. TABLE 244-1  Endothelial Functions in Health and Disease HOMEOSTATIC PROPERTIES DYSFUNCTIONAL PROPERTIES Optimize balance between vasodilation and vasoconstriction Impaired dilation, vasoconstriction Antithrombotic, profibrinolytic Prothrombotic, antifibrinolytic Anti-inflammatory Proinflammatory Antiproliferative Proproliferative Antioxidant Prooxidant Selective permeability Impaired barrier function

PART 6 Disorders of the Cardiovascular System FIGURE 244-3  Assessment of endothelial function in vivo using blood pressure cuff occlusion and release. Upon deflation of the cuff, an ultrasound probe monitors changes in diameter (A) and blood flow (B) of the brachial artery (C). (Reproduced with permission of J. Vita, MD.) Vascular Smooth-Muscle Cell  Contraction and relaxation of vascular smooth-muscle cells in muscular arteries determine blood pressure, regional flow, and the afterload experienced by the left ven­ tricle (see below). Venous tone regulates venous tree capacitance and influences ventricular preload. Smooth-muscle cells in the adult vessel seldom replicate in the absence of arterial injury or inflammatory acti­ vation, but proliferation and migration of arterial smooth-muscle cells contribute to arterial stenoses in atherosclerosis, arteriolar remodeling in hypertension, and the hyperplastic response of arteries to injury. In the pulmonary circulation, smooth-muscle migration and prolifera­ tion underlie the vascular pathology that occurs in sustained high-flow

states such as left-to-right shunts in congenital heart disease with resulting pulmonary hypertension. Smooth-muscle cells secrete the bulk of vascular extracellular matrix. Excessive production of collagen and glycosaminoglycans contributes to the remodeling, altered biomechanics, and physiology of arteries affected by hypertension or atherosclerosis. In larger elastic arteries, such as the aorta, the ability to store the kinetic energy of systole promotes tissue perfusion during diastole. Arterial stiffness, associated with aging or disease, increases left ventricular afterload and portends a poor outcome. Like endothelial cells, vascular smooth-muscle cells not only respond to paracrine stimuli from other cells but can themselves serve as a source of such stimuli. For example, proinflammatory stimuli induce smooth-muscle cells to elaborate cytokines and other mediators that drive thrombosis and fibrinolysis as well as proliferation. Vascular Smooth-Muscle Cell Contraction  The principal mechanism for vascular smooth-muscle cell contraction is increased cytoplasmic calcium concentration due to transmembrane influx and triggered release from intracellular calcium stores (Fig. 244-4). In vas­ cular smooth-muscle cells, voltage-dependent L-type calcium channels open with membrane depolarization. Local influx of calcium, termed calcium sparks, can trigger release from intracellular stores, which results in more contraction and increased vessel tone (see below). Opposing currents balance the effects of individual ionic fluxes pro­ moting homeostasis, which is tightly regulated by neural and metabolic influences. Vasoconstricting agonists also increase intracellular [Ca2+] by vari­ ous mechanisms including receptor-dependent phospholipase C acti­ vation producing hydrolysis of phosphatidylinositol 4,5-bisphosphate to generate diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). These membrane lipid derivatives, in turn, activate protein kinase C and increase intracellular [Ca2+]. In addition, IP3 binds specific sarco­ plasmic reticulum (SR) receptors to increase calcium efflux from this storage pool into the cytoplasm. Vascular smooth-muscle cell contraction depends on myosin light chain phosphorylation that reflects the balance between the activity of relevant kinases and phosphatases. Calcium activates myosin light chain kinase via calmodulin, augmenting myosin ATPase activity and enhancing contraction. Conversely, myosin light chain phosphatase reduces myosin ATPase activity and contractile force. Other kinase/ phosphorylase combinations result in a complex regulatory network that refines vascular tone and links it to physiologic requirements. Control of Vascular Smooth-Muscle Cell Tone  The auto­ nomic nervous system and endothelial cells modulate vascular smoothmuscle cells through similar convergent pathways. Autonomic neurons enter vessel media and modulate vascular smooth-muscle cell tone in response to baroreceptors and chemoreceptors within the aortic arch or carotid bodies and to thermoreceptors in the skin. Rapidly acting reflex arcs modulated by central inputs respond to multiple sensory inputs as well as emotional stimuli through three neuronal classes: sympathetic, whose principal neurotransmitters are epinephrine and norepinephrine; parasympathetic, whose principal neurotransmit­ ter is acetylcholine; and nonadrenergic/noncholinergic, which include two subgroups—nitrergic, whose principal neurotransmitter is NO, and peptidergic, whose principal neurotransmitters are substance P, vasoactive intestinal peptide, calcitonin gene-related peptide, and the nonpeptide, adenosine triphosphate (ATP). Each of these neurotransmitters acts through specific receptors on the vascular smooth-muscle cell to modulate intracellular Ca2+ and, consequently, contractile tone. Norepinephrine activates α-adrenergic receptors, and epinephrine activates both α and β receptors. In most blood vessels, norepinephrine activates postjunctional α1 receptors in large arteries and α2 receptors in small arteries and arterioles, lead­ ing to vasoconstriction. Most blood vessels express β2-adrenergic receptors on their vascular smooth-muscle cells and respond to β agonists by cyclic AMP–dependent relaxation. Acetylcholine released from parasympathetic neurons may bind to muscarinic receptors on either vascular smooth-muscle cells, causing vasoconstriction, or on

Ca2+ NE, ET-1, Ang II VDCC PIP2 G G PLC RhoA Ca2+ “Spark” cAMP DAG IP3R RyrR Plb ATPase IP3 PKC Rho Kinase Caldesmon Calponin FIGURE 244-4  Regulation of vascular smooth-muscle cell calcium concentration and actomyosin ATPase-dependent contraction. AC, adenylyl cyclase; Ang II, angiotensin II; ANP, atrial natriuretic peptide; DAG, diacylglycerol; ET-1, endothelin-1; G, G protein; IP3, inositol 1,4,5-trisphosphate; MLCK, myosin light chain kinase; MLCP, myosin light chain phosphatase; NE, norepinephrine; NO, nitric oxide; pGC, particular guanylyl cyclase; PIP2, phosphatidylinositol 4,5-bisphosphate; PKA, protein kinase A; PKC, protein kinase C; PKG, protein kinase G; PLC, phospholipase C; sGC, soluble guanylyl cyclase; SR, sarcoplasmic reticulum; VDCC, voltage-dependent calcium channel. Solid lines depict stimulatory interaction, and dashed lines represent inhibition. (Reproduced with permission from B Berk, in Vascular Medicine, 3rd ed. Philadelphia, Saunders, Elsevier; 2006.) endothelial cells, causing NO-dependent vasorelaxation. Nitrergic neurons release NO, which relaxes vascular smooth-muscle cell via the cyclic GMP–dependent and –independent mechanisms outlined, and other peptidergic inputs that regulate vascular tone. For the detailed molecular physiology of the autonomic nervous system, see Chap. 451. The release of endothelial effectors of vascular smooth-muscle cell tone integrates the smooth-muscle response to mechanical (e.g., shear stress, cyclic strain) and biochemical stimuli (purinergic agonists, muscarinic agonists, peptidergic agonists). In addition to these local paracrine modulators, a complex system of circulating modulators ranging from norepinephrine to the natriuretic peptides also modify vascular smooth-muscle cell tone. ■ ■ARTERIOGENESIS AND ANGIOGENESIS Recruitment and growth of blood vessels (arteriogenesis) and new capillaries (angiogenesis) can occur in response to conditions such as chronic hypoxemia and tissue ischemia. Growth factors, including vascular endothelial growth factor (VEGF) and fibroblast growth fac­ tor (FGF), can activate a signaling cascade that stimulates endothelial proliferation and tube formation, defined as angiogenesis. Guidance molecules, including members of the semaphorin family of secreted peptides, direct blood vessel patterning by attracting or repelling nascent endothelial tubes. The recruitment and expansion of preexist­ ing collateral vascular networks in response to a blocked artery, an example of arteriogenesis, can result from selective activation of both growth factors and, perhaps, local or circulating endothelial progenitor cells. True vascular regeneration, or the development of a new blood vessel that includes all three cell layers, normally does not occur in adult mammals, but recent scientific advances might help obviate such limitations.

BetaAgonist ANP NO CHAPTER 244 K+ Ch Na-K ATPase pGC AC GTP ATP sGC SR Basic Biology of the Cardiovascular System cGMP PKG PKA Calcium MLCK MLCP CELLULAR BASIS OF CARDIAC CONTRACTION ■ ■CARDIAC ULTRASTRUCTURE Most of the ventricular mass is composed of cardiomyocytes, normally 60–140 μm in length and 17–25 μm in diameter (Fig. 244-5A). Each cell contains multiple myofibrils that run the length of the cell and are com­ posed of series of repeating sarcomeres. The cytoplasm between the myo­ fibrils contains other cell constituents, including a single centrally located nucleus, mitochondria, and the intracellular membrane system, the SR. The sarcomere, the structural and functional unit of contraction, lies between adjacent Z lines, which on transmission electron microscopy are seen as dark repeating bands. The distance between Z lines var­ ies with the degree of contraction or stretch of the muscle and ranges between 1.6 and 2.2 μm. At the center of the sarcomere is a dark band of constant length (1.5 μm), the A band, which is flanked by two lighter bands, the I bands, which are of variable length. The sarcomere of heart muscle, like that of skeletal muscle, consists of interdigitating thick and thin myofilaments. Thicker filaments, composed principally of the protein myosin, traverse the A band; they are about 10 nm (100 Å) in diameter, with tapered ends. Thinner filaments, composed primarily of actin, course from the Z lines through the I band into the A band; they are ~5 nm (50 Å) in diameter and 1.0 μm in length. Thus, thick and thin filaments overlap only within the (dark) A band, whereas the (light) I band contains only thin filaments. On electron-microscopic examina­ tion, bridges extend between the thick and thin filaments within the A band; these are myosin heads (see below) bound to actin filaments. ■ ■THE CONTRACTILE PROCESS The sliding filament model for muscle contraction rests on the central observation that both the thick and the thin filaments are constant in

Myofiber PART 6 Disorders of the Cardiovascular System A Na+ Exchange Ca2+ Pump Myofibril e t y c o y M Myofibril Mitochondrion B Myofibril C Diastole Actin Myosin Titin M Z D FIGURE 244-5  A shows the branching myocytes making up the cardiac myofibers. B illustrates the critical role played by the changing [Ca2+] in the myocardial cytosol. Ca2+ ions are schematically shown as entering through the calcium channel that opens in response to the wave of depolarization that travels along the sarcolemma. These Ca2+ ions “trigger” the release of more calcium from the sarcoplasmic reticulum (SR) and thereby initiate a contraction-relaxation cycle. Eventually the small quantity of Ca2+ that has entered the cell leaves predominantly through an Na+/Ca2+ exchanger, with a lesser role for the sarcolemmal Ca2+ pump. The varying actin-myosin overlap is shown for (B) systole, when [Ca2+] is maximal, and (C) diastole, when [Ca2+] is minimal. D. The myosin heads, attached to the thick filaments, interact with the thin actin filaments. (Reproduced with permission from LH Opie: Heart Physiology: From Cell to Circulation, 4th ed. Philadelphia, Lippincott, Williams & Wilkins, 2004.) length during both contraction and relaxation. With activation, the actin filaments are propelled farther into the A band. In this process, the A band remains constant in length, whereas the I band shortens and the Z lines move toward one another. The myosin molecule is a complex, asymmetric protein with a molecular mass of about 500,000 Da; it has a rod-like portion that is about 150 nm (1500 Å) in length with a globular portion (head) at its end. The globular portions of myosin form the bridges to actin and are the site of ATPase activity. In thick myofilaments, composed of ~300 longitudinally stacked myosin molecules, the rod-like segments of myosin assume an orderly, polarized orientation, with outwardly projecting globular heads interacting with actin to generate force and shorten (Fig. 244-5B). Actin has a molecular mass of about 47,000 Da. Thin filaments consist of a double helix of two chains of actin molecules wound about each other on a larger molecule, tropomyosin. A group of regulatory proteins—troponins C, I, and T—localize at regular intervals on this filament (Fig. 244-6). In contrast to myosin, actin lacks intrinsic enzy­ matic activity but combines reversibly with myosin in the presence of

10 µm Myocyte Ca2+ enters T tubule Ca2+ “trigger” Ca2+ leaves Free Ca2+ SR Contract Relax Systole Z Head 43 nm ATP and Ca2+. Calcium activates the myosin ATPase, which breaks down ATP to supply the energy for contraction (Fig. 244-6). The activ­ ity of myosin ATPase determines the rate of actomyosin cross-bridge formation and breakdown, and ultimately determines contraction velocity. In relaxed muscle, tropomyosin inhibits this interaction. Titin (Fig. 244-5D) an enormous, flexible, myofibrillar protein, connects myosin to the Z line; its elasticity contributes to the passive mechani­ cal characteristics of the heart. Dystrophin, a cytoskeletal protein that binds to the dystroglycan complex at membrane adherens junctions, tethers the sarcomere to the cell membrane at these regions of tight coupling to adjacent myocytes. Mutations in multiple sarcomeric and cytoskeletal proteins cause different Mendelian disorders involving the heart and skeletal muscle and also sensitize individuals to toxic cardiomyopathies (e.g., due to alcohol or chemotherapy) and to those caused by other acquired stressors, such as inflammatory or peripar­ tum cardiomyopathy. During activation of the cardiac myocyte, Ca2+ binds the hetero­ trimer troponin C, resulting in regulatory conformational changes in tropomyosin and exposing actin cross-bridge interaction sites

ATP Relaxed, energized Relaxed Actin 2. 4. Dissociation of actin and myosin ATP Rigor complex Active complex FIGURE 244-6  Four steps in cardiac muscle contraction and relaxation. In relaxed muscle (upper left), ATP bound to the myosin cross-bridge dissociates the thick and thin filaments. Step 1: Hydrolysis of myosin-bound ATP by the ATPase site on the myosin head transfers the chemical energy of the nucleotide to the activated cross-bridge (upper right). When cytosolic Ca2+ concentration is low, as in relaxed muscle, the reaction cannot proceed because tropomyosin and the troponin complex on the thin filament do not allow the active sites on actin to interact with the cross-bridges. Therefore, even though the cross-bridges are energized, they cannot interact with actin. Step 2: When Ca2+ binding to troponin C has exposed active sites on the thin filament, actin interacts with the myosin cross-bridges to form an active complex (lower right) in which the energy derived from ATP is retained in the actin-bound cross-bridge, whose orientation has not yet shifted. Step 3: The muscle contracts when ADP dissociates from the cross-bridge. This step leads to the formation of the low-energy rigor complex (lower left) in which the chemical energy derived from ATP hydrolysis has been expended to perform mechanical work (the “rowing” motion of the cross-bridge). Step 4: The muscle returns to its resting state, and the cycle ends when a new molecule of ATP binds to the rigor complex and dissociates the cross-bridge from the thin filament. This cycle continues until calcium is dissociated from troponin C in the thin filament, which causes the contractile proteins to return to the resting state with the cross-bridge in the energized state. ADP, adenosine diphosphate; ATP, adenosine triphosphate; ATPase, adenosine triphosphatase. (Reproduced with permission from AM Katz: Heart failure: Cardiac function and dysfunction, in Atlas of Heart Diseases, 3rd ed, WS Colucci [ed]. Philadelphia, Current Medicine, 2002.) (Fig. 244-6). Repetitive interaction between myosin heads and actin filaments is termed cross-bridge cycling and results in sliding of the actin along the myosin filaments, with muscle shortening and/or the devel­ opment of tension. The splitting of ATP then dissociates the myosin cross-bridge from actin. In the presence of ATP (Fig. 244-6), actin and myosin filaments bind and dissociate cyclically if sufficient Ca2+ is pres­ ent; these processes cease when [Ca2+] falls below a critical level, and the troponin-tropomyosin complex once more inhibits actin-myosin interactions (Fig. 244-7). Cytoplasmic [Ca2+] is a principal determinant of the inotropic state of the heart. Most agents that stimulate myocardial contractility (posi­ tive inotropic stimuli), including digitalis glycosides and β-adrenergic agonists, increase cytoplasmic [Ca2+], triggering cross-bridge cycling. Increased adrenergic neuronal activity stimulates myocardial con­ tractility through norepinephrine release, activation of β-adrenergic receptors, and, via Gs-stimulated guanine nucleotide-binding proteins, activation of the adenylyl cyclase, which leads to the formation of the intracellular second messenger cyclic AMP from ATP (Fig. 244-7). Cyclic AMP in turn activates protein kinase A (PKA), which phos­ phorylates sarcolemmal Ca2+ channels, thereby enhancing the influx of Ca2+ into the myocyte. The SR (Fig. 244-8), a complex network of anastomosing intracel­ lular channels, invests the myofibrils. The transverse tubules, or T sys­ tem, closely related to the SR, both structurally and functionally, arise as sarcolemmal invaginations that extend into the myofibrillar bundles along the Z lines, i.e., the ends of the sarcomeres. ■ ■CARDIAC ACTIVATION In the inactive state, the cardiomyocyte membrane is electrically polarized; i.e., the interior has a negative charge relative to the outside of the cell, with a transmembrane potential of –80 to –100 mV (Chap. 250). The sarcolemma, which in the resting state is largely impermeable to Na+, and a Na+- and K+-pump energized by ATP extrudes Na+ from the cell and maintains the resting potential. In this resting state, intracellular [K+] is relatively high and [Na+] is far lower;

ADP Pi

  1. ATP hydrolysis CHAPTER 244 Actin Formation of active complex Basic Biology of the Cardiovascular System Pi ADP ADP

Product dissociation conversely, extracellular [Na+] is high and [K+] is low. At the same time, extracellular [Ca2+] greatly exceeds free intracellular [Ca2+]. The action potential has four phases (see Fig. 250-1B). Depolariz­ ing current spreads across the cell membrane, penetrating deeply into the cell via the T tubular system. During the action potential plateau (phase 2), there is a slow inward current through sarcolemmal L-type Ca2+ channels (Fig. 244-8). The absolute quantity of Ca2+ traversing sarcolemmal and T tubular membranes is modest and insufficient to fully activate contraction. However, this initial Ca2+ current, through Ca2+-induced Ca2+ release, triggers substantial Ca2+ release from the SR, inducing contraction. Ca2+ is released from the SR through a Ca2+ release channel, a cardiac isoform of the ryanodine receptor (RyR2). Several regulatory proteins inhibit RyR2 and thus SR Ca2+ release. Inherited disorders or exogenous factors affecting the efficiency or stability of SR Ca2+ han­ dling can impair contraction, leading to heart failure or to ventricular arrhythmias. The Ca2+ released from the SR diffuses to interact with myofi­ brillar troponin C (Fig. 244-7), repressing this protein’s inhibition of contraction, and so activating myofilaments to shorten. During repolarization, the activity of the SR Ca2+-ATPase (SERCA2A) leads to Ca2+ uptake against a concentration gradient into the SR where it complexes with another specialized protein, calsequestrin. The uptake of Ca2+ is ATP (energy)-dependent and lowers cytoplasmic [Ca2+] to a level where actomyosin interaction is inhibited and myocardial relaxation occurs. There is also a sarcolemmal exchange of Ca2+ for Na+ (Fig. 244-8), reducing cytoplasmic [Ca2+]. Additional control of calcium compartmentalization results from cyclic AMP–dependent PKA phosphorylation of the SR protein phospholamban, permit­ ting SERCA2A activation, increasing SR Ca2+ uptake, and so accelerating relaxation rates, and loading the SR with Ca2+ for subsequent cycles of release and contraction. Thus, the combination of the cell membrane, transverse tubules, and SR, transmitting the action potential, releasing and then re-accumulating Ca2+, controls the cyclic contraction and relaxation of heart muscle.

β - Adrenergic agonist PART 6 Disorders of the Cardiovascular System β γ αs Adenyl cyclase SL GTP β Receptor cAMP Via protein kinase A Metabolic • glycolysis • lipolysis • citrate cycle ADP + Pi + ATP Troponin C Myosin ATPase ADP + Pi Increased

  1. rate of contraction
  2. peak force
  3. rate of relaxation β Force FIGURE 244-7  Signal systems involved in positive inotropic and lusitropic (enhanced relaxation) effects of α-adrenergic stimulation. When the β-adrenergic agonist interacts with the β receptor, a series of G protein–mediated changes leads to activation of adenylyl cyclase and the formation of cyclic adenosine monophosphate (cAMP). The latter acts via protein kinase A to stimulate metabolism (left) and phosphorylate the Ca2+ channel protein (right). The result is an enhanced opening probability of the Ca2+ channel, thereby increasing the inward movement of Ca2+ ions through the sarcolemma (SL) of the T tubule. These Ca2+ ions release more calcium from the sarcoplasmic reticulum (SR) to increase cytosolic Ca2+ and activate troponin C. Ca2+ ions also increase the rate of breakdown of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) and inorganic phosphate (Pi). Enhanced myosin ATPase activity explains the increased rate of contraction, with increased activation of troponin C explaining increased peak force development. An increased rate of relaxation results from the ability of cAMP to activate as well the protein phospholamban, situated on the membrane of the SR, that controls the rate of uptake of calcium into the SR. The latter effect explains enhanced relaxation (lusitropic effect). P, phosphorylation; PL, phospholamban; TnI, troponin I. (Reproduced with permission from LH Opie: Heart Physiology: From Cell to Circulation, 4th ed. Philadelphia, Lippincott, Williams & Wilkins, 2004.) Genetic or pharmacologic alterations of any component can disturb any of the functions of this finely tuned system. CONTROL OF CARDIAC PERFORMANCE AND OUTPUT The extent of shortening of heart muscle and, therefore, ventricular stroke volume in the intact heart depends on three major influences: (1) the length of the muscle at the onset of contraction, i.e., the preload; (2) the tension that the muscle must develop during contraction, i.e., the afterload; and (3) muscle contractility, i.e., the extent and velocity of shortening at any given preload and afterload. Table 244-2 lists the major determinants of preload, afterload, and contractility. ■ ■THE ROLE OF MUSCLE LENGTH (PRELOAD) Preload determines sarcomere length at the onset of contraction. Contractile force is optimal at specific sarcomere lengths (~2.2 μm) where both myofilament Ca2+ sensitivity is maximal, and myofilament interactions and activation of contraction are most efficient. The rela­ tionship between initial muscle fiber length and the developed force is the basis of Starling’s law of the heart, which states that, within limits,

Ca2+ P Ca2+ + + SR + P Ca2+ + cAMP via Tnl +

cAMP via PL

Control Time Pattern of contraction the ventricular contraction force depends on the end-diastolic length of the cardiac muscle; in vivo, end-diastolic length relates closely to the ventricular end-diastolic volume. ■ ■CARDIAC PERFORMANCE Ventricular end-diastolic or “filling” pressure can serve as a surrogate for end-diastolic volume. In isolated heart and heart-lung prepara­ tions, stroke volume varies directly with the end-diastolic fiber length (preload) and inversely with the arterial resistance (afterload), and as the heart fails—i.e., as its contractility declines—it delivers a progressively smaller stroke volume from a normal or even elevated end-diastolic volume. The relation between ventricular end-diastolic pressure and the stroke work of the ventricle (the ventricular func­ tion curve) provides a working definition of cardiac contractility in the intact organism. An increase in contractility is accompanied by a shift of the ventricular function curve upward and to the left (greater stroke work at any level of ventricular end-diastolic pressure, or lower end-diastolic volume at any level of stroke work), whereas a shift downward and to the right characterizes reduction of contractility (Fig. 244-9).

Na+ pump Plasma membrane Ca2+ pump Na+/Ca2+ exchanger B2 B1 T tubule Cisterna Plasma membrane Ca2+ channel Ca2+- release channel ('foot' protein) A A1 Mitochondria Calsequestrin C E F Z-line Troponin C Thin filament Contractile proteins Thick filament FIGURE 244-8  The Ca2+ fluxes and key structures involved in cardiac excitation-contraction coupling. The arrows denote the direction of Ca2+ fluxes. The thickness of each arrow indicates the magnitude of the calcium flux. Two Ca2+ cycles regulate excitation-contraction coupling and relaxation. The larger cycle is entirely intracellular and involves Ca2+ fluxes into and out of the sarcoplasmic reticulum, as well as Ca2+ binding to and release from troponin C. The smaller extracellular Ca2+ cycle occurs when this cation moves into and out of the cell. The action potential opens plasma membrane Ca2+ channels to allow passive entry of Ca2+ into the cell from the extracellular fluid (arrow A). Only a small portion of the Ca2+ that enters the cell directly activates the contractile proteins (arrow A1). The extracellular cycle is completed when Ca2+ is actively transported back out to the extracellular fluid by way of two plasma membrane fluxes mediated by the sodium-calcium exchanger (arrow B1) and the plasma membrane calcium pump (arrow B2). In the intracellular Ca2+ cycle, passive Ca2+ release occurs through channels in the cisternae (arrow C) and initiates contraction; active Ca2+ uptake by the Ca2+ pump of the sarcotubular network (arrow D) relaxes the heart. Diffusion of Ca2+ within the sarcoplasmic reticulum (arrow G) returns this activator cation to the cisternae, where it is stored in a complex with calsequestrin and other calcium-binding proteins. Ca2+ released from the sarcoplasmic reticulum initiates systole when it binds to troponin C (arrow E). Lowering of cytosolic [Ca2+] by the sarcoplasmic reticulum (SR) causes this ion to dissociate from troponin (arrow F) and relaxes the heart. Ca2+ also may move between mitochondria and cytoplasm (H). (Reproduced with permission from AM Katz: Physiology of the Heart, 4th ed. Philadelphia, Lippincott, Williams & Wilkins, 2005.) ■ ■VENTRICULAR AFTERLOAD In the intact heart, as ex vivo, the extent and velocity of shortening of ventricular muscle fibers at any level of preload and of myocardial contractility relate inversely to the afterload, i.e., the instantaneous load opposing shortening. In the intact heart, the afterload may be defined as the tension developed in the ventricular wall during ejection. After­ load is determined by the aortic pressure as well as by the volume of the ventricular cavity and myocardial tissue characteristics including thickness. Laplace’s law models the tension of the myocardial fiber as the product of intra-cavitary ventricular pressure and ventricular radius divided by wall thickness. Therefore, at any given aortic pres­ sure, the afterload on a dilated left ventricle exceeds that on a normalsized ventricle. Conversely, at the same aortic pressure and ventricular diastolic volume, the afterload on a hypertrophied ventricle is lower than that on a normal chamber. Aortic pressure in turn depends on the peripheral vascular resistance, the biomechanics of the arterial tree, and the volume of blood it contains at the onset of ejection. Ventricular afterload finely regulates cardiovascular performance (Fig. 244-10). As noted, elevations in both preload and contractility increase myocardial fiber shortening, whereas increases in afterload reduce it. The extent of myocardial fiber shortening and left ventricular size determine stroke volume. An increase in arterial pressure induced by vasoconstriction, for example, augments afterload, which opposes myocardial fiber shortening, reducing stroke volume.

Plasma membrane Extracellular CHAPTER 244 Intracellular (cytosol) Sarcoplasmic reticulum Basic Biology of the Cardiovascular System Sarcotubular network G Sarcoplasmic reticulum Ca2+ pump D H When myocardial contractility is impaired and the ventricle dilates, afterload rises (Laplace’s law) and limits cardiac output. Increased afterload also may result from neural and humoral stimuli that occur in response to a fall in cardiac output. This increased afterload may reduce cardiac output further, thereby increasing ventricular volume and initiating a vicious circle, especially in patients with ischemic heart disease and limited myocardial O2 supply. Treatment with vasodila­ tors has the opposite effect; when afterload falls, cardiac output rises (Chaps. 266–270). Under normal circumstances, the various influences acting on car­ diac performance interact in a complex fashion to maintain cardiac output at a level responsive to the requirements of tissue metabolic demands (Fig. 244-10). Interference with a single mechanism may not influence the cardiac output due to homeostatic adjustments. For example, a moderate reduction of blood volume or the loss of the atrial contribution to ventricular contraction can be tolerated without a reduction in resting cardiac output. Under these circumstances, other factors, such as adrenergic neuronal impulses increasing cardiac contractility, heart rate, and venous tone, will serve as compensa­ tory mechanisms and sustain cardiac output in a normal individual. Ultimately, understanding the complex interactions between so many different phasic variables requires rigorous models to predict relevant outcomes, and led to the early application of systems engineering prin­ ciples in medicine.

TABLE 244-2  Determinants of Stroke Volume I. Ventricular Preload A. Blood volume B. Distribution of blood volume

  1. Body position
  2. Intrathoracic pressure
  3. Intrapericardial pressure
  4. Venous tone
  5. Pumping action of skeletal muscles C. Atrial contraction II. Ventricular Afterload PART 6 Disorders of the Cardiovascular System A. Systemic vascular resistance B. Elasticity of arterial tree C. Arterial blood volume D. Ventricular wall tension
  6. Ventricular radius
  7. Ventricular wall thickness III. Myocardial Contractilitya A. Intramyocardial [Ca2+] ↑↓ B. Cardiac adrenergic nerve activity ↑↓b C. Circulating catecholamines ↑↓b D. Cardiac rate ↑↓b E. Exogenous inotropic agents ↑ F. Myocardial ischemia ↓ G. Myocardial cell death (necrosis, apoptosis, autophagy) ↓ H. Alterations of sarcomeric and cytoskeletal proteins ↓
  8. Genetic
  9. Hemodynamic overload I. Myocardial fibrosis ↓ J. Chronic overexpression of neurohormones ↓ K. Ventricular remodeling ↓ L. Chronic and/or excessive myocardial hypertrophy ↓ aArrows indicate directional effects of determinants of contractility. bContractility rises initially but later becomes depressed. Maximal activity Normal-exercise

C

Normal-rest Ventricular performance Contractile state of myocardium Walking

B Exercise Heart failure 3′ D Rest A E

Fatal myocardial depression Dyspnea Pulmonary edema Ventricular EDV Stretching of myocardium FIGURE 244-9  The interrelations among influences on ventricular end-diastolic volume (EDV) through stretching of the myocardium and the contractile state of the myocardium. Levels of ventricular EDV associated with filling pressures that result in dyspnea and pulmonary edema are shown on the abscissa. Levels of ventricular performance required when the subject is at rest, while walking, and during maximal activity are designated on the ordinate. The broken lines are the descending limbs of the ventricular-performance curves, which are rarely seen during life but show the level of ventricular performance if end-diastolic volume could be elevated to very high levels. For further explanation, see text. (Reproduced with permission from WS Colucci, and E Braunwald: Pathophysiology of heart failure, in Braunwald’s Heart Disease, 7th ed, Philadelphia: Elsevier, 2005.)

Venous return Preload Contractility Stroke volume Cardiac output Arterial pressure Heart rate Afterload Peripheral resistance Medullary vasomotor and cardiac centers Carotid and aortic baroreceptors Higher nervous centers FIGURE 244-10  Interactions in the intact circulation of preload, contractility, and afterload in producing stroke volume. Stroke volume combined with heart rate determines cardiac output, which, when combined with peripheral vascular resistance, determines arterial pressure for tissue perfusion. The characteristics of the arterial system also contribute to afterload, an increase that reduces stroke volume. The interaction of these components with carotid and aortic arch baroreceptors provides a feedback mechanism to higher medullary and vasomotor cardiac centers and to higher levels in the central nervous system to effect a modulating influence on heart rate, peripheral vascular resistance, venous return, and contractility. (Reproduced with permission from MR Starling: Physiology of myocardial contraction, in Atlas of Heart Failure: Cardiac Function and Dysfunction, 3rd ed, WS Colucci and E Braunwald [eds]. Philadelphia: Current Medicine; 2002.) ■ ■EXERCISE The integrated response to exercise illustrates typical interactions among the three determinants of stroke volume: preload, afterload, and contractility (Fig. 244-9). Hyperventilation, the pumping action of the exercising muscles, and venoconstriction during exercise all augment venous return and hence ventricular filling and preload (Table 244-2). Simultaneously, the increase in neuronal and humoral adrenergic stimulation of the myocardium and the tachycardia that occur during exercise combine to augment the myocardial contractility (Fig. 244-9, curves 1 and 2), together elevating stroke volume and stroke work, with little or no change in end-diastolic pressure and volume (Fig. 244-9, points A and B). Vasodilation occurs in the exercising muscles, thus limiting the increase in afterload that otherwise would occur as cardiac output rises to levels as high as five times greater than basal levels dur­ ing maximal exercise. This vasodilation ultimately allows the achieve­ ment of elevated cardiac outputs during exercise at arterial pressures only moderately higher than the resting state. ASSESSMENT OF CARDIAC FUNCTION Several techniques can define impaired cardiac function in clinical practice. Cardiac output and stroke volume may decline in the pres­ ence of heart failure, but these variables are often within normal limits, especially at rest, even late in disease. A more sensitive index of cardiac function is the ejection fraction, i.e., the ratio of stroke volume to end-diastolic volume (normal value = 67 ± 8%), which is frequently depressed in systolic heart failure even when stroke volume is normal. Alternatively, abnormally elevated ventricular end-diastolic volume (normal value = 75 ± 20 mL/m2) or end-systolic volume (normal value = 25 ± 7 mL/m2) signifies left ventricular systolic impairment. Noninvasive techniques, particularly echocardiography, radionu­ clide scintigraphy, and cardiac magnetic resonance imaging (MRI) (Chap. 248), have great value in the clinical assessment of myocardial function. They provide measurements of end-diastolic and end-systolic volumes, ejection fraction, and systolic shortening rate, and they allow assessment of ventricular filling (see below) as well as regional contrac­ tion, relaxation, and tissue characterization. The latter measurements

ESPVR afterload LV pressure preload

LV volume FIGURE 244-11  The responses of the left ventricle to increased afterload, increased preload, and increased and reduced contractility are shown in the pressure-volume plane. Left. Effects of increases in preload and afterload on the pressure-volume loop. Because there has been no change in contractility, the end-systolic pressure-volume relationship (ESPVR) is unchanged. With an increase in afterload, stroke volume falls (1 → 2); with an increase in preload, stroke volume rises (1 → 3). Right. With increased myocardial contractility and constant left ventricular end-diastolic volume, the ESPVR moves to the left of the normal line (lower end-systolic volume at any end-systolic pressure) and stroke volume rises (1 → 3). With reduced myocardial contractility, the ESPVR moves to the right; end-systolic volume is increased, and stroke volume falls (1 → 2). have particular importance in ischemic heart disease, as myocardial infarction causes regional myocardial damage. Strong dependence on ventricular loading conditions influences the precision of measurements of cardiac output, ejection fraction, and ventricular volumes as indices of cardiac function. Thus, a depressed ejection fraction and lowered cardiac output may occur in patients with normal ventricular function but reduced preload, as occurs in hypovolemia, or with increased afterload, as occurs in acutely elevated arterial pressure. The end-systolic left ventricular pressure-volume relationship has particular value as an index of ventricular performance as it does not depend on preload and afterload (Fig. 244-11). At any level of myocar­ dial contractility, left ventricular end-systolic volume varies inversely with end-systolic pressure; as contractility declines, end-systolic vol­ ume (at any level of end-systolic pressure) rises. Invasive measurement of end-systolic left ventricular pressure-volume loops adds rigor to research studies of left ventricular function, but these techniques are less pragmatic than the more readily assessed indices obtained in rou­ tine clinical practice, such as ventricular volumes and ejection fraction. Integrated cardiopulmonary exercise testing with formal analysis of exhaled gases is now more broadly available and can estimate maximal oxygen delivery as an indirect metric of physiologic reserve. Longitu­ dinal measurements of some aspects of cardiovascular physiology are increasingly feasible with implantable or wearable devices. ■ ■DIASTOLIC FUNCTION Ventricular filling is influenced by several characteristics of the myo­ cardium including: (1) the extent and speed of myocardial relaxation; and (2) the passive stiffness of the ventricular wall. The former is largely a function of the rate of uptake of Ca2+ by the SR that may be enhanced by adrenergic activation and reduced by ischemia due to limited ATP available for pumping Ca2+ into the SR (see above). For the latter, ventricular stiffness increases with hypertrophy, fibrosis, and conditions that infiltrate the ventricle, such as amyloid, or can result from an extrinsic constraint (e.g., pericardial constriction) (Fig. 244-12). Ventricular filling can be assessed by measuring flow velocity across the mitral valve using Doppler ultrasound. Normally, inflow velocity is more rapid in early diastole than during atrial systole. However, with mild to moderately impaired relaxation, the rate of early diastolic filling declines, as presystolic filling rates rise. With further stiffening, flow is “pseudo-normalized,” as early ventricular filling becomes more rapid with rising left atrial pressure upstream of the left ventricle.

Normal contractility Contractility CHAPTER 244 Contractility LV pressure

Basic Biology of the Cardiovascular System

LV volume ■ ■CARDIAC METABOLISM The heart requires a continuous supply of energy (ATP) not only to drive mechanical contraction, but also to maintain ionic and biochemi­ cal homeostasis. The development of tension, the frequency of contrac­ tion, and myocardial contractility levels are the principal determinants of the heart’s energy and oxygen requirements, representing ~15% of that of the entire organism. The heart’s ATP production requires the generation of acetyl coen­ zyme A that can be derived from (in descending order) free fatty acids (FFAs), glucose, lactate, amino acids, and ketone bodies. Myocardial FFAs derive from circulating FFAs, whereas the cardiomyocyte’s glu­ cose derives from plasma as well as from myocardial glycogen stores (via glycogenolysis). These two principal sources of acetyl coenzyme Abnormal relaxation Pericardial restraint Left ventricular pressure Chamber dilation Increased chamber stiffness Left ventricular volume FIGURE 244-12  Mechanisms that cause diastolic dysfunction reflected in the pressure-volume relation. The bottom half of the pressure-volume loop is depicted. Solid lines represent normal subjects; broken lines represent patients with diastolic dysfunction. (Reproduced with permission from JD Carroll et al: The differential effects of positive inotropic and vasodilator therapy on diastolic properties in patients with congestive cardiomyopathy. Circulation; 1986; 74: 815.)

04 - 245 Epidemiology of Cardiovascular Disease

245 Epidemiology of Cardiovascular Disease

A are metabolized distinctly in cardiac muscle. Glucose is converted in the cytoplasm into pyruvate, which passes into mitochondria for conversion into acetyl-CoA that then undergoes oxidation. FFAs are converted to acyl-CoA in the cytoplasm and acetyl-CoA in the mitochondria. Acetyl-CoA enters the citric acid (Krebs) cycle to produce ATP by oxidative phosphorylation; ATP then enters the cyto­ plasm from the mitochondrial compartment. Intracellular adenosine diphosphate (ADP), resulting from ATP breakdown, enhances ATP production.

PART 6 Disorders of the Cardiovascular System In the fasted, resting state, circulating FFAs furnish most of the heart’s acetyl-CoA (~70%). In the fed state, with elevations of blood glucose and insulin, glucose oxidation increases and FFA oxidation subsides. Increased cardiac work, inotropic agents, hypoxia, and mild ischemia all enhance myocardial glucose uptake, production (glyco­ genolysis), and metabolism to pyruvate (glycolysis). Exercise raises circulating lactate levels and myocardial utilization of acetyl-CoA. By contrast, β-adrenergic stimulation raises the circulating levels and metabolism of FFAs in favor of glucose. Severe myocardial ischemia inhibits cytoplasmic pyruvate dehydrogenase, producing incomplete glucose metabolism to lactic acid (anaerobic glycolysis). Anaerobic glycolysis produces much less ATP per mole of glucose than does aerobic glucose metabolism. High concentrations of circulating FFAs, which can occur when adrenergic stimulation is superimposed on severe ischemia, reduce oxidative phosphorylation, and the myocar­ dial content of ATP declines, impairing contraction. In addition, FFA breakdown products may exert toxic or arrhythmogenic effects on cardiac cell membranes. Myocardial energy is stored as creatine phosphate (CP), which is in equilibrium with ATP, the immediate energy source. In states of reduced energy availability, the CP stores decline first. Cardiac hypertrophy, fibrosis, tachycardia, increased wall tension due to ven­ tricular dilation, and increased intracytoplasmic [Ca2+] all contribute to increased myocardial energy needs. When coupled with reduced coronary flow reserve, as occurs with obstruction of coronary arteries or abnormalities of the coronary microcirculation, an imbalance in myocardial ATP production relative to demand may occur, and the resulting ischemia can worsen or cause heart failure. ■ ■CARDIAC CELLULAR INTERVENTIONS: REGENERATION AND REPAIR Adult mammalian myocardial cells are fully differentiated and have little or no regenerative potential; however, there is evidence that the immature mammalian heart has some limited regenerative potential that rapidly becomes constrained with increasing maturity and work­ load. Considerable current effort is being devoted to evaluating the utility of various approaches to facilitate the transient release of these constraints on regeneration to enhance cardiac repair after injury. Recent work has also shown that by engineering chimeric antigen receptors on T lymphocytes (CAR-T), it may be possible to reverse fibrosis in the heart. The success of such approaches would offer the exciting possibility of reconstructing an infarcted or failing ventricle. ■ ■FURTHER READING Bautch VL, Caron KM: Blood and lymphatic vessel formation. Cold Spring Harb Perspect Biol 7:a008268, 2015. Dejana E et al: The molecular basis of endothelial cell plasticity. Nat Commun 8:14361, 2017. Green DJ et al: Vascular adaptation to exercise in humans: Role of hemodynamic stimuli. Physiol Rev 97:495, 2017. Libby P et al (eds): Braunwald’s Heart Disease: A Textbook of Cardio­ vascular Medicine, 11th ed. Philadelphia, Elsevier, 2022. MacLeod KT: Recent advances in understanding cardiac contractility in health and disease. F1000Res 5(F1000 Faculty Rev):1770, 2016. Page E et al (eds): Handbook of Physiology: A Critical Comprehensive Presentation of Physiological Knowledge and Concepts. Section 2: The Cardiovascular System, Volume I: The Heart. New York, Oxford University Press, 2002. Rurik JG et al: CAR T cells produced in vivo to treat cardiac injury. Science 375:91, 2022.

Spinale FG: Assessment of cardiac function—Basic principles and approaches. Compr Physiol 5:1911, 2015. Srivastava D: Making or breaking the heart: From lineage determination to morphogenesis. Cell 126:1037, 2006. Taegtmeyer H et al: Cardiac metabolism in perspective. Comp Physiol 6:1675, 2016. J. Michael Gaziano, Thomas A. Gaziano

Epidemiology of

Cardiovascular Disease Cardiovascular disease (CVD) is now the most common cause of death worldwide. Before 1900, infectious diseases and malnutrition were the most common causes, and CVD was responsible for <10% of all deaths. In 2022, CVD accounted for over 19 million deaths worldwide (33%), with the same rate now occurring in both high-income countries and low- and middle-income countries. THE EPIDEMIOLOGIC TRANSITION The global rise in CVD is the result of an unprecedented transforma­ tion in the causes of morbidity and mortality during the twentieth century. Known as the epidemiologic transition, this shift is driven by industrialization, urbanization, and associated lifestyle and demo­ graphic changes and is taking place in every part of the world among all races, ethnic groups, and cultures. The transition is divided into four basic stages: pestilence and famine, receding pandemics, degen­ erative and man-made diseases, and delayed degenerative diseases. A fifth stage, characterized by an epidemic of inactivity and obesity, is emerging in many countries that have moderate economic develop­ ment (Table 245-1). The age of pestilence and famine is marked by malnutrition, infec­ tious diseases, and high infant and child mortality that are offset by high fertility. Tuberculosis, dysentery, cholera, and influenza are often fatal, resulting in a mean life expectancy of about 30 years. CVD, which accounts for <10% of deaths, takes the form of rheumatic heart disease and cardiomyopathies due to infection and malnutrition. Despite advances in treatment of those with rheumatic heart disease, incidence and prevalence rates increased between 1990 and 2019. Per capita income and life expectancy increase during the age of receding pandemics as the emergence of public health systems, cleaner water supplies, and improved nutrition combine to drive down deaths from infectious disease and malnutrition. Infant and childhood mor­ tality also decline, but deaths due to CVD increase to between 10 and 35% of all deaths. Rheumatic valvular disease, hypertension, coronary heart disease (CHD), and stroke are the predominant forms of CVD. Almost 40% of the world’s population is currently in this stage. The age of degenerative and man-made diseases is distinguished by mortality from noncommunicable diseases—primarily CVD—surpassing mortality from malnutrition and infectious diseases. Caloric intake, particularly from animal fat, increases. CHD and stroke are prevalent, and between 35 and 65% of all deaths can be traced to CVD. Typically, the rate of CHD deaths exceeds that of stroke by a ratio of 2:1 to 3:1. During this period, average life expectancy surpasses the age of 50. Roughly 35% of the world’s population falls into this category. In the age of delayed degenerative diseases, CVD and cancer remain the major causes of morbidity and mortality, with CVD accounting for 40% of all deaths. However, age-adjusted CVD mortality declines, aided by preventive strategies (for example, smoking cessation pro­ grams and effective blood pressure control), acute hospital manage­ ment, and technologic advances, such as the availability of bypass

TABLE 245-1  Five Stages of the Epidemiologic Transition STAGE DESCRIPTION Pestilence and famine Predominance of malnutrition and infectious diseases as causes of death; high rates of infant and child mortality; low mean life expectancy Receding pandemics Improvements in nutrition and public health lead to decrease in rates of deaths related to malnutrition and infection; precipitous decline in infant and child mortality rates Degenerative and man-made diseases Increased fat and caloric intake and decrease in physical activity lead to emergence of hypertension and atherosclerosis; with increase in life expectancy, mortality from chronic, noncommunicable diseases exceeds mortality from malnutrition and infectious disease Delayed degenerative diseases CVD and cancer are the major causes of morbidity and mortality; better treatment and prevention efforts help avoid deaths among those with disease and delay primary events; age-adjusted CVD morality declines; CVD affecting older and older individuals Inactivity and obesity Overweight and obesity increase at alarming rate; diabetes and hypertension increase; decline in smoking rates levels off; a minority of the population meets physical activity recommendations Abbreviations: CHD, coronary heart disease; CVD, cardiovascular disease. Source: Data from AR Omran: The epidemiologic transition: A theory of the epidemiology of population change. Milbank Mem Fund Q 49:509, 1971; and SJ Olshansky, AB Ault: The fourth stage of the epidemiologic transition: The age of delayed degenerative diseases. Milbank Q 64:355, 1986. surgery. CHD, stroke, and congestive heart failure are the primary forms of CVD. About 15% of the world’s population is now in the age of delayed degenerative diseases or is exiting this age and moving into the fifth stage of the epidemiologic transition. In the industrialized world, physical activity continues to decline while total caloric intake increases. The resulting epidemic of over­ weight and obesity may signal the start of the age of inactivity and obesity. Rates of type 2 diabetes mellitus, hypertension, and lipid abnor­ malities are on the rise, trends that are particularly evident in children. As these risk factor trends continue, age-adjusted CVD mortality rates that have fallen for decades during the fourth phase have started to increase in recent years during this fifth phase. ■ ■PATTERNS IN THE EPIDEMIOLOGIC TRANSITION Unique regional features have modified aspects of the transition in var­ ious parts of the world. High-income countries experienced declines in CVD death rates by as much as 50–60% over the past 60 years, whereas CVD deaths increased by 15% over the past 20 years in the low- and middle-income range and the rate of change has been faster. However, given the large amount of available data, the United States serves as a useful reference point for comparisons. The age of pestilence and famine occurred before 1900, with a largely agrarian economy and population. Infectious diseases accounted for more deaths than any other cause. By the 1930s, the country proceeded through the age of receding pandemics. The establishment of public health infrastruc­ tures resulted in dramatic declines in infectious disease mortality rates. Lifestyle changes due to rapid urbanization resulted in a simul­ taneous increase in CVD mortality rates, reaching ~390 per 100,000. Between 1930 and 1965, the country entered the age of degenerative and man-made diseases. Infectious disease mortality rates fell to fewer than 50 per 100,000 per year, whereas CVD mortality rates reached peak levels with increasing urbanization and lifestyle changes in diet, physical activity, and tobacco consumption. The age of delayed degen­ erative diseases took place between 1965 and 2000. New therapeutic approaches, preventive measures, and exposure to public health cam­ paigns promoting lifestyle modifications led to substantial declines in age-adjusted mortality rates and a steadily rising age at which a first CVD event occurs. Currently, the United States is entering what appears to be a fifth phase. The decline in the age-adjusted CVD death rate of 3% per year through the 1970s and 1980s has tapered off in the 1990s to 2% through 2010. There was then limited reduction in the 2010–2019 period, and in 2020 and 2021, there was an increase in CVD mortality rates that had not been seen since the early 1960s. Competing trends appear to be at play. On the one hand, an increase in the prevalence of diabetes and obesity, a slowing in the rate of decline in smoking, and a leveling off

Highincome countries… INJ 7.61% Low- and middleincome countries, 80.99% PART 6 Disorders of the Cardiovascular System CMNN 18.03% CVD 32.84% ONC 41.52% CVD ONC CMNN INJ FIGURE 245-1  Global deaths by cause, 2019. CMNN, communicable, maternal, neonatal, and nutritional disorders; CVD, cardiovascular diseases; INJ, injuries; ONC, other noncommunicable diseases. (Based on data from Global Burden of Disease Study 2017. Global Burden of Disease Study 2017 [GBD 2017] Results. Seattle, United States: Institute for Health Metrics and Evaluation [IHME], 2020.) the transition, although there is vast regional heterogeneity with some areas in the second phase of the transition and more in the fourth. The Eastern Europe and Central Asia regions, however, are firmly in the peak of the third phase, with the highest death rates due to CVD (~55%) in the world. Importantly, deaths due to CHD are not limited to the elderly in this region and have a significant effect on working-age populations. South Asia—and more specifically, India, which accounts for the greatest proportion of the region’s population—is experiencing an alarming increase in heart disease. The transition appears to be in the Western style, with CHD as the dominant form of CVD. However, rheumatic heart disease continues to be a major cause of morbidity and Latin America and the Caribbean Middle East and North Africa 26.9% (619 million) 41.8% (437 million) High-income 31.5% (1139 million) Sub-Saharan Africa 13.1% (1087 million) FIGURE 245-2  Cardiovascular disease deaths as a percentage of total deaths and total population in seven economic regions of the world defined by the World Bank. (Based on data from Global Burden of Disease Study 2017. Global Burden of Disease Study 2019 [GBD 2019] Results. Seattle, United States: Institute for Health Metrics and Evaluation [IHME], 2023.)

mortality. As in South Asia, rheumatic heart disease is also an impor­ tant cause of CVD morbidity and mortality in sub-Saharan Africa, which largely remains in the first phase of the epidemiologic transition. Many factors contribute to this heterogeneity among LMICs. First, the regions are in various stages of the epidemiologic transition. Second, vast differences in lifestyle and behavioral risk factors exist. Third, racial and ethnic differences may lead to altered susceptibili­ ties to various forms of CVD. In addition, it should be noted that for most countries in these regions, accurate country-wide data on causespecific mortality are not complete. ■ ■GLOBAL TRENDS IN CARDIOVASCULAR DISEASE Over the past 5 years, there have been changes in the trends of CVD that are reflective of both trends in demographics and management of disease, but also of the way deaths and diseases have been measured and estimated. In 2017, the Global Burden of Disease (GBD) Study updated its estimates with several important changes based on newly available data, refinement in the causes of death, and the introduction of new modeling techniques. The major changes include the addition of an independent estimation of population and fertility, the addition of over 127 country-years of vital registration and verbal autopsy data, revisions of some deaths from “misclassified” to dementia, Parkinson’s disease and atrial fibrillation, and the addition of new diseases such as nonrheumatic calcific aortic and degenerative mitral valve disease. CVD accounts for 32% of deaths worldwide, a number expected to increase. In 2019, CHD accounted for 16.2% of all deaths globally and the largest portion (10%) of global years of life lost (YLLs) and disabilityadjusted life-years (DALYs) (7.2%). Stroke moved from the third to the second largest cause of death (11.6% of all deaths) and remained the third largest contributor to global YLLs (7.5%) and DALYs (5.7%). Together, CHD and stroke accounted for more than a quarter of all deaths worldwide. The burden of stroke is of growing concern among LMICs. The impact of stroke on DALYs and mortality rates is more than three times greater in LMICs as compared to HICs. Europe and Central Asia 55.1% (875 million) South Asia 27.5% (1813 million) Southeast and East Asia and Pacific 40.2% (2257 million)

CVD Deaths per 100,000

Year World Bank lower middle income World Bank high income World Bank upper middle income World Bank low income Global FIGURE 245-3  Age-standardized cardiovascular diseases (CVD) death rate per 100,000 from 1990 to 2019, by World Bank income. (Based on data from Global Burden of Disease Study 2019. Global Burden of Disease Study 2019 [GBD 2019] Results. Seattle, United States: Institute for Health Metrics and Evaluation [IHME], 2023.) With 85% of the world’s population, LMICs largely drive global CVD rates and trends. More than 15 million CVD deaths occurred in LMICs in 2019, compared to 3.5 million in HICs. Globally, there is evidence of significant delays in age of occurrence and/or improve­ ments in case fatality rates; between 1990 and 2019, the number of CVD deaths increased by 54%, but age-adjusted death rates decreased by 32.4% in the same period. Age-standardized death rates, however, have declined faster in HICs than in middle-income and lower-income regions (Fig. 245-3). Population growth has been greater in LMICs compared to HICs. As a result of slower rates of population growth in HICs, overall CVD deaths remained steady. However, in the LMICs, the population aging and growth outstripped gains in age-adjusted mortality reductions such that overall CVD deaths continued to climb over the past 25 years (Fig. 245-4).

Number of CVD Deaths in Millions

Year World Bank high income World Bank lower middle income World Bank upper middle income World Bank low income Global FIGURE 245-4  Number of cardiovascular diseases (CVD) deaths from 1990 to 2019, by World Bank income. (Based on data from Global Burden of Disease Study 2019. Global Burden of Disease Study 2017 [GBD 2019] Results. Seattle, United States: Institute for Health Metrics and Evaluation [IHME], 2023.)

Although HIC population growth will be fueled by immigration from LMICs, the populations of HICs will shrink as a proportion of the world’s population. The modest decline in CVD death rates that began in the HICs in the latter third of the twentieth century will continue, but the rate of decline appears to be slowing. However, these countries are expected to see an increase in the prevalence of CVD, as well as the absolute number of deaths as the population ages.

CHAPTER 245 Significant portions of the population living in LMICs have entered the third phase of the epidemiologic transition, and some are enter­ ing the fourth stage. Changing demographics play a significant role in future predictions for CVD throughout the world. For example, the population in Eastern Europe declined by 3% between 2010 and 2023, whereas it grew by 30% in South Asia. CVD rates will also have an eco­ nomic impact. Even assuming no increase in CVD risk factors, most countries, but especially India and South Africa, will see a large num­ ber of people between 35 and 64 die of CVD over the next 30 years, as well as an increasing level of morbidity among middle-aged people related to heart disease and stroke. Epidemiology of Cardiovascular Disease ■ ■RISK FACTORS Global variation in CVD rates is related to temporal and regional variations in known risk factors and behaviors. Ecologic analyses of major CVD risk factors and mortality demonstrate high correlations between expected and observed mortality rates for the three main risk factors—smoking, serum cholesterol, and hypertension—and suggest that many regional variations are based on differences in conventional risk factors. Behavioral Risk Factors  •  TOBACCO  Over 1.3 billion people use tobacco worldwide. Tobacco use currently causes about 8.7 mil­ lion deaths annually (15.4% of all deaths), 3.2 million of which are CVD related. The population of the HIC group smokes (21.6%) at almost double the rate of the low-income countries (11.2%), whereas the middle-income country group’s smoking rate (19.5%) approxi­ mates the global average (22.3%). From 2007 to 2017, smoking rates decreased across low-, middle-, and high-income country groups, with relative reductions of 19%, 12%, and 20%, respectively. By 2030, the global average smoking rate is expected to decline from 19% to 16% (women, 4%; men, 28%); however, the number of tobacco users is expected to rise owing to population growth. Secondhand smoke is another well-established cause of CVD, responsible for 598,000 CVD deaths of nonsmokers in 2019. Although smoking bans have both immediate and long-term benefits, implementation varies greatly between countries. DIET  Total caloric intake per capita increases as countries develop. With regard to CVD, a key element of dietary change is an increase in intake of saturated animal fats and hydrogenated vegetable fats, which contain atherogenic trans fatty acids, along with a decrease in intake of plant-based foods and an increase in simple carbohydrates. Fat contrib­ utes <20% of calories in rural China and India, <30% in Japan, and over 35% in the United States. Caloric contributions from fat appear to be increasing in the United States but falling in the other HICs. PHYSICAL INACTIVITY  The increased mechanization that accompa­ nies the economic transition leads to a shift from physically demand­ ing, agriculture-based work to largely sedentary industry- and office-based work. Physical inactivity is responsible for 1.3 million global deaths in 2019. The global prevalence of physical inactivity has remained steady between 2001 and 2016 (28.5% to 27.5%). Mor­ tality rates attributable to inactivity are highest in North Africa and the Middle East and in Central and Eastern Europe and lowest in sub-Saharan Africa. ■ ■METABOLIC RISK FACTORS Examination of trends in metabolic risk factors provides insight into changes in the CVD burden globally. Here we describe four metabolic risk factors—lipid levels, hypertension, obesity, and diabetes mellitus— using data from the Global Burden of Disease, Injuries, and Risk Factors Study (GBD 2019). The GBD project identified and compiled mortality and morbidity data from 195 countries from 1980 to 2017.

Lipid Levels  Worldwide, high low-density lipoprotein cholesterol levels are estimated to play a role in 41% of ischemic heart disease deaths and 9% of stroke deaths, amounting to 4 million deaths in 2019. Although mean population plasma cholesterol levels tend to rise as countries move through the epidemiologic transition, mean serum total cholesterol levels have decreased globally between 1980 and 2008 by 0.08 mmol/L per decade in men and 0.07 mmol/L per decade in women. Large declines occurred in Australasia, North America, and Western Europe (0.19–0.21 mmol/L). Countries in the East Asia and Pacific region experienced increases of >0.08 mmol/L in both men and women. More recent research including Mendelian studies sug­ gests that lipoprotein(a) may act as an individual predictor of CVD risk beyond traditional total or low-density lipoprotein cholesterol through increased cellular lipid accumulation, endothelial dysfunction, and impacts on coagulation. It appears to be elevated in ~20% of the global population, although fewer data are available from LMICs. Non­ randomized data suggest higher rates among those of African descent with twice the levels of Caucasians, with East Asians and South Asians having intermediate levels. There are limited clinical trial data on clini­ cal agents that target lipoprotein(a), although PCSK9 inhibitors lower it or other specific targets, so this remains an area of intense research. Hypertension  Elevated blood pressure is an early indicator of the epidemiologic transition. Observational studies show increased risk of CVD beginning with systolic blood pressures (SBPs) >110–115 mmHg. Between 1990 and 2015, the global prevalence of SBP ≥110–115 mmHg increased from 73,119 to 81,373 per 100,000, whereas the prevalence of SBP ≥140 mmHg rose from 17,307 to 20,526 per 100,000. In 2015, of the estimated 3.47 billion adults with SBP ≥110–115 mmHg, 874 million (25%) had SBP ≥140 mmHg. While SBP ≥140 mmHg accounts for only 25% of those with elevated blood pressure, it accounted for 73% (7.8 million) of deaths due to SBP of ≥110–115 mmHg in 2015. Worldwide, 53% of stroke deaths (3.44 million) and 53% of CHD deaths (4.86 million) are attributable to high blood pressure, account­ ing for 10.8 million deaths in 2019. From 1990 to 2015, the number of deaths related to SBP ≥140 mmHg increased in all LMIC groups but fell in HICs. Between 1980 and 2008, the age-standardized prevalence of uncontrolled hypertension decreased even as the number of people with uncontrolled hypertension increased due to population growth and aging. However, concerning trends of declining hypertension control rates were seen in the United States since 2016 with many middle-income countries now outperforming high-income nations. Rising mean population blood pressure also occurs as populations industrialize and move from rural to urban settings. For example, the prevalence of hypertension in urban India is 33.8%, but varies between 14.5 and 31.7% in rural regions. One major concern in LMICs is the high rate of undetected, and therefore untreated, hypertension. This may explain, at least in part, the higher stroke rates in these countries in relation to CHD rates during the early stages of the transition. The high rates of hypertension throughout Asia, especially undiagnosed hypertension, likely contribute to the high prevalence of hemorrhagic stroke in the region.

PART 6 Disorders of the Cardiovascular System Obesity  In 2025, an estimated 892 million adults will be obese. Global obesity prevalence is projected to be 16.1% among adults and is increasing throughout the world, particularly in developing coun­ tries where the trajectories are steeper than those experienced by the developed countries. High body mass index (BMI) contributed to 5.0 million deaths worldwide (7.1% deaths from any cause); CVD was the leading cause of these deaths (1.95 million) and also of associated DALYs (160 million) followed by diabetes (0.6 million deaths, 30.4 million DALYs). Women are more affected by obesity than men; from 1975 to 2014, global mean age-standardized BMI increased from 22.1 to 24.4 kg/m2 in females and from 21.7 to 24.2 kg/m2 in males, whereas the prevalence of obesity increased from 6.4% to 14.9% in females and 3.2% to 10.8% in males. The proportion of the world’s adult women who are either overweight or obese rose from 29.8% to 38.0% between 1980 and 2013, while an increase from 28.8% to 36.9% was observed for men. Country and regional differences are observed. The highest prevalence of male obesity is in the United States, Southern and Central

Latin America, Australasia, and Central and Western Europe. For females, the highest prevalence of obesity is in Southern and North Africa, the Middle East, Central and Southern Latin America, and the United States. The lowest prevalence for both males and females was observed in South and Southeast Asia and in East, Central, and West Africa. Diabetes Mellitus  As a consequence of, or in addition to, increas­ ing BMI and decreasing levels of physical activity, worldwide rates of diabetes—predominantly type 2 diabetes—are on the rise. According to the most recent data from the GBD project, the prevalence of diabe­ tes increased 129.7% for males and 120.9% for females between 1990 and 2017. An estimated 476 million people worldwide have diabetes, and the International Diabetes Foundation predicts this number will reach 693 million by 2045. Nearly 50% of people with diabetes are undiagnosed, and 80% live in LMICs. The Middle East and North Africa have the highest regional age-standardized prevalence (8.7% of the population) and incidence rates (400 per 100,000) of diabetes, whereas East Asia and the Pacific have the lowest (5.8%; 249 per 100,000). Future growth will also largely occur in the Middle East and Africa, along with other LMICs in South Asia and sub-Saharan Africa. COVID-19  The impact of COVID-19 on CVD was significant. First, patients with acute conditions were hesitant to present to hos­ pitals for fear of infection, resulting in delayed presentation for those with acute coronary syndrome (ACS) or stroke and missing critical early care. Additionally, even those who presented with ACS had worse outcomes sometimes related to testing delays. Furthermore, the pres­ ence of obesity and/or diabetes mellitus worsened outcomes. Finally, control rates of hypertension and dyslipidemia may have been exacer­ bated due to difficulty of access to providers. ■ ■GENETIC RISK FACTORS A great deal of effort has recently been invested in understanding how genes affect cardiovascular health in populations. These efforts have focused on germline genetic variants that are related to specific CVDs as well as those that are associated with cardiovascular risk factors. In both cases, every year, the number of associated variants has increased meaningfully to the point that it appears that hundreds or even thou­ sands of variants are associated with these conditions, each explaining a small amount of the population variability in disease and risk fac­ tors. Collections of variants have been combined in polygenomic risk scores, but these too explain only a small amount of the variability of the disease in the population. Much more data will emerge in the com­ ing years about these associations, the mechanisms that explain these associations, the relationships of variants that are specific to certain tis­ sues such as the heart or the brain, and the interactions between genetic and lifestyle factors in causing disease. Currently, most of the data are among those with European ancestry; however, large-scale efforts are underway to understand the relationships between genes and diseases and their risk factors around the world. The early data suggest non­ trivial differences among various world populations. Beyond germline risk, there appears to be increased cardiovascular risk associated with age-related expansion of hematopoietic clones with somatic mutations, including loss-of-function alleles of certain genes. Individuals with these mutations without other hematologic abnormalities are defined as having clonal hematopoiesis of indeterminate potential (CHIP). Recent studies suggest those with CHIP have up to a twofold increased risk of developing CHD. SUMMARY Although CVD rates are declining in the HICs, they are increasing in many other regions of the world. The consequences of this preventable epidemic will be substantial on many levels, including individual mor­ tality and morbidity, family suffering, and staggering economic costs. Three complementary strategies can be used to lessen the impact. First, the overall burden of CVD risk factors can be lowered through population-wide public health measures, such as national campaigns against cigarette smoking, unhealthy diets, and physical inactivity. Sec­ ond, it is important to identify higher risk subgroups of the population

05 - SECTION 2 Diagnosis of Cardiovascular Disorders

SECTION 2 Diagnosis of Cardiovascular Disorders

who stand to benefit the most from specific, low-cost prevention interventions, including screening for and treatment of hypertension and elevated cholesterol. Simple, low-cost interventions, such as the “polypill”—a regimen of aspirin, a statin, and an antihypertensive agent—now show trial data with reductions in events for both primary and secondary prevention and have been added to the WHO Essential Medicines list. Third, resources should be allocated to acute, as well as secondary, prevention interventions. For countries with limited resources, a critical first step in developing a comprehensive plan is better assessment of cause-specific mortality and morbidity, as well as the prevalence, of the major preventable risk factors. In the meantime, the HICs must continue to bear the burden of research and development aimed at prevention and treatment, being mindful of the economic limitations of many countries. The concept of the epidemiologic transition provides insight into how to alter the course of the CVD epidemic. The efficient transfer of low-cost preven­ tive and therapeutic strategies could alter the natural course of this epidemic and thereby reduce the excess global burden of preventable CVD. ■ ■FURTHER READING Boutari C et al: A 2022 update on the epidemiology of obesity and a call to action: As its twin COVID-19 pandemic appears to be reced­ ing, the obesity and dysmetabolism pandemic continues to rage on. Metabolism 133:155217, 2022. Clerkin KJ et al: COVID-19 and cardiovascular disease. Circulation 141:1648, 2020. Gaziano T, Gaziano JM: Global burden of cardiovascular disease, in Heart Disease: A Textbook of Cardiovascular Medicine, 12th ed, Braunwald E (ed). Philadelphia, Elsevier, 2022. Mensah G et al: Global burden of cardiovascular diseases and risks, 1990-2022. J Am Coll Cardiol 82:2350, 2023. Tsao CW et al: Heart disease and stroke statistics–2022 update: A report from the American Heart Association. Circulation 145:e153, 2022. Section 2 Diagnosis of Cardiovascular Disorders

Physical Examination

of the Cardiovascular

System Patrick T. O’Gara, Joseph Loscalzo The approach to a patient with known or suspected cardiovascular disease begins with the time-honored traditions of a directed history and a targeted physical examination. The scope of these activities depends on the clinical context, ranging from an elective ambulatory follow-up visit to a more urgent bedside encounter. There has been a gradual decline in physical examination skills over the past few decades at every level, from student to faculty specialist, a development of great concern to both clinicians and medical educators. Classic cardiac find­ ings are recognized by only a minority of internal medicine and family practice residents. Despite popular perceptions, clinical performance does not improve predictably with experience; instead, the acquisi­ tion of new examination skills may become more difficult for a busy individual practitioner. Less time is now devoted to mentored cardio­ vascular examinations during the training of students and residents. One widely recognized outcome of these trends is the progressive utilization of noninvasive imaging studies to establish the presence and

severity of cardiovascular disease even when the examination findings imply a low pretest probability of significant pathology. Proponents of the use of hand-held ultrasound devices to identify and character­ ize structural cardiac disease have called for its incorporation into educational curricula. Techniques to improve competency in bedside examination skills include repetition, patient-centered teaching con­ ferences, visual display feedback of auscultatory events using Doppler echocardiographic imaging, and simulation-based training. The use of digital stethoscopes may enhance learning and is foundational to the application of computer- or artificial intelligence–assisted evaluation of auscultatory events.

CHAPTER 246 Physical Examination of the Cardiovascular System
The findings from the history and physical examination can help establish the presence, severity, and prognosis of several cardiovascular diseases. For example, observations regarding heart rate and blood pressure, signs of pulmonary congestion, and the presence of mitral regurgitation (MR) contribute importantly to bedside risk assessment in patients with acute coronary syndromes and can inform clinical decision-making before the results of cardiac biomarker testing are known. The prognosis of patients with heart failure can be predicted on the basis of the jugular venous pressure (JVP) and the presence or absence of a third heart sound (S3). Accurate characterization of car­ diac murmurs provides important insight into the natural history of many valvular and congenital heart lesions. Finally, the important role played by the physical examination in enhancing the clinician-patient relationship cannot be overstated. ■ ■THE GENERAL PHYSICAL EXAMINATION The examination begins with an assessment of the general appear­ ance of the patient, with notation of age, posture, demeanor, and overall health status. Is the patient in pain or resting quietly, dyspneic or diaphoretic? Does the patient choose to avoid certain body posi­ tions to reduce or eliminate pain, as might be the case with suspected acute pericarditis? Are there clues indicating that dyspnea may have a pulmonary cause, such as a barrel chest deformity with an increased anterior-posterior diameter, tachypnea, and pursed-lip breathing? Skin pallor, cyanosis, and jaundice can be appreciated readily and provide additional clues. The appearance of a chronically ill-appearing emaci­ ated patient may suggest the presence of long-standing heart failure or another systemic disorder, such as a malignancy. Various genetic syndromes, often with cardiovascular involvement, can also be rec­ ognized easily, such as trisomy 21, Marfan syndrome, and Holt-Oram syndrome. Height and weight should be measured routinely, and both body mass index and body surface area should be calculated. Knowl­ edge of the waist circumference and the waist-to-hip ratio can be used to predict long-term cardiovascular risk. Mental status, level of alert­ ness, and mood should be assessed continuously during the interview and examination. Skin  Central cyanosis occurs with significant right-to-left shunt­ ing at the level of the heart or lungs, allowing deoxygenated blood to reach the systemic circulation. Peripheral cyanosis or acrocyanosis, in contrast, is usually related to reduced extremity blood flow due to small vessel constriction, as seen in patients with severe heart failure, shock, or peripheral vascular disease; it can be aggravated by the use of β-adrenergic blockers with unopposed α-mediated vasoconstriction. Differential cyanosis refers to isolated cyanosis affecting the lower but not the upper extremities in a patient with a large patent ductus arterio­ sus (PDA) and secondary pulmonary hypertension with right-to-left to shunting at the great vessel level. Telangiectasias on the lips, tongue, and mucous membranes, as part of the Osler-Weber-Rendu syndrome (hereditary hemorrhagic telangiectasia), resemble spider nevi and can be a source of right-to-left shunting when also present in the lung. Malar telangiectasias also are seen in patients with advanced mitral ste­ nosis (MS) or scleroderma. An unusually tan or bronze discoloration of the skin may suggest hemochromatosis as the cause of the associated systolic heart failure. Jaundice, which may be visible first in the sclerae, has a broad differential diagnosis but, in the appropriate setting, can be consistent with advanced right heart failure and congestive hepatomeg­ aly. Various hereditary lipid disorders sometimes are associated with

06 - 246 Physical Examination of the Cardiovascular System

246 Physical Examination of the Cardiovascular System

who stand to benefit the most from specific, low-cost prevention interventions, including screening for and treatment of hypertension and elevated cholesterol. Simple, low-cost interventions, such as the “polypill”—a regimen of aspirin, a statin, and an antihypertensive agent—now show trial data with reductions in events for both primary and secondary prevention and have been added to the WHO Essential Medicines list. Third, resources should be allocated to acute, as well as secondary, prevention interventions. For countries with limited resources, a critical first step in developing a comprehensive plan is better assessment of cause-specific mortality and morbidity, as well as the prevalence, of the major preventable risk factors. In the meantime, the HICs must continue to bear the burden of research and development aimed at prevention and treatment, being mindful of the economic limitations of many countries. The concept of the epidemiologic transition provides insight into how to alter the course of the CVD epidemic. The efficient transfer of low-cost preven­ tive and therapeutic strategies could alter the natural course of this epidemic and thereby reduce the excess global burden of preventable CVD. ■ ■FURTHER READING Boutari C et al: A 2022 update on the epidemiology of obesity and a call to action: As its twin COVID-19 pandemic appears to be reced­ ing, the obesity and dysmetabolism pandemic continues to rage on. Metabolism 133:155217, 2022. Clerkin KJ et al: COVID-19 and cardiovascular disease. Circulation 141:1648, 2020. Gaziano T, Gaziano JM: Global burden of cardiovascular disease, in Heart Disease: A Textbook of Cardiovascular Medicine, 12th ed, Braunwald E (ed). Philadelphia, Elsevier, 2022. Mensah G et al: Global burden of cardiovascular diseases and risks, 1990-2022. J Am Coll Cardiol 82:2350, 2023. Tsao CW et al: Heart disease and stroke statistics–2022 update: A report from the American Heart Association. Circulation 145:e153, 2022. Section 2 Diagnosis of Cardiovascular Disorders

Physical Examination

of the Cardiovascular

System Patrick T. O’Gara, Joseph Loscalzo The approach to a patient with known or suspected cardiovascular disease begins with the time-honored traditions of a directed history and a targeted physical examination. The scope of these activities depends on the clinical context, ranging from an elective ambulatory follow-up visit to a more urgent bedside encounter. There has been a gradual decline in physical examination skills over the past few decades at every level, from student to faculty specialist, a development of great concern to both clinicians and medical educators. Classic cardiac find­ ings are recognized by only a minority of internal medicine and family practice residents. Despite popular perceptions, clinical performance does not improve predictably with experience; instead, the acquisi­ tion of new examination skills may become more difficult for a busy individual practitioner. Less time is now devoted to mentored cardio­ vascular examinations during the training of students and residents. One widely recognized outcome of these trends is the progressive utilization of noninvasive imaging studies to establish the presence and

severity of cardiovascular disease even when the examination findings imply a low pretest probability of significant pathology. Proponents of the use of hand-held ultrasound devices to identify and character­ ize structural cardiac disease have called for its incorporation into educational curricula. Techniques to improve competency in bedside examination skills include repetition, patient-centered teaching con­ ferences, visual display feedback of auscultatory events using Doppler echocardiographic imaging, and simulation-based training. The use of digital stethoscopes may enhance learning and is foundational to the application of computer- or artificial intelligence–assisted evaluation of auscultatory events.

CHAPTER 246 Physical Examination of the Cardiovascular System
The findings from the history and physical examination can help establish the presence, severity, and prognosis of several cardiovascular diseases. For example, observations regarding heart rate and blood pressure, signs of pulmonary congestion, and the presence of mitral regurgitation (MR) contribute importantly to bedside risk assessment in patients with acute coronary syndromes and can inform clinical decision-making before the results of cardiac biomarker testing are known. The prognosis of patients with heart failure can be predicted on the basis of the jugular venous pressure (JVP) and the presence or absence of a third heart sound (S3). Accurate characterization of car­ diac murmurs provides important insight into the natural history of many valvular and congenital heart lesions. Finally, the important role played by the physical examination in enhancing the clinician-patient relationship cannot be overstated. ■ ■THE GENERAL PHYSICAL EXAMINATION The examination begins with an assessment of the general appear­ ance of the patient, with notation of age, posture, demeanor, and overall health status. Is the patient in pain or resting quietly, dyspneic or diaphoretic? Does the patient choose to avoid certain body posi­ tions to reduce or eliminate pain, as might be the case with suspected acute pericarditis? Are there clues indicating that dyspnea may have a pulmonary cause, such as a barrel chest deformity with an increased anterior-posterior diameter, tachypnea, and pursed-lip breathing? Skin pallor, cyanosis, and jaundice can be appreciated readily and provide additional clues. The appearance of a chronically ill-appearing emaci­ ated patient may suggest the presence of long-standing heart failure or another systemic disorder, such as a malignancy. Various genetic syndromes, often with cardiovascular involvement, can also be rec­ ognized easily, such as trisomy 21, Marfan syndrome, and Holt-Oram syndrome. Height and weight should be measured routinely, and both body mass index and body surface area should be calculated. Knowl­ edge of the waist circumference and the waist-to-hip ratio can be used to predict long-term cardiovascular risk. Mental status, level of alert­ ness, and mood should be assessed continuously during the interview and examination. Skin  Central cyanosis occurs with significant right-to-left shunt­ ing at the level of the heart or lungs, allowing deoxygenated blood to reach the systemic circulation. Peripheral cyanosis or acrocyanosis, in contrast, is usually related to reduced extremity blood flow due to small vessel constriction, as seen in patients with severe heart failure, shock, or peripheral vascular disease; it can be aggravated by the use of β-adrenergic blockers with unopposed α-mediated vasoconstriction. Differential cyanosis refers to isolated cyanosis affecting the lower but not the upper extremities in a patient with a large patent ductus arterio­ sus (PDA) and secondary pulmonary hypertension with right-to-left to shunting at the great vessel level. Telangiectasias on the lips, tongue, and mucous membranes, as part of the Osler-Weber-Rendu syndrome (hereditary hemorrhagic telangiectasia), resemble spider nevi and can be a source of right-to-left shunting when also present in the lung. Malar telangiectasias also are seen in patients with advanced mitral ste­ nosis (MS) or scleroderma. An unusually tan or bronze discoloration of the skin may suggest hemochromatosis as the cause of the associated systolic heart failure. Jaundice, which may be visible first in the sclerae, has a broad differential diagnosis but, in the appropriate setting, can be consistent with advanced right heart failure and congestive hepatomeg­ aly. Various hereditary lipid disorders sometimes are associated with

subcutaneous xanthomas, particularly along the tendon sheaths or over the extensor surfaces of the extremities. Severe hypertriglyceridemia can be associated with eruptive xanthomatosis and lipemia retinalis. Palmar crease xanthomas are specific for type III hyperlipoprotein­ emia. Pseudoxanthoma elasticum, a disease associated with premature atherosclerosis, is manifested by a leathery, cobblestoned appearance of the skin in the axilla and neck creases and by angioid streaks on funduscopic examination. Extensive lentigenes have been described in a variety of development delay–cardiovascular syndromes, including Carney’s syndrome, which includes multiple atrial myxomas. Cutane­ ous manifestations of sarcoidosis such as lupus pernio and erythema nodosum may suggest this disease as a cause of an associated dilated cardiomyopathy, especially with heart block, intraventricular conduc­ tion delay, or ventricular tachycardia. PART 6 Disorders of the Cardiovascular System Head and Neck  Dentition and oral hygiene should be assessed in every patient both as a source of potential infection and as an index of general health. A high-arched palate is a feature of Marfan syndrome and other connective tissue disease syndromes. Bifid uvula has been described in patients with Loeys-Dietz syndrome, and orange tonsils are characteristic of Tangier disease. The ocular manifestations of hyperthyroidism have been well described. Many patients with con­ genital heart disease have associated hypertelorism, low-set ears, or micrognathia. Blue sclerae are a feature of osteogenesis imperfecta. An arcus senilis pattern lacks specificity as an index of coronary heart dis­ ease risk. The funduscopic examination is an often-underused method by which to assess the microvasculature, especially among patients with established atherosclerosis, hypertension, or diabetes mellitus. A mydriatic agent may be necessary for optimal visualization. A fundu­ scopic examination should be performed routinely in the assessment of patients with suspected endocarditis and those with a history of acute visual change. Branch retinal artery occlusion or visualization of a Hollenhorst plaque can narrow the differential diagnosis rapidly in the appropriate setting. Relapsing polychondritis may manifest as an inflamed pinna or, in its later stages, as a saddle-nose deformity because of destruction of nasal cartilage; granulomatosis with polyan­ giitis can also lead to a saddle-nose deformity. Chest  Midline sternotomy, right anterior thoracotomy, left postero­ lateral thoracotomy, or infraclavicular scars should not be overlooked and may provide the first clue regarding an underlying cardiovascular disorder in patients unable to provide a relevant history. A prominent venous collateral pattern may suggest subclavian or vena caval obstruc­ tion. If the head and neck appear dusky and slightly cyanotic and the venous pressure is grossly elevated without visible pulsations, a diag­ nosis of superior vena cava syndrome should be entertained. Thoracic cage abnormalities have been well described among patients with connective tissue disease syndromes. They include pectus carinatum (“pigeon chest”) and pectus excavatum (“funnel chest”). Obstructive lung disease is suggested by a barrel chest deformity, especially with tachypnea, pursed-lip breathing, and use of accessory muscles. The characteristically severe kyphosis and compensatory lumbar, pelvic, and knee flexion of ankylosing spondylitis should prompt careful auscultation for a murmur of aortic regurgitation (AR). Straight back syndrome refers to the loss of the normal kyphosis of the thoracic spine and has been described in patients with mitral valve prolapse (MVP) and its variants. In some patients with cyanotic congenital heart dis­ ease, the chest wall appears to be asymmetric, with anterior displace­ ment of the left hemithorax. The respiratory rate and pattern should be noted during spontaneous breathing and sleep, with additional attention to depth, audible wheezing, and stridor. Lung examination can reveal adventitious sounds indicative of pulmonary edema, pneu­ monia, or pleuritis. Abdomen  In some patients with advanced obstructive lung dis­ ease, the point of maximal cardiac impulse may be in the epigastrium. The liver is frequently enlarged and tender in patients with chronic heart failure. Systolic pulsations over the liver signify severe tricus­ pid regurgitation (TR). Splenomegaly may be a feature of infective endocarditis, particularly when symptoms have persisted for weeks

or months. Ascites is a nonspecific finding but may be present with advanced chronic right heart failure, constrictive pericarditis, hepatic cirrhosis, or an intraperitoneal malignancy. The finding of an elevated JVP implies a cardiovascular etiology. In nonobese patients, the aorta typically is palpated between the epigastrium and the umbilicus. The sensitivity of palpation for the detection of an abdominal aortic aneu­ rysm (pulsatile and expansile mass) decreases as a function of body size. Because palpation alone is not sufficiently accurate to establish this diagnosis, a screening ultrasound examination is advised when appropriate. The presence of an arterial bruit over the abdomen sug­ gests high-grade atherosclerotic disease, although precise localization is difficult. Extremities  The temperature and color of the extremities, the presence of clubbing, arachnodactyly, and pertinent nail findings can be surmised quickly during the examination. Clubbing implies the presence of central right-to-left shunting, although it has also been described in patients with endocarditis. Its appearance can range from cyanosis and softening of the root of the nail bed, to the classic loss of the normal angle between the base of the nail and the skin, to the skeletal and periosteal bony changes of hypertrophic osteoarthropathy, which is seen rarely in patients with advanced lung or liver disease. Patients with the Holt-Oram syndrome have an unopposable, “fin­ gerized” thumb, whereas patients with Marfan syndrome may have arachnodactyly and a positive “wrist” (overlapping of the thumb and fifth finger around the wrist) or “thumb” (protrusion of the thumb beyond the ulnar aspect of the hand when the fingers are clenched over the thumb in a fist) sign. The Janeway lesions of endocarditis are nontender, slightly raised hemorrhagic lesions on the palms and soles, whereas Osler’s nodes are tender, raised nodules on the pads of the fingers or toes. Splinter hemorrhages are classically identified as linear petechiae in the midposition of the nail bed and should be distinguished from the more common traumatic petechiae, which are seen closer to the distal edge. Lower extremity or presacral edema in the setting of an elevated JVP defines volume overload and may be a feature of chronic heart failure or constrictive pericarditis. Lower extremity edema in the absence of jugular venous hypertension may be due to profound hypoalbu­ minemia as seen in nephrotic syndrome or liver failure. Other causes include lymphatic or venous obstruction or, more commonly, venous insufficiency, as would be further suggested by the appearance of varicosities, venous ulcers (typically medial in location), and brownish cutaneous discoloration from hemosiderin deposition (eburnation). Pitting edema can also be seen in patients who use dihydropyridine calcium channel blockers. A Homans’ sign (posterior calf pain on active dorsiflexion of the foot against resistance) is neither specific nor sensitive for deep venous thrombosis. Muscular atrophy or the absence of hair along an extremity is consistent with severe arterial insuffi­ ciency or a primary neuromuscular disorder. ■ ■CARDIOVASCULAR EXAMINATION Jugular Venous Pressure and Waveform  The JVP is the single most important bedside measurement from which to estimate the vol­ ume status. The internal jugular vein is preferred because the external jugular vein is valved and not directly in line with the superior vena cava and right atrium. Nevertheless, the external jugular vein has been used to discriminate between high and low central venous pressure (CVP). Precise estimation of the central venous or right atrial pressure from bedside assessment of the jugular venous waveform can be dif­ ficult. Venous pressure traditionally has been measured as the vertical distance between the top of the jugular venous pulsation and the ster­ nal inflection point (angle of Louis). A distance >4.5 cm at 30° eleva­ tion is considered abnormal. However, the actual distance between the mid-right atrium and the angle of Louis varies considerably as a func­ tion of both body size and the patient angle at which the assessment is made (30°, 45°, or 60°). The use of the sternal angle as a reference point leads to systematic underestimation of CVP, and this method should be used less for semiquantification than to distinguish a normal from an elevated CVP. The use of the clavicle may provide an easier reference

for standardization. Venous pulsations above this level in the sitting position are clearly abnormal, as the distance between the clavicle and the right atrium is at least 10 cm. The patient should always be placed in the sitting position, with the legs dangling below the bedside, when an elevated pressure is suspected in the semisupine position. It should also be noted that bedside estimates of CVP are made in centimeters of water, and must be converted to millimeters of mercury to provide correlation with accepted hemodynamic norms (1.36 cmH2O = 1.0 mmHg). The venous waveform sometimes can be difficult to distinguish from the carotid pulse, especially during casual inspection. Nev­ ertheless, the venous waveform has several characteristic features, and its individual components can be appreciated in most patients (Fig. 246-1). The arterial pulsation is not easily obliterated with palpation; the venous waveform in patients with sinus rhythm is usually biphasic, while the carotid pulse is monophasic; and the jugular venous pulsation should change with changes in posture or inspiration (unless the venous pressure is quite elevated). The venous waveform is divided into several distinct peaks. The a wave reflects right atrial presystolic contraction and occurs just after the electrocardiographic P wave, preceding the first heart sound (S1). A prominent a wave is seen in patients with reduced right ventricu­ lar compliance; a cannon a wave occurs with atrioventricular (AV) dissociation and right atrial contraction against a closed tricuspid valve. In a patient with a wide complex tachycardia, the apprecia­ tion of cannon a waves in the jugular venous waveform identifies the rhythm as ventricular in origin. The a wave is not present with atrial fibrillation. The x descent defines the fall in right atrial pres­ sure after tricuspid valve opening, and occurs after inscription of the a wave. The c wave, which occurs as the closed tricuspid valve is pushed into the right atrium during early ventricular systole, interrupts this x descent and is followed by a further descent. The v wave represents atrial filling (atrial diastole) and occurs during ventricular systole. The height of the v wave is determined by right atrial compliance as well as the volume of blood returning to the right atrium either antegrade from the cavae or retrograde through an incompetent tricuspid valve. In patients with TR, the v wave is accentuated and the subsequent fall in pressure (y descent) is rapid. With progressive degrees of TR, the v wave merges with the c wave, and the right atrial and jugular vein waveforms become “ventricu­ larized.” The y descent, which follows the peak of the v wave, can become prolonged or blunted with obstruction to right ventricular inflow, as may occur with tricuspid stenosis or pericardial tampon­ ade. Normally, the venous pressure should fall by at least 3 mmHg with inspiration. Kussmaul’s sign is defined by either a rise or a lack of fall of the JVP with inspiration and is classically associated with constrictive pericarditis, although it has been reported in patients with restrictive cardiomyopathy, massive pulmonary embolism, right ventricular infarction, and advanced left ventricular (LV) sys­ tolic heart failure. It is also a common, isolated finding in patients after cardiac surgery without other hemodynamic abnormalities. Venous hypertension sometimes can be elicited by passive leg elevation or performance of the abdominojugular reflux maneuver. When these signs are positive, a volume-overloaded state with lim­ ited compliance of an overly distended or constricted venous system is present. Abdominojugular reflux is produced with firm and consistent pressure over the upper portion of the abdomen, prefer­ ably over the right upper quadrant, for >15 s. A positive response is defined by a sustained rise of >3 cm in the JVP during the applica­ tion of firm abdominal pressure. The response should be assessed after 10 s of continuous pressure to allow for respiratory artifacts and tensing of the abdominal muscles to subside. Patients must be coached to refrain from breath holding or a Valsalva-like maneuver during the procedure. Performance of the abdominojugular reflux maneuver is useful in predicting a pulmonary artery wedge pressure

15 mmHg in patients with heart failure. Although the JVP estimates right ventricular filling pressure, it has a predictable relationship with the pulmonary artery wedge pressure. In a large study of patients with advanced heart failure, the

A V C CHAPTER 246 X Y IV II I A Physical Examination of the Cardiovascular System
V A Severe V Y A C X Mild A V Y C Normal Y X II III I B P ECG A V X V JVP Y II K I C FIGURE 246-1  A. Jugular venous pulse wave tracing (top) with heart sounds (bottom) in a patient with reduced right ventricular compliance. The A wave represents right atrial presystolic contraction and occurs just after the electrocardiographic P wave and just before the first heart sound (I). In this example, the A wave is accentuated and larger than normal due to decreased right ventricular compliance, as also suggested by the right-sided S4 (IV). The C wave may reflect the carotid pulsation in the neck and/or an early systolic increase in right atrial pressure as the right ventricle pushes the closed tricuspid valve into the right atrium. The x descent follows the A wave just as atrial pressure continues to fall. The V wave represents atrial filling during ventricular systole and peaks at the second heart sound (II). The y descent corresponds to the fall in right atrial pressure after tricuspid valve opening.

B. Jugular venous wave forms in mild (middle) and severe (top) tricuspid regurgitation, compared with normal (bottom), with phonocardiographic representation of the corresponding heart sounds below. With increasing degrees of tricuspid regurgitation, the waveform becomes “ventricularized.” C. Electrocardiogram (ECG) (top), jugular venous waveform (JVP) (middle), and heart sounds (bottom) in pericardial constriction. Note the prominent and rapid y descent, corresponding in timing to the pericardial knock (K). (Reproduced with permission from J Abrams: Synopsis of Cardiac Physical Diagnosis, 2nd ed. Boston, Butterworth Heinemann, 2001.) presence of a right atrial pressure >10 mmHg (as predicted on bedside examination) had a positive value of 88% for the prediction of a pulmo­ nary artery wedge pressure of >22 mmHg. In addition, an elevated JVP has prognostic significance in patients with both symptomatic heart failure and asymptomatic LV systolic dysfunction. The presence of an elevated JVP is associated with a higher risk of subsequent hospitaliza­ tion for heart failure, death from heart failure, or both.

Assessment of Blood Pressure  Measurement of blood pressure usually is delegated to a medical assistant but should be repeated by the examining clinician. Accurate measurement depends on body position, arm size, time of measurement, place of measurement, type of device, device size, technique, and examiner. In general, physician-recorded blood pressures are higher than both nurse-recorded pressures and self-recorded pressures at home. Blood pressure is best measured in the seated position with the arm at the level of the heart and the feet on the floor with the back supported, using an appropriately sized cuff, after 5–10 min of relaxation. When it is measured in the supine position, the arm should be raised to bring it to the level of the mid-right atrium. The length and width of the blood pressure cuff bladder should be 80 and 40% of the arm’s circumference, respectively. A common source of error in practice is to use an inappropriately small cuff, resulting in marked overestimation of true blood pressure, or an inappropriately large cuff, resulting in underestimation of true blood pressure. The cuff should be inflated to 30 mmHg above the expected systolic pres­ sure and the pressure released at a rate of 2–3 mmHg/s. Systolic and diastolic pressures are defined by the first and fifth Korotkoff sounds, respectively. Very low (even 0 mmHg) diastolic blood pressures may be recorded in patients with chronic, severe AR or a large arteriove­ nous fistula because of enhanced diastolic “run-off.” In these instances, both the phase IV and phase V Korotkoff sounds should be recorded. Blood pressure is best assessed at the brachial artery level, though it can be measured at the radial, popliteal, or pedal artery level. In gen­ eral, systolic pressure increases and diastolic pressure decreases when measured in more distal arteries. Blood pressure should be measured in both arms, and the difference should be <10 mmHg. A blood pres­ sure differential that exceeds this threshold may be associated with atherosclerotic or inflammatory subclavian artery disease, supravalvu­ lar aortic stenosis, aortic coarctation, or aortic dissection. Systolic leg pressures are usually as much as 20 mmHg higher than systolic arm pressures. Greater leg–arm pressure differences are seen in patients with chronic severe AR as well as patients with extensive and calcified lower extremity peripheral arterial disease. The ankle-brachial index (systolic pressure in the dorsalis pedis and/or posterior tibial artery divided by the higher of the two brachial artery pressures) is a powerful predictor of long-term cardiovascular mortality.

PART 6 Disorders of the Cardiovascular System The blood pressure measured in an office or hospital setting may not accurately reflect the pressure in other venues. “White coat hyperten­ sion” (elevated clinic blood pressure and normal out of clinic blood pressure) is defined by at least three separate clinic-based measure­ ments >130/80 mmHg and at least two non-clinic-based measure­ ments <130/80 mmHg in the absence of any evidence of target organ damage. Individuals with white coat hypertension may not benefit from drug therapy, although they may be more likely to develop sus­ tained hypertension over time. Masked hypertension (normal or low clinic blood pressure but elevated out of clinic blood pressure) should be suspected when normal or even low blood pressures are recorded in the office in patients with advanced atherosclerotic disease, especially when evidence of target organ damage is present or bruits are audible. Higher systolic blood pressures measured with a 24-h ambulatory blood pressure device are associated with a higher risk of cardiovas­ cular disease and all-cause death independent of blood pressures mea­ sured in the outpatient setting. Orthostatic hypotension is defined by a fall in systolic pressure >20 mmHg or in diastolic pressure >10 mmHg within 3 minutes of assump­ tion of the upright posture from a supine position. There may also be a lack of a compensatory tachycardia, an abnormal response that sug­ gests autonomic insufficiency, as may be seen in patients with diabetes mellitus or Parkinson’s disease. Orthostatic hypotension is a common cause of postural lightheadedness/syncope and should be assessed routinely in patients for whom this diagnosis might pertain. It can be exacerbated by advanced age, dehydration, certain medications, food, deconditioning, and ambient temperature/humidity. Arterial Pulse  The carotid artery pulse occurs just after the ascending aortic pulse. The aortic pulse is best appreciated in the epigastrium, just above the level of the umbilicus. Peripheral arterial

pulses that should be assessed routinely include the subclavian, bra­ chial, radial, ulnar, femoral, popliteal, dorsalis pedis, and posterior tibial. In patients in whom the diagnosis of either temporal arteritis or polymyalgia rheumatica is suspected, the temporal arteries also should be examined. Although one of the two pedal pulses may not be palpable in up to 10% of normal subjects, the pair should be sym­ metric. The integrity of the arcuate system of the hand is assessed by Allen’s test, which is performed routinely before instrumentation of the radial artery. The pulses should be examined for their symmetry, volume, timing, contour, amplitude, and duration. If necessary, simul­ taneous auscultation of the heart can help identify a delay in the arrival of an arterial pulse. Simultaneous palpation of the radial and femoral pulses may reveal a femoral delay in a patient with upper extremity hypertension and suspected aortic coarctation. The carotid upstrokes should never be examined simultaneously or before listening for a bruit. Light pressure should always be used to avoid precipitation of carotid hypersensitivity syndrome and syncope in a susceptible elderly individual. The arterial pulse usually becomes more rapid and spiking as a function of its distance from the heart, a phenomenon that reflects the muscular status of the more peripheral arteries and the summation of the incident and reflected waves. In general, the character and con­ tour of the arterial pulse depend on the stroke volume, ejection veloc­ ity, vascular compliance, and systemic vascular resistance. The pulse examination can be misleading in patients with reduced cardiac output and in those with stiffened arteries from aging, chronic hypertension, or peripheral arterial disease. The character of the pulse is best appreciated at the carotid level (Fig. 246-2). A weak and delayed pulse (pulsus parvus et tardus) defines severe aortic stenosis (AS). Some patients with AS may also have a slow, notched, or interrupted upstroke (anacrotic pulse) with a thrill S4 S4 S1 A2 P2 P2 S1 A2 Dicrotic notch A Dicrotic notch B S4 S4 P2 P2 A2 A2 S1 S1 Dicrotic notch C Dicrotic notch D S4 S1 A2 P2 Dicrotic notch E FIGURE 246-2  Schematic diagrams of the configurational changes in carotid pulse and their differential diagnoses. Heart sounds are also illustrated. A. Normal. S4, fourth heart sound; S1, first heart sound; A2, aortic component of second heart sound; P2, pulmonic component of second heart sound. B. Aortic stenosis. Anacrotic pulse with slow upstroke (tardus) to a reduced peak (parvus). C. Bisferiens pulse with two peaks in systole. This pulse is rarely appreciated in patients with severe aortic regurgitation. D. Bisferiens pulse in hypertrophic obstructive cardiomyopathy. There is a rapid upstroke to the first peak (percussion wave) and a slower rise to the second peak (tidal wave). E. Dicrotic pulse with peaks in systole and diastole. This waveform may be seen in patients with sepsis or during intraaortic balloon counterpulsation with inflation just after the dicrotic notch. (Reproduced with permission from K Chatterjee, W Parmley [eds]: Cardiology: An Illustrated Text/ Reference. Philadelphia, Gower Medical Publishers, 1991.)

or shudder. With chronic severe AR, by contrast, the carotid upstroke has a sharp rise and rapid fall-off (Corrigan’s or water-hammer pulse). Some patients with advanced AR may have a bifid or bisferiens pulse, in which two systolic peaks can be appreciated. A bifid pulse is also described in patients with hypertrophic obstructive cardiomyopathy (HOCM), with inscription of percussion and tidal waves. A bifid pulse is easily appreciated in patients on intraaortic balloon counterpulsation (IABP), in whom the second pulse is diastolic in timing. Pulsus paradoxus refers to a fall in systolic pressure >10 mmHg with inspiration that is seen in patients with pericardial tamponade but also is described in those with massive pulmonary embolism, hemorrhagic shock, severe obstructive lung disease, and tension pneumothorax. Pulsus paradoxus is measured by noting the difference between the systolic pressure at which the Korotkoff sounds are first heard (during expiration) and the systolic pressure at which the Korotkoff sounds are heard with each heartbeat, independent of the respiratory phase. Between these two pressures, the Korotkoff sounds are heard only intermittently and during expiration. The cuff pressure must be decreased slowly to appreciate the finding. It can be difficult to mea­ sure pulsus paradoxus in patients with tachycardia, atrial fibrillation, or tachypnea. A pulsus paradoxus may be palpable at the brachial artery or femoral artery level when the pressure difference exceeds 15 mmHg. This inspiratory fall in systolic pressure is an exaggerated consequence of interventricular dependence. Pulsus alternans, in contrast, is defined by beat-to-beat variability of pulse amplitude. It is present only when every other phase I Korotkoff sound is audible as the cuff pressure is lowered slowly, typically in a patient with a regular heart rhythm and independent of the respira­ tory cycle. Pulsus alternans is seen in patients with severe LV systolic Major arteries Ankle-brachial index Ankle systolic pressures Right common carotid a. Axillary a. Deep brachial a. Left arm, systolic pressure in the brachial a. Brachial a. Common iliac a. Radial a. Ulnar a. Deep femoral a. Femoral a. Popliteal a. Posterior tibial artery a. Left ankle, systolic pressure in the posterior tibial a. and the dorsalis pedis a. Anterior tibial artery a. Dorsalis pedis a. A B FIGURE 246-3  A. Anatomy of the major arteries of the leg. B. Measurement of the ankle systolic pressure. The ankle-brachial index (ABI) is calculated by dividing the lower of the two ankle pressures (i.e., the dorsalis pedis or posterior tibia) by the higher of the two arm pressures (i.e., left or right arm). Left and right ABIs should be recorded. (Adapted from NA Khan et al: Does the clinical examination predict lower extremity peripheral arterial disease? JAMA 295:536, 2006.)

dysfunction and is thought to be due to cyclic changes in intracel­ lular calcium and action potential duration. When pulsus alternans is associated with electrocardiographic T-wave alternans, the risk for an arrhythmic event appears to be increased.

Ascending aortic aneurysms can rarely be appreciated as a pulsatile mass in the right parasternal area. Appreciation of a prominent abdom­ inal aortic pulse should prompt noninvasive imaging with ultrasound or computed tomography for better characterization. Femoral and/or popliteal artery aneurysms should be sought in patients with abdomi­ nal aortic aneurysm disease. CHAPTER 246 Physical Examination of the Cardiovascular System
The level of a claudication-producing arterial obstruction can often be identified on physical examination (Fig. 246-3). For example, in a patient with calf claudication, a decrease in pulse amplitude between the common femoral and popliteal arteries will localize the obstruction to the level of the superficial femoral artery, although inflow obstruc­ tion above the level of the common femoral artery may coexist. Aus­ cultation for carotid, subclavian, abdominal aortic, and femoral artery bruits should be routine. However, the correlation between the pres­ ence of a bruit and the degree of vascular obstruction is poor. A cervi­ cal bruit is a weak indicator of the degree of carotid artery stenosis; the absence of a bruit does not exclude the presence of significant luminal obstruction. If a bruit extends into diastole or if a thrill is present, the obstruction is usually severe. Another cause of an arterial bruit is an arteriovenous fistula with enhanced flow. The likelihood of significant lower extremity peripheral arterial disease increases with typical symptoms of claudication, cool skin, abnormalities on pulse examination, or the presence of a vascular bruit. Abnormal pulse oximetry (a >2% difference between finger and toe oxygen saturation) can be used to detect lower extremity peripheral Dorsalis pedis a. Posterior tibial artery a.

arterial disease and is comparable in its performance characteristics to the ankle-brachial index.

Inspection and Palpation of the Heart  The LV apex beat may be visible in the midclavicular line at the fifth intercostal space in thin-chested adults. Visible pulsations anywhere other than this expected location are abnormal. The left anterior chest wall may heave in patients with an enlarged or hyperdynamic left or right ventricle. As noted previously, a visible right upper parasternal pulsation may be suggestive of ascending aortic aneurysm disease. In thin, tall patients and patients with advanced obstructive lung disease and flattened diaphragms, the cardiac impulse may be visible in the epigastrium and should be distinguished from a pulsatile liver edge. PART 6 Disorders of the Cardiovascular System Palpation of the heart begins with the patient in the supine position at 30° and can be enhanced by placing the patient in the left lateral decubitus position. The normal LV impulse is <2 cm in diameter and moves quickly away from the fingers; it is better appreciated at end expiration, with the heart closer to the anterior chest wall. Character­ istics such as size, amplitude, and rate of force development should be noted. Enlargement of the LV cavity is manifested by a leftward and down­ ward displacement of an enlarged apex beat. A sustained apex beat is a sign of pressure overload, such as that which may be present in patients with AS or chronic hypertension. A palpable presystolic impulse corresponds to the fourth heart sound (S4) and is indicative of reduced LV compliance and the forceful contribution of atrial contraction to ventricular filling. A palpable third sound (S3), which is indicative of a rapid early filling wave in patients with heart failure, may be pres­ ent even when the gallop itself is not audible. A large LV aneurysm may sometimes be palpable as an ectopic impulse, discrete from the apex beat and often dyskinetic. HOCM may very rarely cause a triple cadence beat at the apex with contributions from a palpable S4 and the two components of the bisferiens systolic pulse. Right ventricular pressure or volume overload may create a sternal lift. Signs of either TR (cv waves in the jugular venous pulse) and/or pulmonary arterial hypertension (a loud single or palpable P2) would be confirmatory. The right ventricle can enlarge to the extent that left-sided events are obscured. A zone of retraction between the right ventricular and LV impulses sometimes can be appreciated in patients with right ventricle pressure or volume overload when they are placed in the left lateral decubitus position. Systolic and diastolic thrills signify turbulent and high-velocity blood flow. Their locations help identify the origin of heart murmurs. ■ ■CARDIAC AUSCULTATION Heart Sounds  Ventricular systole is defined by the interval between the first (S1) and second (S2) heart sounds (Fig. 246-4). The first heart sound (S1) includes mitral and tricuspid valve closure. Normal split­ ting can be appreciated in young patients and those with right bundle branch block, in whom tricuspid valve closure is relatively delayed. The intensity of S1 is determined by the distance over which the anterior leaflet of the mitral valve must travel to return to its annular plane, leaf­ let mobility, LV contractility, and the PR interval. S1 is classically loud in the early phases of rheumatic MS and in patients with hyperkinetic circulatory states or short PR intervals. S1 becomes softer in the later stages of MS when the leaflets are rigid and calcified, after exposure to β-adrenergic receptor blockers, with long PR intervals, and with LV contractile dysfunction. The intensity of heart sounds, however, can be reduced by any process that increases the distance between the stethoscope and the responsible cardiac event, including mechanical ventilation, obstructive lung disease, obesity, pneumothorax, and a pericardial effusion. Aortic and pulmonic valve closure constitutes the second heart sound (S2). With normal or physiologic splitting, the A2–P2 interval increases with inspiration and narrows during expiration. This physi­ ologic interval will widen with right bundle branch block because of the further delay in pulmonic valve closure and in patients with severe MR because of the premature closure of the aortic valve. An unusually

EXPIRATION INSPIRATION A2 P2 A2 P2 A Normal S1 S2 S1 S2 A2 P2 A2 P2 B Atrial septal

defect S1 S2 S1 S2 A2 P2 A2 P2 C Expiratory splitting

with inspiratory

increase (RBBB,

idiopathic dilatation PA) S1 S2 S1 S2 A2 P2 A2 P2 D Reversed splitting

(LBBB, aortic

stenosis) S1 S2 S1 S2 A2 P2 A2 P2 E Close fixed

splitting

(pulmonary

hypertension) S1 S2 S1 S2 FIGURE 246-4  Heart sounds. A. Normal. S1, first heart sound; S2, second heart sound; A2, aortic component of the second heart sound; P2, pulmonic component of the second heart sound. B. Atrial septal defect with fixed splitting of S2. C. Physiologic but wide splitting of S2 with right bundle branch block (RBBB). PA, pulmonary artery. D. Reversed or paradoxical splitting of S2 with left bundle branch block (LBBB). E. Narrow splitting of S2 with pulmonary hypertension. (Reproduced with permission from NO Fowler: Diagnosis of Heart Disease, Springer Nature; 1991.) narrowly split or even a singular S2 is a feature of pulmonary arterial hypertension. Fixed splitting of S2, in which the A2–P2 interval is wide and does not change during the respiratory cycle, occurs in patients with a secundum atrial septal defect (ASD). Reversed or paradoxical splitting refers to a pathologic delay in aortic valve closure, such as that which occurs in patients with left bundle branch block, right ventricu­ lar pacing, severe AS, HOCM, and acute myocardial ischemia. With reversed or paradoxical splitting, the individual components of S2 are audible at end expiration, and their interval narrows with inspiration, the opposite of what would be expected under normal physiologic conditions. P2 is considered loud when its intensity exceeds that of A2 at the base, when it can be palpated in the area of the proximal main pulmonary artery (second left interspace), or when both components of S2 can be appreciated at the lower left sternal border or apex. The intensity of A2 and P2 decreases with AS and pulmonic stenosis (PS), respectively. In these conditions, a single S2 may result. Systolic Sounds  An ejection sound is a high-pitched early systolic sound that corresponds in timing to the upstroke of the carotid pulse. It usually is associated with congenital bicuspid aortic or pulmonic valve disease; however, ejection sounds are also sometimes audible in patients with isolated aortic or pulmonary root dilation and normal semilunar valves. The ejection sound that accompanies bicuspid aortic valve disease becomes softer and then inaudible as the valve calcifies and becomes more rigid. The ejection sound that accompanies PS moves closer to the first heart sound as the severity of the stenosis increases. In addition, the pulmonic ejection sound is the only rightsided acoustic event that decreases in intensity with inspiration. Ejec­ tion sounds are often heard more easily at the lower left sternal border than they are at the base. Nonejection sounds (clicks), which occur after the onset of the carotid upstroke, are related to MVP and may be single or multiple. The nonejection click may introduce a murmur. This click-murmur complex will move away from the first heart sound with maneuvers that increase ventricular preload, such as squatting. On standing, the click and murmur move closer to S1.

Diastolic Sounds  The high-pitched opening snap (OS) of MS occurs after a very short interval after the second heart sound. The A2–OS interval is inversely proportional to the height of the left atrial–left ventricular diastolic pressure gradient. The intensity of both S1 and the OS of MS decreases with progressive calcification and rigid­ ity of the anterior mitral leaflets. The pericardial knock (PK) is also high-pitched and occurs slightly later than the OS, corresponding in timing to the abrupt cessation of ventricular expansion after tricuspid valve opening and to an exaggerated y descent seen in the jugular venous waveform in patients with constrictive pericarditis. A tumor plop is a lower-pitched sound that rarely can be heard in patients with atrial myxoma. It may be appreciated only in certain positions and arises from the diastolic prolapse of the tumor across the mitral valve. The third heart sound (S3) occurs during the rapid filling phase of ventricular diastole. It can be a normal finding in children, adolescents, and young adults; however, in older patients, it signifies heart failure. A left-sided S3 is a low-pitched sound best heard over the LV apex. A right-sided S3 is usually better heard over the lower left sternal border and becomes louder with inspiration. A left-sided S3 in patients with chronic heart failure is predictive of cardiovascular morbidity and mortality. Interestingly, an S3 is equally prevalent among heart failure patients with preserved and reduced LV ejection fraction. The fourth heart sound (S4) occurs during the atrial filling phase of ventricular diastole and indicates LV presystolic expansion. An S4 is more common among patients who derive significant benefit from the atrial contribution to ventricular filling, such as those with chronic LV hypertrophy or active myocardial ischemia. An S4 is not present with atrial fibrillation. Cardiac Murmurs  Heart murmurs result from audible vibrations that are caused by increased turbulence and are defined by their timing within the cardiac cycle. Not all murmurs are indicative of structural heart disease, and the accurate identification of a benign or functional systolic murmur often can obviate the need for additional testing in healthy subjects, especially children and adolescents. The duration, frequency, configuration, and intensity of a heart murmur are dictated by the magnitude, variability, and duration of the responsible pressure difference between two cardiac chambers, the two ventricles, or the ventricles and their respective great arteries. The intensity of a heart murmur is graded on a scale of 1 to 6; a thrill is present with murmurs of grade 4 or greater intensity. Other attributes of the murmur that aid in its accurate identification include its location, radiation, and response to bedside maneuvers. Although clinicians can detect and correctly identify heart murmurs with only fair reliability, a careful and complete bedside examination usually can identify individuals with valvular heart disease for whom transthoracic echocardiography and clinical follow-up are indicated and exclude subjects for whom no further evaluation is necessary. Systolic murmurs can be early, mid, late, or holosystolic in timing (Fig. 246-5). Acute severe MR results in a decrescendo early systolic murmur, the characteristics of which are related to the progressive attenuation of the LV to left atrial pressure gradient during systole because of the steep and rapid rise in left atrial pressure in this context. Severe MR associated with posterior leaflet prolapse or flail radiates anteriorly and to the base, where it can be confused with the murmur of AS. MR that is due to anterior leaflet involvement radiates posteri­ orly and to the axilla. With acute TR in patients with normal pulmo­ nary artery pressures, an early systolic murmur that may increase in intensity with inspiration may be heard at the left lower sternal border, with regurgitant cv waves visible in the jugular venous pulse. A midsystolic murmur begins after S1 and ends before S2; it is typi­ cally crescendo-decrescendo in configuration. AS is the most com­ mon cause of a midsystolic murmur in an adult. It is often difficult to estimate the severity of the valve lesion on the basis of the physi­ cal examination findings, especially in older hypertensive patients with stiffened carotid arteries or patients with low cardiac output in whom the intensity of the systolic heart murmur is misleadingly soft. Examination findings consistent with severe AS would include parvus et tardus carotid upstrokes, a late-peaking grade 3 or greater

ECG ECG LVP AOP LVP CHAPTER 246 LAP HSM EDM Physical Examination of the Cardiovascular System
S1 S2 S1 A2 ECG ECG LVP LVP AOP LAP MSM PSM MDM S1 A2 S1 S2 A B FIGURE 246-5  A. Top. Graphic representation of the systolic pressure difference (green shaded area) between left ventricle and left atrium with phonocardiographic recording of a holosystolic murmur (HSM) indicative of mitral regurgitation. ECG, electrocardiogram; LAP, left atrial pressure; LVP, left ventricular pressure; S1, first heart sound; S2, second heart sound. Bottom. Graphic representation of the systolic pressure gradient (green shaded area) between left ventricle and aorta in patient with aortic stenosis. A midsystolic murmur (MSM) with a crescendo-decrescendo configuration is recorded. AOP, aortic pressure. B. Top. Graphic representation of the diastolic pressure difference between the aorta and left ventricle (blue shaded area) in a patient with aortic regurgitation, resulting in a decrescendo, early diastolic murmur (EDM) beginning with A2. Bottom. Graphic representation of the diastolic left atrial–left ventricular gradient (blue areas) in a patient with mitral stenosis with a mid-diastolic murmur (MDM) and late presystolic murmurs (PSM). midsystolic murmur, a soft A2, a sustained LV apical impulse, and an S4. It is sometimes difficult to distinguish aortic sclerosis from more advanced degrees of valve stenosis. The former is defined by focal thickening and calcification of the aortic valve leaflets that is not severe enough to result in obstruction. These valve changes are associ­ ated with a Doppler jet velocity across the aortic valve of 2.5 m/s or less. Patients with aortic sclerosis can have grade 2 or 3 midsystolic murmurs identical in their acoustic characteristics to the murmurs heard in patients with more advanced degrees of AS. Other causes of a midsystolic heart murmur include pulmonic valve stenosis (with or without an ejection sound), HOCM, increased pulmonary blood flow in patients with a large ASD and left-to-right shunting, and several states associated with accelerated blood flow in the absence of struc­ tural heart disease, such as fever, thyrotoxicosis, pregnancy, anemia, and normal childhood/adolescence. The murmur of HOCM has features of both obstruction to LV out­ flow and MR, as would be expected from knowledge of the pathophysi­ ology of this condition. The systolic murmur of HOCM usually can be distinguished from other causes on the basis of its response to bedside maneuvers, including Valsalva, passive leg raising, and standing/ squatting. In general, maneuvers that decrease LV preload (or increase LV contractility) will cause the murmur to intensify, whereas maneu­ vers that increase LV preload or afterload will cause a decrease in the intensity of the murmur. Accordingly, the systolic murmur of HOCM becomes louder during the strain phase of the Valsalva maneuver and after standing quickly from a squatting position. The murmur becomes softer with passive leg raising and when squatting. The murmur of AS is typically loudest in the second right interspace with radiation into the carotids, whereas the murmur of HOCM is best heard between the lower left sternal border and the apex. The murmur of PS is best heard in the second left interspace. The midsystolic murmur associated with enhanced pulmonic blood flow in the setting of a large ASD is usually loudest at the mid-left sternal border.

A late systolic murmur, heard best at the apex, indicates MVP. As previously noted, the murmur may or may not be introduced by one or more nonejection clicks. Differential radia­ tion of the murmur, as previously described, may help identify the specific leaflet involved by the myxomatous process. The click-murmur complex behaves in a manner directionally similar to that demonstrated by the murmur of HOCM during the Valsalva and stand/squat maneuvers (Fig. 246-6). The murmur of MVP can be identified by the accompanying nonejec­ tion click.

PART 6 Disorders of the Cardiovascular System Holosystolic murmurs are plateau in con­ figuration and reflect a continuous and wide pressure gradient between the left ventricle and left atrium with chronic MR, the left ventricle and right ventricle with a ventricular septal defect (VSD), and the right ventricle and right atrium with TR. In contrast to acute MR, in chronic MR, the left atrium is enlarged and its compliance is normal or increased to the extent that there is little if any further increase in left atrial pressure from any increase in regurgitant volume. The murmur of MR is best heard over the cardiac apex. The intensity of the murmur increases with maneuvers that increase LV afterload, such as sustained hand grip. The murmur of a VSD (without significant pulmo­ nary hypertension) is holosystolic and loudest at the mid-left sternal border, where a thrill is usually present. The murmur of TR is loud­ est at the lower left sternal border, increases in intensity with inspiration (Carvallo’s sign), and is accompanied by visible cv waves in the jugular venous wave form and, on occasion, by pulsatile hepatomegaly. S1 S1 C C M M S2 S2 FIGURE 246-6  Behavior of the click (C) and murmur (M) of mitral valve prolapse with changes in loading (volume, impedance) and contractility. S1, first heart sound; S2, second heart sound. With standing (left side of figure), volume and impedance decrease, as a result of which the click and murmur move closer to S1. With squatting (right), the click and murmur move away from S1 due to the increases in left ventricular volume and impedance (afterload). Ao, aorta; LV, left ventricle. (Adapted from RA O’Rourke, MH Crawford: Curr Prob Cardiol 1:9, 1976.) Diastolic Murmurs  In contrast to some systolic murmurs, dia­ stolic heart murmurs always signify structural heart disease (Fig. 246-5). The murmur associated with acute, severe AR is relatively soft and of short duration because of the rapid rise in LV diastolic pressure and the progressive diminution of the aortic-LV diastolic pressure gradient. In contrast, the murmur of chronic severe AR is classically heard as a decrescendo, blowing diastolic murmur along the left sternal border in patients with primary valve pathology and sometimes along the right sternal border in patients with primary aortic root pathology. When the jet of AR is directed posteriorly along the anterior leaflet of the mitral valve, the intensity of the murmur may be attenuated, and sever­ ity of the valve lesion underestimated. Detection of subtle AR murmurs can be enhanced by auscultation and end-expiration with the patient leaning forward. With chronic, severe AR, the pulse pressure is wide and the arterial pulses are bounding in character. Signs of significant diastolic run-off are often absent in the acute phase. The murmur of pulmonic regurgitation is also heard along the left sternal border. It is most commonly due to pulmonary hypertension and enlargement of the annulus of the pulmonic valve. S2 is single and loud and may be palpable. There is a right ventricular/parasternal lift that is indicative of chronic right ventricular pressure overload. A less impressive murmur of PR is present after repair of tetralogy of Fallot or pulmonic valve atresia. In this postoperative setting, the murmur is softer and lowerpitched, and the severity of the accompanying pulmonic regurgitation can be underestimated significantly. MS is the classic cause of a mid- to late-diastolic murmur, which is best heard over the apex in the left lateral decubitus position, is lowpitched or rumbling, and is introduced by an OS in the early stages of the rheumatic disease process. Presystolic accentuation refers to an increase in the intensity of the murmur just before the first heart sound and occurs in patients with sinus rhythm. It is absent in patients with atrial fibrillation. The auscultatory findings in patients with rheumatic

Impedance Ao LV Contractility Volume tricuspid stenosis typically are obscured by left-sided events, although they are similar in nature to those described in patients with MS. “Functional” mitral or tricuspid stenosis refers to the generation of mid-diastolic murmurs that are created by increased and accelerated transvalvular diastolic flow, even in the absence of valvular obstruc­ tion, in the setting of severe MR, severe TR, or a large ASD with leftto-right shunting. The Austin Flint murmur of chronic severe AR is a low-pitched mid- to late apical diastolic murmur that sometimes can be confused with MS. The Austin Flint murmur typically decreases in intensity after exposure to vasodilators, whereas the murmur of MS may be accompanied by an OS and also may increase in intensity after vasodilators because of the associated increase in cardiac output. Unusual causes of a mid-diastolic murmur include atrial myxoma, complete heart block, and acute rheumatic mitral valvulitis. Continuous Murmur  A continuous murmur is predicated on a pressure gradient that persists between two cardiac chambers or blood vessels across systole and diastole. The murmurs typically begin in systole, envelop the second heart sound (S2), and continue through some portion of diastole. They can often be difficult to dis­ tinguish from individual systolic and diastolic murmurs in patients with mixed valvular heart disease. The classic example of a continu­ ous murmur is that associated with a PDA, which usually is heard in the second or third interspace at a slight distance from the sternal border. Other causes of a continuous murmur include a ruptured sinus of Valsalva aneurysm with creation of an aortic–right atrial or right ventricular fistula, a coronary or great vessel arteriovenous fistula, and an arteriovenous fistula constructed to provide dialysis access. There are two types of benign continuous murmurs. The cervical venous hum is heard in children or adolescents in the supra­ clavicular fossa. It can be obliterated with firm pressure applied to the diaphragm of the stethoscope, especially when the subject turns their head toward the examiner. The mammary soufflé of pregnancy relates to enhanced arterial blood flow through engorged breasts. The diastolic component of the murmur can be obliterated with firm pres­ sure over the stethoscope.

TABLE 246-1  Effects of Physiologic Interventions on the Intensity of Heart Murmurs and Sounds Respiration Right-sided murmurs and sounds generally increase with inspiration, except for the PES. Left-sided murmurs and sounds are usually louder during expiration. Valsalva Maneuver Most murmurs decrease in length and intensity. Two exceptions are the systolic murmur of HOCM, which usually becomes much louder, and that of MVP, which becomes longer and often louder. After release of the Valsalva maneuver, right-sided murmurs tend to return to control intensity earlier than do left-sided murmurs. After VPB or AF Murmurs originating at normal or stenotic semilunar valves increase in the cardiac cycle after a VPB or in the cycle after a long cycle length in AF. By contrast, systolic murmurs due to AV valve regurgitation do not change or become shorter (MVP). Positional Changes With standing, most murmurs diminish, with two exceptions being the murmur of HOCM, which becomes louder, and that of MVP, which lengthens and often is intensified. With squatting, most murmurs become louder, but those of HOCM and MVP usually soften and may disappear. Passive leg raising usually produces the same results. Exercise Murmurs due to blood flow across normal or obstructed valves (e.g., PS, MS) become louder with both isotonic and submaximal isometric (hand grip) exercise. Murmurs of MR, VSD, and AR also increase with hand grip exercise. However, the murmur of HOCM often decreases with nearly maximum hand grip exercise. Left-sided S4 and S3 sounds are often accentuated by exercise, particularly when due to ischemic heart disease. Abbreviations: AF, atrial fibrillation; AR, aortic regurgitation; HOCM, hypertrophic obstructive cardiomyopathy; MR, mitral regurgitation; MS, mitral stenosis; MVP, mitral valve prolapse; PES, pulmonic ejection sound; PR, pulmonic regurgitation; PS, pulmonic stenosis; TR, tricuspid regurgitation; TS, tricuspid stenosis; VPB, ventricular premature beat; VSD, ventricular septal defect. Dynamic Auscultation  Diagnostic accuracy can be enhanced by the performance of simple bedside maneuvers to identify heart murmurs and characterize their significance (Table 246-1). Except for the pulmonic ejection sound, right-sided events increase in intensity with inspiration and decrease with expiration; left-sided events behave oppositely (100% sensitivity, 88% specificity). As previously noted, the intensity of the murmurs associated with MR, VSD, and AR will increase in response to maneuvers that increase LV afterload, such as hand grip and vasopressors. The intensity of these murmurs will decrease after exposure to vasodilating agents. Squatting is associated with an abrupt increase in LV preload and afterload, whereas rapid standing results in a sudden decrease in preload. In patients with MVP, the click and murmur move away from the first heart sound with squatting because of the delay in onset of leaflet prolapse at higher ventricular volumes. With rapid standing, however, the click and murmur move closer to the first heart sound as prolapse occurs earlier in systole at a smaller chamber dimension. The murmur of HOCM behaves similarly, becoming softer and shorter with squatting (95% sensitivity, 85% specificity) and longer and louder on rapid standing (95% sensitivity, 84% specificity). A change in the intensity of a systolic murmur in the first beat after a premature beat or in the beat after a long cycle length in patients with atrial fibrillation suggests valvular AS rather than MR, particularly in an older patient in whom the murmur of the AS may be well transmitted to the apex (Gallavardin effect). Of note, however, the systolic murmur of HOCM also increases in intensity in the beat after a premature beat. This increase in intensity of any LV outflow murmur in the beat after a premature beat relates to the combined effects of enhanced LV filling (from the longer diastolic period) and postextrasystolic potentiation of LV contractile function. In either instance, forward flow will accelerate, causing an increase in the gradient across the LV outflow tract (dynamic or fixed) and a louder systolic murmur. In contrast, the intensity of the murmur of MR does not change in a postpremature beat, because there is relatively little change in the nearly constant LV to left atrial pressure gradient or

further alteration in mitral valve flow. Bedside exercise can sometimes be performed to increase cardiac output and, secondarily, the intensity of both systolic and diastolic heart murmurs. Most left-sided heart murmurs decrease in intensity and duration during the strain phase of the Valsalva maneuver. The murmurs associated with MVP and HOCM are the two notable exceptions. The Valsalva maneuver also can be used to assess the integrity of the heart and vasculature in the setting of advanced heart failure.

CHAPTER 246 Prosthetic Heart Valves  The first clue that prosthetic valve dysfunction may contribute to recurrent symptoms is frequently a change in the quality of the heart sounds or the appearance of a new murmur. The heart sounds with a bioprosthetic valve resemble those generated by native valves. A mitral bioprosthesis usually may be associated with a grade 1 to 2 midsystolic murmur along the left sternal border (created by turbulence across the valve struts as they project into the LV outflow tract) as well as by a soft mid-diastolic murmur that occurs with normal LV filling. This diastolic murmur often can be heard only in the left lateral decubitus position and after exercise. A high-pitched or holosystolic apical murmur is indicative of pathologic MR due to a paravalvular leak and/or intra-annular bioprosthetic regurgitation from leaflet degeneration, for which diagnostic noninvasive imaging is indicated. Clinical deterioration can occur rapidly after the first expression of mitral bioprosthetic valve failure. A tissue valve in the aortic position is always associated with a grade 1 to 3 midsystolic murmur at the base or just below the suprasternal notch. A diastolic murmur of AR is abnormal in any circumstance. Mechanical valve dysfunction may first be suggested by a decrease in the intensity of either the opening or the closing sound. A high-pitched apical systolic murmur in patients with a mechanical mitral prosthesis and a diastolic decrescendo murmur in patients with a mechanical aortic prosthesis indicate paravalvular regurgita­ tion. Patients with prosthetic valve thrombosis may present clinically with signs of shock, muffled heart sounds, and soft murmurs in both systole and diastole. Pericardial Disease  A pericardial friction rub is nearly 100% specific for the diagnosis of acute pericarditis, although the sensitivity of this finding is not nearly as high, because the rub may come and go over the course of an acute illness or be very difficult to elicit. The rub is heard as a leathery or scratchy three-component or two-component sound, although it may be monophasic. Classically, the three com­ ponents are ventricular systole, rapid early diastolic filling, and late presystolic filling after atrial contraction in patients in sinus rhythm. It is necessary to listen to the heart in several positions. Additional clues to the presence of acute pericarditis may be present from the history and 12-lead electrocardiogram. The rub typically disappears as the volume of any pericardial effusion increases. Pericardial tamponade can be diagnosed with a sensitivity of 98%, a specificity of 83%, and a positive likelihood ratio of 5.9 (95% confidence interval 2.4–14) by a pulsus paradoxus that exceeds 12 mmHg in a patient with a large pericardial effusion. Physical Examination of the Cardiovascular System
The findings on physical examination are integrated with the symptoms previously elicited with a careful history to construct an appropriate differential diagnosis and proceed with indicated imaging and laboratory assessment. The physical examination is an irreplace­ able component of clinician-patient interaction. Educational efforts to enhance competence may result in improved diagnostic efficiency. The adjunctive use of point-of-care ultrasound and artificial intelligence tools is expected to increase. ■ ■FURTHER READING Chamsi-Pasha MA et al: Handheld echocardiography: Current state and future perspectives. Circulation 136:2178, 2017. Drazner MH et al: Value of clinician assessment of hemodynamics in advanced heart failure: The ESCAPE trial. Circ Heart Fail 1:170, 2008. Fanaroff AC et al: Does this patient with chest pain have acute coronary syndrome? The Rational Clinical Examination Systematic Review. JAMA 314:1955, 2015.

07 - 247 Electrocardiography

247 Electrocardiography

Fang LC et al: History, physical examination, and the virtual visit.

An evidence-based approach, in Braunwald’s Heart Disease. A Textbook of Cardiovascular Medicine, 12th ed, RO Bonow et al (eds). Philadelphia, Elsevier/Saunders, 2022, p. 123. Jani V et al: The discerning ear: Cardiac auscultation in the era of artificial intelligence and telemedicine. Eur Heart J Digit Health 2:456, 2021. PART 6 Disorders of the Cardiovascular System Ary L. Goldberger

Electrocardiography An electrocardiogram (ECG or EKG) is a graphical representation of electrical activity generated by the heart. The signals, detected by means of metallic electrodes attached to the extremities and chest wall, are amplified and recorded by the electrocardiograph device. ECG leads are configured to display the instantaneous differences in electrical potentials between specific sets of electrodes. The utility of the ECG derives from its immediate availability as a noninvasive, inexpensive, and highly versatile test. In addition to its use in detecting arrhythmias, conduction disturbances, and myocardial ischemia/infarction, the ECG may reveal findings related to life-threatening metabolic distur­ bances, drug toxicities, and increased susceptibility to sudden cardiac arrest (see also Chaps. 317 and 420). The importance of electrocar­ diologic abnormalities in the diagnosis, prognosis, and management of muscular dystrophies and other hereditary neuromuscular diseases is discussed separately (see Chap. 360). ■ ■ELECTROPHYSIOLOGIC BACKGROUND Depolarization of the heart is the initiating event for cardiac contrac­ tion. The electrical currents that spread through the heart are produced by three components: cardiac pacemaker cells, specialized conduction tissue, and the heart muscle itself. The ECG records only the depolar­ ization (stimulation) and repolarization (recovery) electrical activity generated by the “working” atrial and ventricular myocardium (see also Chaps. 251 and 253). The stimulus initiating the normal heartbeat originates in the sinoatrial (SA) node (Fig. 247-1), which possesses spontaneous auto­ maticity. Spread of the depolarization wave through the right and left atria induces contraction of these chambers. Next, the impulse LA Sinoatrial (SA) node Ventricular myocardium AV junction AV node RA His bundle LV Purkinje fibers RV Left bundle branch Right bundle branch Ventricular septum FIGURE 247-1  Schematic of the cardiac conduction system. AV, atrioventricular; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

stimulates specialized conduction tissues in the atrioventricular (AV) nodal and His-bundle areas; together, these two regions constitute the AV junction. The bundle of His bifurcates into two main divisions, the right and left bundle branches, which rapidly transmit depolariza­ tion wavefronts in a synchronous way to the right and left ventricu­ lar myocardium via the Purkinje fibers. The main left bundle fans out into left anterior and left posterior fascicular subdivisions. The depolarization wavefronts then spread through the ventricular wall, from endocardium to epicardium, triggering coordinated ventricu­ lar contraction. Since the cardiac depolarization and repolarization wavefronts have direction and magnitude, they can be represented by vectors. ■ ■BASIC ECG WAVEFORMS AND INTERVALS The ECG waveforms are labeled alphabetically, beginning with the P wave, which represents atrial depolarization (Fig. 247-2). The QRS complex represents ventricular depolarization; the ST-T-U complex (ST segment, T wave, and U wave) represents ventricular repolariza­ tion. The J point is the junction between the end of the QRS complex and the beginning of the ST segment. Atrial repolarization waveforms (ST-Ta) are usually too low in amplitude to be detected, but they may become apparent in acute pericarditis, atrial infarction, and AV heart block syndromes. The QRS-T waveforms of the surface ECG correspond to sequential phases of simultaneously obtained ventricular action potentials, the intracellular recordings from single myocardial fibers (Chap. 251). The rapid upstroke (phase 0) of the action potential corresponds to the onset of QRS. The plateau (phase 2) corresponds to the isoelectric ST segment, and active repolarization (phase 3) corresponds to the inscription of the T wave. Factors that decrease the slope of phase 0 by impairing the influx of Na+ (e.g., hyperkalemia and drugs such as flecainide) tend to increase QRS duration. Factors that prolong phase 2 or 3 (e.g., amiodarone, hypocalcemia) increase the QT interval. In contrast, factors (e.g., hypercalcemia, digoxin) associated with short­ ening of ventricular repolarization duration abbreviate the QT. The hereditary short QT syndrome and its relationship to sudden cardiac arrest are discussed in Chap. 262. The ECG is usually recorded on graph paper divided into a grid of 1-mm2 boxes. When the recording (sweep) speed is 25 mm/s, the smallest (1 mm) horizontal divisions correspond to 40 ms (0.04 s), with heavier lines at intervals of 200 ms (0.20 s). Vertically, the ECG graph measures the amplitude of a specific wave or deflection (1 mV = 10 mm with standard calibration; the voltage criteria for hypertrophy mentioned below are given in millimeters). There are four major sets of ECG intervals: RR, PR, QRS, and QT/QTc (Fig. 247-2). The instan­ taneous heart rate (beats per minute) can be computed from the inter­ beat (RR) interval by dividing the number of large (0.20 s) time units QRS T P ST U J PR interval QRS interval QT interval FIGURE 247-2  Basic ECG waveforms and intervals. Not shown is the RR interval, the time between consecutive QRS complexes.

between consecutive R waves into 300 or the number of small (40 ms) segments into 1500. The PR interval measures the time (normally 120–200 ms) between atrial and ventricular depolarization, which includes the physiologic delay imposed by stimulation of cells in the AV junction area. The QRS interval (normally 100–110 ms or less) reflects the duration of ventricular depo­ larization. The QT interval subtends both ventricular depolarization and (primarily) repolarization times and varies inversely with the heart rate. A variety of formulas has been proposed for computing a rate-corrected QT interval, termed QTc, but without formal consensus. The classic “square root” formula (QTc = QT/√RR, computed in second units) has been criticized for systematic errors at both lower and higher heart rates. One alternative is the Framingham formula (given here for units of mil­ liseconds): QTc = QT + 0.154 (1000 – RR). The following upper normal limits (based visually on the longest QT) have been proposed: QTc of 460 ms in women and 450 ms in men. Lower limits are less well defined. Visual or electronic QT/QTc mea­ surements should be assessed in light of inherent limitations in their precise determination from standard ECGs waveforms. Right Left A FIGURE 247-3  The six frontal plane (A) and six horizontal plane (B) leads provide a threedimensional representation of cardiac electrical activity. ■ ■ECG LEADS The 12 conventional ECG leads are divided into two groups: six limb (extremity) leads and six chest (precordial) leads. The limb leads record potentials transmitted onto the frontal plane (Fig. 247-3A); the chest leads record potentials transmitted onto the horizontal plane (Fig. 247-3B). The orientation and polarity of the frontal plane leads are repre­ sented on a hexaxial diagram (Fig. 247-4). The six chest leads are obtained by exploring electrodes as shown in Fig. 247-5. Each lead is analogous to a different video camera angle “look­ ing” at the same events—atrial and ventricular depolarization and repolarization—from different spatial orientations. The 12-lead ECG can be supplemented with additional leads in special circumstances. For example, right precordial leads V3R to V6R are useful in detect­ ing evidence of acute right ventricular ischemia/infarction. Bedside monitors and ambulatory ECGs (e.g., Holter monitors, event recorders, patch electrode and other medical wearable devices) usually employ

Le ft on ax ti is ia d ev ev d ia is –90° –aVF –60° –III ti ax on –120° –II e m e tr Ex –150° +aVR –30° +aVL

0° +I 180° –I

+30° –aVR +150° –aVL

Ri gh t ax s +60° +II +90° +aVF xi is +120° +III a d al ev m ia or ti N on

FIGURE 247-4  The frontal plane (limb or extremity) leads are represented on a hexaxial diagram. Each ECG lead has a specific spatial orientation and polarity. The positive pole of each lead axis (solid line) and the negative pole (hatched line) are designated by their angular position relative to the positive pole of lead I (0°). The mean electrical axis of the QRS complex is measured with respect to this display.

Posterior Superior CHAPTER 247 – – – – – Right Left + aVR aVL – ––– + + V6 – I + – – + V5 Electrocardiography + + + + + + + V4 V3 V2 V1 II III aVF B Anterior Inferior only one or two modified leads. The standard ECG leads are config­ ured such that a positive (upright) deflection is recorded in a lead if a wave of depolarization spreads toward the positive pole of that lead, and a negative deflection is recorded if the wave spreads toward the negative pole. If the mean orientation of the depolarization vector is at right angles to a particular lead axis, a biphasic (equally positive and negative) deflection will be inscribed. GENESIS OF THE NORMAL ECG ■ ■P WAVE The normal atrial depolarization vector is oriented downward and toward the subject’s left, reflecting the spread of depolarization from the sinus node to the right and then the left atrial myocardium. Since this vector points toward the positive pole of lead II and toward the negative pole of lead aVR, the sinus-generated P wave will be positive in lead II and negative in aVR. By contrast, activation of the atria from an ectopic pacemaker in the lower part of either atrium or in the AV junc­ tion region may produce retrograde P waves (negative in II, positive in aVR). The normal P wave in lead V1 may be biphasic with a positive component reflecting right atrial depolarization, followed by a small (<1 mm2) negative component reflecting left atrial depolarization. ■ ■QRS COMPLEX Normal ventricular depolarization proceeds as a rapid, continuous spread of activation wave fronts. This complex process can be divided V1 V2 V3R V3 V4 V5 V6 V4R FIGURE 247-5  The horizontal plane (chest or precordial) leads are obtained with electrodes in the locations shown. Additional posterior leads are sometimes placed on the same horizontal plane as V4 to facilitate detection of acute posterolateral infarction (V7, midaxillary line; V8, posterior axillary line; and V9, posterior scapular line). Right chest leads (V3R–V6R) may enhance detection of right ventricular involvement in the context of inferior infarction.

r RV LV

q V6 V1 PART 6 Disorders of the Cardiovascular System A V1 R r RV LV V1 V6

q B S – – – – – –

V6 + V5 + + + + V1 V2 V3 V4 C FIGURE 247-6  Ventricular depolarization can be divided into two major phases, each represented by a vector. A. The first phase (arrow 1) denotes depolarization of the ventricular septum, beginning on the left side and spreading to the right. This process is represented by a small “septal” r wave in lead V1 and a small septal q wave in lead V6. B. Simultaneous depolarization of the left and right ventricles (LV and RV) constitutes the second phase. Vector 2 is oriented to the left and posteriorly, reflecting the electrical predominance of the LV. C. Vectors (arrows) representing these two phases are shown in reference to the horizontal plane leads. (Reproduced with permission from AL Goldberger et al: Goldberger’s Clinical Electrocardiography: A Simplified Approach, 10th ed. Philadelphia, Elsevier, 2024.) into two major sequential phases, and each can be represented by a mean vector (Fig. 247-6). The first and shortest phase is depolarization of the interventricular septum, proceeding from the left to the right and anteriorly (vector 1). The second and major phase results from the simultaneous depolarization of the right and left ventricles (vector 2). This phase is normally dominated by the more massive left ventricle, so that vec­ tor 2 points leftward and posteriorly. Therefore, a right precordial lead (V1) will record this biphasic depolarization process with a small positive deflection (septal r wave) followed by a larger negative deflection (S wave). A left precordial lead, for example, V6, will record the same sequence with a small negative deflection (septal q wave) fol­ lowed by a relatively tall positive deflec­ tion (R wave). Intermediate leads show a relative increase in R-wave amplitude (normal R-wave progression) and a decrease in S-wave amplitude progress­ ing across the chest from right to left. The lead where the R and S waves are of about equal amplitude is referred to as the transition zone (usually V3 or V4) (Fig. 247-7). aVR I II III FIGURE 247-7  Normal electrocardiogram from a healthy male subject. Sinus rhythm is present with a heart rate of 75 beats per minute. PR interval is 160 ms; QRS interval (duration) is 80 ms; QT interval is 360 s; QTc (Framingham formula) is about 390 ms; the mean QRS axis is about +70°. The precordial leads show normal R-wave progression with the transition zone (R wave ≈ S wave) in lead V3.

The QRS pattern in the extremity leads may vary considerably from one normal subject to another depending on the electrical axis of the QRS, which describes the mean orientation of the QRS vector with reference to the six frontal plane leads. Normally, the QRS axis ranges from –30° to +100° (Fig. 247-4). An axis more negative than –30° is referred to as left axis deviation, and an axis more positive than +90 to +100° is referred to as right axis deviation. Left axis deviation may occur as a normal variant but is more commonly associated with left ventricular hypertrophy, a block in the anterior fascicle of the left bundle system (left anterior fascicular block or hemiblock), or inferior myocardial infarction. Right axis deviation also may occur as a normal variant (particularly in children and young adults), as a spurious find­ ing due to reversal of the left and right arm electrodes, or in conditions such as right ventricular overload (acute or chronic), lateral infarction, dextrocardia, left pneumothorax, and left posterior fascicular block. ■ ■T WAVE AND U WAVE Normally, the mean T-wave vector is oriented roughly concordant with the mean QRS vector (within about 45° in the frontal plane). Since depolarization and repolarization are electrically opposite processes, this normal QRS–T-wave vector concordance indicates that repolarization normally must proceed in the reverse direction from depolarization (i.e., from ventricular epicardium to endocardium). The normal U wave is a small, rounded deflection (≤1 mm) that follows the T wave and usually has the same polarity as the T wave. An abnormal increase in U-wave amplitude is most commonly due to hypokalemia or drugs (e.g., dofetilide, amiodarone, sotalol, quinidine). Very prominent U waves, as part of prolonged ventricular repolarization syndromes, are a marker of increased susceptibility to torsades de pointes (Chap. 253). MAJOR ECG ABNORMALITIES ■ ■CARDIAC ENLARGEMENT AND HYPERTROPHY Right atrial overload (acute or chronic) may lead to an increase in P-wave amplitude (≥2.5 mm) (Fig. 247-8), previously referred to as “P-pulmonale.” Left atrial overload typically produces a biphasic P wave in V1 with a broad negative component or a broad (≥120 ms), often with a notched P wave in one or more limb leads (Fig. 247-8). This pattern, historically referred to as “P-mitrale,” may occur with interatrial con­ duction delays in the absence of actual atrial enlargement, leading to the more general designation of left atrial abnormality. Right ventricular hypertrophy due to a sustained, severe pressure load (e.g., with pulmonic valve stenosis or certain pulmonary artery hypertension syndromes) is characterized by a relatively tall R wave in lead V1 (R ≥ S wave), usually with right axis deviation (Fig. 247-9); alternatively, there may be a qR pattern in V1 or V3R. ST depression and T-wave inversion in the right to mid-precordial leads are also V1 V4 V2 V5 aVL V3 V6 aVF

LA RA V1 Normal Right Left RA LA RA RA LA LA II RA RA RA V1 LA LA LA FIGURE 247-8  Right atrial (RA) overload may cause tall, peaked P waves in the limb or precordial leads. Left atrial (LA) abnormality may cause broad, often notched P waves in the limb leads and a biphasic P wave in lead V1 with a prominent negative component representing delayed depolarization of the LA. (Reproduced with permission from MK Park, WG Guntheroth: How to Read Pediatric ECGs, 4th ed. St. Louis, Mosby/Elsevier, 2006.) often present. This pattern, formerly called right ventricular “strain,” is attributable to repolarization abnormalities in acutely or chroni­ cally overloaded muscle. Prominent S waves may occur in the left lateral precordial leads. Right ventricular hypertrophy due to ostium secundum atrial septal defects, with the accompanying right ventricu­ lar volume overload, is commonly associated with an incomplete or complete right bundle branch block pattern in concert with a right­ ward QRS axis. Main QRS vector QRS in hypertrophy V1 V6 V1 Normal LVH RVH or or FIGURE 247-9  Left ventricular hypertrophy (LVH) increases the amplitude of electrical forces directed to the left and posteriorly. In addition, repolarization abnormalities may cause ST-segment depression and T-wave inversion in leads with a prominent R wave. Right ventricular hypertrophy (RVH) may shift the QRS vector to the right; this effect usually is associated with an R, RS, or qR complex in lead V1. T-wave inversions may be present in right precordial leads.

Acute cor pulmonale due to pulmonary thromboembolism (Chap. 290) or acute respiratory distress syndromes (e.g., COVID-19) may be associated with a normal ECG or a variety of abnormalities. Sinus tachycardia is the most common arrhythmia, although other tachyarrhythmias, such as atrial fibrillation or flutter, may occur. The QRS axis may shift to the right, sometimes in concert with the so-called S1Q3T3 pattern (prominence of the S wave in lead I and the Q wave in lead III, with T-wave inversion in lead III). Acute right ventricular dilation also may be associated with slow R-wave progression and ST-T abnormalities in V1 to V4 simulating acute anterior infarction. A right ventricular conduction disturbance may appear.

CHAPTER 247 Electrocardiography Chronic cor pulmonale due to obstructive lung disease (Chap. 307) usually does not produce the classic ECG patterns of right ventricular hypertrophy noted above. Instead of tall right precordial R waves, emphysema is more typically associated with diminished r waves in right to mid-precordial leads (slow R-wave progression) due in part to downward displacement of the diaphragm and the heart. Low-voltage complexes are commonly present, owing to hyperaeration. Multiple voltage criteria for left ventricular hypertrophy (Fig. 247-9) have been proposed based on the presence of tall left precordial R waves and deep right precordial S waves (e.g., SV1 + [RV5 or RV6] >35 mm). Repolar­ ization abnormalities (ST depression with T-wave inversions, formerly called the left ventricular “strain” pattern) may appear in leads with prominent R waves. However, prominent precordial voltages occur as a common normal variant, especially in athletic or young individu­ als. Left ventricular hypertrophy may increase limb lead voltage with or without increased precordial voltage (e.g., RaVL + SV3 >20 mm in women and >28 mm in men). The presence of left atrial abnormality increases the likelihood of underlying left ventricular hypertrophy in cases with borderline voltage criteria. Left ventricular hypertrophy often progresses to incomplete or complete left bundle branch block. The sensitivities of conventional voltage criteria for left ventricular hypertrophy are low in middle age to older adults and may be decreased further in obese persons and smokers, as well as with right bundle branch block. ECG evidence for left ventricular hypertrophy is a major noninvasive marker of increased risk of cardiovascular morbidity and mortality rates, including sudden cardiac death. However, because of false-positive and false-negative diagnoses, the ECG is of limited util­ ity in diagnosing atrial or ventricular enlargement. More definitive anatomic and functional information is provided by echocardiographic and cardiac magnetic resonance imaging studies (Chaps. 248 and A9). V6 ■ ■BUNDLE BRANCH BLOCKS AND RELATED PATTERNS Intrinsic impairment of conduction in either the right or the left bundle system (intraventricular conduction disturbances) leads to prolonga­ tion of the QRS interval. With complete bundle branch blocks, the widest QRS interval is ≥120 ms in duration; with incomplete blocks, the QRS interval is between about 110 and 120 ms. The QRS vector usually is oriented in the direction of the myocardial region where depolariza­ tion is delayed (Fig. 247-10). Thus, with right bundle branch block, the terminal QRS vector is oriented to the right and anteriorly (rSR′ in V1 and qRS in V6, typically). Left bundle branch block alters both early and later phases of ventricular depolarization. The major QRS vector is directed to the left and posteriorly. In addition, the normal early left-toright pattern of septal activation is disrupted such that septal depolar­ ization proceeds from right to left as well. As a result, left bundle branch block generates wide, predominantly negative (QS) complexes in lead V1 and entirely positive (R) complexes in V6. Waveform patterns identi­ cal to those of left bundle branch block, preceded by a sharp (sometimes very low amplitude) spike, are seen in most cases of electronic right ventricular pacing due to the relative delay in left ventricular activation. Bundle branch block may occur in a variety of conditions. In sub­ jects without structural heart disease, right bundle branch block is seen more commonly than left bundle branch block. Right bundle branch block also occurs with heart disease, both congenital (e.g., atrial septal defect) and acquired (e.g., valvular, ischemic). Left bundle branch block is often a marker of one of four underlying conditions associated with increased risk of cardiovascular morbidity and mortality rates: coronary

V6 V1 Normal PART 6 Disorders of the Cardiovascular System R′ R r RBBB T q S S LBBB T FIGURE 247-10  Comparison of typical QRS-T patterns in right bundle branch block (RBBB) and left bundle branch block (LBBB) with the normal pattern in leads V1 and V6. Note the secondary T-wave inversions (arrows) in leads with an rSR′ complex with RBBB and in leads with a wide R wave with LBBB. heart disease (frequently with impaired left ventricular function), hyper­ tensive heart disease, aortic valve disease (including after transcatheter aortic valve replacement), and cardiomyopathy. Bundle branch blocks may be chronic or intermittent. A bundle branch block may be raterelated, most commonly observed when the heart rate exceeds some critical value. Bundle branch blocks and depolarization abnormalities second­ ary to artificial pacemakers not only affect ventricular depolariza­ tion (QRS) but also are characteristically associated with secondary repolarization (ST-T) abnormalities. With bundle branch blocks, the

T wave is typically opposite in polarity to the last deflection of the QRS (Fig. 247-10). This discordance of the QRS–T-wave vectors is caused by the altered sequence of repolarization that occurs as a consequence of altered depolarization. In contrast, primary repolarization abnor­ malities are independent of QRS changes and are related instead to actual alterations in the electrical properties of the myocardial fibers themselves (e.g., in the resting membrane potential or action potential duration), not just to changes in the sequence of repolarization. Isch­ emia, electrolyte imbalance, and drugs such as digoxin all cause such primary ST–T-wave changes. Primary and secondary T-wave changes may coexist. For example, T-wave inversions in the right precordial leads with left bundle branch block or in the left precordial leads with right bundle branch block may be important markers of underlying ischemia or other abnormalities. A distinctive abnormality simulating right bundle branch block with ST-segment elevations in the right chest leads is seen with the Brugada pattern (Chap. 262). Partial blocks in the left bundle system (left anterior or posterior fascicular blocks; formerly called hemiblocks) generally do not prolong ST V5 ST A B FIGURE 247-11  Acute ischemia causes a current of injury. A. With predominant subendocardial ischemia, the resultant ST vector will be directed toward the inner layer of the affected ventricle and the ventricular cavity. Overlying leads therefore will record ST depression. B. With ischemia involving the outer ventricular layer (transmural or epicardial injury), the ST vector will be directed outward. Overlying leads will record ST elevation.

the QRS duration substantially. Instead, they are associated with shifts in the frontal plane QRS axis (leftward or rightward, respectively). Left anterior fascicular block (QRS axis more negative than –45°) is prob­ ably the most common cause of marked left axis deviation in adults. In contrast, left posterior fascicular block (QRS axis more rightward than +110–120°) is extremely rare as an isolated finding and requires exclusion of other factors causing right axis deviation. Intraventricular conduction delays also can be caused by factors extrinsic (toxic) to the conduction system that slow ventricular conduction, particularly hyperkalemia or drugs (e.g., class 1 antiarrhythmic agents, tricyclic antidepressants, phenothiazines). Prolongation of QRS duration does not necessarily indicate a conduction delay but may be due to preexci­ tation of the ventricles via a bypass tract, as in Wolff-Parkinson-White (WPW) patterns (Chap. 256) and related variants. ■ ■MYOCARDIAL ISCHEMIA AND INFARCTION (See also Chap. 286) The ECG is central to the diagnosis of acute and chronic ischemic heart disease. Ischemia exerts complex timedependent effects on the electrical properties of myocardial cells. Severe, acute ischemia lowers the resting membrane potential and shortens the duration of the action potential. Such changes cause a voltage gradient between normal and ischemic zones. As a con­ sequence, current flows between those regions. These currents of injury are represented on the surface ECG by deviation of the ST segment (Fig. 247-11). When the acute ischemia is transmural, the ST vector usually is shifted in the direction of the outer (epicardial) layers, producing ST elevations and sometimes, in the earliest stages of ischemia, tall, positive so-called hyperacute T waves over the ischemic zone. With ischemia confined primarily to the subendocardium, the ST vector typically shifts toward the subendocardium and ventricular cav­ ity, so that overlying (e.g., anterior precordial) leads show ST-segment depression (with ST elevation in lead aVR). Multiple factors affect the amplitude of acute ischemic ST deviations. Profound ST elevation or depression in multiple leads usually indicates very severe ischemia. The division of acute myocardial infarction due to obstructive coronary artery disease into ST-segment elevation and non-ST elevation types is useful since the consistent efficacy of emergency (minutes to hours) reperfusion therapy is limited to the former group. Indications for acute reperfusion therapy in non-ST elevation myocardial infarction are a focus of ongoing investigation (Chap. 285). Takotsubo syndrome, as well as other causes of myocardial infarction without atherosclerotic coronary disease, can simulate the patterns of acute or evolving ST-seg­ ment elevation or non-ST-segment elevation infarction (Chap. 285). The ECG leads are usually more helpful in localizing regions of ST elevation than non-ST elevation ischemia. For example, acute transmu­ ral anterior (including apical and lateral) wall ischemia is reflected by ST elevations or increased T-wave positivity in one or more of the precor­ dial leads (V1–V6) and leads I and aVL. Inferior wall ischemia produces changes in leads II, III, and aVF. “Posterior” wall ischemia (almost always associated with lateral or inferior involvement) may be indirectly recognized by reciprocal ST depressions in leads V1 to V3 (thus constitut­ ing an ST elevation “equivalent” acute coronary syndrome). Acute right ventricular ischemia usually produces ST elevations in right-sided chest leads (Fig. 247-5). When ischemic ST elevations occur as the earliest sign of acute infarction, they typically are followed within a period ranging from hours to days by evolving T-wave inversions and often by Q waves occurring in the same lead distribution. Reversible transmural ST ST V5

V1 V2 V4 V5 V6 V3 FIGURE 247-12  Severe anterior wall ischemia (with or without infarction) may cause prominent T-wave inversions in the precordial leads and in leads I and aVL. This pattern (sometimes referred to as the Wellens T wave sign) is usually associated with a high-grade stenosis of the left anterior descending coronary artery. ischemia, for example, due to coronary vasospasm (Prinzmetal’s angina) may cause transient ST-segment elevations without development of Q waves. Depending on the severity and duration of ischemia, ischemic ST elevations may resolve completely in minutes or be followed by T-wave inversions that persist for hours or even days. Patients with ischemic chest pain who present with deep T-wave inversions in mul­ tiple precordial leads (e.g., V1–V4, and sometimes I and aVL) with or without cardiac enzyme elevations typically have severe obstruction in the left anterior descending coronary artery (Fig. 247-12). With infarction, depolarization (QRS) changes often accompany repolarization (ST-T) abnormalities. Necrosis of sufficient myocardial tissue may lead to decreased R-wave amplitude or abnormal Q waves (even in the absence of transmural ischemia) in the anterior or inferior leads (Fig. 247-13). Abnormal Q waves were once considered markers of transmural myocardial infarction, whereas subendocardial infarcts were thought not to produce Q waves. However, transmural infarcts may occur without Q waves, and subendocardial (nontransmural) infarcts may be associated with Q waves. Therefore, evolving or chronic infarcts are more appropriately classified as “Q-wave” or “non-Q-wave” (Chap. A7). Loss of depolarization forces due to posterior or lateral infarction may cause reciprocal increases in R-wave amplitude in leads V1 and V2 without diagnostic Q waves in any of the conventional leads. (Additional leads V7–V9 may show acute changes.) In the weeks and months after infarction, these ECG changes may persist or begin to resolve. Complete normalization of the ECG after Q-wave infarction is uncommon but may occur, particularly with smaller infarcts. In con­ trast, ST-segment elevations that persist for several weeks or more after a Q-wave infarct usually correlate with a severe underlying wall motion disorder, although not necessarily a frank ventricular aneurysm. A ECG sequence with anterior ST-elevation/Q-wave infarction I II III Acute Evolving ECG sequence with inferior ST-elevation/Q-wave infarction B I II III Acute Evolving FIGURE 247-13  Sequence of depolarization and repolarization changes with acute and evolving anterior (A) and (B) inferior ST-elevation/Q-wave infarctions. With anterior infarcts, ST elevation in leads I and aVL and the precordial leads may be accompanied by reciprocal ST depressions in leads II, III, and aVF. Conversely, acute inferior (or posterolateral) infarcts may be associated with reciprocal ST depressions in leads V1 to V3. (Reproduced with permission from AL Goldberger et al: Goldberger’s Clinical Electrocardiography: A Simplified Approach, 10th ed. Philadelphia, Elsevier, 2024.)

CHAPTER 247 Electrocardiography The ECG has important limitations in both sensitivity and speci­ ficity in the diagnosis of acute and chronic ischemic heart disease. Although a single normal ECG does not exclude ischemia or even acute infarction, a normal ECG throughout the course of an acute infarct is distinctly uncommon. Prolonged chest pain without diagnostic ECG changes therefore should always prompt a careful search for other non­ coronary causes of chest pain (Chap. 15). Furthermore, the diagnostic changes of acute or evolving ischemia are often masked by the presence of left bundle branch block, electronic ventricular pacemaker patterns, and WPW preexcitation. However, clinicians may also overdiagnose ischemia or infarction based on the presence of ST-segment elevations or depressions; T-wave inversions; tall, positive T waves; or Q waves not related to ischemic heart disease (pseudoinfarct patterns). For example, ST-segment elevations simulating acute ischemia/infarction may occur with acute pericarditis or myocarditis, including COVID-19 infections, as a normal variant (including the typical “early repolarization” pat­ tern), or in a variety of other conditions (Table 247-1). Similarly, tall T waves do not invariably represent hyperacute ischemic changes but may also be caused by normal variants, hyperkalemia, or cerebrovas­ cular injury, among other causes. ST-segment elevations and tall, positive T waves are common find­ ings in leads V1 and V2 in left bundle branch block or left ventricular hypertrophy in the absence of ischemia. The differential diagnosis of Q waves includes physiologic or positional variants, ventricular hyper­ trophy, acute or chronic noncoronary myocardial injury, hypertrophic cardiomyopathy, and ventricular conduction disorders. Ventricular hypertrophy, hypokalemia, drugs such as digoxin, and a variety of other factors may cause ST-segment depression mimicking suben­ docardial ischemia. Prominent T-wave inversion may occur with aVR aVL aVF V2 V4 V6 aVR aVL aVF V2 V4 V6

TABLE 247-1  Differential Diagnosis of ST-Segment Elevations Myocardial ischemia/infarction   Noninfarction transmural ischemia (e.g., Prinzmetal’s syndrome)   Acute myocardial infarction     Due to atherosclerotic coronary occlusion     Due to nonatherosclerotic causes (e.g., takotsubo syndrome, coronary PART 6 Disorders of the Cardiovascular System dissection)   Post-myocardial infarction (left ventricular motion abnormality/aneurysm) Acute pericarditis Normal variants (including benign “early repolarization” patterns)   Left ventricular hypertrophy/left bundle branch blocka Other (rarer)   Acute pulmonary embolisma   Brugada patterns (right bundle branch block–like morphology with ST elevations in right precordial leads)   Class 1C antiarrhythmic drugsa   DC cardioversion (transient)   Hypercalcemiaa   Hyperkalemiaa   Hypothermia (J [Osborn] waves)   Nonischemic myocardial injury     Myocarditis syndromes (infectious and noninfectious)     Tumor invading left ventricle     Trauma to ventricles aUsually localized to V1–V2 or V3. Source: Modified from AL Goldberger et al: Goldberger’s Clinical Electrocardiography: A Simplified Approach, 10th ed. Elsevier, 2024. ventricular hypertrophy, cardiomyopathies, myocarditis, and “stress cardiomyopathies” associated with takotsubo syndrome and cerebro­ vascular injury (particularly intracranial bleeds), among others causes. Diagnostic confusion may also occur when nonischemic T-wave inver­ sions (“cardiac memory” effect) appear in normally conducted beats in patients with intermittent wide QRS complexes, most commonly due to ventricular pacing or to left bundle branch block. ■ ■METABOLIC FACTORS AND DRUG EFFECTS A variety of metabolic abnormalities and pharmacologic agents alter the ECG and, in particular, cause changes in repolarization (ST-T-U) and sometimes QRS prolongation. Certain life-threatening electrolyte disturbances may be diagnosed initially and monitored from the ECG. Hyperkalemia produces a sequence of changes (Fig. 247-14), usually Hyperkalemia Mild-Moderate Moderate-Severe Very Severe T V1 V1 P T V2 V2 P FIGURE 247-14  The earliest ECG change with hyperkalemia is usually peaking (“tenting”) of the T waves. With further increases in the serum potassium concentration, the QRS complexes widen, the P waves decrease in amplitude and may disappear, and finally a sine-wave pattern leads to asystole unless emergency therapy is given. (Reproduced with permission from AL Goldberger et al: Goldberger’s Clinical Electrocardiography: A Simplified Approach, 10th ed. Philadelphia, Elsevier, 2024.)

beginning with narrowing and peaking (tenting) of the T waves. Fur­ ther elevation of extracellular K+ leads to AV conduction disturbances, diminution in P-wave amplitude, and widening of the QRS interval. Severe hyperkalemia eventually causes cardiac arrest with a slow sinu­ soidal type of mechanism (“sine-wave” pattern) followed by asystole. Hypokalemia (Fig. 247-15) prolongs ventricular repolarization, often with prominent U waves. Prolongation of the QT interval is also seen with drugs that increase the duration of the ventricular action poten­ tial: class 1A antiarrhythmic agents and related drugs (e.g., quinidine, procainamide, tricyclic antidepressants, phenothiazines) and class III agents (e.g., amiodarone [Fig. 247-15], dofetilide, sotalol, ibutilide). Systemic hypothermia (Fig. 247-15) also prolongs repolarization, usu­ ally with a distinctive convex elevation of the J point (Osborn wave) and bradycardia. Marked QT prolongation, sometimes with deep, wide T-wave inversions, may occur with intracranial bleeds, particularly subarachnoid hemorrhage (“CVA T-wave” pattern) (Fig. 247-15). Hypocalcemia typically prolongs the QT interval (ST portion), whereas hypercalcemia shortens it (Fig. 247-16). Digitalis glycosides also shorten the QT interval, often with a characteristic “scooping” of the ST–T-wave complex (digitalis effect). ■ ■NONSPECIFIC ST-T CHANGES AND LOW QRS VOLTAGE Many other factors are associated with ECG changes, particularly alter­ ations in ventricular repolarization. T-wave flattening, minimal T-wave inversions, or slight ST-segment depression (“nonspecific ST–T-wave changes”) may occur with a variety of electrolyte and acid-base distur­ bances, infectious or inflammatory processes, central nervous system disorders, endocrine abnormalities, many drugs, ischemia, hypoxia, and virtually any type of cardiopulmonary abnormality, in addition to physiologic changes (e.g., with posture or after meals). Low QRS volt­ age is arbitrarily defined as peak-to-trough QRS amplitudes of ≤5 mm in the six limb leads and/or ≤10 mm in the chest leads. Multiple factors may be responsible. Among the most serious include pericardial (Fig. 247-17) or pleural effusions, chronic obstructive pulmonary disease, cardiac amyloid, and anasarca. ■ ■ELECTRICAL ALTERNANS SYNDROMES Electrical alternans—a beat-to-beat alternation in one or more com­ ponents of the ECG signal—is a common type of nonlinear cardio­ vascular response to a variety of hemodynamic and electrophysiologic perturbations. Total electrical alternans (P-QRS-T) with sinus tachy­ cardia is a relatively specific sign of pericardial effusion, usually with cardiac tamponade (Fig. 247-17). In contrast, pure repolarization Lead I Lead II 1mV 1s

Hypokalemia Hypothermia Amiodarone V3 II U Tricyclic overdose III V3 V2 I FIGURE 247-15  A variety of metabolic derangements, drug effects, and other factors may prolong ventricular repolarization with QT prolongation or prominent U waves. Prominent repolarization prolongation, particularly if due to hypokalemia, inherited “channelopathies,” or certain pharmacologic agents, indicates increased susceptibility to torsades des pointes ventricular tachycardia (Chap. 261). Marked systemic hypothermia is associated with a distinctive convex “hump” at the J point (Osborn wave, arrow) attributed to altered transmural ventricular action potential characteristics. Note QRS and QT prolongation along with sinus tachycardia in the case of tricyclic antidepressant overdose. Hypocalcemia Normal Hypercalcemia I I I II II II QT=480 ms QTc=500 ms QT=360 ms QTc=400 ms QT=260 ms QTc=350 ms FIGURE 247-16  Prolongation of the Q-T interval (ST-segment portion) is typical of hypocalcemia. Hypercalcemia may cause abbreviation of the ST segment with relative or absolute shortening of the QT interval. FIGURE 247-17  Classic triad of findings for pericardial effusion with cardiac tamponade: (1) sinus tachycardia; (2) low QRS voltages and (3) electrical alternans (best seen in leads V3 and V4 in this case; arrows). This triad is highly suggestive of pericardial effusion, usually with tamponade physiology, but is of limited sensitivity. (Adapted from LA Nathanson et al: ECG Wave-Maven. ecg.bidmc.harvard.edu.)

V5 V4 T CHAPTER 247 Electrocardiography Subarachnoid hemorrhage

10 - SECTION 3 Disorders of Rhythm

SECTION 3 Disorders of Rhythm

PART 6 Disorders of the Cardiovascular System FIGURE 249-8  Fractional flow reserve. The fractional flow reserve is measured using a coronary pressure-sensor guidewire that measures the ratio of the pressure in the coronary artery distal to the stenosis (Pd, green) divided by the pressure in the artery proximal to the stenosis (Pa, red) at maximal hyperemia following the injection of adenosine. A fractional flow reserve of <0.80 indicates that revascularization would be beneficial. ■ ■FURTHER READING Bangalore S et al: Evidence-based practices in the cardiac catheter­ ization laboratory. Circulation 144:e107, 2021. Moscucci M (ed): Grossman & Baim’s Cardiac Catheterization, Angiography, and Intervention, 9th ed. Philadelphia, Lippincott Williams & Wilkins, 2020. Nishimura R et al: Hemodynamics in the cardiac catheterization laboratory of the 21st century. Circulation 125:2138, 2012. Räber L et al: Clinical use of intracoronary imaging. Part 1: guidance and optimization of coronary interventions. An expert consensus document of the European Association of Percutaneous Cardiovascular Interventions. Eur Heart J 39:3281, 2018. Samuels BA et al: Comprehensive management of angina with nonobstructive coronary artery disease (ANOCA), Part 1 defini­ tion, patient population, and diagnosis. J Am Coll Cardiol 82:1245, 2023. Principles of Clinical Cardiac Electrophysiology William H. Sauer, Bruce A. Koplan, Paul C. Zei

HISTORICAL PERSPECTIVE Clinical cardiac electrophysiology is the subspecialty of cardiology that focuses on the study and management of heart rhythm disorders. The development of the modern surface electrocardiogram (ECG) by Willem Einthoven more than 100 years ago enabled an understanding of the relationship between cardiac electrical potentials, mechanical cardiac function, and pathophysiology of cardiac arrhythmias. In the mid-twentieth century, the recording of cellular membrane currents enabled the understanding that the surface ECG represents the sum of cellular cardiac electrical activity. An understanding of cellular electro­ physiology also ushered in the development of antiarrhythmic drugs utilized by cardiac electrophysiologists. The modern era of clinical cardiac electrophysiology began with the first recordings of human intracardiac electrograms in the 1960s. Ini­ tially, invasive electrophysiology studies were limited to diagnostic tools. This included serial electrophysiologic testing to evaluate arrhythmia mechanisms and evaluate arrhythmia suppression by antiarrhythmic drugs, and programmed stimulation of the ventricle for risk stratifica­ tion of sudden cardiac death. In the 1960s and 1970s, cardiac surgery was the only available invasive treatment for cardiac arrhythmias. The subsequent development of radiofrequency catheter ablation in the 1980s ushered in the era of interventional cardiac electrophysiology. In addition, with the development of implanted cardiac rhythm manage­ ment devices including pacemakers and defibrillators, clinical cardiac electrophysiology became a distinct medical subspecialty. Developments in catheter ablation techniques, cardiac resynchronization and conduc­ tion system pacing, subcutaneous defibrillator implantation, leadless pacemaker implantation, left atrial appendage closure, and laser-assisted lead extraction have broadened the procedural aspects of the specialty over the past 30 years; however, the principles of arrhythmia patient management have remained the same. CELLULAR ELECTROPHYSIOLOGY The cardiac action potential (AP) drives the electrophysiologic behav­ ior of all cardiac myocytes. The AP is characterized morphologically by five distinct phases, termed phases 0–4, as shown in Fig. 250-1. Moreover, as ventricular electrophysiologic activity accounts for the QRS and T complexes of the surface ECG, each AP phase in ventricular tissues corresponds to distinct phases in the surface ECG: Phase 0, the rapid upstroke, corresponds to the QRS deflection; phases 1–2 account for the ST segment; phase 3 accounts for the T wave; while phase 4 corresponds to the segment between the end of the T wave and the sub­ sequent QRS deflection. In addition, the P wave corresponds to atrial depolarization, while the PR interval corresponds to the time between Section 3 Disorders of Rhythm

11 - 250 Principles of Clinical Cardiac Electrophysiology

250 Principles of Clinical Cardiac Electrophysiology

PART 6 Disorders of the Cardiovascular System FIGURE 249-8  Fractional flow reserve. The fractional flow reserve is measured using a coronary pressure-sensor guidewire that measures the ratio of the pressure in the coronary artery distal to the stenosis (Pd, green) divided by the pressure in the artery proximal to the stenosis (Pa, red) at maximal hyperemia following the injection of adenosine. A fractional flow reserve of <0.80 indicates that revascularization would be beneficial. ■ ■FURTHER READING Bangalore S et al: Evidence-based practices in the cardiac catheter­ ization laboratory. Circulation 144:e107, 2021. Moscucci M (ed): Grossman & Baim’s Cardiac Catheterization, Angiography, and Intervention, 9th ed. Philadelphia, Lippincott Williams & Wilkins, 2020. Nishimura R et al: Hemodynamics in the cardiac catheterization laboratory of the 21st century. Circulation 125:2138, 2012. Räber L et al: Clinical use of intracoronary imaging. Part 1: guidance and optimization of coronary interventions. An expert consensus document of the European Association of Percutaneous Cardiovascular Interventions. Eur Heart J 39:3281, 2018. Samuels BA et al: Comprehensive management of angina with nonobstructive coronary artery disease (ANOCA), Part 1 defini­ tion, patient population, and diagnosis. J Am Coll Cardiol 82:1245, 2023. Principles of Clinical Cardiac Electrophysiology William H. Sauer, Bruce A. Koplan, Paul C. Zei

HISTORICAL PERSPECTIVE Clinical cardiac electrophysiology is the subspecialty of cardiology that focuses on the study and management of heart rhythm disorders. The development of the modern surface electrocardiogram (ECG) by Willem Einthoven more than 100 years ago enabled an understanding of the relationship between cardiac electrical potentials, mechanical cardiac function, and pathophysiology of cardiac arrhythmias. In the mid-twentieth century, the recording of cellular membrane currents enabled the understanding that the surface ECG represents the sum of cellular cardiac electrical activity. An understanding of cellular electro­ physiology also ushered in the development of antiarrhythmic drugs utilized by cardiac electrophysiologists. The modern era of clinical cardiac electrophysiology began with the first recordings of human intracardiac electrograms in the 1960s. Ini­ tially, invasive electrophysiology studies were limited to diagnostic tools. This included serial electrophysiologic testing to evaluate arrhythmia mechanisms and evaluate arrhythmia suppression by antiarrhythmic drugs, and programmed stimulation of the ventricle for risk stratifica­ tion of sudden cardiac death. In the 1960s and 1970s, cardiac surgery was the only available invasive treatment for cardiac arrhythmias. The subsequent development of radiofrequency catheter ablation in the 1980s ushered in the era of interventional cardiac electrophysiology. In addition, with the development of implanted cardiac rhythm manage­ ment devices including pacemakers and defibrillators, clinical cardiac electrophysiology became a distinct medical subspecialty. Developments in catheter ablation techniques, cardiac resynchronization and conduc­ tion system pacing, subcutaneous defibrillator implantation, leadless pacemaker implantation, left atrial appendage closure, and laser-assisted lead extraction have broadened the procedural aspects of the specialty over the past 30 years; however, the principles of arrhythmia patient management have remained the same. CELLULAR ELECTROPHYSIOLOGY The cardiac action potential (AP) drives the electrophysiologic behav­ ior of all cardiac myocytes. The AP is characterized morphologically by five distinct phases, termed phases 0–4, as shown in Fig. 250-1. Moreover, as ventricular electrophysiologic activity accounts for the QRS and T complexes of the surface ECG, each AP phase in ventricular tissues corresponds to distinct phases in the surface ECG: Phase 0, the rapid upstroke, corresponds to the QRS deflection; phases 1–2 account for the ST segment; phase 3 accounts for the T wave; while phase 4 corresponds to the segment between the end of the T wave and the sub­ sequent QRS deflection. In addition, the P wave corresponds to atrial depolarization, while the PR interval corresponds to the time between Section 3 Disorders of Rhythm

Ventricular AP Current GENE (Protein) INa INa SCN5A (Nav1.5) Depolarizing Repolarizing ICa-L ICa-L CACNA1C (Cav1.2) INCX SLC8A1 (NCX1.1)

Voltage 0 1

Time

IK1 IK1 KCNJ2 (Kir2.1) Ito Ito KCND3/KCNIP2 (Kv4.3/KChIP2) IKr IKr KCNH2/KCNE2 (HERG/MiRP-1) IKs IKs KCNQ1/KCNE1 (KVLQT1/minK) IKur KCNA5 (Kvt.5) A FIGURE 250-1  A. Cellular atrial and ventricular action potentials. Phases 0–4 are the rapid upstroke, early repolarization, plateau, late repolarization, and diastole, respectively. The ionic currents and their respective genes are shown above and below the action potentials. The currents that underlie the action potentials vary in atrial and ventricular myocytes. Potassium current (IK1) is the principal current during phase 4 and determines the resting membrane potential of the myocyte. Sodium current generates the upstroke of the action potential (phase 0); activation of Ito with inactivation of the Na current inscribes early repolarization (phase 1). The plateau (phase 2) is

generated by a balance of repolarizing potassium currents and depolarizing calcium current. Inactivation of the calcium current with persistent activation of potassium currents (predominantly IKr and IKs) causes phase 3 repolarization. Currents that result in membrane depolarization are grouped at the top of the figure above the action potentials, while repolarizing currents are shown below the action potentials. B. A surface electrocardiogram (ECG) representation of sinus rhythm is shown with respective intracardiac action potentials that are active during each phase of the ECG. Each cardiac conduction region’s action potential is shown in the upper portion of the panel, with colors reflected in the ECG segment shown in the lower portion of the panel. Note that during the P wave, atrial depolarization is active. During the PR interval, the atrioventricular (AV) nodal, His, bundle branches, and Purkinje fibers are active (in sequence), although these action potentials are not discernible on the surface ECG. During the QRS interval, ventricular action potentials are active, with the QRS morphology most reflective of the sequence of ventricular tissue action potential activation. The ST segment is predominantly determined by the plateau phase 2 of the ventricular action potential. The T wave is determined largely by ventricular repolarization (phase 3), while the isoelectric segment is the result of the electrically neutral phase 4 of the ventricular action potential. the initiation of atrial depolarization to the initiation of ventricular depolarization, comprised (typically) for the most part by the conduc­ tion time through the atrioventricular (AV) node. AP morphologies are the result of the precise and carefully timed sequences of opening, closing, and inactivation of an array of membrane ion channels in response to cellular membrane potential changes, ligands that bind to the ion channel complex, or membrane stretch in a timedependent fashion. The open ion channel allows flux of specific charged ions through a central pore, resulting in electrical (ionic) currents that drive the AP. The activity of different subsets of ion channels drives the different phases of the AP. Specific ionic currents that flux through an open channel are driven by the electrochemical gradient of that particular ion across the membrane, which in turn are driven by ion pumps or transport­ ers/exchangers, which in turn are catalyzed by ATP (Fig. 250-2). Ion channels are complex, multi-subunit transmembrane glycopro­ teins that contain a central pore that is selective for particular ionic spe­ cies (selectivity); a “gating” apparatus that regulates the opening, closing, and inactivation apparatus; and often one or more regulatory subunits. Most channels gate in response to changes in membrane potential, a spe­ cific ligand, or mechanical deformation. The molecular underpinnings of these specific functional properties of channels have become well understood through decades of basic electrophysiologic study using the tools of voltage clamp and patch clamp techniques, and more recently, molecular, genetic, and structural/crystallographic techniques. The structural makeup of most ion channels contains several com­ mon motifs. All channels form a central conducting pore, with ionic selectivity determined by specific amino acids that line the central pore. The central pore of most channels is formed by the P domain, a series of hydrophilic amino acid residues, with one of several structural variants: four separate homologous alpha subunits, each with homolo­ gous P domains (voltage-gated K channels); a single alpha subunit with four internally homologous P domains (voltage-gated Na or Ca channels); or two internally homologous P domains from two separate subunits (most ligand-gated K channels). A series of one or

Atrial AP CHAPTER 250 SA node Atrial myocardium AV node Voltage His bundle Time Principles of Clinical Cardiac Electrophysiology Bundle branches Purkinje fibers Myocardium P QRS T B more transmembrane segments surrounds the central pore. In voltagegated channels, the fourth of six segments, the S4 segment, contains a series of charged amino acid residues that functions as a voltage sensor, responding to changes in membrane potential by facilitating protein conformational changes that result in channel opening or closing (gat­ ing). In ligand-activated channels, the binding of a ligand (transmitters, molecules, or other ions) results in channel opening or closing, while deformations in membrane shape determine gating in stretch-activated channels. In addition, in many ion channels, a complex of auxiliary proteins is associated with the primary alpha subunit; most auxiliary subunits appear to facilitate regulation of ion channel expression and activity. A distinct type of transmembrane protein complex is the gap junction complex. A large multimeric complex of connexin subunits forms a large, nonselective pore that spans and thereby connects adja­ cent myocytes. This allows free flux of ions between adjacent myocytes, facilitating impulse propagation across myocardial tissues. Due to the physiologic gradient of their respective ions across the cell membrane, Na and Ca channels account for most inward, or depo­ larizing, currents in cardiac myocytes, and these channels respond to membrane depolarization with rapid opening, relatively rapid closing, and inactivation. Na and Ca currents therefore drive phase 0 depolar­ ization of the AP. Potassium channels, on the other hand, account for most of the repolarizing currents seen in cardiac myocytes. Relatively slow K channel opening, as well as Na and Ca channel closing and inactivation, drives the plateau of phases 1–2 as well as the repolarizing phase 3 of the AP. Mutations in K channel subtypes are causative of many inherited channelopathies. Mutations that either inherently delay the closing or inactivation of K channels result in prolongation of the QT interval, leading to many forms of inherited long QT syndrome. The morphologic and functional properties of APs vary across different regions of the heart. These variations are the result of varia­ tions in the active ionic currents during each phase of the AP, which in turn reflects regional variation in ion channel expression. In atrial and ventricular myocytes, Na currents dominate the rapid upstroke

K channels N α Subunits β Subunits PART 6 Disorders of the Cardiovascular System C N C X4 Extracellular K+ N Intracellular Pore segments Na channels N N + + + + + + + + + + + + β1 C P C C N P P P P P Inactivation LA binding Ca channels α2 S S γ δ α1 β FIGURE 250-2  Topology and subunit composition of the voltage-dependent ion channels. Potassium channels are formed by the tetramerization of α or pore-forming subunits and one or more β subunits; only single β subunits are shown for clarity. Sodium and calcium channels are composed of α subunits with four homologous domains and one or more ancillary subunits. In all channel types, the loop of protein between the fifth and sixth membrane-spanning repeat in each subunit or domain forms the ion-selective pore. In the case of the sodium channel, the channel is a target for phosphorylation, the linker between the third and fourth homologous domain is critical to inactivation, and the sixth membrane-spanning repeat in the fourth domain is important in local anesthetic antiarrhythmic drug binding. The Ca channel is a multi-subunit protein complex with the α1 subunit containing the pore and major drug-binding domain. (phase 1) of the AP, while in nodal tissues, Ca currents, which activate more slowly, dominate phase 1. Hence, for instance, drugs that bind and block the cardiac Na channel demonstrate efficacy in treating tachyarrhythmias arising from the atria and ventricles, whereas Ca channel blocking agents demonstrate efficacy at nodal tissues. During

the pre-depolarizing phase 4 of the AP, ionic currents remain relatively quiescent in atrial and ventricular myo­ cytes as they await local depolarization that triggers the next AP. In contrast, in sinus nodal tissues, which possess the property of automaticity, or intrinsic rhythmic depo­ larization, there is gradual depolarization observed dur­ ing phase 4, until a threshold is reached that initiates the next AP. In these nodal tissues, this depolarizing phase 4 current is generated by a semiselective Na/Ca channel, termed the “funny current” or If, which is the target for the medication ivabradine. NORMAL CARDIAC IMPULSE PROPAGATION The normal cardiac impulse initiates and travels through specialized conduction fibers, often referred to as the cardiac conduction system. Each impulse is initiated in the sinoatrial (SA) node, located at the lateral junction between the superior vena cava (SVC) and right atrium (RA). SA nodal tissues exhibit automaticity, such that a reliable, rhythmic impulse emanates from the SA node. The SA node (along with the AV node) is richly inner­ vated by autonomic fibers, allowing precise and dynamic control of heart rate and overall function by the central nervous system. The normal impulse then travels across the RA then the LA across preferential conduction path­ ways, initiating atrial systole. Once the impulse reaches the AV node, conduction occurs in a relatively slow time frame through the AV nodal tissues. This conduction time not only serves to provide physiologic AV synchrony but also is reflected in the surface ECG as the PR interval, or time between the atrial inscription and the subsequent ventricular, or QRS, complex. In normal hearts, the AV node serves as the only electrical connection between atria and ventricles. Both the SA and AV nodes respond exquisitely to autonomic input; for instance, with exercise and increased adrenergic tone, the PR interval physiolog­ ically shortens. After the AV node, the impulse travels through a network of specialized conduction fibers: the bundle of His divides into a right and left bundle branch, which transmit conduction to the right and left ventricles, respectively. The left bundle then divides further into the left anterior and posterior fascicles. The fascicles then further divide into a network of Purkinje fibers. The conduction velocity of electrical impulses is much higher in Purkinje fibers (2–3 m/s) than in myocardial cells (0.3–0.4 m/s). Different connexins in gap junctions of Purkinje networks are partially responsible for more rapid conduction. This network of conductive Purkinje fibers is located endocardially and serves to rapidly transmit depolarization throughout the ventricles, such that myocardial depolarization, and hence mechanical contraction, occur rapidly and in a coordinated, synchro­ nized fashion, optimizing mechanical contraction of the ventricles. Repolarization of the ventricular myocardium, on the other hand, occurs relatively slowly and progresses from the epicardial surface back toward the endocar­ dium. Hence, the T wave inscription in most ECG leads is concordant with the QRS complex. β2 MECHANISMS OF CARDIAC ARRHYTHMIAS Cardiac arrhythmias are the manifestation of abnormalities in the initiation and/or propagation of the cardiac electrical impulse. Bradyarrhythmias result most commonly from abnormalities in the specialized conduction tissues. Abnormal function of the SA node may result in pathologic sinus bradycardia; AV node disease may result in conduction block; pathology in the His-Purkinje system may result in conduction block as well. Tachyarrhythmias may arise from not only

TABLE 250-1  Overview of the Mechanisms of Cardiac Tachyarrhythmias TACHYARRHYTHMIA CATEGORY MECHANISM PROTOTYPICAL ARRHYTHMIAS Abnormal automaticity   Enhanced (acceleration of phase 4 repolarization) Idiopathic VT; AT Suppressed (absent or decelerated phase 4 repolarization) Sinus node dysfunction Triggered activity   EADs TdP in long QT syndrome, PVCs DADs Reperfusion PVCs/ VT, AT and VT with digitalis toxicity Reentry (1) Anatomic or functional confinement of a circuit (i.e., scar, accessory pathway); (2) unidirectional block after a premature impulse; (3) wave of excitation that travels in a single direction returning to its point of origin AVNRT, AVRT, atrial flutter, scarrelated VT Abbreviations: AT, atrial tachycardia; AVRT, atrioventricular reentry tachycardia; AVNRT, atrioventricular nodal reentry tachycardia; DADs, delayed afterdepolarizations; EADs, early afterdepolarizations; PVC, premature ventricular contraction; TdP, torsades des pointes; VT, ventricular tachycardia. nearly every location within the conduction tissues, but also within atrial or ventricular tissues. Tachyarrhythmias are typically classified by mechanism: enhanced automaticity refers to abnormal spontaneous depolarization, which can occur along the conduction system, the atria, or ventricles; triggered arrhythmias result from abnormal afterdepo­ larizations that occur in either phase 2/3 (early afterdepolarizations) or phase 4 (delayed afterdepolarizations) of the AP; reentry results from cir­ cus movement of an electrical impulse (see Table 250-1 and Fig. 250-3). ■ ■ENHANCED AUTOMATICITY Automaticity, defined as spontaneous depolarizations occurring dur­ ing phase 4 of the AP, is a normal property of several myocardial tis­ sues, including the SA node, AV node, and the His-Purkinje system. The automaticity of the SA node triggers the normal cardiac impulse. When the automaticity of a more proximal conduction system tissue Abnormal automaticity Reentry Triggered activity Early afterdepolarizations Triggered activity Delayed afterdepolarizations FIGURE 250-3  Schematic action potentials with early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs).

is unreliable or slow, the automaticity of a more distal aspect of the conduction system may result in an “escape rhythm” that may maintain cardiac output. Automaticity in these tissues results from phase 4 depo­ larization of cellular membranes driven by several ionic currents. In the SA node, the nonselective Na/Ca If current drives this depolarization, while in other tissues, K currents, Ca currents, or even the Na/Ca and ATP-driven Na/K exchangers contribute.

CHAPTER 250 The rate of depolarization during phase 4 drives the frequency of APs and hence automaticity rate of these tissues. In nodal tissues, this rate of depolarization is highly regulated by the autonomic system. Parasympathetic input results in local acetylcholine (ACh) release, which then binds the IKACh potassium channel complex (specifically via a G protein–mediated mechanism). The opening of IKACh channels, resulting in K efflux, hyperpolarizes these cells, resulting in slow­ ing of phase 4 depolarization, thereby slowing the automaticity rate. Sympathetic input, via catecholamines, activates both alpha- and betaadrenergic receptors. Beta-1 adrenergic stimulation results in activation of L-type Ca channels, Ca influx, and as a result, enhanced depolarization rates during phase 4, and increased automaticity rates. The normal range of SA automaticity rates is between 30 and 220 beats/min, corresponding to the normal range of rates during sinus rhythm. The sinus rate at any instant is therefore a dynamic balance between sympathetic and para­ sympathetic input, with the latter dominating in the restful state. The intrinsic heart rate (IHR) is defined as the “native” automaticity rate of the SA node, absent any autonomic input. Principles of Clinical Cardiac Electrophysiology Abnormally enhanced automaticity may occur at any site that exhibits automaticity, including the SA node, AV node, or His-Purkinje system, resulting in pathologic tachycardia. In addition, in pathologic states, other stereotyped regions in the heart may exhibit enhanced automaticity, including the pulmonary veins, coronary sinus superior vena cava, and ventricular outflow tracts. Injury to myocardium, whether through ischemia or other mechanisms, may alter its cel­ lular membrane properties, resulting in automaticity in these tissues. For instance, the border zones of infarcted ventricular myocardium, or rapidly reperfused ischemic myocardium, often exhibit automatic arrhythmias including premature ventricular contractions (PVCs) or automatic idioventricular rhythms (AIVR). Abnormal automaticity in the pulmonary veins is believed to underpin the triggers that drive paroxysmal atrial fibrillation, while automaticity elsewhere in the atria drives atrial tachycardias. ■ ■AFTERDEPOLARIZATIONS AND TRIGGERED ARRHYTHMIAS Afterdepolarizations and triggered arrhythmias refer to abnormal depolarizations that occur in the late phases of the AP (afterdepolar­ izations) that can initiate sustained arrhythmias. Early afterdepolariza­ tions (EADs) occur typically during phases 2–3 of the AP and may be facilitated by intracellular Ca loading. When the QT interval prolongs, typically in a heterogeneous fashion across the ventricles, EADs may trigger wavefronts of abnormal depolarizations, resulting in torsades des pointes (TdP), a nonsustained or sustained ventricular arrhythmia that may result in cardiac arrest. Medications that prolong QT inter­ val, as well as other QT-prolonging factors including hypokalemia, hypomagnesemia, and bradycardia, predispose the ventricles to EADs, leading to TdP. Electrical remodeling in cardiomyopathies may also predispose to QT prolongation and risk of EADs and TdP. Delayed afterdepolarizations (DADs) are abnormal depolarizations occurring in phase 4 of the AP. The mechanism underlying DADs is increased intracellular Ca, which then enhances repetitive depolariza­ tions during the late phases of the AP. As a result, repetitive depolariza­ tions ensue, including the well-described phenomenon of bidirectional ventricular tachycardia (VT). Digitalis glycoside toxicity, ischemia, and catecholamines are the most commonly described causes for DADs. ■ ■REENTRY Reentry refers to the circus movement of a wavefront of electri­ cal activation. Reentry can occur around a fixed anatomic barrier, referred to as anatomic reentry, or around a functionally blocked or

refractory barrier or anchor, termed functional reentry. Initiation and maintenance of a reentrant arrhythmia require (1) unidirec­ tional block, where the electrical wavefront can only propagate in one direction, and (2) slow conduction, a zone within the reentrant circuit where conduction is relatively slow, allowing the remainder of the circuit to repolarize and recover from refractoriness (the inability to reexcite).

PART 6 Disorders of the Cardiovascular System The more common form of reentry is anatomic, which requires a defined electrical/anatomic circuit with a pathway around a fixed barrier. A wavefront of depolarization encounters a barrier to con­ duction that allows propagation in only one direction (unidirectional block), forcing activation preferentially along one limb or pathway. Due to slow conduction, the depolarization wavefront travels through the remaining circuit and continually encounters tissues that have recovered from refractoriness and are hence excitable. This results in perpetual circus movement. Moreover, if the total length of the cir­ cuit exceeds a distance determined by the product of the conduction velocity (theta) of the tissue and the refractory period (duration) of that tissue (tr), referred to as the wavelength of tachycardia (lambda = theta × tr), an excitable gap, where tissue is recovered from refrac­ tory and able to depolarize, is created, allowing reentry. Reentry is the mechanism for several clinically important and common cardiac arrhythmias, including atrial flutter, AV nodal reentry, AV recip­ rocating tachycardia utilizing an accessory pathway, and scar-based reentrant VT. When reentry occurs in the absence of a fixed anatomic bar­ rier, it is termed functional reentry. A nidus of partially refractory tissue anchors the depolarization wavefront, resulting in a circular or rotational reentrant wavefront. In this case, the reentrant circuit or activity tends to be less stable than that from anatomic reentry, resulting in variations in depolarization rate and propensity to easily terminate and/or reinitiate. There is evidence that functional reen­ try is the underlying mechanism for perpetuation and maintenance of both atrial fibrillation (AF) and ventricular fibrillation (VF). In both of these apparently chaotic and disorganized arrhythmias, mul­ tiple wavefronts resulting from multiple functional reentrant circuits appear to drive arrhythmia in many, if not most, instances. Underlying pathology of the myocardium resulting in heterogeneous electrophysi­ ologic properties, altered activation, and repolarization properties pre­ dispose myocardial tissues to initiation and propagation of functional reentry-based arrhythmias. In addition to intrinsic alterations in cellular membrane electro­ physiologic properties that underpin most arrhythmias, extrinsic factors may precipitate other architectural and tissue changes that contribute to proarrhythmia. Ischemia and infarct may create regions of heterogeneous fibrosis, resulting in islands of scar surrounded by injured tissue. This creates the anatomic substrate that can sustain ana­ tomic reentry, which underlies scar-based VT, as well as many macroreentrant atrial arrhythmias. Peri-infarct border zones often contain injured myocardium as well, and the resultant alterations in cellular membrane properties may promote enhanced automaticity or trig­ gered arrhythmias. Chronic ischemia also results in downregulation of connexin proteins and gap junctions, resulting in slowed impulse prop­ agation, which is one of the factors required for reentrant arrhythmias. Alterations in ion channel function, either through inherited mutations or through drug effect, can promote arrhythmias. QT prolongation can occur when the closing of potassium channels that should hyperpolar­ ize cells is delayed or slowed, or when the closing or inactivation of Na channels is impaired. ■ ■UNDERPINNINGS OF THE TREATMENT OF ARRHYTHMIAS Pharmacologic therapies for arrhythmias are directed toward the specific underlying mechanism. For enhanced automaticity-based arrhythmia, medications that target phase 4 depolarization, including Ca channel blockers, beta-adrenergic blockers (via indirect action on adrenergic input), or ivabradine may be used. For triggered activitybased arrhythmia, correcting the precipitating factor is most effective. This includes, among other therapies, removal of digitalis glycosides

from the body, discontinuation of QT-prolonging medications, or even increasing heart rate, thereby shortening QT interval. For reen­ trant arrhythmia, medications that increase the refractory period, in particular K channel blocking agents, will increase the wavelength of conduction beyond the circuit length of tachycardia, resulting in the inability to sustain reentry. Medications that slow conduction velocity may have the paradoxical effect of promoting reentrant arrhythmias due to the creation of a larger excitable gap. This explains much of the proarrhythmic effect of many antiarrhythmic medications. Therefore, for these agents, which typically include Na channel blockers, sufficient dosing is required to slow conduction velocity to the point of extin­ guishing meaningful arrhythmia circuit conduction. A major aspect of clinical cardiac electrophysiology that has evolved over several decades is the ability to disrupt arrhythmic substrates through catheter-based (or rarely surgical) myocardial ablation. For automaticity-based arrhythmias, precise localization and elimination or isolation through ablation of the site of focal automaticity is effective in eliminating arrhythmia. For anatomically bound reentrant arrhythmias, interruption of the reentrant circuit with a series of ablation lesions is effective. In contrast, given the lack of a fixed anatomic circuit, and perhaps also due to the pres­ ence of multiple, often migratory, circuits, it appears that mechanical disruption, typically through catheter-based ablation, of identified sites of functional reentry appears to be ineffective in eliminating arrhythmia. CARE OF THE ARRHYTHMIA PATIENT ■ ■EVALUATION AND DIAGNOSIS The evaluation of a patient with suspected arrhythmia begins with a directed history and physical examination, which must include an ECG. The history and examination should focus on determining the nature of symptoms attributable to the arrhythmia itself and clues to potential underlying cardiac, medical, or metabolic conditions that may predispose to specific arrhythmias, and hence direct further stud­ ies and evaluations, ultimately directing appropriate therapy, prognosis, and counseling. Family history may also provide clues toward possible inherited arrhythmia syndromes. Symptoms attributable to arrhythmia can vary from a vague sensation of fatigue, chest pain, dyspnea, or lightheadedness to more specific sensations of rapid, slow, or irregular heart rate. Premature contractions, whether atrial or ventricular, may be sensed as extra beats, or if these extrasystoles result in diminished stroke volume for that particular beat, a sensation of a missed beat. Second, the hemodynamic sequelae of impaired cardiac output may result in symptoms, from presyncope to frank syncope, dyspnea, chest discomfort, or generalized weakness. Importantly, as the cadence and duration of arrhythmia episodes are highly variable, the temporal man­ ifestations of arrhythmia symptoms may vary significantly. Sporadic episodes of arrhythmia will result in intermittent symptoms, including syncope if hemodynamic compromise is significant; protracted epi­ sodes of arrhythmia may cause persistent symptoms. In patients with underlying compromise in cardiac function, most typically in patients with structural heart disease, arrhythmia leading to diminished cardiac output may trigger or exacerbate symptoms associated with the under­ lying condition such as angina, congestive heart failure, or hypoxiaassociated symptoms. Inciting factors or associations may also provide clues to the diag­ nosis. Arrhythmias associated with activities that increase adrenergic tone, such as exercise, stimulant intake, or emotional stress, may suggest not only tachyarrhythmias but also automaticity-triggered arrhythmias. However, keep in mind that exceptions will occur. Medi­ cation use may be highly suggestive of an etiology: use of Ca channel blockers or beta blockers may suggest bradycardia exacerbated by these medications. Medications known to potentially prolong QT interval may suggest a malignant ventricular arrhythmia, specifically TdP. Eliciting a thorough family history, not only for known arrhythmia diagnoses, but of unexplained sudden death, may point toward a heri­ table syndrome. Demographic factors may point toward or away from certain diagnoses. For instance, AF rarely occurs in children and young

adults, save rare familial forms, or AF associated with structural heart disease; a strong male predominance, as well as a higher prevalence in certain ethnic populations such as Southeast Asians, is seen in Brugada syndrome; inappropriate sinus tachycardia is nearly exclusively a con­ dition affecting young women; degenerative conduction system disease leading to symptomatic bradycardia is most commonly a condition seen in older patients. Arrhythmias may run the gamut from benign to malignant, lifethreatening etiologies. Therefore, an important aspect of the evalu­ ation of suspected arrhythmia is to discern patient prognosis, which then informs treatment. Arrhythmias that result in more significant hemodynamic compromise, and therefore more profound symptoms, tend to correlate with more malignant disease. In turn, the higher the suspicion for a malignant arrhythmia, the more aggressive the evalu­ ation will likely be. Loss of consciousness, which may be the result of cardiac arrhythmia but also other etiologies that may be more benign, presents a particularly challenging yet common diagnostic dilemma. Therefore, careful thought into the appropriate evaluation for a patient with syncope is critical. In general, the presence of underlying struc­ tural abnormality of ventricular myocardium favors more malignant arrhythmias, both due to the increased risk of lethal ventricular arrhythmias and to potential inability to hemodynamically tolerate any particular arrhythmia. A careful history of circumstances, symptoms, and associated findings during the syncopal episode(s) can be very helpful in formulating a differential diagnosis. The ECG is the cornerstone and most important diagnostic test that should be performed on every patient with suspected arrhythmia. A 12-lead resting ECG may offer clues to the diagnosis. Most simply, if active arrhythmia is captured on the ECG, a definitive diagnosis can be made. In addition, evidence suggesting underlying cardiac disease, such as prior myocardial infarction, left ventricular hypertrophy and possible hypertrophic cardiomyopathy, atrial disease, or baseline conduction system disease, may suggest a diagnosis. A subset of condi­ tions that predispose to arrhythmia, both inherited or acquired, may be discerned as well, including ventricular preexcitation, prolonged or shortened QT interval, or ECG findings suggestive of specific inherited conditions such as Brugada syndrome or right ventricular cardiomyopathy. However, the ECG typically records only 6 s of cardiac electrical activity, and therefore more intermittent and transient arrhythmias, particularly those not typically associated with abnormalities on the resting ECG, may not be seen. Many arrhythmias, including forms of both supraventricular tachycardia (SVT) and VT, can only be diag­ nosed definitively if an ECG is performed during active arrhythmia and/or symptoms from arrhythmia or, alternatively, provoked in the electrophysiology laboratory. Therefore, various forms of ambulatory monitoring may be performed to attempt to capture ECG activity during active arrhythmia. A growing variety of monitoring options are available; the most appropriate option should be primarily guided by the cadence of suspected arrhythmia episodes. For instance, if daily symptoms occur, a 24- or 48-h continuous Holter monitor is appropri­ ate. On the other hand, a patient-activated event recorder is inappro­ priate in a patient with syncope, as the arrhythmic event will likely have passed once the patient reawakens. Attempts at provoking arrhythmia may be warranted in the appro­ priate circumstances. An ECG-monitored treadmill test may elicit exercise-induced arrhythmias, or if long QT is suspected, a QT interval that fails to shorten appropriately with increased heart rate may be helpful. Pharmacologic provocation may be indicated for certain sus­ pected diagnoses, such as Brugada syndrome. Judicious and appropri­ ate use of carotid sinus massage or other means to enhance vagal tone may be helpful to diagnose carotid hypersensitivity or overall vagally mediated syncope. Tilt table testing (TTT) involves having a patient strapped to a tiltable table. While monitoring heart rate and blood pressure, the patient is moved from a supine to upright position. In patients with suspected autonomic dysfunction–mediated syncope or presyncope, this provocation may elicit a paradoxical vagal response, resulting in bradycardia and/or sinus pauses as well as hypotension, and perhaps

frank syncope. However, given the significant lack of both sensitivity and specificity, the current role of TTT is unclear, and it is seldom indicated after a careful history elucidates a neurally mediated cause for syncope.

Invasive electrophysiologic (EP) testing is the most useful diag­ nostic modality for many arrhythmias. Catheter-based recordings of intracardiac electrograms, with or without provocative pacing or pharmacologic maneuvers, may elicit the clinical arrhythmia. This will, in turn, help to define the mechanism of arrhythmia. However, one must keep in mind that for certain arrhythmia mechanisms, such as automaticity-driven tachycardia, EP study may fail to elicit arrhythmia due to the often transient and multifactorial nature of initiation of these arrhythmias. The nature of arrhythmia elicited will aid in determination of the patient’s prognosis. In a typical EP study, catheters are placed within the heart via femoral venous access. Baseline conduction properties are measured. Provocative maneuvers including electrical pacing maneuvers, programmed stimulation, and pharmacologic provocation are performed. In the modern era, the vast majority of invasive EP studies are performed in conjunction with planned catheter ablation, although programmed ventricular stimula­ tion for risk stratification of sudden death may still be utilized. EP study during catheter ablation is performed to confirm the diagnosis, localize appropriate ablation targets, and evaluate the efficacy of abla­ tion performed during the procedure. CHAPTER 250 Principles of Clinical Cardiac Electrophysiology Depending on the suspected arrhythmia diagnosis, further testing may be indicated. If structural heart disease is suspected, echocar­ diography is most often the best next test, as it can assess for underly­ ing structural disease, evaluate left ventricular function, and assess atrial dimensions and mitral valve function if AF is suspected, both of which are fair prognostic indicators. In patients in whom underlying coronary artery disease is suspected, an evaluation for coronary isch­ emia is indicated. Further evaluation for underlying structural heart disease will be directed based on the differential diagnosis. Cardiac computed tomography provides broad diagnostic utility, depending on the scanning protocol, including evaluation for ischemia, ven­ tricular scar, anatomic evidence of coronary artery disease, congeni­ tal anomalies, and left atrial anatomy. Cardiac magnetic resonance imaging provides significant resolution of soft-tissue characteristics and may be used to assess for ischemia, infarct, cardiomyopathy, or infiltrative disease. Cardiac positron emission tomography can also discern underlying ischemia, as well as metabolic/inflammatory/ infiltrative conditions. TREATMENT Cardiac Arrhythmias ANTIARRHYTHMIC DRUG THERAPY The effects of pharmacologic agents on cardiac electrophysio­ logic properties are often complex and, in some instances, remain incompletely understood. The complexity is the result of complex pharmacodynamics and pharmacokinetics, in particular significant cross-reactivity of certain drugs across different targets as well as variable effects on drug targets across drugs within the same category. There are regional differences in drug effect within the myocardium, and interpatient variations in drug metabolism play important roles. This has, in part, led to many instances of harm that have come from the adverse effects of many agents used over the years. In fact, many antiarrhythmic agents currently in use carry significant risks of side effects, some of which may be significant and even lethal. Therefore, judicious use of antiarrhythmic medi­ cations by those with appropriate knowledge base and experience is warranted. The practical result of the narrow therapeutic index of this class of medications has rendered their use increasingly as ancillary options (Table 250-2). The traditional nomenclature of antiarrhythmic drugs (AADs) is known as the Vaughan-Williams classification schema. In this schema, there are four classes (I–IV; Table 250-2). Class I AADs primarily target the Na channel, class II agents target the

PART 6 Disorders of the Cardiovascular System beta-adrenergic receptor, class III agents target potassium channels, and class IV agents target Ca channels. Class I agents are further subdivided into three subclasses based on the kinetics of drug to Na channel interactions. Class IA agents, including procainamide and quinidine, possess intermediate binding kinetics and potency. Class IB agents, including lidocaine and mexiletine, possess rapid binding kinetics and relatively low potency. Class IC agents (flecainide, propafenone) possess slow kinetics and high potency. Class II agents consist entirely of beta-adrenergic blocking agents. Class III agents (sotalol, dofetilide, ibutilide) specifically target the Kv11.1 potassium channel (encoded by the KCNH2 gene) and risk prolon­ gation of the QT interval through these effects on phases 2/3 of the AP and hence ventricular repolarization. Class IV agents are cardi­ oselective Ca channel blockers including verapamil and diltiazem. This classification has significant limitations, however. Many AADs interact with multiple ion channels, and as a result, many exhibit behavior consistent with multiple classes. Amiodarone, in particu­ lar, exhibits properties of all AAD classes. Adenosine, with primary antiarrhythmic effects as an acute and transient, intravenously administered AV nodal blocking agent, as well as digitalis glycoside, which blocks the Na+/K+ pump, which in turn inhibits the Na+/Ca++ exchanger, resulting in antiarrhythmic effect, do not neatly fit into this classification schema. CATHETER ABLATION The rationale that underlies catheter ablation for cardiac arrhyth­ mia is that an anatomic substrate can be identified and localized, and disruption or isolation of that substrate will eliminate the cardiac arrhythmia. For automaticity-driven arrhythmias, a focal source of automaticity is identified, localized, and ablated. For anatomic reentrant arrhythmias, a critical zone of slow conduc­ tion that sustains arrhythmia and can be reasonably targeted is ablated. Moreover, the ablation target must be in a location deemed at acceptable risk of not damaging critical structures such as the native conduction system, coronary arteries, or extracardiac structures including the esophagus and phrenic nerve. Advances in electroanatomic mapping, a technology that uses alterations in electrical impedance and a magnetic field as measured by an intra­ cardiac mapping catheter, have allowed for real-time reconstruc­ tion of cardiac chambers and identification of arrhythmogenic tissue to be targeted for ablation while safely avoiding nontargeted critical structures. Intracardiac echocardiography has also been used to enhance the safety and efficacy of invasive electrophysi­ ologic procedures with real-time visualization of cardiac structures (Fig. 250-4). In the 1950s–1960s, as the underlying anatomic substrates for arrhythmias became better understood, open surgical disruption of arrhythmia circuits was the only available interventional and cura­ tive therapy for many arrhythmias. Surgical ligation of accessory pathways or resection of ischemic VT substrates was performed at specialized surgical centers. The first attempts at clinical catheter ablation utilized direct current (DC) electrical energy. This resulted in a high-voltage pulse of electrical energy that would ablate cardiac tissue, but with a difficult-to-control scope, often leading to sig­ nificant complications. Radiofrequency (RF) energy was adapted to catheter-based cardiac ablation in the 1980s. RF alternating electri­ cal current (300–550 kHz) delivered through a catheter tip results in local tissue heating and permanent injury, rendering the targeted tissue electrically inert. This type of ablation is similar to the tech­ nology used in electrosurgical techniques using a Bovie electro­ cautery device. For >35 years, RF delivery via catheters has been iteratively optimized such that it has become the most common and mainstay energy source for catheter ablation. Catheter ablation is indicated for a wide variety of clinical arrhythmias, including SVT, accessory pathways, atrial flutter, AF, PVCs, and VT. Alternative TABLE 250-2  Antiarrhythmic Drug Actions DRUG CLASS ACTIONS OTHER ACTIONS/COMMON SIDE EFFECTS I II III IV Quinidine ++   ++   Anticholinergic Flecainide +++   +   Can promote reentrant arrhythmias (atrial flutter, ventricular tachycardia) Propafenone ++ +     Mild beta-blocker effect Amiodarone ++ ++ +++ + Multiorgan toxicity with long-term use Sotalol   ++ +++   Prominent beta-blocker effect Dofetilide     +++   Prolongation of QT at slower heart rates Dronedarone + + + + Mild effect Ibutilide     +++   Used only for acute cardioversion Ranolazine ++   ++   Late sodium channel blockade Lidocaine ++       Used for reperfusion arrhythmias A B FIGURE 250-4  Catheter ablation of cardiac arrhythmias. A. A schematic of the catheter system and generator in a patient undergoing radiofrequency catheter ablation (RFCA); the circuit involves the catheter in the heart and a dispersive patch placed on the body surface (usually the back). The inset shows a diagram of the heart with a series of intracardiac catheters placed via the inferior vena cava (IVC), typically through femoral venous access. Catheters are located at the high right atrium, His bundle location, right ventricular (RV) apex, and through a transseptal puncture within the left atrium. B. Images from an electroanatomic mapping system are shown during mapping and ablation of typical cavo-tricuspid isthmus-dependent atrial flutter. This system allows three-dimensional real-time localization and annotation of catheter position and cardiac anatomy to guide mapping and ablation. In this instance, two projections of the map are shown at the top of the right atrium (RA), a right anterior oblique (RAO) and left anterior oblique (LAO) caudal view. Annotations of ablation lesion delivery are shown as red dots. In the left lower aspect of this panel, a simultaneous image from intracardiac echocardiography (ICE) is shown of the RA, with the ablation catheter in view in all three images. In the lower right aspect of this panel, surface electrocardiogram and intracardiac electrograms acquired in real time are shown.

12 - 251 The Bradyarrhythmias- Disorders of the Sinoatrial Node

251 The Bradyarrhythmias: Disorders of the Sinoatrial Node

ablative energy sources have been explored over the years, includ­ ing cryothermy, light spectrum (laser), microwave, ultrasound, and more recently pulsed field electroporation, which injures targeted myocardium through high-energy, ultra-short pulses of electrical current that disrupts the lipid cell membrane, resulting in perma­ nent cell death. Recently, the well-established ablative technique of stereotactic (focused and directed) external beam ionizing radiation has been applied to the heart to treat various arrhythmias, includ­ ing VT and AF. This particular treatment modality holds promise given its ability to target regions of the heart that may be inacces­ sible to catheters, as well as the completely noninvasive nature of the procedure. A widely applied non-RF ablative energy source today is cryo­ thermy, where an ablative catheter tip is cooled to a temperature range (typically below –40°C) that results in permanent tissue death. Cryothermy is most widely applied to ablation of paroxysmal atrial ablation, via an expandable balloon introduced sequentially into each pulmonary vein and cooled to produce a circumferen­ tial ablative lesion at the ostium/antrum of each pulmonary vein. Similar catheter-based tools utilizing pulsed field ablation (PFA) have also been introduced for the purpose of electrically isolating pulmonary veins during AF ablation. IMPLANTED ELECTRICAL DEVICE THERAPY Implanted cardiac rhythm management devices are commonly utilized to manage arrhythmia. The first definitive pacemaker was implanted in 1958, and this technology has evolved to be the mainstay in the management of bradyarrhythmias. Sinus node dysfunction and AV conduction disease, particularly with symp­ toms, are the primary indications for most implanted pacemakers. Pacemakers are typically implanted percutaneously, with insulated wires, or leads, inserted through the upper extremity venous sys­ tem into the right atrial and/or ventricular myocardium, with the lead tip secured to the myocardium mechanically. The leads are connected to a pulse generator placed in the prepectoral space, which contains electronic circuitry and a battery, allowing sensing and/or delivery of pacing stimuli to maintain adequate heart rate. More recently, a completely leadless pacemaker inserted through a large femoral venous sheath directly into the RA or right ventricle endocardium has become available. Although these devices possess more limited pacing options, they likely reduce the risks associated with transvenous lead systems, including infection or lead fracture requiring extraction. Implanted cardioverter-defibrillators (ICDs) are placed in a simi­ lar fashion to pacemakers. However, ICDs have the ability to sense abnormal ventricular arrhythmias and deliver either anti­ tachycardia pacing or defibrillation to prevent sudden death. In patients who experience a potentially lethal ventricular arrhyth­ mia, ICD therapy may be lifesaving. Indications for ICD therapy are considered for either primary prevention of sudden cardiac death (SCD) due to arrhythmia in an at-risk patient or as second­ ary prevention in a patient who has survived an SCD event. More recently, a completely subcutaneous ICD system has become available, avoiding intravenous leads that increase risk for sys­ temic infection, and potentially the procedure to extract a poten­ tially fibrosed lead in cases of lead malfunction or endovascular infection. ■ ■FURTHER READING Callans DJ: Josephson’s Clinical Cardiac Electrophysiology: Techniques and Interpretations, 7th ed. Philadelphia, Wolters Kluwer, 2024. Ellenbogen K et al (eds): Clinical Cardiac Pacing, Defibrillation, and Resynchronization Therapy, 5th ed. Philadelphia, Elsevier, 2016. Jalife J, Stevenson W (eds): Zipes and Jalife’s Cardiac Electrophysiology: From Cell to Bedside, 8th ed. Philadelphia, Elsevier, 2021.

William H. Sauer, Bruce A. Koplan

The Bradyarrhythmias:

Disorders of the

Sinoatrial Node CHAPTER 251 The Bradyarrhythmias: Disorders of the Sinoatrial Node
The sinoatrial (SA) node serves as the natural pacemaker of the heart and has variable rates in response to parasympathetic and sympathetic stimulation. If the sinus node is dysfunctional or suppressed, a subsid­ iary pacemaker in the atrioventricular node or specialized conduction system will take over, leading to a junctional or ventricular rhythm. Symptoms of sinus node dysfunction can vary but typically present as fatigue, exercise intolerance, or dyspnea. The diagnostic evaluation includes an investigation into reversible causes of sinus bradycardia, confirmation of sinus node dysfunction with outpatient telemetry monitoring or exercise testing, and possibly cardiac imaging if struc­ tural heart disease is suspected. Once irreversible sinus node dysfunc­ tion is confirmed, permanent pacemaker implantation is the only reliable long-term therapy for symptomatic bradycardia. ■ ■STRUCTURE AND PHYSIOLOGY OF THE SA NODE The SA node region is complex in structure. Clusters of myocytes with pacemaker activity are surrounded by fibroblasts, endothelial cells, and transitional cells. These clusters of small fusiform cells in the sulcus terminalis on the epicardial surface of the heart at the right atrial–supe­ rior vena cava junction envelop the SA nodal artery. The SA node is structurally heterogeneous, but the central prototypic nodal cells have fewer distinct myofibrils than does the surrounding atrial myocar­ dium, no intercalated disks visible on light microscopy, a poorly devel­ oped sarcoplasmic reticulum, and no T tubules. Cells in the peripheral regions of the SA node are transitional in both structure and function. The SA nodal artery arises from the right coronary artery in 55–60% and the left circumflex artery in 40–45% of persons. This feature, along with a protective extracellular matrix of connective tissue, insulates the SA node from the hyperpolarizing influence of the larger atrium. In addition, the alignment of this complex matrix is associated with nearly unidirectional electrical propagation to the atrium (Fig. 251-1). Pacemaker cells spontaneously depolarize in a continuous manner setting the natural rate of depolarization and myocardial contraction. Action potential depolarization in the SA node is normally at a rest­ ing rate of 60–100 beats/min. The autonomic nervous system exhibits control over the sinus node, with a preponderance of parasympathetic innervation at baseline. Removal of parasympathetic tone or an increase in sympathetic innervation leads to an increase in rate of depolarization. In denervated hearts, the rate of electrical depolariza­ tion (intrinsic heart rate) is approximately 100 beats/min, reflecting the rate of automaticity of the sinus node uninhibited by parasympathetic tone. The complement of ionic currents present in nodal cells results in a less negative resting membrane potential compared with atrial or ventricular myocytes. Electrical diastole in nodal cells is characterized by slow diastolic depolarization (phase 4), which generates an action potential as the membrane voltage reaches threshold. The action potential upstrokes (phase 0) are slow compared with atrial or ventric­ ular myocytes, being mediated by calcium rather than sodium current. Cells with properties of SA nodal tissue are electrically connected to the remainder of the myocardium by cells with an electrophysiologic phenotype between that of nodal cells and that of atrial or ventricular myocytes. Cells in the SA node exhibit the most rapid phase 4 depo­ larization and thus are the dominant pacemakers in a normal heart. Myocytes within the SA node complex include specialized cells surrounded by fibrous tissue. Unlike atrial and ventricular cells, sinus node pacemaker cells have no true resting potential, but instead depo­ larize automatically and repetitively after the end of an action potential, and the depolarizing current in the SA node myocytes results primarily from slow calcium currents instead of fast sodium channels, which are

Sinus Node Pacemaker Cells +30 mV PART 6 Disorders of the Cardiovascular System 0 mV Phase 0 Phase 3 –30 mV Threshold Phase 4 –60 mV iK if iCa-T iCa-L FIGURE 251-1  Cellular ion currents involved in depolarization and automaticity of sinoatrial (SA) nodal pacemaker cells. Phase 4 spontaneous depolarization results from if (funny) current, along with T- and L-type calcium channels. Phase 0 is the depolarization phase of the action potential. This is followed by phase 3 repolarization, which results from the outward directed hyperpolarizing K+ currents. if, funny current; iCa-T, T-type calcium current; iCa-L, L-type calcium current; iK, potassium current. absent in SA node cells. Spontaneous phase 4 depolarization results from a combination of slow inward depolarizing sodium current (If, “funny current”), along with inward calcium current controlled by T-type and L-type calcium channels. The upstroke of depolarization in SA node myocytes is slower and lower in amplitude than in ventricular myocytes. In patients <85 years of age, the resting heart rate is strongly influ­ enced by parasympathetic tone at baseline. The absence or elimination of autonomic influence on the SA node (e.g., after atropine adminis­ tration) leads to an intrinsic heart rate that is normally 100–110 beats/ min. The myocytes within the SA node that initiate pacing will change with different rates with a superior shift at higher heart rates and an inferior shift at lower rates. This shift may lead to a slightly different

P wave inscribed on electrocardiograms (ECGs) recorded during dif­ ferent rates of sinus rhythm. In addition, a progressive decline in maximum heart rate occurs with age, although the resting heart rate normally remains unchanged. Intrinsic heart rate declines 5–6 beats/min for each decade of age. However, the constancy of resting heart rate is associated with a grad­ ual decrease in parasympathetic tone and a transition to predominant sympathetic tone by the ninth decade. ■ ■DIAGNOSIS OF SA NODAL DISEASE Intrinsic sinus node disease is sometimes referred to as sick sinus syn­ drome or sinus node dysfunction (SND) and can manifest as fatigue, exercise intolerance, or syncope resulting from either reduced heart rate or pauses. Electrocardiographic recording plays a central role in the diagnosis and management of SA node dysfunction. The correla­ tion between symptoms and slow heart rate or pauses is essential in determining whether bradycardia may be considered pathologic and necessitating intervention. Baseline ECG can detect baseline sinus bra­ dycardia but may not indicate symptom correlation in certain settings. To address the limitations of the resting ECG, longer-term recording employing mobile telemetry devices such as Holter monitors or mobile cardiac telemetry can also be helpful in correlating symptoms with rate abnormalities (Fig. 251-2). In addition, commercially available wearable devices, such as watches with ECG recording capabilities, can have electrograms with excellent fidelity that may also be utilized. Contemporary event monitors may be automatically triggered to record the ECG when certain programmed heart rate criteria are met and implantable monitors permit very longterm recording (years) in particularly challenging patients. Treadmill testing can be utilized to assess for maximum heart rate. It is worth noting, however, that standard Bruce protocol treadmill testing may

Phase 4 be helpful in detecting abnormalities in maximum heart rate, but more insidious chronotropic incompetence that manifests as abnormalities of rate increase during submaximal exercise may be more evident with treadmill protocols that have more gradual effort increases. Once there is evidence of SND, it is important to rule out reversible causes of resting sinus bradycardia or chronotropic incompetence. Table 251-1 lists the potentially reversible causes of sinus node dis­ ease and includes hypothyroidism and rate-slowing medications. Many patients with sleep apnea will have high vagal tone during sleep, especially during apneic events. Sinus bradycardia and sinus pauses frequently are seen if a patient is being monitored during this period. Sleep apnea, a common reversible cause, should be suspected if marked sinus bradycardia and prolonged sinus pauses are observed in a telemetry monitoring period during sleep. It is also worth noting that asymptomatic sinus bradycardia and pauses during sleep are typi­ cally not an indication for pacing, and it is, therefore, important when interpreting a wearable monitor to determine the timing of bradycardia events with regard to the sleep versus awake periods. If structural heart disease is suspected, transthoracic echocardiog­ raphy should be used to detect potential cardiac abnormalities associ­ ated with SND (Fig. 251-3). Advanced cardiac imaging is indicated for evaluation of possible myocardial diseases such as amyloidosis, infiltrative cardiomyopathy, or myocarditis. Invasive electrophysiology testing solely to assess sinus node function is rarely utilized beyond the noninvasive techniques mentioned. In patients who are undergoing electrophysiology studies (EPS) for other indications, evaluation of sinus node function as part of the EPS may be considered. In symp­ tomatic patients with suspected SND, EPS may rarely be considered when the diagnosis remains uncertain and after initial noninvasive evaluation is inconclusive. Investigation of the sinus node during EPS can consist of determination of sinus node recovery time (SNRT) and sinoatrial conduction time (SACT). In addition, the intrinsic heart rate [118.1 – (0.57 × age)] can be assessed via pharmacologic blockade of autonomic tone with intravenous propranolol and atropine. EPS is not widely used, however, as there is no evidence that abnormal SNRT or SACT alone can be used as an absolute indication for permanent pac­ ing (PPM). There is no indication for EPS in asymptomatic patients with sinus bradycardia. ■ ■SA NODAL DYSFUNCTION SUBTYPES SND can be categorized into problems with impulse formation and problems with impulse conduction. The term sick sinus syndrome may be used interchangeably with SND and refers to a group of related

Sinus (55 bpm), pause (3.4 seconds) 400 ms FIGURE 251-2  Sinoatrial exit block. A pause in the heart rhythm is seen that results from a sinus pause. On the second line of the tracing, there is a pause that results from the absence of a sinus beat (absent P wave) and no subsequent QRS. This is followed by a junctional escape beat and eventually recovery of the presence of sinus rhythm P waves. conditions comprising problems of both impulse formation and impulse conduction. Sinus Node Exit Block (See Fig. 251-4)  “Sinus arrest” results from failure of impulse formation within the sinus node. Sinoatrial exit block results from failure of sinus node activity to propagate to the atrium. Sinoatrial exit block can have similar pattern characteristics of types of atrioventricular (AV) node block. It can manifest as complete SA block. Type I SA block involves fixed delay out of the sinus node. Type II SA block can occur with either progressive delay and then intermittent failure to propagate to the atrium (Mobitz I type) or fixed delay with intermittent failure to conduct (Mobitz II). The mass of the sinus node is not large enough to have an appearance on the ECG. Instead, the P waves that result from atrial depolarization can provide information that reflects the health of the sinus node. Type II seconddegree SA block can be inferred on the ECG if the sinus rate abruptly transitions to a sinus rate that is half the previous rate (every other sinus depolarization is blocked from exiting to the atrium). Sinoatrial Wenckebach can be inferred from the ECG in the setting of progres­ sive shortening of the P-P interval leading up to a sinus pause. This is due to progressive prolongation of SA conduction, but to a lesser extent with each successive prolongation. This is similar to the typical progressive shortening of the R-R interval that is observed with AV nodal Wenckebach. Other types of SA block require invasive EPS to decipher. The exercise of determining the type of SA block with inva­ sive electrophysiology testing is typically not necessary because it does not alter management. Tachy-Brady Syndrome  Tachycardia-bradycardia (tachy-brady) syndrome is a subset of sick sinus syndrome/sinus node disease that consists of high heart rates (most commonly atrial fibrillation) with alternating symptomatic bradycardia or offset pauses (Fig. 251-5). Commonly, medications that are needed for rate control of tachycardia exacerbate bradycardia episodes, and thus the presence of tachy-brady syndrome is often a reason to consider pacemaker implantation.

CHAPTER 251 The Bradyarrhythmias: Disorders of the Sinoatrial Node
Chronotropic Incompetence  Chronotropic incompetence (CI) is broadly defined as the inability of the heart to increase its rate to meet activity or demand. Compared to an increased stroke volume, the increase in heart rate is a stronger contributor to the increase in oxygen uptake (VO2) during aerobic exercise. Therefore, CI can be the primary cause of severe exercise intolerance and increased cardiovas­ cular events and overall morality. Unfortunately, CI lacks a consistent definition, leading to a lack of clarity on its overall prevalence. CI can take many forms, including failure to achieve a percentage (e.g., 85%) of age-predicted maximal heart rate [(220 – age) × 0.85] during stress testing. Other definitions that have been used include an overall a max­ imum heart rate [208 – (0.7 × age)], heart rate instability with exercise, or failure to achieve submaximal heart rate. Due to this latter category, standard exercise testing can, at times, fail to recognize a patient with CI because some patients can achieve an appropriate maximum heart rate but may exhibit heart rate instability or inadequate heart rate during activities of daily living (ADLs). Ambulatory heart rate moni­ toring along with a diary can be helpful to correlate symptoms with abnormally slow heart rates. Because CI can be insidious and multiple definitions exist, it can be easily overlooked. Sinus Node Fibrosis  Clinical SND is most common in older adults. This is due to normally occurring age-associated increase in fibrotic tissue in the SA node, which can exacerbate any degree of SND. A loss of pacemaker cells in the sinus node is also seen with age. It is worth noting, however, that while increased fibrosis in the SA node and decreased numbers of pacemaker myocytes are part of a normal process of aging, SND is pathologic and there are many elderly patients with extensive fibrosis and normal heart rate. SA Nodal Ischemia and Infarction  Sinus bradycardia is com­ mon in patients with acute inferior or posterior myocardial infarction (MI) and can be exacerbated by increased vagal tone (Bezold-Jarisch reflex) or with the use of drugs such as morphine and beta blockers. Ischemia of the SA nodal artery occurs in acute coronary syndromes

TABLE 251-1  Reversible Causes of Sinus Node Dysfunction Medical Conditions Associated with Sinus Bradycardia • Hypothyroidism • Sleep apnea • Hypoxia • Hypothermia • Increased intracranial pressure • Lyme disease • Myocarditis • COVID-19 • Vagal reflex (cough, pain, etc.) PART 6 Disorders of the Cardiovascular System Medications Associated with Sinus Node Dysfunction Antihypertensive Medications • Beta-adrenergic receptor blockers • Clonidine • Methyldopa • Nondihydropyridine calcium channel blockers Antiarrhythmic Medications • Amiodarone • Dronedarone • Flecainide • Procainamide • Propafenone • Quinidine • Sotalol • Ivabradine Psychiatric Medications • Donepezil • Lithium • Opioid analgesics • Phenothiazine antiemetics and antipsychotics • Phenytoin • Selective serotonin reuptake inhibitors • Tricyclic antidepressants Other • Anesthetic drugs (propofol) • Cannabis • Digoxin • Muscle relaxants more typically with involvement with the right coronary artery, and even with infarction, the effect on SA node function most often is transient. However, there are rare cases where SA infarction can affect sinus node function. One potential rare complication of atrial fibrilla­ tion catheter ablation is the inadvertent injury to the SA nodal artery that may be coursing over a targeted ablation region in the right and left atrium. SND and arrest have been described following ablation of atrial fibrillation and flutter. Carotid Sinus Hypersensitivity and Neurally Mediated Bradycardia  Sinus bradycardia is a prominent feature of carotid sinus hypersensitivity and neurally mediated bradycardia associ­ ated with the cardioinhibitory variant of vasovagal syncope. Carotid hypersensitivity with recurrent syncope or presyncope associated with a predominant cardioinhibitory component responds to pacemaker implantation. Although the vasodepressor effect of the enhanced vagal tone may be unaffected by the pacing support, the lack of bradycardia often prevents injury with this subtype of vasovagal syncope. Several randomized trials have investigated the efficacy of permanent pac­ ing in patients with drug-refractory vasovagal syncope, with mixed results. Although initial trials suggested that patients undergoing pacemaker implantation have fewer recurrences and a longer time to recurrence of symptoms, at least one follow-up study did not confirm these results.

TREATMENT SA Nodal Disease TEMPORARY PACING FOR TRANSIENT SUPPORT In symptomatic patients presenting with sinus node disease, remov­ ing any possible reversible cause remains the initial strategy. Acute myocardial infarction, electrolyte abnormalities, medications, and hypothyroidism should all be considered as potentially reversible causes. Unnecessary medications that may be causing bradycardia should be eliminated. Beta blockers, calcium channel blockers, and digoxin are some of the more common medications in use that may cause bradycardia. These drugs may have a wide range of indica­ tions in patients after MI and with chronic systolic dysfunction. If stopping the medication or decreasing the dose is an option, this should be tried first. If the medication is felt to be unavoidable, a pacemaker may be indicated. In patients with tachy-brady syndrome, alleviation of the tachy­ cardia, whether it is atrial fibrillation or other forms of supra­ ventricular tachyarrhythmias, can prevent bradycardia events. Treatment of the tachycardia can sometimes be accomplished with antiarrhythmic drug therapy or catheter ablation. If arrhythmia control cannot be achieved, permanent pacing may be necessary. Hypoxia from decrease in blood flow to the SA node, which can occur with cardiac ischemia or MI, can lead to slowing of phase 4 depolarization and resultant bradycardia. Further ischemia and necrosis of pacemaker cells can cause irreversible sinus node dis­ ease. On occasion, reversal of ischemia with revascularization can alleviate bradycardia. Sinus pauses in the setting of tachy-brady syndrome may be eliminated if atrial tachyarrhythmias can be suc­ cessfully treated. It is also important to recognize when bradycardia may be transient. Acute illness associated with episodes of extreme vagal tone may lead to transient SA node abnormalities. Typically, this may be observed as sinus slowing, followed by transient sinus arrest and/or AV block. Although a pacemaker may be needed in extreme instances of prolonged arrest, recovery from the acute ill­ ness may make the pacemaker unnecessary in follow-up. Sinus bradycardia may also be observed after heart transplanta­ tion and cardiac surgery. Due to cardiac denervation, a normal resting heart rate in heart transplant recipients is generally 90–110 beats/min. Therefore, a heart rate that may be normal in a non­ transplant patient may represent CI in a transplanted patient. In the case of heart transplantation, sinus bradycardia may be due to accumulated drugs such as amiodarone that affect the donor heart or ischemic injury to the SA node upon transplantation. If the SA nodal artery is injured at the time of right atriotomy during cardiac surgery, sinus arrest with junctional rhythm may be observed. Tem­ porary pacing or pharmacologic support with beta-1 adrenergic agonists may be needed in these circumstances while awaiting SA nodal recovery. In addition, sinus bradycardia and sinus pauses are common after spinal cord injury. The mechanism of bradycardia is enhanced parasympathetic tone and autonomic dysreflexia. Common trig­ gers can be tracheal suctioning and turning the patient. Atropine and inotropes have shown mixed success. Adenosine blockade with theophylline or aminophylline can sometimes be successful. Temporary and sometimes permanent pacing may be necessary in extreme circumstances. PERMANENT PACEMAKER IMPLANTATION Pacing in SA nodal disease is indicated to alleviate symptoms of bradycardia. Consensus guidelines published by the American Heart Association (AHA)/American College of Cardiology (ACC)/ Heart Rhythm Society (HRS) outline the indications for the use of pacemakers and categorize them by class based on levels of evi­ dence (Fig. 251-6). Since the first implementation of permanent pacing in the 1950s, many advances in technology have resulted in miniaturization, increased longevity of pulse generators, improve­ ment in leads, and increased functionality. To better understand

Treat underlying cause as needed, e.g., sleep apnea (Class I) Treatment effective or unnecessary Yes Observe Yes Transthoracic echocardiography (Class IIa) Suspicion for infiltrative CM, endocarditis, ACHD Yes No Advanced imaging (Class IIa) Treat identified abnormalities If not already performed: Exercise ECG testing (Class IIa) FIGURE 251-3  Evaluation of bradycardia and conduction disease. In patients with sinus node dysfunction, reversible causes should be identified and eliminated when possible. If no reversible cause can be identified, structural heart disease should be considered and evaluated for, if appropriate. If no symptoms are present, an observation strategy is appropriate. In patients who are symptomatic, further evaluation with ambulatory monitoring or exercise testing to identify symptom-rhythm correlation should be considered. ACHD, adult congenital heart disease; CM, cardiomyopathy. (Reproduced with permission from FM Kusumoto et al: 2018 ACC/AHA/HRS guideline on the evaluation and management of patients with bradycardia and cardiac conduction delay. Heart Rhythm 16:e128, 2019.)

Evidence for sinus node dysfunction CHAPTER 251 Reversible or physiologic cause Yes No The Bradyarrhythmias: Disorders of the Sinoatrial Node
No Suspicion for structural heart disease No Symptoms Observe No Yes Exercise related Yes No Diagnostic If not already performed: Ambulatory ECG monitoring (Class I) No Yes Electrophysiology study (if performed for other reasons) (Class IIb) Sinus node dysfunction treatment algorithm

SAN EG VI PART 6 Disorders of the Cardiovascular System A III V B FIGURE 251-4  A. Mobitz type I sinoatrial (SA) nodal exit block. A theoretical SA node electrogram (SAN EG) is shown. Note that there is grouped beating producing a regularly irregular heart rhythm. The SAN EG rate is constant with progressive delay in exit from the node and activation of the atria, inscribing the P wave. This produces subtly decreasing P-P intervals before the pause, and the pause is less than twice the cycle length of the last sinus interval. B. Mobitz type II SA nodal exit block. This panel shows sinus rhythm in the first four beats followed by a sinus pause with the absence of a P wave. The interval comprising the absent P wave is exactly twice as long as the preceding P-P interval consistent with type II SA exit block. pacemaker therapy for bradycardias, it is important to be familiar with the fundamentals of pacemaker function. There is no established heart rate below which pacemaker treat­ ment is indicated (Table 251-2). Well-conditioned athletes can have resting sinus rates below 40 beats/min, and some individuals can have similar levels of bradycardia during sleep. Permanent pacing is typically not indicated for sleep-related pauses felt secondary to high vagal tone in the absence of other symptoms. Asymptomatic sinus bradycardia has not been associated with adverse outcomes and does not typically warrant permanent pacing. In situations such as asymptomatic sinus bradycardia, sinus pauses secondary to physiologically elevated parasympathetic tone, transient pauses during sleep, or asymptomatic SND where symptoms have been documented to occur in the absence of bradycardia, a pacemaker is generally not indicated. Medications to improve heart rate in order to avoid PPM are very rarely utilized. Medications such as methylxanthines (e.g., theoph­ ylline) or beta agonists (e.g., terbutaline) are sometimes utilized on Termination of Atrial Fibrillation (90-105 bpm), Pause (7.4 seconds) 400 ms FIGURE 251-5  Offset pause and tachy-brady syndrome. An offset pause after termination of atrial fibrillation is seen and is consistent with tachy-brady syndrome.

a temporary basis when a pacemaker may need to be delayed due to unique circumstances such as active infection. In addition, oral theophylline may be considered to determine if an increase in heart rate is associated with improvement in symptoms in a patient with sinus bradycardia to suggest that a PPM may be beneficial. This lat­ ter strategy is rarely utilized in more equivocal situations. PPM is the principal treatment for SND, and the decision to pursue this treatment is largely driven by a correlation between symptoms and bradycardia. The stronger the correlation between symptoms and bradycardia, the greater is the likelihood of improve­ ment. PPM is most commonly achieved through transvenous implantation of one or more leads through the left or right sub­ clavian veins into the cardiac chambers. The leads are attached to a pacemaker generator that is placed subcutaneously in the pectoral chest region. Less commonly, pacing leads can be placed in the epicardium via surgical approaches including sternotomy or thoracotomy. This latter approach can be accomplished as a standalone procedure but is more commonly performed concomitantly 10 mm/mV, 24 s

Due to required GDMT (no reasonable alternative) No Yes No (or asymptomatic) Yes Permanent pacing (Class I) Infrequent pacing? Significant comorbidities? Yes No No Single chamber ventricular pacing (Class IIa) Normal AV conduction and reason to avoid an RV lead? No Yes Dual chamber pacing (Class I) Single chamber atrial pacing (Class I) Program to minimize ventricular pacing (Class IIa) FIGURE 251-6  Management of sinus node dysfunction. Management of sinus node dysfunction begins with eliminating reversible causes and confirming whether symptoms correlate with bradycardia. If symptoms are clearly correlated, permanent pacing should be offered. If it is unclear, a trial of oral theophylline can be considered diagnostically. If there is no correlation between symptoms and bradycardia, then observation is appropriate. Class I recommendations should be performed or are indicated. Class IIa recommendations are considered reasonable to perform. Class IIb recommendations may be considered. Class III recommendations are associated with harm more than benefit. AV, atrioventricular; GDMT, guideline-directed management and therapy; PPM, permanent pacemaker; RV, right ventricular. (Reproduced with permission from FM Kusumoto et al: 2018 ACC/AHA/HRS guideline on the evaluation and management of patients with bradycardia and cardiac conduction delay. Heart Rhythm 16:e128, 2019.) TABLE 251-2  Indications for Permanent Pacing in Sinus Node Dysfunction (SND) • Symptoms that are directly attributable to SND • Symptomatic sinus bradycardia because of essential medication therapy for which there is no alternative treatment • Tachy-brady syndrome and symptoms attributable to bradycardia • Symptomatic chronotropic incompetence • In patients with symptoms that are possibly attributable to SND, a trial of oral theophylline may be considered to increase heart rate and determine if permanent pacing may be beneficial Source: FM Kusumoto et al: Heart Rhythm 16:e128, 2019.

Sinus node dysfunction Confirm symptoms Rule out reversible causes CHAPTER 251 The Bradyarrhythmias: Disorders of the Sinoatrial Node
Symptoms correlate with bradycardia Likely/uncertain Observation Oral theophylline (Class IIb) Permanent pacing (Class III: Harm) Response suggests symptomatic sinus node dysfunction? Yes Willing to have a PPM? No Yes Oral theophylline (Class IIb) during another primary cardiac surgery. Leadless pacemakers that are totally self-contained pacing devices can also be placed in the right atrium and right ventricle to provide dual chamber pacing. Some leadless pacemakers can also incorporate technology to sense atrial activity to attempt to coordinate atrial sensing with ventricu­ lar pacing. A standard nomenclature for pacing mode programming uti­ lizes a four-letter code. The first letter indicates the chamber(s) paced (O, none; A, atrium; V, ventricular; D, dual; S, single). The second letter indicates the chamber(s) sensed. The third letter is the response to a sensed event (O, none; I, inhibited; T, triggered;

14 - 253 Approach to Supraventricular Arrhythmias

253 Approach to Supraventricular Arrhythmias

■ ■FURTHER READING Jalife J, Stevenson W (eds): Zipes and Jalife’s Cardiac Electrophysiology:

From Cell to Bedside, 8th ed. Philadelphia, Elsevier, 2022. Kusumoto FM et al: 2018 ACC/AHA/HRS guideline on the evaluation and management of patients with bradycardia and cardiac conduc­ tion delay: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm 16:e128, 2019. Sidhu S, Marine JE: Evaluating and managing bradycardia. Trends PART 6 Disorders of the Cardiovascular System Cardiovasc Med 30:265, 2020. William H. Sauer, Paul C. Zei

Approach to

Supraventricular

Arrhythmias Supraventricular arrhythmias refer to all abnormal heart rhythms originating above the level of the ventricle including the atria and the atrioventricular (AV) junction. Supraventricular arrhythmias include premature atrial contractions (PACs), wandering atrial pacemaker, sinus arrhythmia, nonphysiologic sinus tachycardia, atrial tachycardia, junctional tachycardia, atrial flutter, and atrial fibrillation. Supraven­ tricular arrhythmias that result in an elevated heart rate (>100 beats/ min) are broadly defined as supraventricular tachycardias (SVTs). SVTs originate from or are dependent on conduction through the atrium or AV node to the ventricles. Most produce narrow QRS complex tachycardia (QRS duration <120 ms) characteristic of ventricular activation over the Purkinje system and, thus, are sometimes referred to as a narrow-complex tachycardias. The QRS morphology of the SVT is usually identical to the sinus rhythm QRS. Conduction block in the left or right bundle branch or activation of the ventricles from an accessory pathway produces a wide QRS complex during SVT that must be distinguished from ventricular tachycardia (VT). Mechanisms of supraventricular tachyarrhythmia can be divided into physiologic sinus tachycardia and pathologic tachycardia (Table 253-1). Pathologic tachycardia can be further subclassified by mechanism as reentrant arrhythmias dependent on AV nodal conduction (e.g., AV nodal reentry tachycardia), large reentry circuits within the atrial tissue alone (e.g., atrial flutter), or focal atrial tachycardias that can be due to automaticity or small reentry circuits. The prognosis and treatment vary considerably depending on the mechanism and underlying heart disease. SVT can be of brief duration, termed nonsustained, or can be sustained such that an intervention, such as cardioversion, catheter ablation, or drug administration, is required for termination and main­ tenance of sinus rhythm. Episodes that occur with sudden onset and termination are referred to as paroxysmal. Paroxysmal supraventricular tachycardia (PSVT) refers to a family of tachycardias including AV node reentry, AV reciprocating tachycardia using an accessory pathway, and atrial tachycardia described in subsequent chapters (Fig. 253-1). Other supraventricular arrhythmias that may or may not be symp­ tomatic include PACs, sinus arrhythmia, ectopic atrial rhythm, and accelerated junctional rhythm. Atrial flutter and atrial fibrillation may present as a tachycardia or may be adequately rate controlled with or without AV nodal blocking agents; these entities are discussed sepa­ rately (see Chaps. 255, 256, 257, and 258). CLINICAL PRESENTATION Symptoms of supraventricular arrhythmia vary depending on the rate, duration, associated heart disease, and comorbidities and include palpitations, chest pain, dyspnea, diminished exertional capacity, and

TABLE 253-1  Mechanisms of Supraventricular Arrhythmias Physiologic Sinus Tachycardia Defining feature: normal sinus mechanism precipitated by exertion, stress, exogenous or endogenous stimulants, concurrent illness Pathologic Supraventricular Tachycardia (SVT) A.  Tachycardias originating from the atrium Defining feature: tachycardia may continue despite beats that fail to conduct to the ventricles, indicating that the atrioventricular (AV) node is not participating in the tachycardia circuit 1.  Inappropriate sinus tachycardia Defining feature: tachycardia from the normal sinus node area that occurs without an identifiable precipitating factor as a result of dysfunctional autonomic regulation 2.  Focal atrial tachycardia (AT) Defining feature: regular atrial tachycardia with defined P wave; may be sustained, nonsustained, paroxysmal, or incessant; frequent sites of origin occur along the valve annuli of left or right atrium, pulmonary veins, coronary sinus musculature, superior vena cava 3.  Atrial flutter and macroreentrant atrial tachycardia Defining feature: macroreentry reflected as organized atrial activity on an electrocardiogram (ECG), commonly seen as sawtooth flutter waves at rates typically faster than 200 beats/min 4.  Atrial fibrillation Defining feature: chaotic rapid atrial electrical activity with variable ventricular rate; the most common sustained cardiac arrhythmia in older adults 5.  Multifocal atrial tachycardia Defining feature: multiple discrete P waves often seen in patients with pulmonary disease during acute exacerbations of pulmonary insufficiency B.  AV nodal reentry tachycardia (AVNRT) Defining feature: paroxysmal regular tachycardia with P waves visible at the end of the QRS complex or not visible at all; the most common paroxysmal sustained tachycardia in healthy young adults; more common in women C.  Tachycardias associated with accessory atrioventricular pathways 1.  Orthodromic AV reciprocating tachycardia (AVRT) Defining feature: paroxysmal sustained tachycardia similar to AV nodal reentry; during sinus rhythm, evidence of ventricular preexcitation may be present (Wolff-Parkinson-White syndrome) or absent (concealed accessory pathway) 2.  Preexcited tachycardia Defining feature: wide QRS tachycardia with QRS morphology similar to ventricular tachycardia a. Antidromic AV reciprocating tachycardia—regular paroxysmal tachycardia b. Atrial fibrillation with preexcitation—irregular wide-complex or intermittently wide-complex tachycardia, some with dangerously rapid rates faster than 250/min c. Atrial tachycardia or flutter with preexcitation Other Supraventricular Arrhythmias A.  Premature atrial contractions (PACs) Defining feature: sinus rhythm with an early atrial complex distinct from the sinus P wave resulting in an irregular rhythm. A pattern of ectopy (i.e., trigeminy, bigeminy) is sometimes seen with PACs B.  Sinus arrhythmia Defining feature: irregular rhythm with a sinus P wave and with P-P intervals varying with respiration C.  Accelerated junctional rhythm Defining feature: paroxysmal regular rhythm with P waves visible at the end of the QRS complex or not visible at all D.  Ectopic atrial rhythm Defining feature: regular rhythm with a rate <100 beats/min but usually faster than sinus rhythm and with a P wave distinct from sinus that may or may not sustain  occasionally syncope. Rarely, a supraventricular arrhythmia precipi­ tates cardiac arrest in patients with Wolff-Parkinson-White (WPW) syndrome or severe heart disease, such as hypertrophic cardiomyopa­ thy. Asymptomatic supraventricular arrhythmias are often captured on routine electrocardiographic (ECG) recordings and sometimes prompt

NARROW-COMPLEX TACHYCARDIA – OBTAIN FULL 12-LEAD ECG WITH LONG RHYTHM STRIP Regular atrial rate Atrial fibrillation VA block: more V’s than A’s AV block: more A’s than V’s 1:1 AV response • Junctional tachycardia • AVNRT • ORT • AT • Rarely atrial flutter • Atrial flutter • Atrial tachycardia • Rarely AVNRT with 2:1 block below the His bundle FIGURE 253-1  Diagnostic possibilities based on the appearance of the 12-lead electrocardiogram (ECG) recorded during an episode of supraventricular tachycardia (SVT). AT, focal atrial tachycardia; AVNRT, atrioventricular (AV) nodal reentry tachycardia; ORT, orthodromic AV reentry tachycardia. referral to a cardiologist. Most asymptomatic supraventricular arrhyth­ mias do not require treatment or further evaluation. ■ ■INITIAL EVALUATION The diagnosis of SVT is most often entertained when evaluating a patient for arrhythmia-related symptoms or when evidence of ven­ tricular preexcitation is seen on an ECG as an outpatient. Diagnosis of SVT requires obtaining an ECG at the time of symptoms (Fig. 253-2). Ventricular preexcitation on the resting ECG suggests AV reciprocat­ ing tachycardia using an accessory pathway. When the arrhythmia is ongoing at the time of recording, the ECG usually establishes or sug­ gests the diagnosis. In the urgent care or inpatient setting, treatment of SVT will often involve vagal maneuvers or carotid sinus massage (CSM) to achieve AV block (Table 253-2). In the appropriate patient, CSM should be used cautiously, if at all, if there is concern for carotid atherosclerosis that may be embolized during manipulation. If this is unsuccessful, the administration of 6 or 12 mg of adenosine to cause transient AV block is usually successful in terminating an AV nodal– dependent SVT or diagnosing a non-AV nodal–dependent SVT such as atrial tachycardia or atrial flutter. There are some atrial tachycardias AV nodal blockade (Adenosine or vagal reflex maneuver) Atrial rate continues with AV block SVT terminated SVT slows No effect • Fascicular VT • Inadequate dose/effect • Sinus tachycardia • Junctional tachycardia FIGURE 253-2  Diagnostic effect of increasing atrioventricular (AV) node blockade with vagal maneuvers, carotid sinus massage, adenosine, verapamil, or beta blockers. AT, focal atrial tachycardia; AVNRT, atrioventricular nodal reentry tachycardia; AVRT, atrioventricular reciprocating tachycardia; SVT, supraventricular tachycardia.

Irregular atrial and ventricular rates CHAPTER 253 Multifocal atrial tachycardia Approach to Supraventricular Arrhythmias
that are adenosine sensitive, and thus, termination of an SVT with adenosine does not exclude this potential diagnosis. For transient arrhythmias, ambulatory ECG recording is warranted. Patients will often have access to ECG recording devices, such as a watch or smartphone-enabled ECG recording electrode pair. Therefore, a patient may have an ECG diagnosis before seeing a physician (Fig. 253-3). Exercise testing is useful for assessing exercise-related symptoms and potentially evoking the arrhythmia. Additional evaluation for underly­ ing cardiac disease and to exclude potentially dangerous arrhythmias should be performed based on the clinical scenario. Occasionally, an invasive electrophysiology study is warranted to provoke the arrhyth­ mia with pacing, confirm the mechanism, and risk stratify the patient, but most commonly, this is performed at the time of intended catheter ablation to treat the arrhythmia. Paroxysmal SVT is most commonly encountered in patients who do not have structural heart disease. Other supraventricular arrhythmias, particularly atrial fibrillation, are often associated with a variety of heart diseases. At initial evaluation, history and examination should assess possible underlying heart disease. Any abnormal findings may warrant further cardiac evaluation. • AVNRT • AVRT • Adenosine sensitive Focal AT • Atrial flutter • Atrial tachycardia

TABLE 253-2  Vagal Maneuvers Larynx Chest muscles PART 6 Disorders of the Cardiovascular System Lungs 15s Diaphragm Abdominal muscles Abdominal cavity Rectus muscles Holding breath while bearing down to increase intrathoracic pressure Breathing hard into a syringe against pressure to increase intrathoracic pressure Sternocleidomastoid muscle Cardiac plexus Submerge face into cold water (diver’s reflex) Carotid sinus massage Heart Rate Over 120 — 200 BPM Average This ECG was not checked for AFib because your heart rate was over 120 BPM. Reported Symptoms • Rapid pounding, or fluttering heartbeat • Chest tightness or pain • Fainting If you repeatedly get this result or you’re not feeling well, you should talk to your doctor. 0s 1s 2s 3s 4s 5s 6s 7s 8s 9s 10s 11s 12s 13s 14s 15s 16s 17s 18s 19s 20s 21s 22s 23s 24s 25s 26s 27s 28s 29s 25 mm/s, 10 mm/mV, Lead I, 511Hz, iOS 12.1.4, watchOS 5.1.3, Watch4,2 — The waveform is similar to a Lead I ECG. For more information, see Instructions for Use. FIGURE 253-3  Narrow-complex tachycardia recorded by a consumer wearable monitor (Apple watch). Afib, atrial fibrillation; ECG, electrocardiogram.

Raise legs abruptly to increase venous return Carotid sinus Vagus nerve Right common carotid artery Adenosine Adenosine

15 - 254 Physiologic and Nonphysiologic Sinus Rhythm

254 Physiologic and Nonphysiologic Sinus Rhythm

The most common SVT is sinus tachycardia in response to physi­ ologic stress, such as exercise, but it can also be a manifestation of acute illness. The first step in diagnosis of SVT is to consider the possibility of sinus tachycardia. Therapy is then determined by the clinical findings and probable diagnosis. If sinus tachycardia is diagnosed, treatment of the underlying inciting cause is the primary approach. If the arrhythmia is ongoing and is not due to sinus tachy­ cardia, initial assessment determines whether immediate therapy is needed to terminate the arrhythmia or slow the rate. Arrhythmias that cause hypotension, impaired consciousness, angina, or heart failure warrant immediate therapy, guided by the type of arrhythmia. Treat­ ment options for specific types of SVT are discussed in more detail in subsequent chapters and include pharmacologic and procedural interventions. ■ ■FURTHER READING Brugada J et al: 2019 ESC guidelines for the management of patients with supraventricular tachycardia. The task force for the management of patients with supraventricular tachycardia of the European Society of Cardiology (ESC) developed in collaboration with the Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J 41:655, 2020. Callans DJ: Josephson’s Clinical Cardiac Electrophysiology: Techniques and Interpretations, 7th ed. Philadelphia, Wolters Kluwer, 2024. William H. Sauer, Paul C. Zei

Physiologic and

Nonphysiologic Sinus

Rhythm The sinus node is composed of a group of cells located in the lateral superior aspect of the junction between the right atrium and superior vena cava, within the superior aspect of the thick ridge of muscle II, III, aVF SVC Sinus node V1 Compact AVN FO CS Os aVR Eustachian ridge IVC A B FIGURE 254-1  Right atrial anatomy pertinent to normal sinus rhythm and supraventricular tachycardia. A. Typical P-wave morphology during normal sinus rhythm based on standard 12-lead electrocardiogram. There is a positive P wave in leads II, III, and aVF and a biphasic, initially positive P wave in aVR. B. Right atrial anatomy seen from a right lateral perspective with lateral wall opened to view the septum. AVN, atrioventricular node; CS Os, coronary sinus ostium; FO, fossa ovalis; IVC, inferior vena cava; TVA, tricuspid valve annulus.

known as the crista terminalis where the posterior smooth atrial wall derived from the sinus venosus meets the trabeculated anterior portion of the right atrium. Patients with sinus tachycardia will often seek medical attention with the uncomfortable awareness of their heartbeat as their chief complaint. Often, an arrhythmia is suspected because of the similar constellation of symptoms that accompanies supraventricular and ventricular tachycardia or atrial and ventricular ectopy. However, a careful review of the 12-lead electrocardiogram (ECG) reveals a characteristic P wave originating from the superior and lateral aspect of the right atrium with a positive deflection in leads I, II, and III and a biphasic morphology in lead V1. Sinus P waves are characterized by a frontal plane axis directed inferiorly and leftward, with positive P waves in leads II, III, and aVF; a nega­ tive P wave in aVR; and an initially positive biphasic P wave in V1. Normal sinus rhythm has a range of rates between 60 and 100 beats/ min (Fig. 254-1).

CHAPTER 254 Physiologic and Nonphysiologic Sinus Rhythm
SINUS ARRHYTHMIA Sinus arrhythmia is a common finding that is usually asymptomatic and related to normal physiology in healthy individuals. The rhythm is defined as arising from a sinus node origin but with irregular­ ity between P-P intervals of >120 ms. When there is an irregularity in the heart rhythm and there are different P-wave morphologies observed, then this arrhythmia is most likely due to premature atrial contractions (PACs) and not sinus arrhythmia. Sinus arrhythmia usu­ ally occurs at rest and is often eliminated with higher rates observed with exertion due to removal of vagal tone. The three types of sinus arrhythmias observed are respirophasic, ventriculophasic, and non­ phasic. Respirophasic sinus arrhythmia occurs when vagal tone is inhibited reflexively during inspiration and is restored with expira­ tion. A similar phenomenon is seen with breath-holding leading to exaggerated pauses most often seen with obstructive sleep apnea. Ventriculophasic sinus arrhythmia is most often observed with heart block or after a premature ventricular contraction (PVC). The P-P interval is shortened when there is an interposed ventricular complex seen in these conditions possibly related to the triggered baroreceptor reflex from the subsequent beat after a longer ventricular filling time and increased stroke volume. Nonphasic sinus arrhythmia refers to variations in sinus P-P intervals unrelated to the cardiac or respiratory cycle. Regardless of the mechanism, asymptomatic sinus arrhythmia does not warrant further cardiac evaluation and is not considered pathogenic. Crista terminalis Pectinate muscles TVA Triangle of Koch

12 am 6 am 12 pm 6 pm 12 am

PART 6 Disorders of the Cardiovascular System

A 6 am 12 pm 6 pm 12 am 12 am

B FIGURE 254-2  Outpatient telemetry monitor in a patient with intermittent atrial tachycardia (A) and normal physiologic sinus tachycardia (B). PHYSIOLOGIC SINUS TACHYCARDIA Sinus tachycardia (>100 beats/min) typically occurs in response to sympathetic stimulation and/or vagal withdrawal, whereby the rate of spontaneous depolarization of the sinus node increases and the focus of earliest activation within the node typically shifts more leftward and closer to the superior septal aspect of the crista terminalis, thus pro­ ducing taller P waves in the inferior limb leads when compared to nor­ mal sinus rhythm. Sinus bradycardia is defined as rates <60 beats/min; however, bradycardia can be normal during sleep and in fit individuals. Sinus tachycardia is considered physiologic when it is an appropriate response to exercise, stress, or illness. Sinus tachycardia can be difficult to distinguish from focal atrial tachycardia (see below) that originates near the sinus node. A causative factor (e.g., exertion) and a gradual rate increase favor a diagnosis of sinus tachycardia, whereas abrupt tachycardia onset and offset favor atrial tachycardia (Fig. 254-2). The distinction can be difficult and occasionally requires extended ECG monitoring or invasive electrophysiology study. Treatment for physiologic sinus tachycardia is aimed at the underlying condition, but frequently, no therapy is necessary. Consideration to abnormal thyroid conditions and anemia should be given in patients with sinus tachy­ cardia as these represent reversible causes. In addition, structural and functional cardiovascular abnormalities can present as sinus tachycar­ dia, especially pulmonary embolism, and thus must be ruled out in the appropriate clinical scenario before considering sinus tachycardia as nonphysiologic. Finally, as sinus rate varies widely between individu­ als, a relatively elevated sinus rate (whether at rest or during exercise) without underlying cause, particularly without symptoms, typically does not warrant treatment (Table 254-1). TABLE 254-1  Common Causes of Sinus Tachycardia Physiologic Causes Emotion, physical exercise, sexual intercourse, pain, pregnancy Pathologic Causes Anxiety, panic attack, anemia, fever, dehydration, infection, malignancies, hyperthyroidism, hypoglycemia, pheochromocytoma, Cushing’s disease, diabetes mellitus with evidence of autonomic dysfunction, pulmonary embolus, myocardial infarction, pericarditis, valve disease, decompensated heart failure, shock, alcohol withdrawal Drugs Epinephrine, norepinephrine, dopamine, dobutamine, atropine, β2-adrenergic receptor agonists (salbutamol), methylxanthines, doxorubicin, daunorubicin, beta blocker withdrawal, caffeine, alcohol Illicit Drugs Amphetamines, cocaine, lysergic acid diethylamide, psilocybin, ecstasy, cocaine

NONPHYSIOLOGIC SINUS TACHYCARDIA Inappropriate sinus tachycardia is an uncommon condition in which the sinus rate increases spontaneously at rest or out of proportion to physiologic stress or exertion and is within a spectrum of ill-defined conditions associated with autonomic dysregulation. The underly­ ing mechanism remains elusive, but it may be related to imbalance between sympathetic and parasympathetic inputs to the sinus node, altered membrane automaticity of sinus node cells, or a combination of both. Affected individuals are often women in the third or fourth decade of life. Fatigue, dizziness, and even syncope may accompany palpitations, which can be disabling. Additional symptoms of chest pain, headaches, and gastrointestinal upset are common. Inappropri­ ate sinus tachycardia must be distinguished from appropriate sinus tachycardia and from focal atrial tachycardia arising from a region near the sinus node. The distinction between physiologic sinus tachycardia due to an anxiety disorder and inappropriate sinus tachycardia can be difficult. Therapy is often ineffective or poorly tolerated. Careful titra­ tion of beta blockers may reduce symptoms. Clonidine and serotonin reuptake inhibitors have also been used. Ivabradine, a drug that blocks the If current that causes spontaneous sinus node depolarization, is approved in the United States for use in heart failure but has also been effective in the treatment of inappropriate sinus tachycardia. Catheter ablation of the sinus node to modify and thereby decrease the sinus rate has been performed, but long-term control of symptoms is usu­ ally poor and can result in a permanent pacemaker requirement due to resultant symptomatic sinus bradycardia or arrest, or chronotropic incompetence (Fig. 254-3). Postural orthostatic tachycardia syndrome (POTS) is characterized by symptomatic sinus tachycardia that occurs with postural change from a supine position to standing. The sinus rate increases by 30 beats/min or to >120 beats/min within 10 min of standing and in the absence of hypotension. Symptoms are often similar to those in patients with inappropriate sinus tachycardia. POTS is sometimes due to autonomic dysfunction following a viral illness and may resolve spontaneously over 3–12 months. Prolonged postviral symptoms after COVID-19 infection, sometimes referred to as “long COVID,” have been ascribed to autonomic dysfunction and a POTS-like presentation. Volume expansion with salt supplementation, oral fludrocortisone, compres­ sion stockings, and the α-agonist midodrine, often in combination, can be helpful. Exercise training has also been shown to improve symptoms Sinus tachycardia Identify and treat reversible causes (See Table 254-1) Evaluate for POTS Treatment of POTS • Recumbent exercise and conditioning regimen • High-salt diet • Compression stockings • Fludrocortisone • Midodrine IST suspected Beta blocker and/or ivabradine Consider catheter ablation FIGURE 254-3  Evaluation and treatment of sinus tachycardia. For the patient who presents with sinus tachycardia, reversible causes of appropriate sinus tachycardia must be excluded and treated as indicated. Otherwise, evaluation for a spectrum of syndromes resulting in inappropriate sinus tachycardia should be undertaken. Potential directed therapies are shown. IST, inappropriate sinus tachycardia; POTS, postural orthostatic tachycardia syndrome.

16 - 255 Focal Atrial Tachycardia

255 Focal Atrial Tachycardia

and should be a part of a treatment strategy to reduce symptoms. While it is sometimes difficult to differentiate inappropriate sinus tachycardia from POTS, recognition of these distinct clinical syndromes is criti­ cal for treatment. Sinus node modification will be ineffective for the treatment of POTS and will possibly exacerbate the nontachycardia components of the condition. Likewise, treatment strategies aimed at increasing blood pressure will not be appropriate for inappropriate sinus tachycardia. ■ ■FURTHER READING Mayuga KA et al: Sinus tachycardia: A multidisciplinary expert focused review. Circ Arrhythm Electrophysiol 15:e007960, 2022. Vernino S et al: Postural orthostatic tachycardia syndrome (POTS): State of the science and clinical care from a 2019 National Insti­ tutes of Health Expert Consensus Meeting-Part 1. Auton Neurosci 235:102828, 2021. William H. Sauer, Paul C. Zei

Focal Atrial Tachycardia The underlying mechanisms of focal atrial tachycardia (AT) include abnormal automaticity, triggered automaticity, or a small reentry cir­ cuit in diseased atrial tissue. The term focal is used to differentiate this form of AT from typical and atypical atrial flutter but does not define a mechanism of the arrhythmia. ATs can originate from most regions of the atria, including atrial tissue extending into a pulmonary vein, the coronary sinus, or vena cava. It can be sustained, nonsustained, paroxysmal, or incessant. Focal AT accounts for ~10% of paroxysmal supraventricular tachycardia (PSVTs) in patients referred for catheter ablation. Nonsustained focal AT is commonly observed on ambulatory electrocardiogram (ECG) recordings, and the prevalence increases with age. Asymptomatic nonsustained ATs are often labeled as “SVT” on monitor reports, prompting patients to seek advice on catheter ablation. However, treatment is not recommended for asymptomatic nonsustained AT identified on ECG monitoring. Frequent atrial ectopy and nonsustained AT are often precursors to more significant arrhyth­ mias such as atrial fibrillation and atrial flutter. Occasionally, nonsus­ tained, frequent atrial ectopy or short bursts of AT may be symptomatic and require therapy similar to that required for focal AT (Fig. 255-1). AT AVNRT • AV node reentry AVRT A B FIGURE 255-1  Common mechanisms underlying paroxysmal supraventricular tachycardia along with typical R-P relationships. A. Schematic showing a four-chamber view of the heart with atrioventricular (AV) node and specialized conduction tissue (His-Purkinje) in yellow. Atrial tachycardia (AT; red circuit) is confined completely to atrial tissue. Atrioventricular nodal reentry tachycardia (AVNRT; green circuit) uses AV nodal and perinodal atrial tissue. Atrioventricular reentry tachycardia (AVRT; blue circuit) uses atrial and ventricular tissue, accessory pathway between the ventricle and atrium, AV node, and His-Purkinje tissue as part of the reentry circuit. B. Typical relation of the P wave to QRS, commonly described as the R-P to P-R relationship, for the different tachycardia mechanisms.

AT can occur in the absence of structural heart disease or may be associated with any condition that causes atrial fibrosis, including atrial tissue targeted with prior catheter ablation. Areas of fibrosis can act as a nidus for abnormal automaticity from injured but partially living cells or microreentry in zones of slow conduction within and on the border of fibrotic areas. Sympathetic stimulation is a promoting factor, and the emergence of AT can be a sign of underlying illness or drug toxic­ ity. In particular, AT with atrioventricular (AV) block is characteristic of digitalis toxicity. Symptoms from AT are highly variable but similar to other supraventricular tachycardias (SVTs), and incessant AT can cause tachycardia-induced cardiomyopathy.

CHAPTER 255 Focal Atrial Tachycardia AT typically presents with 1:1 AV conduction or with AV block in a Wenckebach or fixed (e.g., 2:1 or 3:1) pattern. Because it is not depen­ dent on AV nodal conduction, AT will not terminate with AV block, and the atrial rate will not be affected, which distinguishes AT from most AV nodal–dependent SVTs, such as AV nodal reentry and AV reentry using an accessory pathway (see below). A so-called warmup phase when the atrial activation rate increases after initiation or a cool-down phase when the rate slows prior to termination also favors AT rather than AV nodal–dependent SVT, as this is a common observation with enhanced automaticity. P waves are often discrete, with an intervening isoelectric segment, in contrast to atrial flutter and macroreentrant AT because atrial activation from a focal source occurs through a small portion of the tachycardia cycle (Fig. 255-2). When 1:1 conduction to the ventricles is present, the arrhythmia can resemble sinus tachycardia typically with a P-R interval shorter than the R-P interval, particularly when sympathetic tone results in rapid AV nodal conduction. It can be distinguished from sinus tachycardia by the P-wave morphology, which usually differs from sinus P waves depend­ ing on the location of the focus. Focal AT tends to originate in areas of complex atrial anatomy, such as the crista terminalis, valve annuli, atrial septum, and atrial muscle extending along cardiac thoracic veins (superior vena cava, coronary sinus, and pulmonary veins), and the location can often be approximated by the P-wave morphology. AT from the atrial septum will frequently have a narrower P-wave duration than sinus rhythm. AT from the left atrium will usually have a mono­ phasic, positive P wave in lead V1 and negative P waves in I and aVL, indicating an activation wavefront away from the left atrial free wall. AT that originates from superior atrial locations, such as the superior vena cava or superior pulmonary veins, will be positive in the inferior limb leads II, III, and aVF, whereas AT from a more inferior loca­ tion, such as the ostium of the coronary sinus, will inscribe negative P waves in these same leads. When the focus is in the superior aspect of the crista terminalis, close to the sinus node, however, the P wave will resemble that of sinus tachycardia. Abrupt onset and offset then favor AT rather than sinus tachycardia. Depending on the atrial rate, the P wave may fall on top of the T wave, or during 2:1 conduction, No P-wave visible No P wave visible RP < PR RP < PR • AV node reentry • AV reentry using an accessory pathway • Focal atrial tachycardia RP > PR RP > PR • AV reentry using an accessory pathway • AV node reentry uncommon form

17 - 256 Paroxysmal Supraventricular Tachycardias

256 Paroxysmal Supraventricular Tachycardias

I aVR I II II PART 6 Disorders of the Cardiovascular System III III VI VI III III V5 V5 FIGURE 255-2  Focal atrial tachycardia. In the right panel, a surface 12-lead electrocardiogram shows focal intermittent atrial tachycardia. Note the discrete P waves, with isoelectric segments between, as well as the sinus rhythm. The left panel shows an electroanatomic map of the same focal atrial tachycardia originating from the anterior interatrial septum, as viewed in an anterior-posterior (AP) view of the left atrium obtained during electrophysiology study and ablation. The colors represent the timing of local electrical activation during each tachycardia atrial activation, showing a focal early (red) site. Additional markers of white “flecks” represent conduction direction, demonstrating activation of the atrium dispersing from this focal site. Of note, the pink and red dots represent ablation lesions, in this case, for pulmonary vein isolation. (Adapted from J Brugada et al: 2019 ESC Guidelines for the management of patients with supraventricular tachycardia. The Task Force for the management of patients with supraventricular tachycardia of the European Society of Cardiology (ESC). Eur Heart J 41:655, 2020.) every other P wave may fall coincident with the QRS. Maneuvers that increase AV block, such as carotid sinus massage, Valsalva maneuver, or administration of AV nodal–blocking agents, such as adenosine, are useful to create AV block that will expose the P wave. Acute management of sudden-onset, sustained AT is the same as for other forms of PSVT, but the response to pharmacologic therapy is variable, likely depending on the mechanism (Fig. 255-3). For AT due to reentry, administration of adenosine or vagal maneuvers may transiently increase AV block without terminating tachycardia. Some ATs terminate with a sufficient dose of adenosine, consistent with triggered activity as the mechanism. Cardioversion can be effective in some but fails in others because of immediate recur­ rence, suggesting automaticity as the mechanism in these cases. Beta blockers and calcium channel blockers may slow the ventricular rate by increasing AV block, which can improve tolerance of the arrhythmias, but large doses are sometimes required. Potential precipitating factors Focal atrial tachycardia Hemodynamic instability No Yes Adenosine Cardioversion Ineffective Non-DHP CCB and/or beta blocker Recurrent or incessant Ineffective Ineffective Antiarrhythmic therapy Catheter ablation (see Table 250-2) Recurrent or incessant FIGURE 255-3  Clinical approach and treatment algorithm for management of focal atrial tachycardia. CCB, calcium channel blocker; DHP, dihydropyridine. (Adapted from J Brugada et al: 2019 ESC Guidelines for the management of patients with supraventricular tachycardia The Task Force for the management of patients with supraventricular tachycardia of the European Society of Cardiology (ESC) [published correction appears in Eur Heart J 41:4258, 2020]. Eur Heart J 41:655, 2020.)

aVR V4 V1 aVR aVR V1 V4 V5 V2 aVL aVL V2 V5 V6 V3 aVF aVF V3 V6 and intercurrent illness should be sought and corrected. Underlying heart disease should be considered and excluded. For patients with recurrent episodes, beta blockers, calcium chan­ nel blockers such as diltiazem or verapamil, and antiarrhythmic drugs such as flecainide, propafenone, disopyramide, sotalol, and amioda­ rone can be effective, but potential toxicities and adverse effects often warrant avoidance of long-term use. Catheter ablation targeting the AT focus is effective in >80% of patients and is recommended for recurrent symptomatic AT when drugs fail or are not desired or for incessant AT causing tachycardiainduced cardiomyopathy. Although AT is often a precursor to atrial fibrillation or atrial flutter, the associated risk for stroke and, hence, indications for long-term anticoagulation are unclear but not consid­ ered equivalent. ■ ■FURTHER READING Brugada J et al: 2019 ESC Guidelines for the management of patients with supraventricular tachycardia. The Task Force for the Manage­ ment of Patients with Supraventricular Tachycardia of the European Society of Cardiology (ESC) developed in collaboration with the Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J 41:655, 2020. Callans DJ: Josephson’s Clinical Cardiac Electrophysiology: Techniques and Interpretations, 7th ed. Philadelphia, Wolters Kluwer, 2024. William H. Sauer, Paul C. Zei

Paroxysmal

Supraventricular

Tachycardias In this chapter, sustained supraventricular tachycardias (SVTs) dependent on the atrioventricular (AV) node are discussed. These include AV nodal reentry tachycardia (AVNRT), junctional tachycar­ dia, AV reciprocating tachycardia (AVRT) utilizing an accessory path­ way, and a group of additional various SVTs that involve an accessory

II P waves V1 A B FIGURE 256-1  Atrioventricular (AV) node reentry. A. Leads II and V1 are shown. P waves are visible at the end of the QRS complex and are negative in lead II and may give the impression of S waves in the inferior limb leads II, III, and aVF and an R′ in lead V1. B. Stylized version of the AV nodal reentry circuit within the triangle of Koch (see Fig. 254-1) that involves AV node and its extensions along with perinodal atrial tissue. CS, coronary sinus. pathway, termed preexcited tachycardias. The term SVT encompasses a broad group of tachyarrhythmias based on anatomic origin and techni­ cally includes sinus tachycardia, atrial tachycardia (AT), atrial flutter, and atrial fibrillation; however, for the purposes of describing an orga­ nized approach to diagnosis and treatment of SVT, a separate discus­ sion for these non-AV nodal–dependent SVTs are discussed elsewhere. ATRIOVENTRICULAR NODAL REENTRY TACHYCARDIA AVNRT is the most common form of paroxysmal supraventricular tachycardia (PSVT), representing ~60% of cases referred for catheter ablation. It most commonly manifests in the second to fourth decades of life, more often in women. It is usually well tolerated, but rapid tachycardia, particularly in the elderly, may cause angina, pulmonary edema, hypotension, or syncope. It is not usually associated with structural heart disease. In patients without associated heart disease, AVNRT is not a life-threatening arrhythmia; however, it may cause significant symptoms. The mechanism is reentry involving the AV node and the perinodal atrium, made possible by the existence of multiple pathways for con­ duction from the atrium into the AV node that are capable of conduc­ tion in two directions (Fig. 256-1). Most forms of AVNRT utilize a slowly conducting AV nodal path­ way (right inferior extension) that extends from the compact AV node near the His bundle, inferiorly along the tricuspid valve annulus to the floor of the coronary sinus. The reentry wavefront propagates up this slowly conducting pathway to the compact AV node and then exits from the fast pathway at the top of the AV node. The path back to the I aVR V1 V4 II aVL V2 V5 III aVF V3 V6 V1 FIGURE 256-2  Atrioventricular nodal reentry tachycardia with retrograde P waves before and after adenosine termination.

CHAPTER 256 Inferior AV node extension: Slow pathway Compact AV node: Fast pathway Paroxysmal Supraventricular Tachycardias
CS Tricuspid valve slow pathway probably involves the left atrial septum, which has con­ nections to the coronary sinus musculature. More unusual forms of AVNRT utilize a left inferior extension that connects to the compact AV node through the roof of the coronary sinus or, in extremely rare cases, directly from the mitral valve annulus avoiding the coronary sinus musculature altogether. In typical forms, the conduction time from the compact AV node region to the atrium is similar to that from the compact node to the His bundle and ventricles, such that atrial activation occurs at about the same time as ventricular activation. The P wave is therefore inscribed during, slightly before, or slightly after the QRS and can be difficult to discern. Often the P wave is seen at the end of the QRS complex as a pseudo-r′ in lead V1 and pseudo-S waves in leads II, III, and aVF (Fig. 256-2). More unusual forms of AVNRT have P waves falling later, any­ where between QRS complexes, in which case, an inverted P wave is seen in the inferior limb leads with the inverted P wave seen in the subsequent T wave. The rate can vary with sympathetic tone through its effect on the conduction time of AV nodal tissues. Simultaneous atrial and ventricular contraction results in atrial contraction against a closed tricuspid valve, producing a cannon A wave visible in the jugular venous pulse often perceived as a fluttering sensation in the neck. Elevated venous pressures may also lead to release of natriuretic peptides that cause post-tachycardia diuresis. In contrast to ATs, maneuvers or medications that produce AV nodal block terminate the arrhythmia. Acute treatment is the same as for other forms of PSVT (discussed below). Whether ongoing therapy is warranted depends on the severity of symptoms and frequency of episodes. Reassurance and instruction as to how to perform the Valsalva maneuver or other vagal I V4 V1 aVR V5 V2 aVL II V6 V3 aVF III V1

nerve–stimulating maneuvers to terminate episodes are sufficient for many patients. Administration of an oral beta blocker, verapamil, or diltiazem at the onset of an episode can be used to facilitate termina­ tion. Chronic therapy with these medications or flecainide is an option if prophylactic therapy is needed. Catheter ablation of the slow AV nodal pathway is recommended for patients with recurrent or severe episodes or when drug therapy is ineffective, not tolerated, or not desired by the patient. Catheter ablation is curative in >95% of patients. The major risk is AV block requiring permanent pacemaker implanta­ tion, which occurs in <1% of patients.

PART 6 Disorders of the Cardiovascular System JUNCTIONAL TACHYCARDIA Junctional ectopic tachycardia (JET) is due to automaticity within the AV node. It is rare in adults and more frequently encountered as an incessant tachycardia in children, often in the perioperative period of surgery for congenital heart disease. It presents as a narrow QRS tachycardia, often with ventriculoatrial (VA) block, such that AV dis­ sociation is present. JET can occur as a manifestation of increased adrenergic tone and may be seen after administration of isoproterenol, particularly after catheter ablation in the perinodal region. It may also occur for a short period of time after ablation for AVNRT. Accelerated junctional rhythm is a junctional automatic rhythm between 50 and 100 beats/min. Initiation may occur with gradual acceleration in rate, suggesting an automatic focus, or after a premature ventricular con­ traction, suggesting a focus of triggered automaticity. VA conduction is usually present, with P-wave morphology and timing such that it resembles AVNRT at a slow rate. It can be related to increased sympa­ thetic tone and may produce palpitations. It usually does not require specific therapy. ACCESSORY PATHWAYS AND THE

WOLFF-PARKINSON-WHITE SYNDROME Accessory pathways (APs) occur in 1 in 1500–2000 people and are associated with a variety of arrhythmias including narrow-complex PSVT, wide-complex tachycardias, and, rarely, sudden death. Most patients have structurally normal hearts, but APs are associated with Ebstein’s anomaly of the tricuspid valve and forms of hypertrophic cardiomyopathy including PRKAG2 mutations, Danon’s disease, and Fabry’s disease (Fig. 256-3). APs are abnormal connections that allow conduction between the atrium and ventricles across the AV ring. They are present from birth and are due to failure of complete partitioning of atrium and ventricle by the fibrous AV rings. They occur across either an AV valve annulus or the septum, most frequently between the left atrium and free wall of the left ventricle, followed by posteroseptal, right free wall, and antero­ septal locations. If the impulse from the sinus node conducts through the AP to the ventricle (antegrade) before the impulse conducts through the AV node and His bundle, then the ventricles are preexcited during sinus rhythm, and the electrocardiogram (ECG) shows a short P-R interval (<0.12 s), slurred initial portion of the QRS (delta wave), and prolonged QRS duration produced by slow conduction through direct activation of ventricular myocardium over the AP. The mor­ phology of the QRS and delta wave is determined by the AP location and associated site of earliest ventricular activation, and the degree of fusion between the excitation wavefronts from conduction over the AV node and conduction over the AP (Fig. 256-4). Right-sided pathways preexcite the right ventricle, producing a left bundle branch block–like configuration in lead V1, and often create marked preexcitation because of their relatively close proximity of the AP to the sinus node (Fig. 256-4). Left-sided pathways preexcite the left ventricle and may produce a right bundle branch–like configuration in lead V1 and a negative delta wave in aVL, indicating initial depolariza­ tion of the lateral portion of the left ventricle that can mimic Q waves of lateral wall infarction (Fig. 256-4). Because of the relatively large distance between the sinus node and left free wall APs, preexcitation may be minimal or absent on 12-lead ECG. Preexcitation due to an AP at the diaphragmatic surface of the heart, typically in the paraseptal region, produces delta waves that are negative in leads III and aVF,

A B Sinus rhythm— antegrade AP conduction Orthodomic AV reentry—retrograde AP conduction Antidromic AV reentry—antegrade AP conduction p p Delta-wave C FIGURE 256-3  Wolff-Parkinson-White (WPW) syndrome. A. A 12-lead electrocardiogram in sinus rhythm (SR) of a patient with WPW demonstrating short P-R interval, delta waves, and widened QRS complex. This patient had an anteroseptal location of the accessory pathway (AP). B. Orthodromic atrioventricular (AV) reentry in a patient with WPW syndrome using a posteroseptal AP. Note the P waves in the ST segment (arrows) seen in lead III and normal appearance of QRS complex. C. Three most common rhythms associated with WPW syndrome: sinus rhythm demonstrating antegrade conduction over the AP and AV node; orthodromic AV reentry tachycardia (AVRT) using retrograde conduction over the AP and antegrade conduction over the AV node; and antidromic AVRT using retrograde conduction over the AV node and antegrade conduction over the AP. mimicking the Q waves of inferior wall infarction (Fig. 256-4). Preexci­ tation can be intermittent and disappear during exercise as conduction over the AV node accelerates and may take over ventricular activation completely. Wolff-Parkinson-White (WPW) syndrome is defined as a preexcited QRS during sinus rhythm and episodes of PSVT. There are a number of variations of APs that may not cause preexcitation and/or arrhythmias. Concealed APs allow only retrograde conduction, from ventricle to atrium, so no preexcitation is present during sinus rhythm, but SVT

Left lateral Right free wall aVL V1 PV PV AV TV MV Coronary sinus (CS) Postero septal II aVF III FIGURE 256-4  Potential locations for accessory pathways in patients with WolffParkinson-White syndrome and typical QRS appearance of delta waves that can mimic underlying structural heart disease such as myocardial infraction of bundle branch block. AV, aortic valve; MV, mitral valve; PV, pulmonary valve; TV, tricuspid valve. can occur. Other unusual forms of APs exist. Fasciculoventricular connections between the His bundle and ventricular septum produce preexcitation but do not cause arrhythmia, probably because the circuit is too short to promote reentry. Atriofascicular pathways, also known as Mahaim fibers, probably represent a duplicate AV node and HisPurkinje system that connect the right atrium to fascicles of the right bundle branch and produce a wide-complex tachycardia having a left bundle branch block configuration. ATRIOVENTRICULAR RECIPROCATING TACHYCARDIA The most common tachycardia caused by an AP is the PSVT desig­ nated orthodromic AV reciprocating tachycardia. The circulating reentry wavefront propagates from the atrium anterogradely over the AV node and His-Purkinje system to the ventricles and then reenters the atria via retrograde conduction over the AP. The QRS is narrow or may have typical right or left bundle branch block, but without preexcita­ tion during tachycardia. Because excitation through the AV node and AP are necessary, AV or VA block results in tachycardia termination. During sinus rhythm, preexcitation is seen if the pathway also allows anterograde conduction. Most commonly, during tachycardia, the R-P interval is shorter than the P-R interval and can resemble AVNRT. Unlike typical AVNRT, P waves always follow the QRS and are never simultaneous with a narrow QRS complex because the ventricles must be activated before the reentry wavefront reaches the AP and conducts back to the atrium. The morphology of the P wave during tachycardia is determined by the pathway location, but it can be difficult to assess because it is usually inscribed during the ST segment. The P wave in posteroseptal APs is negative in leads II, III, and aVF, similar to that in AV nodal reentry, but P-wave morphology will differ from AV nodal reentry for pathways in other locations. Occasionally, an AP conducts extremely slowly in the retrograde direction, resulting in tachycardia with a long R-P interval, similar to most ATs. These pathways are

usually located in the septal region and have negative P waves in leads II, III, and aVF. Slow AP conduction facilitates reentry, often leading to nearly incessant tachycardia, known as permanent junctional recip­ rocating tachycardia (PJRT). Tachycardia-induced cardiomyopathy can occur. Without an invasive electrophysiology study, it may be difficult to distinguish this form of orthodromic AV reentry from atypical AV nodal reentry or AT.

CHAPTER 256 PREEXCITED TACHYCARDIAS Preexcited tachycardia occurs when the ventricles are activated by antegrade conduction over the AP. The most common mechanism is antidromic AV reciprocating tachycardia in which activation propagates from atrium to ventricle via the AP and then conducts retrogradely to the atria via the His-Purkinje system and the AV node (or rarely a sec­ ond AP). The wide QRS complex is produced entirely via ventricular excitation over the AP because there is no contribution of ventricular activation over more rapidly conducting specialized His-Purkinje fibers. This tachycardia is often indistinguishable from monomorphic ventricular tachycardia. The presence of preexcitation in sinus rhythm suggests the diagnosis. Paroxysmal Supraventricular Tachycardias
Preexcited tachycardia also occurs if an AP allows antegrade con­ duction to the ventricles during AT, atrial flutter, atrial fibrillation (AF), or AV nodal reentry, otherwise known as bystander AP conduc­ tion. AF and atrial flutter are potentially life-threatening if the AP allows very rapid repetitive conduction (Fig. 256-5). Approximately 25% of APs causing preexcitation allow minimum R-to-R intervals of <250 ms during AF and are associated with a higher risk of inducing ventricular fibrillation and sudden death. Preexcited AF presents as a wide-complex, very irregular rhythm. During AF, the ventricular rate is determined by the conduction properties of the AP and AV node. The QRS complex can appear quite bizarre and change on a beat-to-beat basis due to the variability in the degree of fusion from activation over the AV node and AP, or all beats may be due to conduction over the AP. Ventricular activation from the Purkinje system may depolarize the ventricular aspect of the AP and prevent atrial wavefront conduction over the AP. Slowing AV nodal conduction without slowing AP conduction can thereby facilitate AP conduction and dangerously accelerate the ventricular rate. Administration of AV nodal–blocking agents, including oral or intravenous verapamil, diltiazem, beta blockers, intravenous adenosine, and intravenous amiodarone, is contraindicated during preexcited AF. Rapid preexcited tachycardia should be treated with electrical cardioversion or intrave­ nous procainamide or ibutilide, which may terminate the arrhythmia or slow the ventricular rate. MANAGEMENT OF PATIENTS WITH ACCESSORY PATHWAYS Acute management of orthodromic AV reentry is discussed below for PSVT. Patients with WPW syndrome may have wide-complex tachy­ cardia due to antidromic AV reentry, orthodromic AV with bundle branch block, or a preexcited tachycardia, and treatment depends on the underlying rhythm. Initial patient evaluation should include assess­ ment for aggravating factors, including intercurrent illness and factors that increase sympathetic tone. Examination should focus on excluding underlying heart disease. An echocardiogram is reasonable to exclude Ebstein’s anomaly, forms of hypertrophic cardiomyopathy that can be associated with APs, or tachycardia-mediated cardiomyopathy. Patients with preexcitation who have symptoms of arrhythmia are at risk for developing AF and sudden death if they have an AP that allows rapid antegrade conduction. The risk of cardiac arrest is in the range of 2 per 1000 patients in adults but is likely greater in children. An invasive electrophysiology study is recommended to assess whether the pathway can support dangerously rapid heart rates if AF were to occur, and it is usually combined with potentially curative catheter ablation. Catheter ablation is warranted for recurrent arrhythmias when drugs are ineffective, not tolerated, or not desired by the patient. Efficacy is in the range of 95% depending on the location of the AP. Serious complications occur in <3% of patients but can include AV

PART 6 Disorders of the Cardiovascular System I I aVR aVR II aVL II aVL III aVF III aVF V1 V1 II II V5 V5 25mm/s 10mm/mV 150Hz 9.0.9 12SL 243 CID: 0 FIGURE 256-5  Preexcited atrial fibrillation (AF) due to conduction over a left free wall accessory pathway (AP). The electrocardiogram shows rapid irregular QRS complexes that represent fusion between conduction over the atrioventricular node and left free wall AP. Shortest R-R intervals between preexcited QRS complexes of <250 ms, as in this case, indicate a risk of sudden death with this arrhythmia. block, cardiac tamponade, thromboembolism, coronary artery injury, and vascular access complications. The risk of AV block is higher when the AP is located near the AV node and/or His bundle, in the so-called anteroseptal or mid-septal locations. Procedure mortality is <1 in 1000 patients. Ambulatory monitoring or exercise testing is often used to gain reassurance that the AP is not high risk, evaluating for abrupt loss of conduction (preexcitation) at physiologic heart rates consistent with a low-risk pathway, but this is not completely reliable. Gradual loss of AP conduction with increased sympathetic tone does not reliably indicate low risk since this can occur as AV nodal conduction time shortens, and therefore, the possibility of rapid antegrade AP conduc­ tion is not excluded definitively. For patients with concealed APs or known low-risk APs causing orthodromic AVRT, chronic therapy is guided by symptoms and fre­ quency of events. Vagal maneuvers may terminate episodes, as may a dose of beta blocker, verapamil, or diltiazem taken at the onset of an episode. Chronic therapy with these agents or flecainide can reduce the frequency of episodes in some patients. Adults who have preexcitation but no arrhythmia symptoms have a risk of sudden death estimated to be 1 per 1000 patient-years. Electro­ physiology study is usually advised for people in occupations for which an arrhythmia occurrence would place them or others at risk, such as police, military, and pilots, or for individuals who desire evaluation for risk. Routine follow-up without therapy is reasonable in others. Children are at greater risk of sudden death, ~2 per 1000 patient-years.

V1 V4 V1 V4 V2 V5 V2 V5 V3 V6 V3 V6 TREATMENT Paroxysmal Supraventricular Tachycardia Acute management of narrow QRS PSVT is guided by the clinical presentation. Continuous ECG monitoring should be implemented, and a 12-lead ECG should always be obtained when possible, since this may be useful in determining the mechanism. In the presence of hypotension with unconsciousness or respiratory distress, QRSsynchronous direct current cardioversion is warranted, but this is rarely needed, because intravenous adenosine works promptly in most situations (see below). For stable individuals, initial therapy takes advantage of the fact that most PSVTs are dependent on AV nodal conduction (AV nodal reentry or orthodromic AV reentry) and, therefore, likely to respond to sympatholytic and vagotonic maneuvers and drugs. As these are administered, the ECG should be continuously recorded because the response can establish the diagnosis. AV block with only transient slowing of tachycardia may expose ongoing P waves, indicating AT or atrial flutter as the mechanism (Fig. 256-6). Carotid sinus massage is reasonable provided the risk of carotid vascular disease is low, as indicated by absence of carotid bruits and no prior history of stroke. A Valsalva maneuver should be attempted in cooperative individuals, and if effective, the patient can be taught to perform this maneuver as needed. If vagal maneuvers fail or

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258 Atrial Fibrillation

■ ■FURTHER READING Brugada J et al: 2019 ESC Guidelines for the management of patients with supraventricular tachycardia. The task force for the management of patients with supraventricular tachycardia of the European Society of Cardiology (ESC) developed in collaboration with the Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J 41:655, 2020. Callans DJ: Josephson’s Clinical Cardiac Electrophysiology: Techniques and Interpretations, 7th ed. Philadelphia, Wolters Kluwer, 2024. Jalife J, Stevenson W (eds): Zipes and Jalife’s Cardiac Electrophysiol­ ogy: From Cell to Bedside, 8th ed. Philadelphia, Elsevier, 2022. Joglar JA et al: 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 83:109, 2024. William H. Sauer, Jorge E. Romero,

Paul C. Zei

Atrial Fibrillation PATHOPHYSIOLOGY AND EPIDEMIOLOGY Atrial fibrillation (AF) is a cardiac arrhythmia characterized by seemingly disorganized, rapid, and irregular atrial electrical activation, resulting in loss of organized atrial mechanical contraction. These rapid and irregular electrical signals input into the atrioventricular (AV) node, which deter­ mines ventricular activation and rate. The conducted ventricular rate is variable, resulting in an irregular, usually rapid ventricular rate, ranging typically between 110 and 160 beats/min in most. In some patients, the sustained ventricular rate can exceed 200 beats/min, whereas in others with either high vagal tone or AV nodal conduction disease, the ven­ tricular rate may be excessively slow (Fig. 258-1). The disorganized atrial activation is best appreciated in lead V1 for this patient. AF is the most common sustained arrhythmia; as a result, it is a major public health issue. Prevalence increases with age, with

95% of AF patients >60 years of age. The prevalence in humans over age 80 is ~20%. The lifetime risk of developing AF for men aged 40 years old is ~25%. AF is slightly more common in men than women and more common in whites than blacks. Risk factors for developing AF in addition to age and underlying cardiac disease include hypertension, diabetes mellitus, cardiac disease, family history of AF, obesity, thyroid disease, and sleep-disordered breathing. AF is not a benign condition, with a 1.5- to 1.9-fold increased risk of mortality after controlling for underlying cardiac disease. Perhaps the most important consequence of AF is a significantly increased risk of stroke compared to the general population, causing ~25% of all strokes. AF has been detected up to 8.9% of patients within 6 months following cryptogenic stroke using insertable cardiac monitors. The risk of dementia is increased in patients with AF, as is the risk of magnetic resonance imaging (MRI)-detected asymptomatic embolic infarct. AF, most often when ventricular rate remains uncontrolled for prolonged periods, increases the risk of developing congestive heart failure and cardiomyopathy. Moreover, as a corollary, patients with underlying heart disease, in particular cardiomyopathy and conges­ tive heart failure, are at higher risk for developing AF. AF is a marker for worsened morbidity and mortality in patients with existing heart disease, although the precise extent of the independent risk increase associated with AF in heart disease is unclear. AF may, on occasion, be associated with an identifiable precipitating factor, such as hyperthy­ roidism, acute alcohol intoxication, myocardial infarction, pulmonary

embolism, pericarditis, and cardiac surgery, where AF occurs in up to 50% of patients postoperatively.

AF is clinically most typically defined by the pattern of episodes. Paroxysmal AF is defined as a pattern of AF episodes that occur and terminate with a relatively short duration either spontaneously or by pharmacologic or electrical cardioversion, most commonly defined as 7 days or less. Persistent AF refers to AF that occurs continuously for

7 days but <1 year, whereas long-standing persistent AF refers to AF that has been persistent for >1 year. These descriptors for AF correlate somewhat with the underlying pathophysiology of AF. AF tends to be a progressive condition, with, at this point, no definitive “cure” that will completely eliminate AF durably in a predictable fashion. The patho­ physiology of AF, however, remains incompletely understood. Most data support a multifactorial process that leads to the development of manifest AF. Clinical and epidemiologic studies have demonstrated that, in addition to cardiovascular disease, age, alcohol use, obesity, hypertension, diabetes mellitus, and sleep-disordered breathing are associated with higher risk of developing AF. The proposed pathophys­ iology suggests a “final common pathway” of these risk factors leading to electrophysiologic changes in atrial tissues. Alterations in regulation of membrane channels and other proteins result in abnormal electrical excitability. Atrial tissues, in particular pulmonary vein musculature, exhibit enhanced automaticity, resulting in ectopic beats (premature atrial contractions), as shown in Fig. 258-2. Bouts of rapid atrial ectopy may then initiate either atrial tachycardia or frank AF. Additional cel­ lular and, eventually, tissue remodeling results in abnormal conduction properties throughout the atria, including, in particular, shortening of atrial tissue refractory periods. This enables sustained AF through a combination of rapid automaticity-based “drivers” and areas of func­ tional reentry. Further remodeling leads to the development of fibrosis and left atrial enlargement (Table 258-1). CHAPTER 258 Atrial Fibrillation These functional and anatomic changes in atrial tissues appear to correlate with the progression of clinical AF. AF tends to be a progres­ sive disease in most, although exceptions occur. Typically, for a period of time, patients experience sporadic ectopic beats and short runs of atrial tachycardia, likely originating from the pulmonary veins, preced­ ing the onset of frank AF. Other regions of the atria have been demonstrated to produce ecto­ pic depolarizations that may trigger AF; these include the posterior wall of the left atrium and muscular tissue sleeves within the superior vena cava, coronary sinus, or the remnant of the vein of Marshall. When enough frequent bursts of ectopic beats/tachycardia and/or changes in underlying substrate support the maintenance of AF for short periods, the patient develops episodes of paroxysmal AF. In the untreated patient, over time, as the electrical, contractile, and structural remodeling continues to progress, episodes of paroxysmal AF may be prolonged to the point of not terminating spontaneously, the hallmark of persistent AF. After further remodeling, not only do patients con­ tinue to long-standing persistent AF but also the efficacy of therapeutic interventions to restore sinus rhythm diminishes. CLINICAL PRESENTATION AND MANIFESTATIONS The clinical manifestations of AF result from (1) symptoms related to the irregular, often rapid but sometimes slow ventricular rates that result; (2) the hemodynamic consequences of altered cardiac function; (3) the consequences of cardioembolic phenomena; and/or (4) the impact of AF on cardiovascular function over time. AF is diagnosed by electrocardiogram (ECG), either by 12-lead standard ECG, limited lead ambulatory monitor ECG and implantable loop recorders, with findings of lack of organized atrial activity (no P wave), with an irregu­ lar ventricular response. The role of screening populations for AF is evolving with the use of wearable monitors and home ECG capabilities. With irregular, rapid ventricular rates, there is variable cardiac dis­ placement and contraction, resulting in the sensation of palpitations and awareness of the heartbeat, when of course, in a normal rhythm, most humans do not sense each heartbeat. Interestingly, many patients are, for the most part, unaware of the irregular ventricular beating for unknown reasons.

PART 6 Disorders of the Cardiovascular System I II III aVR aVL aVF V1 V2 V3 V4 V5 V6 I II III aVR aVL aVF V1 V2 V3 V4 V5 V6 FIGURE 258-1  Electrocardiogram of an irregularly irregular heart rhythm without discernable P waves. The disorganized atrial activation is best appreciated in lead V1 for this patient. Sinus P wave Blocked PAC PAC initiates AF Sinus P wave 25 mm/sec 10 mm/mV 0.5–40 Hz FIGURE 258-2  Surface electrocardiogram (ECG) of atrial ectopy initiating atrial fibrillation (AF). In this single-lead surface ECG recording, the tracing begins with two conducted sinus beats. A nonconducted premature atrial contraction (PAC) (labeled “blocked PAC”) is shown after the second QRS complex. After the next sinus P wave and QRS, an ectopic beat (PAC) initiates atrial fibrillation, as demonstrated by (somewhat organized) erratic atrial activity and an irregular ventricular response. TABLE 258-1  Categorization of Atrial Fibrillation (AF) by Clinical Temporal Characteristics and Associated Features

  PAROXYSMAL AF PERSISTENT AF LONG-STANDING PERSISTENT AF Definition Episodes self-terminate or via phar macologic or electrical CV in <7 days Episodes lasting >7 days and <1 year Persistent AF >1 year LA size Normal to mildly enlarged Mild to severely enlarged Typically, severely enlarged LA scar burden Low Moderate High Efficacy of AAD Often effective Not as effective Usually refractory When to offer ablation? First-line therapy reasonable First-line appropriate but usually offered after AAD failure After AAD failure, not always a good option Ablation technique PV isolation alone usually effective PV isolation and any identified non-PV AF source PV isolation; additional ablation for substrate modification likely needed Note: With paroxysmal, persistent, and long-standing persistent AF, definitions are based on duration of events and diagnosis overall. These categorizations correlate with LA size, LA scar burden, and resultant efficacy of medical and ablative therapies. Abbreviations: AAD, antiarrhythmic drugs; CV, cardioversion; LA, left atrium; PV, pulmonary vein.

During AF, there is loss of the contribution of atrial systole to overall cardiac output and, with irregular ventricular rates, variable ventricular filling and, consequently, variable stroke volume. The resultant impact on overall cardiac output may result in exercise intolerance, fatigue, weakness, presyncope, or dyspnea. In patients with underlying cardiac disease, the additional hemodynamic compromise resulting from AF may result in exacerbation of the disease and/or heart failure symp­ toms. Patients with hypertrophic cardiomyopathy, coronary artery disease, valvular disease, heart failure with either depressed or pre­ served ejection fraction, or amyloidosis are particularly susceptible. In patients with concomitant AV nodal conduction disease, bradycardia during AF may result in presyncope or syncope. Pauses at the time of spontaneous conversion from AF to sinus rhythm, a manifestation of sinus node dysfunction that commonly occurs in patients with AF, may result in presyncope or syncope as well. With the loss of atrial mechanical contraction, blood stasis may pro­ mote in situ thrombosis, which, when embolized, may result in a range of clinical consequences, most importantly, ischemic stroke. Thrombus formation occurs primarily in the left atrial appendage. Over time, recurrent thromboembolism to the brain, even if asymptomatic, may result in debilitating neurologic sequelae, including cognitive impair­ ment. An increased risk of dementia in patients with AF may be the consequence of this phenomenon, although the contribution of chronic hypoperfusion in patients with long-standing persistent atrial fibrillation is unclear. In patients with prolonged periods of rapid ventricular rates resulting from AF, there is risk of developing a tachycardia-induced cardiomyopathy, with associated depressed left ventricular function. Tachycardia-induced myopathy appears generally to be reversible once ventricular rates are controlled. In patients with long-standing persis­ tent AF, the atria, especially the left atrium, tend to be more dilated and to contain a higher burden of fibrotic, noncontractile atrial tis­ sue. The hemodynamic consequences of a noncompliant, fibrotic left atrium, including elevated left atrial filling pressures, volume overload, and congestive heart failure, have been described as “stiff left atrial syndrome.” TREATMENT Atrial Fibrillation The treatment and management of the patient with AF centers on three aims: (1) control of patient symptoms through a strategy of rate control and/or rhythm control; (2) appropriate mitigation of thromboembolism risk; and (3) addressing modifiable risk factors for progression of AF. In the acute onset of AF, if significant hemo­ dynamic compromise, pulmonary edema, or evidence of coronary ischemia is present, emergent cardioversion is recommended. Elec­ trical cardioversion can be achieved with a QRS synchronous shock, preferably in a sedated patient, or via pharmacologic cardioversion, most typically with the intravenous administration of the class III antiarrhythmic ibutilide. Ibutilide should be avoided in patients with baseline prolonged QT interval or severe left ventricular dys­ function, given the risk of torsades des pointes. In the hemodynam­ ically stable patient with new-onset AF, therapy should focus on control of ventricular rate to prevent hemodynamic sequelae, con­ sideration of anticoagulation to mitigate thromboembolic risk, and consideration of restoration and maintenance of sinus rhythm—a so-called rhythm control strategy. If restoration of sinus rhythm is being considered, a more immediate risk of thromboembolism must be factored into the management strategy. Although there is a lack of definitive data, it is presumed that if the presenting epi­ sode of AF is >48 h or if the episode duration is unknown, there is risk for precipitating a thromboembolic complication through cardioversion, whether electrically or pharmacologically achieved. Therefore, in this circumstance, the patient should be either initi­ ated on anticoagulation, with cardioversion deferred for at least 3 weeks after uninterrupted anticoagulation, or evaluated to exclude the presence of left atrial appendage thrombus. Most commonly,

transesophageal echocardiography (TEE) is used to evaluate for left atrial appendage thrombus, although cardiac computed tomogra­ phy (CT) angiography using delayed acquisition imaging has been demonstrated to have excellent sensitivity and specificity as well.

CHAPTER 258 CARDIOVERSION AND ANTICOAGULATION The major source of thromboembolism and stroke in nonvalvular AF is formation of thrombus in the left atrial appendage where flow is relatively stagnant, although thrombus occasionally forms in other locations as well, particularly in patients with mitral valvular disease and severely dilated left atrium. Following conversion from prolonged AF to sinus rhythm, atrial mechanical function can be delayed for weeks (i.e., atrial stunning), such that thrombi can form even during sinus rhythm. When AF has been present for >48 h and in patients at high risk for thromboembolism, such as those with mitral stenosis or hypertrophic cardiomyopathy, conversion to sinus rhythm is associated with an increased risk of thrombo­ embolism. Thromboembolism can occur soon or several days after restoration of sinus rhythm if appropriate anticoagulation measures are not taken. In patients with AF and left atrial appendage closure devices (e.g., Watchman device), electrical cardioversion is feasible without the need for oral anticoagulation if preprocedural trans­ esophageal echocardiography shows good device position, absence of device-related thrombus, and peri-device leak of ≤5 mm. Atrial Fibrillation Cardioversion within 48 h of the onset of AF without TEE or cardiac CT is common practice in patients who have not been anticoagulated, provided that they are not at high risk for stroke due to a prior history of embolic events, rheumatic mitral stenosis, or hypertrophic cardiomyopathy with marked left atrial enlarge­ ment. These low-risk patients with occasional episodes of AF can be instructed to notify their physician when AF occurs to arrange for cardioversion to be done within 48 h. If the duration of AF exceeds 48 h or is unknown, there is greater concern for thromboembolism after cardioversion, even in patients considered low risk (CHA2DS2-VASc of 0 or 1 [see below]) for stroke. There are two approaches to mitigate the risk related to car­ dioversion. One option is to anticoagulate continuously for 3 weeks before and a minimum of 4 weeks after cardioversion. A second more frequently used approach is to start anticoagulation and per­ form a TEE or high-resolution cardiac CT scan to detect the pres­ ence of thrombus in the left atrial appendage. If thrombus is absent, electrical or pharmacologic cardioversion can be performed and anticoagulation continued for a minimum of 4 weeks to allow time for recovery of atrial mechanical function. In either case, cardiover­ sion of AF is associated with a substantial risk of recurrence, which may not be symptomatic. It should be noted that these recommen­ dations for short-term anticoagulation and thrombus exclusion at the time of cardioversion lack contemporary robust data to support these strategies. Longer-term maintenance of anticoagulation is considered based on the patient’s individual risk for stroke, com­ monly assessed using the CHA2DS2-VASc score. ACUTE RATE CONTROL The goal of rate control in AF is to allow more diastolic filling time, improving cardiac output and reducing patient symptoms. In the longer term, adequate rate control will minimize the risk of congestive heart failure and tachycardia-induced cardiomyopathy. Acute rate control can be achieved with beta blockers and/or the calcium channel blockers verapamil and diltiazem administered either intravenously or orally, as warranted by the urgency of the clinical situation. Digoxin has been used for several years for rate control, particularly in patients with labile blood pressure and in patients with cardiomyopathy susceptible to congestive heart fail­ ure, because it lacks the negative inotropic effect seen in calcium channel blockers and beta blockers. It acts synergistically with beta blockers and calcium channel blockers and, therefore, may be useful as an added agent when rate control is inadequate. However, recent evidence suggests increased mortality with its chronic use, and so its utilization has declined.

CHRONIC RATE CONTROL For patients who remain in AF chronically, the goal of rate control is to both alleviate symptoms and prevent deterioration of ventricular function from excessive rates. β-Adrenergic blockers and calcium channel blockers are often used either alone or in combination. Exertion-related symptoms are often an indication of inadequate rate control. Rate should be assessed with exertion and medications adjusted accordingly. Adequate rate control is defined as a resting heart rate of <80 beats/min that increases to <100 beats/min with light exertion, such as walking. If it is difficult to slow the ventricu­ lar rate to that degree, allowing a resting rate of up to 110 beats/min is acceptable provided it does not cause symptoms and ventricular function is normal; however, periodic assessment of ventricular function is warranted because some patients develop tachycardiainduced cardiomyopathy. In patients with permanent atrial fibrilla­ tion, a lenient rate-control strategy (resting heart rate <110 beats/ min) is as effective as strict rate-control strategy (resting heart rate <80 beats/min and heart rate during moderate exercise <110 beats/ min) in terms of death from cardiovascular causes, hospitalization for heart failure and stroke, systemic embolism, bleeding, and lifethreatening arrhythmic events, and this strategy is easier to achieve.

PART 6 Disorders of the Cardiovascular System If adequate rate control in AF is difficult to achieve, further con­ sideration should be given to restoring sinus rhythm (see below). Catheter ablation of the AV junction to create permanent AV block and implantation of a permanent pacemaker reliably achieve rate control without the need for AV nodal–blocking agents, a so-called “ablate and pace” strategy. These patients not only remain in AF but also become dependent on the pacemaker to support ventricular rate. The typical pacing configuration with placement of a ventricu­ lar lead in the right ventricular apex may induce dyssynchronous ventricular activation that can depress ventricular function in some patients. Biventricular pacing or direct pacing of the left bundle branch area may be used to minimize the degree of ventricular dyssynchrony. AV nodal ablation and cardiac resynchronization therapy have been demonstrated to be superior to pharmacologic therapy in improving quality of life and in reducing the develop­ ment of heart failure, heart failure hospitalizations, and all-cause mortality in patients with permanent AF and a narrow QRS, irre­ spective of their baseline left ventricular ejection fraction. STROKE PREVENTION IN ATRIAL FIBRILLATION Thromboembolic complications, in particular, stroke, are the most significant and potentially life-threatening sequelae of AF. There­ fore, appropriate stroke prevention strategies are a key aspect of AF management. The mainstay of stroke prevention is continuous anticoagulation therapy, most commonly using an oral medication. Specific patient populations have a high risk of stroke, includ­ ing patients with hypertrophic cardiomyopathy, mitral stenosis, and prior stroke history, and therefore, anticoagulation is recom­ mended, barring contraindications. AF in patients without mitral stenosis is commonly referred to as nonvalvular AF. In most patients with AF, the decision about whether a stroke prevention regimen is indicated is largely based on an assessment of stroke risk, balanced by the risk of the preventative therapy. The risk of stroke appears to be most accurately predicted by the presence of underly­ ing risk factors known to increase stroke risk. The CHA2DS2-VASc scoring system (Fig. 258-3) is a widely used tool to estimate stroke risk. Anticoagulation is currently recommended in the United States and Europe for patients with a score of ≥1 unless the lone risk factor is female gender. Stroke risk increases with increasing CHA2DS2-VASc score, such that annual stroke risk may be as high as nearly 20% without anticoagulation. On the other hand, antico­ agulation carries a risk of serious and potentially life-threatening bleeding complications, in particular, intracranial hemorrhage and gastrointestinal bleed. Bleeding risk is often assessed using the HAS-BLED scoring system (Fig. 258-3). If bleeding risk is deemed to be outweighed by stroke risk, anticoagulation is recommended. It is important to note the conventional wisdom that the perceived burden of AF has not been shown to predict stroke risk. The

CHA2DS2-VASc HAS-BLED Risk Criteria Congestive heart failure

Hypertension

Age >75

Abnormal renal or liver function 1 each Hypertension

Bleeding diasthesis Stroke history

Diabetes mellitus

Labile INR (on warfarin)

Prior stroke or TIA

Elderly (Age >65)

Vascular disease

Drugs that predispose to bleeding or alcohol 1 each Age >65

Sex category (F)

Annual Stroke or Major Bleeding Rate (%) as a Function of Score

CHA2DS2-VASc HAS-BLED

FIGURE 258-3  CHA2DS2-VASc and HAS-BLED systems. The CHA2DS2-VASc scoring system gives a point for each outlined stroke risk factor, whereas the HAS-BLED scoring system gives a point for each bleeding risk factor, as outlined in the table. In the chart below the table, the corresponding risk of stroke (CHA2DS2-VASC) or major bleed event (HAS-BLED) is plotted as a percent risk per annum as a function of score. F, female; INR, international normalized ratio; TIA, transient ischemic attack. approach to patients with paroxysmal AF is therefore the same as for persistent AF. It is recognized that many patients who appear to have infrequent AF episodes based on office visits often have asymptomatic episodes that put them at risk. Absence of AF during periodic monitoring is not sufficient to indicate low risk. The role of continuous monitoring with implanted recorders or pacemakers as a guide for anticoagulation in patients with a borderline risk profile is not clear. Subclinical AF is short-lasting and asymptomatic and can usually be detected only by long-term continuous monitoring with implantable loop recorders, pacemakers, or defibrillators. Subclinical AF is associated with an increased risk of stroke by a factor of 2.5. In patients with subclinical AF lasting 6 min to 24 h, apixaban has been shown to decrease the risk of stroke or systemic embolism but increases the risk of major bleeding. Therefore, a more accurate accounting for the impact of AF burden on stroke risk remains to be clarified. Antiplatelet agents alone are generally not sufficient. In non­ valvular AF, warfarin reduces the annual risk of stroke by 64% compared to placebo and by 37% compared to antiplatelet therapy. Patients with AF with an increased risk of stroke also have an increased risk of venous thromboembolism, which appears to be lower with oral anticoagulation. The direct-acting anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban were noninferior to warfarin in individual trials of nonvalvular AF patients, and intent-to-treat analysis of pooled data suggests superiority to warfa­ rin by small absolute margins of 0.4–0.7% in reduction of mortality, stroke, major bleeding, and intracranial hemorrhage. Warfarin is required for patients with rheumatic mitral stenosis or mechanical heart valves. Among patients with rheumatic heart disease–associ­ ated AF, warfarin therapy has led to a lower rate of a composite of cardiovascular events or death than rivaroxaban therapy, without

a higher rate of bleeding. Similarly, apixaban and dabigatran have failed to demonstrate noninferiority to warfarin and are less effec­ tive than warfarin for the prevention of valve thrombosis or throm­ boembolism in patients with mechanical heart valves. Warfarin can be an inconvenient agent that requires several days to achieve a therapeutic effect (prothrombin time [PT]/international normalized ratio [INR] >2), requires monitoring of PT/INR to adjust dose, and has many drug and food interactions that can hin­ der patient compliance and render maintaining a therapeutic effect challenging. The direct-acting agents are easier to use and achieve reliable anticoagulation promptly without requiring dosage adjust­ ment based on blood tests. Dabigatran, rivaroxaban, and apixaban have renal excretion and require dose adjustment for modest renal impairment, which is of particular concern in the elderly, who are at increased bleeding risk. Limited experience with apixaban and rivaroxaban demonstrates safety and efficacy in patients undergo­ ing chronic hemodialysis for end-stage kidney disease. Excretion can also be influenced by P-glycoprotein inducers and inhibitors. Warfarin anticoagulation can be reversed by administration of fresh frozen plasma, prothrombin complex concentrate, and vitamin K. Reversal agents are available for dabigatran (idarucizumab), and Xa inhibitors are available (andexanet alfa), and both are admin­ istered intravenously. These agents may be prothrombotic, and administration must be judicious. The antiplatelet agents aspirin and clopidogrel are inferior to warfarin for stroke prevention in AF and do not have less risk of bleeding. Clopidogrel combined with aspirin is better than aspirin alone for stroke prevention, but this combination is inferior to warfarin and has a greater bleeding risk than aspirin alone. Bleeding is the major risk of anticoagulation. Major bleeding requiring transfusion and intracranial bleeding occur in ~1% of patients per year with warfarin. Direct-acting anticoagulants appear to have a lower risk of intracranial bleeding compared with warfarin without sacrificing protective effects against thromboembolism. Risk factors for bleeding include age >65–75 years, heart failure, renal insufficiency, prior bleeding, and excessive alcohol or non­ steroidal anti-inflammatory drug use. In patients who require dual antiplatelet therapy (e.g., aspirin and clopidogrel) after coronary or peripheral arterial stenting, there is a substantially increased bleeding risk when standard oral anticoagulation with warfarin or a direct-acting anticoagulant is added. In AF patients undergo­ ing percutaneous coronary intervention, the combination of oral platelet inhibition with a P2Y12 inhibitor (preferably clopidogrel) is recommended. Triple antithrombotic therapy, preferably including a direct-acting anticoagulant, should be considered in patients with high ischemic risk (e.g., acute coronary syndrome) and for up to 30 days. Chronic anticoagulation is contraindicated in some patients due to bleeding risks. Because most atrial thrombi likely originate in the left atrial appendage, surgical removal of the appendage, combined with atrial maze surgery, may be considered for patients undergoing surgery, although removal of the appendage has not been unequivocally shown to reduce the risk of thromboembolism. Percutaneously deployed devices that occlude or ligate the left atrial appendage are also available, appear to be noninferior to warfarin in reducing stroke risk, and are considered in patients who have a high risk of thromboembolism but serious bleeding risk from TABLE 258-2  Novel Oral Anticoagulant Dosing   DABIGATRAN RIVAROXABAN APIXABAN EDOXABAN Standard dose 150 mg bid 20 mg qd 5 mg bid 60 mg qd Reduced dose 110 mg bid 15 mg qd 2.5 mg bid 30 mg qd Dose reduction criteria Dabigatran 110 mg bid in patients with: age ≥80 years, concomitant use of verapamil, or increased bleeding risk Creatine clearance 15–49 mL/min Note: As of publication, four novel or direct oral anticoagulants are available and indicated for stroke prevention for atrial fibrillation. The standard dosing, reduced dosing, and criteria for reduced dosing are shown for each agent.

chronic oral anticoagulation (Table 258-2). Importantly, left atrial appendage closure devices (i.e., Watchman) provide stroke preven­ tion comparable to warfarin, with additional significant reductions in major bleeding, particularly hemorrhagic stroke, and all-cause mortality. Furthermore, left atrial appendage closure devices appear to be noninferior to direct-acting anticoagulants in preventing major AF-related cardiovascular, neurologic, and bleeding events.

CHAPTER 258 RHYTHM CONTROL The decision to administer antiarrhythmic drugs or perform cath­ eter ablation to attempt maintenance of sinus rhythm (commonly referred to as the rhythm control strategy) is mainly guided by patient symptoms and preferences regarding the benefits and risks of therapies. In general, patients who maintain sinus rhythm have better survival than those who continue to have AF. This may be because continued AF is a marker of disease severity or that AF promotes deterioration in cardiac function. In older randomized trials, administration of antiarrhythmic medications to maintain sinus rhythm did not improve survival or symptoms compared to a rate control strategy, and the drug therapy group had more hospitalizations. Disappointing efficacy and toxicities of available antiarrhythmic drugs, in retrospect inappropriate discontinuation of anticoagulation in the rhythm control arms, and patient selec­ tion bias may be factors that influenced the results of these trials. Recently, a randomized trial evaluating an early rhythm control strategy (within 1 year of initial presentation) compared to standard rate control demonstrated a reduction in cardiovascular events, including death from cardiovascular causes and stroke. Differences between this study and earlier randomized trials that failed to show a significant difference in outcomes in rate versus rhythm control included the use of catheter ablation and a high adherence rate to anticoagulation despite apparent rhythm control. In patients with heart failure due to depressed left ventricular function, a catheter ablation–based strategy to maintain sinus rhythm appears to pro­ vide all-cause mortality benefit compared with a medical rhythm control strategy. Furthermore, the combination of catheter ablation and guideline-directed medical therapy in patients with symp­ tomatic AF and end-stage heart failure who are referred for heart transplantation evaluation is associated with a lower likelihood of a composite of death from any cause, implantation of a left ven­ tricular assist device, or urgent heart transplantation than medical therapy alone. Atrial Fibrillation A rhythm control strategy is usually selected for patients with symptomatic paroxysmal AF, recurrent episodes of symptomatic persistent AF, AF with difficult rate control, and AF that has resulted in depressed ventricular function or that aggravates heart failure. A rhythm control strategy is more likely to be favored in younger patients than in sedentary or elderly patients in whom rate control is more easily achieved. Even if sinus rhythm is apparently maintained, anticoagulation is recommended according to the CHA2DS2-VASc stroke risk profile because asymptomatic episodes of AF are common. Following a first episode of persistent AF, a strategy using AV nodal–blocking agents, cardioversion, and anti­ coagulation is reasonable, in addition to addressing possible aggra­ vating factors. If recurrences are infrequent, periodic cardioversion is reasonable. However, if a patient has frequent symptomatic AF despite rate control, then a rhythm control strategy incorporating At least 2 of 3 criteria: age

≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL

(133 mol/L) If any of the following: creatinine clearance 30–50 mL/min, body weight ≤60 kg, or concomitant use of dronedarone, cyclosporine, erythromycin, or ketoconazole

catheter ablation and/or antiarrhythmic medications is indicated. Based on recent randomized trial data demonstrating superiority of ablation over medications for maintenance of sinus rhythm and benefits of an early rhythm control strategy, catheter ablation is considered first-line therapy, especially for individuals with parox­ ysmal AF.

PART 6 Disorders of the Cardiovascular System Pharmacologic Therapy for Maintaining Sinus Rhythm  The goal of pharmacologic therapy is to maintain sinus rhythm or reduce episodes of AF. Risks and side effects of antiarrhythmic drugs are a major consideration in selecting therapy. Drug therapy can be instituted once sinus rhythm has been established or in anticipa­ tion of cardioversion. However, antiarrhythmic medications may in some instances pharmacologically cardiovert the patient into sinus rhythm. Therefore, an appropriate anticoagulation strategy approach similar to electrical cardioversion is recommended, par­ ticularly at the time of initiation of therapy. β-Adrenergic blockers and calcium channel blockers help control ventricular rate, improve symptoms, and possess a low-risk profile, but have low efficacy for preventing or terminating AF episodes. Class I sodium channel– blocking agents (e.g., flecainide, propafenone, disopyramide) are options for patients without significant structural heart disease, but negative inotropic and proarrhythmic effects warrant avoidance in patients with coronary artery disease or heart failure. The class III agents sotalol and dofetilide can be administered to patients with coronary artery disease or structural heart disease but have ~3% risk of inducing excessive QT prolongation and torsades des pointes. Dofetilide should be initiated only in a hospital with ECG monitoring, and many physicians take this approach with sotalol as well. Dronedarone increases mortality in patients with heart failure or long-standing persistent AF. All these agents have modest efficacy in patients with paroxysmal AF, of whom ~30–50% will benefit. Amiodarone is more effective, maintaining sinus rhythm in approximately two-thirds of patients. It can be administered to patients with heart failure and coronary artery disease. However,

40% of patients experience amiodarone-related toxicities during long-term therapy, and thus, careful monitoring of potential toxici­ ties, including skin, liver, lung, and thyroid abnormalities, must be accompanied with this therapy. Catheter and Surgical Ablation for Maintaining Sinus Rhythm  Suc­ cessful catheter ablation avoids antiarrhythmic drug toxicities, but procedural risks and efficacy depend on operator experience. For patients with previously untreated but recurrent paroxysmal AF, catheter ablation has superior efficacy compared to antiarrhythmic drug therapy, and ablation is even more clearly superior to antiar­ rhythmic drugs for patients who have recurrent AF despite drug treatment. Long-term control of AF is more difficult to achieve in patients with persistent and long-standing persistent AF, likely because of more extensive atrial abnormalities and associated greater comorbidities in these patients that may promote ongo­ ing progression of atrial abnormalities that in turn promote AF recurrence. FIGURE 258-4  A. (Left) Electroanatomic map superimposed on a cardiac computed tomography reconstruction of a left atrium with mapping catheter in the posterior wall of this chamber. (Middle) Final radiofrequency lesion set around the pulmonary veins. (Right) Multipolar catheter in the right inferior pulmonary vein B. Spontaneous pulmonary vein (PV) ectopy initiating fibrillatory conduction contained within the isolated vein while 12-lead electrocardiogram shows normal sinus rhythm.

Catheter ablation involves percutaneous venous access (typically via the femoral veins), trans (atrial) septal puncture, and radiofre­ quency ablation or cryoablation to electrically isolate the left atrial regions around the pulmonary vein antra, abolishing the ability of triggering foci in these regions to initiate AF and also likely impact­ ing the substrate for reentry in the left atrium (Fig. 258-4). Gaps in healed ablation areas or emergence of new trigger sites outside the pulmonary veins necessitate a repeat procedure in 10–30% of patients. Several alternative energy sources to create ablative lesions are being evaluated for ablation of AF and other arrhythmias, includ­ ing laser, external beam radiation, and pulsed field electroporation. Pulsed-field ablation uses electric fields generated by short pulses of high energy and has shown promise by specifically targeting myocardium without generating heat or damaging adjacent tissue (Fig. 258-5). Myocardial cells are uniquely sensitive to high-voltage, short-duration electric fields with electroporation thresholds of 268–375 V/cm compared to other tissue types including nerves, endothelium, vascular smooth muscle, and blood cells, all of which have electroporation thresholds >1600 V/cm. The pulse waveforms used to generate an electric field can have many different character­ istics including voltage amplitude, pulse width, cycle period, voltage polarity (monophasic vs. biphasic), electrode polarity (unipolar vs. bipolar), and the number of pulses delivered in a train. There are limited data evaluating the impact of how each of these variables affect lesion safety and efficacy (Fig. 258-5). Therefore, unlike radiofrequency ablation, pulsed-field ablation in its current clinical iteration lacks the ability to titrate and tailor energy delivery during ablation. In patients with paroxysmal AF, sinus rhythm is maintained for >1 year after a single ablation procedure in ~80% of patients and is achieved in >90% of patients after multiple procedures in some studies. Among patients with paroxysmal AF receiving a catheter-based therapy, pulsed-field ablation has demonstrated to be noninferior to conventional thermal ablation (i.e., radiofre­ quency ablation and cryoablation) with respect to freedom from a composite of initial procedural failure, documented atrial tachyar­ rhythmia after a 3-month blanking period, antiarrhythmic drug use, cardioversion, or repeat ablation and with respect to device- and procedure-related serious adverse events at 1 year. Many patients become more responsive to antiarrhythmic drugs or become less symptomatic with a reduced AF burden after a pulmonary vein isolation procedure, and thus, repeat ablation may not be required for symptom control in some. Ablation is less effective in patients with persistent AF, particularly long-standing persistent AF, especially when associated with more extensive car­ diac disease, comorbidities, and evidence of moderate and severe left atrial enlargement. More extensive ablation is often required, targeting areas that likely support reentry and/or AF maintenance and regions outside but adjacent to the pulmonary venous antra. Most ablation targets and strategies beyond pulmonary vein isolation have failed to show systematic outcome improvement in randomized controlled clinical trials. However, individualized

Smooth Muscle Cells 1600 V/cm Nerve 3800 V/cm Red Blood Cells 1600 V/cm Pulse Train Voltage Voltage Pulse Width Cycle Waveform Variables • Pulse amplitude (voltage) • Pulse polarity (monophasic-biphasic) • Number of pulses in a train • Pulse width • Cycle period FIGURE 258-5  Pulsed-field electroporation. (Top) Pulsed-field ablation has the potential to target specifically myocardial tissue without negatively affecting adjacent structures or cells such as red blood cells, nerves, the esophagus, or arteries. (Bottom) Numerous factors are involved in creating long-lasting transmural lesions with pulse-field ablation; a combination of most of these parameters will eventually help in delivering electroporation effectively and safely into the myocardial tissue. Catheters currently undergoing clinical evaluation for pulsed-field ablation (PFA). (Reproduced from CD Matos et al: Pulsed Field Ablation of Atrial Fibrillation: A Comprehensive Review. Rev Cardiovasc Med 24:337, 2023 and Reproduced with permission from NA Steiger, JE Romero. Pulsed-field ablation: What are the unknowns and when will they cease to concern us. J Cardiovasc Electrophysiol 33:1489, 2022.) (A) Farawave, reproduced with permission from Boston Scientific; (B) PVAC, reproduced with permission from Medtronic; (C) Sphere-9, reproduced with permission from Medtronic; (D) Varipulse. ablation of atrial low-voltage myocardium in addition to pulmonary vein isolation significantly improved outcomes in patients with persistent AF in one study. Similarly, in patients with persistent AF, treatment with combined catheter ablation and vein of Marshall ethanol infusion had better outcomes compared with catheter abla­ tion alone. Ablation of areas of rapid activity during AF and cre­ ation of empiric ablation lines to block conduction across regions of the atria have not been proven to improve outcomes in unselected patients. Other ablation targets include non–pulmonary vein foci that fire in response to high-dose isoproterenol and regions with repetitive rotational or focal activation during AF. More than one ablation procedure is often required to maintain sinus rhythm in patients with persistent and long-standing persistent AF because of lack of lesion durability and complex atrial substrate with non–pul­ monary vein sources that may be incompletely treated at the initial ablation session (Table 258-3).

Endothelium 1750 V/cm CHAPTER 258 Nerve 3800 V/cm Atrial Fibrillation Myocardium 375 V/cm A D C Time B Catheter Variables • Contact force • Electrode surface area • Electrode polarity (uni vs bipolar) • Electrode shape (torus vs ring) • Electrode and tissue orientation Catheter ablation has a 2–7% risk of major procedure-related complications, with the long-term trend suggesting steady improve­ ment in complication rates. Complication rates are clearly lowest with high-volume operators and centers. Complications include stroke (0.5–1%), cardiac tamponade (1%), phrenic nerve paraly­ sis, bleeding from femoral access sites, and fluid overload with heart failure, which can emerge 1–3 days after the procedure. It is important to recognize the potential for delayed presentation of some complications. Ablation within the pulmonary vein can lead to pulmonary vein stenosis, presenting weeks to months after the procedure with dyspnea or hemoptysis. The esophagus abuts the posterior wall of the left atrium where it is subject to injury, and esophageal ulcers can form immediately after the procedure and may rarely lead to a fistula between the left atrium and esophagus (estimated incidence of <0.1%) that presents as endocarditis and stroke 10 days to 3 weeks after the procedure. Early diagnosis

20 - 259 Approach to Ventricular Arrhythmias

259 Approach to Ventricular Arrhythmias

TABLE 258-3  Recommendations for Catheter Ablation in Patients with Atrial Fibrillation (AF) LEVEL OF EVIDENCE RECOMMENDATIONS CLASS

A In patients with symptomatic AF in whom antiarrhythmic drugs have been ineffective, contraindicated, not tolerated or not preferred, and continued rhythm control is desired, catheter ablation is useful to improve symptoms. PART 6 Disorders of the Cardiovascular System

A In selected patients (generally younger with few comorbidities) with symptomatic paroxysmal AF in whom rhythm control is desired, catheter ablation is useful as first-line therapy to improve symptoms and reduce progression to persistent AF.

A In patients with symptomatic or clinically significant atrial flutter, catheter ablation is useful for improving symptoms. 2a B In patients who are undergoing ablation for AF, ablation of additional clinically significant supraventricular arrhythmias can be useful to reduce the likelihood of future arrhythmia. 2a B In patients (other than younger with few comorbidities) with symptomatic paroxysmal or persistent AF who are being managed with a rhythm-control strategy, catheter ablation as first-line therapy can be useful to improve symptoms. Source: Reproduced with permission from JA Joglar et al: 2023 ACC/AHA/ACCP/ HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 83:109, 2024. of atrioesophageal fistula is important because delayed diagnosis leads to likely death. Diagnosis is made by chest CT scan with water-soluble oral and IV contrast. Endoscopy should be avoided in patients with a suspected fistula because of the risk of air/ esophageal fluid embolus. Definitive repair of the atrioesophageal fistula with emergent surgery is required. Pulsed-field ablation is associated with a significantly reduced risk of pulmonary vein stenosis, phrenic nerve injury, and left atrial esophageal fistula. Surgical ablation of AF is most frequently performed concomitant with cardiac valve or coronary artery surgery and less commonly as a stand-alone procedure. There is no significant difference in the rate of freedom from AF between patients who undergo pulmonary vein isolation and those who undergo the biatrial maze procedure. However, for patients with persistent AF, surgical or hybrid pro­ cedures (a combination of a surgical and catheter-based approach, most often in separate procedures) appear to have comparable effi­ cacy to catheter ablation. Risks include sinus node injury requiring pacemaker implantation and higher morbidity with surgical abla­ tion. Surgical removal of the left atrial appendage may reduce stroke risk, although thrombus can form in the remnant of the appendage or if the appendage is not completely ligated. RISK FACTORS FOR AND LIFESTYLE IMPACT ON ATRIAL FIBRILLATION There is strong evidence that AF is associated with a sedentary lifestyle, obesity, hypertension, smoking, alcohol use, and sleep apnea. Aggres­ sive treatment of these risk factors can substantially reduce AF episodes in some patients and is warranted in all patients, as additional benefits to the patient are likely beyond AF improvement. The amount of exer­ cise appears to have a complex relationship with the risk of AF develop­ ment. In males, a U-shaped curve exists, where AF risk is high among those with sedentary lifestyles and those who participate extensively in endurance athletics such as long-distance running or cycling. Moder­ ate exercise appears to confer a lower risk of AF. On the other hand, in females, a linear relationship exists between exercise and AF risk, with risk of AF decreasing continuously with increasing exercise activity. Although caffeine intake is often invoked as a risk for AF development or as a trigger for AF episodes in patients with a known AF diagnosis, large cohort studies have demonstrated, in contrast, a modest decrease in AF risk with modest caffeine intake. Other proposed risk factors are

being evaluated, including psychological stress. Genetic predisposition to AF is seen in those with first-degree relatives with AF, and a small subset of AF patients can be determined have a familial form of AF. There is emerging emphasis on an integrated approach to manage­ ment of AF patients, with coordinated management of risk factor modification, stroke prevention, rate control, rhythm control, and management of associated comorbidities of critical importance. The previous classification of AF, which was based only on arrhythmia duration (i.e., paroxysmal, persistent, and long-standing persistent), although useful, tended to emphasize therapeutic interventions. A more recent classification using four stages (i.e., at risk of AF, pre-AF, AF, and permanent AF) has been proposed and recognizes AF as a disease continuum that requires a variety of strategies at the different stages, including prevention, lifestyle and risk factor modification, screening, and therapy. ■ ■FURTHER READING Joglar JA et al: 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 83:109, 2024. Packer DL et al: Effect of catheter ablation vs antiarrhythmic drug therapy on mortality, stroke, bleeding, and cardiac arrest among patients with atrial fibrillation: The CABANA randomized clinical trial. JAMA 321:1261, 2019. William H. Sauer, Usha B. Tedrow

Approach to Ventricular Arrhythmias There are myriad types of ventricular arrhythmias (VAs), ranging from benign to life-threatening, occurring both in patients with normal hearts and in those with structural heart disease. An understanding of an approach to these arrhythmias is critical to being appropriately parsimonious with benign forms, while understanding timely workup and management of the malignant forms. TYPES OF VAs VAs can arise from focal sites of origin or from reentrant circuits. Focal VAs can originate from myocardial or specialized Purkinje cells capa­ ble of automaticity or triggered activity. Reentrant VAs often involve areas of scar such as old myocardial infarction or a cardiomyopathic process. Less commonly, diseased Purkinje conduction pathways can also result in reentrant circuits. VAs are characterized by their electro­ cardiographic appearance and duration. Conduction away from the ventricular focus or reentrant circuit exit, propagating through the ven­ tricular myocardium, is slower than activation of the ventricles over the normal Purkinje system. For this reason, the QRS complex duration during VAs will be wide, typically >0.12 s, though there are unusual situations that can arise with narrow QRS duration as well. Premature ventricular beats (also referred to as a premature ventricular contractions or premature ventricular complexes [PVCs]) are single ven­ tricular beats that occur earlier than the next anticipated supraventricu­ lar beat (Fig. 259-1). PVCs that originate from the same focus will have the same QRS morphology and are referred to as unifocal (Fig. 259-1A). PVCs that originate from different ventricular sites have different QRS morphologies and are referred to as multifocal (Fig. 259-1B). Two con­ secutive ventricular beats are ventricular couplets. Ventricular tachycardia (VT) is three or more consecutive beats at a rate faster than 100 beats/min. Three or more consecutive beats at

1000 ms I Art. Pr. A B C FIGURE 259-1  A. Unifocal premature ventricular contractions (PVCs) at bigeminal frequency. Trace shows electrocardiogram lead 1 and arterial pressure (Art. Pr.). Sinus rhythm beats are followed by normal arterial waveform. The arterial pressure following premature beats is attenuated (arrows) and imperceptible to palpation. The pulse in this patient is registered at half the heart rate. B. Multifocal PVCs. The two PVCs shown have different morphologies. C. Example of accelerated idioventricular rhythm. (See text for details.) slower rates are designated an idioventricular rhythm. VT that termi­ nates spontaneously within 30 s is designated nonsustained, whereas sustained VT persists for >30 s or is terminated by an active interven­ tion, such as administration of an intravenous medication, external I II aVR V1 V4 aVL III aVF V1 II FIGURE 259-2  Repetitive monomorphic nonsustained ventricular tachycardia (VT) of right ventricular outflow tract origin. The VT has a left bundle branch block pattern with inferior axis with tall QRS complexes in the inferior leads.

CHAPTER 259 Approach to Ventricular Arrhythmias cardioversion, antitachycardia pacing, or a shock from an implanted cardioverter-defibrillator (Fig. 259-2). Monomorphic VT has the same QRS complex from beat to beat, indicating that the activation sequence is the same from beat to beat V5 V2 V3 V6

and that each beat likely originates from the same source (Fig. 259-3A). The initial site of ventricular activation largely determines the sequence of ventricular activation. Therefore, the QRS morphology of PVCs and monomorphic VT provides an indication of the site of origin within the ventricles (Fig. 259-4). The likely origin often suggests whether an arrhythmia is idiopathic or associated with structural disease. Arrhyth­ mias that originate from the right ventricle or septum result in late activation of much of the left ventricle, thereby producing a prominent S wave in V1 referred to as a left bundle branch block–like configura­ tion. Arrhythmias that originate from the free wall of the left ventricle have a prominent positive deflection in V1, thereby producing a right bundle branch block–like morphology in V1. The frontal plane axis of the QRS is also useful. An axis that is directed inferiorly, as indicated by dominant R waves in leads II, III, and AVF, suggests initial activation of the cranial portion of the ventricle, whereas a frontal plane axis that is directed superiorly (dominant S waves in II, III, and AVF) suggests initial activation at the inferior wall.

PART 6 Disorders of the Cardiovascular System Very rapid monomorphic VT has a sinusoidal appearance, also called ventricular flutter, because it is not possible to distinguish the QRS com­ plex from the T wave (Fig. 259-3B). Relatively slow sinusoidal VTs have a wide QRS indicative of slowed ventricular conduction (Fig. 259-3C). Hyperkalemia, toxicity from excessive effects of drugs that block sodium channels (e.g., flecainide, propafenone, or tricyclic antidepressants), and severe global myocardial ischemia are possible causes. Polymorphic VT has a continually changing QRS morphology indi­ cating a changing ventricular activation sequence. Polymorphic VT that occurs in the context of congenital or acquired prolongation of the QT interval often has a waxing and waning QRS amplitude, creating a characteristic shifting axis referred to as torsades des pointes after the classic ballet sequence (Fig. 259-3D). Ventricular fibrillation (VF) has continuous irregular activation with no discrete QRS complexes. Monomorphic or polymorphic VT may transition to VF in susceptible patients. Cardiac ischemia is the most common cause of VF (Fig. 259-3E). The term idiopathic ventricular arrhythmia generally refers to PVCs or VT that occurs in patients with a normal electrocardiogram (ECG), without structural heart disease, and not associated with an underlying genetic syndrome or risk of sudden death. CLINICAL MANIFESTATIONS Common symptoms of VAs include palpitations, dizziness, exercise intolerance, episodes of lightheadedness, syncope, or sudden cardiac arrest leading to sudden death if not resuscitated. VAs can also be asymptomatic and encountered unexpectedly as an irregular pulse or heart sounds on examination or may be seen on a routine ECG, exer­ cise test, or cardiac ECG monitoring. Occasionally when every other beat is a PVC (bigeminy), pulse measurements for heart rate can be erroneously low (pseudobradycardia) because the PVCs may not gener­ ate a separate pulse wave. Syncope is a concerning symptom, particularly when occurring without prodrome, during exercise, or in the setting of abnormal ECG or structural heart disease. Such episodes can be due to VT that pro­ duces severe hypotension, warranting concern for risk of cardiac arrest and sudden death with arrhythmia recurrence. Although benign pro­ cesses such as reflex-mediated neurocardiogenic (vasovagal) episodes and orthostatic hypotension are the most common causes of syncope, it is important to consider the possibility of underlying heart disease or a genetic syndrome causing VT. When these are suspected, hospitaliza­ tion for further evaluation and monitoring is often appropriate. Sustained VT may present as a wide QRS complex tachycardia that must be distinguished from supraventricular tachycardia with aberrancy (Chap. 253). Symptoms can be minor but more commonly include hypotension with syncope and even imminent cardiac arrest, particularly in patients with structural heart disease. Sustained VT may degenerate to VF, most commonly if it is rapid and polymorphic. Many patients who are at risk for VT have known heart disease, and many have an implantable cardioverter-defibrillator (ICD). In patients with an ICD, VT episodes may cause transient lightheadedness, palpitations, or syncope followed by a shock from the ICD (see below).

A B C D E FIGURE 259-3  A. Monomorphic ventricular tachycardia (VT) with dissociated P waves (short arrows). B. Ventricular flutter. C. Sinusoidal VT due to electrolyte disturbance or drug effects. D. Polymorphic VT resulting from prolongation of QT interval (torsade de pointe VT). E. Ventricular fibrillation. (See text for details.) EVALUATION OF PATIENTS WITH DOCUMENTED OR SUSPECTED VENTRICULAR ARRHYTHMIAS There are several important considerations that guide evaluation of patients with documented or suspected cardiac arrhythmias. First, establish whether a VA is the cause of the symptoms or clinical presen­ tation. Second, determine whether the arrhythmia is associated with a cardiac disease, and establish the prognostic significance of that disease and, in particular, whether it is associated with a risk of sudden cardiac death. Finally, define the likelihood of arrhythmia recurrence and the symptoms and risk imposed by the recurrence. The risks of cardiac arrest and sudden cardiac death are largely determined by the cause of the arrhythmia and the associated underlying heart disease. The diagnosis of VAs can be established by recording the arrhythmia on an ECG, by an ambulatory or implanted cardiac monitor, by an implanted rhythm management device such as a pacemaker or ICD, or in some cases, initiation of the arrhythmia during an electrophysiologic

II III II, III AVF = Inferior axis superior origin LV RV V1 = LBBB Septal or RV origin V1 = RBBB LV origin II III II, III AVF = Superior axis inferior origin FIGURE 259-4  Site of ventricular tachycardia origin based on QRS morphology. (See text for details.) LBBB, left bundle branch block; LV, left ventricle; RBBB, right bundle branch block; RV, right ventricle. study. A 12-lead ECG of the arrhythmia should be obtained when pos­ sible and often provides clues to the potential site of origin and possible presence of underlying heart disease (see above) (Fig. 259-4). For patients with sustained wide-complex tachycardia, initial man­ agement is guided by the patient’s hemodynamic stability. The approach to sustained wide-complex tachycardia is discussed in Chap. 261. The management of VT that causes cardiac arrest is discussed in Chap. 317. Once hemodynamic stability is restored, further management is guided by the possibility of a recurrence and the risk imposed by a recurrence. ■ ■EVALUATION OF THE PATIENT WITH ARRHYTHMIA SYMPTOMS When symptoms are intermittent, initial evaluation aims to establish symptom severity, provocative factors, and presence of underlying heart disease. Syncope or near syncope raises concern that an arrhyth­ mia is causing episodes of hypotension and that there may be a risk of cardiac arrest. Symptoms that occur with exertion suggest arrhythmias that are provoked by sympathetic stimulation but can also be related to exertional ischemia in patients with coronary artery disease, although nonarrhythmia causes must also be considered. A past history of any cardiac disease is important. A review of all medications is relevant. Medications that prolong the QT interval predispose to polymorphic VT (Chap. 262). Adrenergic stimulants can provoke PVCs. Family history should determine the presence of premature coro­ nary artery disease, cardiomyopathy, or cardiac arrhythmias, particu­ larly a history of sudden death. Family history may also suggest that the possibility of a genetic cause of an arrhythmia warrants careful consideration. Details of premature deaths are relevant. Sudden death victims are often said to have died of a “massive heart attack” despite absence of definite confirmation of thrombotic myocardial infarction and when other causes such as arrhythmia may have been possible. The physical examination focuses on evidence of structural heart disease with assessment of pulse, jugular venous pressure lung fields, and cardiac auscultation. Stigmata of neuromuscular disease or dys­ morphic features may suggest a genetic arrhythmia syndrome.

A 12-lead ECG should be obtained even if the patient is not having symptoms at the time of evaluation. Occasionally, premature ventricular con­ tractions will be detected. Patients with benign idio­ pathic arrhythmias usually have a completely normal ECG during sinus rhythm. Any ECG abnormality warrants further evaluation. Particularly relevant findings include Q waves that indicate prior myo­ cardial infarction, which may have been silent, and ventricular hypertrophy, which may indicate hyper­ trophic cardiomyopathy or other ventricular disease. An ECG finding is the major diagnostic manifesta­ tion of several genetic arrhythmia syndromes in patients without structural heart disease, including the long QT syndrome, Brugada syndrome, and short QT syndrome.

CHAPTER 259 Approach to Ventricular Arrhythmias V1 If there is suspicion of structural heart disease, cardiac imaging is warranted to assess ventricu­ lar function and structure. Transthoracic echocar­ diography is most frequently employed for initial evaluation. Depressed ventricular function increases concern for a risk of sudden death and warrants fur­ ther evaluation to establish the cause, which may be cardiomyopathy, coronary artery disease, or valvular heart disease. Ventricular thickening may indicate hypertrophic cardiomyopathy or infiltrative diseases such as amyloidosis. Cardiac magnetic resonance imaging with gadolinium contrast imaging provides similar assessment but also can detect areas of ven­ tricular scar, evident as regions of delayed hyper­ enhancement, which are usually present in patients who have sustained monomorphic VT (Fig. 259-5). The nature and location of abnormalities are helpful in assessing the type of heart disease. Evaluation to exclude atherosclerotic coronary artery disease should be performed in patients at risk, guided by age and other risk factors. ■ ■TREATMENT OPTIONS FOR VENTRICULAR ARRHYTHMIAS Treatment of VAs is guided by the severity and frequency of symptoms. For those with structurally normal hearts and normal ECGs, reassur­ ance and removal of aggravating factors (e.g., caffeine or alcohol) may be all that is needed. For arrhythmias associated with a sudden death risk, ICD implantation is usually indicated and will provide a “safety net” to terminate life-threatening VT or VF, preventing sudden death but without preventing the arrhythmia. When suppression of the arrhythmia is required, antiarrhythmic drug therapy or catheter abla­ tion is a major consideration. ■ ■ANTIARRHYTHMIC DRUGS Use of antiarrhythmic drugs is based on consideration of the risks and potential benefit for the individual patient. Efficacy and side effects for the individual patient are not always predictable and are assessed by individual therapeutic trial. Causes of drug intolerance are mostly non­ cardiac and minor but can sometimes be severe enough to limit their use. Cardiac adverse events, however, include the potential for “proar­ rhythmia,” whereby a drug can increase the frequency of arrhythmia or cause a new arrhythmia. Aggravation of bradyarrhythmias is also a common concern. Although antiarrhythmic drugs are classified based on their actions on receptors or ion channels, most have multiple effects, affecting more than one channel. ■ ■a-ADRENERGIC BLOCKERS Many VAs are sensitive to sympathetic stimulation, and β-adrenergic stimulation may also interact with the electrophysiologic effects of many membrane-active antiarrhythmic drugs. The safety of β-blocking agents makes them the first choice of therapy for most VAs. β-Blockers are particularly useful for exercise-induced arrhythmias and idiopathic arrhythmias but have limited efficacy for most arrhythmias associated

PART 6 Disorders of the Cardiovascular System FIGURE 259-5  Imaging studies of the left ventricle (LV) used to assist ablation for ventricular tachycardia (VT). Left panel is a magnetic resonance image of a longitudinal section demonstrating thinning of the anterior wall and late gadolinium enhancement in a subendocardial scar (white arrows). The middle panel shows a two-dimensional image of the LV in long axis corresponding to the sector through the mid-LV (arrow in figure on right panel) obtained by an intracardiac echocardiography probe positioned in the right ventricle. An electroanatomic three-dimensional map of the LV in the left anterior oblique projection is displayed in the right panel. The purple areas depict areas of normal voltage (>1.5 mV). Blue, green, and yellow represent progressively lower voltages, with the red areas indicating scar (<0.5 mV). Channels of viable myocardium with slow conduction within the scar are identified with the light blue dots. Areas of ablation delivered to regions involved in reentrant VT are indicated by maroon dots. with heart disease. Bradyarrhythmias and negative inotropic effects are the major cardiac adverse effects. ■ ■CALCIUM CHANNEL BLOCKERS The nondihydropyridine calcium channel blockers diltiazem and vera­ pamil can be effective for some idiopathic VTs. The risk of proarrhyth­ mia is low, but they have negative inotropic and vasodilatory effects that can aggravate hypotension. ■ ■SODIUM CHANNEL–BLOCKING AGENTS Drugs whose major effect is mediated through sodium channel blockade include mexiletine, quinidine, disopyramide, flecainide, and propafenone, which are available for chronic oral therapy. Blockade of the fast inward sodium current has been referred to as a class I antiarrhythmic drug effect. Antiarrhythmic actions are the result of depressing cardiac conduction and membrane excitability. Conduction slowing can be manifest as a prolongation of QRS duration. Lidocaine, quinidine, and procainamide are available as intravenous formula­ tions. Quinidine, disopyramide, and procainamide also have potas­ sium channel–blocking effects that may prolong the QT interval (class III antiarrhythmic drug action), contributing to their antiarrhythmic effect. Quinidine also blocks a particular potassium current, Ito, the blockade of which can be important in Brugada syndrome. These agents have potential proarrhythmic effects and, with the possible exception of quinidine, also have negative inotropic effects that may have contributed to the increased mortality observed when some were administered chronically to patients with prior myocardial infarction. Long-term therapy is generally avoided in patients with structural heart disease but may be used to reduce symptomatic arrhythmias in patients with ICDs. ■ ■POTASSIUM CHANNEL BLOCKING AGENTS Sotalol and dofetilide block the delayed rectifier potassium channel IKr, thereby prolonging action potential duration (QT interval) and the cardiac refractory period, known as the class III antiarrhythmic drug effect. Sotalol also has nonselective β-adrenergic–blocking activity. It has been shown to have a modest effect on reducing ICD shocks due to ventricular and atrial arrhythmias. Proarrhythmia due to the poly­ morphic VT torsade de pointe that is associated with QT prolongation occurs in 3–5% of patients. Both sotalol and dofetilide are excreted via the kidneys, necessitating dose adjustment or avoidance in renal insufficiency. These drugs must be avoided in patients with other risk factors for torsades de pointes, including QT prolongation, other administered medications that prolong the QT interval, hypokalemia, and significant bradycardia. ■ ■AMIODARONE Amiodarone blocks multiple cardiac ionic currents and has sym­ patholytic activity. It is the most effective antiarrhythmic drug for suppressing VAs. It is administered intravenously for life-threatening

arrhythmias. During chronic oral therapy, electrophysiologic effects develop over several days. It is more effective than sotalol in reducing ICD shocks and is often used for VAs in patients with heart disease. Bradyarrhythmias are the major cardiac adverse effect. Ventricular proarrhythmia can occur, but torsades de pointes VT is rare. Noncar­ diac toxicities are a major problem and contribute to drug discontinua­ tion in at least a third of patients during long-term therapy. Hyper- and hypothyroidism are related to the iodine content of the drug. Pneumo­ nitis or pulmonary fibrosis occurs in ~1% of patients. Photosensitivity is common, and neuropathy and ocular toxicity can occur. Systematic monitoring is recommended during chronic therapy including assess­ ment for thyroid, liver, and pulmonary toxicity. Intravenous adminis­ tration of amiodarone via a peripheral vein for >24 h can cause severe peripheral thrombophlebitis. Dronedarone has structural similarities to amiodarone but without the iodine moiety. Efficacy for VAs is poor, and dronedarone increases mortality in patients with heart failure, so dronedarone is not typically used for treatment of VAs. ■ ■IMPLANTABLE CARDIOVERTER-DEFIBRILLATORS ICDs detect sustained VT, largely based on heart rate, and then ter­ minate the arrhythmia. In transvenous devices, VF is terminated by a shock applied between a lead in the right ventricle and the ICD pulse generator. The lead can provide pacing for bradycardia if needed. This transvenous form of ICD has the disadvantages of vascular occlusion, risk of lead fracture, endocarditis in the event of infection, and dif­ ficulty with removal. Monomorphic VT can also be terminated by a burst of rapid pacing faster than the VT, known as antitachycardia pacing (ATP) (Fig. 259-6A). If ATP fails or is not a programmed treatment, as is often the case for rapid VT or VF, a shock is deliv­ ered (Fig. 259-6B). ICDs can also be subcutaneous or extravascular, without a transvenous lead. The rhythm is also sensed by this lead, in a manner similar to a surface ECG. The lead is placed overlying the left chest with a coil parallel and next to or underneath the sternum. No matter the type of ICD, shocks are uncomfortable and distressing if the patient is conscious, sometimes leading to a posttraumatic stress disorder (PTSD). The most common ICD complication is the delivery of unnecessary therapy (either ATP or shocks) in response to an inap­ propriately detected rapid supraventricular tachycardia or electrical noise as a result of an ICD lead fracture or electromagnetic interference from an external source. ICDs record and store electrograms from arrhythmia episodes that can be retrieved by interrogation of the ICD, which can be performed remotely and communicated via the internet. This assessment is critical after an ICD shock to determine the arrhyth­ mia diagnosis and exclude unnecessary therapy. Device infection is an important problem long term and occurs in ~1% of patients. This risk may be less for subcutaneous or extravascular implants. ICDs decrease mortality in patients at risk for sudden death due to structural heart diseases. In all cases, ICDs are recommended only if there is also an expectation for survival of at least a year with acceptable

A Anti-tachycardia pacing B ICD shock FIGURE 259-6  Implantable cardioverter-defibrillator (ICD) and therapies for ventricular arrhythmias. A. A monomorphic ventricular tachycardia (VT) is terminated by a burst of pacing impulses at a rate faster than VT (antitachycardia pacing). B. A rapid VT is converted with a high-voltage shock (arrow). The chest x-ray in the panel C shows the components of an ICD capable of biventricular pacing (yellow arrows). ICD generator in the subcutaneous tissue of the left upper chest, pacing leads in the right atrium and the left ventricular (LV) branch of the coronary sinus (LV lead), and a pacing/defibrillating lead in the right ventricle (RV lead) are shown. functional capacity. The exception is in cases of patients with endstage heart disease who are awaiting cardiac transplantation outside the hospital or who have left bundle branch block QRS prolongation such that they are likely to have improvement in ventricular function with cardiac resynchronization therapy from a biventricular ICD or conduction system pacing (Fig. 259-6C). In these cases, an ICD may be warranted despite a guarded prognosis. A wearable ICD system with electrodes incorporated into a vest and an external battery pack is also available for short-term use in patients pending a decision regarding a permanent implanted system, or when a permanent system cannot be implanted for other reasons such as an ongoing infection. Despite prompt termination of VT or VF by an ICD, the occur­ rence of these arrhythmias predicts subsequent increased mortality and risk of heart failure. Occurrence of VT or VF should therefore prompt assessment for potential causes including worsening heart failure, electrolyte abnormalities, and ischemia. Repeated shocks, even if appropriate, often induce posttraumatic stress disorder. Antiarrhyth­ mic drug therapy, most commonly amiodarone, or catheter ablation is often required for suppression of recurrent arrhythmias. Antiarrhyth­ mic drug therapy can alter the VT rate and the energy required for defibrillation, thereby necessitating programming changes in the ICD’s algorithms for detection and therapy. ■ ■CATHETER ABLATION FOR VT Catheter ablation is usually performed by applying radiofrequency (RF) current to cause thermal injury by resistive heating of cardiac tissue responsible for the arrhythmia. An electrode catheter with an electroanatomic mapping system is used to map local electrical activity to identify the ventricular myocardium that is causing the arrhythmia, referred to as the arrhythmia substrate. The size and location of the arrhythmia substrate determine the ease and likely effectiveness of the procedure, as well as the potential complications. When the arrhythmia originates from the endocardium, as is most commonly the case, it can be reached from an endovascular approach via a femoral vein or artery. Less commonly, arrhythmias originate from the subepicardium, and percutaneous pericardial puncture, similar to pericardiocentesis,

CHAPTER 259 Approach to Ventricular Arrhythmias Atrial lead ICD LV lead RV lead C is required to insert a catheter into the pericardial space for mapping and ablation. In patients with scar-related VT due to prior infarction or cardiomyopathy, ablation typically targets abnormal regions in the scar or region of fibrosis. Because these scars often contain multiple reentry circuits over relatively large regions, extensive areas of ablation can be required, and these areas are often identified as regions of low voltage displayed on electroanatomic reconstructions of the ventricle (Fig. 259-5). Catheter ablation is often performed in patients with recurrent VAs associated with poor cardiac function, and the procedure-related mortality in this situation is 0.5–3%. Outcomes are better for patients with prior infarction and VT than for patients with nonischemic car­ diomyopathies in which the scar locations are more variable and often intramural or subepicardial. Ablation can be lifesaving for patients with very frequent or incessant VT. Methods of delivering ablative energy to intramural areas or areas requiring very extensive ablation are under development. These include needle catheters capable of delivering ablative energy into intramural sources, and bipolar ablation where radiofrequency energy is delivered across two ablation catheters. Stereotactic body radiation therapy (SBRT), classically used for treating thoracic tumors, has been used to direct radiation therapy to a specific portion of the scar substrate to noninvasively ablate VT with encourag­ ing early studies. Idiopathic VTs and PVCs that occur in the absence of structural heart disease usually originate from a small focus, for which catheter ablation typically has a higher success rate for preventing recurrent arrhythmia. Long-term arrhythmia-free survival in these patients is excellent. ARRHYTHMIA SURGERY When antiarrhythmic drug therapy and catheter ablation fail or are not an option, surgical cryoablation, often combined with aneurysmec­ tomy, can be effective therapy for recurrent VT due to prior myocardial infarction and has also been used successfully in a few patients with nonischemic heart disease. Few centers now maintain the expertise for this therapy, though some use this therapy as an adjunct to ventricular assist device implantation.

22 - 261 Sustained Ventricular Tachycardia

261 Sustained Ventricular Tachycardia

aVR I aVL II aVF III V1 FIGURE 260-4  Accelerated idioventricular rhythm. Shown is an example of a slow regular wide-complex rhythm. Fusion beats are seen on complexes 4 and 10, which are more positive in lead V1 and narrower than the rest of the beats. These features are consistent with an accelerated idioventricular rhythm. myocardium can cause AIVR. Idioventricular rhythms are common during acute MI and may emerge during sinus bradycardia. Often, they are not symptomatic, but hemodynamic compromise may occur with the loss of atrioventricular synchrony in susceptible patients. Atropine may be administered to increase the sinus rates if this is a concern. This rhythm is also common in patients with cardiomyopathies or sleep apnea. It can also be idiopathic, often emerging when the sinus rate slows during sleep. Therapy should target any underlying cause and correction of bradycardia. Specific antiarrhythmic therapy for asymp­ tomatic idioventricular rhythm is not necessary. FUTURE DIRECTIONS Recently, it has been appreciated that inflammation plays a role in the genesis of PVCs in specific patients with inflammatory cardiomy­ opathies and even in inherited cardiomyopathies. The roles of early identification of this process and targeted treatment are areas of active research. ■ ■FURTHER READING Al-Khatib SM et al: 2017 AHA/ACC/HRS guideline for manage­ ment of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm 15:e73, 2018. Callans DJ: Josephson’s Clinical Cardiac Electrophysiology: Techniques and Interpretations, 7th ed. Philadelphia, Wolters Kluwer, 2024. Cronin EM et al: 2019 HRS/EHRA/APHRS/LAHRS expert consensus statement on catheter ablation of ventricular arrhythmias. EP Euro­ pace 21:1143, 2019. Jalife J, Stevenson W (eds): Zipes and Jalife’s Cardiac Electrophysiol­ ogy: From Cell to Bedside, 8th ed. Philadelphia, Elsevier, 2022. Zeppenfeld K et al: 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: Developed by 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) Endorsed by the Association for European Paediatric and Congenital Cardiol­ ogy (AEPC). Eur Heart J 43:3997, 2022.

V1 V4 CHAPTER 261 V2 V5 V3 V6 Sustained Ventricular Tachycardia William H. Sauer, Usha B. Tedrow

Sustained Ventricular Tachycardia Sustained monomorphic ventricular tachycardia (VT) is a ventricular arrhythmia with a wide QRS lasting for at least 30 s or requiring an intervention such as antitachycardia pacing from a defibrillator or a cardioversion for termination. Each QRS complex resembles the others, indicating either a focal site of origin or a repetitive exit from a fixed arrhythmia reentry circuit. In structural heart disease, the arrhythmia substrate is most often an area of patchy replacement fibro­ sis due to infarction, fibrosis, inflammation, or prior cardiac surgery that creates anatomic or functional reentrant pathways. Less com­ monly, VT is related to reentry or automaticity in diseased conduction pathways in the Purkinje system. While scar-related reentrant VTs are associated with risk of sudden death, idiopathic VT is a more benign form of VT that occurs in structurally normal hearts and can be due to a focal region of automaticity in the myocardium or reentry involving a portion of the Purkinje system. The clinical presentation varies depending on the rate of the arrhythmia, underlying cardiac function, and autonomic adaptation in response to the arrhythmia. Rapid VT can produce hypotension that may present as syncope, particularly in patients with significant ven­ tricular dysfunction. In contrast, patients with normal cardiac function might tolerate sustained VT, even presenting with simple palpitations, despite rapid rates. Monomorphic VT that is rapid or associated with structural heart disease may eventually deteriorate to ventricular fibril­ lation (VF), which may be the initial cardiac rhythm recorded at the time of resuscitation of an out-of-hospital cardiac arrest. DIAGNOSIS Sustained monomorphic VT (Table 261-1) has to be distinguished from other causes of uniform wide QRS tachycardia. These include supraventricular tachycardia with left or right bundle branch block

TABLE 261-1  Sustained Ventricular Arrhythmias 1.  Idiopathic ventricular tachycardia (VT) without structural heart disease A. Outflow tract origin • Right ventricular (RV) outflow tract: left bundle branch block pattern in V1 with inferior axis (tall QRS in inferior leads) and late transition in the precordial leads • Left ventricular (LV) outflow tract: similar inferiorly directed axis but PART 6 Disorders of the Cardiovascular System with early precordial transition with prominent R wave in V2–V3 B. LV fascicular VT: Typical right bundle branch block pattern in V1 with sharp intrinsicoid deflection and left axis deviation (arising from left posterior fascicle in its most common form) C. Papillary muscle VT • Posteromedial: atypical right bundle branch block pattern in V1 with monophasic R wave and left axis deviation • Anterolateral: atypical right bundle branch block pattern in V1 with positive deflection in lead III and negative deflection in lead I 2.  Ischemic cardiomyopathy • Monomorphic VT is common with prior large myocardial infarction • Polymorphic VT and ventricular fibrillation (VF) should prompt ischemia evaluation 3.  Nonischemic cardiomyopathy • Fibrotic scars can cause monomorphic VT, especially with sarcoidosis or other inflammatory cardiomyopathies, Chagas’ disease, and familial arrhythmogenic cardiomyopathies such as Lamin A/C genetic cardiomyopathy • Polymorphic VT and VF can also occur independently or related to degeneration of monomorphic VT 4.  Arrhythmogenic RV cardiomyopathy • Monomorphic VT usually of RV origin (left bundle branch morphology in V1) • Polymorphic VT and VF can occur independently or related to degeneration of monomorphic VT 5.  Repaired tetralogy of Fallot • Monomorphic VT of RV origin (usually left bundle branch morphology in V1) 6.  Hypertrophic cardiomyopathy • Polymorphic VT or ventricular fibrillation • Less commonly, monomorphic VT associated with myocardial scars, particularly apical aneurysms 7.  Genetic arrhythmia syndromes A. Long QT syndrome • Torsades des pointes VT B. Brugada syndrome • Ventricular fibrillation episodes, often nocturnal C. Catecholaminergic polymorphic VT • Polymorphic VT or bidirectional VT D. Short QT and early repolarization syndromes • Ventricular fibrillation 8.  Idiopathic polymorphic VT or ventricular fibrillation • Usually triggered by recurrent premature ventricular contractions; the most common site of origin is the left posterior fascicle (right bundle branch block/left anterior fascicular block pattern) aberrant conduction, supraventricular tachycardias conducted to the ventricles over an accessory pathway, and rapid cardiac pacing, appro­ priate or inappropriate, in a patient with a ventricular pacemaker or defibrillator. In the presence of known heart disease, VT is the most likely diagnosis of a wide QRS tachycardia, independent of QRS mor­ phology. When left ventricular (LV) function is depressed or there is evidence of structural myocardial disease, scar-related reentry is the most likely cause of sustained monomorphic VT. Scars are suggested by pathologic Q waves on the electrocardiogram (ECG), segmental LV or right ventricular wall motion abnormalities on echocardiogram or nuclear imaging, and areas of delayed gadolinium enhancement during magnetic resonance imaging (MRI). Hemodynamic stability during the arrhythmia does not help dis­ tinguish between VT and other mechanisms of wide-complex tachy­ cardia. A number of ECG criteria have been evaluated to distinguish supraventricular tachycardia with aberrancy from VT. The presence of

VT versus Supraventricular Tachycardia (SVT) with Aberrancy Yes AV dissociation VT No aVR aVR Yes VT aVR = R or Rs No V1 V2 V3 V4 V5 V6 Yes No rS or Rs in any of V1 to V6 VT No V1 V2 V3 V4 V5 V6 Possible SVT with aberrancy VT still possible FIGURE 261-1  Algorithm for differentiation of ventricular tachycardia (VT) from supraventricular tachycardia with aberration. AV, atrioventricular. ventriculoatrial (VA) dissociation is a reliable marker for VT, provided the atrial rate is slower than the ventricular rate. Sometimes, P waves can be difficult to define, and the VA relationship cannot be assessed in a patient with an ongoing atrial arrhythmia such as atrial fibrillation. A P wave following each QRS does not exclude VT because 1:1 conduc­ tion from ventricle to atrium can occur. A monophasic R wave or Rs complex in aVR or concordance from V1 to V6 of monophasic R or

S waves is also relatively specific for VT (Fig. 261-1). A number of other QRS morphology criteria have also been described, but all have limitations and are not very reliable in patients with severe heart disease. In patients with known bundle branch block, the same QRS morphology during tachycardia as during sinus rhythm suggests supraventricular tachycardia rather than VT, but even this is not abso­ lutely reliable. Patients with reentry involving the bundle branches of the Purkinje system can have a VT morphology that resembles their native QRS in sinus rhythm. An electrophysiologic study is sometimes required for definitive diagnosis. Occasionally, noise and movement artifacts on telemetry recordings can simulate VT, and prompt recogni­ tion of this can avoid unnecessary tests and interventions. TREATMENT AND PROGNOSIS Initial management follows Advanced Cardiac Life Support (ACLS) guidelines. If hypotension, impaired consciousness, or pulmonary edema is present, QRS synchronous electrical cardioversion should be performed, ideally after sedation if the patient is conscious. For stable tachycardia, a trial of adenosine is reasonable as this may clarify a supraventricular tachycardia with aberrancy. Adenosine should not be used if the patient has a heart transplant or if the wide-complex rhythm is irregular or unstable. Intravenous amiodarone is the drug of choice if heart disease is present. Following restoration of sinus rhythm, hospitalization and evaluation to define underlying heart disease are required. Assessment of cardiac biomarkers for evidence of myocar­ dial infarction (MI) is appropriate, but acute MI is rarely a cause of sustained monomorphic VT. Elevations in troponin or creatine kinase (CK)-MB are more likely to indicate myocardial injury that is second­ ary to hypotension and ischemia from fixed coronary lesions during the VT rather than an acute coronary event. Subsequent management is determined by the underlying heart disease and frequency of VT. If VT recurs frequently or is incessant, administration of antiarrhythmic medications or catheter ablation may be required to restore stabil­ ity. More commonly, sustained monomorphic VT occurs as a single episode but with a high risk of recurrence. Implantable cardioverterdefibrillators (ICDs) are warranted for secondary prevention of sud­ den death in patients who present with sustained VT associated with structural heart disease (Fig. 261-2).

aVR I aVL II aVF III V1 V5 FIGURE 261-2  Monomorphic ventricular tachycardia in a patient with prior myocardial infarction. Shown is a wide-complex tachycardia. Complexes 3, 6, 9, and 18 are narrower and are examples of fusion beats, proving ventriculoatrial (VA) dissociation and proving that this rhythm is in fact ventricular tachycardia. SUSTAINED MONOMORPHIC VT IN SPECIFIC DISEASES ■ ■CORONARY ARTERY DISEASE Patients who present with sustained monomorphic VT associated with coronary artery disease typically have a history of a remote prior large MI. Patients typically present years after the acute infarct with a remod­ eled ventricle and markedly depressed LV function. Even when there is biomarker evidence of acute MI, a preexisting scar from previous MI should be suspected as the cause of the VT. Infarct scars provide a durable substrate for sustained VT, and up to 70% of patients have a recurrence of the arrhythmia within 2 years. Scar-related reentry is not usually dependent on recurrent acute myocardial ischemia, so coro­ nary revascularization is unlikely to prevent recurrent VT, although it may be appropriate for treatment of angina or other indications. Depressed ventricular function, which is a risk factor for sudden death, is usually present. Implantation of an ICD is clearly indicated for sec­ ondary prevention provided that there is a reasonable expectation of survival for 1 year with acceptable functional status. Compared with antiarrhythmic drug therapy, ICDs reduce annual mortality from 12.3 to 8.8% and lower arrhythmic deaths by 50% in patients with hemody­ namically significant sustained VT or a history of cardiac arrest. Anti­ arrhythmic drugs may have some utility for palliation of VT symptoms and prevention of ICD therapies, such as shocks and antitachycardia pacing; however, without an ICD, these drugs do not improve survival. Following ICD implantation, patients with depressed ejection frac­ tion remain at risk for clinical heart failure, recurrent ischemic events, and recurrent VT, with a 5-year mortality that exceeds 30%. Attention to guideline-directed medical therapy for patients with heart failure and coronary artery disease, including β-adrenergic blocking agents and angiotensin-converting enzyme inhibitors, is important. ICD therapies, whether shocks or antitachycardia pacing, constitute an adverse event for the patient and are associated with increased rates of heart failure, mortality, and psychological stress. For this reason, recurrent VT episodes in patients with an ICD warrant treatment with medications or catheter ablation. In a randomized study of catheter ablation versus escalated medical therapy (Ventricular Tachycardia Ablation versus Escalation of Antiarrhythmic Drugs [VANISH]), patients receiving catheter ablation fared better than those receiving increasing doses of antiarrhythmic drugs, in particular, amiodarone.

V1 V4 CHAPTER 261 V2 V5 Sustained Ventricular Tachycardia V3 V6 Another randomized trial (BERLIN VT) examined a preventative versus deferred ablation strategy in patients who had not yet failed an antiarrhythmic drug. This trial was stopped early for futility, with more procedural complications but fewer VT episodes in the catheter ablation group. For this reason, the most recent consensus statement most strongly recommends catheter ablation for patients with ischemic cardiomyopathy failing or intolerant of antiarrhythmic drugs but also allows for consideration of catheter ablation when long-term therapy with an antiarrhythmic drug (such as amiodarone, which has signifi­ cant long-term toxicities) is not desired (Table 261-2). ■ ■NONISCHEMIC DILATED CARDIOMYOPATHY Sustained monomorphic VT associated with nonischemic cardiomy­ opathy is usually due to scar-related reentry. The etiology of scar is often unclear, but progressive replacement fibrosis is the likely cause. Patients with nonischemic cardiomyopathy (NICM) have historically been presumed to have a postviral etiology, although increasingly, genetic causes are found in many. Inflammatory etiologies (myocar­ ditis, sarcoidosis) are also increasingly appreciated. On cardiac MRI, scars are detectable as areas of delayed gadolinium enhancement and are more often intramural (Fig. 261-3) or subepicardial in location as compared with patients with prior MI. Scars that cause VT are often located adjacent to a valve annulus and can occur in either ventricle. Any cardiomyopathic process can cause scars and VT, but cardiac sarcoidosis, Chagas’ disease, and cardiomyopathy due to Lamin A/C mutations are particularly associated with monomorphic VT. An ICD is indicated for patients with a history of sustained VT, syncope, or New York Heart Association class II or III heart failure symptoms, with additional drugs or catheter ablation for control of recurrent VT. In addition, for patients with malignant familial arrhythmogenic cardiomyopathies, an ICD may be considered earlier in the clinical course. Overall, there are fewer studies of catheter ablation for VT in NICM. Reported success rates are lower than VT ablation in ischemic cardiomyopathy in most observational series. Additionally, inability to reproduce the clinical VT at ablation attempts and epicardial and intra­ mural reentry circuits are important causes of failure of endocardial VT ablation in NICM. Imaging with MRI or computed tomography (CT) scans with late contrast administration to define areas of fibrosis can be useful to guide ablation (Table 261-2).

TABLE 261-2  Summary of Randomized Controlled Studies Assessing Catheter Ablation of Ventricular Tachycardia in Patients with Structural Heart Disease SAMPLE SIZE STUDY, YEAR STUDY PERIOD FOLLOW-UP (months) CA OC INCLUSION CRITERIA CONTROL ARM SMASH-VT,

2000–2006

Prior MI, ICD for VF or unstable VT Medical therapy 67 ± 10

32 ± 9 22.5 ± 5.5 PART 6 Disorders of the Cardiovascular System VTACH, 2010 2002–2006

Prior MI, LVEF ≤50%, ICD indicated for stable VT CALYPSO,

2012–2014

IHD, ≥1 ICD shock or ≥3 ATP therapies for monomorphic VT in last 6 months VANISH,

2009–2015

Prior MI, ICD in situ, ≥1 episode of VT while on a class I/III AAD SMS, 2017 2002–2010

IHD, LVEF ≤40%, unstable VT ICD + medical therapy 67 ± 8

31 ± 7 27.0 ± 13.2 BERLIN-VT,

2015–2018

Prior MI, LVEF 30–50%, ICD in situ for life-threatening VT PARTITA,

2012–2021

Cardiomyopathy, had first ICD shock SURVIVE-VT,

2010–2017

Prior MI, sustained VT causing ICD shock or syncope PAUSE-SCD,

2015–2020

LVEF <50%, ICD indicated for secondary prevention or inducible monomorphic VT on EPS Abbreviations: AAD, antiarrhythmic drug; ATP, antitachycardia pacing; BERLIN VT, Preventive Ablation of Ventricular Tachycardia in Patients with Myocardial Infarction; CA, catheter ablation; CALYPSO, Catheter Ablation for Ventricular Tachycardia in Patients with an Implantable Cardioverter Defibrillator; EPS, electrophysiology study; ICD, implantable cardioverter-defibrillator; ICM, ischemic cardiomyopathy; IHD, ischemic heart disease; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NR, not reported; OC, other care; PARTITA, Does Timing of VT Ablation Affect Prognosis in Patients with an Implantable Cardioverter-Defibrillator?; PAUSE-SCD, Pan-Asia United States Prevention of Sudden Cardiac Death Catheter Ablation Trial; SMASH VT, Substrate Mapping and Ablation in Sinus Rhythm to Halt Ventricular Tachycardia; SMS, Substrate Modification Study; SURVIVE-VT, Substrate Ablation Versus Antiarrhythmic Drug Therapy for Symptomatic Ventricular Tachycardia; VANISH, Ventricular Tachycardia Ablation Versus Escalated Antiarrhythmic Drug Therapy in Ischemic Heart Disease; VF, ventricular fibrillation; VT, ventricular tachycardia; VTACH, Ventricular Tachycardia Ablation in Coronary Heart Disease. Source: Reproduced with permission from SA Virk, S Kumar: Catheter ablation of ventricular tachycardia in patients with structural heart disease: A meta-analysis. JACC Clin Electrophysiol 9: 255; 2023. ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare genetic disorder most commonly due to mutations in genes encoding for cardiac desmosomal proteins; however, it is increasingly appreciated FIGURE 261-3  Cardiac magnetic resonance image (MRI). Shown is an MRI of the heart with the right ventricle on the left and the left ventricle on the right. Between the ventricles (arrows) is a stripe of late gadolinium enhancement, indicating midmyocardial fibrosis in the interventricular septum. This type of scar pattern is often seen in patients with nonischemic cardiomyopathies and ventricular tachycardia.

AGE (years) MALE (%) ICM (%) BASELINE LVEF (%) ICD + medical therapy 66 ± 8

34 ± 9 22.5 ± 9 AAD therapy 63 ± NR

30 ± NR

Escalation of AAD therapy 69 ± 8

31 ± 11 27.9 ± 17.1 Medical therapy until third ICD shock (then VT ablation) 66 ± 10

41 ± 6 13.2 ± 9.5 Medical therapy 68 ± 9

32 ± 9 24.2 (8.5–24.4) AAD therapy 70 ± 9

33 ± 11

ICD + medical therapy 55 (46–64)

40 (30–49) 31.3 (20.1–40) that other cardiomyopathic processes may produce a similar pheno­ type. Approximately 50% of patients have a familial transmission with autosomal dominant inheritance. A less common, autosomal recessive form is classically associated with cardiocutaneous syndromes that include Naxos disease and Carvajal syndrome. The former is most com­ monly related to mutations in plakophilin-2 and plakoglobin, while the latter is most commonly due to a mutation in desmoplakin. Patients are typically diagnosed between the second and fifth decades with pal­ pitations, syncope, or cardiac arrest owing to sustained monomorphic VT, although polymorphic VT can also occur. Fibrosis and fibrofatty replacement most commonly involve the right ventricular myocardium and provide the substrate for reentrant VT that usually has a left bundle branch block–like configuration in ECG lead V1, consistent with the right ventricular origin, and can resemble idiopathic VT. The sinus rhythm ECG suggests the disease in >85% of patients, most often show­ ing T-wave inversions in V1–V3. Delayed activation of the right ventricle may cause a widened QRS (>110 ms) in the right precordial leads (V1–V3) and a prolonged S-wave upstroke in those leads and, occasion­ ally, a notched deflection at the end of the QRS known as an epsilon wave. Cardiac imaging may show right ventricular enlargement or areas of abnormal motion or reveal areas of scar on contrast-enhanced MRI. LV involvement can occur and can occasionally precede manifest right ventricular disease. Clinical heart failure is rare except in late stages, and survival to advanced age can be anticipated provided that VT can be controlled. An ICD is recommended. When VT is exercise induced, it may respond to β-adrenergic blockers and limiting exercise. Sotalol, flecainide, and amiodarone have been used to reduce ventricu­ lar arrhythmias. Catheter ablation prevents or reduces VT episodes in 70% of patients, but epicardial mapping and ablation are often required. ADULT CONGENITAL HEART DISEASE Among all patients with adult congenital heart disease (ACHD), sus­ tained monomorphic VT is quite rare. However, the most common substrate for sustained VT is seen in those with repairs of a ventricular

septal defect, in particular tetralogy of Fallot (TOF). The prevalence of VT after TOF repair is estimated to be 3–14%, and risk of sudden car­ diac death may reach as high as 1% per year in adulthood by the fourth or fifth decade of life. The greatest risk for ventricular arrhythmias is posed via two potential mechanisms: (1) those who have undergone repair involving a ventriculotomy and (2) those with long-standing hemodynamic overload causing ventricular dysfunction and/or hyper­ trophy independent of surgical incisions. Monomorphic VT in TOF most commonly occurs in stereotyped circuits due to reentry around areas of surgically created scar in the right ventricle. Factors associated with VT risk include age >5 years at the time of repair, high-grade ventricular ectopy, inducible VT on an electrophysiologic study, abnormal right ventricular hemodynamics, and sinus rhythm QRS duration >180 ms. An ICD is usually warranted for patients who have a spontaneous episode of VT, but ICDs are also considered for patients with multiple risk factors. Catheter ablation or antiarrhythmic drug therapy is used to control recurrent episodes. BUNDLE BRANCH REENTRY VT Reentry through the Purkinje system occurs in ~5% of patients with monomorphic VT in the presence of structural heart disease. The reentry circuit typically revolves retrograde via the left bundle and anterograde down the right bundle, thereby producing VT that has a left bundle branch block configuration. The VT QRS morphology may closely resemble the QRS morphology in sinus rhythm. Catheter abla­ tion of the right bundle branch abolishes this VT. Bundle branch reen­ try is usually associated with severe underlying heart disease. Other scar-related VTs are often present and often require additional therapy. IDIOPATHIC MONOMORPHIC VT Idiopathic VT in patients without structural heart disease usually pres­ ents with palpitations, lightheadedness, and, rarely, syncope. Episodes can be provoked either by sympathetic stimulation or acute withdrawal of sympathetic tone, as in the immediate postexercise period. The QRS morphology of the arrhythmia suggests the diagnosis (see below). The sinus rhythm ECG is normal. Family history suggests no familial cardiomyopathy or sudden death. Cardiac imaging, including echocar­ diography and cardiac MRI, shows normal ventricular function and no evidence of ventricular scar. Occasionally, a patient with structural heart disease is found to have concomitant idiopathic VT unrelated to I II III aVR aVL aVF V1 V2 V3 V4 V5 V6 FIGURE 261-4  Idiopathic monomorphic ventricular tachycardia (VT). This is a 12-lead electrocardiogram showing the onset of idiopathic VT in a young patient without structural heart disease. The VT has a left bundle branch block configuration in V1 and an inferiorly directed axis consistent with an outflow tract origin. Note that the narrow (normal sinus) beats have a normal QRS configuration, consistent with the patient’s lack of structural heart disease.

the structural disease, in which case, the underlying disease should be treated as per the guidelines, separate from the VT. Repeated bursts of nonsustained VT, which may occur incessantly, are known as repetitive monomorphic VT and can cause a tachycardia-induced cardiomyopa­ thy with depressed ventricular function that recovers after suppression of the arrhythmia. Sudden death in isolated idiopathic VT is rare, and an ICD is not recommended.

CHAPTER 261 Outflow tract VTs originate from a focus near the pulmonic or aortic valve annuli, usually with features consistent with triggered auto­ maticity. The arrhythmia may present with sustained VT, nonsustained VT, or premature ventricular contractions (PVCs). Most originate in the right ventricular outflow tract, which gives rise to VT that has a left bundle branch block configuration in V1 and an axis that is directed inferiorly, with tall R waves in II, III, and aVF. Idiopathic VT can also arise in the LV outflow tract or in sleeves of myocardium that extend along the aortic root. LV origin is suspected when lead V1 or V2 has prominent R waves. Although this typical outflow tract QRS morphol­ ogy favors idiopathic VT, some cardiomyopathies, notably ARVC, can cause PVCs or VT from this region. Excluding these diseases is an initial focus of evaluation (Fig. 261-4). Sustained Ventricular Tachycardia LV fascicular VT, sometimes referred to as Belhassen’s VT or verapamil-sensitive VT, is the second most common form of idiopathic VT after outflow tract VTs. It often presents with sustained VT that has a right bundle branch block–like configuration and is negative in the inferior leads. It is often exercise induced and occurs more often in men than women. The mechanism was originally thought to be focal but has been demonstrated to be due to a small reentry circuit in or near the septal ramifications of the LV Purkinje system. There can be an LV false tendon associated with this rhythm. Despite its reentrant nature, the course of this type of VT is typically benign. Other sites of origin for idiopathic VT exist, including papillary muscles, mitral and tricuspid valve annuli, and the moderator band in the right ventricle. Even focal sites from the epicardial surface have been described. The presence of VT from these more unusual sites should prompt even more careful assessment for structural heart disease. MANAGEMENT OF IDIOPATHIC VT Treatment is required for symptoms or when frequent or incessant arrhythmias depress ventricular function. Symptoms can be controlled with medications including beta blockers, calcium channel blockers,

24 - 263 Electrical Storm and Incessant Ventricular Tachycardia

263 Electrical Storm and Incessant Ventricular Tachycardia

■ ■FURTHER READING Callans DJ: Josephson’s Clinical Cardiac Electrophysiology: Techniques

and Interpretations, 7th ed. Philadelphia, Wolters Kluwer, 2024. Jalife J, Stevenson W (eds): Zipes and Jalife’s Cardiac Electrophysiol­ ogy: From Cell to Bedside, 8th ed. Philadelphia, Elsevier, 2022. Zeppenfeld K et al: 2022 ESC Guidelines for the management of PART 6 Disorders of the Cardiovascular System patients with ventricular arrhythmias and the prevention of sudden cardiac death: Developed by 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) Endorsed by the Association for European Paediatric and Congenital Cardiol­ ogy (AEPC). Eur Heart J 43:3997, 2022. William H. Sauer, Usha B. Tedrow

Electrical Storm and

Incessant Ventricular

Tachycardia ELECTRICAL STORM Electrical storm or ventricular tachycardia (VT) storm refers to the occurrence of three or more episodes of VT or ventricular fibrillation (VF) within 24 h requiring intervention for termination. Although this disorder is uncommon in the general population, it is of great concern to internists because of its rapid course leading to patient death in the absence of treatment. Therefore, prompt recognition and therapeutic intervention are required. Electrical storms occur in 4% of patients with a primary prevention implantable cardioverter-defibrillator (ICD) but in as many as 20% of patients with a history of known VT or resus­ citated sudden death. Catheter ablation, antiarrhythmic drug therapy, and other adjunctive therapies in electrical storms can be life-saving. INCESSANT VT VT is designated incessant when VT continues to recur shortly after electrical, pharmacologic, or spontaneous conversion to sinus rhythm (Fig. 263-1). Typically, VT is monomorphic. Rarely, a slow incessant monomorphic VT will fail detection by an ICD because it falls outside of the programmed detection parameters. If the arrhythmia is hemo­ dynamically stable acutely, patients can present with symptoms of gradual cardiac decompensation. VT may become incessant due to the proarrhythmic effect of an antiarrhythmic drug such as amiodarone or a sodium channel blocker such as flecainide. Hemodynamic support may be required acutely until the precipitating factors can be corrected. Urgent catheter ablation is often warranted. MANAGEMENT OF PATIENTS PRESENTING WITH ICD SHOCKS A substantial number of patients who receive an ICD can be expected to have an arrhythmia that is terminated by the ICD, either by a shock or antitachycardia pacing. Although this is an expected event, it can VT Antitachycardia pacing terminates VT Spontaneous recurrence of VT II FIGURE 263-1  Example of incessant monomorphic ventricular tachycardia (VT). In the initial portion of this electrocardiogram tracing, monomorphic VT is present. A train of antitachycardia pacing (area bracketed by arrows) that is initiated at the fourth VT complex results in ventricular capture with fusion by the eighth beat and termination of VT at cessation of pacing. The patient has underlying atrial fibrillation. Multifocal premature ventricular contractions are present. VT similar in morphology to the initial VT restarts spontaneously toward the latter part of the trace (arrow).

be a sign of impending instability, deterioration of cardiac function, or emergence of a new arrhythmia and therefore requires evaluation. Interrogation of the ICD is crucial after a patient reports a shock or symptoms of arrhythmia to confirm that the therapy was indeed deliv­ ered for a ventricular arrhythmia and not for lead malfunction or an atrial arrhythmia. After a shock and in the absence of other symptoms to suggest arrhythmia or ischemia, patients have the option of waiting until the next working day or using remote monitoring to transmit device interrogation data to their physician. However, occurrence of multiple ICD shocks constitutes a medical emergency and warrants immediate medical attention by activating the emergency medical system. Patients should never drive to the hospital themselves after receiving a shock from their ICD. Spontaneous arrhythmias, particularly those that are converted with a shock, are associated with a subsequent increased risk of death and hospitalization in patients with depressed ventricular function. The occurrence of an arrhythmia, therefore, warrants a reevaluation for possible decline in cardiac function, emergence of ischemia, or intercurrent illness. If the ICD therapy is appropriate for VT or VF, consideration is given to whether therapy is warranted to reduce further episodes with either antiarrhythmic drug therapy or catheter ablation. Patients who have a rare episode of VT that is appropriately terminated and who have no other evidence of instability may not need any additional therapy, par­ ticularly if the VT is terminated by antitachycardia pacing rather than a shock. Shocks reduce quality of life and can lead to posttraumatic stress disorder. In many patients, the possibility of a shock can be reduced with appropriate ICD programming. Studies have shown that antitachycar­ dia pacing effectively terminates >70% of VT episodes, even when VT is very rapid. Most ICDs can be programmed to attempt overdrive pace termination during capacitor charge. If the arrhythmia then terminates, the shock is aborted. Appropriate programming of antitachycardia pac­ ing is therefore critical for reducing shocks. For patients implanted with ICDs as primary prevention, programming of VF detection zones >220 beats/min significantly reduces unnecessary and inappropriate shocks. Long detection times will also help avoid unnecessary therapies for VT episodes liable to terminate spontaneously. Recurrent symptomatic episodes of VT or VF (Fig. 263-2) warrant specific therapy with antiarrhythmic drugs or ablation as discussed for the specific arrhythmia. The beta blockers sotalol and amiodarone are the most common pharmacologic options. Amiodarone combined with beta blockers is more effective than sotalol or beta blockers alone. It is important to recognize that although VT/VF episodes may rep­ resent a deterioration of clinical status in these patients, interventions to control the arrhythmia itself may have adverse effects on outcome. Most antiarrhythmic drugs have the potential to induce bradycardia to the point of requiring pacing from the ICD that, in itself, may have deleterious effects on ventricular function. Catheter ablation is an important option for patients with monomorphic VT. MANAGEMENT OF THE PATIENT WITH ELECTRICAL STORM Patients should be adequately sedated to allay anxiety and provide pain relief. Recurrent VT/VF is treated using standard Advanced Cardiac Life Support guidelines; treatment includes the use of medications such as beta blockers, amiodarone, and lidocaine with correction of any metabolic abnormalities. Recordings from electrocardiogram (ECG) monitoring or an implanted ICD are important to assess whether VT

6.0 sec 0.0 sec S S S S S S S S S • 6.0 sec 12.0 sec S S • S • S S S S • 18.0 sec 12.0 sec S S S S S S S S S S S S • 18.0 sec 24.0 sec S S S S S S S S S S S S 24.0 sec 30.0 sec • S S S S S S S S S S S S 30.0 sec 36.0 sec • S S S S S S S S S S S 42.0 sec 36.0 sec • S S S S T T T T T T T T T T T T T T T T T T T T T T C 48.0 sec 42.0 sec • S S S S T T T T T T T T T T T T T T T T T T T T T T T 55.6 sec 48.0 sec T T T T • • • T T T S S S S S S S C S 61.6 sec 55.6 sec S S S S S S S S S S S S S 113.1 sec 61.6 sec S S S S S S S T T T T T T T T T T T T 120.7 sec 113.1 sec T T T T T T T T T T T T T T T T T C S S S S 120.7 sec 124.3 sec S S S S S FIGURE 263-2  Multiple implantable cardioverter-defibrillator (ICD) shocks from a subcutaneous ICD. Shown is a tracing from a patient with a subcutaneous ICD with recurrent episodes of ventricular fibrillation. The first five lines show gradually increasing amounts of ventricular ectopy and then ventricular fibrillation on the sixth line, which is terminated by a shock (thunderbolt) on the ninth line. The sequence repeats itself, and the patient receives a second shock that successfully terminates the arrhythmia.

CHAPTER 263 Electrical Storm and Incessant Ventricular Tachycardia

Electrical storm treatments Speed of Deployment Stabilize rhythm Relieve triggers Reduce sympathetic drive • Electrolyte management • Volume removal • Coronary revascularization • Defibrillation • Amiodarone • Lidocaine Rapid PART 6 Disorders of the Cardiovascular System • Overdrive pacing • Mechanical support (ECMO/IABP) • Quinidine • Ranolazine • Procainamide • Catheter ablation • Consideration of biopsy/anti- inflammatory therapies Delayed FIGURE 263-3  Global strategy for managing electrical storm. Shown are considerations for stabilization of electrical storm with medication strategies and procedures. ECMO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon pump. is monomorphic or polymorphic. The initiation and termination of tachycardia in the stored ICD electrograms may also suggest possible precipitating or aggravating factors. Sedation or general anesthesia should be considered for suppression of recurrent hemodynamically unstable ventricular arrhythmia. Percutaneous stellate ganglion block and upper thoracic epidural anesthesia may reduce cardiac sympa­ thetic outflow and have been used to restore stability in some patients. Rarely, mechanical ventricular support with extracorporeal membrane oxygenation, percutaneous left ventricular assist device, or intra-aortic balloon pump may be considered (Fig. 263-3). In addition to this global strategy of stabilizing the heart rhythm, reducing sympathetic drive, and relieving any triggering mechanisms for the management of electrical storm, there are some specific thera­ pies to be considered for patients with unique electrophysiologic sub­ strate (Fig. 263-4). Electrical Storm (>3 episodes of VT/VF in 24 h) MMVT PMVT/VF Long QT Normal QT/ ischemic PVC-initiated Brugada Inflammatory Electrolyte repletion Magnesium Pacing Isoproterenol Lidocaine SGB Beta blockade Amiodarone Lidocaine IABP Revascularization Beta blockade Amiodarone Lidocaine Sedation ECMO SGB Catheter ablation FIGURE 263-4  Management algorithm for electrical storm. Shown is a suggested strategy for managing electrical storm based on the underlying rhythm and substrate. CCB, calcium channel blocker; DHP, dihydropyridine; ECMO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon pump; MMVT, monomorphic ventricular tachycardia; PMVT, polymorphic ventricular tachycardia; PVC, premature ventricular contraction; SGB, stellate ganglion block; VF, ventricular fibrillation; VT, ventricular tachycardia.

■ ■VT/VF IN THE SETTING OF MYOCARDIAL ISCHEMIA Ischemia should be considered especially if polymorphic VT or VF is identified as the primary arrhythmia. If electrical storm is occurring in the setting of an acute coronary syndrome, emergent revascularization and alleviation of anginal symptoms should be attempted. Within the infarcted myocardium, surviving Purkinje cells can exhibit triggered automaticity and lead to recurrent episodes of polymorphic VT/VF requiring frequent car­ dioversions before and after revascularization. Catheter ablation of premature ventricular contractions (PVCs) that are observed to repeatedly initiate the arrhythmia can be effective (Fig. 263-5). • Beta blockers • Sedation and intubation • Anxiolytics • Stellate ganglion block (SGB) • Cardiac surgical sympathetic denervation ■ ■PVC-INITIATED POLYMORPHIC VT/VF Similar to the post–myocardial infarction electrical storm, patients without myocardial infarction or ischemia can have PVC-initiated polymorphic VT/VF storm. This idiopathic form of VF is usually caused by triggering PVCs originating from fascicular tissue or papillary muscles. Often, the ventricular ectopy is from scarred myocardial tissue detected on cardiac magnetic resonance imaging. Catheter ablation is indicated for this condition when antiarrhythmic medication is ineffective. ■ ■ACQUIRED OR CONGENITAL LONG QT SYNDROME If QT prolongation causing torsades des pointes (TdP) is possible, intra­ venous magnesium should be administered for its immediate effect on repolarization. In addition, electrolyte repletion, especially potassium, should be aggressively pursued. Increasing the heart rate can some­ times normalize the QT interval, and thus, pharmacologic or pacing support should be considered. Isoproterenol can be used to increase a patient’s sinus rate, but there is the possibility of increased ectopy with high doses of isoproterenol possibly exacerbating ventricular Beta blockade Amiodarone Lidocaine SGB Sedation Catheter ablation Quinidine Non-DHP CCB Isoproterenol Catheter ablation Steroid pulse Amiodarone SGB

26 - 264 Heart Failure- Pathophysiology and Diagnosis

264 Heart Failure: Pathophysiology and Diagnosis

N V V N V V V V V V V V V V V V V V V V V V V V V V V V V V N N V V N N V V V N V V V V V V V V V V V V V V V T 1mV Scale (0.0/40.0/80.0/120.0) FIGURE 263-5  Premature ventricular contraction (PVC)–triggered ventricular fibrillation (VF) after myocardial infarction electrical storm. Shown is a series of monitoring strips from a patient with VF occurring in a PVC-triggered fashion after myocardial infarction. A single electrocardiogram lead and the blood pressure tracings are shown. The triggering PVCs are indicated with red arrows. The VF results in prompt hemodynamic collapse as evidenced by the blood pressure tracing. arrhythmias. Although lidocaine can reduce the QT interval, other antiarrhythmic agents should be avoided because of their effect on repolarization. ■ ■BRUGADA SYNDROME If the QT interval is not prolonged and a Brugada pattern of Rsr′ with ST elevation in leads V1 or V2 is seen on resting ECG, administration of quinidine and/or isoproterenol may abolish recurrent polymorphic VT/VF episodes. Nondihydropyridine calcium channel blockers and isoproterenol have also been used to reduce arrhythmic events. An epicardial substrate-based catheter ablation over the right ventricular outflow tract has been described as a strategy for drug-refractory ven­ tricular tachyarrhythmias in Brugada syndrome. ■ ■INFLAMMATORY CARDIOMYOPATHY If the patient has no known previous cardiac disease, consider­ ation should be given to an inflammatory myocarditis causing the frequent ventricular arrhythmias. Giant cell myocarditis, cardiac sarcoidosis, and certain viral myocarditis can present with VT/VF storm. An endomyocardial biopsy should be considered to poten­ tially identify new-onset inflammatory cardiomyopathies that may require urgent anti-inflammatory therapy. Once the acute episode is controlled, strategies to prevent recurrent VT or VF should be considered. ■ ■FURTHER READING Callans DJ: Josephson’s Clinical Cardiac Electrophysiology: Techniques and Interpretations, 7th ed. Philadelphia, Wolters Kluwer, 2024. Jalife J, Stevenson W (eds): Zipes and Jalife’s Cardiac Electrophysiol­ ogy: From Cell to Bedside, 8th ed. Philadelphia, Elsevier, 2022. Zeppenfeld K et al: 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: Developed by 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) Endorsed by the Association for European Paediatric and Congenital Cardiol­ ogy (AEPC). Eur Heart J 43:3997, 2022.

CHAPTER 264 Heart Failure: Pathophysiology and Diagnosis
Section 4 Disorders of the Heart,

Muscles, Valves, and Pericardium Michael M. Givertz, Mandeep R. Mehra

Heart Failure:

Pathophysiology and

Diagnosis CLINICAL DEFINITIONS, EPIDEMIOLOGY, AND PHENOTYPES ■ ■DEFINITIONS Heart failure (HF) is a common final pathway for most chronic car­ diovascular diseases including hypertension, coronary artery disease, and valvular heart disease. The American Heart Association/American College of Cardiology/Heart Failure Society (AHA/ACC/HFSA) guideline defines HF as a complex clinical syndrome with symptoms and signs that result from any structural or functional impairment of ventricular filling or ejection of blood. The European Society of Cardiology’s (ESC) definition emphasizes cardinal symptoms (e.g., breathlessness, ankle swelling, and fatigue) that may be accompanied by signs (e.g., elevated jugular venous pressure, pulmonary crackles, and peripheral edema) due to a structural and/or functional abnormal­ ity of the heart that results in elevated intracardiac pressures and/or inadequate cardiac output at rest and/or during exercise. An interna­ tional consensus conference proposed a universal definition of HF that is comprehensive and practical enough to encompass formal disease stages, with universal applicability, prognostic and therapeutic validity, and acceptable sensitivity and specificity (Fig. 264-1). Because some patients present without signs or symptoms of vol­ ume overload, the term heart failure is preferred over the older term

Symptoms and/or signs of HF caused by a structural and/or functional cardiac abnormality PART 6 Disorders of the Cardiovascular System and corroborated by at least one of the following Elevated natriuretic peptide levels or Objective evidence of cardiogenic pulmonary or systemic congestion FIGURE 264-1  Universal definition of heart failure (HF). This contemporary universal definition of HF is simple but conceptually comprehensive, with near universal applicability, prognostic and therapeutic validity, and acceptable sensitivity and specificity. (Reproduced with permission from B Bozkurt et al: Universal Definition and Classification of Heart Failure. J Card Fail 27:387, 2021.) congestive heart failure. Cardiomyopathy and left ventricular dysfunction are more general terms that describe disorders of myocardial structure and/or function, which may lead to HF. In pathophysiologic terms, HF has been defined as a syndrome characterized by elevated cardiac filling pressure and/or inadequate peripheral oxygen delivery, at rest or during stress, caused by cardiac dysfunction. Chronic heart failure describes patients with longstanding (e.g., months to years) symptoms and/or signs of HF typically treated with medical and device therapy as described in Chap. 265. Such patients are at risk of worsening heart failure, and when the episode resolves, the use of the term remission rather than stable HF is preferred, since these patients continue to retain the risk for further decompensation and sudden death. Acute heart failure, previously termed acute decom­ pensated HF, refers to the rapid onset or worsening of symptoms of HF. Most episodes of acute HF result from worsening of chronic HF, but ~20% are due to new-onset HF that can occur in the setting of acute coronary syndrome, acute valvular dysfunction, hypertensive urgency, or postcardiotomy syndrome. Similarly, acute pulmonary edema in HF describes a clinical scenario in which a patient presents with rapidly worsening signs and symptoms of pulmonary congestion, typically due to severe elevation of left heart filling pressures. ■ ■EPIDEMIOLOGY Global Incidence and Prevalence  HF is a major cause of mor­ bidity and mortality worldwide. An estimated 6.7 million American adults are being treated for HF, with >600,000 new cases diagnosed each year. Globally, it is estimated that 56.2 million people are living with HF with prevalence varying greatly by country. The prevalence of HF increases significantly with age, occurring in 1–2% of the population aged 40–49 years and 10% or more in adults >80 years old (Fig. 264-2). The lifetime risk of HF has increased to 24%; approxi­ mately one in four persons will develop HF in their lifetime. Projec­ tions based on National Health and Nutrition Examination Survey and U.S. Census Bureau data show that the prevalence of HF is expected to rise to 8.5 million Americans by 2030. According to the Nationwide Readmission Database, rates of HF hospitalizations in the United States declined from 2010 to 2014, followed by an increase from 2014 to 2017. HF readmissions after index hospitalization followed a similar trend. While prevalence of HF continues to rise, incidence may be decreasing due to improved recognition and treatment of cardiovascular disease

10.14%

6.96% Percent 4.93% 0.35% 1.73% 20–39 40–49 60–69 70–79 80+ FIGURE 264-2  Heart failure prevalence by age categories. Prevalence of heart failure among U.S. adults ≥20 years of age by age, from the National Health and Nutrition Examination Survey (NHANES), 2017–2020. (Reproduced with permission from B Bozkurt et al: J Card Fail 29:1412, 2023.) and its comorbidities as well as disease prevention. However, as rates of obesity rise globally, these favorable trends in HF incidence may reverse. There are distinct racial and ethnic differences in HF epidemiol­ ogy (Fig. 264-3). In community-based studies, black individuals have the highest risk of developing HF, followed by Hispanic, white, and Chinese Americans. These differences are attributed to disparities in cardiometabolic risk factors (e.g., obesity, hypertension, diabetes) as well as social determinants of health including socioeconomic status and access to health care. Similarly, studies have shown that age-adjusted rates of HF hospitalization are highest for black men, fol­ lowed by black women, white men, and white women. Accurate data on HF prevalence from emerging nations are lacking. As developing nations undergo socioeconomic development, the epidemiology of HF is becoming like that of Western Europe and North America, with coronary artery disease emerging as the most common cause of HF, although hypertension remains the highest population attributable risk for HF occurrence. Morbidity and Mortality  In primary care, the overall 5-year sur­ vival following the diagnosis of HF is ~50%. For patients with severe HF, the 1-year mortality may be as high as 40%. In the United States, one in eight deaths list HF on the death certificate. The majority of these patients die of cardiovascular causes, most commonly progres­ sive HF or sudden cardiac death. A number of clinical and laboratory parameters are independent predictors of mortality (Table 264-1). In a population-based study, hospitalizations were common after an HF diagnosis, with 83% hospitalized at least once, and 67%, 54%, and 43% hospitalized at least two, three, and four times, respectively. Following an HF admission, mortality rates range from 8–14% at 30 days to 26–37% at 1 year to up to 75% at 5 years. Readmission with HF is also common, ranging from 20–25% at 60 days to nearly Incidence of HF in 1,000 Person (Years) 5.0 4.6 Median follow-up: 4.0 years (log-rank test: P=0.01) 4.5 4.0 3.5 3.5 3.0 2.4 2.5 2.0 1.5 1.0 1.0 0.5 Black 0.0 Hispanic White Race/Ethnicity Chinese FIGURE 264-3  Incidence of heart failure (HF). HF incidence rates by race/ethnicity in the United States. (Reproduced with permission from IL Pina et al: J Am Coll Cardiol 78:2589, 2021.)

TABLE 264-1  Independent Predictors of Adverse Outcomes in Heart Failure Clinical Male sex Older age Diabetes mellitus Chronic kidney disease Coronary artery disease Advanced NYHA classa Presence of third heart sound or elevated JVP Decreased exercise capacity Cardiac cachexia Depression Structural Reduced left ventricular ejection fraction Reduced right ventricular ejection fraction Increased ventricular volumes and mass Secondary mitral or tricuspid regurgitation Hemodynamic Elevated pulmonary capillary wedge pressure Reduced cardiac index Reduced peak oxygen consumption Pulmonary hypertension Diastolic dysfunction Biochemical Worsening renal function Hyponatremia Hyperuricemia Elevated cardiac biomarkers (troponin and natriuretic peptides) Elevated plasma neurohormones (norepinephrine, renin, aldosterone, and endothelin-1) Electrophysiologic Tachycardia Widened QRS interval or LBBB Atrial fibrillation Ventricular ectopic activity Ventricular tachycardia and sudden death aSee Table 264-4. Abbreviations: JVP, jugular venous pressure; LBBB, left bundle branch block; NYHA, New York Heart Association. 50% at 6 months. With each subsequent admission, the risk of death rises. There are racial disparities in outcomes, with black patients having higher case–fatality rates compared to white patients. Men have higher age-adjusted mortality rates for death related to HF than women; and in the United States, mortality rate from HF varies by region (highest in Midwest) and population density (highest in rural areas). Despite these statistics, the overall prognosis for patients with HF is improving due to treatment of risk factors and increased use of guideline-directed therapies. Costs  The overall cost of HF care is high (estimated $22.3 billion in the United States in 2018) and rising. Projections for 2030 are that hospitalization costs for HF in the United States will increase to $70 billion. Indirect costs due to lost work and productivity may equal or exceed this amount. The global economic burden of HF in 2012 was estimated at $108 billion, with direct costs accounting for 60%. For pediatric patients with acute HF, inpatient costs are estimated at $1 billion annually and rising. ■ ■PHENOTYPES AND CAUSES HF with Reduced Versus Preserved Ejection Fraction  Epi­ demiologic studies have shown that approximately one-half of patients who develop HF have reduced left ventricular ejection fraction (EF; ≤40%), while the other half have near normal or preserved EF (≥50%) or are classified as having HF with mildly reduced EF (41–49%). Because most patients with HF (regardless of EF) have abnormalities in both systolic and diastolic function, the older terms of systolic heart

TABLE 264-2  Selected Causes of Heart Failure Heart Failure with Reduced Ejection Fraction Coronary artery disease   Myocardial infarction   Myocardial ischemia Nonischemic cardiomyopathy   Infiltrative disorders   Familial disorders   Tachycardia induced CHAPTER 264 Valvular heart disease   Aortic stenosis or regurgitation   Mitral or tricuspid regurgitation Toxic cardiomyopathy   Chemotherapy, immunotherapy   Drugs such as hydroxychloroquine   Alcohol, cocaine Heart Failure: Pathophysiology and Diagnosis
Congenital heart disease   Intracardiac shunts   Repaired defects   Systemic right ventricular failure Chronic lung/pulmonary vascular disease   Cor pulmonale   Pulmonary arterial hypertension Infectious   Chagas   HIV Autoimmune disease   Giant cell myocarditis   Lupus myocarditis Heart Failure with Preserved Ejection Fraction Hypertension Coronary artery disease Valvular heart disease   Aortic stenosis   Mitral stenosis Restrictive cardiomyopathy   Amyloidosis   Sarcoidosis   Hemochromatosis   Glycogen storage disease Hypertrophic cardiomyopathy Radiation therapy Constrictive pericarditis Aging Myocarditis Endomyocardial fibroelastosis Obesity End-stage renal disease High-Output Heart Failure Thyrotoxicosis Arteriovenous shunt Obesity Cirrhosis Anemia Vitamin B deficiency (beriberi) Chronic lung disease Myeloproliferative disorder Abbreviation: HIV, human immunodeficiency virus. failure and diastolic heart failure have been abandoned. Classifying patients based on their EF (HF with reduced EF [HFrEF], HF with mildly reduced EH [HFmrEF], or HF with preserved EF [HFpEF]) is important due to differences in demographics, comorbidities, and response to therapies (Chap. 265). Underlying causes of HF may be associated with reduced or preserved EF and include disorders of the coronary arteries, myocardium, pericardium, heart valves, and great vessels (Table 264-2). The diagnosis of HFpEF is often more challeng­ ing due to the need to rule out noncardiac causes of shortness of breath and/or fluid retention. HF with Recovered EF  A subgroup of patients who are diag­ nosed with HFrEF and treated with guideline-directed therapy have rapid or gradual improvement in EF to the normal range and are referred to as having HF with recovered EF (HFrecEF). Predictors of HFrecEF include younger age, shorter duration of HF, nonischemic eti­ ology, smaller ventricular volumes, and absence of myocardial fibrosis. Specific clinical examples include fulminant myocarditis, stress car­ diomyopathy, peripartum cardiomyopathy, and tachycardia-induced cardiomyopathy, as well as reversible toxin exposures such as chemo­ therapy, immunotherapy, or alcohol. Despite recovery of EF, patients may remain symptomatic due to persistent abnormalities in dia­ stolic function, exercise-induced pulmonary hypertension, or related comorbidities (e.g., obesity). For patients who become asymptomatic, withdrawal of disease-modifying therapy can lead to recurrence of HF symptoms and decrease in EF in up to half of such patients within 6 months. In general, prognosis of patients with HFrecEF is superior to that of patients with either HFrEF or HFpEF.

Men Women Valvular disease Hypertension LVH 7% Diabetes 4% PART 6 Disorders of the Cardiovascular System 6% Angina pectoris 5% 39% 34% Myocardial infarction FIGURE 264-4  Population attributable risk of heart failure (HF) incidence. Based on longitudinal data from the Framingham Heart Study, the risk factors contributing most significantly to the population attributable risk (PAR) of HF in men were previous myocardial infarction and hypertension (in men, both represented equal contributions to HF PAR). In contrast, hypertension was the risk factor accounting for the majority of total PAR in women. In women, previous myocardial infarction accounted for only 13% of the PAR of HF compared with 34% in men. PAR values are developed based on individual calculations for each variable using hazard ratio and prevalence statistics. Thus, they may not, in aggregate, equal 100%. LVH, left ventricular hypertrophy. (Reproduced with permission from Givertz MM and Colucci WS. Heart failure. In: Libby P, editor. Essential Atlas of Cardiovascular Disease. Philadelphia: Current Medicine; 2009.) HF with Mildly Reduced EF (HFmrEF)  Patients with HF and an EF between 40 and 50% represent an intermediate group that are often treated for risk factors and comorbidities and with guidelinedirected medical therapy similar to patients with HFrEF. They are felt to have primarily mild systolic dysfunction, but with features of dia­ stolic dysfunction. They may also include either patients with reduced EF who experience partial improvement in their EF or those with ini­ tially preserved EF who suffer a decline in their systolic performance. The AHA/ACC/HFSA guideline requires evidence of spontaneous or provokable increased left ventricular filling pressures in their classifica­ tion of HFmrEF. Acquired Versus Familial, Congenital, and Other Disorders  In developed countries, coronary artery disease is responsible for approximately two-thirds of the cases of HF, with hypertension as a principal contributor in up to 75% and diabetes mel­ litus in 10–40% (Fig. 264-4). Notably, population attributable risk for hypertension, obesity, diabetes mellitus, and coronary artery disease varies according to sex, race, and ethnicity (Fig. 264-5). While most cardiovascular disease underlying HF is acquired in mid and later life (Chaps. 272, 284, and 288), a wide range of congenital and inherited disorders leading to HF may be diagnosed in children and younger adults. It is currently estimated that 13.3 million people globally and approximately 467,000 U.S. adults are living with congenital heart disease (CHD). In general, adults with CHD who develop HF can be divided into one of three pathophysiologic groups: uncorrected defects with late presentation due to missed diagnosis, nonintervention, or lack of access to care; repaired or palliated defects with late valvular and/or ventricular failure; or failing single-ventricle physiology. In addition, each adult with CHD often presents with unique anatomic and physiologic challenges that affect HF and its treatment. Inherited cardiomyopathies are also increasingly recognized in adults presenting with HF. These include more common disorders, such as hypertrophic and arrhythmogenic cardiomyopathies, and lesser known heart muscle disease related to pathogenic variants in genes encoding lamin and titin, muscular dystrophies, and mitochondrial disease. Most forms of familial cardiomyopathy are inherited in an autosomal domi­ nant fashion. Society guidelines have been published documenting the importance of taking a detailed three-generational family history and indications for (and limitations of) clinical genetic testing. A myriad of systemic diseases with cardiac and extracardiac manifestations (e.g., amyloidosis, sarcoidosis), autoimmune disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis), infectious diseases (e.g., Chagas, HIV), and drug toxicities (chemotherapy, other prescribed or illicit agents) can result in HF with either reduced or preserved EF. In Africa and Asia, rheumatic heart disease remains a major cause of HF, especially in the young. Finally, disorders associated

Valvular disease Hypertension LVH 5% 8% Diabetes 12% 59% Angina pectoris 5% 13% Myocardial infarction with a high cardiac output state (e.g., anemia, thyrotoxicosis) are sel­ dom associated with HF in the absence of underlying structural heart disease. However, diagnosis and treatment of high-output HF will be missed if not considered in the differential diagnosis of patients with predisposing conditions (e.g., severe obesity, severe anemia, cirrhosis, end-stage renal disease with arteriovenous fistula, Paget’s disease, or nutritional deficiency such as beriberi). PATHOPHYSIOLOGY ■ ■PROGRESSIVE DISEASE HFrEF is a progressive disease that typically involves an index event followed by months to years of structural and functional cardiovas­ cular remodeling (Fig. 264-6). The primary event may be sudden in onset, such as an acute myocardial infarction; more gradual, as occurs in the setting of chronic pressure or volume overload (with valvular heart disease); inherited, as seen with genetic cardiomyopathies; or congenital disease in origin. Despite an initial reduction in cardiac performance, patients may be asymptomatic or mildly symptom­ atic for prolonged periods due to the activation of compensatory mechanisms (described below) that ultimately contribute to disease progression. Ventricular Remodeling  As demonstrated in both animal and human studies, different patterns of ventricular remodeling occur in response to excess cardiac workload. Concentric hypertrophy, in which increased mass is out of proportion to chamber volume, effec­ tively reduces wall stress under conditions of pressure overload (e.g., hypertension, aortic stenosis). By contrast, an increase in cavity size or volume (eccentric hypertrophy) occurs in volume overload condi­ tions (e.g., aortic regurgitation, mitral regurgitation). In both forms of remodeling, an increase in ventricular mass is accompanied by changes at the cellular level with myocyte hypertrophy and interstitial fibrosis, at the protein level with alterations in calcium-handling and cytoskel­ etal protein abundance and/or function, and at the molecular level by reexpression of fetal genes (Table 264-3). In addition to cell loss from necrosis, myocytes that are unable to adapt to remodeling stimuli may be triggered to undergo apoptosis or programmed cell death. Further impairment in pump function and increased wall stress in the face of systemic vasoconstriction and loss of neurohormonal adaptation (discussed below) can lead to afterload mismatch. These events feed back on remodeling stimuli, setting up a cycle of deleterious processes resulting in clinical HF. While our understanding of ventricular remodeling in HFrEF is well supported by animal and human studies, the mechanisms underlying HFpEF are less clear. The original descriptions of HFpEF focused on diastolic dysfunction as the primary mediator of HF

60.0 50.0 Population Attributable Risk (%) 40.9 39.0 40.0 30.0 25.8 22.3 20.0 14.8 9.6 12.1 10.1 10.1 10.0 0.0 Overall Caucasian African American Hispanic A

53.6 CHAPTER 264 40.4 38.4 34.0 CHD Diabetes 25.0 Heart Failure: Pathophysiology and Diagnosis
Hypertension Obesity 13.1 12.3 8.2 52.2 45.7 41.1 CHD 25.9 Diabetes Hypertension 19.0 16.5 Obesity 13.5 6.6 4.5 ■ ■MECHANISMS OF DISEASE PROGRESSION Several compensatory mechanisms become activated during the development of HF and contribute to disease progression. Our under­ standing of these mechanisms derives from preclinical studies, in vivo human studies, and randomized clinical trials demonstrating benefit of therapies targeted to attenuating or reversing these biologic processes. Neurohormonal Activation  Activation of the sympathetic ner­ vous system (SNS) and renin-angiotensin-aldosterone system (RAAS) plays a critical role in the development and progression of HF. Initially, neurohormonal activation leads to increases in heart rate, blood pres­ sure, and cardiac contractility and retention of sodium and water to augment preload and maintain cardiac output at rest and during exercise. Over time, these unchecked compensatory responses lead to excessive vasoconstriction and volume retention, electrolyte and renal abnormalities, baroreceptor dysfunction, direct myocardial toxicity, and cardiac arrhythmias. At the tissue level, neurohormonal activation

Remodeling stimuli Wall stress Cytokines Neurohormonal Oxidative stress Increased wall stress PART 6 Disorders of the Cardiovascular System Myocyte hypertrophy Ventricular enlargement Altered interstitial matrix Fetal gene expression Systolic or diastolic dysfunction Altered calcium-handling proteins Myocyte death FIGURE 264-6  Remodeling stimuli in heart failure. Chronic hemodynamic stimuli such as pressure and volume overload lead to ventricular remodeling through increases in myocardial wall stress, inflammatory cytokines, signaling peptides, neuroendocrine signals, and oxidative stress. The myocardium responds with adaptive as well as maladaptive changes. Reexpression of fetal contractile proteins and calcium handling proteins may contribute to impaired contraction and relaxation. Myocytes unable to adapt might be triggered to undergo programmed cell death (apoptosis). The net result of these changes is further impairment in pump function and increased wall stress, thus completing a vicious cycle that leads to further progression of myocardial dysfunction. (Reproduced with permission from Givertz MM and Colucci WS. Heart failure. In: Libby P, editor. Essential Atlas of Cardiovascular Disease. Philadelphia: Current Medicine; 2009.) contributes to remodeling of the heart, blood vessels (atherosclero­ sis), kidneys, and other organs (Fig. 264-7) and the development of symptomatic HF. Landmark clinical trials in HF have demonstrated that antagonism of the RAAS and SNS with renin-angiotensin system inhibitors, mineralocorticoid receptor antagonists, and beta blockers attenuates or reverses ventricular and vascular remodeling and reduces morbidity and mortality (Chap. 265). Vasodilatory Hormones  While RAAS and SNS activation con­ tributes to disease progression in HF, a number of counterregulatory hormones are upregulated and exert beneficial effects on the heart, kidney, and vasculature. These include the natriuretic peptides (atrial TABLE 264-3  Mechanisms of Ventricular Remodeling Changes in Myocyte Biology   Abnormal excitation-contraction coupling and crossbridge interaction   Fetal gene expression (e.g., β-myosin heavy chain)   β-Adrenergic receptor desensitization   Myocyte hypertrophy   Impaired cytoskeletal proteins Changes in Myocardial Composition   Myocyte necrosis, apoptosis, and autophagy   Interstitial and perivascular fibrosis   Matrix degradation Changes in Ventricular Geometry   Ventricular dilation and wall thinning   Increased sphericity and displacement of papillary muscles   Atrioventricular valve regurgitation

natriuretic peptide [ANP] and B-type natriuretic peptide [BNP]), prostaglandins (prostaglandin E1 [PGE1] and prostacyclin [PGI2]), bra­ dykinin, adrenomedullin, and nitric oxide. ANP and BNP are stored and released primarily from the atria and ventricles, respectively, in response to increased stretch or pressure. Beneficial actions are medi­ ated through stimulation of guanylate cyclase and include systemic and pulmonary vasodilation, increased sodium and water excretion, inhibition of renin and aldosterone, and baroreceptor modulation. Bradykinin and natriuretic peptides are inactivated by neprilysin, a membrane-bound peptidase, which explains in part the beneficial clinical impact of angiotensin receptor–neprilysin inhibition in HF (Chap. 265). As described below, natriuretic peptide levels can be used to assist in the diagnosis and risk stratification of patients with HF. Endothelin, Inflammatory Cytokines, and Oxidative Stress  Endothelin is a potent vasoconstrictor peptide with growthpromoting effects that may play an important role in pulmonary hypertension and right ventricular failure. Endothelin is released from a variety of vascular and inflammatory cells within the pulmonary circulation and myocardium in response to increased pressure and has direct deleterious effects on the heart, leading to myocyte hypertrophy and interstitial fibrosis. Unlike RAAS and SNS inhibition, however, endothelin blockade has not been shown to slow the progression of clinical HF due to left ventricular failure but is beneficial for treat­ ment of pulmonary arterial hypertension and consequent right HF (Chap. 294). Other factors that have the potential to cause or contrib­ ute to ventricular remodeling in HF include inflammatory cytokines such as tumor necrosis factor (TNF) α and interleukin (IL) 1β and reactive oxygen species such as superoxide and peroxynitrite. Potential sources of these biologically active substances are the liver and gastro­ intestinal tract, as described below. The role of anti-inflammatory and antioxidant therapies remains unproven. Novel Biologic Targets  Sodium-glucose cotransporter 2 (SGLT-2) is a protein located on the proximal tubule of the kidney that is respon­ sible for reabsorption of up to 90% of filtered glucose. In patients with HF, activity of SGLT-2 contributes to sodium and water reten­ tion, endothelial dysfunction, abnormal myocardial metabolism, and impaired calcium handling. Inhibitors of SGLT-2 were developed for the treatment of type 2 diabetes mellitus to take advantage of their glycosuric and metabolic effects (Chap. 416). Subsequent large clini­ cal trials in cardiovascular disease including HF (with or without dia­ betes mellitus) have demonstrated not only safety of these agents (as required by the U.S. Food and Drug Administration) but also, more importantly, beneficial effects on morbidity and mortality. Whether benefits of SGLT-2 inhibitors in HF are due primarily to diuretic effects or to effects on cardiac and vascular remodeling, proarrhyth­ mia, renal function, and/or metabolic function, inflammation or dys­ regulated autophagy remains to be conclusively determined. Another pathway that is downregulated in HF and contributes to endothelial dysfunction involves cyclic guanosine monophosphate (cGMP). Oral soluble guanylate cyclase stimulators enhance the cGMP pathway and exert beneficial myocardial and vascular effects in experimental and clinical HF. Dyssynchrony and Electrical Instability  In up to one-third of patients with HF, disease progression is associated with prolongation of the QRS interval. Electrical dyssynchrony in the form of left bundle branch block (LBBB) or intraventricular conduction delay results in abnormal ventricular contraction. As discussed in Chap. 265, cor­ rection of electrical dyssynchrony with left or biventricular pacing can improve contractile function, decrease mitral regurgitation, and reverse ventricular remodeling. In patients with symptomatic HFrEF and LBBB on guideline-directed medical therapy, cardiac resynchroni­ zation therapy or LBBB (or His bundle) pacing is suggested to reduce morbidity and mortality. Other forms of electrical instability, including atrial fibrillation with inadequate rate control and frequent prema­ ture ventricular complexes, can also contribute to worsening HF. In addition to the direct impact of tachycardia and irregular rhythm on disease progression, the link between these arrhythmias and cardiac

Baroreceptor dysfunction ↑ Sympathetic nervous system activity ↑ Vasopressin secretion ↓ Limb blood flow ↓ Renal blood flow ↑ Aldosterone secretion ↑ Sodium reabsorption ↑ Water reabsorption ↓ Limb blood flow FIGURE 264-7  Activation of neurohormonal systems in heart failure. Decreased cardiac output in heart failure (HF) results in an “unloading” of high-pressure baroreceptors (circles) in the left ventricle, carotid sinus, and aortic arch, which in turn causes reduced parasympathetic tone. This decrease in afferent inhibition results in a generalized increase in efferent sympathetic tone and nonosmotic release of arginine vasopressin from the pituitary. Vasopressin is a powerful vasoconstrictor that also leads to reabsorption of free water by the kidney. Afferent signals to the central nervous system also activate sympathetic innervation of the heart, kidney, peripheral vasculature, and skeletal muscles. Sympathetic stimulation of the kidney leads to the release of renin, with a resultant increase in circulating levels of angiotensin II and aldosterone. The activation of the renin-angiotensin-aldosterone system promotes salt and water retention, peripheral vasoconstriction, myocyte hypertrophy, cell death, and myocardial fibrosis. Although these neurohormonal mechanisms facilitate short-term adaptation by maintaining blood pressure and organ perfusion, they also result in end-organ changes in the heart and circulation. (Modified from A Nohria et al: Atlas of Heart Failure: Cardiac Function and Dysfunction, 4th ed, WS Colucci [ed]. Philadelphia, Current Medicine Group, 2002, p. 104, and J Hartupee, DL Mann: Nat Rev Cardiol 14:30, 2017.) remodeling (atrial and ventricular) involves increased wall stress, neu­ rohormonal activation, and inflammation. Secondary Mitral Regurgitation  A large number of patients with HFrEF demonstrate evidence of mitral regurgitation. This occurs due to a distortion in the mitral valve apparatus and includes the effects of various pathophysiologic mechanisms including reduced contractile force, which leads to decreased coaptation of the leaflets, a spheri­ cal shape of the ventricle that influences length and function of the chordal-papillary muscle structure, increased dimension of the mitral annulus (and inability of the annulus to contract during systole) with reduced leaflet alignment, and dilation of the posterior wall of the left atrium, which distorts the posterior leaflet of the valve. This worsening in regurgitant volume contributes to progression in HF and adversely influences prognosis. Ensuring that this vicious cycle is interrupted is now a therapeutic target in HF. Some success has been noted by treating the mitral valve using transcatheter techniques when patients are carefully selected after exposure to optimal medical therapy when residual and significant secondary mitral regurgitation persists. Simi­ larly, progressive tricuspid regurgitation can result from and promote adverse right ventricular remodeling. Current interventional studies are underway to assess the impact of transcatheter tricuspid valve repair or replacement in patients with advanced HF. ■ ■CARDIORENAL AND ABDOMINAL INTERACTIONS An important concept underlying the pathophysiology of HF recog­ nizes the systemic nature of disease. Thus, while the primary hemo­ dynamic problem in HF is related to abnormalities in myocardial function (preload, afterload, and contractility), many of the present­ ing signs and symptoms are related to end-organ failure, including dysfunction of the kidneys, liver, and lungs. The heart and kidney interaction increases circulating volume, worsens symptoms of HF, and results in disease progression, referred to as the cardiorenal syndrome. Traditionally, this relationship was deemed to be a consequence of an

↓ Afferent inhibitory signals CHAPTER 264 Vasomotor center Heart Failure: Pathophysiology and Diagnosis
↑ Angiotensin II ↑ Renin secretion impairment in forward flow (cardiac output) leading to a decrease in renal arterial perfusion, worsening renal function, and neurohormonal activation with release of arginine vasopressin, resulting in water and sodium retention. However, evidence has emerged that renal dysfunc­ tion may not be adequately explained simply by arterial underfilling and a decline in cardiac output. Systemic venous congestion in HF with increased backward pressure may be operative in determining the development of the cardiorenal syndrome, and relief of venous conges­ tion is associated with significant improvement in renal function in HF. Increased intraabdominal pressure, as noted in right-sided HF, and a rise in abdominal congestion are correlated with renal dysfunc­ tion in worsening HF. The interaction is not only confined to the renal component of the abdominal compartment but also involves the liver and spleen. The splanchnic veins serve as a blood reservoir and actively function in regulation of cardiac preload during changes in volume status, regulated by transmural pressure changes or mechanisms of systemic sympathetic activation. The liver and spleen participate in determining volume regulation in HF in addition to several additional interactive pathways. Splanchnic congestion results in portal vein dis­ tension and activation of the hepatorenal reflex as well as the spleno­ renal reflex, which induces renal vasoconstriction. Thus, decongestion in HF by diuretic therapy or mechanical means such as ultrafiltration reduces volume, but also facilitates a decrease in pressure within the abdominal compartment, and this combination of therapeutic effect may serve to improve or stabilize renal function in HF. ■ ■GUT CONGESTION, THE MICROBIOME, AND INFLAMMATION As noted above, circulating levels of proinflammatory cytokines are elevated in a number of cardiovascular disease states, including HF, and have been associated with disease progression. While the primary source of inflammation is unknown, emerging evidence suggests that an alteration in gut microbial composition and loss of microbial diver­ sity may play an important role. The potential role of gut congestion

and also altered gut microbial composition may propagate the chronic state of inflammation and immune system dysregulation, eventu­ ally leading to progression of HFrEF. Lipopolysaccharide (LPS) is a gram-negative bacterial cell wall product whose levels are increased in patients with HF in the setting of increased intestinal permeability during periods of congestion, which is reduced with diuretic treatment. LPS is a strong stimulator of the immune system and can lead to dys­ regulated systemic inflammation via macrophage activation. Resulting increases in cytokines such as TNF-α, IL-1, and IL-6 in these pathways can cause progressive loss of cardiac function and also contribute to cardiac cachexia. A mechanistic link has been shown between gut microbe–dependent generation of trimethylamine N-oxide derived from specific dietary nutrients such as choline and carnitine and poor outcomes in patients with both acute and chronic HF. Microbegenerated uremic toxins, such as indoxyl sulfate, may play an impor­ tant role in the development of HF, particularly in interaction with renal insufficiency. Thus, bowel ischemia and/or congestion depending on HF severity may be associated with morphologic and functional alterations in the intestines and result in bacterial endotoxemia and a proinflammatory state.

PART 6 Disorders of the Cardiovascular System ■ ■HIGH-OUTPUT STATES Although most patients with HF, with either reduced or preserved EF, have low or normal cardiac output (CO) accompanied by elevated sys­ temic vascular resistance (SVR), a minority of patients with HF pres­ ent with a high-output state with low SVR (Table 264-2). High-output states by themselves are seldom responsible for HF, but their develop­ ment in the presence of underlying cardiovascular disease can precipi­ tate HF. For example, chronic anemia is associated with high CO when hemoglobin reduces significantly, for example, to a level that is ≤8 g/dL. An increase in vasodilatory metabolites and arteriolar vasodilation in response to decreased oxygen-carrying capacity of the blood in addi­ tion to a decrease in blood viscosity contributes to low SVR. Even when severe, anemia rarely causes high-output HF in the absence of a specific cardiac abnormality such as ischemic or valvular heart disease. Patients with end-stage renal disease (Chap. 323) are at particular risk of developing high-output HF when chronic anemia is exacerbated by increased flow through an arteriovenous fistula. In a recent analysis of the National Readmission Database, the most common causes of highoutput HF included pulmonary disease (19.8%), severe obesity (9.9%), sepsis (9.6%), cirrhosis (8.9%), myelodysplastic syndrome (7.9%), hyperthyroidism (5.5%), and sickle cell disease (3.3%). EVALUATION ■ ■HISTORY Symptoms of Congestion: Pulmonary Versus Systemic  The most common symptoms of HF are related to volume overload with elevation in pulmonary and/or systemic venous pressures. Shortness of breath is a cardinal manifestation of left HF and may arise with increas­ ing severity as exertional dyspnea, orthopnea, paroxysmal nocturnal dyspnea, and dyspnea at rest. Mechanisms of dyspnea include pulmo­ nary venous congestion and transudation of fluid into the interstitium and/or alveoli, leading to decreased lung compliance, increased airway resistance, hypoxemia, and ventilation/perfusion mismatch. Stimula­ tion of juxtacapillary J receptors leading to an increased ventilatory drive and reduced blood flow to respiratory muscles may cause lactic acidosis and a sensation of dyspnea. The New York Heart Associa­ tion (NYHA) functional classification (Table 264-4) may be used to categorize patients based on the amount of effort required to provoke breathlessness. Notably, however, NYHA class does not correlate well with other objective measures of cardiac structure (e.g., left ventricular size, EF) or function (e.g., peak oxygen consumption). Shortness of breath when bending forward (e.g., to put on socks or tie a shoe) has been associated with an increase in cardiac filling pressure, especially in the presence of a low CO, a symptom referred to as “bendopnea.” Orthopnea refers to dyspnea that occurs in the recumbent position and is due to redistribution of fluid from the abdo­ men and lower body into the chest, increased work of breathing due

TABLE 264-4  New York Heart Association Functional Classification FUNCTIONAL CLASS LIMITATION CLINICAL ASSESSMENT Class 1 None Ordinary physical activity does not cause undue fatigue, dyspnea, palpitations, or angina. Class II Mild Comfortable at rest. Ordinary physical activity (e.g., carrying heavy packages) may result in fatigue, dyspnea, palpitations, or angina. Class III Moderate Comfortable at rest. Less than ordinary physical activity (e.g., getting dressed) leads to symptoms. Class IV Severe Symptoms of heart failure or angina are present at rest and worsen with any activity. to decreased lung compliance, and, in patients with ascites or hepato­ megaly, an elevation of the diaphragm. Orthopnea typically occurs in the awake patient within 1–2 min of lying down and may be relieved by raising the head and chest with pillows or an adjustable bed. With more severe HF, patients may end up sleeping in a recliner chair or sitting up, although for some, orthopnea may diminish as symptoms of right HF appear. Orthopnea may be accompanied by nocturnal cough related to pulmonary congestion. Paroxysmal nocturnal dyspnea (PND) refers to episodes of short­ ness of breath that awaken a patient suddenly from sleep with feelings of anxiety and suffocation and require sitting upright for relief. In con­ trast to orthopnea, PND usually occurs after prolonged recumbency, is less predictable in occurrence, and may require 30 min or longer in the upright position for relief. Episodes are often accompanied by coughing and wheezing (so-called cardiac asthma) thought to be due to increased bronchial arterial pressure leading to airway compression and interstitial pulmonary edema causing increased airway resistance. Acute pulmonary edema, due to marked elevation of the pulmonary capillary wedge pressure, is manifested by severe shortness of breath and pink, frothy sputum (Chap. 316). Cheyne-Stokes respiration and central sleep apnea may precipitate episodes of PND in HF and are related to increased sensitivity of the respiratory center to arterial PCO2 and a prolonged circulatory time. Unlike obstructive sleep apnea, which can be treated with positive airway pressure, oral appliance, or surgical therapy, central sleep apnea has no proven therapy beyond the directed treatment of HF (Chap. 308). In contrast to symptoms of left HF due to pulmonary venous con­ gestion, symptoms of right HF are typically related to systemic venous congestion. Weight gain and lower extremity edema may be the initial manifestations followed by a range of gastrointestinal symptoms due to edema of the bowel wall and hepatic congestion. Abdominal bloating, anorexia, and early satiety are common. Some patients develop right upper quadrant pain related to stretching of the hepatic capsule with consequent nausea and vomiting. When these symptoms are associated with abnormal liver function tests (see below), misdiagnosis of bili­ ary tract disease may occur. For patients with refractory right HF, the development of massive edema involving the entire body with recur­ rent pleural effusions and/or ascites is termed anasarca. Symptoms of Reduced Perfusion  Some patients with advanced HF present with symptoms related to decreased CO, sometimes referred to as low-output syndrome. Fatigue and weakness, particularly of the lower extremities, are nonspecific symptoms that can occur with exertion or at rest. Pathophysiology includes reduced blood flow to exercising muscles with endothelial dysfunction and increased SVR from neurohormonal activation. Chronic alterations in skeletal muscle structure and metabolism have also been demonstrated. In older patients with HF and cerebrovascular disease, reduced systemic perfu­ sion may result in mental dullness, depressed affect, and confusion. In addition to low CO, fatigue may be caused by volume depletion, hypo­ natremia, iron deficiency, and medication effect (e.g., beta blockers). Other Symptoms  Patients with HF may present with mood distur­ bances and poor sleep, both of which may be exacerbated by nocturnal

TABLE 264-5  Precipitating Factors in Heart Failure Patient-Related   Excess exertion or emotional stress   Excess fluid and/or sodium intake   Nonadherence with medications   Heavy alcohol use Provider-Related   Use of medications that cause salt and water retention (e.g., NSAIDs)   Prescribed use of medications with negative inotropic properties (e.g., CCBs)   Unrecognized congestion and inadequate use of diuretics Heart Failure–Related   Uncontrolled hypertension   Myocardial ischemia or infarction   Atrial or ventricular arrhythmias   Pulmonary embolism Other Disease States   Systemic infection   Worsening renal or hepatic failure   Hyperthyroidism   Untreated sleep apnea   Anemia or iron deficiency syndrome Abbreviations: CCB, calcium channel blocker; NSAID, nonsteroidal antiinflammatory drug. dyspnea and obstructive and/or central sleep apnea. Nocturia due to improved CO and renal perfusion in the supine position, in addition to delayed diuretic effects, can also contribute to sleep disturbances. Oliguria due to severe reductions in renal blood flow may be a sign of advanced-stage HF. Precipitating Factors  Patients with HF may be asymptomatic or mildly symptomatic either because the cardiac impairment is mild or because compensatory mechanisms help to balance or normalize cardiac function. Symptoms of HF may develop when one or more precipitating factors increase cardiac workload and disrupt the bal­ ance in favor of decompensation. Specific factors may be identified in 50–90% of admissions and can be divided into patient-related factors, provider-related factors, HF-related disease states, and other causes (Table 264-5). Inability to recognize and correct these factors promptly may lead to persistent HF despite adequate treatment. ■ ■PHYSICAL EXAMINATION General Appearance  Most patients with mild-moderate HF will appear well nourished and comfortable at rest. Even patients with more advanced disease may be in no distress after resting for a few minutes but may demonstrate immediate dyspnea with limited exertion such as walking across the room. In contrast, patients with severe HF may need to sit upright and appear anxious, diaphoretic, and dyspneic at rest with pallor due to anemia or duskiness due to low output. Other signs of severe HF include cool extremities and peripheral cyanosis. Cardiac cachexia (Table 264-6), defined partially as unintentional edema-free weight loss of >5% over 12 months, may be observed in patients with longstanding, severe HF as bitemporal or upper body muscle wast­ ing. Contributing factors include poor oral intake due to anorexia, decreased fat absorption due to bowel wall edema, and catabolic/meta­ bolic imbalance from activation of inflammatory cytokines (see above) and dysregulation of the growth hormone–insulin-like growth factor 1 pathway. Rarely, scleral icterus and jaundice may result from severe right HF. Others may demonstrate frailty, which can be diagnosed in the presence of sarcopenia and is exemplified by poor hand-grip strength or severely reduced gait speed. Vital Signs  With new-onset HF, heart rate rises and blood pressure may initially be increased due to sympathetic activation. In patients

TABLE 264-6  Diagnostic Criteria for Cachexia in Adults • Underlying disease and body weight loss ≥5% in ≤12 months (or BMI <20 kg/m2) • Plus at least three of the following five criteria • Decrease in muscle strength • Fatigue • Anorexia • Low fat-free mass index • Abnormal biochemistry: inflammation, anemia, low serum albumin levels CHAPTER 264 Abbreviations: BMI, body mass index. Source: Reproduced with permission from S von Haehling et al: Nat Rev Cardiol 14:323, 2017. Heart Failure: Pathophysiology and Diagnosis
with chronic HF on guideline-directed medical therapy, resting heart rate ideally should be <70–75 beats/min, and blood pressure should be in the normal to low-normal range. An irregular rhythm may be due to atrial fibrillation or flutter or frequent premature atrial or ventricular complexes. Severe HF may be associated with hypotension and narrow pulse pressure along with a rapid, thready pulse. An alternating strong and weak pulse, known as pulsus alternans, is attributed to reduced left ventricular contraction in every other cardiac cycle due to incomplete recovery causing reduction in the left ventricular stroke volume with each alternate beat. Respiratory rate may be normal at rest but may increase on lying down or on minimal exertion. Advanced HF may be associated with periodic breathing or Cheyne-Stokes respirations. The patient is usually unaware of the altered breathing pattern, but family members or friends may become alarmed or attribute this incor­ rectly to anxiety. Oxygen saturation is typically normal on room air unless there is acute pulmonary edema, underlying CHD with shunt­ ing, severe pulmonary arterial hypertension, or concomitant acute or chronic lung disease. A low-grade fever resulting from cytokine activation may occur in severe HF and subside when compensation is restored. Jugular Venous Pulse  Examination of the jugular veins provides an estimate of the right atrial pressure. Typically, the patient is exam­ ined at a 45° angle, and jugular venous pressure (JVP) is quantified in centimeters of water by estimating the height of the venous column of blood above the sternal angle in centimeters and then adding 5. In patients with mild right HF, JVP may be normal at rest (≤8 cm H2O) but increase with compression of the right upper quadrant. Hepato­ jugular reflux is elicited by applying firm continuous pressure over the liver for 15–30 s while observing the neck veins. The patient must breathe normally and not strain during the maneuver. Higher levels of venous pressure approaching the angle of the jaw are common in chronic right HF. If significant tricuspid regurgitation is present, prom­ inent V waves and Y descents may be noted. The abdominojugular test, defined as an increase in right atrial pressure during 10 s of firm mida­ bdominal compression followed by an abrupt drop on pressure release, suggests elevated left-sided filling pressure. Elevation in JVP during inspiration or Kussmaul’s sign may be due to severe biventricular HF and is a marker of poor outcome; it can also be seen with constrictive pericarditis or restrictive cardiomyopathy. Lung Examination  Pulmonary rales result from transudation of fluid from the intravascular space into the alveoli and airways. In gen­ eral, rales are heard at the lung bases, but in severe HF or acute pulmo­ nary edema, they may be heard throughout the lung fields. Wheezing and rhonchi can occur with congestion of the bronchial mucosa and sometimes lead to a misdiagnosis (and inappropriate treatment) of asthma or chronic obstructive pulmonary disease (COPD). Rales may be absent in patients with longstanding HF and chronically elevated pulmonary capillary wedge pressures due to increased lymphatic drainage, which prevents spillage from the interstitium into the alveoli. In biventricular or predominant right HF, bilateral pleural effusions are recognized as dullness to percussion and decreased breath sounds at the bases. When pleural effusions are unilateral, they typically involve the right side.

Cardiac Examination  As discussed above, chronic HF with ven­ tricular remodeling is typically accompanied by cardiac enlargement. The apical impulse is displaced downward and to the left and may be diffuse in dilated cardiomyopathy or sustained in pressure overloaded states such as aortic stenosis. In biventricular or severe right HF, a right ventricular heave or parasternal lift may be palpated along the left sternal border. Uncommonly, a palpable third heart sound may be present. In patients with HFpEF, precordial palpation is often normal. On auscultation, an S3 gallop is most commonly present in patients with volume overload and tachycardia, suggests severe hemodynamic compromise, and carries negative prognostic significance. An S4 gallop is not specific to HF but may be present in patients with HFpEF due to hypertension. Holosystolic murmurs of mitral and tricuspid regurgita­ tion are present in the setting of advanced HF, often in the absence of structural valvular abnormalities. In patients with secondary pulmo­ nary hypertension, a loud pulmonary component of the second heart sound may be heard. Abdomen and Extremities  Hepatomegaly is an early sign of systemic venous congestion. The liver edge may be tender due to stretching of the capsule, but with progression of right HF, tender­ ness may disappear. The liver edge may be pulsatile in patients with tricuspid regurgitation. Longstanding hepatic congestion may result in cardiac cirrhosis with congestive splenomegaly and mild-moderate ascites. The presence of massive ascites should lead to a search for other causes such as constrictive pericarditis or primary liver failure. Dependent lower extremity edema is common in chronic HF and is typically symmetric and pitting. Over time, chronic edema may cause reddening and induration of the skin, become weeping, or lead to cellulitis. Anasarca is used to describe massive, generalized edema involving the legs, sacrum, and abdominal wall. In patients with acute HF or younger adults with chronic HF, lower extremity edema may be absent despite marked systemic venous hypertension. Unilateral lower extremity edema may be due to deep venous thrombosis, prior trauma, or history of vein harvest for bypass surgery. Nonpitting edema that does not respond to increasing doses of diuretics may represent lymphedema that requires alternative diagnostic workup and treatment.

PART 6 Disorders of the Cardiovascular System ■ ■DIAGNOSIS The diagnosis of HF is relatively straightforward when the patient presents with typical signs and symptoms; however, the signs and symptoms of HF are neither specific nor sensitive. It is therefore important for clinicians to have a high index of suspicion for HF, par­ ticularly in patients who are at increased risk, including older patients with underlying cardiovascular disease and those with comorbidities such hypertension, diabetes, and chronic kidney disease. In this set­ ting, additional laboratory testing and imaging should be performed (Fig. 264-8). Routine Laboratories  Standard laboratory testing in patients with HF includes a comprehensive metabolic panel, complete blood count, coagulation studies, and urinalysis. Selected patients should have assessment for diabetes, hyperlipidemia, and thyroid function. Blood urea nitrogen and creatinine levels are often elevated in mod­ erate-severe HF due to reduced renal blood flow and/or increased renal venous pressure. Worsening renal function (Chaps. 321 and 322) due to diuretics, RAAS inhibitors, and noncardiac medications (e.g., nonsteroidal anti-inflammatory drugs) is also common. Pro­ teinuria may be present in the setting of longstanding hypertension or diabetes or suggest an underlying systemic disease. Chronic right HF with congestive hepatomegaly can lead to modest elevations in transaminases, alkaline phosphatase, and bilirubin that should not be confused with biliary tract disease. Marked elevation in transaminases and lactic acid suggests cardiogenic shock with severe low output. In patients with cardiac cirrhosis, hypoalbuminemia may exacerbate fluid accumulation, whereas hyperammonemia contributes to altered mental status. In general, inflammatory markers such as erythrocyte sedimentation rate, C-reactive protein, and uric acid are nonspecific and do not aid in the diagnosis of HF. Other laboratories, including

History and physical examination Laboratories Chest x-ray Electrocardiogram Echocardiogram Determine cause Risk stratification CMR/CT/PET Ischemia/viability imaging Tissue characterization Coronary angiography Angina or ischemia Chest pain or risk factors Screening for: Hemochromatosis Amyloidosis Sarcoidosis Endomyocardial biopsy NYHA functional class Cardiopulmonary exercise test Natriuretic peptide level Ambulatory rhythm monitor Hemodynamics Family history FIGURE 264-8  Initial assessment of patients presenting with heart failure. The initial evaluation starts with a thorough history and physical examination, focusing on detection of comorbidities including hypertension, diabetes, and hyperlipidemia. In addition, identification of valvular heart disease, vascular disease, history of mediastinal radiation, or exposure to cardiotoxins (e.g., chemotherapy, alcohol, or illicit drugs) may help determine underlying cause. A family history of sudden death, heart failure, arrhythmias, or cardiomyopathy is also useful. Routine laboratory evaluation (see text) should also be performed. Chest x-ray is useful to detect cardiomegaly and fluid overload and to rule out pulmonary disease. A 12-lead electrocardiogram should be performed to detect abnormalities of cardiac rhythm and conduction, left ventricular hypertrophy, and evidence of myocardial ischemia or infarction. Two-dimensional echocardiography with Doppler imaging is indicated to assess cardiovascular structure and function and detect abnormalities of the myocardium, heart valves, or pericardium. Further imaging and laboratory studies aimed at identifying a specific cause of cardiomyopathy depend on information obtained from the history and physical examination. In all patients, risk stratification should be performed to assess severity of illness, guide therapy, and provide prognosis to patient and family. CMR, cardiac magnetic resonance imaging; CT, computed tomography; NYHA, New York Heart Association; PET, positron emission tomography. antinuclear antibodies, rheumatoid factor, serum free light chains, serum protein electrophoresis, ferritin, ceruloplasmin, hepatitis C, and HIV, are reserved for targeted testing. Electrolyte abnormalities seen in HF include hyponatremia due to sodium restriction, diuretic therapy, and vasopressin-mediated free water retention. Hyponatremia is a negative prognostic indicator at the time of HF hospitalization and predicts decreased long-term sur­ vival (Table 264-1). Hypokalemia is most often due to thiazide or loop diuretics given without oral potassium supplementation but may also result from increased aldosterone levels. Hyperkalemia may result from marked reductions in glomerular filtration rate and is exacerbated by use of RAAS inhibitors, potassium-sparing diuretics, and potassium supplements (Chap. 265). Hypo- or hyperkalemia may lead to atrial or ventricular arrhythmias. Hypophosphatemia and hypomagnesemia are commonly associated with chronic alcohol use. Anemia is not diagnostic of HF, but when present, it may exacerbate underlying ischemic heart disease or decrease quality of life in patients with HF due to any cause and should be corrected. Rarely, severe

anemia may cause high-output HF typically in the presence of under­ lying cardiovascular disease. The presence of iron deficiency (with or without anemia) is increasingly recognized in patients with chronic HF and has been attributed to decreased gut absorption, impaired hepatic storage, and chronic blood loss. Repletion with IV iron (but not oral iron) results in improved symptoms and exercise capacity and reduced HF hospitalizations, but its effect on survival remains uncertain. Chest X-Ray  Major abnormalities on chest imaging associated with left HF include enlarged cardiac silhouette (cardiothoracic ratio >0.5) and pulmonary venous congestion. Early radiologic signs of acute HF include upper zone venous redistribution and thickening of interlobu­ lar septa. When the pulmonary capillary wedge pressure is moderate to severely elevated, alveolar edema can present as diffuse haziness extending downward toward the lower lung fields. The absence of these findings in patients with chronic HF reflects the increased capacity of the lymphatics to remove interstitial and/or pulmonary fluid. Pleural effusions of varying size and distribution are common in biventricular HF. Chest x-ray can also be used to identify noncardiac causes of dys­ pnea (e.g., pneumonia, COPD). Electrocardiogram  No specific electrocardiographic (ECG) pat­ tern is diagnostic of HF. Rather, the ECG may provide important information regarding presence of underlying cardiac disease. For example, left ventricular hypertrophy and left atrial enlargement suggest HFpEF due to hypertension, aortic stenosis, or hypertrophic cardiomyopathy. The presence of Q waves or infarction is suggestive of ischemic heart disease, whereas Q waves with reduced QRS voltage (pseudo-infarct pattern) may be seen with restrictive or infiltrative cardiomyopathies (e.g., amyloid). Conduction system disease should raise concern for cardiac sarcoid or Chagas cardiomyopathy in the right clinical setting. Paroxysmal or persistent atrial fibrillation is present in up to 40% of patients with chronic HF and is an indication for anticoagulation. Premature ventricular complexes (PVCs) and nonsustained ventricular tachycardia can reflect worsening HF and are markers of increased risk. Conversely, frequent PVCs can cause cardiomyopathy that may be treated successfully with ablation (Chap. 260). Finally, determination of the QRS width and presence of LBBB is used to ascertain whether the patient may benefit from cardiac resynchronization or left bundle branch (or His bundle) pacing therapy. Noninvasive Imaging  Noninvasive cardiac imaging (Chap. 248) is essential for the diagnosis, evaluation, and management of HF. Two-dimensional echocardiography provides an accurate and rapid determination of ventricular size and function and valvular mor­ phology and function and can detect intracavitary thrombi and pericardial effusions. When left ventricular ejection fraction (LVEF) is ≥50%, systolic function is deemed to be normal. Myocardial strain rate imaging using speckle tracking can add incremental value to LVEF and carries prognostic value. Doppler techniques can be used to estimate CO, pulmonary artery pressures, and valve areas, and may detect abnormalities in left ventricular diastolic filling in patients with HFpEF. For patients with end-stage HF, echocardiography is critical for assessment of right ventricular function before and after mechanical circulatory support and heart transplant. Transesopha­ geal echocardiogram (TEE) or cardiac computed tomography (CT) with contrast is indicated to rule out left atrial appendage thrombus prior to cardioversion and can assess aortic or mitral valve pathology in planning for transcatheter valvular replacement or repair. TEE can also be used to assess for endocarditis in patients with bacteremia or acute valvular regurgitation. Cardiac magnetic resonance imaging (CMR) has emerged as a highly accurate and quantitative tool for evaluation of left ventricular mass, volumes, and function and for determining specific causes of HF (e.g., ischemic cardiomyopathy, myocarditis, amyloidosis, hemochro­ matosis). CMR is particularly helpful in defining multiple anatomic and functional abnormalities in adults with CHD. Serial CMR studies can assess ventricular remodeling in response to therapy and are useful in clinical research. For patients who cannot undergo CMR (e.g., due

to implantable devices), cardiac CT is particularly helpful to rule out pericardial disease or left ventricular apical thrombus. Coronary CT angiography has also emerged as a useful noninvasive test to rule out obstructive coronary artery disease as a cause of HF. While limited by availability and cost, cardiac positron emission tomography (PET) plays a role in evaluating the extent of ischemia, infarction, or hibernat­ ing myocardium in patients with coronary artery disease and, in the case of sarcoidosis, can reliably determine the severity and distribution of cardiac inflammation.

CHAPTER 264 Cardiopulmonary Exercise Testing  While not routinely per­ formed in HF, cardiopulmonary exercise testing using a symptomlimited, ramp protocol can provide an objective assessment of peak functional capacity in patients being evaluated for mechanical circu­ latory support or heart transplant (Chap. 271). Several parameters including absolute and percent-predicted peak oxygen consumption (VO2) and ventilatory efficiency (VE; assessed by the VE/VCO2 slope) are independent predictors of survival. Additional data including heart rate and blood pressure response to exercise and exercise-induced arrhythmias can also be assessed. This test may also be useful in defin­ ing the cause of dyspnea when the diagnosis is uncertain. Heart Failure: Pathophysiology and Diagnosis
Biomarkers  Circulating levels of natriuretic peptides are useful, adjunctive tools in the diagnosis of HF. BNP and N-terminal pro-BNP (NT-proBNP) are released from the atria and ventricles in response to increased wall stress. Patients with HFrEF tend to have higher levels than patients with HFpEF, whereas levels may be falsely low in obesity. In ambulatory patients with dyspnea, the measurement of BNP or NTproBNP is useful to support clinical decision-making regarding the diagnosis of HF, especially in the setting of clinical uncertainty or with concomitant lung disease. Moreover, natriuretic peptide levels can be used to establish disease severity and prognosis in chronic HF and may help to guide optimal dosing of medical therapy in stable outpatients. Importantly, many noncardiac factors, including age, female sex, and chronic kidney disease, increase natriuretic peptide levels. Other car­ diovascular diseases including atrial fibrillation, pulmonary embolism, and pulmonary arterial hypertension can also increase BNP levels. Galectin-3 and soluble ST2 (suppression of tumorigenicity 2 protein) are newer biomarkers that have been approved for assessment of prog­ nosis in HF but are not widely used. Biomarkers of renal injury require further study in HF, although use of cystatin C to measure renal func­ tion may be more accurate than a creatinine, which can be influenced by muscle mass. Invasive Studies  In the intensive care setting, assessment of cardiac filling pressures and CO may be necessary to differentiate cardiogenic from noncardiogenic pulmonary edema and manage hemodynamic instability. Placement of a pulmonary artery catheter can be performed safely at the bedside and used to determine response to intravenous vasoactive and diuretic therapy in severe HF. Simultaneous measure­ ment of right and left heart filling pressures in the cardiac catheterization laboratory can be used to distinguish restrictive cardiomyopathy from constrictive pericarditis. Coronary angiography is indicated to exclude ischemic heart disease as an underlying, potentially reversible cause of left ventricular dysfunction. The management of coronary artery disease in the setting of chronic HF is discussed in Chaps. 285–287. If echocardiographic windows are suboptimal, left ventriculography can provide an assessment of left ventricular size and function and severity of mitral regurgitation. The role of right ventricular endomyocardial biopsy in the management of HF and cardiomyopathy remains con­ troversial. Indications include detection of myocarditis (lymphocytic, eosinophilic, sarcoid, or giant cell), diagnosis of cardiac amyloidosis and chemotherapy- or immunotherapy-related left ventricular failure, and screening for cardiac allograft rejection following heart transplant. COMORBIDITIES ■ ■DIABETES Type 2 diabetes mellitus is a risk factor for the development of HF (Table 264-7) and increases the risk of morbidity and mortality in

TABLE 264-7  Mechanisms That Contribute to Development of Heart Failure in Patients with Type 2 Diabetes Mellitus Altered myocardial substrate Abnormal mitochondrial bioenergetics Oxidative stress and inflammation PART 6 Disorders of the Cardiovascular System Lipotoxicity Endoplasmic reticulum stress Impaired insulin signaling β2-Adrenergic receptor signaling G protein–coupled receptor kinase 2 signaling RAAS activation Advanced glycation end products Autophagy Abbreviation: RAAS, renin-angiotensin-aldosterone system. Source: Modified with permission from TA Zelniker: Mechanisms of cardiorenal effects of sodium-glucose cotransporter 2 inhibitors: JACC state-of-the-art review. J Am Coll Cardiol 75:422, 2020. patients with established disease. In ambulatory HF cohorts, the preva­ lence of diabetes ranges from 10 to 40%, with prevalence even higher in patients hospitalized with HF. When the two diseases coexist, patients are at increased risk for adverse outcomes, worse quality of life, and higher costs of care. Recent data from cardiovascular outcomes trials demonstrate that HF is a critical outcome in patients with diabetes and that glucose-lowering therapies can impact morbidity and mortal­ ity. As discussed above, SGLT-2 inhibitors in particular have not only been shown to be safe in patients with HF but can also improve renal function, enhance quality of life, increase LVEF, and decrease the risk of hospitalization and death. Use of other guideline-directed medical therapy is indicated in patients with HF regardless of diabetes status. ■ ■SLEEP APNEA Sleep-disordered breathing is common in HF, with increased incidence of both obstructive sleep apnea and central sleep apnea (Chap. 308). The pathophysiologic link between these disorders has been studied in both animal models and humans and includes increased afterload, decreased preload, intermittent hypoxia, and sympathetic activation. Increase in sympathetic tone can provoke ischemia and arrhythmias and complicate blood pressure management. Approximately one-third of patients with HF and sleep-disordered breathing have central sleep apnea, which is associated with increased mortality independent of other known risk factors. In patients with HFrEF and obstructive sleep apnea, continuous positive airway pressure has been shown to improve quality of life, decrease blood pressure and arrhythmias, and increase LVEF. Unlike obstructive sleep apnea, there is no proven therapy for central sleep apnea, although phrenic or hypoglossal nerve pacing may provide benefit in some cases. ■ ■OBESITY Similar to diabetes, obesity is both a risk factor for the development of HF and highly prevalent in patients with HF. In particular, obesity is common in patients with HFpEF and complicates the assessment of volume status in both ambulatory and inpatient settings. Unlike diabetes, the risk of morbidity and mortality in patients with obesity and HF is complex. The obesity paradox refers to the observation that obese patients diagnosed with HF have a more favorable prognosis than patients with low or even normal body mass index. While weight loss has been shown to improve quality of life and exercise capacity and may contribute to reverse ventricular remodeling in patients with HF, the impact on survival is unknown. Large randomized clinical trials are assessing safety and efficacy of glucagon-like peptide-1 (GLP-1) agonists such as semaglutide in patients with heart failure and obesity. ■ ■DEPRESSION Depression is an independent risk factor for adverse outcomes in HF (Table 264-1), especially in older women. The mechanisms

TABLE 264-8  Differential Diagnosis of Heart Failure SYMPTOM OR SIGN DIFFERENTIAL DIAGNOSIS Dyspnea Chronic lung disease Pulmonary arterial hypertension Neuromuscular disease Anemia Iron-deficiency anemia Edema Venous insufficiency Nephrotic syndrome Deep vein thrombosis Lymphedema Ascites Hepatic cirrhosis Portal vein thrombosis Malignant carcinomatosis Pleural effusion(s) Chronic infection Lung cancer Collagen vascular or rheumatologic disease Jugular venous distension Constrictive pericarditis Pericardial effusion Superior vena cava syndrome underlying this risk remain unknown but may involve neuroendo­ crine dysfunction and systemic inflammation, as well as contribu­ tions from poor sleep, decreased appetite, and adverse effects of medications and alcohol. The AHA recommends screening for depression among patients with cardiovascular disease including HF using validated patient health questionnaires. Selective serotonin reuptake inhibitors are safe for treating depression in HF but do not appear to affect the natural history of disease. The effects of cognitive behavioral therapy and the collaborative care model, as well as newer therapies such as transcranial magnetic stimulation, on HF morbidity and mortality require further study. DIFFERENTIAL DIAGNOSIS Many symptoms and signs suggesting HF may be caused by other conditions (Table 264-8). In a patient with dyspnea, the clinician must distinguish cardiac from pulmonary causes, although the differentiation may be difficult. For example, orthopnea may be a well-established symptom in some patients with severe chronic lung disease. Patients with underlying pulmonary disease may also experi­ ence episodic shortness of breath during sleep that mimics PND. In chronic lung disease, this is usually due to accumulation of tracheo­ bronchial secretions and is relieved by coughing and expectoration, whereas in cardiac disease, the patient has to sit upright. Wheezing caused by bronchoconstriction may be a prominent symptom when left ventricular failure supervenes in individuals with reactive airways disease. Patients with cardiac asthma may be more likely to exhibit diaphoresis and varying degrees of cyanosis compared to patients with bronchial asthma. Differentiating dyspnea related to HF versus pulmonary disease may be impossible when the diseases coexist, a situation that is common in chronically ill older patients with active or prior smoking. Following effective diuresis, pulmonary function tests may help to determine the predominant cause of dyspnea. In ambulatory patients with advanced HF, cardiopulmonary exercise testing can also help to make this distinction. Finally, a very low BNP or NT-proBNP level may be helpful in excluding HF as the cause of dyspnea in nonobese patients. Apart from pulmonary disease, HF needs to be distinguished from conditions in which congestion results from abnormal salt and water retention but in which cardiac structure and function are normal (e.g., acute or chronic kidney disease) and from noncardiac causes of pulmo­ nary edema (e.g., acute respiratory distress syndrome). Non-HF causes of lower extremity edema such as venous insufficiency, lymphedema, and obesity should also be considered.

27 - 265 Heart Failure- Management

265 Heart Failure: Management

■ ■FURTHER READING Aimo A et al: Cardiac remodeling - Part 2: Clinical, imaging and labo­ ratory findings. A review from the Study Group on Biomarkers of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 24:944, 2022. Alcaide P et al: Myocardial inflammation in heart failure with reduced and preserved ejection fraction. Circ Res 134:1752, 2024. Boorsma EM et al: Congestion in heart failure: A contemporary look at physiology, diagnosis and treatment. Nat Rev Cardiol 17:641, 2020. Bozkurt B et al: Heart failure epidemiology and outcomes statistics: A report of the Heart Failure Society of America. J Card Fail 29:1412, 2023. Bozkurt B et al: Universal definition and classification of heart failure: A report of the Heart Failure Society of America, Heart Failure Asso­ ciation of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure. J Card Fail 27:387, 2021. Campbell P et al: Heart failure with preserved ejection fraction: Everything the clinician needs to know. Lancet 403:1083, 2024. Dunlay SM et al: Type 2 diabetes mellitus and heart failure: A scien­ tific statement from the American Heart Association and the Heart Failure Society of America. Circulation 140:e294, 2019. Heidenreich PA et al: 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 145:e895, 2022. Houston BA et al: Right ventricular failure. N Engl J Med 388:1111, 2023. Lam CSP et al: Classification of heart failure according to ejection frac­ tion. J Am Coll Cardiol 77:3217, 2021. Lembo M et al: Obesity: The perfect storm for heart failure. ESC Heart Fail 11:1841, 2024. McDonagh TA et al: 2021 ESC guidelines for the diagnosis and treat­ ment of acute and chronic heart failure. Eur Heart J 42:3599, 2021. Pandey A et al: Exercise intolerance in older adults with heart failure with preserved ejection fraction: JACC State-of-the-Art Review. J Am Coll Cardiol 78:1166, 2021. Talha KM et al: Frailty and heart failure: State-of-the-art review. J Cachexia Sarcopenia Muscle 14:1959, 2023. Xanthopoulos A et al: Heart failure and liver disease: Cardiohepatic interactions. JACC Heart Fail 7:87, 2019. Akshay Desai, Mandeep R. Mehra

Heart Failure:

Management Clinical management of patients with heart failure (HF) varies widely based on the clinical phenotype at presentation. Those in the earliest stage of disease with asymptomatic ventricular dysfunction (American College of Cardiology [ACC]/American Heart Association [AHA] stage B) may be amenable to treatment with neurohormonal antago­ nists, including angiotensin-converting inhibitors and β-adrenergic receptor antagonists, with the goal of facilitating ventricular recovery and preventing the development of clinical HF (not further discussed). Those with symptomatic HF (ACC/AHA stage C) comprise a het­ erogeneous group in whom the approach to therapy is differentiated largely based on measurement of the left ventricular ejection frac­ tion (LVEF). Data from prospective, randomized clinical outcomes trials enrolling patients with symptomatic chronic HF and reduced

ejection fraction (HFrEF; LVEF ≤40%) have provided a rich evidence base that supports the efficacy of stepped pharmacologic therapy with renin-angiotensin-aldosterone system (RAAS) antagonists (including angiotensin-converting enzyme inhibitors, angiotensin receptor block­ ers, and mineralocorticoid receptor antagonists), neprilysin inhibitors, β-adrenergic receptor antagonists, and sodium-glucose cotransporter 2 (SGLT-2) inhibitors as a complement to device-based treatment with cardiac resynchronization therapy and implantable cardioverterdefibrillators. By contrast, treatment of patients with symptomatic chronic HF and mildly reduced (HFmrEF; LVEF 41–49%) or pre­ served ejection fraction (HFpEF; LVEF ≥50%) has, until recently, been symptom-focused owing to the lack of evidence-based therapies but is evolving in the wake of favorable results from recently reported trials of SGLT-2 inhibitors, glucagon-like peptide 1 (GLP-1) agonists, and angiotensin-neprilysin inhibitors. Even with effective therapy, patients with HFrEF, HFmrEF, and HFpEF are at risk for clinical deterioration, typically because of progressive sodium and fluid retention that fuels the development of congestive symptoms and acute decompensated HF (ADHF). Management of these exacerbations (frequently hospitalbased) is heavily focused on hemodynamic stabilization, decongestion, and institution of appropriate disease-modifying therapy in the transi­ tion back to chronic ambulatory management. Recurrent episodes of ADHF despite careful follow-up and effective treatment may signal the onset of an advanced or refractory HF phenotype (ACC/AHA stage D) in which the risk of mortality from sudden death or end-stage HF is high, and consideration of salvage therapies including cardiac trans­ plant or mechanical circulatory support may be appropriate prior to escalation to palliative measures (Chap. 271).

CHAPTER 265 Heart Failure: Management HEART FAILURE WITH MILDY REDUCED OR PRESERVED EJECTION FRACTION ■ ■GENERAL PRINCIPLES Although clinical trials of RAAS antagonists, digoxin, β-adrenergic receptor blockers, and neprilysin inhibitors have been conducted in patients with HFpEF, none has conclusively demonstrated a mortal­ ity reduction. Variable benefits, measured in the form of reduced HF hospitalizations, have been seen with mineralocorticoid receptor antagonists, angiotensin receptor blockers, and angiotensin receptorneprilysin inhibitors, but benefits are principally confined to those with LVEF below the normal range (<0.60). This has led many to rec­ ommend that patients with HFmrEF should be treated with the same therapies as those with HFrEF. Patients with higher ejection fraction (EF) remain a therapeutic challenge. In the absence of specific phar­ macologic therapies proven to improve clinical outcomes, management of patients with HFpEF has historically been focused on improving symptoms and effort tolerance through lifestyle modification, control of congestion, stabilization of heart rhythm (particularly in those with atrial fibrillation), control of blood pressure to guideline-recommended targets, and management of comorbidities that may contribute to disease progression (including, for example, obesity, obstructive lung disease, obstructive sleep apnea, diabetes/insulin resistance, anemia, iron deficiency, and chronic kidney disease). More recently, however, targeted pharmacologic therapy is emerging, with clinical trials of SGLT-2 inhibitors supporting use of these agents to reduce cardiovascu­ lar mortality and HF hospitalizations in HFmrEF and HFpEF. Trials of angiotensin receptor-neprilysin inhibitors and GLP-1 agonists (in obese patients) also suggest possible benefits in selected HFpEF patients. ■ ■CLINICAL TRIALS IN HFPEF Attempts to export the benefits of drugs that improve clinical outcomes in patients with HFrEF, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), β-adrenergic receptor blockers, digoxin, and mineralocorticoid receptor antago­ nists, to those with HFpEF have generally been unsuccessful. The Candesartan in Heart Failure—Assessment of Mortality and Morbidity (CHARM) Preserved study showed a statistically significant reduc­ tion in HF hospitalizations but no difference in all-cause mortality in patients with HFpEF who were treated with the ARB candesartan.

Similarly, the Irbesartan in Heart Failure with Preserved Systolic Func­ tion (I-PRESERVE) trial demonstrated no differences in the composite of cardiovascular death or HF hospitalization during treatment with the ARB irbesartan compared with placebo. Apparent early benefits of the ACE inhibitor perindopril on HF hospitalizations and functional capacity in the Perindopril in Elderly People with Chronic Heart Fail­ ure (PEP-CHF) study were attenuated over longer-duration follow-up. The Digitalis Investigation Group (DIG) Ancillary Trial found no impact of digoxin on all-cause mortality or on all-cause or cardiovas­ cular hospitalization among patients with chronic HF, EF >45%, and sinus rhythm, although a modest reduction in HF hospitalizations was noted. While no dedicated study of beta blockers has been conducted in HFpEF, the subgroup of elderly patients with prior hospitalization and HFpEF enrolled in the Study of the Effects of Nebivolol Interven­ tion on Outcomes and Rehospitalization in Seniors with Heart Failure (SENIORS) trial of nebivolol, a vasodilating beta blocker, did not appear to experience significant reductions in all-cause or cardiovas­ cular mortality.

PART 6 Disorders of the Cardiovascular System Regarding mineralocorticoid receptor antagonists, which have potent antifibrotic effects in HFrEF, the Treatment of Preserved Cardiac Func­ tion Heart Failure with an Aldosterone Antagonist (TOPCAT) trial explored the potential benefit of spironolactone compared to placebo in HFpEF. This trial demonstrated no improvement in the primary composite endpoint of cardiovascular death, HF hospitalizations, or aborted cardiac arrest but did show a reduction in HF hospitalizations among those allocated to spironolactone. Post hoc analyses of the study suggested significant regional differences in the baseline charac­ teristics, event rates, adverse effects, and adherence to spironolactone among patients randomized in Russia and the Republic of Georgia compared with those randomized in the Americas that raised concerns about study conduct in Russian and Georgian sites. Apparent reduc­ tions in cardiovascular death and HF hospitalization associated with spironolactone among the subgroup of patients randomized in the Americas suggest that these study design issues may have obscured a signal of spironolactone benefit. These data have supported a weak recommendation for spironolactone in patients with HFpEF who meet the inclusion criteria for the TOPCAT trial and are at low risk for adverse effects, including hyperkalemia and worsening renal func­ tion, in the most recent U.S. and European guidelines. However, the results of the Aldosterone Receptor Blockade in Diastolic Heart Failure (ALDO-DHF) study in which spironolactone improved echocardio­ graphic indices of diastolic dysfunction but failed to improve exercise capacity, symptoms, or quality-of-life (QOL) measures highlight the need for further study. Ongoing trials, including the registry-based Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction (SPIRRIT-HFpEF) (SPIRRIT-HFpEF; clinicaltrials.gov identifier NCT02901184) and the randomized Study to Evaluate the Efficacy and Safety of Finerenone on Morbidity and Mortality in Participants with Heart Failure and Left Ventricular Ejection Fraction Greater than or Equal to 40% (FINEARTS-HF, clinicaltrials.gov identifier: NCT04435626) may provide additional insight in this regard. Addition of the SGLT-2 inhibitors dapagliflozin and empagliflozin to guideline-directed medical therapy of HFrEF has been associated with reductions in cardiovascular mortality and HF hospitalization among patients with and without diabetes mellitus enrolled in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Fail­ ure (DAPA-HF) and Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction (EMPERORREDUCED) trials. These benefits have recently been extended to the population of patients with symptomatic HF and LVEF >40% based on observed reductions in the composite of cardiovascular death or HF hospitalization among those assigned to SGLT-2 inhibitors compared to placebo in the Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) and Empagliflozin Outcome Trial in Patients with Chronic Heart Fail­ ure with Preserved Ejection Fraction (EMPEROR-PRESERVED) trials. Pooled analysis of the data from these trials is associated with a reduc­ tion in the composite or cardiovascular death or HF hospitalization.

These results have driven updates to treatment guidelines in the United States and Europe, which now embrace use of SGLT-2 inhibitors as foundational therapy in patients with symptomatic HF regardless of EF. However, cost-effectiveness analyses suggest that these agents may be of low to intermediate economic value, which may limit access until price reductions ensue. ■ ■OTHER THERAPEUTIC TARGETS Beyond pharmacologic therapy, small studies of exercise training and cardiac rehabilitation in patients with HFpEF have suggested benefits on functional capacity and QOL, indicating a possible role for lifestyle interventions to improve cardiorespiratory fitness in this population. For obese patients with HFpEF, aggressive efforts at weight loss (includ­ ing bariatric surgery) may also be associated with improvements in hemodynamics and exercise capacity. Recently, the randomized STEPHFpEF trial of the once-weekly GLP-1 agonist semaglutide in obese (body mass index ≥30 kg/m2) HFpEF patients without diabetes mellitus demonstrated improvements in functional capacity and QOL associated with incremental weight loss of nearly 12% relative to placebo. Several ongoing trials including STEP-HFpEF DM (Semaglutide Treatment Effect in People with Obesity and HFpEF and Type 2 Diabetes; clinical­ trials.gov identifier: NCT04916470) and the SUMMIT trial of the dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonist tirzepatide (clinicaltrials.gov identifier: NCT04847557) will provide further data for clinical utility in this population. A novel paradigm for understanding the pathophysiology of HFpEF has focused on the role of microvascular endothelial inflammation driven by comorbidities that results in impaired nitric oxide (NO) signaling and associated increases in myocardial stiffening. This para­ digm has emphasized the potential for improving outcomes in HFpEF by enhancing NO bioavailability and improving downstream protein kinase G–based signaling. In this regard, a small trial demonstrated that the phosphodiesterase-5 inhibitor sildenafil improved filling pres­ sures and right ventricular function in a cohort of HFpEF patients with pulmonary venous hypertension. This finding led to the phase 2 trial, Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exer­ cise Capacity in Diastolic Heart Failure (RELAX), in HFpEF patients (LVEF >50%) with New York Heart Association (NYHA) functional class II or III symptoms, who received sildenafil at 20 mg three times daily for 3 months, followed by 60 mg three times daily for another 3 months, compared with a placebo. There was no improvement in functional capacity, QOL, or other clinical and surrogate parameters in those allocated to sildenafil compared to placebo. On the premise that nitrates, which are NO donors, might improve preload, coronary perfusion, endothelial function, and exercise tolerance, the Nitrate’s Effect on Activity Tolerance in Heart Failure with Preserved Ejection Fraction (NEAT-HFpEF) study was conducted. Isosorbide mono­ nitrate did not improve QOL or submaximal exercise capacity and decreased overall activity levels in treated patients. Inorganic nitrate compounds have also been shown to enhance NO signaling but did not improve functional capacity compared to placebo among patients with HFpEF randomized in the Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure with Preserved Ejection Fraction (INDIE-HFpEF) trial. Neprilysin inhibition is known to increase circulating levels of various vasoactive peptides, including the natriuretic peptides, which may facilitate cyclic guanosine 3′,5′-monophosphate–based signaling, enhance myocardial relaxation, and reduce ventricular hypertrophy. Composite angiotensin receptor-neprilysin inhibition (ARNI) with sacubitril-valsartan reduced cardiovascular mortality, overall mortality, and HF hospitalization compared with enalapril among patients with HFrEF randomized in the PARADIGM-HF trial. The PARAGONHF trial randomized 4822 patients with symptomatic HFpEF (LVEF ≥45%), elevated natriuretic peptides, and structural heart disease to treatment with either sacubitril-valsartan or valsartan with the novel composite primary endpoint of cardiovascular death and total hospi­ talizations for HF. Although there was a 13% reduction in the rate of the primary composite endpoint in those allocated to sacubitril-valsartan, this result narrowly missed the margin for statistical significance in the

Heart Failure with Preserved Ejection Fraction: Pathology and Management Pathology Hypertrophy Fibrosis/altered collagen Infarction/ischemia General Therapeutic Principles • Reduce the congestive state – Caution to not reduce preload excessively – Use of implantable hemodynamics monitors to guide management

is useful • Control blood pressure – Central aortic blood pressure control may be more relevant • Maintain atrial contraction and prevent tachycardia – Efforts to maintain sinus rhythm in atrial fibrilation may be beneficial

(atrial fibrillation ablation may reduce morbidity and mortality) • Treat and prevent myocardial ischemia – May mimic HF as an “angina equivalent” • Detect and treat sleep apnea – Common co-morbidity causing systemic hypertension, pulmonary

hypertension, and right heart dysfunction (adaptive servo-ventilation

ineffective) • Lifestyle modification – Diet and exercise to promote weight reduction and improve

functional capacity FIGURE 265-1  Pathophysiologic correlations, general therapeutic principles, and results of specific “directed” therapy in heart failure (HF) with preserved ejection fraction. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; GLP-1, glucagon-like peptide 1; SGLT-2, sodium-glucose cotransporter 2; QOL, quality of life. primary statistical analysis (p = .06). Directional benefits in secondary endpoints including QOL, NYHA class, and renal function favoring sacubitril-valsartan support a possible modest benefit of neprilysin inhibition in this population, particularly among patients with lower (i.e., mildly reduced) EF and in women, subgroups who appeared to derive greater benefit. Based on these data, sacubitril-valsartan has recently been approved in the United States for treatment of symptom­ atic HF across the full spectrum of EF, with benefits acknowledged to be greatest in those with LVEF below normal. The PARAGLIDE-HF trial randomly assigned patients with HF and EF >40% within 30 days of a worsening HF event to treatment with sacubitril-valsartan or valsartan. Although those assigned to sacubitril-valsartan experienced greater reductions in N-terminal prohormone of brain natriuretic peptide (NTproBNP) at 8 weeks, clinical benefits were modest and appeared to be confined to those with EF ≤60%, suggesting this therapy may be most effective in that subgroup. ■ ■CLINICAL GUIDING PRINCIPLES Beyond disease-modifying therapy, treatment of HFpEF should focus on decongestion, aggressive management of medical comorbidities, and relief of exacerbating factors. A careful diagnostic approach is critical, since patients with HF and a normal or near-normal LVEF compose a heterogenous group that includes patients with infiltrative heart disease (amyloidosis, hemochromatosis, sarcoidosis), storage disease (Fabry’s disease, Gaucher’s disease), hypertrophic cardiomy­ opathy, pericardial disease, pulmonary arterial hypertension, valvular heart disease, and primary right ventricular failure who may require a different management approach. For those with true HFpEF, aggres­ sive control of blood pressure to guideline-recommended targets and

CHAPTER 265 Risk markers Hypertension Aging Atherosclerosis Heart Failure: Management Diabetes Obesity Specific Therapy Targets (beyond general management) • Renin-angiotensin-aldosterone–directed therapy – ACEIs and ARBs ineffective (except in “prevention”) – Aldosterone antagonists (may be beneficial) • Digoxin – Ineffective (may reduce hospitalizations) • Beta blockers and calcium channel blockers – Ineffective (useful in preventing tachycardia in patients

with AF) • Phosphodiesterase-5 inhibitors – Sildenafil ineffective • Novel Therapy – ARNIs (may be effective in selected patients) – SGLT-2 inhibitors (reduce HF hospitalization) • Chronotropic insufficiency – ? Targeted pacing (likely ineffective) • Obesity treatment – GLP-1 agonists (improve QOL irrespective of diabetes mellitus) relief of volume overload with diuretics are critical to symptom relief. Excessive decrease in preload with diuretics and vasodilators may lead to underfilling the ventricle and subsequent azotemia, hypotension, and syncope. For patients at risk for coronary heart disease, deliberate evaluation for ischemia and consideration of coronary revasculariza­ tion may be important. Since clinical outcomes in HFpEF are worse in the setting of atrial fibrillation, aggressive rate control, anticoagulation, and early consideration of sinus rhythm restoration are important. Comorbidities such as obesity, obstructive lung disease, sleep apnea, chronic kidney disease, and anemia/iron deficiency are increasingly recognized as important contributors to diminished functional capac­ ity and QOL in patients with HFpEF and may be additional targets for therapy. Some investigators have suggested that the exercise intolerance in HFpEF is a manifestation of chronotropic insufficiency. While this hypothesis appears to be supported by small trials randomized trials of beta blocker withdrawal, improving chronotropic response through rate-adaptive atrial pacing did not improve functional capacity in the randomized RAPID-HF trial (Fig. 265-1). ACUTE DECOMPENSATED HEART FAILURE ■ ■GENERAL PRINCIPLES ADHF is a heterogeneous clinical syndrome most often resulting in need for hospitalization due to confluence of interrelated abnormali­ ties of decreased cardiac performance, renal dysfunction, and altera­ tions in vascular compliance. Admission with a diagnosis of ADHF is associated with excessive morbidity and mortality, with nearly half of these patients readmitted for management within 6 months, and a high short-term (5% in-hospital) and long-term cardiovascular mortality

Heterogeneity of ADHF: Management Principles Hypertensive Acute Decompensation “Typical” (usually volume overloaded) (usually not volume overloaded) PART 6 Disorders of the Cardiovascular System Vasodilators Renal insufficiency Biomarkers of injury Acute coronary syndrome, arrhythmia, hypoxia, pulmonary embolism, infection Severe Pulmonary Congestion with Hypoxia Acute Decompensation “Pulmonary edema” Opiates Vasodilators Hypoperfusion with End-Organ Dysfunction Acute Decompensation “Low output” Vasodilators Hypotension, Low Cardiac Output, and End-Organ Failure Acute Decompensation “Cardiogenic shock” Inotropic therapy (usually catecholamines) FIGURE 265-2  The distinctive phenotypes of acute decompensated heart failure (ADHF), their presentations, and suggested therapeutic routes. (Unique causes of ADHF, such as isolated right heart failure and pericardial disease, and rare causes, such as aortic and coronary dissection or ruptured valve structures or sinuses of Valsalva, are not delineated and are covered elsewhere.) CNS, central nervous system; IABP, intraaortic balloon pump; VAD, ventricular assist device. (20% at 1 year). Importantly, long-term outcomes remain poor, with a combined incidence of cardiovascular deaths, HF hospitalizations, myocardial infarction, strokes, or sudden death reaching 50% at 12 months after hospitalization. The management of these patients remains difficult and principally revolves around volume control and hemodynamic optimization to maximize end-organ perfusion. The first principle of management in ADHF is to identify and address the factors that precipitated decompensation. Important his­ torical factors to consider are nonadherence to medications, dietary salt indiscretion, and usage of medications (including over-the-counter preparations) that may exacerbate HF, including nonsteroidal antiinflammatory drugs, thiazolidinediones, tumor necrosis factor inhibi­ tors, selected antidepressants, selected cancer therapies, cold and flu preparations with cardiac stimulants, and some herbal preparations. Coronary ischemia frequently drives HF exacerbation in patients with atherosclerotic cardiovascular disease and should be systematically investigated (either invasively or noninvasively) in all patients at risk to identify candidates for revascularization. Atrial and ventricular arrhythmias are common contributors to HF exacerbation and may trigger the need for antiarrhythmic drug suppression, cardioversion, or catheter ablation. Valvular heart disease is increasingly recognized as a target for therapy in patients with recurrent HF exacerbations and can be readily identified through echocardiography. Systemic infec­ tion and pulmonary thromboembolism are additional triggers of HF decompensation and should be routinely considered. Concurrent with the identification of HF precipitants, effective management of ADHF requires pharmacologic therapy directed at hemodynamic optimization, including relief of congestion, reduction in afterload, and maximization of vital organ perfusion. The routine use of a pulmonary artery catheter is not recommended and should be restricted to those who present with features typical of low-output HF

Normotensive High-Risk Features Diuretics New onset arrhythmia Valvular heart disease Inflammatory heart disease Myocardial ischemia CNS injury Drug toxicity O2 and noninvasive ventilation Diuretics Low pulse pressure Cool extremities Cardio-renal syndrome Hepatic congestion Inotropic therapy (if low blood pressure or diuretic refractoriness) Hemodynamic monitoring (suboptimal initial therapeutic response) Extreme distress Pulmonary congestion Renal failure Mechanical circulatory support (IABP, percutaneous VAD, ultrafiltration) or cardiogenic shock who may require vasopressor or mechanical circu­ latory support, those who are resistant or refractory to diuretic therapy, those with combined cardiorenal dysfunction in whom therapeutic goals are difficult to define at the bedside, and those with known or sus­ pected pulmonary arterial hypertension in whom vasodilator therapy may be appropriate. Analysis of in-hospital registries has identified several parameters associated with worse outcomes: a blood urea nitro­ gen level >43 mg/dL (to convert to mmol/L, multiply by 0.357), systolic blood pressure <115 mmHg, a serum creatinine level >2.75 mg/dL (to convert to μmol/L, multiply by 88.4), and elevated cardiac biomarkers including natriuretic peptides and cardiac troponins. A useful clinical schema to identify treatment targets for the various phenotypic presen­ tations and management goals in ADHF is depicted in Fig. 265-2. ■ ■VOLUME MANAGEMENT Intravenous Diuretic Agents  Intravenous loop diuretic agents rapidly and effectively relieve symptoms of congestion and are essential when oral drug absorption is impaired. When high doses of diuretic agents are required or when the effect of bolus dosing is suboptimal, a continuous infusion may be needed to reduce toxicity and maintain stable serum drug levels. Randomized clinical trials of high- versus low-dose and bolus versus continuous infusion diuresis have not pro­ vided clear justification for the best diuretic strategy in ADHF, and as such, the use of diuretic regimens remains an art rather than science. For those refractory to loop diuretic treatment alone, addition of a thiazide diuretic agent such as chlorothiazide or metolazone to provide sequential nephron blockade may enhance natriuresis and facilitate decongestion, but also increases the risk of significant hypokalemia. Addition of acetazolamide to loop diuretic therapy in the randomized ADVOR trial was demonstrated to facilitate greater decongestion but was not associated with reduction in HF readmissions or mortality.

Heart Failure: Management

CHAPTER 265 Change in weight is often used as a surrogate for adequate diuresis, but this objective measure of volume status may be surprisingly difficult to interpret, and weight loss during hospitalization does not necessarily correlate closely with outcomes. Effective decongestion may also be confirmed by improvement in clinical symptoms as well as the bedside examination documenting normalization of the jugular venous pres­ sure, clearance of pulmonary rales, suppression of cardiac gallops, and resolution of peripheral edema, hepatomegaly, and abdominal ascites. It is generally advisable to continue diuresis until euvolemia has been achieved, since residual congestion or volume overload is strongly associated with risk for recurrent decompensation. Predischarge mea­ surement of natriuretic peptide levels, which are highly correlated with risk for postdischarge mortality and readmission, may also be useful in assessing the adequacy of therapy and stratifying risk. Chronic oral loop diuretic therapy is appropriate at discharge for most patients to maintain decongestion. The TRANSFORM-HF trial did not demon­ strate any mortality or morbidity advantage of torsemide compared to furosemide for this purpose despite its greater oral bioavailability, longer half-life, and other potential beneficial effects on myocardial fibrosis, aldosterone production, sympathetic activation, ventricular remodeling, and natriuretic peptides noted in small studies. The Cardiorenal Syndrome  The cardiorenal syndrome is increas­ ingly being recognized as a complication of ADHF. Multiple definitions have been proposed for the cardiorenal syndrome, but at its simplest, it can be thought to reflect the interplay between abnormalities of heart and kidney function, with deteriorating function of one organ while therapy is administered to preserve the other. Approximately 30% of patients hospitalized with ADHF exhibit abnormal renal func­ tion at baseline, and this is associated with longer hospitalizations and increased mortality. However, mechanistic studies have been largely unable to find correlation between deterioration in renal function, cardiac output, left-sided filling pressures, and reduced renal perfusion; most patients with cardiorenal syndrome demonstrate a preserved car­ diac output. It is hypothesized that in patients with established HF, this syndrome represents a complex interplay of neurohormonal factors, potentially exacerbated by “backward failure” resulting from increased intraabdominal pressure and impairment in return of renal venous blood flow. Continued use of diuretic therapy may be associated with a reduction in glomerular filtration rate and a worsening of the car­ diorenal syndrome when right-sided filling pressures remain elevated. In patients in the late stages of disease characterized by profound low cardiac output state, inotropic therapy or mechanical circulatory sup­ port has been shown to preserve or improve renal function in selected individuals in the short term until more definitive therapy such as assisted circulation or cardiac transplantation is implemented. Ultrafiltration  Ultrafiltration (UF) is an invasive fluid removal technique that may supplement the need for diuretic therapy. Proposed benefits of UF include controlled rates of fluid removal, neutral effects on serum electrolytes, and decreased neurohormonal activity. This technique has also been referred to as aquapheresis in recognition of its electrolyte depletion–sparing effects. In an initial study evaluating UF versus conventional therapy, fluid removal was improved, and subsequent HF hospitalizations and urgent clinic visits were reduced with UF; however, no improvement in renal function and no subjec­ tive differences in dyspnea scores or adverse outcomes were noted. In the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial, 188 patients with ADHF and worsening renal failure were randomized to stepped pharmacologic care or UF. The primary endpoint was a change in serum creatinine and change in weight (reflecting fluid removal) at 96 h. Although similar weight loss occurred in both groups (~5.5 kg), there was a rise in serum creatinine among patients allocated to the UF group. Deaths and hospitaliza­ tions for HF were no different between groups, but there were more adverse events in the UF group, mainly due to kidney failure, bleeding complications, and intravenous catheter-related complications. This investigation argues against using UF as a primary strategy in patients with ADHF who are diuretic-responsive. Whether UF is useful as a res­ cue strategy in diuretic refractory patients with advanced renal disease remains an open question, and this strategy continues to be employed judiciously in such situations. ■ ■VASOACTIVE THERAPY Vasodilators including intravenous nitroglycerin, sodium nitroprusside, and nesiritide (a recombinant brain-type natriuretic peptide) are fre­ quently used in ADHF to lower intracardiac filling pressures and reduce systemic vascular tone. Rapid reduction in ventricular preload and after­ load with these therapies may be effective in providing symptom relief in patients with pulmonary edema and in restoring end-organ perfusion for those with low cardiac output and high systemic vascular resistance. Nitroglycerine principally impacts venous tone and ventricular preload, whereas sodium nitroprusside is a potent arterial and venous vasodila­ tor with more comprehensive effects on both preload and afterload. While intravenous nitroglycerine is commonly utilized as an adjunct to diuretics for acute management of symptomatic HF and pulmonary edema, nitroprusside is typically reserved for use in those with adequate arterial pressure or invasive hemodynamic monitoring due to the risk for hypotension. The hemodynamic effects of nesiritide are intermediate between those of nitroglycerine and nitroprusside, with head-to-head comparisons with nitroglycerine suggesting more rapid reduction in pulmonary capillary wedge pressure and pulmonary vascular resistance. Clinical utilization of nesiritide has waned due to concerns raised regarding heightened risks of renal insufficiency and mortality identified in early trials. The Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) randomizing 7141 patients with ADHF to nesiritide or placebo did not confirm this risk but identified no clear clinical benefit regarding subsequent HF admissions, mortality, or symptom relief (reduction in dyspnea). Renal function did not worsen, but increased rates of hypotension were noted. A smaller study of low-dose nesiritide in acute HF (Renal Optimization Strategies Evaluation Acute Heart Failure Study [ROSE-AHF]) also showed no incremental benefit over intravenous diuretics for relief of congestion or preservation of renal function. Despite apparent safety in ADHF, the routine use of nesiritide is accordingly not recommended. Other novel vasodilators have been explored for the management of ADHF. Recombinant human relaxin-2, or serelaxin, is a vasodilatory hormone known to contribute to cardiovascular and renal adaptations during pregnancy. In the Relaxin in Acute Heart Failure (RELAXAHF) trial, 1161 patients hospitalized with ADHF, evidence of conges­ tion, and systolic pressure >125 mmHg were randomized to treatment with serelaxin or placebo in addition to standard HF therapy. Serelaxin improved dyspnea, reduced signs and symptoms of congestion, and was associated with less early worsening of HF. A positive signal of reduced mortality identified in an exploratory analysis prompted a second study (RELAX-AHF2), which did not confirm an effect on cardiovascular death or worsening HF. Accordingly, this agent was not approved for use in clinical practice. One hypothesis for the failure of vasodilator therapies to improve clinical outcomes in ADHF despite favorable hemodynamic effects is related to the acute injury hypothesis; in this model, acute HF is analogous to presentation with an acute coronary syndrome, with the initial hours of presentation representing a period of vulnerability to myocardial damage (reflected in a rise in markers of myocyte injury such as cardiac troponins) as a consequence of abrupt increases in ven­ tricular wall stress related to acute plasma volume expansion. To test this hypothesis, the Trial of Ularitide Safety and Efficacy in Acute Heart Failure (TRUE-AHF) randomly allocated 2157 patients with acute HF to early treatment with the synthetic natriuretic peptide ularitide (at a dose sufficient to reduce ventricular wall stress) or placebo. Despite a very short duration between initial clinical presentation and phar­ macologic intervention (<6 h) and early hemodynamic benefits, no improvement in clinical outcomes was observed in patients allocated to ularitide at 6 months. Ularitide was associated with a higher rate of hypotension and worsening serum creatinine. These data under­ mine the notion that acute myocardial damage related to ventricular distension associated with HF exacerbation drives subsequent clinical outcomes and argue against the clinical importance of early vasodilator therapy in ADHF.

■ ■INOTROPIC THERAPY Impairment of myocardial contractility often accompanies ADHF, and pharmacologic agents that increase intracellular concentration of cyclic adenosine monophosphate via direct or indirect pathways, such as sympathomimetic amines (dopamine, dobutamine) and phosphodies­ terase-3 inhibitors (milrinone), respectively, serve as positive inotropic agents. Their activity leads to an increase in cytoplasmic calcium. Ino­ tropic therapy in those with a low-output state augments cardiac output, reduces systemic vascular resistance, improves perfusion, and relieves congestion acutely. Although systematic head-to-head comparisons are available to identify a “best” agent, slight variations in the hemodynamic effects of inotropic drugs may condition selection of the appropriate drug for a given clinical context. Dopamine exhibits dose-dependent effects on dopaminergic, α-, and β-adrenergic receptors, with vaso­ dilatory effects predominating at lower doses (<2 μg/kg per min), β-adrenergic (inotropic) effects at moderate doses, and α-adrenergic effects (vasoconstriction) at higher doses (typically >10 μg/kg per min). Low-dose (“renal dose”) dopamine has been explored as an adjunctive strategy for preservation of renal function and augmentation of diuresis in acute HF but does not appear to provide incremental advantage over routine therapy with intravenous diuretics (ROSE-AHF).

PART 6 Disorders of the Cardiovascular System Milrinone is typically associated with a greater reduction in sys­ temic and pulmonary vascular resistance than dobutamine and, accord­ ingly, carries a higher risk of systemic hypotension. Moreover, because milrinone has a longer half-life and is renally excreted, it requires dose adjustments in the setting of kidney dysfunction. Because milrinone acts downstream from the β1-adrenergic receptor, it may provide an advantage in patients receiving beta blockers when admitted to the hospital. Long-term inotropic therapy is associated with a heightened risk of mortality in HF, perhaps due to the increased risk of arrhythmia and sudden death. Routine, short-term use of milrinone in patients hospitalized with ADHF in the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) trial was associated with increased risk of atrial arrhythmias and prolonged hypotension, but no benefit regarding subsequent mortality or HF hospitalization. Accordingly, routine use of inotropic support in ADHF is discouraged, and these agents are currently indicated principally for short-term use as bridge therapy (to either left ventricular assist device support or to transplant) in cardiogenic shock or as selectively applied palliation in end-stage HF. Novel inotropic agents that leverage the concept of myofilament calcium sensitization rather than increasing intracellular calcium levels have been introduced. Levosimendan is a calcium sensitizer that provides inotropic activity but also possesses phosphodiesterase-3 inhibition properties that are vasodilatory. Two trials, the second Randomized Multicenter Evaluation of Intravenous Levosimendan Efficacy (REVIVE II) and Survival of Patients with Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE), have tested this agent in ADHF. SURVIVE compared levosimendan with dobuta­ mine, and despite an initial reduction in circulating B-type natriuretic peptide levels in the levosimendan group compared with patients in the dobutamine group, this drug did not reduce all-cause mortality at 180 days or affect any secondary clinical outcomes. The second trial compared levosimendan against traditional noninotropic therapy and found a modest improvement in symptoms with worsened short-term mortality and ventricular arrhythmias. Although levosimendan has been approved for use to support management of HF in several coun­ tries worldwide, it is not approved for use in the United States, largely owing to the lack of compelling data for incremental efficacy in com­ parison with conventional inotropic drugs or standard HF therapies. (Table 265-1 depicts typical inotropic, vasodilator, and diuretic drugs used in ADHF.) ■ ■OTHER THERAPIES FOR ADHF Other trials testing unique agents have yielded disappointing results in the situation of ADHF. Adenosine has been implicated as a mediator of worsening renal function and diuretic resistance, and accordingly, treatment with adenosine receptor antagonists was postulated to be

potentially beneficial in relieving symptoms and preserving renal func­ tion in patients with acute HF. Among patients with acute HF and renal dysfunction enrolled in the Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Func­ tion (PROTECT) trial, no cardiovascular or renal benefit was observed. Similarly, despite compelling theoretical benefit of vasopressin receptor antagonism in acute HF (based on the central role of vasopressin in mediating the fluid retention that contributes to worsening HF), no benefit of the oral selective vasopressin-2 antagonist tolvaptan was seen regarding mortality or HF-associated morbidity in the Efficacy of Vaso­ pressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial. ■ ■CLINICAL GUIDING PRINCIPLES In the absence of data to support specific pharmacologic interven­ tions in ADHF, management is largely goal-directed and focused on decongestion to relieve symptoms, investigation and suppression of triggers for recurrent decompensation, and careful transition to lon­ gitudinal HF management. Patients who fail to respond adequately to medical therapy or who develop hemodynamic instability may benefit from pulmonary artery catheter placement to guide titration of vasoactive therapy or inotropic support; in those with hemody­ namics suggestive of cardiogenic shock, mechanical assist devices may be required (Chap. 271). Following stabilization, all patients should receive education regarding HF self-management prior to dis­ charge, including guidance regarding diet and lifestyle modification, identification of worsening HF symptoms, and whom to contact in the event of clinical deterioration. Early postdischarge follow-up of patients following hospitalization for management of worsening HF is associated with lower rates of hospital readmission. For patients with HFrEF hospitalized with ADHF, data suggest that institution of appropriate guideline-directed medical therapy prior to hospital discharge is associated with higher rates of adherence to appropriate pharmacologic treatment in longitudinal follow-up and may be asso­ ciated with improved outcomes in the early postdischarge interval. In the Comparison of Sacubitril-Valsartan Versus Enalapril on Effect on NTproBNP in Patients Stabilized from an Acute Heart Failure Episode (PIONEER-HF) study of patients with HFrEF stabilized after hospital admission for ADHF, predischarge initiation of sacubitril-valsartan compared with enalapril was associated with greater reductions in natriuretic peptides as well as lower rates of composite death and HF readmission at 8 weeks. Similarly, in the EMPULSE trial, predischarge initiation of the SGLT-2 inhibitor empagliflozin in hospitalized HF patients across the spectrum of EF was associated with reductions in a hierarchical clinical composite outcome at 90 days. More recently, in the STRONG-HF trial, an intensive postdischarge treatment strategy of frequent follow-up and rapid uptitration of guidelinerecommended medical therapy was associated with lower rates of death and HF readmission at 180 days compared with usual care. These results were consistent in those with EF ≤40% and those with EF >40%, underscoring the need for early postdischarge follow-up and medical optimization in high-risk patients following a worsening HF event, regardless of EF. HEART FAILURE WITH REDUCED EJECTION FRACTION The past 50 years have witnessed great strides in the manage­ ment of HFrEF. Treatment of symptomatic HF has evolved from a renocentric (diuretics) and hemodynamic therapy model (digoxin, inotropic therapy) to an era of disease-modifying therapy with neu­ rohormonal antagonism. In this regard, RAAS blockers (including ARNIs), β-adrenergic receptor blockers, and, most recently, SGLT-2 inhibitors form pillars of pharmacotherapy and facilitate stabiliza­ tion and even improvement in cardiac structure and function with consequent reduction in symptoms, improvement in QOL, decreased burden of hospitalizations, and a decline in mortality from both pump failure and arrhythmic deaths (Fig. 265-3).

TABLE 265-1  Vasoactive Therapy in Acute Decompensated Heart Failure DRUG CLASS GENERIC DRUG USUAL DOSING SPECIAL CAUTION COMMENTS Inotropic therapy       Use in hypotension, end-organ hypoperfusion, or shock states Dobutamine 2–20 μg/kg per min Increased myocardial oxygen demand, arrhythmia Milrinone 0.375–0.75 μg/kg per min Hypotension, arrhythmia Decrease dose in renal insufficiency; avoid initial bolus; effectiveness retained in presence of beta blockers Levosimendan 0.1 μg/kg per min; range, 0.05–0.2 μg/kg per min Hypotension, arrhythmia Long acting; should not be used in presence of low blood pressure; similar effectiveness as dobutamine but effectiveness retained in presence of beta blockers Vasodilators       Use in presence of pulmonary congestion for rapid relief of dyspnea, in presence of a preserved blood pressure Nitroglycerin 10–20 μg/min, increase up to 200 μg/min Headache, flushing, tolerance Nesiritide Bolus 2 μg/kg and infusion at 0.01 μg/kg per min Hypotension Decrease in blood pressure may reduce renal perfusion pressure; bolus may be avoided since it increases hypotension predilection Nitroprusside 0.3 μg/kg per min titrated to 5 μg/kg per min Thiocyanate toxicity in renal insufficiency (>72 h) Serelaxin N/A (tested at 30 μg/kg per d) Baseline blood pressure should be >125 mmHg Ularitide 15 ng/kg per min (48 h) Baseline blood pressure

116 mmHg Diuretics       First line of therapy in volume overload with congestion; may use bolus or continuous dosing; initial low dose (1 × home dose) or high dose (2.5 × home dose) equally effective with higher risk of renal worsening with higher dose Furosemide 20–240 mg daily Monitor for electrolyte loss Torsemide 10–100 mg daily Monitor for electrolyte loss Bumetanide 0.5–5 mg daily Monitor for electrolyte loss Adjuvant diuretics for augmentation N/A Metolazone, chlorthalidone, spironolactone, acetazolamide Abbreviation: N/A, not applicable. Ineffective Adjuncts Higher • Erythropoietin for anemia • Warfarin/low-dose rivaroxaban to prevent thromboembolism (absent high-risk features) • SSRI for depression • Statins for HF • Adaptive servo-ventilation for central sleep apnea (increased mortality) Placebo ACE inhibitor/ARB Risk of mortality β-Blockers (carvedilol, metoprolol succinate, bisoprolol) Mineralocorticoid receptor antagonist ARNI (instead of ACEI/ARB) SGLT-2 i Vericiguat Lower FIGURE 265-3  Progressive decline in mortality with angiotensin-converting enzyme (ACE) inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), angiotensin receptorneprilysin inhibitors (ARNIs), beta blockers, mineralocorticoid receptor antagonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and balanced vasodilators (*selected populations such as African Americans). Addition of selected therapies (ivabradine, vericiguat) may further reduce heart failure (HF) hospitalization but does not substantially impact mortality. Further stack-on neurohormonal therapy is ineffective or results in worse outcome. Management of comorbidity (e.g., iron deficiency, sleep apnea) is of unproven efficacy. HFrEF, heart failure with reduced ejection fraction; PUFA, polyunsaturated fatty acid; SSRI, selective serotonin reuptake inhibitor.

Short acting, an advantage; variable efficacy in presence of beta blockers (requires higher doses); clinical tolerance to prolonged infusions; concerns with hypersensitivity carditis (rare) CHAPTER 265 Heart Failure: Management Most common vasodilator but often underdosed; effective in higher doses Requires arterial line placement for titration for precise blood pressure management and prevention of hypotension Not widely commercially available; ineffective in confirmatory trials Excess hypotension and increased serum creatinine In severe congestion, use intravenously and consider continuous infusion (not trial supported) High bioavailability, can be given orally; anecdotally more effective in advanced heart failure states if furosemide less bioavailable (due to gut congestion) Can be used orally; intermediate bioavailability Acetazolamide is useful in presence of alkalosis (bicarbonate level

27mEq/L); metolazone given in 2.5- to 10-mg doses; concomitant use of loop diuretics and thiazides associated with risk for severe hypokalemia, careful laboratory monitoring advised; spironolactone is useful in presence of severe hypokalemia and normal renal function Potentially Effective • N-3 PUFA • Iron supplementation Special Populations • Hydralazine/isosorbide • Ivabradine Oral inotropes (vesnarinone, flosequinan) Moxonidine (imidazoline receptor agonist) Xamoterol (mixed β-agonist/antagonist) Endothelin antagonists Omecamtiv mecarbil

■ ■NEUROHORMONAL ANTAGONISM Meta-analyses suggest a 23% reduction in mortality and a 35% reduc­ tion in the combined endpoint of mortality and hospitalizations for HF in patients with symptomatic HFrEF treated with ACE inhibitors (ACEIs). Addition of β-adrenergic receptor blockers to background therapy with ACEIs provides a further 35% reduction in mortality. Although placebo-controlled studies are lacking, several noninferior­ ity trials have demonstrated comparable efficacy of ARBs and ACEIs in patients with HFrEF, making ARBs a suitable alternative for patients who are intolerant to ACEIs due to cough or angioedema. Abundant data support the efficacy across the full spectrum of HF severity (including those with NYHA class III–IV functional capacity), as well as the safety data of these agents. These observations demonstrate the basis for the tolerability of these agents even in subgroups at higher risk for adverse effects such as those with mild-moderate chronic kid­ ney disease. In diabetes mellitus and chronic obstructive lung disease, these agents have been established as foundational therapy for HFrEF as directed by consensus guidelines. Both agents are generally recom­ mended for all patients with HFrEF, independent of symptom burden, and should be titrated to the doses proven to provide clinical benefit or to the maximally tolerated dose. The inability to tolerate initiation or dose titration of neurohumoral antagonists due to hypotension, worsening HF, or progressive renal insufficiency is a poor prognos­ tic marker and may be a cardinal manifestation of transition to an advanced HF phenotype.

PART 6 Disorders of the Cardiovascular System Class Effect and Sequence of Administration  ACEIs and ARBs exert their beneficial effects in HFrEF as a class; however, the beneficial effects of beta blockers are thought to be limited to spe­ cific drugs. Beta blockers with intrinsic sympathomimetic activity (xamoterol) and other agents, including bucindolol, have not dem­ onstrated a survival benefit. Based on the available data, beta blocker use in HFrEF should ideally be restricted to carvedilol, bisoprolol, and metoprolol succinate—agents tested and proven to improve survival in clinical trials. Whether beta blockers or ACEIs should be started first was answered by the Cardiac Insufficiency Bisoprolol Study (CIBIS) III, in which outcomes did not vary based on the sequence of drug initiation. Thus, it matters little which agent is initiated first; what does matter is that optimally titrated doses of both ACEIs and beta blockers be established in a timely manner. Dose and Outcome  In general, the benefits of neurohumoral antagonists in HFrEF are closely related to the dose achieved, gird­ ing the rationale for aggressive titration to target doses as defined by clinical trials. Prospective trials of high- versus low-dose ACEIs (ATLAS), ARBs (HEAAL), and beta blockers (MOCHA) consistently favor the higher dose, with lower rates of death and HF hospitaliza­ tion seen in the higher-dose group. Clinical experience suggests that, in the absence of symptoms to suggest hypotension (fatigue and diz­ ziness), pharmacotherapy may be uptitrated every 2 weeks in stable ambulatory patients as tolerated. Notably, data from large registries in the United States and Europe suggest that guideline-directed medi­ cal therapy for patients with HFrEF is frequently underutilized and underdosed, leaving considerable room for quality improvement. ■ ■MINERALOCORTICOID RECEPTOR ANTAGONISTS Addition of mineralocorticoid receptor antagonists to treatment with ACEI/ARBs and beta blockers in patients with symptomatic HFrEF (NYHA class II–IV) is associated with further reductions in morbidity and mortality. Elevated aldosterone levels in HFrEF promote sodium retention, electrolyte imbalance, and endothelial dysfunction and may directly contribute to myocardial fibrosis. Hyperkalemia and worsen­ ing renal function are concerns, especially in patients with underly­ ing chronic kidney disease, and renal function and serum potassium levels must be closely monitored. Spironolactone is the most utilized agent in this class based on efficacy demonstrated in the Randomized Aldactone Evaluation Study (RALES) in patients with HFrEF and NYHA class III–IV symptoms. Eplerenone (studied principally in patients with milder NYHA class II symptoms and those with HF or

left ventricular dysfunction complication myocardial infarction) lacks the antiandrogen effects of spironolactone and may be a suitable alter­ native for patients who experience sexual side effects (gynecomastia, erectile dysfunction, diminished libido). ■ ■RAAS THERAPY AND NEUROHORMONAL “ESCAPE” Since angiotensin II can be generated by non-ACE pathways, levels of angiotensin II may recover to pretreatment levels during long-term ACEI therapy. This phenomenon of neurohormonal “escape” has fueled interest in dual blockade of the RAAS using ACEI and ARBs in combination. In both the Valsartan Heart Failure Trial (Val-HeFT) and the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM-Added) trial, addition of an ARB to an ACEI and other HF therapy was associated with a lower risk of HF hospitalizations. Since neither trial mandated an evidence-based dose of an ACEI, it remains unclear whether combination therapy was clearly superior to a strategy of maximizing a single agent through dose titration. Subsequent data from the Valsartan in Acute Myocar­ dial Infarction (VALIANT) trial suggested that the addition of the ARB valsartan to an evidence-based dose of the ACEI captopril in patients with HF complicating myocardial infarction was associated with an increase in adverse events without any added benefit compared with monotherapy for either group. The findings of the VALIANT trial are also informed by the Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure (ATMOSPHERE), which randomly allocated 7016 patients with HFrEF to treatment with enalapril (targeted dose 10 mg twice daily as recommended by guidelines), the plasma renin inhibitor aliskiren, or the combination on top of standard HF therapy. In that study, combination treatment with aliskiren and enalapril was associ­ ated with higher rates of hyperkalemia, hypotension, and worsening renal function, but no incremental benefit regarding HF hospital­ ization or cardiovascular mortality. Together, these data argue for a ceiling of benefit of angiotensin inhibition in HFrEF, beyond which further inhibition brings more adverse effects without additional effi­ cacy. Guidelines discourage the combination of an ACEI, ARB, and spironolactone in HFrEF due to the risks of hyperkalemia and renal dysfunction, and for patients, treatment with either an ACEI or ARB and spironolactone is deemed most appropriate. ■ ■ALTERNATIVE VASODILATORS The combination of hydralazine and nitrates has been demonstrated to improve survival in HFrEF. Hydralazine reduces systemic vascular resistance and induces arterial vasodilatation by affecting intracellular calcium kinetics; nitrates are transformed in smooth muscle cells into NO, which stimulates cyclic guanosine monophosphate produc­ tion and consequent arterial-venous vasodilation. This combination improves survival but to a lesser extent than ACEIs. However, in individuals with HFrEF unable to tolerate RAAS-based therapy for reasons such as renal insufficiency or hyperkalemia, this combina­ tion is preferred as a disease-modifying approach. A trial conducted in self-identified African Americans, the African-American Heart Failure Trial (A-HeFT), studied a fixed dose of isosorbide dinitrate with hydralazine in patients with advanced symptoms of HFrEF who were receiving standard background therapy including an ACEI and beta blocker. The study demonstrated improvements in survival and hospital admission for HF in the treatment group. Adherence to this regimen is limited by the thrice-daily dosing schedule. ■ ■NOVEL NEUROHORMONAL ANTAGONISTS Despite an abundance of animal and clinical data demonstrating deleterious effects of activated neurohormonal pathways beyond the RAAS and sympathetic nervous system, targeting such pathways with incremental blockade has been largely unsuccessful. As an example, the endothelin antagonist bosentan is associated with worsening HF in HFrEF despite demonstrating benefits in right-sided HF due to pul­ monary arterial hypertension. Similarly, the centrally acting sympa­ tholytic agent moxonidine worsens outcomes in left HF. The combined drug omapatrilat hybridizes an ACEI with a neutral endopeptidase (neprilysin) inhibitor, and this agent was tested in the Omapatrilat

TABLE 265-2  Guideline-Directed Pharmacologic Therapy and Target Doses in Heart Failure with Reduced Ejection Fraction MEAN DAILY DOSE IN CLINICAL TRIALS (mg) INITIATION (mg) TARGET DOSE (mg) DRUG CLASS GENERIC DRUG Angiotensin-Converting Enzyme Inhibitors   Lisinopril 4.5–33 2.5–5 qd 20–35 qd Enalapril

2.5 bid 10–20 bid Captopril

6.25 tid 50 tid Trandolapril N/A 0.5–1 qd 4 qd Angiotensin Receptor Blockers   Losartan

50 qd 150 qd Valsartan

40 bid 160 bid Candesartan

4–8 qd 32 qd Aldosterone Antagonists   Eplerenone 42.6 25 qd 50 qd Spironolactone

12.5–25 qd 25–50 qd Beta Blockers   Metoprolol succinate CR/XL

12.5–25 qd 200 qd Carvedilol

3.125 bid 25–50 bid Bisoprolol 8.6 1.25 qd 10 qd Arteriovenous Vasodilators   Hydralazine isosorbide dinitrate 270/136 37.5/20 tid 75/40 tid Fixed-dose hydralazine/isosorbide dinitrate 143/76 37.5/20 qid 75/40 qid Angiotensin Receptor-Neprilysin Inhibitor   Sacubitril-valsartan

100 bid 200 bid SGLT-2 Inhibitor   Dapagliflozin Empagliflozin Sotagliflozin

Novel Therapies   Vericiguat (sGC stimulator) 9.2 2.5 qd 10 qd Omecamtiv mecarbil (myosin activator) Not reported 25 bid Up to 50 mg bid (based on plasma concentrations) Abbreviations: sGC, soluble guanylyl cyclase; SGLT-2, sodium-glucose cotransporter 2. Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE) trial. This drug did not favorably influence the primary outcome measure of the combined risk of death or hospitalization for HF requiring intravenous treatment compared with enalapril alone, and notably, the risk of angioedema was increased in patients assigned to omapatrilat. The risk of angioedema with composite ACE/neprilysin inhibition appears to be related to excessive blockade of bradykinin breakdown by this combination. Blockade of angiotensin at the receptor level with an ARB leaves the ACE pathway for bradykinin breakdown intact and is associated with lower angioedema risk. Recently, a composite ARNI, sacubitril-valsartan (formerly LCZ696), was developed and applied to the treatment of patients with HFrEF. In the PARADIGM-HF trial, 8399 patients with HFrEF treated with guideline-directed medical therapy were randomly allocated to treatment with either enalapril or sacubitril-valsartan after a run-in period designed to ensure tolerabil­ ity of both drugs at target doses. Compared to those assigned to enala­ pril, patients assigned to sacubitril-valsartan experienced a dramatic 20% reduction in the composite primary endpoint of cardiovascular death or HF hospitalization and a 16% reduction in all-cause mortal­ ity, as well as clinically important improvements in QOL measures. Sacubitril-valsartan was well tolerated and associated with lower rates of hyperkalemia and worsening renal function, but greater rates of symptomatic hypotension, than enalapril. Guidelines now advocate a switch to ARNI for patients with symptomatic HFrEF who tolerate ACEIs and ARBs, and emerging data suggest that up-front utilization of ARNI in patients with de novo HF naïve to ACEIs/ARBs may also

CHAPTER 265 Heart Failure: Management 10 qd 10 qd 200 qd 10 qd 10 qd 200 qd be appropriate for those with adequate blood pressure to tolerate it. Given ongoing concern for angioedema, use of ARNI is contraindi­ cated in patients with prior history of angioedema, and those being transitioned from ACEIs should receive ARNI only after a 36-h gap to limit the risk of overlap. Table 265-2 lists the common neurohormonal and vasodilator regimens for HFrEF. ■ ■HEART RATE MODIFICATION Distinct from β-adrenergic receptor blockers, ivabradine, an inhibi­ tor of the If current in the sinoatrial node, selectively reduces heart rate without affecting cardiac contractility or vascular tone. The Systolic Heart Failure Treatment with Ivabradine Compared with Placebo Trial (SHIFT) was conducted in patients with NYHA class II or III HFrEF, prior HF hospitalization, sinus rhythm, and heart rate >70 beats/min. Ivabradine reduced the combined endpoint of cardiovascular-related death and HF hospitalization in proportion to the degree of heart rate reduction, which supports the notion that heart rate may be a therapeutic target in patients with HFrEF in sinus rhythm. Importantly, despite a protocol requirement for patients to be treated with a maximally tolerated dose of a beta blocker prior to study entry, 10% of patients randomized were not treated with a beta blocker, and 75% were treated at subtarget doses. Accordingly, it remains unclear whether this agent would have been effective in patients receiving robust, guideline-recommended therapy for HF; however, these data do support the potential value of ivabradine as an adjunct or alternative in those who are intolerant to initiation or dose titration of beta blockers. Clinical guidelines have been adapted

to encourage consideration of ivabradine in patients with HFrEF who remain symptomatic after treatment with guideline-based ACEI/ARB/ ARNIs, beta blockers, and mineralocorticoid receptor antagonists; are in sinus rhythm; and have a residual heart rate >70 beats/min.

■ ■SGLT-2 INHIBITION Inhibitors of SGLT-2 have been shown to reduce cardiovascular events and mortality among patients with type 2 diabetes mellitus at high cardiovascular risk or with established atherosclerotic cardiovascular disease. A particular signal of benefit has been seen regarding the inci­ dence of HF hospitalization, which was reduced by 35% in comparison to placebo in the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOMES) study. Because the cardiovascular benefits of SGLT-2 inhibition appear to be unrelated to the degree of reduction in hemoglobin A1c, it has been postulated that the HF benefits of this therapy might be extended to patients without diabetes mellitus. Recently, the Dapagliflozin in Heart Failure (DAPA-HF) study randomized 4744 patients with symptom­ atic HFrEF treated with guideline-directed medical therapy (includ­ ing a beta blocker, ACEI/ARB/ARNI, and spironolactone in >70% of patients) to treatment with either the SGLT-2 inhibitor dapagliflozin (dosage 10 mg daily) or placebo over a median duration of followup of 18.2 months. Patients allocated to dapagliflozin experienced a highly significant 26% reduction in the primary composite endpoint of worsening HF or death from cardiovascular causes, an effect that was consistent in both patients with (42%) and without diabetes mellitus at baseline. These results have been reinforced by the results of the EMPEROR-Reduced trial, in which 3730 patients with symptomatic HF and EF of ≤40% were randomized to treatment with empagliflozin (dosage 10 mg once daily) or placebo in addition to recommended therapy. Over a median 16-month follow-up, patients allocated to empagliflozin experienced a 25% reduction in the primary composite endpoint of cardiovascular death or hospitalization for HF, an effect that was again consistent regardless of the presence or absence of diabetes mellitus. Together, these studies have driven consensus guide­ lines to consider use of SGLT-2 inhibitors as foundational therapy for HF alongside ARNIs, beta blockers, and mineralocorticoid receptor antagonists. PART 6 Disorders of the Cardiovascular System ■ ■SOLUBLE GUANYLYL CYCLASE STIMULATION Soluble guanylyl cyclase (sGC) is a key enzyme of the NO signaling pathway that catalyzes synthesis of cyclic guanosine monophosphate (GMP), producing vasodilation. Vericiguat is a novel oral sGC stimu­ lator that enhances cyclic GMP and NO signaling by directly stimu­ lating sGC and sensitizing sGC to endogenous NO. The Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA) randomly assigned 5050 patients with chronic HF, NYHA class II–IV symptoms, LVEF <45%, elevated natriuretic peptide levels, and evidence of worsening HF (requiring recent hospi­ talization or intravenous diuretic therapy) despite guideline-directed medical therapy to treatment with vericiguat (target dose 10 mg) or matching placebo over a median follow-up of 11 months. The primary study results were notable for a modest 10% relative risk reduction in the primary composite outcome of cardiovascular death or HF hospitalization among those assigned to vericiguat, an effect driven principally by effects on HF hospitalization, rather than cardiovas­ cular death. As vericiguat was generally well tolerated with a low rate of serious adverse events, these data suggest a potential role for sGC stimulation as an adjunct to guideline-directed medical therapy in the high-risk group of HFrEF patients with recent congestive exacerba­ tions requiring treatment, although these data await further review by regulatory agencies and guidelines committees. ■ ■MYOSIN ACTIVATION A novel approach to augmentation of cardiac output is to prolong ventricular systole without increasing myocardial contractility. As a selective myosin activator, omecamtiv mecarbil prolongs the ejection period and increases fractional shortening without altering the force of contraction. This agent, distinct from inotropic agents, is not asso­ ciated with an increase in myocardial oxygen demand. Importantly,

the drug is available for oral, rather than intravenous, administration, enabling chronic use in the ambulatory setting. In the COSMIC-HF (Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure) trial of 448 patients with chronic HF and left ventricular systolic dysfunction, treatment with omecamtiv mecarbil for 20 weeks was associated with significant improvements in cardiac function and indices of left ventricular remodeling, as well as reductions in natriuretic peptide levels. Notably, the safety profile was comparable to placebo, with no increase in cardiac adverse events despite a mod­ est increase in cardiac troponins in patients allocated to omecamtiv mecarbil. These promising preliminary data fueled a larger clinical outcomes trial (GALACTIC-HF), in which 8256 patients with symp­ tomatic chronic HF and EF of ≤35% were randomized to treatment with omecamtiv mecarbil (25–50 mg twice daily based on plasma levels) or placebo in addition to standard HF therapy. Over a median follow-up of 21.8 months, patients allocated to omecamtiv mecarbil experienced a 14% reduction in the primary composite endpoint of death from cardiovascular causes or first HF event (hospitalization or urgent visit for HF), an outcome driven principally by reduction in HF events (no measurable effect on cardiovascular death alone). A pos­ sible signal of greater benefit in patients with features of advanced HF (lower EF, higher natriuretic peptide levels, more severe symptoms) combined with a favorable safety and tolerability profile suggests a possible role for this agent in patients with late-stage disease, although additional study is needed. ■ ■DIGOXIN Digitalis glycosides exert a mild inotropic effect, attenuate carotid sinus baroreceptor activity, and are sympatho-inhibitory. These effects decrease serum norepinephrine levels, plasma renin levels, and pos­ sibly aldosterone levels. The Digitalis Investigation Group (DIG) trial demonstrated a reduction in HF hospitalizations in the treatment group (patients with HF and sinus rhythm) but no reduction in mor­ tality or improvement in QOL. Importantly, treatment with digoxin resulted in a higher mortality rate and hospitalizations in women than men. It should be noted that low doses of digoxin are sufficient to achieve any potentially beneficial outcomes, and higher doses breach the therapeutic safety index. Although digoxin levels should be checked to minimize toxicity and although dose reductions are indi­ cated for higher levels, no adjustment is made for low levels. Generally, digoxin is now relegated as late-line therapy for patients who remain profoundly symptomatic despite optimal neurohormonal blockade and adequate volume control. ■ ■ORAL DIURETICS Neurohormonal activation results in avid salt and water retention. Diuretic therapy is typically required in patients with symptomatic HF to remedy congestive symptoms as a prelude to initiation and titration of neurohormonal therapy. Because of their potent effect on renal sodium excretion, loop diuretic agents are the preferred agents, with thiazide diuretics reserved for use in combination with loop diuretics for those with refractory volume overload. Frequent dose adjustments of loop diuretics may be necessary during longitudinal follow-up of patients with HF because of variable oral absorption and fluctuations in renal function. Patients who fail to respond to furosemide at high doses may benefit from transition to torsemide or bumetanide, which have greater oral bioavailability, but recent studies have not confirmed a greater benefit for alternatives to furosemide as a loop diuretic. Importantly, clinical trial data confirming efficacy are limited, and no data suggest that these agents improve survival. Since loop diuretics do enhance neurohumoral activation, dosing should be minimized as possible to maximize the balance of risk and benefit. ■ ■CALCIUM CHANNEL ANTAGONISTS Amlodipine and felodipine, second-generation calcium channel– blocking agents, safely and effectively reduce blood pressure in HFrEF but do not affect morbidity, mortality, or QOL. The first-generation agents, including verapamil and diltiazem, may exert negative inotro­ pic effects and destabilize previously asymptomatic patients. Accord­ ingly, their use should be discouraged in patients with HFrEF.

■ ■ANTI-INFLAMMATORY THERAPY Targeting inflammatory cytokines such as tumor necrosis factor α (TNF-α) for the management of HF by using anticytokine agents such as infliximab and etanercept has been unsuccessful and associated with worsening HF. Use of intravenous immunoglobulin therapy in nonischemic etiology of HF has not been shown to result in beneficial outcomes. Nonspecific immunomodulation has been tested in the Advanced Chronic Heart Failure Clinical Assessment of Immune Modulation Therapy (ACCLAIM-HF) trial where ex vivo exposure of a blood sample from systolic HF patients to controlled oxidative stress was hypothesized to initiate apoptosis of leukocytes soon after intramuscular gluteal injection of the treated sample. The physiologic response to apoptotic cells results in a reduction in inflammatory cytokine production and upregulation of anti-inflammatory cyto­ kines. This promising hypothesis was not proven, although certain subgroups (those with no history of previous myocardial infarction and those with mild HF) showed signals in favor of immunomodula­ tion. Most recently, in the Canakinumab Anti-inflammatory Throm­ bosis Outcomes Study (CANTOS), treatment of post–myocardial infarction patients with elevated high-sensitivity C-reactive protein using a monoclonal antibody targeted at interleukin 1β was associ­ ated with a dose-dependent reduction in hospitalization for HF and HF-associated mortality in post hoc analyses. Whether this approach might have relevance for patients with established HF remains unclear. ■ ■HMG-CoA REDUCTASE INHIBITORS (STATINS) Potent lipid-altering and pleiotropic effects of statins reduce major cardiovascular events and improve survival in non-HF populations. Once HF is well established, this therapy may not be as beneficial and theoretically could even be detrimental by depleting ubiquinone in the electron transport chain. Two trials, Controlled Rosuvastatin Mul­ tinational Trial in Heart Failure (CORONA) and Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza Cardiac (GISSI-HF), have tested low-dose rosuvastatin in patients with HFrEF and demon­ strated no improvement in aggregate clinical outcomes. If statins are required to treat progressive atherosclerotic vascular disease or signifi­ cant dyslipidemia in the background setting of HF, then they should be employed. However, no clear rationale appears to exist for routine use of statin therapy in nonischemic HF. ■ ■ANTICOAGULATION AND ANTIPLATELET THERAPY HFrEF is accompanied by a hypercoagulable state and therefore a high risk of thromboembolic events, including stroke, pulmonary embolism, and peripheral arterial embolism. Although the value of long-term oral anticoagulation is established in certain groups, including patients with atrial fibrillation, the data are insufficient to support the use of warfarin in patients in normal sinus rhythm without a history of thromboembolic events or echocardiographic evidence of left ventricular thrombus. In the large Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial, full-dose aspi­ rin or international normalized ratio–controlled warfarin was tested with follow-up for 6 years. Among patients with reduced LVEF in sinus rhythm, there was no significant overall difference in the pri­ mary outcome between treatment with warfarin and treatment with aspirin. A reduced risk of ischemic stroke with warfarin was offset by an increased risk of major hemorrhage. A recent trial of the direct oral anticoagulant rivaroxaban at low dose (2.5 mg daily) for patients with ischemic heart disease, HFrEF, and sinus rhythm also indicated no reduction in stroke or ischemic events compared with placebo. Aspirin blunts ACEI-mediated prostaglandin synthesis, but the clini­ cal importance of this finding remains unclear. Current guidelines support the use of aspirin in patients with ischemic cardiomyopathy who do not have a contraindication, although the risk-benefit balance in older patients at higher risk for bleeding complications may be less favorable. ■ ■FISH OIL Treatment with long-chain omega-3 polyunsaturated fatty acids (ω-3 PUFAs) has been shown to be associated with modestly improved

clinical outcomes in patients with HFrEF. This observation from the GISSI-HF trial was extended to measurements of ω-3 PUFAs in plasma phospholipids at baseline and after 3 months. Three-month treatment with ω-3 PUFAs enriched circulating eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Low EPA levels are inversely related to total mortality in patients with HFrEF.

CHAPTER 265 ■ ■MICRONUTRIENTS A growing body of evidence suggests an association between HF and micronutrient status. Reversible HF has been described because of severe thiamine and selenium deficiency. Thiamine deficiency has received attention in HF because malnutrition and diuretics are prime risk factors for thiamine loss. Small exploratory randomized studies have suggested a benefit of supplementation with thiamine in HFrEF with evidence of improved cardiac function. This finding is restricted to chronic HF states and does not appear to be beneficial in the ADHF phenotype. Due to the exploratory nature of the evidence, no recom­ mendations for routine supplementation or testing for thiamine defi­ ciency can be made. Heart Failure: Management ■ ■ENHANCED EXTERNAL COUNTERPULSATION Peripheral lower extremity therapy using graded external pneumatic compression at high pressure is administered in 1-h sessions for 35 treatments (7 weeks) and has been proposed to reduce angina symp­ toms and extend time to exercise-induced ischemia in patients with coronary artery disease. The Prospective Evaluation of Enhanced External Counterpulsation in Congestive Heart Failure (PEECH) study assessed the benefits of enhanced external counterpulsation in the treatment of patients with mild-to-moderate HF. This random­ ized trial improved exercise tolerance, QOL, and NYHA functional classification but without an accompanying increase in peak oxygen consumption. A placebo effect due to the nature of the intervention simply cannot be excluded. ■ ■EXERCISE The Heart Failure: A Controlled Trial Investigating Outcomes of Exer­ cise Training (HF-ACTION) study investigated short-term (3-month) and long-term (12-month) effects of a supervised exercise train­ ing program in patients with moderate HFrEF. Exercise was safe, improved patients’ sense of well-being, and correlated with a trend toward mortality reduction. Maximal changes in 6-min walk distance were evident at 3 months with significant improvements in cardiopul­ monary exercise time and peak oxygen consumption persisting at 12 months. Therefore, exercise training is recommended as an adjunctive treatment in patients with HF. ■ ■MANAGEMENT OF SELECTED COMORBIDITY Sleep-disordered breathing is common in HF and particularly in HFrEF. A range of presentations exemplified by obstructive sleep apnea, central sleep apnea, and its extreme form of Cheyne-Stokes breathing are noted. Frequent periods of hypoxia and repeated micro- and macro-arousals trigger adrenergic surges, which can worsen hypertension and impair systolic and diastolic function. A high index of suspicion is required, especially in patients with difficult-to-control hypertension or with predominant symptoms of fatigue despite reverse remodeling in response to optimal medical therapy. Worsening of right heart function with improvement of left ventricular function noted on medical therapy should immediately trigger a search for underlying sleep-disordered breathing or pulmonary complications such as occult embolism or pulmonary hypertension. Treatment with nocturnal positive airway pressure improves oxygenation, LVEF, and 6-min walk distance. However, no conclusive data exist to support this therapy as a disease-modifying approach with reduction in mortality. A recent trial using adaptive servo-ventilation triggered by a minute ventilation sensor in patients who had HFrEF and predominantly central sleep apnea increased all-cause and cardiovascular mortality, so this approach should be avoided; however, modification of this approach using lower background pressures and an alternative trigger based on peak airflow appeared to be safe in patients with sleep apnea and HFrEF enrolled in the ADVENT-HF trial, although there was

no discernible benefit with regard to clinical outcomes. Whether this modified approach to adaptive servo-ventilation will be appropriate for management of selected patients with HFrEF and central sleep apnea requires further study.

Anemia is common in HF patients, reduces functional status and QOL, and is associated with increased proclivity for hospital admis­ sions and mortality. Anemia in HF is more common in the elderly, in those with advanced stages of HFrEF, in the presence of renal insuf­ ficiency, and in women and African Americans. The mechanisms include iron deficiency, dysregulation of iron metabolism, and occult gastrointestinal bleeding. Intravenous iron using either iron sucrose or carboxymaltose (Ferric Carboxymaltose Assessment in Patients with Iron Deficiency and Chronic Heart Failure [FAIR-HF] trial) has been shown to correct anemia and improve functional capacity. Another trial, CONFIRM-HF, enrolled similar patients with iron deficiency (ferritin <100 ng/mL or 100–300 ng/mL if transferrin saturation <20%) and demonstrated that use of ferric carboxymaltose in a simplified high-dose schedule resulted in improvement in functional capacity, symptoms, and QOL. These symptomatic benefits of iron repletion, however, do not appear to translate clearly to benefits on longer term clinical outcomes. In the AFFIRM-AHF trial of patients with HF, LVEF <50%, and iron deficiency, randomization to ferric carboxymaltose compared with placebo was associated with a lower rate of cardio­ vascular death and total HF hospitalizations that narrowly missed the margin for statistical significance. Similar results were seen in the IRONMAN trial of another iron polysaccharide, ferric derisomaltose. The results of both of these trials may have been confounded by the coronavirus disease 2019 (COVID-19) pandemic, and pooled data suggested a possible favorable effect on HF hospitalizations. However, the HEART-FID trial, which randomized 3065 ambulatory HF patients with LVEF ≤40% and iron deficiency to treatment with ferric carboxy­ maltose or placebo, showed no benefit with regard to the primary hierarchical composite of death, hospitalizations for HF, or 6-minute walk distance. Accordingly, it seems that benefits of iron repletion in this population are likely confined to reduction in symptoms, and perhaps HF hospitalizations, particularly among those with iron defi­ ciency. Oral iron supplementation does not appear to be effective in treating iron deficiency in HF. Erythropoiesis-regulating agents such as erythropoietin analogues have been studied with disappointing results. The Reduction of Events by Darbepoetin Alfa in Heart Failure (REDHF) trial demonstrated that treatment with darbepoetin alfa did not improve outcomes in patients with systolic HF but increased the risk of thromboembolism-related adverse events. PART 6 Disorders of the Cardiovascular System Depression is common in HFrEF, with a reported prevalence of one in five patients, and is associated with a poor QOL, limited functional status, and increased risk of morbidity and mortality in this popula­ tion. However, the largest randomized study of depression in HFrEF, the Sertraline Against Depression and Heart Disease in Chronic Heart Failure (SADHART-CHF) trial, showed that although sertraline was safe, it did not provide greater reduction in depression or improve car­ diovascular status among patients with HF and depression compared with nurse-driven multidisciplinary management. Atrial arrhythmias, especially atrial fibrillation, are common and serve as a harbinger of worse prognosis in patients with HF. When rate control is inadequate or symptoms persist, pursuing a rhythm control strategy is reasonable. Rhythm control may be achieved via pharmacotherapy or by percutaneous or surgical techniques, and referral to practitioners or centers experienced in these modalities is recommended. Antiarrhythmic drug therapy should be restricted to amiodarone and dofetilide, both of which have been shown to be safe and effective but do not alter the natural history of the underlying disease. The Antiarrhythmic Trial with Dronedarone in Moderateto-Severe Congestive Heart Failure Evaluating Morbidity Decrease (ANDROMEDA) studied the effects of the novel antiarrhythmic agent dronedarone and found an increased mortality due to worsening HF. Given the potential adverse effects and limited efficacy of pharma­ cologic strategies for maintenance of sinus rhythm, catheter ablation has been explored as an alternative. In the CASTLE-AF trial, among

363 patients with HF, LVEF ≤35%, and paroxysmal or persistent atrial fibrillation randomized to treatment with catheter ablation or medical therapy, those assigned to catheter ablation experienced a significantly lower rate of death or hospitalization. These results are supported by similar outcomes in the CASTLE-HTX trial, which sought to include patients with advanced HF; however, this aspect is disputed. These data argue for consideration of restoration of sinus rhythm with catheter ablation as a preferred strategy to antiarrhythmic drugs in patients with HF and reduced EF. Diabetes mellitus is a frequent comorbidity in HF. Prior stud­ ies using thiazolidinediones (activators of peroxisome proliferatoractivated receptors) have been associated with worsening HF. GLP-1 agonists such as liraglutide have also been tested and do not lead to worsening in HF but require more study. The role of SGLT-2 inhibitors in HF has been previously discussed, and they represent an important disease-modifying therapy in diabetic patients with HF. ■ ■NEUROMODULATION USING DEVICE THERAPY Autonomic dysfunction is common in HF, and attempts at using devices to modulate the sympathetic and parasympathetic systems have been undertaken. Broadly, devices that achieve vagal nerve stimulation, baroreflex activation, renal sympathetic denervation, spinal cord stimulation, or left cardiac sympathetic denervation have been employed. While small preclinical and clinical studies have dem­ onstrated benefits, large, randomized trials, when conducted, have failed. The INOVATE-HF study tested vagal nerve stimulation versus optimal medical therapy among individuals with stable HF. Vagus nerve stimulation did not reduce the rate of death or hospitalization for HF. However, functional capacity and QOL were favorably affected by vagus nerve stimulation. The ANTHEM-HFrEF trial, which enrolled only half its intended population, did not show a signal for benefit of vagal nerve stimulation. ■ ■CARDIAC CONTRACTILITY MODULATION Cardiac contractility modulation (CCM) is a device-based therapy for HF that involves nonexcitatory electrical stimulation to the right ven­ tricular septal wall during the absolute myocardial refractory period to augment the strength of subsequent myocardial contraction. A series of small, randomized, prospective clinical trials, as well as several realworld observational registries, have suggested that application of CCM to selected patients with HF may improve symptoms, functional capac­ ity, and QOL, although no effect on hard clinical outcomes such as HF hospitalization or mortality has been established. The predominant benefits of CCM appear to accrue to those with symptomatic HFrEF (EF 25–45%) and narrow QRS duration (for whom cardiac resynchro­ nization therapy is not an option), and the approach can be combined with an implantable defibrillator. The device is not currently endorsed for routine use by clinical treatment guidelines in the United States or Europe and is deemed to require more evidence prior to widespread adoption. CARDIAC RESYNCHRONIZATION THERAPY Nonsynchronous contraction between the walls of the left ventricle (intraventricular) or between the ventricular chambers (interven­ tricular) impairs systolic function, decreases mechanical efficiency of contraction, and adversely affects ventricular filling. Mechanical dys­ synchrony results in an increase in wall stress and worsens functional mitral regurgitation. The single most important association of extent of dyssynchrony is a widened QRS interval on the surface electrocardio­ gram, particularly in the presence of a left bundle branch block pattern. With placement of a pacing lead via the coronary sinus to the lateral wall of the ventricle, cardiac resynchronization therapy (CRT) enables a more synchronous ventricular contraction by aligning the timing of activation of the opposing walls. Early studies showed improved exercise capacity, reduction in symptoms, and evidence of reverse remodeling. The Cardiac Resynchronization in Heart Failure Study (CARE-HF) trial was the first study to demonstrate a reduction in allcause mortality with CRT placement in patients with HFrEF on opti­ mal therapy with continued moderate-to-severe residual symptoms of

NYHA class III or IV HF. More recent clinical trials have demonstrated disease-modifying properties of CRT in even minimally symptomatic patients with HFrEF, including the Resynchronization–Defibrillation for Ambulatory Heart Failure Trial (RAFT) and Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Ther­ apy (MADIT-CRT), both of which sought to use CRT in combination with an implantable defibrillator. Most benefit in mildly symptomatic HFrEF patients accrues from applying this therapy in those with a QRS width of >149 ms and a left bundle branch block pattern. Attempts to further optimize risk stratification and expand indications for CRT using modalities other than electrocardiography have proven disap­ pointing. Echocardiographically derived measures of dyssynchrony vary tremendously, and narrow QRS dyssynchrony has not proven to be a good target for treatment. Uncertainty surrounds the benefits of CRT in those with ADHF, a predominant right bundle branch block pattern, atrial fibrillation, and evidence of scar in the lateral wall, which is the precise location where the CRT lead is positioned. His-Purkinje conduction system or left bundle branch area pacing are evolving alter­ natives to biventricular pacing; however, the evidence supporting their benefits over conventional CRT remains less certain. SUDDEN CARDIAC DEATH PREVENTION IN HEART FAILURE Sudden cardiac death (SCD) due to ventricular arrhythmias is the mode of death in approximately half of patients with HF and is par­ ticularly proportionally prevalent in HFrEF patients with early stages of the disease. Patients who survive an episode of SCD are at very high risk and qualify for placement of an implantable cardioverterdefibrillator (ICD). Although primary prevention is challenging, the degree of residual left ventricular dysfunction despite optimal medical therapy (≤35%) to allow for adequate remodeling and the underlying etiology (post–myocardial infarction or ischemic cardiomyopathy) are the two single most important risk markers for stratification of need and benefit. Currently, patients with NYHA class II or III symptoms of HF and an LVEF <35%, irrespective of etiology of HF, are appropriate candidates for ICD prophylactic therapy. In patients with a myocardial infarction and optimal medical therapy with residual LVEF ≤30% (even when asymptomatic), placement of an ICD is appropriate. A recent Danish trial suggested that prophylactic ICD implantation in patients with symptomatic systolic HF not caused by coronary artery disease was not associated with a significantly lower long-term rate of death from any cause than was usual clinical care. In this trial, benefits were noted in those aged <60 years. In patients with a terminal illness and a predicted life span of <6 months or in those with NYHA class IV symptoms who are refractory to medications and who are not candi­ dates for transplant, the risks of multiple ICD shocks must be carefully weighed against the survival benefits. If a patient meets the QRS crite­ ria for CRT, combined CRT with ICD is often employed (Table 265-3). SURGICAL THERAPY IN HEART FAILURE Coronary artery bypass grafting (CABG) is considered in patients with ischemic cardiomyopathy with multivessel coronary artery disease. The recognition that hibernating myocardium, defined as myocardial tissue with abnormal function but maintained cellular function, could recover after revascularization led to the notion that revasculariza­ tion with CABG would be useful in those with living myocardium. Revascularization is most robustly supported in individuals with ongoing angina and left ventricular failure. Revascularizing those with left ventricular failure in the absence of angina remains controversial. The Surgical Treatment for Ischemic Heart Failure (STICH) trial in patients with an EF of ≤35% and coronary artery disease amenable to CABG demonstrated no significant initial benefit compared to medi­ cal therapy. However, patients assigned to CABG had lower rates of death from cardiovascular causes and of death from any cause or hos­ pitalization for cardiovascular causes over 10 years than among those who received medical therapy alone. An ancillary study of this trial also determined that the detection of hibernation (viability) before revascularization did not materially influence the efficacy of this

TABLE 265-3  Principles of ICD Implantation for Primary Prevention of Sudden Death PRINCIPLE COMMENT Arrhythmia–sudden death mismatch Sudden death in heart failure patients is generally due to progressive LVD, not a focal arrhythmia substrate (except in patients with post-MI HF with scar) CHAPTER 265 Diminishing returns with advanced disease Intervention at early stages of HF most successful since sudden death incidence diminishes as cause of death with increasing severity of HF Timing of benefits LVEF should be evaluated on optimal medical therapy or after revascularization before ICD therapy is employed; no benefit to ICD implant within 40 days of an MI (unless for secondary prevention) Heart Failure: Management Estimation of benefits and prognosis Patients and clinicians often overestimate benefits of ICDs; an ICD discharge is not equivalent to an episode of sudden death (some ventricular arrhythmias terminate spontaneously); appropriate ICD discharges are associated with a worse near-term prognosis; recent trials with uncertain benefit in nonischemic cardiomyopathy (especially in those >68 years old) Abbreviations: HF, heart failure; ICD, implantable cardioverter-defibrillator; LVD, left ventricular disease; LVEF, left ventricular ejection fraction; MI, myocardial infarction. approach, nor did it help to define a population unlikely to benefit if hibernation was not detected. Notably, a strategy of percutaneous cor­ onary revascularization in patients with ischemic left ventricular dys­ function in the REVIVED-BCIS2 study did not show clinical benefit. Surgical ventricular restoration (SVR), a technique character­ ized by infarct exclusion to remodel the left ventricle by reshaping it surgically in patients with ischemic cardiomyopathy and dominant anterior left ventricular dysfunction, has been proposed. However, in a 1000-patient trial in patients with HFrEF who underwent CABG alone or CABG plus SVR, the addition of SVR to CABG had no disease-modifying effect. However, left ventricular aneurysm surgery is still advocated in those with refractory HF, ventricular arrhythmias, or thromboembolism arising from an akinetic aneurysmal segment of the ventricle. Other remodeling procedures, such as use of an external mesh-like net attached around the heart to limit further enlargement, have not been shown to provide hard clinical benefits, although favor­ able cardiac remodeling was noted. Functional (or secondary) mitral regurgitation (MR) occurs with varying degrees in patients with HFrEF and dilated ventricles, and its severity is correlated inversely with prognosis. Annular dilatation and leaflet noncoaptation related to distorted papillary muscle geom­ etry in the context of ventricular remodeling is typically responsible, although in patients with ischemic heart disease and prior myocardial infarction, leaflet tethering and displacement may contribute. The primary approach to management of functional MR is optimization of guideline-directed medical therapy, followed by CRT in eligible patients, but relief may be incomplete for many patients with advanced HF. In these patients with HF and severe left ventricular dysfunc­ tion who are not candidates for surgical coronary revascularization, surgical mitral valve repair (MVR) to remedy functional MR car­ ries significant risk and remains controversial. The development of percutaneous approaches to edge-to-edge MVR has provided a less invasive approach that enables reduction in functional MR at lower risk than conventional surgery. Recently, two large, randomized tri­ als of transcatheter MVR using this approach have been conducted in patients with symptomatic HFrEF and moderate-severe functional MR. In the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) study, patients allocated to MVR versus standard HF therapy experienced a marked reduction in both HF hospitalizations and mortality at 2 years, supporting the efficacy of this approach. In the second trial, Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgi­ tation (MITRA-FR), which employed a similar design, the rates of

death or HF hospitalization did not differ between the percutaneous MVR and medical therapy groups. The precise reason for discrepant results between these studies remains unclear but may be related to differences in background utilization of guideline-directed medical therapy, procedural success rates, and patient selection (particularly whether the severity of MR is proportionate or disproportionate to the degree of left ventricular cavity dilation). Because mortality rates at 2 years remain high even with percutaneous MVR, patients with advanced symptoms of HF in whom MR severity is driven principally by end-stage left ventricular remodeling should also be considered for advanced therapies such as mechanical circulatory support if symp­ toms remain refractory to medical therapy.

PART 6 Disorders of the Cardiovascular System CELLULAR AND GENE-BASED THERAPY The cardiomyocyte possesses regenerative capacity, and such renewal is accelerated under conditions of stress and injury, such as an isch­ emic event or HF. Investigations that use either bone marrow–derived precursor cells or autologous cardiac-derived cells have gained trac­ tion but have not generally improved clinical outcomes in a convinc­ ing manner. More promising, however, are cardiac-derived stem cells. Two preliminary pilot trials delivering cells via an intracoronary approach have been reported. In one, autologous c-kit–positive cells isolated from the atria obtained from patients undergoing CABG were cultured and reinfused. In another, cardiosphere-derived cells grown from endomyocardial biopsy specimens were used. These small trials demonstrated improvements in left ventricular function but require far more work to usher in a clinical therapeutic success. Efforts to utilize mesenchymal stem cells to facilitate left ventricular recovery and weaning from mechanical circulatory support in patients with left ventricular assist devices have also been disappointing. The appropri­ ate route of administration, the quantity of cells to achieve a minimal therapeutic threshold, the constitution of these cells (single source or mixed), the mechanism by which benefit accrues, and short- and longterm safety remain to be elucidated. Targeting molecular aberrations using gene transfer therapy, mostly with an adenoviral vector, has been tested in HFrEF. A cel­ lular target includes calcium cycling proteins such as inhibitors of phospholamban such as SERCA2a, which is deficient in patients with HFrEF. Primarily responsible for reincorporating calcium into the sarcoplasmic reticulum during diastole, this target was tested in the CUPID (Efficacy and Safety Study of Genetically Targeted Enzyme Replacement Therapy for Advanced Heart Failure) trial. This study used coronary arterial infusion of adeno-associated virus type 1 carrying the gene for SERCA2a and initially demonstrated that natriuretic peptides were decreased, reverse remodeling was noted, and symptomatic improvements were forthcoming. However, a confirmatory trial failed to meet its primary efficacy endpoint. The DREAM-HF trial was a randomized, double-blind, multicenter study of a single transendocardial administration of mesenchymal precur­ sor cells in patients in HFrEF. The primary and secondary endpoints of the trial were negative. More advanced therapies for late-stage HF such as left ventricu­ lar assist devices and cardiac transplantation are covered in detail in Chap. 271. DISEASE MANAGEMENT AND SUPPORTIVE CARE Despite stellar outcomes with medical therapy, admission rates fol­ lowing HF hospitalization remain high, with nearly half of all patients readmitted to hospital within 6 months of discharge. Recurrent HF and related cardiovascular conditions account for only half of read­ missions in patients with HF, whereas other comorbidity-related conditions account for the rest. The key to achieving enhanced out­ comes must begin with the attention to transitional care at the index hospitalization with facilitated discharge through comprehensive discharge planning, patient and caregiver education, appropriate use of visiting nurses, and planned follow-up. Early postdischarge followup, whether by telephone or clinic-based, may be critical to ensuring

stability because most HF-related readmissions tend to occur within the first 2 weeks after discharge. The results of the recent STRONG-HF trial suggest that a strategy of intensive titration of medical therapy to guideline-recommended targets within 2 weeks of hospital discharge and frequent ambulatory follow-up through 2 months is associated with a substantial reduction in all-cause mortality and HF readmis­ sion at 180 days, underscoring the importance of timely application of targeted pharmacologic therapy and intensive clinical surveillance in the early postdischarge interval. Although routinely advocated, intensive surveillance of weight and vital signs with use of telemonitoring has not decreased hospi­ talizations. Serial measurement of intrathoracic impedance has been utilized to identify early signals of worsening congestion to guide preemptive management to obviate the need for hospitalization. How­ ever, when systematically studied in randomized trials, this approach has not been proven to improve outcomes in comparison with routine HF care and may even enhance the rate of hospitalization due to the high frequency of impedance threshold crossings and device alerts. Implantable hemodynamic monitoring systems that directly measure pulmonary artery pressure tend to provide signals for early decom­ pensation, and in patients with HF and moderately advanced symp­ toms across the full spectrum of EF, such systems have been shown to provide information that can allow implementation of therapy to avoid hospitalizations by as much as 39% (in the CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients [CHAMPION] trial). More recently, in the larger Hemodynamic Guided Management of Heart Failure (GUIDE-HF) Trial, hemodynamic-guided management with the same sensor did not result in a lower rate of composite mortality and total HF events in the primary analysis, the results of which were confounded by the impact of the COVID-19 pandemic on overall hos­ pitalization rates. In a prespecified analysis of patients enrolled prior to the pandemic onset, there was a statistically significant reduction in the composite endpoint driven by lower rates of HF hospitalization in those assigned to the hemodynamic-guided therapy arm. Benefits were consistent across patients with prior HF hospitalization within 12 months and in those with elevated natriuretic peptide levels but no recent hospitalization. These data in aggregate suggest that hemody­ namic-guided management is a useful adjunct to routine clinical care in selected high-risk patients with chronic HF across the spectrum of EF. Alternate approaches to longitudinal HF monitoring that lever­ age multiparameter signals derived from implantable cardiac rhythm devices such as pacemakers and defibrillators to provide a global index of congestion are also being explored as adjuncts to longitudinal HF management. Once HF becomes advanced, regularly scheduled review of the disease course and options with the patient and family is recom­ mended, including discussions surrounding end-of-life preferences when patients are comfortable in an outpatient setting. As the disease state advances further, integrating care with social workers, pharma­ cists, and community-based nursing may be critical in improving patient satisfaction with the therapy, enhancing QOL, and avoid­ ing HF hospitalizations. Equally important is attention to seasonal influenza vaccinations and periodic pneumococcal vaccines that may obviate non-HF hospitalizations in these ill patients. When nearing end of life, facilitating a shift in priorities to outpatient and hospice palliation is key, as are discussions around advanced therapeutics and continued use of ICD prophylaxis, which may worsen QOL and prolong death. Small, randomized trials have suggested that systematic integration of palliative care considerations in high-risk HF patients by a specialized team has been demonstrated to improve QOL, anxiety, depression, and spiritual well-being and to facilitate goal-concordant care. GLOBAL CONSIDERATIONS Substantial differences exist in the practice of HF therapeutics and outcomes by geographic location. The penetrance of CRT and ICD is higher in the United States than in Europe. Conversely, therapy unavailable in the United States, such as levosimendan, is designated

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266 Classification of Cardiomyopathy

as useful in Europe, although the usefulness is disputable. Variation in the benefits of beta blockers based on world region remains an area of controversy. In oral pharmacologic therapy trials of HFrEF, patients from southwest Europe have a lower incidence of ischemic cardiomy­ opathy and those in North America tend to have more diabetes and prior coronary revascularization. There is also regional variation in medication use even after accounting for indication. In trials of HF, disparate effects are noted across populations. As a recent example, in TOPCAT, the drug spironolactone was effective when used in the U.S. population, whereas patients recruited from Russia and con­ tiguous territories showed no difference. Whether this represents population differences or trial conduct disparity remains a serious question. ADHF patients in Eastern Europe tend to be younger, with higher EFs and lower natriuretic peptide levels. Patients from South America tend to have the lowest rates of comorbidities, revascular­ ization, and device use. In contrast, patients from North America have the highest comorbidity burden with high revascularization and device use rates. Given geographic differences in baseline char­ acteristics and clinical outcomes, the generalizability of therapeutic outcomes in patients in the United States and Western Europe may require verification. ■ ■FURTHER READING Anker SD et al: Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med 385:1451, 2021. Borlaug BA: The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 11:507, 2014. Braunwald E: Heart failure. JACC Heart Fail 1:1, 2013. Heidenreich PA et al: 2022 AHA/ACC/HFSA guideline for the management of heart failure: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 145:e895, 2022. Hein AM et al: Medical management of heart failure with reduced ejection fraction in patients with advanced renal disease. JACC Heart Fail 7:371, 2019. Hollenberg SM et al: 2019 ACC Expert Consensus Decision Pathway on Risk Assessment, Management, and Clinical Trajectory of Patients Hospitalized with Heart Failure: A report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 74:1966, 2019. Hussein AA, Wilkoff BL: Cardiac implantable electronic device therapy in heart failure. Circ Res 124:1584, 2019. Kittleson MM et al: 2023 ACC Expert Consensus Decision Pathway on Management of Heart Failure With Preserved Ejection Fraction: A report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 81:1835, 2023. Kusumoto FM et al: HRS/ACC/AHA expert consensus statement on the use of implantable cardioverter-defibrillator therapy in patients who are not included or not well represented in clinical trials. Circu­ lation 130:94, 2014. McMurray JJ et al: Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 371:993, 2014. McMurray JJV et al: Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 381:1995, 2019. Obadia JF et al: Percutaneous mitral valve repair or medical ther­ apy for secondary mitral regurgitation. N Engl J Med 379:2297, 2018. Packer M, Grayburn PA: Neurohormonal and transcatheter repair strategies for proportionate and disproportionate functional mitral regurgitation in heart failure. JACC Heart Fail 7:518, 2019. Packer M et al: Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 383:1413, 2020. Solomon SD et al: Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med 381:1609, 2019. Solomon SD et al: Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med 387:1089, 2022. Stone GW et al: Transcatheter mitral valve repair in patients with heart failure. N Engl J Med 379:2307, 2018.

in systolic heart failure. N Engl J Med 384:105, 2021. Velazquez EJ et al: Coronary-artery bypass surgery in patients with ischemic cardiomyopathy. N Engl J Med 374:1511, 2016. CHAPTER 266 Classification of Cardiomyopathy Lynne Warner Stevenson, Neal K. Lakdawala,

Joseph Loscalzo

Classification of

Cardiomyopathy The term cardiomyopathy describes primary disease of the heart muscle itself, originally excluding myocardial dysfunction resulting from other cardiovascular disease. Common usage, however, often includes diagnoses of ischemic cardiomyopathy, valvular cardiomyopa­ thy, and hypertensive cardiomyopathy. The traditional morphologic classification defines the three major phenotypes of hypertrophic car­ diomyopathy (HCM), dilated cardiomyopathy (DCM), and restrictive cardiomyopathy (RCM) (Table 266-1). Left ventricular wall thickness is increased (≥13–15 mm depending on context) and ejection fraction is normal or high with HCM. DCM is defined when the left ventricular ejection fraction (LVEF) is ≤0.50, but most clinical presentations are with LVEF ≤0.40. RCMs typically pres­ ent with mildly decreased ejection fraction and variably increased wall thickness and are often defined less by morphology than by evidence of abnormal diastolic physiology on echocardiography or invasive hemodynamic measurement. Although these phenotypes are helpful to guide initial evalua­ tion of clinical disease, the phenotypes increasingly overlap over time as there is increasing recognition that DCMs can respond to recommended therapies with “reverse remodeling” to higher ejec­ tion fraction and smaller ventricles, while HCM evolves in ~5% of patients to a reduced ejection fraction (HCM-rEF) with more restric­ tive physiology. A fourth evolving phenotype with predominantly genetic causes is arrhythmogenic right ventricular cardiomyopathy (ARVC), originally termed arrhythmogenic right ventricular dysplasia, characterized by life-threatening arrhythmias and abnormal right ventricular structure and function, with variable expression in the left ventricle. As new phenotype-genotype connections are revealed, the terminology continues to evolve, as arrhythmogenic right ven­ tricular dysplasia may also be termed ACM-RV (arrhythmogenic cardiomyopathy–right ventricle predominant), in line with ACM-LV, in which the arrhythmias and structural changes are predominantly in the left ventricle. If the ACM terminology is expanded to include acquired disease, the granulomatous disease of sarcoidosis and the protozoal myocarditis of Chagas’ disease can both cause phenotypes with cardiomyopathy and ventricular arrhythmias that qualify as ACM-RV and ACM-LV. Reliance upon phenotypic presentation is diminishing as more is learned about the underlying causes of cardiomyopathy. The cata­ log is rapidly growing of pathogenic genetic variants that can lead to heritable cardiomyopathies, which new imaging techniques can now sometimes identify prior to clinical disease. Expanding knowledge of immune response pathways reveals how some aspects of myocardi­ tis may also be inherited and how they contribute to infectious and noninfectious inflammation that can cause clinical myocarditis and cardiomyopathy. Diagnosis and outcomes of clinical cardiomyopathies are further complicated by the frequent two-hit models where the clinical expression of a genetic predisposition to cardiomyopathy may

TABLE 266-1  Classification of Cardiomyopathies CARDIOMYOPATHY (CM) PHENOTYPE DIAGNOSTIC CRITERIA OTHER MORPHOLOGY COMMON CHALLENGES IN DIAGNOSIS Hypertrophic cardiomyopathy (HCM) Mid-range LVEF includes rare transition to HCM with LV systolic dysfunction (LVEF <0.50) Septal thickness in men ≥15 mm,

≥13 mm in women. 13–14 mm may be diagnostic in relatives of proband with known HCM or with positive genetic test. LVEF ≥ normal, usually >0.60 LV chamber volume ≤normal. PART 6 Disorders of the Cardiovascular System Mid-range LVEF (0.40–0.50) Restrictive cardiomyopathy (RCM) Least common cardiomyopathy (CM) phenotype Functional diagnosis based on moderate-severe diastolic dysfunction and/or elevated cardiac filling pressures. Wall thickness often increased but can appear normal. LVEF usually mildly reduced, occasionally normal. Mid-range LVEF is often a transition in DCM, either deterioration from early DCM or improvement into DCM remission LV dilated cardiomyopathy (DCM) • Early: LVEF ≤0.50 and/or LVEDV >112% normal for age/sex or LVEDD >95% predicted sex/height • LVEF ≤0.40: threshold for traditionally recommended therapies for heart failure with low LVEF • Persistent LVEF ≤0.30–0.35: threshold for primary prevention ICD Arrhythmogenic CM Dominant in LV (ACM-LV) Usually DCM, occasionally RCM Morphologic criteria generally those for DCM. Ventricular tachyarrhythmias dominate without or before severely reduced LVEF and heart failure. Primary prevention ICD considered even when LVEF >0.35. Arrhythmogenic CM Dominant in RV (ACM-RV; also termed ARVC) Modified task force criteria from 2010 include combinations of major and minor criteria Ventricular arrhythmias and evidence of both ACM-RV and ACM-LV Biventricular arrhythmogenic CM Trait of LV noncompaction (LVNC) Implications determined by CM phenotype and genotype Often assessed by maximum ratio of noncompacted/compacted LV myocardium >2.3 and other criteria Abbreviations: ICD, implantable cardioverter-defibrillator; LGE, late gadolinium enhancement; LV, left ventricle; LVEDD, left ventricular end-diastolic dimension; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; NSVT, nonsustained ventricular tachycardia; PVC, premature ventricular contraction. be triggered by acquired conditions such as infections, toxic exposures, pregnancy, or tachycardia. CLINICAL PRESENTATION AND EVALUATION OF CARDIOMYOPATHY Early symptoms of cardiomyopathy often reflect exertional intolerance with breathlessness or fatigue. Arrhythmias are often presenting events of unrecognized cardiomyopathy, which can also present with embolic events related to atrial fibrillation or apical ventricular thrombi. Car­ diomyopathy may often present first with the syndrome of congestion, with fluid retention and elevated left heart filling pressures causing shortness of breath with minimal activity or even at rest, particularly with orthopnea. It may be accompanied by elevated right-sided filling pressures causing edema and often abdominal symptoms. The non­ specific historical term congestive heart failure describes the syndrome

Patterns of LV hypertrophy (LVH) in HCM: • Asymmetric septal hypertrophy • Inverse (sigmoid pattern) septal Distinction from athlete’s heart and severe chronic hypertension The storage diseases of GLA (AndersonFabry), PRKAG2, and LAMP2 (Danon’s), which can mimic HCM morphology Exclude aortic stenosis In older patients, exclude amyloidosis, which can also cause asymmetric septal thickening hypertrophy • Concentric LVH • Apical hypertrophy Usually marked atrial enlargement Although both ventricles affected, clinical right heart failure often dominates. Marked wall thickness suggests: • Amyloidosis • Inherited storage diseases • Inborn metabolic diseases Common etiologies of radiation, scleroderma-type connective tissue diseases, doxorubicin and other medications Some sarcomeric variants and storage diseases can appear with RCM as well as HCM phenotypes Although traditionally listed as restrictive, sarcoidosis more often has morphology of regional wall motion abnormalities, DCM phenotype, or right ventricular (RV) involvement with systolic dysfunction Can involve LV alone or with RV involvement either from primary cause or from secondary RV failure due to chronically elevated pulmonary artery pressures Structural heart disease such as coronary artery disease or infarction from other cause, primary valve disease Suggestive but not necessarily conclusive differences in patterns of late gadolinium enhancement between different variants Occasional ACM-LV with RCM phenotype For frequent PVCs or NSVT, may be difficult to distinguish PVC-related CM from genetic CM causing both the arrhythmias and the CM Abnormal RV function or structure Biventricular ACM often diagnosed from LGE in ventricle with less involvement Cardiac sarcoidosis can cause predominantly RV involvement with ventricular arrhythmias, RV wall motion abnormalities, aneurysms, and dilation Can occur with HCM, DCM, some dystrophies, and other syndromic presentations Can occur in normal hearts, pregnancy Increased prevalence in athletic hearts of congestion, which is common to diverse cardiac diagnoses such as congenital heart disease, primary pulmonary hypertension, and struc­ tural valve disease. “Congestive heart failure” should not be considered a diagnosis or an etiology of cardiomyopathy but a nonspecific syn­ drome requiring thorough evaluation of possible etiology/ies. Initial evaluation of possible cardiomyopathy begins with a detailed clinical history and examination seeking clues to cardiac, genetic, and systemic causes of heart disease, which help to guide subsequent evaluation (Table 266-2). Echocardiography remains the initial imaging modality to define morphology and function, with increasing use of magnetic resonance imaging to provide further information on myocardial tissue charac­ terization, patterns of fibrosis indicated by late gadolinium enhance­ ment, and T1 and T2 mapping for evidence of focal and diffuse inflammation.

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267 Genetic Cardiomyopathies

TABLE 266-2  Initial Evaluation of Cardiomyopathy Clinical Evaluation Thorough history and physical examination to identify cardiac and noncardiac disorders Detailed family history of heart failure, cardiomyopathy, skeletal myopathy, conduction disorders, tachyarrhythmias, and sudden death History of alcohol, illicit drugs, chemotherapy or radiation therapy Assessment of changing ability to perform routine and desired activities Assessment of jugular venous pressure, edema, orthostatic blood pressure, adequacy of perfusion Laboratory Evaluation Electrocardiogram Chest radiograph Two-dimensional and Doppler echocardiogram Magnetic resonance imaging for evidence of myocardial inflammation and fibrosis Chemistry:   Serum sodium, potassium, calcium, magnesium   Fasting glucose (glycohemoglobin in diabetes mellitus)   Creatinine, blood urea nitrogen   Albumin, total protein, liver function tests   Lipid profile   Thyroid-stimulating hormone   Serum iron, transferrin saturation   Urinalysis   Creatine kinase isoforms   Cardiac troponin level Hematology:   Hemoglobin/hematocrit   White blood cell count with differential   Total eosinophil count if abnormal % on differential   Erythrocyte sedimentation rate Evaluation When Specific Diagnoses Are Suspected Respiratory pathogen panel during acute respiratory syndromes Diagnosis of other specific infections such as:   Human immunodeficiency virus   Chagas’ disease (Trypanosoma cruzi)   Lyme disease (Borrelia burgdorferi) and other tick-borne diseases   Toxoplasmosis   Trichinosis Genetic counseling and testing with multigene cardiomyopathy panel Serologies for active rheumatologic disease Endomyocardial biopsy including sample for electron microscopy when suspecting specific diagnosis with therapeutic implications Catheterization with coronary angiography in patients who have evidence of ischemia/infarction and are candidates for intervention ■ ■FURTHER READING Arbelo E et al: 2023 ESC guidelines for the management of cardiomy­ opathies. Eur Heart J 44:3503, 2023. Elliott P: Towards a new classification of cardiomyopathies. Curr Cardiol Rep 25:229, 2023. Kontorovich AR: Approaches to genetic screening in cardiomy­ opathies: Practical guidance for clinicians. JACC Heart Fail 11:133, 2023. Merlo M et al: Clinical application of CMR in cardiomyopathies: Evolving concepts and techniques: A position paper of myocardial and pericardial diseases and cardiac magnetic resonance work­ ing groups of Italian Society of Cardiology. Heart Fail Rev 28:77, 2023.

Neal K. Lakdawala, Lynne Warner

Stevenson, Joseph Loscalzo

Genetic

Cardiomyopathies CHAPTER 267 Each of the traditional morphologic forms of cardiomyopathy, hyper­ trophic, dilated, and restrictive, can be caused or modified by under­ lying genetic factors (Table 267-1). Estimates for the prevalence of a genetic etiology for cardiomyopathy continue to rise, with increasing availability of genetic testing and attention to the family history. Wellrecognized in hypertrophic cardiomyopathy, heritability is also pres­ ent in at least 30% of dilated cardiomyopathy (DCM) without other clear etiology. Careful family history should elicit information about not only known cardiomyopathy and heart failure, but also family members who have had sudden death, often incorrectly attributed to a “heart attack,” who have had atrial fibrillation or pacemaker implanta­ tion by middle age, or who have muscular dystrophy. Genetic Cardiomyopathies Most familial cardiomyopathies are inherited in an autosomal domi­ nant pattern, with occasional autosomal recessive, matrilineal (mito­ chondrial), and X-linked inheritance (Table 267-1). Missense variants with amino acid substitutions and truncating variants are the most common genetic abnormalities in cardiomyopathy. Expressed mutant proteins may interfere with function of the normal allele through a dominant negative mechanism. Variants introducing a premature stop codon (nonsense) or shift in the reading frame (frameshift) may create a truncated or unstable protein, the lack of which causes cardiomyopa­ thy (haploinsufficiency). In some forms of genetic DCM, both haplo­ insufficiency and the dominant negative effect of a truncated allele may contribute to pathophysiology. Deletions or duplications of an entire exon or gene are uncommon causes of cardiomyopathy, except for the dystrophinopathies. Many different genes have been implicated in human cardiomyopa­ thy (locus heterogeneity), and many pathogenic or likely pathogenic variants (i.e., variants) within those genes have been associated with disease (allelic heterogeneity). Although most identified variants are “private” to individual families, several specific variants are found repeatedly, either due to a founder effect or recurrent variants at a com­ mon residue. While most patients with genetic cardiomyopathy have a single rare, “high effect,” disease allele, there is a growing appreciation for the effect of multiple less rare “intermediate effect” alleles on pen­ etrance and expression. While the additive effects of multiple common alleles/variants captured as a polygenic risk score have shown greatest utility in common diseases such as atherosclerosis, they may also pro­ vide insight into the subset of patients with primary cardiomyopathy without an identifiable “high effect” allele. Genetic cardiomyopathy is characterized by age-dependent and incomplete penetrance. The defining phenotype of cardiomyopathy is rarely present at birth and, in some individuals, may never mani­ fest. Related individuals who carry the same variant may differ in the severity and rate of progression of cardiac dysfunction and associ­ ated rhythm disorders, indicating the important role of other genetic, epigenetic, and environmental modifiers in disease expression. Sex appears to play a role, as penetrance and clinical severity may be greater in men for most cardiomyopathies. The clinical course of a patient usu­ ally cannot be predicted based on which variant is present; thus, cur­ rent therapy is based on the phenotype rather than the genetic defect. Currently, the greatest utility of genetic testing for cardiomyopathy is to inform family evaluations. However, genetic testing can provide risk stratification in some forms of cardiomyopathy and occasion­ ally enables the detection of a disease for which specific therapy is indicated, such as the replacements for defective metabolic enzymes in Fabry’s disease and Gaucher’s disease. Moreover, clinical trials are interrogating the role of gene therapies for cardiomyopathy, which will provide greater impetus for genetic testing.

TABLE 267-1  Selected Genetic Defects Associated with Cardiomyopathy   GENE PRODUCT INHERITANCE CARDIAC PHENOTYPE Sarcomere ACTC1 (cardiac actin) AD HCM, DCM Yes     MYH7 (β myosin heavy chain) AD HCM, DCM, LVNC Yes Skeletal myopathy PART 6 Disorders of the Cardiovascular System MYBPC3 (myosin binding protein C) AD HCM Yes   TNNT2 (cardiac troponin T) AD HCM, DCM, LVNC Yes   TNNI3 (cardiac troponin I) AD, AR HCM, DCM, RCM Yes   TTN (Titin) AD DCM Yes   TPM1 (α-tropomyosin) AD HCM, DCM Yes   TNNC1 (cardiac troponin C) AD DCM Yes   MYL2 (myosin regulatory light chain) AD HCM Yes Skeletal myopathy MYL3 (myosin essential light chain) AD HCM Yes   Z-disk and cytoskeleton DES (desmin) AD RCM, DCM Yes Skeletal myopathy FLNC (filamin C) AD DCM Yes Skeletal myopathy NEXN (nexilin) AD DCM Yes   VCL (vinculin) AD DCM Yes   Nuclear membrane LMNA (lamin A/C) AD, AR CDDC Yes Skeletal myopathy   EMD (emerin) X-linked CDDC No Skeletal myopathy, contractures Excitationcontraction coupling PLN (phospholamban) AD DCM, ARVC Yes     SCN5A (NAV 1.5) AD CDDC Yes Note other variants associated with Brugada syndrome RYR2 (cardiac ryanodine receptor) AD ARVC Yes   CASQ2 (calsequestrin 2) AR ARVC Yes   Cellular metabolism PRKAG2 (γ-subunit of AMP kinase) AD HCM+ Yes   LAMP2 (lysosomal associated membrane protein) X-linked HCM+ Nob Danon’s disease: skeletal myopathy, cognitive impairment TAZ (tafazzin) X-linked DCM, LVNC No Barth’s syndrome: skeletal myopathy, cognitive impairment, neutropenia FXN (frataxin) AR HCM No Friedreich’s ataxia: ataxia, diabetes mellitus type 2 TMEM43 (transmembrane protein 43) AD ARVC Yes   GLA (α-galactosidase-A) X-linked HCM+ No Fabry’s disease: renal failure, angiokeratomas and painful neuropathy Mitochondria Mitochondrial DNA Maternal transmission Sarcolemmal membrane DMD (dystrophin) X-linked DCM Nob Duchenne’s and Becker’s muscular dystrophy DMPK (dystrophica myotonica protein kinase) AD DCM No Myotonic dystrophy type 1 Desmosome DSP (desmoplakin), JUP (plakoglobin) AD, AR ARVC, DCM Yes Carvajal syndrome (AR), Naxos syndrome (AR), “woolly hair” and hyperkeratosis of palms and soles DSG2 (desmoglein 2), DSC2 (desmocollin 2), PKP2 (plakophilin 2) AD ARVC Yes   Other examples RBM20 (RNA binding motif 20) AD DCM Yes     BAG3 (BCL2-associated athanogene 3) AD DCM Yes   ALPK3 (α-kinase 3) AR HCM Yes   aIndicates that the usual clinical presentation is of isolated cardiomyopathy; however, occasionally present extracardiac manifestations are also provided. bIndicates that isolated cardiac phenotype can occur in women with the X-linked defects. Abbreviations: AD, autosomal dominant; AR, autosomal recessive; ARVC, arrhythmogenic right ventricular cardiomyopathy; CDDC, conduction disease with dilated cardiomyopathy; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; HCM+, HCM with preexcitation; LVNC, left ventricular noncompaction; MELAS, (mitochondrial) myopathy, encephalopathy, lactic acidosis, and strokelike episodes syndrome; MERRF, myoclonic epilepsy with ragged red fibers; RCM, restrictive cardiomyopathy. The genetic architecture of hypertrophic, dilated, arrhythmogenic, and restrictive cardiomyopathy are overlapping, summarized in Table 267-1 and Fig. 267-1 and detailed in the subsequent sections organized by phenotype. For any patient with suspected or proven genetic disease, family members should be considered and evaluated in a longitudinal fashion.

ISOLATED CARDIAC PHENOTYPEa EXTRACARDIAC MANIFESTATIONS DCM, HCM No MELAS, MERRF, Kearns-Sayre syndrome, ocular myopathy Screening generally includes both an echocardiogram and electrocar­ diogram (ECG). The indications and implications for confirmatory specific genetic testing vary depending on the specific variant. The profound questions raised by families about diseases shared and passed down merit serious and sensitive discussion, ideally provided by a trained genetic counselor.

FIGURE 267-1  Drawing of myocyte indicating multiple sites of abnormal gene products associated with cardiomyopathy. Major functional groups include the sarcomeric proteins (actin, myosin, tropomyosin, and the associated regulatory proteins), the dystrophin complex stabilizing and connecting the cell membrane to intracellular structures, the desmosome complexes associated with cell-cell connections and stability, and multiple cytoskeletal proteins that integrate and stabilize the myocyte. ATP, adenosine triphosphate. (Figure adapted from Jeffrey A. Towbin, MD, University of Tennessee Health Science Center.) HYPERTROPHIC CARDIOMYOPATHY ■ ■EPIDEMIOLOGY, ETIOLOGY, AND PATHOLOGY Hypertrophic cardiomyopathy is defined as left ventricular hypertro­ phy that develops in the absence of causative hemodynamic factors, such as hypertension, aortic valve disease, or systemic infiltrative or storage diseases (Figs. 267-2 and 267-3). It has previously been termed hypertrophic obstructive cardiomyopathy (HOCM); however, the accepted terminology is now hypertrophic cardiomyopathy with or without obstruction. Prevalence in North America, Africa, and Asia is about 1:500. It is a leading cause of sudden death in the young and is an important cause of heart failure. Pediatric presentation is associated with increased early morbidity and mortality, and patients diagnosed as adults have decreased survival compared to age-matched individuals without hypertrophic cardiomyopathy. A sarcomere gene variant is present in ~40–50% of patients with hypertrophic cardiomyopathy and is more common in those with familial disease and characteristic asymmetric septal hypertrophy. More than nine different genes with >1500 variants have been impli­ cated, although ~80% of patients have a variant in either MYH7 or MYBPC3 (Table 267-1), which encode the thick myofilament of the sarcomere. Hypertrophic cardiomyopathy is characterized by age-dependent and incomplete penetrance. The defining phenotype of left ventricular hypertrophy is rarely present at birth and usually develops later in life.

CHAPTER 267 Genetic Cardiomyopathies Women appear to have lower penetrance of sarcomere variants and an older age at hypertrophic cardiomyopathy diagnosis but subsequently increased rates of heart failure and mortality thereafter. Accordingly, screening of family members should begin in childhood, usually at adolescence, and extend through adulthood. In MYBPC3 variant carriers, the average age of disease development is ~40 years, while 30% remain free from hypertrophy after 70 years. Related individuals who carry the same variant may have a different extent and pattern of hypertrophy (e.g., asymmetric vs concentric), occurrence of outflow tract obstruction, and associated clinical outcomes, although sudden death and progression to heart failure occur more commonly in fami­ lies with that history. At the level of the sarcomere, hypertrophic cardiomyopathy variants lead to enhanced calcium sensitivity, maximal force generation, and ATPase activity. Calcium handling is affected through modification of regulatory proteins. Sarcomere variants lead to abnormal energetics and impaired relaxation, both directly and as a result of hypertrophy. Hypertrophic cardiomyopathy is characterized by misalignment and disarray of the enlarged myofibrils and myocytes (Fig. 267-4), which can also occur to a lesser extent in other cardiac diseases. Although hypertrophy is the defining feature of hypertrophic cardiomyopathy, fibrosis and microvascular disease are also present. Interstitial fibrosis is detectable before overt hypertrophy develops and likely results from early activation of profibrotic pathways. In the majority of patients with overt cardiomyopathy, focal areas of replacement fibrosis can be readily

PART 6 Disorders of the Cardiovascular System LV Septum MV LA FIGURE 267-2  Hypertrophic cardiomyopathy. This echocardiogram of hypertrophic cardiomyopathy shows asymmetric hypertrophy of the septum compared to the lateral wall of the left ventricle (LV). The mitral valve (MV) is moving anteriorly toward the hypertrophied septum in systole. The left atrium (LA) is enlarged. Note that the echocardiographic and pathologic images are vertically opposite, such that the LV is by convention on the top right in the echocardiographic image and bottom right in the pathologic images. (Image courtesy of Justina Wu, MD, Brigham and Women’s Hospital, Boston.) Mitral valve Tricuspid valve RV free wall LV free wall RV Chamber LV Chamber IVS FIGURE 267-3  Hypertrophic cardiomyopathy. Gross specimen of a heart with hypertrophic cardiomyopathy removed at the time of transplantation, showing asymmetric septal hypertrophy (septum much thicker than left ventricular free wall) with the septum bulging into the left ventricular outflow tract causing obstruction. The forceps are retracting the anterior leaflet of the mitral valve, demonstrating the characteristic plaque of systolic anterior motion, manifest as endocardial fibrosis on the interventricular septum in a mirror-image pattern to the valve leaflet. There is patchy replacement fibrosis, and small thick-walled arterioles can be appreciated grossly, especially in the interventricular septum. IVS, interventricular septum; LV, left ventricle; RV, right ventricle. (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.)

FIGURE 267-4  Hypertrophic cardiomyopathy. Microscopic image of hypertrophic cardiomyopathy showing the characteristic disarrayed myocyte architecture with swirling and branching rather than the usual parallel arrangement of myocyte fibers. Myocyte nuclei vary markedly in size, and interstitial fibrosis is present. (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.) detected with magnetic resonance imaging (MRI). These areas of “scar” may represent substrate for the development of ventricular arrhyth­ mias. Increased thickness and decreased luminal area of the intramural vessels in hypertrophied myocardium contribute to microvascular ischemia and angina. Microinfarction of hypertrophied myocardium is a hypothesized mechanism for replacement scar formation. Macroscopically, hypertrophy is typically manifest as nonuniform ventricular thickening (Fig. 267-3). The interventricular septum is the typical location of maximal hypertrophy, although other patterns of hypertrophic remodeling include concentric and midventricular. Hypertrophy confined to the ventricular apex (apical hypertrophic car­ diomyopathy) is less often familial and has a different genetic substrate, with sarcomere variants present in only ~15%. Left ventricular outflow tract obstruction represents the most common focus of diagnosis and intervention, although diastolic dysfunction, myocardial fibrosis, and microvascular ischemia also contribute to contractile dysfunction and elevated intracardiac pressures. Obstruction is present in ~30% of patients at rest and can be provoked by exercise in another ~30%. Systolic obstruction is initiated by drag forces, which push an anteri­ orly displaced and enlarged anterior mitral leaflet into contact with the hypertrophied ventricular septum. Mitral leaflet coaptation may ensue, leading to posteriorly directed mitral regurgitation. To maintain stroke volume across outflow tract obstruction, the ventricle generates higher pressures, leading to higher wall stress and myocardial oxygen demand. Smaller chamber size and increased contractility exacerbate the sever­ ity of obstruction. Conditions of low preload, such as dehydration, and low afterload, such as arterial vasodilation, may lead to transient hypotension and near-syncope. The systolic ejection murmur of left ventricular outflow tract obstruction is harsh and late peaking and can be enhanced by bedside maneuvers that diminish ventricular volume and transiently worsen obstruction, such as the Valsalva maneuver or standing from a squatting position. ■ ■DIAGNOSIS The substantial variability of hypertrophic cardiomyopathy pathology is reflected in the diversity of clinical presentations. Patients may be diagnosed after undergoing evaluations triggered by the abnormal physical findings (murmur) or by symptoms of exertional dyspnea, angina, or syncope. Alternatively, diagnosis may follow evaluations prompted by the detection of disease in family members. Cardiac imaging (Fig. 267-2) is central to diagnosis, for which the physical examination and ECG are insensitive. The identification of a diseasecausing variant in a proband can focus family evaluations on variant carriers, but this strategy requires a high degree of certainty that the

variant is truly pathogenic and not a benign DNA variant. Biopsy is not recommended to diagnose hypertrophic cardiomyopathy but can be used to exclude infiltrative and metabolic diseases. Rigorous athletic training (athlete’s heart) may cause intermediate degrees of physiologic hypertrophy difficult to differentiate from mild hypertrophic cardio­ myopathy. Unlike hypertrophic cardiomyopathy, hypertrophy in the athlete’s heart regresses with cessation of training and is accompanied by supernormal exercise capacity (VO2max >50 mL/kg per min), mild ventricular dilation, and normal diastolic function. TREATMENT Hypertrophic Cardiomyopathy Management focuses on treatment of symptoms and prevention of sudden death and stroke (Fig. 267-5). Left ventricular outflow tract obstruction can be controlled medically in the majority of patients. β-Adrenergic blocking agents and L-type calcium channel block­ ers (e.g., verapamil) are first-line agents that reduce the severity of obstruction by slowing heart rate, enhancing diastolic filling, and decreasing contractility. Persistent symptoms of exertional dyspnea or chest pain can be controlled occasionally with the addition of disopyramide, an antiarrhythmic agent with potent negative ino­ tropic properties. The recently introduced small-molecule cardiac myosin inhibitors mavacamten (U.S. Food and Drug Administra­ tion approved) and aficamten (under investigation) have shown high efficacy in the treatment of symptomatic obstructive hyper­ trophic cardiomyopathy, including in patients with persistent symptoms despite treatment with a beta blocker and/or those Hypertrophic Cardiomyopathy In all patients, evaluate risk for sudden death No Titrate beta blocker and/or calcium channel blocker If high, consider ICD Evidence of fluid retention? If low, follow with serial evaluation Use diuretics with caution to avoid hypovolemia, particularly in presence of outflow gradient Reevaluate cause of symptoms FIGURE 267-5  Treatment algorithm for hypertrophic cardiomyopathy depending on the presence and severity of symptoms and the presence of an intraventricular gradient with obstruction to outflow. Note that all patients with hypertrophic cardiomyopathy should be evaluated for atrial fibrillation and risk of sudden death, whether or not they require treatment for symptoms. ICD, implantable cardioverter-defibrillator; LV, left ventricular.

considering septal reduction therapy. The principal risk of cardiac myosin inhibitors is a transient reduction in left ventricular ejec­ tion fraction (LVEF), which warrants frequent echocardiographic monitoring.

Patients with or without obstruction may develop heart failure symptoms due to fluid retention and require diuretic therapies for venous congestion. Severe medically refractory symptoms develop in ~5% of patients, for whom septal reduction therapy with surgical myectomy or alcohol septal ablation may be effec­ tive. Developed over 60 years ago, surgical myectomy effectively relieves outflow tract obstruction by excising part of the septal myocardium involved in the dynamic obstruction. In selected patients, perioperative mortality is extremely low with excellent long-term survival free from recurrent obstruction and symp­ toms. Mitral valve repair or replacement is usually unnecessary as associated eccentric mitral regurgitation resolves with myectomy alone. Alcohol septal ablation in patients with suitable coronary anatomy can relieve outflow tract obstruction via a controlled infarction of the proximal septum, which produces similar peri­ procedural outcomes and gradient reduction as surgical myec­ tomy. Although head-to-head comparisons between the two septal reduction therapies do not exist, septal ablation is relegated pri­ marily to patients who wish to avoid surgery or who have limiting comorbidities. Neither procedure has been shown to improve outcomes other than symptoms. With both procedures, the most common complication is the development of complete heart block necessitating permanent pacing. However, ventricular pacing as a primary therapy for outflow tract obstruction is ineffective and not generally advised. CHAPTER 267 Genetic Cardiomyopathies Symptomatic? Yes Yes Persistent symptoms Outflow gradient? No Yes Try mavacamten or disopyramide Evidence of severe progressive LV dysfunction? No Yes Refractory severe symptoms Rarely, consider cardiac transplantation Consider procedure Septal ablation Septal myectomy

Patients with hypertrophic cardiomyopathy have an increased risk of sudden cardiac death from ventricular tachyarrhythmias. Vigorous physical activity and competitive sports have been his­ torically prohibited; however, recent studies have failed to identify a relationship between exertion and ventricular arrhythmias in hypertrophic cardiomyopathy, empowering patients and provid­ ers to make shared decisions about exercise. Factors that increase the risk of sudden death from a baseline of 0.5% per year are pre­ sented in Table 267-2. As sudden death has not been reduced by medical or procedural interventions, traditionally an implantable cardioverter-defibrillator has been advised for patients with one or more major risk factors and advised on a selected basis for patient with more than one modifying risk factor. Nevertheless, the posi­ tive predictive value of most risk factors is low, and many patients receiving a defibrillator never receive an appropriate device therapy. A complementary approach to sudden death risk stratification and discussion with patients is the application of an externally validated European Society of Cardiology risk score using major criteria from Table 267-2 and continuous variables such as outflow tract gradi­ ent and left atrial size. Shared decision-making around implantable

PART 6 Disorders of the Cardiovascular System TABLE 267-2  Risk Stratification for Sudden Death in Hypertrophic Cardiomyopathy MAJOR RISK FACTOR   SCREENING TECHNIQUE History of cardiac arrest or spontaneous sustained ventricular tachycardiaa   History Syncope Nonvagal, often with or after exertion History Family history of sudden cardiac death   Family history Left ventricular apical aneurysm Generally applicable to patients with apical hypertrophy Echocardiography with contrast, cardiac magnetic resonance imaging LV thickness >30 mm Present in <10% of patients Echocardiography or cardiac magnetic resonance imaging LV systolic dysfunction (ejection fraction <50%) Present in <10% of patients Echocardiography or cardiac magnetic resonance imaging Variables Utilized in the European Society of Calculator for Estimated Risk of Sudden Death LV outflow tract gradient Peak gradient measured at rest or with the Valsalva maneuver, mmHg Echocardiography Left atrial diameter Diameter measured in the parasternal long axis, mm Echocardiography LV thickness Maximal wall thickness, mm Echocardiography Age     Syncope, family history, nonsustained ventricular tachycardia As above As above Modifying Risk Factors Late gadolinium enhancement As a percentage of myocardial mass Cardiac magnetic resonance imaging Spontaneous nonsustained ventricular tachycardia

3 beats at rate >120 Exercise or 24-h to 48-h ambulatory recording aImplantable cardioverter-defibrillator advised for patients with prior arrest or sustained ventricular tachycardia regardless of other risk factors if life expectancy is estimated to be >1 year. The European Society of Cardiology risk calculator can be found at https://doc2do.com/hcm/webHCM.html and provides an estimated 5-year risk of cardiac arrest. Patients with estimated risk of ≥6% are generally advised placement of an implantable cardioverter-defibrillator; those with risk between 4 and 6% can be considered for implant, and implant is not advised when risk is <4%. Emerging risk factors merit further clinical validation. Abbreviation: LV, left ventricle.

cardioverter-defibrillator implantation for primary prevention has emphasized discussions of estimated risk levels rather than dichoto­ mous yes–no criteria. Long-term use of a defibrillator may be associated with serious device-related complications, particularly in young active patients. Refinement of sudden death risk through the application of contemporary technologies such as cardiac MRI is ongoing. Atrial fibrillation is common in patients with hypertrophic cardiomyopathy and may lead to hemodynamic deterioration and embolic stroke. Rapid ventricular response is poorly tolerated and may worsen outflow tract obstruction. β-Adrenergic blocking agents and L-type calcium channel blockers slow atrioventricular (AV) nodal conduction and improve symptoms; cardiac glyco­ sides should be avoided, as they may increase contractility and worsen obstruction. Even with adequate rate control, symptoms exacerbated by atrial fibrillation may persist due to loss of AV syn­ chrony and may require restoration of sinus rhythm. Disopyramide and amiodarone are the preferred antiarrhythmic agents, with radiofrequency ablation considered for medically refractory cases. Anticoagulation to prevent embolic stroke in atrial fibrillation is recommended. ■ ■PROGNOSIS The general prognosis for hypertrophic cardiomyopathy is better than in early studies of referral populations, but mortality remains higher than in an age-matched population without cardiomyopathy. The sud­ den death risk is <1% per year; however, up to 1 in 20 patients will progress to overt systolic dysfunction with a reduced ejection fraction (<50%) with or without dilated remodeling (i.e., “burned out” or endstage hypertrophic cardiomyopathy). These patients may suffer from low cardiac output and have an increased risk of death from progres­ sive heart failure and sudden death unless they undergo timely cardiac transplantation. GENETIC DILATED AND ARRHYTHMOGENIC CARDIOMYOPATHY ■ ■EPIDEMIOLOGY, ETIOLOGY, AND PATHOLOGY As outlined in Chap. 266, an enlarged left ventricle with reduced systolic function as measured by LVEF characterizes DCM, which is considered to be present when the LVEF is ≤0.50 and/or the left ven­ tricular diastolic dimension is >95% predicted for age and sex. In some patients with reduced LVEF, the left ventricular dilation is minimal, sometimes referred to as nondilated or minimally dilated cardiomy­ opathy (Figs. 267-6, 267-7, and 267-8). While diverse etiologies may cause DCM and arrhythmogenic car­ diomyopathy (ACM), familial clustering is present in ~30–40% of cases and monogenic etiologies can be identified in ~25%. Sarcomere variants are most associated with hypertrophic cardio­ myopathy; however, they are also implicated in DCM. The most com­ mon genetic causes of DCM are truncating variants of the giant protein titin, encoded by TTN, which maintains sarcomere structure and acts as a key signaling molecule. As cytoskeletal proteins play crucial roles in the structure, connec­ tion, and stability of the myocyte, multiple defects in these proteins can lead to dilated cardiomyopathy (Fig. 267-1). For example, desmin forms intermediate filaments that connect the nuclear and plasma membranes, Z-lines, and the intercalated disks between muscle cells. Desmin variants impair the transmission of force and signaling for both cardiac and skeletal muscle and may cause combined cardiac and skeletal myopathy, more commonly with a restrictive phenotype (RCM) than dilated phenotype (DCM). Defects in the sarcolemmal membrane proteins are associated with DCM. The best known is dystrophin, encoded by the X chromosome gene DMD, abnormalities of which cause Duchenne’s and Becker’s muscle dystrophy. This protein provides a network that supports the sarcolemma and also connects to the sarcomere. The progressive func­ tional defect in both cardiac and skeletal muscle reflects vulnerability

FIGURE 267-6  Dilated cardiomyopathy. This gross specimen of a heart removed at the time of transplantation shows massive left ventricular dilation and moderate right ventricular dilation. Although the left ventricular wall in particular appears thinned, there is significant hypertrophy of this heart, which weighs >800 g (upper limit of normal = 360 g). A defibrillator lead is seen traversing the tricuspid valve into the right ventricular apex. (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.) LV RV LA RA FIGURE 267-7  Dilated cardiomyopathy. This echocardiogram of a young man with dilated cardiomyopathy shows massive global dilation and thinning of the walls of the left ventricle (LV). The left atrium (LA) is also enlarged compared to normal. Note that the echocardiographic and pathologic images are vertically opposite, such that the LV is by convention on the top right in the echocardiographic image and bottom right in the pathologic images. RA, right atrium; RV, right ventricle. (Image courtesy of Justina Wu, MD, Brigham and Women’s Hospital, Boston.)

CHAPTER 267 Genetic Cardiomyopathies FIGURE 267-8  Dilated cardiomyopathy. Microscopic specimen of a dilated cardiomyopathy showing the nonspecific changes of interstitial fibrosis and myocyte hypertrophy characterized by increased myocyte size and enlarged, irregular nuclei. Hematoxylin and eosin–stained section, 100× original magnification. (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.) to mechanical stress. Defects in the sarcolemmal channel proteins (channelopathies) are generally associated with primary arrhythmias, but variants in SCN5A, the α subunit of the Nav 1.5 ion channel pro­ tein, distinct from those that cause the Brugada or long QT syndromes, have been implicated in DCM with conduction disease. Nuclear membrane protein defects in cardiac and skeletal muscle occur in either autosomal (lamin A/C) or X-linked (emerin) pat­ terns. These defects are associated with a high prevalence of atrial and ventricular arrhythmias and conduction system disease, which can occur in some family members without or before detectable cardiomy­ opathy and underlie gene-specific risk stratification for sudden death and different utilization criteria for primary prevention implantable cardioverter-defibrillators in these patients. Intercalated disks contribute to intracellular connections, allowing mechanical and electrical coupling between cells and also connec­ tions to desmin filaments within the cell. Variants in proteins of the desmosomal complex compromise attachment of the myocytes, which can become disconnected and die via activation of Wnt/β-catenin and proinflammatory signaling pathways, to be replaced by fat and fibrous tissue. These areas are highly arrhythmogenic and may dilate to form aneurysms. Although more often noted in the right ventricle (arrhyth­ mogenic right ventricular cardiomyopathy), this condition can be restricted to the left ventricle (especially when secondary to truncating variants in DSP, which encodes desmoplakin) or affect both ventricles and has also been termed “arrhythmogenic cardiomyopathy.” The recognized frequency of familial involvement in DCM has increased to >30%. Truncating variants in TTN, encoding the giant sar­ comeric protein titin, are the most common cause of DCM, accounting for up to 25% of familial disease. On average, men with TTN truncat­ ing variants develop cardiomyopathy a decade before women, without distinctive clinical features. Variants in thick and thin filament genes account for ~8% of DCM and may manifest in early childhood. ■ ■PROGNOSIS Prognosis and therapy of DCM and ACM are dictated primarily by the stage of clinical disease and the risk for sudden death, which also varies based on disease gene (higher for patients with variants in DES, DSP, DSC2, DCG2, FLNC, LMNA, PKP2, PLN, RBM20, SCN5A, and TMEM43). The rate of progression of disease is also heritable, with marked variation based on disease gene observed (e.g., patients with TTN truncating variants frequently experience recovery with medical therapy). Medical therapy is generally guided by the phenotype, such that patients with DCM and reduced LVEF are treated with thera­ pies recommended for heart failure with reduced ejection fraction

(Chap. 264). As for HCM, shared decision-making is needed regarding implantable cardioverter-defibrillators. However, the specific genotype plays a greater role in decisions regarding DCM, for which some fea­ tures may warrant implantable cardioverter-defibrillator placement before the LVEF has declined to 0.35, such as the presence of patho­ genic LMNA or FLNC variants or a family history of sudden death at early ages.

PART 6 Disorders of the Cardiovascular System Arrhythmogenic right ventricular cardiomyopathy (ARVC) has an established diagnostic framework (task force criteria) that rests upon identifying and quantifying right ventricular dilation, dyski­ nesis, and ECG abnormalities (repolarization, depolarization, and arrhythmias) in the context of a suggestive family history of genetic test results. Overlapping with ARVC and DCM is ACM, in which ventricular arrhythmias may precede or supersede the severity of predominantly left ventricular remodeling. Unlike ARVC, consensus diagnostic criteria for ACM are lacking. Early stages of ARVC and ACM may be restricted to ventricular arrhythmias, and over years, ventricular dilation, hypokinesis, and failure may ensue. Patients with an initial presentation of right ventricular cardiomyopathy who progress to include left ventricular dysfunction are at high risk for adverse events.  CARDIOMYOPATHY DUE TO INHERITED DISORDERS OF METABOLISM Multiple genetic disorders of metabolic pathways can cause myocardial disease, due to infiltration of abnormal products or cells containing them between the myocytes, and storage disease, due to their accumu­ lation within cells (Table 267-1). Hypertrophic cardiomyopathy may be mimicked by the myocardium thickened with these abnormal products causing “pseudohypertrophy,” usually with an abnormally short PR interval. The pseudohypertrophic phenotype is most common, but restrictive cardiomyopathy and DCM may occur. Most of these dis­ eases are diagnosed during childhood. Fabry’s disease results from a deficiency of the lysosomal enzyme alpha-galactosidase A caused by variants in GLA. This disorder of glycosphingolipid metabolism is an X-linked disorder that may also cause clinical disease in female carriers. Glycolipid accumulation may be limited to the cardiac tissues but usually also involves the skin, peripheral nerve, and kidney. Electron microscopy of endomyocardial biopsy tissue shows diagnostic vesicles containing concentric lamellar figures (Fig. 267-9). Diagnosis can be made through assessment of enzyme activity and/or GLA sequencing and is crucial because enzyme replacement can reduce abnormal deposits and improve cardiac and clinical function. The magnitude of clinical impact has not been well established for this therapy, which requires frequent infusions of the enzyme at a cost of >$100,000 a year. The oral chaperone therapy, migalastat, stabilizes mutant forms of alpha-galactosidase, increases enzymatic activity, and was approved for use in a subset of patients with Fabry’s disease bearing variants amenable to this therapy. Carnitine is an essential cofactor in long-chain fatty acid metabo­ lism. Multiple defects have been described that lead to carnitine deficiency, causing intracellular lipid inclusions and restrictive car­ diomyopathy or DCM, often presenting in children. Fatty acid oxida­ tion requires many metabolic steps with specific enzymes that can be deficient, with complex interactions with carnitine. Depending on the defect, cardiac and skeletal myopathy can be ameliorated with replace­ ment of fatty acid intermediates and carnitine. Two monogenic metabolic cardiomyopathies cause increased ven­ tricular wall thickness without an increase of muscle subunits or an increase in contractility. Variants in the gamma-2 regulatory subunit of the adenosine monophosphate (AMP)-activated protein kinase important for glucose metabolism (PRKAG2) have been associated with a high prevalence of conduction abnormalities, such as AV block and ventricular preexcitation. Several defects have been reported in an X-linked lysosome-associated membrane protein (LAMP2). This defect can be maternally transmitted or sporadic and has occasion­ ally been isolated to the heart, although it often leads to a syndrome of skeletal myopathy, intellectual disability, and hepatic dysfunction

FIGURE 267-9  Fabry’s disease. Transmission electron micrograph of a right ventricular endomyocardial biopsy specimen at high magnification showing the characteristic concentric lamellar inclusions of glycosphingolipids accumulating as a result of deficiency of the lysosomal enzyme alpha-galactosidase A. Image taken at 15,000× original magnification. (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.) referred to as Danon disease. Extreme left ventricular hypertrophy appears early, often in childhood, and can progress rapidly to end-stage heart failure with low ejection fraction. Electron microscopy of these metabolic disorders shows that the myocytes are enlarged by multiple intracellular vacuoles of metabolic by-products. Gene therapy using a viral vector to deliver functional LAMP2 to cardiomyocytes is currently under study in humans with Danon disease. RESTRICTIVE CARDIOMYOPATHY Most restrictive cardiomyopathy (RCM) is due to acquired causes, and there is increasing emphasis to diagnose amyloidosis due to transthyre­ tin variants (see Chap. 266). Inherited metabolic and storage diseases can cause RCM, as can variants in DES causing combined cardiac and skeletal myopathy and sarcomere variants causing an overlap of RCM and hypertrophic cardiomyopathy. ■ ■FURTHER READING Arbelo E et al: ESC guidelines for the management of cardiomyopa­ thies. Eur Heart J 44:3503, 2023. Gasperetti A et al: Arrhythmic risk stratification in arrhythmogenic right ventricular cardiomyopathy. Europace 25:euad312, 2023. Groh WJ et al: 2022 HRS expert consensus statement on evaluation and management of arrhythmic risk in neuromuscular disorders. Heart Rhythm 19:e61, 2022. Helms AS et al: Translation of new and emerging therapies for genetic cardiomyopathies. JACC Basic Transl Sci 7:70, 2021. Heymans S et al: Dilated cardiomyopathy: Causes, mechanisms, and current and future treatment approaches. Lancet 402:998, 2023. Ho CY et al: Genotype and lifetime burden of disease in hypertrophic cardiomyopathy insights from the Sarcomeric Human Cardiomyopa­ thy Registry (SHaRe). Circulation 138:1387, 2018. Lampert R et al: Vigorous exercise in patients with hypertrophic car­ diomyopathy. JAMA Cardiol 8:595, 2023. Mazzarotto F et al: Reevaluating the genetic contribution of mono­ genic dilated cardiomyopathy. Circulation 141:387, 2020. Olivotto I et al: Mavacamten for treatment of symptomatic obstruc­ tive hypertrophic cardiomyopathy (EXPLORER-HCM): A random­ ized, double-blind, placebo-controlled, phase 3 trial. Lancet 396:759, 2020. Orsborne C et al: Disease-specific therapy for the treatment of car­ diovascular manifestations of Fabry disease: A systemic review. Heart 110:19, 2023.

30 - 268 Acute and Chronic Myocarditis

268 Acute and Chronic Myocarditis

Neal K. Lakdawala,

Lynne Warner Stevenson, Joseph Loscalzo

Acute and Chronic

Myocarditis Myocarditis is defined as inflammation of the heart muscle, which may present acutely, subacutely, or insidiously. Outcomes can include resolution, relapsing course, or progression to chronic cardiomyopathy. Myocarditis is generally considered acute when presenting with less than a month of symptoms, often only a few days. The profile of acute myocarditis is changing as the use of sensitive troponin assays and car­ diac magnetic resonance imaging (MRI) are increasing recognition of mild cases with good outcomes. Acute myocarditis is most often attrib­ uted to active infection but can be caused by multiple types of nonin­ fectious inflammation, such as sarcoidosis, giant cell and eosinophilic myocarditis, and systemic autoimmune disease or immunotherapies. It is uncertain as to how often chronic myocardial inflammation contrib­ utes to dilated cardiomyopathy. As with other cardiomyopathies, there is increasing implication of genetic predisposition to inflammatory responses and of independent pathogenic variants as primary cause of myocyte pathology, with almost one in five patients with inflamma­ tory myocarditis harboring genetic variants considered pathogenic for cardiomyopathy. MODELS OF INFECTIOUS MYOCARDITIS Infectious agents can injure the myocardium through direct invasion with disruption of normal cellular processes and through activation of different phases of immune responses with or without persistent infection. Although myocarditis has been reported with most types of infectious agents, it is most often associated with viruses and the pro­ tozoal disease Trypanosoma cruzi (Chagas’ disease). The pathogenesis of viral myocarditis has been traditionally portrayed in three phases, arising from extensive study in murine models of enteroviruses, with much less known about human infection. As defined by infection with coxsackie B virus, phase I includes direct invasion of the myocar­ dium. Cellular entry may be enhanced by some genetic variants of the coxsackie/adenovirus receptors. The enteroviral protease A degrades the myocyte structural protein dystrophin and interacts with other proteins to induce apoptosis and interfere with autophagy. Direct myocardial invasion with entry of the viral genome has been shown to occur with the enteroviruses, HIV, and dengue virus. However, most common viruses do not appear to inflict cardiac damage directly. Early cardiac effects may result primarily from cytokine storm and other nonspecific immune responses leading to myocardial depression. This initial immune response appears to be crucial to recovery, as early immunosuppression increased viral replication and worsened cardiac injury in animal models. The second phase is host response to infection in recognition of common antigenic patterns, triggering macrophage activation and expansion of specific T- and B-cell populations. Myocarditis due to this phase of immune response without direct viral-mediated injury is considered to be virally “triggered” myocarditis, implicated with respi­ ratory viruses including adenovirus, influenza, and COVID-19. Molec­ ular mimicry between viral and cardiac antigens may be the cause of some cases of myocardial injury caused by autoreactive T cells in the absence of ongoing viral infection. There is increasing study of the role of viral “hijacking” of cellular machinery to produce extracellular vesicles containing viral RNA that may then gain protected entry into other cells. A third phase of progression to chronic cardiomyopathy has been demonstrated in animal models of enteroviruses. However, myocarditis is rarely due to enteroviruses in adults. There are limited data providing direct links between chronic cardiomyopathy and previous viral infection (see “Chronic Myocarditis and Cardiomyopathy” below). The MRI pattern of intramyocardial late gadolinium enhancement

in chronic cardiomyopathy was previously considered as evidence of prior viral myocarditis, but this pattern is now recognized to be com­ mon in genetic cardiomyopathy as well.

CHAPTER 268 ACUTE MYOCARDITIS ■ ■PRESENTATION AND DIAGNOSIS Acute myocarditis in adults typically occurs between 30 and 45 years and is more common in men than women, who tend to present at over 45 years of age. Prodromal symptoms typical of influenza, gas­ troenteritis, or upper respiratory infection may have occurred days to a few weeks earlier. Fever is present in over half of cases. Chest pain is the most common symptom of acute myocarditis, occurring in

80% of patients, who also often present with dyspnea or arrhythmias. Arrhythmias can manifest as palpitations or syncope but can also cause sudden cardiac death, as in an autopsy series in which inflammatory myocarditis was diagnosed 3–10% of previously healthy young adults. At presentation, about one-fourth of acute myocarditis cases include left ventricular ejection fraction (LVEF) <0.50, ventricular arrhyth­ mias, or clinical shock, which is reported in ~3–9% of cases and termed fulminant myocarditis. Acute and Chronic Myocarditis Viral titers are not often helpful to guide initial therapy of acute myocarditis. Respiratory viral panels can confirm recent infection with influenza and adenovirus, most implicated in acute myocarditis in adults with a viral prodrome. Finding of COVID-19 may alert to extracardiac involvement. Specific infectious serologies for HIV, Chagas’ disease, cytomegalovirus, dengue fever, and Lyme disease and serologies for systemic autoimmune disease should be sent in selected patients. Eosinophil counts should be routinely checked because hype­ reosinophilia is present in most cases of eosinophilic myocarditis. The common definition for “probable myocarditis” includes new appearance of least one symptom listed above and at least one sup­ porting finding, which can be elevated troponin levels, consistent ECG findings, or imaging findings of decreased LVEF or obvious wall motion abnormality. Other laboratory findings may include elevated creatine phosphokinase levels, indicating cardiac or skeletal muscle involvement, and elevated C-reactive protein levels. The most com­ mon electrocardiogram (ECG) findings are ST elevation suggesting infarction, but also include conduction block, tachyarrhythmias, and nonspecific ST-T changes. Because the combination of chest pain, ECG changes, and elevated troponin is typical of both acute myocarditis and myocardial infarction, the first step in the differential diagnosis is often coronary artery imaging. Subsequent diagnosis of acute myocar­ ditis has been reported in up to one-third of patients with myocardial infarction and nonobstructed coronary arteries (MINOCA). “Definite myocarditis” previously required positive biopsy findings of typical inflammatory lymphocytic infiltrate on myocardial biopsy (Fig. 268-1). Newer techniques of immunohistochemistry may increase sensitiv­ ity of biopsies and advance our understanding of the inflammatory cell populations. However, the diagnosis can now be confirmed noninva­ sively when typical symptomatic presentation is accompanied by com­ bination of elevated troponin levels and consistent findings on MRI, which include evidence of both myocardial edema and nonischemic myocardial injury in the absence of other known cause (Fig. 268-2). Although cardiac MRI may often be sufficient to diagnose acute myocarditis, endomyocardial biopsy should be performed when ven­ tricular arrhythmias, conduction block, elevated eosinophil count, or evidence of systemic autoimmune disease suggests causes of acute myocarditis with specific implications for therapy and prognosis, as discussed below in “Noninfective Inflammatory Myocarditis.” ■ ■THERAPY AND OUTCOMES The prognosis is good for “uncomplicated” acute myocarditis, present­ ing with LVEF ≥0.50 without ventricular arrhythmias or circulatory shock. In the largest series, this low-risk group accounted for about three-fourths of patients with acute myocarditis, in which spontaneous recovery was common without specific therapies other than diuretics and nonsteroidal analgesics for chest pain. Almost all of these patients

PART 6 Disorders of the Cardiovascular System FIGURE 268-1  Acute myocarditis. Microscopic image of an endomyocardial biopsy showing massive infiltration with mononuclear cells and occasional eosinophils associated with clear myocyte damage. The myocyte nuclei are enlarged and reactive. Such extensive involvement of the myocardium would lead to extensive replacement fibrosis even if the inflammatory response could be suppressed. Hematoxylin and eosin–stained section, 200× original magnification. (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.) still had LVEF ≥0.50 on follow-up imaging and survived without trans­ plantation at 5 years of follow-up. In the one-fourth of patients with complicated presentations, ~18% died or underwent heart transplanta­ tion in the next 5 years. Patients with reduced LVEF are generally dis­ charged on the recommended therapies for heart failure with reduced ejection fraction (HFrEF). There are no data supporting routine immu­ nosuppression in patients with acute myocarditis with presumed viral etiology. Fulminant myocarditis requiring high-dose inotropic therapy or mechanical circulatory support occurs in 3–9% of acute myocarditis, with early outcomes of refractory cardiogenic shock but recovery to near-normal LVEF in >50% of affected patients. CHRONIC MYOCARDITIS AND CARDIOMYOPATHY Patients with reduced LVEF at the time of presentation with acute myocarditis are at higher risk of developing chronic cardiomyopathy. When the LVEF does not resolve in the initial months after diagnosis, FIGURE 268-2  Magnetic resonance image of myocarditis showing the typical midwall location (arrow) for late gadolinium enhancement from cardiac inflammation and scarring. (Image courtesy of Ron Blankstein, MD, and Marcelo Di Carli, MD, Division of Nuclear Medicine, Brigham and Women’s Hospital, Boston.)

particularly with persistent elevation of troponin, cardiac magnetic resonance imaging (CMRi) or endomyocardial biopsy may reveal ongoing inflammation and developing fibrosis. Evaluation should again be considered for specific etiologies of myocarditis including noninfectious causes of inflammatory disease and for other causes of dilated cardiomyopathy (Chap. 266, Table 266-2). Evidence of chronic inflammatory disease may also be found in some patients presenting with gradual onset of dilated cardio­ myopathy without prior acute myocarditis. Immunosuppression for nonspecific lymphocytic myocarditis in the chronic setting has been tried in multiple series but has not demonstrated convinc­ ing benefit. Additional findings of anticardiac antibodies and viral genome fragments are of uncertain significance, as they could be either causes of ongoing cardiac injury or neutral bystanders. Assay for anticardiac antibodies and viral genome analysis in chronic cardiomyopathy continue to be investigated but are not in routine clinical use. In the past, dilated cardiomyopathy without other cause was gener­ ally assumed to result from previously unrecognized viral myocarditis, in part because CMRi patterns of fibrosis suggested prior inflamma­ tion. However very similar patterns are typical of genetic cardiomy­ opathies. The expanding access to genetic testing reveals that 20–40% of patients with dilated cardiomyopathy have pathogenic variants suf­ ficient to cause their cardiomyopathy, and the prevalence and nature of these variants are similar in acute myocarditis. Mapping of the interconnections between genetic predisposition, inflammation, and cardiomyopathy is evolving rapidly. ■ ■SPECIFIC CAUSES OF INFECTIOUS MYOCARDITIS The first viruses implicated in infectious myocarditis were the picor­ navirus family of RNA viruses, principally the enteroviruses, coxsackie virus, echovirus, and poliovirus. Influenza, another RNA virus, is implicated with varying frequency every winter and spring as epitopes change. Of the DNA viruses, adenovirus, vaccinia, and the herpes­ viruses (varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, and human herpesvirus 6 [HHV6]) can cause myocarditis but also occur commonly in the healthy population. Polymerase chain reaction (PCR) detects viral genomes in some patients with dilated cardio­ myopathy and persistent lymphocytic infiltrates defined as “chronic myocarditis,” such as the DNA viruses parvovirus B19 and HHV6, but these are also found in normal “control” hearts, so their contribution to chronic cardiomyopathy is uncertain. COVID-19 is an RNA virus for which infection was associated with substantial rates of cardiac involvement in patients hospitalized with severe disease, including acute coronary syndrome, thromboemboli, pericarditis, and myocarditis, for which the diagnosis was limited to clinical findings and elevated enzymes rather than demonstration of lymphocytic infiltrates, as biopsies were rarely performed. From broad population data, the rate of myocarditis during the pandemic was estimated at 150/100,000 people, a 15-fold increase over pre-COVID incidence. As for most causes of viral myocarditis, the most common adult patients are young men under the age of 40. As for other viruses, there are multiple potential mechanisms of cardiac injury. Viral par­ ticles were identified by PCR in myocardial samples but in low levels at which pathogenicity was uncertain. Other mechanisms include cytokine storm, activated T cells and macrophages, and potential molecular mimicry by which autoimmune reactions may be triggered, as for some animal models of myocarditis with other viruses. As with multiple other viruses, extracellular vesicles containing viral RNA have been identified in myocardium during COVID infection, potentially promoting protected entry into other cells for further injury. In addi­ tion, the endothelium is also vulnerable, leading to prothrombotic endotheliopathy that may contribute to myocardial ischemia and stroke, along with the systemic coagulopathy. HIV was associated with a dilated cardiomyopathy incidence of 1–2%, but this is declining with the availability of highly active anti­ retroviral therapy. Cardiomyopathy in HIV may also result from other associated viruses, such as cytomegalovirus and hepatitis C. Antiviral drugs to treat chronic HIV can cause cardiomyopathy, both directly

and through drug hypersensitivity. The clinical picture may be com­ plicated by pericardial effusions and pulmonary hypertension. There is an increased frequency of lymphocytic myocarditis found at autopsy; HIV viral particles have been demonstrated in the myocardium in some cases. For any serious infection, the systemic inflammatory response can cause nonspecific depression of cardiac function, which is generally reversible if the patient survives. Other viruses implicated specifically in myocarditis include mumps, respiratory syncytial virus, the arbovi­ ruses (dengue fever and yellow fever), and arenaviruses (Lassa fever). ■ ■OTHER INFECTIOUS CAUSES Parasitic Myocarditis  Chagas’ disease is the third most com­ mon parasitic infection in the world and the most common infective cause of cardiomyopathy. The protozoan T. cruzi is transmitted by the bite of the reduviid bug, endemic in the rural areas of South and Central America. Transmission can also occur through blood transfu­ sion, organ donation, from mother to fetus, and occasionally orally. Programs to eradicate the insect vector have decreased the global prevalence from about 18 million in 1990 to 6 million, with the highest number of cases in Brazil and Argentina and increased prevalence also in Spain. It is estimated that >300,000 residents in the United States are infected with Chagas’ disease, a minority of whom have acquired it locally. Initial infection with T. cruzi is usually silent but, in 5–10% of cases, can present with systemic illness and acute myocarditis with systemic dense parasitic infiltration in the myocardium forming pseudocysts that rupture and lead to diffuse myocyte necrosis. After initial infection, patients enter an “indeterminate phase,” which can last for decades. The silent progression during this phase was at one time attributed to secondary immune activation, but a degree of per­ sistent parasitemia can now be detected and is recognized as the major determinant of ongoing inflammation and progression to chronic heart failure. Depopulation of parasympathetic neurons in the heart and gastrointestinal tract likely contributes to clinical disease. Under­ standing of the disease patterns has improved in part from the ability to test blood donors for infection. Better detection of the organism has revealed that both the prevalence and survival of patients in the indeterminate phase are higher than previously recognized, with over half of patients remaining asymptomatic. T. cruzi infection should be considered during evaluation of acute myocarditis or cardiomyopathy in all patients from endemic regions and for other patients with suggestive features. These include sinus and atrioventricular node conduction system disease and right bundle branch block, with frequent atrial and ventricular arrhythmias, some of which may cause sudden death before symptomatic disease. The dilated ventricles are thrombogenic and sometimes have aneurysms. For acute myocarditis, PCR is the most sensitive test and trypomasti­ gotes may also be detected in blood when parasite levels are high. In the chronic phase with low parasite burden, multiple serologic tests may be necessary for diagnosis, but their sensitivity and specificity are improving. Antiparasitic treatment with nifurtimox or benznidazole is recom­ mended for acute myocarditis with Chagas’ cardiomyopathy. During the indeterminate phase prior to clinical symptoms, therapy is widely recommended for children. For the indeterminate phase, there is controversy over the routine use of antiparasitic treatment, which is associated with significant toxicity. Therapy is more often advocated for patients <50 years old, who are more likely to tolerate chronic suppressive therapy. Treatment is recommended for premenopausal women and for patients on immunosuppression, such as after cardiac transplantation. A large multinational trial showed no benefit for benznidazole given to patients with chronic heart failure from Chagas’ cardiomyopathy. In these patients, general therapy is as indicated for other HFrEF, with increased indications for anticoagulation and for pacemaker defibrillators. Improvement of LVEF is uncommon and survival is lower than for other cardiomyopathies after the onset of overt clinical heart failure.

Trichinellosis (trichinosis) is caused by the Trichinella genus of nematodes (roundworms). The larvae are ingested with undercooked meat, with an initial intestinal phase after which larvae migrate into skeletal muscles, causing myalgias, weakness, and fever. Periorbital and facial edema and conjunctival and retinal hemorrhage may also be seen. Although the larva may occasionally invade the myocardium, clinical heart failure is rare and, when observed, attributed to the eosinophilic inflammatory response. The diagnosis is made from the serologies and is further supported by the presence of eosinophilia. Treatment includes anthelminthic drugs and glucocorticoids if inflam­ mation is severe.

CHAPTER 268 Acute and Chronic Myocarditis Bacterial Infections  Most bacterial infections can involve the heart occasionally through direct invasion and abscess formation but do so rarely. More commonly, systemic inflammatory responses to severe infection and sepsis depress myocardial contractility. Diphtheria is caused by bacillus Corynebacterium diphtheriae, usu­ ally presenting with an upper respiratory illness particularly affecting the pharynx, where a pseudomembrane is formed in response to the diphtheria toxin. This toxin interferes with protein synthesis in the heart and may particularly affect the conduction system. Cardiac involvement is the most common cause of death from this infection but rarely occurs with the occasional dominant cutaneous presenta­ tion. The prevalence of vaccines has shifted the incidence of diphtheria to countries without routine immunization and to older populations who have lost their immunity. The diagnosis is made from pharyngeal bacterial culture, which requires special culture media and a positive assay for the toxin but can be suspected from gram-positive rods on a Gram stain. Clinical suspicion is sufficient indication for the specific antitoxin, which should be administered as soon as possible, with higher priority than antibiotic therapy. Streptococcal infection with β-hemolytic streptococci is most com­ monly associated with acute rheumatic fever and is characterized by inflammation and fibrosis of cardiac valves and systemic connective tissue, but it can also lead to a myocarditis with focal or diffuse infil­ trates of mononuclear cells. Other systemic bacterial infections that can involve the heart include brucellosis, legionella, meningococcus, mycoplasma, psittacosis, and salmonellosis, for which specific treat­ ment is directed at the systemic infection. Tuberculosis can involve the myocardium directly as well as through tuberculous pericarditis but rarely does so when the disease is treated with antibiotics. Whipple’s disease is caused by Tropheryma whipplei. The usual manifestations are in the gastrointestinal tract, but pericarditis, coronary arteritis, valvular lesions, and occasionally clini­ cal heart failure may also occur. Multidrug antituberculous regimens are effective, but the disease tends to relapse even with appropriate treatment. Tick-Borne Infections  Spirochetal myocarditis has been diag­ nosed from myocardial biopsies containing Borrelia burgdorferi, which causes Lyme disease. Lyme carditis most often presents with arthritis and conduction system disease that resolves within 1–2 weeks of anti­ biotic treatment and is only rarely implicated in chronic heart failure. Other borrelia species carried by either ticks or lice can cause relapsing fever. Additional tick-borne illnesses associated with febrile illnesses and myocarditis include Rocky Mountain spotted fever, Q fever, and ehrlichiosis, all of which are treated with doxycycline alone or in com­ bination with other agents. ■ ■NONINFECTIVE INFLAMMATORY MYOCARDITIS Myocardial inflammation can occur in the absence of infectious causes. The paradigm of noninfective inflammatory myocarditis is cardiac transplant rejection, from which we have learned that myocardial depression can develop and reverse quickly, that noncellular mediators such as antibodies and cytokines play a major role in addition to lym­ phocytes, and that myocardial antigens are exposed by prior physical injury and viral infection. In the largest registry of acute myocarditis, chronic systemic inflammatory diseases were implicated in 7% of cases and in 15% of those with high-risk features.

The most commonly diagnosed noninfective inflammatory process affecting the myocardium is sarcoidosis. Sarcoidosis, as discussed in Chap. 379, is a multisystem granulomatous disease most commonly affecting the lungs, but involving many organs including skin, eyes, liver, nervous system, and bones, as well as the heart. The epidemiology appears to be changing, now recognized in men and women of all races and ethnic groups, typically between 30 and 50 years old but often after the age of 50 in women. Sarcoidosis is now understood as a com­ bination of foreign antigen presentation and a dysregulated immune response that leads to ongoing inflammation, including activated macrophages. Occupational exposures include agriculture, firefight­ ing, metal-working, and construction work, with silica dust, pesticides, mold, and other inhaled particles as examples of implicated antigens. The occurrence of sarcoidosis is increased in family members, reflect­ ing potential sharing of environments and of genetic variants, which have been identified in loci affecting immune responses.

PART 6 Disorders of the Cardiovascular System Cardiac sarcoidosis often accompanies pulmonary sarcoidosis but frequently occurs without detectable lung disease. The time course, burden and activity of cardiac granulomata, and the degree of extra­ cardiac involvement are remarkably variable. Patients may present with rapid-onset heart failure and ventricular tachyarrhythmias, conduction block, chest pain syndromes, or minor cardiac findings in the setting of pulmonary sarcoidosis, ocular involvement, an infiltrative skin rash, or a nonspecific febrile illness. Chronic sarcoidosis may go unrecognized for months or years. When ventricular tachycardia or conduction block dominates the initial presentation of heart failure without coronary artery disease, suspicion should be high for sarcoidosis as a cause of cardiomyopathy. Right bundle branch block should raise suspicion for sarcoidosis but is uncommon with other cardiomyopathies, in which left bundle branch block is more common. The pathology of cardiac sarcoidosis often shows a spectrum from metabolically active granulomas to bland fibrosis at the sites of previ­ ous inflammation. Regional wall-motion abnormalities are common, but global ventricular function may be preserved early during mild disease. When left ventricular function is only mildly reduced, ventric­ ular size may be near normal, sometimes described as “nondilated” or “minimally dilated cardiomyopathy.” Although occasionally listed with restrictive cardiomyopathies, sarcoidosis with a reduced ejection frac­ tion generally has the phenotype of dilated or minimally dilated car­ diomyopathy. There may be a right ventricular predominance of both dilation and ventricular arrhythmias, in which case potential diagnoses include genetic arrhythmogenic right ventricular cardiomyopathy, with which sarcoidosis shares multiple features. Diagnosis of cardiac sarcoidosis is easiest in the presence of biopsyproven sarcoidosis of other organs. Imaging of the heart can show regional wall motion abnormalities or small ventricular aneurysms. MRI of the heart can identify late gadolinium enhancement in a pat­ tern of fibrosis not compatible with myocardial infarction. Computed tomography of the chest often reveals pulmonary lymphadenopathy even in the absence of clinical lung disease. Positron emission tomog­ raphy (PET) of the whole chest can highlight active sarcoid lesions that are avid for glucose in heart or lung. When metabolically active adenopathy is detected, biopsy is often necessary to rule out malig­ nancy or chronic granulomatous infections such as tuberculosis or his­ toplasmosis before treating with immunosuppression for sarcoidosis. The scattered granulomata of sarcoidosis are commonly missed on cardiac biopsy (Fig. 268-3). Immunosuppression for sarcoidosis is generally initiated with glucocorticoids. Initial dosing was traditionally high but now is more often started at 30–40 mg daily or less, with early addition or substitu­ tion of steroid-sparing agents like methotrexate or mycophenolate. Third-line treatment may include tumor necrosis factor-alpha inhibi­ tors or other immunomodulators under investigation. The impact of treatment is usually more apparent for suppression of arrhythmias than for improvement of markedly impaired left ventricular dysfunction. Devices are often indicated for tachyarrhythmias or for conduction disease and usually include both pacing and defibrillation capability. Patients with sarcoidosis are immunosuppressed, and their manage­ ment should be supervised by an experienced multidisciplinary team.

FIGURE 268-3  Sarcoidosis. Microscopic image of an endomyocardial biopsy showing a noncaseating granuloma and associated interstitial fibrosis typical of sarcoidosis. No microorganisms were present on special stains, and no foreign material was identified. Hematoxylin and eosin–stained section, 200× original magnification. (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.) Cardiac sarcoidosis may respond to the initial immunosuppression course without recurrence, may fluctuate over a chronic course, or occasionally may lead to end-stage heart failure requiring heart transplantation. Giant cell myocarditis is less common than sarcoidosis, but accounts for 10–20% of biopsy-proven myocarditis, typically presenting acutely with rapidly progressive heart failure and tachyarrhythmias. Giant cell myocarditis occurs equally in men and women, usually of older age than those with acute viral myocarditis, and is more often associated with systemic autoimmune disorders. Unlike sarcoidosis, the more dif­ fuse involvement with giant cell myocarditis usually leads to diagnostic endomyocardial biopsy, revealing granulomatous lesions surrounded by extensive inflammation infiltrate, often with eosinophilic infiltra­ tion. However, the occasional finding of giant cell myocarditis in explanted hearts after a previous diagnosis of sarcoidosis suggests that they may share the same disease spectrum. Glucocorticoid therapy alone is rarely effective, but in combination with other immunosup­ pression therapies similar to those used for severe transplant rejection, the rate of death or heart transplantation has decreased for patients who are stable at the time of presentation. Most patients presenting with cardiogenic shock from giant cell myocarditis progress to need urgent mechanical support or transplantation, for which they may be rendered ineligible by severe infection resulting from intensive immunosuppression. Eosinophilic myocarditis is one of the causes of fulminant myocarditis but may be missed on milder presentation that does not include assess­ ment for hypereosinophilia, which is present in about three-fourths of diagnosed cases. Myocardial toxicity of eosinophils may lead to apical thrombi on cardiac imaging, and MRI reveals inflammation acutely and subendocardial fibrosis in chronic cases. Endomyocardial biopsies show infiltration with lymphocytes, neutrophils, and a high proportion of eosinophils. Hypersensitivity to chronic medications accounts for up to one-third of cases and is often cured by withdrawal of the agent and acute steroid therapy. Particularly in Mediterranean and African coun­ tries, hypereosinophilia can result from chronic parasitic infection, for which treatment may cure the myocarditis. About 12% of cases are due to eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome), which responds to immunosuppression but may have a relapsing course. The hypereosinophilic syndrome (HES) accounts for 10–15% of cases, resulting from myeloproliferative vari­ ants or overproduction of eosinophil production, for which combined immunosuppression may soon include therapies under investigation to decrease eosinophil production. About 30% of HES cases are currently

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269 Dilated Cardiomyopathies

unexplained. Without curative therapy, the initial inflammatory necro­ sis can lead to thrombosis, valve disease, and progressive endomyocar­ dial fibrosis with restrictive physiology, termed Loeffler endocarditis, which presents as a restrictive cardiomyopathy. Myocarditis is often associated with systemic inflammatory diseases, such as polymyositis and dermatomyositis, which can affect cardiac as well as proximal skeletal muscle and are usually diagnosed from autoantibodies. Myocarditis with lymphocytic infiltrates on endomyo­ cardial biopsy can be seen in some patients with systemic lupus erythe­ matosus, but multiple cardiac manifestations also include accelerated coronary artery disease, valvular involvement from sterile endocarditis, pericarditis, vasculitis, and chloroquine cardiotoxicity. Vaccines have occasionally been implicated in myocarditis. This has been best studied after the smallpox vaccine in military popula­ tions. As this is a live vaccine, it is unclear whether this is direct injury, but it is generally assumed to be a hypersensitivity response. More recent concern relates to COVID-19 vaccines, after which the overall rate of myocarditis is estimated to be about 1/100,000 vaccine doses (increased to 2–3/100,000 for recipients age 18–39 years). Most cases of vaccine-induced myocarditis resolve without hospitalization. Male adults under 40 are at highest risk of myocarditis from the COVID-19 vaccines, as they are for primary infectious myocarditis after COVID19 and other viruses. The risk for men under 40 increases after repeat COVID-19 vaccines, for which the benefit/risk for individuals should be considered. The most dramatic form of noninfectious inflammatory myocarditis is that seen with combined immune checkpoint inhibitors. Targeted monoclonal antibody therapy to unblock the host immune response has produced remarkable remission of multiple advanced tumors. Inhibitory receptors on T lymphocytes (such as CTLA-4 and PD-1) and the programmed death ligands, such as PD-L1, interact in nor­ mal self-regulation to inhibit overactivation of immune responses. Tumor cells can upregulate these ligands to hide from immune recognition. Therapeutic antibodies against these inhibitory recep­ tors or ligands can heighten host defenses against the tumor but also unleash immune attack against host tissues expressing PD-L1, which include skeletal and cardiac muscle, endothelial cells, and multiple other organs, such as lung, liver, pancreas, thyroid, and skin. With cardiac involvement, troponin is often elevated, B-type natriuretic peptide may be elevated, and creatine phosphokinase may be high, particularly with skeletal involvement. The diagnosis should be suspected immediately with acute cardiac presentation in patients treated with checkpoint inhibitors. Admission to the coronary care unit is currently recommended for an elevated troponin levels and ECG changes, which may be nonspecific but can also include conduc­ tion blocks and bizarre arrhythmias. Echocardiography may suggest myocardial edema, but initial ejection fraction may not be markedly reduced. Initial care should generally not be delayed for endomyocar­ dial biopsy, which typically shows extensive lymphocytic infiltration. Patients may also present initially with other acute organ system involvement, which warrants urgent multidisciplinary management in intensive care. Therapy with high-dose glucocorticoids should be initiated rapidly and may be followed soon by more targeted immune inhibition. Reports of fatality in checkpoint inhibition myocarditis were initially very high, but outcomes are improving with earlier recognition and therapy. ■ ■FURTHER READING Ammirati E et al: Management of acute myocarditis and chronic inflammatory cardiomyopathy. Circ Heart Failure 13:e007405, 2020. Drent M et al: Challenges of sarcoidosis and its management. N Engl J Med 385:1018, 2021. Fairweather D et al: COVID-19, myocarditis and pericarditis. Circ Res 132: 1302, 2023. Moslehi J, Salem JE: Immune checkpoint inhibitor myocarditis treatment strategies and future directions. JACC CardioOncol 4:704, 2022.

Neal K. Lakdawala, Lynne Warner Stevenson,

Joseph Loscalzo

Dilated

Cardiomyopathies CHAPTER 269 As described in Chap. 266, the phenotype of dilated cardiomyopathy (DCM) is characterized by decreased left ventricular systolic function, typically with increased left ventricular dimensions, although dilation may be minimal in some cases. Multiple causes and contributing fac­ tors have been implicated (Table 269-1). Dilated Cardiomyopathies As discussed in Chaps. 267 and 268, many cases are attributed to prior myocarditis, and an increasing number are associated with pathogenic genetic variants, but other causes include toxic and meta­ bolic disorders and peripartum cardiomyopathy, which are discussed in this chapter, along with takotsubo cardiomyopathy, which has a distinct presentation and phenotype that often resolves. Despite the multiple etiologies and variable initial presentations, DCM often progresses into a convergent clinical phenotype similar to that of other injury such as acute myocardial infarction. Some myo­ cytes may die early in the course, while others survive only to have later programmed cell death (apoptosis), and remaining myocytes develop hypertrophy in response to increased wall stress. Local and circulating neurohormonal factors stimulate deleterious secondary responses that contribute to progression of disease. Dynamic remod­ eling of the interstitial scaffolding affects diastolic function and the amount of ventricular dilation. Mitral regurgitation commonly devel­ ops as the ventricle dilates and the valvular apparatus is distorted and is commonly moderate to severe by the time heart failure is advanced. There is increasing evidence for the role of chronic inflammation in disease progression even when not initially implicated. Many cases that present “acutely” have progressed silently through these stages of injury over months to years. Dilation and decreased function of the right ventricle may result directly from the initial injury but more often develop later in response to elevated afterload presented by sec­ ondary pulmonary hypertension and in relation to mechanical interac­ tions with the failing left ventricle. The secondary responses are often modifiable or reversible. Almost a third of patients with recent-onset cardiomyopathy in the absence of coronary artery disease demonstrate substantial spontaneous recovery to normal ejection fraction. Partial recovery to left ventricular ejec­ tion fraction (LVEF) >0.40 (“heart failure with improved ejection fraction”) is common in chronic DCM during recommended therapy with neurohormonal modulation, cardiac resynchronization therapy for left bundle branch block, and diuretics as needed to maintain fluid balance, as recommended for other heart failure with reduced LVEF (Chap. 265) regardless of the initial cause of DCM. Additional aspects of diagnosis, therapy, and outcomes for specific etiologies of DCM other than the infectious, inflammatory, and genetic cardiomyopathies are discussed below. CARDIOTOXICITY AND CARDIOMYOPATHY Cardiotoxicity has been reported with multiple environmental and pharmacologic agents. Often these associations are seen only with very high levels of exposure or acute overdoses, in which acute elec­ trocardiographic and hemodynamic abnormalities may reflect both direct drug effect and systemic toxicity. Alcohol is the most common toxin implicated in chronic DCM. Although excess consumption may contribute to >10% of cases of heart failure, including exacerbation of heart failure with structural heart disease, alcoholic cardiomyopa­ thy is relatively rare and remains a diagnosis of exclusion. Moreover, Mendelian randomization studies have not identified a link between genetically predicated alcohol consumption and heart failure, sug­ gesting that the population attributable risk of alcohol to the overall heart failure epidemic is modest. Alcoholic cardiomyopathy causes

TABLE 269-1  Major Causes of Dilated Cardiomyopathy

(with Common Examples) Inflammatory Myocarditis (see Chap. 268) Infective   Viral (coxsackie,a adenovirus,a COVID-19, HIV) PART 6 Disorders of the Cardiovascular System   Parasitic (Trypanosoma cruzi—Chagas’ disease, trypanosomiasis, toxoplasmosis)   Bacterial (diphtheria)   Spirochetal (Borrelia burgdorferi—Lyme disease)   Rickettsial (Q fever)   Fungal (with systemic infection) Noninfective   Granulomatous inflammatory disease     Sarcoidosis     Giant cell myocarditis   Eosinophilic myocarditis   Polymyositis, dermatomyositis   Collagen vascular disease   Checkpoint inhibitor chemotherapy   Transplant rejection Toxic Alcohol Catecholamines: amphetamines, cocaine Chemotherapeutic agents (anthracyclines, trastuzumab) Interferon Other therapeutic agents (hydroxychloroquine, chloroquine) Drugs of misuse (testosterone and other anabolic steroids emetine) Heavy metals: lead, mercury Occupational exposure: hydrocarbons, arsenicals Metabolica Nutritional deficiencies: thiamine, selenium, carnitine Electrolyte deficiencies: calcium, phosphate, magnesium Endocrinopathy   Thyroid disease   Pheochromocytoma   Diabetes mellitus Obesity Hemochromatosis Inherited metabolic pathway defects (see Chap. 267) Familiala (see Table 267-1) Cardiomyopathies without extracardiac involvement Cardiomyopathy with skeletal myopathy, for example:   Dystrophin-related dystrophy (Duchenne’s, Becker’s)   Mitochondrial myopathies (e.g., Kearns-Sayre syndrome) Hemochromatosis Susceptibility to immune-mediated myocarditis Associated with other systemic diseases Miscellaneous (Shared Elements of Above Etiologies) Arrhythmogenic ventricular cardiomyopathy Peripartum cardiomyopathy Left ventricular noncompactiona Tachycardia-related cardiomyopathy   Supraventricular arrhythmias with uncontrolled rate   Very frequent nonsustained ventricular tachycardia or high burden of premature ventricular complexes aSome specific cases can be linked now to specific genetic mutation in a familial cardiomyopathy; others with similar phenotypes that appear to be acquired or idiopathic may represent genetic factors not yet identified.

many more hospital admissions in men than women, but prevalence is similar between men and women with alcoholism, with left ventricular dysfunction detected in about a third of asymptomatic patients. Esti­ mates of the alcohol intake necessary to cause cardiomyopathy have been 3–4 ounces or ≥60–80 g of pure ethanol daily for ≥5 years, about 750 mL of wine, 6 beers, or a half pint of hard liquor, although women may develop cardiomyopathy with lower amounts of consumption. Frequent binge drinking may also be sufficient. Toxicity is attributed both to alcohol and to its primary metabolite, acetaldehyde. Chronic heavy exposure may cause neurohormonal activation and alter metab­ olism, protein synthesis, substrate utilization, and oxidative stress. Polymorphisms of the genes encoding alcohol dehydrogenase and the angiotensin-converting enzyme may influence the likelihood of alco­ holic cardiomyopathy. Superimposed vitamin deficiencies and toxic alcohol additives are rarely implicated currently. Mutations in TTN and other DCM disease genes can be identified in ~10% of patients with presumed alcohol cardiomyopathy. Many patients with alcoholic cardiomyopathy are fully functional in their daily lives without apparent stigmata of alcoholism. The cardiac impairment in severe alcoholic cardiomyopathy is the sum of both permanent damage and a substantial component that is reversible after cessation of alcohol consumption. Atrial fibrillation occurs commonly both early in the disease (“holiday heart”) and in advanced stages. Medical therapy includes conventional guideline-directed medical therapies with neurohormonal, mineralocorticoid receptor, and β adr­ enoreceptor antagonists as well as sodium-glucose cotransporter 2 inhibitors with diuretics as needed for fluid management and careful attention to electrolyte repletion. Withdrawal should be supervised to avoid exacerbations of heart failure or arrhythmias and ongoing sup­ port arranged. Even with severe disease, marked improvement can occur within 3–6 months of abstinence, but the prognosis is grim if heavy alcohol consumption continues. Cocaine, amphetamines, and related catecholaminergic stimulants can produce chronic cardiomyopathy as well as acute ischemia, tachyarrhythmias, malignant hypertension, aortic dissection, and stroke. Cardiac pathology reveals microinfarcts consistent with small vessel ischemia, similar to those seen with pheochromocytoma, and thrombosis secondary to endothelial dysfunction in the case of cocaine. Regular cannabis use has been linked to increased risk of atrial fibrillation, myocardial infarction, and stroke in patients with and without other known risk factors. Cannabis is not specifically implicated as a cause of cardiomyopathy in population studies but is of concern as the potency of both inhaled and edible products continues to increase. Chemotherapy agents are the most common drugs implicated in toxic cardiomyopathy. Judicious use balances risks of the malignancy and the risks of cardiotoxicity presented not only by the drug regimens but also by the patient’s cardiovascular profile and possibly genetic factors influencing myocyte response to injury. Receipt of cardiotoxic drugs or radiation may warrant designation as “stage B” heart failure, with asymptomatic changes in cardiac structure and biomarkers. Clini­ cal recognition can be delayed as some symptoms can overlap with cancer and the prognosis with heart failure may be worse than for the underlying cancer. Anthracyclines (e.g., doxorubicin) cause characteristic histologic changes of vacuolar degeneration and myofibrillar loss. Multiple mech­ anisms have been implicated, involving reactive oxygen species and iron compounds, mitochondrial damage, transcription factors such as hypoxia-induced factor, and, most recently, inhibition of topoisomer­ ase II involved in DNA repair. Risk for cardiotoxicity increases with older age, obesity, hypertension, diabetes mellitus, preexisting cardiac disease, higher doses or combination therapies, and left chest irradia­ tion. Systolic dysfunction can occur acutely with symptoms of heart failure noted soon after drug administration, but more often is detected by surveillance echocardiography during the first year after exposure. Doxorubicin cardiotoxicity generally does not result in marked left ventricular dilation, such that stroke volume and systemic perfusion can be low with only a modest reduction of ejection fraction. Therapy

for reduced ejection fraction due to anthracycline therapy includes β-adrenergic receptor blockade and inhibition of the renin-angiotensin system, with conflicting data on whether these agents decrease toxicity when given in parallel with chemotherapy. The use of dexrazoxane, an intracellular iron chelating agent, can prevent anthracycline cardio­ myopathy, but there is no consensus on when it should be used owing to concerns that it might attenuate the efficacy of cancer therapies. Once thought to have an inexorable downward course, many patients with symptomatic heart failure can improve to near-normal function with careful management, including prevention of “second-hit” insults such as atrial fibrillation or hypertension. The course differs for some children treated with these agents before puberty, in whom inadequate growth of the heart may lead to refractory heart failure as they reach their twenties. Trastuzumab (Herceptin) is one of the humanized monoclonal anti­ bodies that interfere with human epidermal growth receptor 2 (HER2), which is crucial for growth of some tumors, such as breast cancer, and for cardiac adaptation. Cardiotoxicity is highest when anthracyclines are administered in conjunction with trastuzumab; however, less toxic­ ity is seen now when these agents are combined compared with the toxicity observed previously with paclitaxel for breast cancer. Although more often reversible than anthracycline cardiotoxicity, trastuzumab cardiomyopathy may persist in about a third of affected patients and can progress to clinical heart failure and death. For cardiotoxicity with anthracyclines or trastuzumab, therapy is recommended as for other causes of reduced ejection fraction. Cardiotoxicity with cyclophosphamide and ifosfamide generally occurs acutely and with very high doses. 5-Fluorouracil, cisplatin, and some other alkylating agents can cause recurrent coronary spasm that occasionally leads to depressed contractility. Acute administration of interferon-α, interleukin 2, and other cytokine-based therapies can cause pericarditis, hypotension, and arrhythmias. Clinical heart failure occurring during their chronic administration usually resolves after discontinuation. Vascular endothelial growth factor (VEGF), produced endogenously or by tumors, enhances angiogenesis by activating the VEGF signaling pathways. Monoclonal antibodies and many small-molecule tyrosine kinase inhibitors that affect VEGF are in use for different malignancies. Although these agents are “targeted” at specific tumor receptors or pathways, the biologic conservation of signaling pathways means that some of these drugs also find targets in the cardiovascular and other organ systems. Blood pressures increase in most patients during ther­ apy, attributed to an imbalance between endogenous vasodilators and vasoconstrictors and alteration of glomerular function. Hypertension and proteinuria can develop with these agents, similar to preeclampsia, and presentation is associated with increased risk of future cardiac disease. Recognition of cardiotoxicity during therapy with these agents is complicated because they occasionally cause peripheral fluid accumulation (ankle edema, periorbital swelling, pleural effusions) due to local factors rather than elevated central venous pressures. Therapeutic approaches include management of associated hyperten­ sion, withdrawal of the tyrosine kinase inhibitor (when possible), and conventional treatment for heart failure. Newer tyrosine kinase inhibi­ tors effective against multiple kinases may have more complex offtarget effects. This includes the Bruton tyrosine kinase inhibitors (e.g., ibrutinib), which are used as primary therapy for lymphoid malignan­ cies, with predominant cardiovascular risks of atrial and ventricular arrhythmias in addition to heart failure. Proteasome inhibitors used to treat multiple myeloma are associated with an increased risk of hypertension, ischemic events, thromboem­ bolism, and heart failure. The more potent agent, carfilzomib, appears more cardiotoxic than bortezomib. Other treatments for myeloma include immunomodulatory drugs including lenalidomide and tha­ lidomide, which may cause heart failure in addition to risks of venous thromboembolism. Mitogen-activated extracellular signal regulated kinase (MEK) inhibitors used for metastatic melanoma may cause hypertension and cardiomyopathy, especially when co-administered with rapidly accelerated fibrosarcoma (RAF) inhibitors.

The most dramatic toxicity of contemporary cancer therapy results from combined immune checkpoint inhibitors, which block the natu­ ral counterregulatory T-cell suppression and unleash potentially fatal inflammation directed toward multiple organs that can include the heart and vessels. These are discussed in Chap. 268 on noninfectious myocarditis.

CHAPTER 269 Other therapeutic drugs that can cause cardiotoxicity during chronic use include tumor necrosis factor α antagonists for rheumatologic conditions, and carbamazepine, clozapine, and lithium for neurologic and psychiatric diagnoses. Antiretroviral therapies for HIV have been implicated in cardiomyopathy. Chloroquine and hydroxychloroquine, which are widely used for systemic lupus erythematosus and rheuma­ toid arthritis, can decrease ejection fraction with either restrictive or dilated phenotype, often in association with conduction block. The presumed mechanism of toxicity is impaired lysosomal function, with accumulation of inclusion bodies that can be seen on cardiac biopsy. Dilated Cardiomyopathies Toxic exposures can cause arrhythmias or respiratory injury acutely during accidents. Chronic exposures implicated in cumulative car­ diotoxicity include cobalt, arsenicals, lead, and mercury. Treatment for these disorders includes removing exposure to the toxin and stan­ dard medical therapy for heart failure with reduced ejection fraction. Cardiomyopathy secondary to cobalt toxicity may be secondary to impaired myocardial energetics and is more common in the setting of hypothyroidism and dietary protein and thiamine deficiency. Cobalt cardiomyopathy usually presents with polycythemia, hypothyroid­ ism, and goiter due to the effects of cobalt on red cell production and thyroxine. Most historical causes of pathologic cobalt exposure are no longer relevant (e.g., treatment of anemia associated with end-stage disease, beer foam stabilization), and recent cases have been attributed to industrial exposures and cobalt alloy prosthetic hips. Diagnosis occurs in the setting of cobalt exposure and can be confirmed by the presence of electron microscopy dense intramitochondrial particles. PERIPARTUM CARDIOMYOPATHY Peripartum cardiomyopathy (PPCM) develops during the last trimes­ ter or within the first 5–6 months after pregnancy, most commonly within the first 2 weeks after delivery. Between 1:1000 and 1:4000 deliveries in the United States are affected. Risk factors include older maternal age, increased parity, twin pregnancy, malnutrition, and tocolytic therapy for premature labor. Up to half of cases occur in the setting of hypertensive disorders of pregnancy, including preeclampsia. Risk of PPCM is fourfold higher in black women, in whom recovery of normal LVEF takes longer and is less likely than in white women. Several of the risk factors contribute to antiangiogenic signaling through secreted inhibitors of VEGF, such as soluble FLT1 (sFLT1), high levels of which predict worse outcome. An abnormal cleavage fragment of the nursing hormone prolactin has also been implicated in decreased vascular response during oxidative stress, and investi­ gation is ongoing with the prolactin inhibitor bromocriptine after mixed results of small trials. Multiple other hormonal changes of pregnancy and secretory products from the placenta may interact to cause cardiac dysfunction, suggesting a “vasculohormonal model” in the development of PPCM. Genetic contribution has also been rec­ ognized. Similar to other DCM populations, truncating mutations in TTN are found in ~15% of cases of PPCM and associated with lower rates of recovered systolic function. Pregnancy thus represents another environmental trigger for accelerated phenotypic expression of genetic cardiomyopathy. PPCM usually presents with evidence of congestion, and criteria generally include an LVEF ≤0.45 presenting toward the end of preg­ nancy in the absence of another cardiac diagnosis. Pregnancy can unmask previously unrecognized heart disease but usually does so by the second trimester, when the major circulatory changes have already occurred. Toward the end of pregnancy, edema and dyspnea may be mistakenly attributed to the pregnancy itself, but elevated levels of brain natriuretic peptide or troponin or evidence of elevated central venous pressures are clues to cardiac dysfunction, particularly in the setting of hypertension. Echocardiography is usually sufficient for

diagnosis, but in complex cases, cardiac magnetic resonance imaging (MRI) can be considered, but gadolinium should not be used.

Most cases of PPCM present within the first week after delivery, usually with increasing edema and dyspnea when urine output does not keep up with mobilization of fluid. Both atrial and ventricular arrhythmias can occur. It is important to exclude other complications of pregnancy such as pulmonary emboli and coronary artery dissec­ tion. Genetic testing should be considered as the results may impact the mother, in whom positive genetic testing predicts less recovery, and also other family members, too. PART 6 Disorders of the Cardiovascular System Initial treatment for PPCM includes loop diuretics as needed to restore normal volume status. Prior to delivery, close collaboration with the maternal-fetal medicine team is necessary to adjust therapies to stabilize the gravid mother while protecting the fetus. Digoxin and beta blockers can be used if needed for arrhythmias, and hydrala­ zine/nitrate combinations can be used for hypertension, but reninangiotensin system inhibitors should not be given due to adverse fetal effects. Hemodynamic instability may require ongoing hemodynamic monitoring, and plans should be in place for emergency delivery if nec­ essary. When the mother is hemodynamically stable in the postpartum period, metoprolol tartrate, enalapril, and spironolactone have been shown to be compatible with breastfeeding. PPCM with LVEF <0.35 or marked dilation carries increased incidence of left ventricular throm­ bus and embolic risk, so anticoagulation is usually prescribed for the first 6 weeks once obstetric bleeding has resolved. Breastfeeding was once prohibited but now is generally encouraged in patients in whom fluid balance can be maintained through the high oral fluid intake required. For patients who are not breastfeeding, there is an ongoing large, randomized trial to determine the impact of bromocriptine on PPCM outcomes. Improvement of LVEF to ≥0.50 occurs in 50–80% of PPCM, often within 6 months, when other cardiac diagnoses have been carefully excluded. Recovery is less likely with LVEF <0.30, left ventricular enddiastolic dimension ≥0.60, black race, and presentation >6 weeks after delivery. Elevated levels of natriuretic peptides, troponin, and sFLT1 have also been associated with less recovery. Patients with LVEF <0.35 have a higher risk of life-threatening arrhythmias during initial presen­ tation and early after discharge, for which consideration of wearable defibrillators is reasonable. This is burdensome both physically and psychologically to a new mother, and more data are needed to help stratify risk. One-year mortality rates after PPCM have ranged in the United States from 4% in one study to 11% in a population of black women, and have been reported as up to twofold higher in Africa. METABOLIC CAUSES OF CARDIOMYOPATHY Endocrine disorders affect multiple organ systems, including the heart. Hyperthyroidism and hypothyroidism do not often cause clinical heart failure in an otherwise normal heart but commonly exacerbate heart failure. Clinical signs of thyroid disease may be masked, so tests of thyroid function are part of the routine evaluation of cardiomyopathy. Hyperthyroidism should always be considered with new-onset atrial fibrillation or ventricular tachycardia or atrial fibrillation in which the rapid ventricular response is difficult to control. The most common current reason for thyroid abnormalities in the cardiac population is the treatment of tachyarrhythmias with amiodarone, a drug with sub­ stantial iodine content. Hypothyroidism should be treated with very slow escalation of thyroid supplements to avoid exacerbating tachyar­ rhythmias and heart failure. Hyperthyroidism and heart failure create a dangerous combination that merits very close supervision, often hos­ pitalization, during titration of antithyroid medications, during which decompensation of heart failure may occur precipitously and fatally. Pheochromocytoma is rare but should be considered when a patient has heart failure and very labile blood pressure and heart rate, sometimes with episodic palpitations (Chap. 399). Patients with pheochromocytoma often have postural hypotension. In addition to α-adrenergic receptor antagonists, definitive therapy requires surgi­ cal extirpation. Very high renin states, such as those caused by renal

artery stenosis, can lead to modest depression in ejection fraction with little or no ventricular dilation and markedly labile symptoms with flash pulmonary edema, related to sudden shifts in vascular tone and intravascular volume. Controversies remain regarding whether diabetes mellitus and obesity are sufficient to cause cardiomyopathy with reduced ejection fraction. Most heart failure in diabetes mellitus results from epicardial coronary disease, with further increase in coronary artery risk due to accompanying hypertension and renal dysfunction. Cardiomyopathy may result in part from insulin resistance and increased advancedglycosylation end products, which impair both systolic and diastolic function. However, much of the dysfunction can be attributed to scat­ tered focal ischemia resulting from distal coronary artery tapering and limited microvascular perfusion even without proximal focal stenoses. Diabetes mellitus is a typical factor in heart failure with “preserved” ejection fraction, along with hypertension, advanced age, and female gender. The existence of a cardiomyopathy due to obesity is generally accepted, but the overlap is not well defined with the syndrome of heart failure with preserved ejection fraction (HFpEF). In addition to cardiac involvement from associated diabetes mellitus, hypertension, and vascular inflammation of the metabolic syndrome, obesity alone is associated with impaired excretion of excess volume load, which, over time, can lead to increased wall stress and secondary adaptive neuro­ humoral responses. Fluid retention may be aggravated by large fluid intake and the rapid clearance of natriuretic peptides by adipose tissue. In the absence of another obvious cause of cardiomyopathy in an obese patient with systolic dysfunction without marked ventricular dilation, effective weight reduction is often associated with major improvement in ejection fraction and clinical function. Improvement in cardiac function has been described after successful bariatric surgery, although all major surgical therapy poses increased risk for patients with heart failure. Postoperative malabsorption and nutritional deficiencies, such as calcium and phosphate deficiencies, may be particularly deleterious for patients with cardiomyopathy. Nutritional deficiencies can occasionally cause DCM but are not commonly implicated in developed countries. Beriberi heart disease due to thiamine deficiency can result from poor nutrition in under­ nourished populations and in patients deriving most of their calories from alcohol and has been reported in teenagers subsisting only on highly processed foods. This disease is initially a vasodilated state with very-high-output heart failure that can later progress to a low-output state; thiamine repletion can lead to prompt recovery of cardiovascu­ lar function. Abnormalities in carnitine metabolism can cause dilated or restrictive cardiomyopathies, usually in children. Deficiency of trace elements such as selenium can cause cardiomyopathy (Keshan’s disease). Calcium is essential for excitation-contraction coupling. Chronic deficiencies of calcium, such as can occur with hypoparathyroidism (particularly postsurgical) or intestinal dysfunction (from diarrheal syndromes and following extensive resection), can cause severe chronic heart failure that responds over days or weeks to vigorous cal­ cium repletion. Phosphate is a component of high-energy compounds needed for efficient energy transfer and multiple signaling pathways. Hypophosphatemia can develop during starvation and early refeeding following a prolonged fast and occasionally during hyperalimentation. Hemochromatosis is variably classified as a metabolic or storage disease (Chap. 426). It is included among the causes of restrictive car­ diomyopathy, but the clinical presentation is often that of a DCM. The autosomal recessive form is related to the HFE gene. With up to 10% of the population heterozygous for one mutation, the clinical prevalence might be as high as 1 in 500. The lower observed rates highlight the limited penetrance of the disease, suggesting the role of additional genetic and environmental factors such as alcoholism affecting clinical expression. Cardiac siderosis can also be acquired from iron overload due to hemoglobinopathies in patients treated with recurrent transfu­ sions. Excess iron is deposited in the perinuclear compartment of car­ diomyocytes, with resulting disruption of intracellular architecture and

FIGURE 269-1  Hemochromatosis. Microscopic image of an endomyocardial biopsy showing extensive iron deposition within the cardiac myocytes with the Prussian blue stain (400× original magnification). (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.) mitochondrial function. A diagnosis of systemic iron overload is made from measurement of serum iron and transferrin saturation, with a threshold of >60% for men and >45–50% for women. MRI is used to quantitate iron stores in the liver and heart. While endomyocardial biopsy tissue can be stained for iron (see Chap. 270 and Fig. 269-1), a diagnosis of cardiac iron overload is made principally by MRI and biopsy is not usually needed. If diagnosed early, hemochromatosis can often be managed by repeated phlebotomy to remove iron. For more severe iron overload, iron chelation therapy with desferrioxamine (deferoxamine) or deferasirox can help to improve cardiac function if myocyte loss and replacement fibrosis are not too severe. Inborn disorders of metabolism occasionally present with DCM, although they are most often associated with restrictive cardiomyopa­ thy (Chap. 267, Table 267-1). FIGURE 269-2  Takotsubo cardiomyopathy. Four-chamber view of cardiac magnetic resonance imaging demonstrating a mildly dilated left ventricle in diastole (left panel) with diffuse hypokinesis of the mid and apical segments and relative sparing of the basal segment wall motion at end systole (right panel) with left ventricular ejection fraction 46%. (Image courtesy of Raymond Kwong, MD, and Zariyat M. Mannan, MD, Cardiovascular Imaging, Brigham and Women’s Hospital, Boston.)

TAKOTSUBO SYNDROME OR CARDIOMYOPATHY Apical ballooning or “takotsubo” syndrome, also referred to as stressinduced cardiomyopathy or “broken heart syndrome,” is often clas­ sified as a cardiomyopathy, although its distinct acute presentation, typical ventricular shape, and frequent rapid recovery differ from most other cardiomyopathies. It occurs typically in older women after sudden intense emotional or physical stress. The ventricle shows global ventricular dilation with basal contraction, forming the shape of the narrow-necked jar (takotsubo) used in Japan to trap octopuses. Originally described in Japan, it is well recognized elsewhere during emergency cardiac catheterization and intensive care unit admissions for noncardiac conditions. Presentations include pulmonary edema, hypotension, and chest pain with electrocardiogram (ECG) changes mimicking an acute infarction. The left ventricular dysfunction extends beyond a specific coronary artery distribution and generally resolves within days to weeks. Animal models and ventricular biop­ sies suggest that this acute cardiomyopathy may result from intense sympathetic activation with heterogeneity of myocardial autonomic innervation, diffuse microvascular spasm, and/or direct catecholamine toxicity. Cardiac MRI (Fig. 269-2) demonstrates diffuse myocardial edema without necrosis and abnormal myocardial calcium handling. Coronary angiography may be required to rule out acute coronary occlusion.

CHAPTER 269 Dilated Cardiomyopathies A similar picture to takotsubo can also be caused a coronary embolus in the absence of atherosclerotic coronary artery disease. No therapies have been proven beneficial, but reasonable strategies include nitrates for pulmonary edema; combined alpha and beta blockers rather than selective beta blockade if hemodynamically stable; and magnesium for arrhythmias related to QT prolongation. An intra-aortic balloon pump is occasionally employed to improve critically low cardiac output, but only if there is no left ventricular outflow tract obstruction. The longterm prognosis is generally good, with the lowest mortality associated with episodes triggered by emotional rather than physical triggers. In-hospital complications and mortality are similar to those with acute myocardial infarction. Recurrence occurs in 10% of patients at an esti­ mated rate of 2%/year.

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270 Amyloidosis and Other Restrictive Cardiomyopathies

■ ■FURTHER READING Arany Z: Peripartum cardiomyopathy. N Engl J Med 390:154, 2024. Cardinale D et al: Early detection of anthracycline cardiotoxicity and

improvement with heart failure therapy. Circulation 131:1981, 2015. Davis MB et al: Peripartum cardiomyopathy. J Am Coll Cardiol 75: 207, 2020. Lyon AR et al: 2022 ESC Guidelines on cardio-oncology developed in PART 6 Disorders of the Cardiovascular System collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS): Developed by the task force on cardio-oncology of the European Society of Car­ diology (ESC). Eur Heart J 43:4229, 2022. Packer M: Cobalt cardiomyopathy: A critical reappraisal in light of a recent resurgence. Circ Heart Fail 9:e003604. 2016. Rasoul D et al: Alcohol and heart failure. Eur Cardiol 18:e65, 2023. Quiroz-Aldave JE et al: Thyrotoxic cardiomyopathy: State of the art. touchREV Endocrinol 19:78, 2023. Singh T et al: Manganese-enhanced magnetic resonance imaging in takotsubo syndrome. Circulation 146:1823, 2022. Wood JC: Guidelines for quantifying iron overload. Hematology Am Soc Hematol Educ Program 1:210, 2014.

Amyloidosis and

Other Restrictive Cardiomyopathies Rodney H. Falk, Neal K. Lakdawala,

Lynne Warner Stevenson, Joseph Loscalzo RESTRICTIVE CARDIOMYOPATHY Restrictive cardiomyopathy (RCM) is dominated by abnormal diastolic function within a noncompliant ventricle, often with mildly decreased contractility and ejection fraction (usually 30–50%). Both atria are enlarged, sometimes massively. Mild left ventricular dilation can be present. End-diastolic pressures are usually elevated in both ventricles, with preservation of resting cardiac output until late in the disease. Subtle exercise intolerance is usually the first symptom but is often not recognized until after clinical presentation with congestive symptoms. The restrictive diseases often present with relatively more right-sided symptoms, such as edema, abdominal discomfort, and ascites, although filling pressures are elevated in both ventricles. The cardiac impulse is less displaced than in dilated cardiomyopathy and less dynamic than in hypertrophic cardiomyopathy. A fourth heart sound is more common than a third heart sound in sinus rhythm, but atrial fibrillation is com­ mon. Jugular venous pressures often show rapid Y descents and may increase during inspiration (positive Kussmaul sign). Most causes of RCM are “infiltrative,” due to infiltration of abnor­ mal substances between myocytes, with the amyloidoses being the most common causes of RCM. RCM can also result from storage of abnormal metabolic products within myocytes. RCM due to acquired fibrotic injury is most commonly caused by radiation or connective tissue disease and less commonly by hypereosinophilic injury (see Chap. 268 and Table 270-1). RCM can also be secondary to genetic causes of primary cardiomy­ opathy, including variants in DES or as a forme fruste of hypertrophic cardiomyopathy caused by sarcomere variants. The most common differential diagnosis is between RCM and constrictive pericardial disease, as both often present with dominant right-sided heart failure. In the absence of specific therapy for the etiology of RCM, such as is now available for some patients with amyloidosis, general strategies are

TABLE 270-1  Causes of Restrictive Cardiomyopathies (RCM) Infiltrative (Between Myocytes) Amyloidosis   Light chain (AL) amyloid   Familial (variant transthyretin)a   Wild-type (normal) transthyretin Inherited metabolic defectsa Storage (Within Myocytes) Hemochromatosis (iron),a also with dilated cardiomyopathy phenotype when advanced Inherited metabolic defectsa   Fabry’s disease   Glycogen storage disease (II, III) Fibrotic Radiation Scleroderma Endomyocardial Possibly related fibrotic diseases   Tropical endomyocardial fibrosis   Hypereosinophilic syndrome (Löffler’s endocarditis) Carcinoid syndrome Radiation Drugs: e.g., serotonin, ergotamine Genetic Variants Affecting Cardiomyocyte Function Occasional RCM due to genetic variants more commonly associated with dilated or hypertrophic cardiomyopathy RCM and skeletal muscle involvement with desminopathy due to pathogenic DES variants aContribution of genetic background. focused on maintenance of optimal volume status, which is generally a compromise between adequate ventricular filling and systemic decon­ gestion. As ventricular filling and stroke volume are often restricted, therapy with beta blockers can reduce heart rate, contractility, cardiac output, and functional reserve. Vasodilation may not be well tolerated. Other than diuretics, therapies proven effective for dilated cardiomy­ opathy and other heart failure with reduced ejection fraction are not recommended for routine use in RCM. AMYLOIDOSIS Amyloidosis is a systemic disease characterized by the deposition of fibrillar proteinaceous material primarily in the extracellular space of one or more organs. Although there are many precursor proteins that have been shown to cause amyloidosis (see Chap. 117), the unifying feature of all types of amyloid is its staining characteristics. Amyloid is a noncellular material deposited in the extracellular space that stains with Congo red and exhibits “apple-green birefringence” when viewed under polarized light microscopy. When viewed with electron microscopy, amyloid deposits are seen to consist of nonbranching fibrils ~10 nm in diameter and a few micrometers in length. From a cardiac standpoint, there are two main precursor proteins that cause most cases of amyloid cardiomyopathy: transthyretin (TTR), produced in the liver, and light chains produced by abnormal plasma cells. TTR amyloidosis may be caused by a genetic variant of TTR (ATTRv) or by wild-type TTR (ATTRwt), and variant TTR is generally considered to be less stable than wild-type TTR. Once a diagnosis of amyloidosis has been made, it is critically important to determine the precise precursor protein because treatment is specific to the type of amyloid and incor­ rect typing will lead to inappropriate therapy. ■ ■PATHOLOGIC MECHANISMS OF HEART FAILURE IN CARDIAC AMYLOIDOSIS All forms of cardiac amyloidosis have a similar appearance on gross and microscopic examination (Figs. 270-1 and 270-2).

FIGURE 270-1  Gross pathology of the heart in amyloid cardiomyopathy. The left ventricle (LV) is severely thick due to amyloid infiltration. The LV cavity is small with markedly thick walls due to amyloid infiltration. The right ventricle is mildly thickened, and the left atrium (partly excised) is dilated. (Courtesy of Dr. Richard Mitchell, Brigham and Women’s Hospital Department of Pathology.) The extracellular deposits of amyloid result in an increase in the mass of the heart, due to expansion of the extracellular space. Both left and right ventricular walls demonstrate increased thickness, and decreased compliance and the left ventricular cavity may be relatively small, leading to a restrictive pathophysiology. The right ventricular cavity is often normal in size but may dilate in advanced disease. The atria are usually dilated due to the chronic elevation of biventricular diastolic filling pressure and may dilate further with the onset of atrial arrhythmias. Histologically, amyloid deposits are widespread through­ out the heart so that endomyocardial biopsy is almost always diagnos­ tic in cases of cardiac amyloidosis. FIGURE 270-2  Histology of amyloid cardiomyopathy. Left panel: Hematoxylin and eosin stain showing extensive extracellular cardiac amyloid deposition resulting in separation and distortion of cardiomyocytes. The amyloid stains light pink and the myocytes are nucleated and stain a deeper pink. Right panel: Specimen from same patient stained with sulfated Alcian blue. The amyloid stains “sea green,” and the myocytes are pale yellow-gray. Magnification ×60. (Courtesy of Dr. Richard Mitchell, Brigham and Women’s Hospital Department of Pathology.)

■ ■CLINICAL FEATURES OF CARDIAC AMYLOIDOSIS There are some clinical features of light chain (AL) amyloidosis and TTR amyloidosis that suggest one or the other diagnosis, but the cardiac features are similar enough that the final diagnosis of amy­ loid type often relies upon precise typing of a cardiac or extracardiac tissue biopsy. The most common clinical presentation is congestive heart failure. Although both ventricles are usually heavily infiltrated by the time congestive heart failure occurs, patients tend to present with symptoms of predominant right heart failure, namely peripheral edema and, not infrequently, ascites. Despite the clinical predominance of right ventricular failure, cardiac catheterization will reveal consider­ able elevation of both left and right ventricular filling pressure. Atrial arrhythmia, particularly atrial fibrillation, is a common presenting feature, particularly in TTR amyloidosis, and may occur at a time when the left ventricle is only mildly thick, precipitating heart failure in a previously asymptomatic patient. The onset of atrial fibrillation may be associated with symptoms of dyspnea, often more severe than is seen in nonamyloid patients with this arrhythmia. Refractory atrial arrhyth­ mia, whether to antiarrhythmic drugs or characterized by failure to maintain sinus rhythm after repeated ablation procedures, should raise the possibility of TTR cardiac amyloidosis, particularly if occurring in a patient in the mid-60s or older without other apparent reason for the atrial fibrillation.

CHAPTER 270 Amyloidosis and Other Restrictive Cardiomyopathies Cardiovascular physical examination in the symptomatic patient with cardiac amyloidosis reveals a normal or low pulse pressure. The apex beat may be difficult to palpate but, if felt, is usually only mildly displaced. The jugular venous pressure is almost always elevated and frequently demonstrates a paradoxical rise on inspiration (Kussmaul sign). The first and second heart sounds tend to be normal. Despite congestive heart failure, a third heart sound is very rarely heard, due to the restrictive pathophysiology and its associated impairment of ven­ tricular relaxation. Similarly, a fourth heart sound is also unusual as the infiltrated atrium is rarely able to generate much contractile pressure. Pleural effusions, primarily caused by heart failure (but occasionally aggravated by associated hypoalbuminemia from nephrotic syndrome or by the presence of pleural amyloidosis) are quite common. Cardiac murmurs due to amyloid-associated valve disease are relatively uncom­ mon, although a tricuspid regurgitation murmur may occasionally be present. There is an association between aortic valve stenosis and TTR amyloidosis, and a murmur of aortic stenosis may be present. Whether amyloid causes aortic stenosis or simply aggravates or precipitates heart failure in a patient with unrelated aortic valve disease is unclear. In addition to the cardiovascular examination, a careful systemic physical examination is mandatory. In advanced heart failure, hepatomegaly due to congestive heart failure is common, but an unusually hard liver may represent amyloid infiltration of the liver—something that occurs in AL amyloidosis but not TTR. The blood pressure should be checked in the supine, seated, and standing positions, seeking an abnormal pos­ tural drop. If present, this likely represents associated autonomic neu­ ropathy, which is a feature of AL amyloidosis and some forms of variant TTR amyloidosis but not wild-type TTR amyloidosis. Macroglossia or periorbital bruising, if present, strongly suggest AL amyloidosis, whereas a history of bilateral carpal tunnel syndrome or the finding of a ruptured biceps tendon points toward TTR amyloidosis. ■ ■DIFFERENTIAL DIAGNOSIS The differential diagnosis of a patient with biventricular failure mani­ festing predominantly as edema, in association with a thick left ventri­ cle but without a history of severe hypertension, is small. Hypertensive heart disease is usually associated with left ventricular hypertrophy on the electrocardiogram (ECG), whereas this ECG finding is uncommon in amyloidosis, and it requires several years of severe uncontrolled hypertension to produce the degree of wall thickening equal to that seen in amyloidosis. While amyloidosis, particularly ATTR, can have asymmetric left ventricular thickening, the clinical distinction between hypertrophic cardiomyopathy and amyloidosis is usually fairly clear, since the former rarely presents with peripheral edema and usually has left ventricular hypertrophy (LVH) on the ECG. Other infiltra­ tive cardiomyopathies such as Fabry disease may have typical skin

manifestations and usually LVH on the ECG. The rare mitochondrial cardiomyopathies may have an echocardiographic appearance similar to amyloidosis but have different noncardiac clinical features, such as maternally inherited diabetes, deafness, and recurrent strokes. Patients with advanced diabetes may have heavy proteinuria and heart failure, but their history of diabetes is obvious, and the echocardiogram does not show features suggestive of amyloid heart disease. In the era before echocardiography, constrictive pericarditis, often presenting with edema, ascites, and elevated jugular venous pressure with a Kussmaul sign, was the major differential of amyloid heart disease. Constrictive pericarditis is less common nowadays, and echocardiography can eas­ ily distinguish between the two entities.

PART 6 Disorders of the Cardiovascular System ■ ■AL AMYLOIDOSIS OF THE HEART AL amyloidosis is a plasma cell disorder closely related to multiple myeloma. It is described in detail in Chap. 117. An excessive produc­ tion of abnormal lambda, or (less commonly) kappa, free light chains produced by abnormal clonal bone marrow plasma cells results in amyloid deposits in multiple organs, with heart and kidney being the most common organs involved. AL amyloidosis is closely related to multiple myeloma, with which it may occasionally overlap. It is an aggressive disease, and cardiac involvement, either alone or in combi­ nation with other major organ involvement, carries the worst survival, with a median survival from onset of heart failure to death in untreated patients of ~6 months. This short survival underscores the urgency of pursuing a diagnosis of AL amyloidosis once suspected, as therapy can markedly improve duration and quality of life and must be instituted as soon as the diagnosis is made. In addition to the general features of heart failure noted above, there are several clinical noncardiac clues to AL amyloidosis as the etiology of congestive heart failure. These indicate the presence of a multisystem disease and include significant proteinuria, neuropathy, periorbital purpura (virtually pathognomonic of AL amyloidosis and occurring in 20–30% of cases), and macroglos­ sia (~10% of cases). ■ ■TTR AMYLOIDOSIS OF THE HEART Patients with wild-type TTR amyloidosis cardiomyopathy and those with amyloid cardiomyopathy caused by variant TTR may have subtle differences in presentation. The less common variant TTR cardiomy­ opathy may be associated with amyloid neuropathy, which can vary between mild sensory neuropathy and a rapidly progressive severe sensorimotor neuropathy with or without autonomic nervous system involvement. Myocardial infiltration may be extensive in patients with severe variant transthyretin neuropathy, but cardiac symptoms can be relatively mild in these patients, either because the limitation of physical activity due to the neuropathy masks exercise intolerance or because autonomic neuropathy acts to reduce peripheral resistance, decreasing the work of the heart. If autonomic neuropathy is present, postural hypotension can be highly symptomatic and postural mea­ surements of blood pressure are mandatory. A family history of neu­ ropathy or cardiomyopathy may be elicited in these patients and, when neuropathy is present, may have been misdiagnosed as other neuro­ logic conditions. In the United States, the most common TTR variant causing TTR amyloid cardiomyopathy is the substitution of valine for isoleucine at position 122, Val122Ile. This variant is present in ~3.5% of the U.S. population of African descent and presents as a late-onset restrictive cardiomyopathy usually in the seventh decade onward. The penetrance of clinical disease is incomplete, and the family history is often lacking or unknown. Neuropathy in this mutation is very mild or absent, although carpal tunnel syndrome, often preceding the onset of heart failure by several years, is commonly present. The clinical fea­ tures of other forms of variant TTR amyloidosis can vary considerably, somewhat dependent on the transthyretin mutation, but in the case of the Val122Ile variant, it tends to be a relatively rapid progressive infil­ trative cardiomyopathy with a median survival of 2–3 years following the onset of heart failure in untreated patients. Once considered a rare form of cardiac amyloidosis, TTR deposition derived from native (wild-type) transthyretin is now considered the

most common form of amyloidosis. It affects mainly men in the latter half of their seventh decade and eighth decades but may occasionally present at a younger age and often presents in the ninth decade onward. Men are almost 20 times more likely than women to be diagnosed with wild-type TTR amyloidosis, and when it does occur in women, it tends to present at a later age and to have a more indolent course. On average, the untreated median survival from the onset of heart failure to death is around 4–5 years, with death being due primarily to pro­ gressive congestive heart failure rather than to sudden death. Current therapies have slowed the disease progression and improved survival. Both wild-type and mutant TTR cardiomyopathy have a subclinical phase, probably of several years, during which there is a progressive infiltration of the heart with amyloid, and by the time heart failure occurs, 30–50% of the involved heart weight is due to amyloid. Atrial arrhythmias, most commonly atrial fibrillation or atrial flutter, may be the presenting feature of the disease, and when they occur, they often precipitate or worsen heart failure. In contrast to AL amyloidosis, the heart in ATTRwt is the sole major organ to be clinically involved, although histologic examination of the lungs and gut often shows fairly extensive amyloid deposits. TTR also had a predilection for ligaments and tendons, and a history of carpal tunnel syndrome, spinal stenosis, or ruptured bicep tendon, often occurring 5–8 years before heart fail­ ure, can be elicited in about half the patients with this disorder. ■ ■DIAGNOSIS The diagnosis of cardiac amyloidosis rests upon a clinical suspicion combined with imaging findings and, in many cases, a confirmatory biopsy. ECG voltage may be abnormally low, particularly in AL amyloi­ dosis, but this is not always the case. Echocardiography is an extremely useful imaging modality. The echocardiogram in all forms of cardiac amyloidosis with heart failure shows increased left ventricular wall thickness without ventricular dilation and, frequently, biatrial enlarge­ ment (Fig. 270-3). The right ventricle may also show increased thickness of the free wall. Diastolic function is abnormal, and a restrictive pattern, con­ sistent with elevated left ventricular diastolic pressures, is often seen. Although the left ventricular ejection fraction may be normal or near-normal, left ventricular longitudinal strain imaging, a tool for measuring the contraction of the left ventricle in the longitudinal plane, often shows a pattern in which strain is relatively preserved at the left ventricular apex and severely impaired at the base of the heart. Color-coding of this pattern results in a “bull’s-eye” appearance, which is highly suggestive of cardiac amyloidosis (Fig. 270-4). Atrial function is often impaired, particularly in AL amyloidosis, and this is characterized by a very small transmitral A wave in patients FIGURE 270-3  Echocardiogram (apical four-chamber view) showing typical appearance of amyloidosis. The left ventricular cavity is normal in size with thick walls, and there is biatrial enlargement. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

FIGURE 270-4  Left ventricular strain in amyloidosis. Left panels show outline of left ventricle divided into seven segments with numbers in bottom panel representing the percentage longitudinal systolic shortening of each segment. Right top panel shows corresponding curves for each segment, and bottom right panel shows color coding in which the apex codes bright red and base pink due to near-normal apical contraction, resulting in typical “bull’s-eye” pattern of amyloidosis. in sinus rhythm. This appearance may be associated with an increased risk of thromboembolism. Echocardiography with the typical appearance may be enough to proceed to further laboratory evaluation for amyloidosis, but cardiac magnetic resonance is increasingly used in the diagnosis of suspected cardiomyopathy. The ventricle is seen to be abnormally thick, measure­ ment of extracellular volume demonstrates marked expansion of the extracellular space due to amyloid deposition, and there is often exten­ sive delayed gadolinium enhancement of the myocardium, associated with abnormal nulling of the images (Figs. 270-5 and 270-6). Taken together, these features are virtually pathognomonic of amy­ loid cardiomyopathy. Once amyloid cardiomyopathy is suspected, it is critical to determine the specific type of amyloid deposition. Tracers developed for bone imaging (technetium pyrophosphate or technetium 3,3-diphosphono-1,2-propanodicarboxylic acid [DPD]) are not usually taken up by the normal heart or in other forms of cardiac pathology, but there may be avid tracer uptake in patients with transthyretin amy­ loid cardiomyopathy (Fig. 270-7). Because patients with AL amyloid cardiomyopathy may occasion­ ally have myocardial uptake of these tracers, it is critically important to measure serum free light chains, serum and urine protein electropho­ resis, and serum and urine immunofixation to rule out a plasma cell dyscrasia. If these lab tests are all negative and the nuclear scan is posi­ tive, a diagnosis of transthyretin amyloidosis can be confidently made, provided that echocardiography or cardiac magnetic resonance is consistent with this diagnosis. Monoclonal gammopathy of unknown significance not uncommonly coexists with transthyretin amyloidosis and will be associated with abnormalities in testing for plasma cell dys­ crasia. Thus, if light chain amyloidosis remains a possibility, despite the presence of a strongly positive pyrophosphate scan, consultation with

CHAPTER 270 Amyloidosis and Other Restrictive Cardiomyopathies a hematologist is important to help clarify the diagnosis. If uncertainty remains, an endomyocardial biopsy (or biopsy from other tissue) with definitive tissue typing (ideally by mass spectrometry) is required. Almost all patients with light chain amyloidosis will have evidence of a plasma cell dyscrasia, and almost all of them will have elevation of either serum free lambda light chains or (less commonly) serum free kappa light chains. If light chain amyloidosis is clinically suspected and serum free light chains are elevated, it is mandatory to obtain a tissue biopsy to confirm the presence of amyloid deposits. Most patients with light chain amyloidosis have widespread systemic involvement, and a subcutaneous fat pad aspirate or deep skin biopsy will show amyloid deposits in the majority of cases, thus avoiding the necessity for a car­ diac biopsy. If skin/fat biopsy is negative, it is reasonable to proceed to an endomyocardial biopsy. If amyloid heart disease is present, this will be positive in well over 90% of cases. In all cases, appropriate typing of the amyloid should be done to confirm the appropriate therapy. An algorithm with a suggested workup of suspected amyloidosis is shown in Fig. 270-8. ■ ■DIAGNOSIS AND TYPING OF CARDIAC AMYLOIDOSIS Laboratory evaluation in patients with cardiac amyloidosis is generally nonspecific but may give some support to a suspected diagnosis. Elec­ trolytes and complete blood count are usually normal or near normal. N-terminal prohormone of brain natriuretic peptide (NTproBNP) may be higher than anticipated for the degree of congestive heart failure, often in the range of 1000 to 2000 pg/mL even in the presence of relatively mild congestive heart failure. High-sensitivity troponin is frequently mildly elevated and may lead to a misdiagnosis of isch­ emic heart disease. In AL amyloidosis with renal involvement, heavy

PART 6 Disorders of the Cardiovascular System LV RV PE A FIGURE 270-5  Typical cardiac magnetic resonance imaging (MRI) in amyloidosis. A. A typical cardiac MRI appearance in amyloid cardiomyopathy. The left ventricular (LV) cavity is small with a mildly dilated right ventricular (RV) cavity and thick LV walls. B. The appearance of late gadolinium enhancement after injection of gadolinium in the same patient. Two typical appearances are seen: the distinction between myocardium (straight line) and LV cavity is poor, due to delayed nulling of the myocardium, a near pathognomonic feature of cardiac amyloidosis. There is also extensive, transmural delayed gadolinium myocardial uptake due to severe amyloid infiltration. Another aspect of cardiac amyloidosis quantifiable by MRI (not shown) is measurement of extracellular volume, which is markedly increased in cardiac amyloidosis and helps to differentiate amyloid infiltration from true LV hypertrophy. PE, pericardial effusion. (Image courtesy of Dr. Sarah A. M. Cuddy, Brigham and Women’s Hospital, Section of Cardiology.) proteinuria is often found, and this may cause hypoalbuminemia. Renal involvement is not a feature of transthyretin amyloidosis. Rarely, in AL amyloidosis with hepatic involvement, the alkaline phospha­ tase is significantly elevated. Although AL amyloidosis is a plasma cell disorder closely related to multiple myeloma, the sedimentation rate is usually normal or only minimally elevated, unlike the marked elevation that may be seen in myeloma. Hypogammaglobulinemia may be present in AL amyloidosis, but serum and urine protein elec­ trophoresis often do not reveal a monoclonal gammopathy, as the paraprotein level is low. Thus, in suspected AL amyloidosis, serum and urine immunofixation should be performed as these are more sensitive (although nonquantitative) than serum or urine protein electrophoresis. In almost all patients with AL amyloidosis, the level of circulating serum free light chains, either lambda or, less commonly, FIGURE 270-6  Technetium pyrophosphate (PYP) scan in a patient with wild-type transthyretin amyloidosis. The top three images are obtained in three separate views with single-photon emission computed tomography (CT) imaging alone, and the bottom three views with added cardiac CT imaging. Both modalities show marked myocardial uptake (orange) with absence of blood pool uptake (central clearing) and normal bone uptake. The lower images more precisely localize the uptake to the fused CT images of the heart, which in more equivocal cases helps to localize uptake to the myocardium and prevents misinterpretation as a positive scan due to blood pool uptake without myocardial uptake. PYP uptake is highly sensitive and specific for transthyretin amyloidosis but can occasional be present in AL amyloidosis; thus, exclusion of a plasma cell dyscrasia is mandatory when interpreting this imaging. In the normal heart and almost all other pathologies, there is no myocardial uptake of bone tracers such as PYP.

LV CAVITY LV WALL B kappa free light chains, is elevated. It is important to recognize that findings suggestive of a plasma cell dyscrasia in a patient with a cardio­ myopathy needs to be interpreted in the context of the clinical picture, as monoclonal gammopathy of unknown significance is common in the older population and may be unrelated to the cardiomyopathy. Unlike TTR cardiomyopathy, there is no definitive noninvasive test to diagnose AL amyloid cardiomyopathy, and thus a tissue biopsy is always needed. A subcutaneous fat pad aspirate or deep-skin needle aspiration biopsy has a high yield of positivity, but needs to be evalu­ ated by a skilled pathologist. A biopsy positive for AL amyloid from a noncardiac site in the presence of imaging consistent with amyloid cardiomyopathy is adequate to conclude that cardiac involvement is present. Immunohistochemistry, performed by many pathology labs, is fraught with diagnostic uncertainty and should be used with great

A B FIGURE 270-7  Technetium pyrophosphate (PYP) scan. A. A normal (negative) PYP scan. The planar images (top) show rib and sternal isotope uptake, but there is no uptake in the heart. Bottom panel shows single-photon emission computed tomography–computed tomography (SPECT-CT) fusion showing normal appearance of nonamyloid heart after PYP imaging (no isotope uptake). B. Positive PYP scan in a patient with cardiac transthyretin amyloidosis. There is intense cardiac uptake on the planar imaging (top) which is confirmed to be in the wall of the heart on feud SPECT-CT images (lower panel). (Courtesy of Dr. Sharmila Dorbala, Brigham and Women’s Hospital.) caution and always interpreted in the setting of the clinical picture. It is thus strongly recommended that typing of the amyloid ideally be done by mass spectrometry (available as a “send-out test” in the United States). Unless a diagnosis of AL amyloidosis is clear, sequencing of the TTR gene should be done to rule out familial transthyretin amyloidosis as this has obvious ramifications for the family.

CHAPTER 270 Amyloidosis and Other Restrictive Cardiomyopathies TREATMENT Cardiac Amyloidosis The treatment of systemic amyloidosis is addressed in detail in Chap. 117. Here, we will concentrate on specific issues related to

Suspicion for CA based on echocardiogram, CMR, or strongly suggestive clinical scenario PART 6 Disorders of the Cardiovascular System Assess for plasma cell dyscrasia by serum and urine PEP and IFE, and serum free light chains ABNORMAL* Assessment of other possible organ involvement (renal, hepatic, neurologic) Referral to hematology for full evaluation including bone marrow biopsy Fat pad or deep skin biopsy with staining for amyloid POSITIVE with positive typing for light chain amyloid*** NEGATIVE Proceed to cardiac or other affected organ biopsy AL (LIGHT CHAIN) AMYLOIDOSIS Genetic testing positive for variant TTR gene NEGATIVE FOR AMYLOID DEPOSITS AMYLOIDOSIS EXCLUDED FAMILIAL TTR AMYLOIDOSIS WILD-TYPE TTR AMYLOIDOSIS FIGURE 270-8  Diagnostic algorithm. Algorithm for the workup of suspected cardiac amyloidosis (CA). This is a suggested algorithm but, depending on initial degree of suspicion for amyloidosis type, may vary slightly in order. Asterisk footnotes are as follows: *Normal values in workup for a plasma cell dyscrasia are negative serum and urine protein electrophoresis and immunofixation, with normal values for free serum kappa and lambda light chains adjusted for renal function. Abnormalities may not always reflect light chain amyloidosis, as monoclonal gammopathy of unknown significance not uncommonly coexists with TTR amyloidosis and thus expert evaluation of all abnormalities is mandatory. **Patients with bone-imaging uptake present but less than rib uptake should be carefully evaluated to ensure that this is not just blood pool isotope uptake and, if not, should be considered as possible amyloidosis with further evaluation based on expert evaluation of likely cardiac amyloid. ***Typing for amyloidosis should ideally be performed by mass spectrometry, generally only available in specialized centers. Immunohistochemistry, while often used, may be misleading and should be interpreted cautiously within the context of the clinical features of the disease. CMR, cardiac magnetic resonance; CT computed tomography; DPD, technetium-99m 3,3-diphosphono-1,2-propanodicarboxylic acid; HMDP, technetium-99m–hydroxymethylene diphosphonate; IFE, immunofixation electrophoresis; PYP, technetium-99m–pyrophosphate; PEP, protein electrophoresis; SPECT, single-photon emission computed tomography. the cardiac disease. It is important, when considering treatment of cardiac amyloidosis, not simply to focus on therapies aimed at slowing or stopping the production of the precursor protein but also to address the manifestations of the disease. Sodium restric­ tion is an integral part of management of heart failure in all forms of cardiac amyloidosis with congestive heart failure. The restrictive pathophysiology renders the patient particularly vulnerable to small changes in blood volume, and sodium restriction can significantly improve the response to diuretics. There are no specific clinical trials that evaluate the best way to treat congestive heart failure in cardiac amyloidosis, but it is generally recognized that diuretics are the mainstay of therapy. The combination of a loop diuretics such as furosemide or (preferably) torsemide with spironolactone or eplere­ none is usually well tolerated. Renal function should be monitored while adjusting diuretic dose, particularly in patients with ATTRw amyloidosis who tend to be older and to have more baseline renal impairment. The use of other drugs commonly used in congestive

NEGATIVE Technetium imaging PYP, DPD or HMDF with SPECT imaging and, ideally, cardiac CT Cardiac uptake equal or greater than ribs No cardiac uptake** AMYLOIDOSIS UNLIKELY AND WORKUP CAN STOP BUT if suspicion still high, proceed to cardiac biopsy to exclude rare forms of amyloidosis including rare variant TTR forms that have negative TTR imaging TTR AMYLOIDOSIS Genetic testing negative for variant TTR gene Biopsy positive Biopsy negative AMYLOIDOSIS EXCLUDED MASS SPECTROMETRY TO DETERMINE PRECISE AMYLOID PROTEIN heart failure is more controversial. In light chain amyloidosis, auto­ nomic function is often impaired even in the absence of postural hypotension, and the use of angiotensin-converting enzyme inhibi­ tors or angiotensin receptor blockers may be associated with pro­ found hypotension. Thus, they are generally avoided. Beta-blockade is also often problematic and associated with decreased exercise tolerance. If a patient is receiving beta blockers when initially seen, we routinely taper and stop their use and reassess the patient’s sense of well-being, which, not infrequently, improves. For patients with atrial fibrillation and a rapid ventricular response, beta-blockade may be needed but digoxin can also be used. However, restoration of sinus rhythm is preferable. The use of sodium-glucose cotrans­ porter 2 (SGLT2) inhibitors appears to be clinically well-tolerated. This class of drug has efficacy across the spectrum of patients with heart failure and preserved ejection fraction and those with heart failure and reduced ejection fraction and may be of value in cardiac amyloidosis.

Cardiac arrhythmias in both AL and TTR amyloidosis are com­ mon. Most frequently seen is atrial fibrillation or flutter, the onset of which is often associated with clinical deterioration. There is a high risk of thromboembolism in patients with cardiac amyloido­ sis, and anticoagulation in patients with atrial fibrillation or flutter is mandatory. There does not appear to be increased risk of major bleeding among patients taking anticoagulants in either light chain or transthyretin amyloidosis. Restoration of sinus rhythm should be considered in all patients, particularly since rate-controlling agents are poorly tolerated. Amiodarone appears to be the most effective antiarrhythmic drug for atrial arrhythmias and should ideally be given, starting with a loading dose, prior to elective elec­ trical cardioversion. If a patient is adequately anticoagulated before and during electrical cardioversion, there is no reason to perform transesophageal echocardiography prior to the procedure. If atrial arrhythmias are associated with clinical deterioration and sinus rhythm cannot be maintained despite antiarrhythmic therapy, con­ sideration should be given to an invasive electrophysiologic proce­ dure. Pulmonary venous isolation/atrial fibrillation ablation is often more complex than in nonamyloid patients, with a higher recur­ rence rate, and we therefore tend to limit ablation procedures to patients with atrial flutter and no evidence of atrial fibrillation. For those with symptomatic atrial fibrillation, atrioventricular nodal ablation with the implantation of a biventricular pacemaker is an effective way of both controlling and regularizing the ventricular rate. Sudden cardiac death may occur in cardiac amyloidosis, being more common in advanced AL amyloidosis, but a prophylactic implantable defibrillator is generally ineffective in preventing this. Thus, consideration of an implantable defibrillator should be highly selective and probably limited to patients with a prior resuscitated cardiac arrest or a history of sustained ventricular tachycardia. Patients with TTR amyloidosis are at a high risk for the develop­ ment of high-degree atrioventricular block. This is usually preceded on ECG by bifascicular block or left bundle branch block. Patients should be questioned about unexplained, nonpostural dizzy spells or syncope, and if these occur in the setting of one of these ECG abnormalities, strong consideration should be given to cardiac pac­ ing. If a pacemaker is to be placed, we would generally recommend biventricular pacing, as right ventricular pacing produces abnor­ malities of septal contraction that, in the presence of a small cavity ventricle, may decrease cardiac output. SPECIFIC THERAPY OF CARDIAC AMYLOIDOSIS:

AL AMYLOIDOSIS The most common regimen for treating patients with light chain amyloidosis includes daratumumab, bortezomib, cyclophospha­ mide, and dexamethasone. Dexamethasone may aggravate sodium retention, and it is critical that the cardiologist experienced in TABLE 270-2  Rare Forms of Amyloidosis FREQUENCY OF CARDIAC DISEASE AMYLOID TYPE PRECURSOR PROTEIN AA Serum amyloid A (an inflammatory protein) <5% Kidney, liver Usually associated with longstanding chronic inflammation. Uncommon in developed countries, and cardiac involvement rarely the predominant factor. AApoA1 Apolipoprotein 1 25–30% Kidney, liver, spleen, nervous system, larynx AapoA4 Apolipoprotein 4 65–70% Kidney Family history often not present. Renal involvement without proteinuria is common, and cardiac involvement is usually present but often relatively mild. Afib Fibrinogen A-alpha (gene mutation) Not described Kidney, spleen Rare. Proteinuria that progresses to renal failure. Typical renal biopsy with glomerular obliteration by amyloid. Typical amyloid cardiomyopathy absent. ALECT2 Leukocyte cell-derived chemotaxin 2 Not described Kidney Liver involvement common. ALECT2 predominantly found in Hispanics. Gelsolin Gelsolin Unknown prevalence. Usually mild, and manifesting as conduction disease

amyloidosis co-manages AL amyloidosis patients with cardiac involvement along with the treating hematologist. During therapy, an increased diuretic dose may be needed and/or a reduction in the dexamethasone dose. The other medications are generally well tolerated, but rarely, bortezomib may cause acute, reversible cardiac toxicity. Bortezomib may also cause a neuropathy and aggravate autonomic neuropathy of AL amyloidosis. High-dose melphalan chemotherapy with autologous stem cell transplantation is used in some patients with light chain amyloidosis and may be associated with considerable fluid retention or atrial arrhythmias in patients with cardiac involvement. For patients with AL cardiac amyloidosis, it is mandatory that the patient being considered for this therapy have a pretherapy cardiac evaluation to assess the risk-benefit ratio, along with regular posttransplant follow-up in the acute stage. Fol­ lowing successful chemotherapy (defined as a hematologic remis­ sion, with normalization of the serum free light chains), congestive heart failure often improves and is associated with an improvement in left ventricular longitudinal strain. However, some patients remain with very poor cardiac function. Such patients may benefit from cardiac transplantation, but this requires a very careful evalu­ ation at an expert center to determine the extent of extracardiac amyloidosis and its likely effect on posttransplant prognosis.

CHAPTER 270 Amyloidosis and Other Restrictive Cardiomyopathies SPECIFIC THERAPY OF CARDIAC AMYLOIDOSIS: TTR AMYLOIDOSIS Currently, the aim of treatment of TTR cardiac amyloidosis is focused on reducing or stopping any further amyloid deposition. Tafamidis, a small molecule that stabilizes the tetrameric structure of transthyretin, is effective at slowing disease progression and may halt progression among patients treated early in the clinical presentation of the disease. It is extremely well tolerated. A similar drug, acoramidis, has shown similar efficacy in a pivotal clinical trial. An alternative class of drugs, the TTR silencers, significantly reduce the production of transthyretin by the liver and are approved in the United States for the treatment of familial amyloid polyneu­ ropathy. At the time of writing, two drugs (both of which are only approved for amyloid neuropathy), eplontersen and vutrisiran, both administered subcutaneously, are completing clinical trials for the treatment of transthyretin amyloid cardiomyopathy. Rarer forms of cardiac amyloidosis are listed in Table 270-2. Their rarity relates to the very uncommon nature of the type of amyloid with which they are associated or, as in the example of AA amyloido­ sis, the uncommon nature of cardiac involvement despite extensive other involvement. The diagnosis of most of these forms of cardiac amyloidosis will be made on mass spectrometry of a tissue biopsy after cardiac amyloidosis is suspected but when there is no evidence of a plasma cell dyscrasia or abnormality on technetium imaging. OTHER ORGAN INVOLVEMENT COMMENT Rare condition, with family history in many cases. Cardiac disease, when present, may be predominantly right-sided with tricuspid valve involvement. Corneal lattice dystrophy Skin and neurologic features Predominantly found in Finnish patients.

34 - 272 Aortic Stenosis

272 Aortic Stenosis

■ ■NOVEL DEVICES Newer pumps are in development that are designed to overcome chal­ lenges inherent in current-generation LVAS. Engineering continues to advance in this field, and we await devices that provide physiologic and synchronized pulsatile flow (rather than the unnatural transapical to aortic flow with current LVADs). The next paradigm shift will likely require a return to natural and pulsatile flow LVAS that are more bio­ compatible (as opposed to hemocompatible), responsive to physiologic requirements (smart pumps), and forgettable (without an external driveline to power its components). ■ ■TOTAL ARTIFICIAL HEART Not all patients are candidates for an LVAS, particularly those with severe right-sided heart failure or conditions that do not allow place­ ment of an LVAS (restrictive cardiomyopathy, cardiac amyloidosis, massive anterior myocardial infarction, complex congenital heart disease). In such patients, either a biventricular assist device approach or a total artificial heart pump can be considered. The SynCardia total artificial heart is a pulsatile, implantable pump that consists of two polyurethane ventricles with pneumatically driven diaphragms and four tilting disc valves. This requires excision of the native ventricles and thus cannot be employed as a myocardial recovery strategy. There are specific clinical issues that are unique to the total artificial heart management. This device operates on a steep physiologic curve and has little adaptability to tolerate either systemic blood pressure changes or large shifts in blood volume. As the ventricles are excised, most patients exhibit a sharp decline in renal function due to the loss of natriuretic peptide expression by the myocardium. Severe hemolysis is common due to the presence of four mechanical valves, and aberrant erythropoi­ esis is noted, leading to a severe anemia. Newer artificial hearts using biocompatible surfaces are under study (CARMAT), as well as those that use continuous flow technology (BIVACOR). ■ ■XENOTRANSPLANTATION On January 7, 2022, the first genetically edited pig-to-human heart xenotransplantation was performed. The porcine xenograft was derived from a 10-gene edited animal with four genes that were knocked out (targeting three carbohydrate antigens associated with hyperacute rejection and one anticardiac growth gene) and six genes that were knocked in (targeting human complement regulation, coagulation, and anti-inflammatory pathways). Two transplants have been performed in living human recipients with limited survival of 2 months or less, with death occurring due to delayed graft dysfunction and subsequent loss. There are substantial ongoing concerns with continued immunologic barriers (despite gene modification), costs of donor organ development and recovery, ethical considerations, and considerations of transmis­ sion of zoonoses. ■ ■GLOBAL CONSIDERATIONS While LVAS are available worldwide, their use and indications vary from country to country. In the United States, payers used to require discrete discrimination of indication into either a bridge to transplant or destination therapy, whereas in most European countries, this artificial segregation was not used. Cost-effectiveness studies suggest improvement with the newer devices, yet some countries only allow use of this technology as a bridge to transplantation (United King­ dom) while awaiting more definitive long-term studies for lifetime use. The use of LVAS in moderately symptomatic ambulatory patients with chronic systolic heart failure is still discouraged throughout the world, awaiting the availability of devices that can be fully internal­ ized without the need for an external driveline. Globally, the rates of myocardial recovery allowing for decommissioning or removal of devices remain low, although in young patients with nonischemic heart failure of relatively recent onset, this could be an important consideration. ■ ■FURTHER READING Crespo-Leiro MG et al: Heart transplantation: Focus on donor recov­ ery strategies, left ventricular assist devices, and novel therapies. Eur Heart J 43:2237, 2022.

Mehra MR et al: International Society for Heart and Lung Trans­

plantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy-2010. J Heart Lung Transplant 29:717, 2010. Mehra MR et al: The 2016 International Society for Heart Lung Trans­ CHAPTER 272 plantation listing criteria for heart transplantation: A 10-year update. J Heart Lung Transplant 35:1, 2016. Mehra MR et al: A fully magnetically levitated left ventricular assist device: Final report. N Engl J Med 380:1618, 2019. Mehra MR et al: Five-year outcomes in patients with fully mag­ Aortic Stenosis netically levitated vs axial-flow left ventricular assist devices in the MOMENTUM 3 randomized trial. JAMA 328:1233, 2022. Mehra MR et al: The panvascular interplay in pathophysiology and prognosis of cardiac allograft vasculopathy. J Am Coll Cardiol 80:1629, 2022. Mehra MR et al: Aspirin and hemocompatibility events with a left ventricular assist device in advanced heart failure: The ARIES-HM3 randomized clinical trial. JAMA 330:2171, 2023. Mehra MR et al: Life-prolonging benefits of LVAD therapy in advanced heart failure: A clinician’s action and communication aid. JACC Heart Fail 11:1011, 2023. Schroder JN et al: Transplantation outcomes with donor hearts after circulatory death. N Engl J Med 388:2121, 2023. Patrick T. O’Gara, Joseph Loscalzo

Aortic Stenosis GLOBAL BURDEN OF VALVULAR HEART DISEASE Valvular heart disease ranks well below ischemic heart disease, stroke, hypertension, obesity, and diabetes as a major threat to the public health. Nevertheless, it can cause significant morbidity and lead to premature death. Rheumatic fever (Chap. 371) is the dominant cause of valvular heart disease in low- and middle-income countries. Its prevalence has been estimated to range from as low as 1 per 100,000 school-age children in Costa Rica to as high as 150 per 100,000 in China (Fig. 272-1). Prevalence is higher among females than males, especially for individuals age 20–40 years. Rheumatic heart disease accounts for 12–65% of hospital admissions related to cardiovascular disease and 2–10% of hospital discharges in some endemic countries. Prevalence and mortality rates vary among communities even within the same country as a function of overcrowding, the availability of medical resources, education level, and population-wide programs for detection and treatment of group A streptococcal pharyngitis. In economically deprived areas, tropical and subtropical climates (par­ ticularly on the Indian subcontinent and in Southeast Asia), Central America, and the Middle East, rheumatic valvular disease progresses more rapidly than in more developed nations and frequently causes serious symptoms in patients aged <20 years. This accelerated natural history may be due to repeated infections with more virulent strains of rheumatogenic streptococci. Approximately 45–50 million people (575.5 per 100,000) live with rheumatic heart disease worldwide, an estimated prevalence characterized by 300,000 new cases and 233,000 case fatalities (5 per 100,000) per year, with the highest prevalence and age-adjusted mortality rates in sub-Saharan Africa, South Asia, Central Asia, and Oceania. In the United States, rheumatic heart disease accounted for 3876 deaths in 2020. Although globally the agestandardized mortality rate from rheumatic heart disease declined by nearly 50% between 1990 and 2022, the prevalence of heart failure attributable to rheumatic heart disease increased by nearly 90% over the same time interval.

PART 6 Disorders of the Cardiovascular System < 2.16 2.16 to < 4.17 4.17 to < 6.19 6.19 to < 8.2 8.2 to < 10.21 10.21 to < 12.23 12.23 to < 14.24 14.24 to < 16.25 16.25 to < 18.27

= 18.27 A YLDs (Years Lived with Disability)

YLLs (Years of Life Loot)

Rate per 100,000

DALYs (Disability Adjusted Life Years)

Year B FIGURE 272-1  The global burden of rheumatic heart disease. (A) Global map of age-standardized rheumatic heart disease morality rate per 100,000 in 2022. Mortality rates are highest in South Asia and Oceania. (B) Global rheumatic heart disease estimates per 100,000 by measure with shaded 95% uncertainty interval, 1990–2022. DALYs, disability-adjusted life-years; YLDs, years lived with disability; YLLs, years of life lost. (Reproduced with permission from GA Mensah et al: Global burden of cardiovascular diseases and risks, 1990-2022. J Am Coll Cardiol 82:2350, 2023.)

Prevalence

Mortality

All Ages Age-standardized

Prevalence of moderate or severe valve All valve disease Mitral valve disease Aortic valve disease

disease (%)

<45 45–54 53–64 65–74 ≥75 FIGURE 272-2  The burden of moderate or severe mitral and aortic valve disease in the United States. Prevalence estimates are derived from three population-based studies comprising a total of 11,911 individuals: The Coronary Artery Risk Development in Young Adults (CARDIA), the Atherosclerosis Risk in Communities (ARIC), and the Cardiovascular Health Study (CHS). (Reproduced with permission from VT Nkomo, JM Gardin, TN Skelton, et al: Burden of valvular heart diseases: a population-based study, Lancet 368(9540):1005-1011, 2006.) Valve disease in high-income countries is dominated by degen­ erative or nonrheumatic inflammatory processes that lead to valve thickening, fibrosis, calcification, and dysfunction. The prevalence of valvular heart disease increases significantly with age. Community echocardiographic screening identifies previously undiagnosed, pre­ dominantly mild valvular heart disease in ~50% of the population aged >65 years. In this age group, the prevalence of previously undi­ agnosed moderate or severe valvular heart disease is ~6%. Significant left-sided valve disease may affect as many as 12–13% of adults aged

75 years (Fig. 272-2). Severe aortic stenosis (AS) is estimated to affect 3.5% of the population aged >75 years. A Swedish epidemio­ logic study estimated the incidence of newly diagnosed valvular heart disease at 64 per 100,000 person-years, with approximately 70% of incident disease observed in individuals 65 years of age or older. AS and mitral regurgitation contributed approximately one-half and one-quarter, respectively, of the valvular heart disease diagnoses in this study. The incidence of infective endocarditis (Chap. 133) has increased with the aging of the population, the more widespread prevalence of vascular grafts and intracardiac devices, the emergence of more viru­ lent multidrug-resistant microorganisms, and the growing epidemic of injection drug use. North American age-standardized incidence rates for endocarditis increased from in 10.1 per 100,000 population in 1990 to 12.54 per 100,000 population in 2019. The more restricted use of antibiotic prophylaxis since 2007 has not been convincingly associated with an increase in incidence rates for infective endocar­ ditis cases attributable to oropharyngeal pathogens. Infective endo­ carditis has become a relatively more frequent cause of acute valvular regurgitation. Valve surgery during the acute phase of infective endo­ carditis is performed in ~50–60% of hospitalized patients. Duration of intravenous antibiotic use may be shortened in selected cases. Bicuspid aortic valve (BAV) disease affects as many as 0.5–1.4% of the general population and is accompanied by an associated aor­ topathy in ~30–40% of individuals, a disease process expressed as root or ascending aortic aneurysm formation or descending thoracic aortic coarctation. An increasing number of childhood survivors of congenital heart disease present later in life with valvular dysfunction. The global burden of valvular heart disease will continue to progress. As is true for many other chronic health conditions, disparities in access to and quality of care for patients with valvular heart dis­ ease have been well documented, especially for those patients with rheumatic heart disease in low- and middle-income countries. In the Society for Thoracic Surgeons (STS)/American College of Cardiology (ACC) Transcatheter Valve Therapy (TVT) registry, black patients

compose <5% of patients in the United States who have received a transcatheter valve for AS. Management decisions and outcome differences based on age, sex, race, geography, and other social determinants of health require intensification of educational efforts and prioritization of resources.

CHAPTER 272 The role of the physical examination in the evaluation of patients with valvular heart disease is also considered in Chaps. 44 and 246; of electrocardiography (ECG) in Chap. 247; of echocardiography and other noninvasive imag­ ing techniques in Chap. 248; and of cardiac catheterization and angiography in Chap. 249. Aortic Stenosis AORTIC STENOSIS AS is the most common valve lesion among adult patients with chronic valvular heart disease; the majority of adult patients with symptomatic, valvular AS are male. ■ ■ETIOLOGY AND PATHOGENESIS (Table 272-1) AS in adults is due to degenerative calcification of the aortic cusps and occurs most commonly on a substrate of congenital disease (BAV), chronic (trileaflet) deterioration, or previous rheumatic inflammation. A pathologic study of specimens removed at the time of aortic valve replacement (AVR) for AS in adults showed that 53% were bicuspid and 4% were unicuspid. The process of aortic valve deterioration and calcification is not a passive one, but, rather, one that shares many features with vascular atherosclerosis, including endothelial dys­ function, lipid accumulation, inflammatory cell activation, cytokine release, and upregulation of several signaling pathways (Fig. 272-3). Eventually, a fibrocalcific response is established wherein collagen is deposited and valvular myofibroblasts differentiate phenotypically into osteoblasts and actively produce bone matrix proteins that allow for the deposition of calcium hydroxyapatite crystals. Genetic poly­ morphisms involving the vitamin D receptor, the estrogen receptor in postmenopausal women, interleukin 10, and apolipoprotein E4 have been linked to the development of calcific AS, and a strong familial clustering of cases with trileaflet valves has been reported from west­ ern France. Several traditional atherosclerotic risk factors have also been associated with the development and progression of calcific AS, including hypertension, low-density lipoprotein (LDL) cholesterol, lipoprotein(a) (Lp[a]), diabetes mellitus, smoking, chronic kidney disease, and the metabolic syndrome. In a Canadian observational cohort study, the incidence of severe AS was 144 per 100,000 personyears. Hypertension, diabetes mellitus, and dyslipidemia accounted for approximately one-third of the population-attributable risk for severe AS. The presence of aortic valve sclerosis (focal thickening and calcification of the leaflets not severe enough to cause obstruction) is associated with an excess risk of cardiovascular death and myocardial infarction (MI) among persons aged >65. Approximately 30% of per­ sons aged >65 years exhibit some degree of aortic valve sclerosis. Rate and extent of progression to valve obstruction (stenosis) vary among individual patients. Rheumatic disease of the aortic leaflets produces commissural fusion, sometimes resulting in a bicuspid-appearing valve. This con­ dition, in turn, makes the leaflets more susceptible to trauma and ultimately leads to fibrosis, calcification, and further narrowing. By the time obstruction to left ventricular (LV) outflow causes serious clinical disability, the valve is usually a rigid calcified mass, and care­ ful examination may make it difficult or even impossible to determine TABLE 272-1  Major Causes of Aortic Stenosis VALVE LESION ETIOLOGIES Aortic stenosis Congenital (bicuspid, unicuspid)   Degenerative calcific disease   Rheumatic fever   Radiation

Lipid infiltration Inflammation Fibro-calcific response Radiation Mechanical stress Lipid-derived species Cytokines PART 6 Disorders of the Cardiovascular System LDL Lp(a) NOS uncoupling ROS ACE Chymase Ox-LDL Ox-PL Lp-PLA2 MMPs VEGF TNF IL-1β IysoPC ATX IysoPA IL-6 WNT3a ATX sPLA2 TGFβ LPAR BMP2 ENPP1 VIC AA ATP AMP +PPi COX2 5-LO ALP Prostaglandins Leukotrienes Pi FIGURE 272-3  Pathogenesis of calcific aortic stenosis. Lipid and inflammatory cell infiltration occurs across damaged endothelium. A cascade of events follows that leads eventually to formation of disorganized collagen (fibrosis) and calcium hydroxyapatite (bone) deposition. Valvular interstitial cells (VIC) are critical participants in this active process. AA, arachidonic acid; ACE, angiotensin-converting enzyme; ALP, alkaline phosphatase; ApoB, apolipoprotein B; AMP, adenosine monophosphate; ATP, adenosine triphosphate; ATX, autotaxin; A2AR, adenosine A2A receptor; BMP, bone morphogenetic protein; COX2, cyclooxygenase 2; ENPP, ectonucleotide pyrophosphatase/ phosphodiesterase; IL, interleukin; 5-LO, 5-lipoxygenase; LDL, low-density lipoprotein; Lp(a), lipoprotein(a); LPAR, lysophosphatidic acid receptor; Lp-PLA2, lipoproteinassociated phospholipase A2; lysoPA, lysophosphatidic acid; lysoPC, lysophosphatidylcholine; MMP, matrix metalloproteinase; NOS, nitric oxide synthase; Ox-PL, oxidized phospholipid; Ox-LDL, oxidized LDL; RANKL, receptor activator of nuclear factor-κB ligand; ROS, reactive oxygen species; RUNX2, runt-related transcription factor 2; sPLA2, secreted PLA2; TGFβ, transforming growth factor β; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor; VIC, valvular interstitial cell. (Reproduced with permission from B Lindman et al: Calcific aortic stenosis. Nat Rev Dis Primers 2:16006, 2016.) the etiology of the underlying process. Rheumatic AS is almost always associated with involvement of the mitral valve and with aortic regur­ gitation (AR). Mediastinal radiation can also result in late scarring, fibrosis, and calcification of the aortic leaflets. In this context, the calcification process also affects the mitral annulus. ■ ■BICUSPID AORTIC VALVE DISEASE A bicuspid aortic valve (BAV) is the most common congenital heart valve defect and occurs in 0.5–1.4% of the population with a 2–4:1 male-to-female predominance. The inheritance pattern appears to be autosomal dominant with incomplete penetrance, although some have questioned an X-linked component as suggested by the preva­ lence of BAV disease among patients with Turner’s syndrome. The prevalence of BAV disease among first-degree relatives of an affected individual is ~10%. A single gene defect to explain the majority of cases has not been identified, although mutations in the NOTCH1, GATA5, and GATA4 genes have been described in some families. Abnormalities in endothelial nitric oxide synthase and NKX2.5 have been implicated as well. Medial degeneration with ascending aortic aneurysm formation occurs commonly among patients with BAV disease; aortic coarctation is less frequently encountered. Patients with BAV disease have larger aortas than patients with comparable tricuspid aortic valve disease. The aortopathy develops independently of the hemodynamic severity of the valve lesion, but directional shear forces dictated by the anatomic configuration of the valve appear to influence its expression. For example, enlargement of the

Lipids Calcium hydroxyapatite Blood vessel Angiotensin I VEGF LDL Osteoprogenitor cell Angiotensin II inflammation RANKL TNF Collagen Apoptosis Osteogenic transition RUNX2 MSX2 Fibrosis A2AR NT5E Macrophage Monocyte Mineralization Mastocyte Calcifying microvesicles Adenosine +Pi T cell Time ascending aorta along its greater curvature is most often associated with right-left cusp fusion (Sievers classification type 1), the most common bicuspid variant. Patients with BAV disease are at risk for aneurysm formation and/or dissection. A BAV can be a component of more complex congenital heart disease with or without other left heart obstructing lesions, as seen in Shone’s complex (supravalvar mitral membrane, parachute mitral valve, subvalvar AS, and aortic coarctation). ■ ■OTHER FORMS OF OBSTRUCTION TO LEFT VENTRICULAR OUTFLOW In addition to valvular AS, three other lesions may be responsible for obstruction to LV outflow: hypertrophic obstructive cardiomyopathy (Chaps. 266–270), discrete fibromuscular/membranous subaortic ste­ nosis, and supravalvular AS (Chap. 280). The causes of LV outflow obstruction can usually be differentiated on the basis of the cardiac examination and Doppler echocardiographic findings. ■ ■PATHOPHYSIOLOGY The obstruction to LV outflow produces a systolic pressure gradi­ ent between the LV and aorta. When severe obstruction is suddenly produced experimentally, the LV responds by dilation and reduction of stroke volume. However, in some patients, the obstruction may be present at birth and/or increase gradually over the course of many years, and LV contractile performance is maintained by the presence of concentric LV hypertrophy. Initially, this serves as an adaptive

mechanism because it reduces toward normal the systolic stress developed by the myocardium, as predicted by the Laplace relation wall tension normalized to wall thickness (S = Pr/h, where S = systolic wall stress, P = pressure, r = radius, and h = wall thickness). A large transaortic valve pressure gradient may exist for many years without a reduction in cardiac output (CO) or the development of LV dilation. Ultimately, however, excessive hypertrophy becomes maladaptive, LV systolic function declines because of afterload mismatch, abnormali­ ties of diastolic function progress, and irreversible myocardial fibrosis develops. A mean systolic pressure gradient >40 mmHg with a normal CO or an effective aortic orifice area of ~<1 cm2 (or ~<0.6 cm2/m2 body surface area in a normal-sized adult)—i.e., less than approximately one-third of the normal orifice area—is generally considered to represent severe obstruction to LV outflow. The elevated LV enddiastolic pressure observed in many patients with severe AS and preserved ejection fraction (EF) signifies the presence of diminished compliance of the hypertrophied LV. Although the CO at rest is within normal limits in most patients with severe AS, it usually fails to rise normally during exercise. Loss of an appropriately timed, vigorous atrial contraction, as occurs in atrial fibrillation (AF) or atrioventricular dissociation, may cause rapid progression of symptoms. Late in the course, contractile function deteriorates because of afterload excess, the CO and LV–aortic pressure gradient declines, and the mean left atrial (LA), pulmonary artery (PA), and right ventricular (RV) pressures rise. LV performance can be further compromised by superimposed epicardial coronary artery disease (CAD). Stroke volume (and thus CO) can also be reduced in patients with significant hypertrophy and a small LV cavity despite a normal EF. Low-flow (defined as a stroke volume index <35 mL/m2), lowgradient (defined as a mean pressure gradient <40 mmHg) AS (with either reduced or normal LV systolic function) is both a diagnostic and therapeutic challenge. The hypertrophied LV causes an increase in myocardial oxygen requirements. In addition, even in the absence of obstructive CAD, coronary blood flow is impaired to the extent that ischemia can be precipitated under conditions of excess demand. Capillary density is reduced relative to wall thickness, compressive forces are increased, and the elevated LV end-diastolic pressure reduces the coronary driv­ ing pressure. The subendocardium is especially vulnerable to ischemia by this mechanism. ■ ■SYMPTOMS AS is rarely of clinical importance until the valve orifice has narrowed to ~1 cm2. Even severe AS may exist for many years without produc­ ing any symptoms because of the ability of the hypertrophied LV to generate the elevated intraventricular pressures required to maintain a normal stroke volume. Once symptoms occur, or the LV ejection frac­ tion falls below normal, valve replacement is indicated. Most patients with pure or predominant AS have gradually increasing obstruction over years but do not become symptomatic until the sixth to eighth decades. Adult patients with BAV disease, however, develop significant valve dysfunction and symptoms one to two decades sooner. Exertional dyspnea, angina pectoris, and syncope are the three cardinal symptoms. Often, there is a history of insidious progression of fatigue and dyspnea associated with gradual curtailment of activities and reduced effort tolerance. Dyspnea results primarily from elevation of the pulmonary capillary pressure caused by elevations of LV diastolic pressures secondary to impaired relax­ ation and reduced LV compliance. Angina pectoris usually develops somewhat later and reflects an imbalance between the increased myocardial oxygen requirements and reduced oxygen availability. CAD may or may not be present, although its coexistence is com­ mon among AS patients age >65. Exertional syncope may result from a decline in arterial pressure caused by vasodilation in exercising muscles and inadequate vasoconstriction in nonexercising muscles in the face of a fixed CO, or from a sudden fall in CO produced by an arrhythmia.

Because the CO at rest is usually well maintained until late in the course, marked fatigability, weakness, peripheral cyanosis, cachexia, and other clinical manifestations of a low CO are usually not promi­ nent until this stage is reached. Orthopnea, paroxysmal nocturnal dyspnea, and pulmonary edema, i.e., symptoms of LV failure, also occur only in the advanced stages of the disease. Severe pulmonary hypertension leading to RV failure and systemic venous hypertension, hepatomegaly, AF, and tricuspid regurgitation (TR) are usually late findings in patients with isolated severe AS.

CHAPTER 272 When AS and mitral stenosis (MS) coexist, the reduction in flow (CO) caused by MS lowers the pressure gradient across the aortic valve and, thereby, masks many of the clinical findings produced by AS. The transaortic pressure gradient can be increased in patients with con­ comitant AR due to higher aortic valve flow rates. Aortic Stenosis ■ ■PHYSICAL FINDINGS The heart rhythm is generally regular until late in the course; at other times, AF should suggest the possibility of associated mitral valve disease. Hypertension occurs commonly among older adults with AS. In the late stages, however, when stroke volume declines, the systolic pressure may fall and the pulse pressure narrow. The carotid arterial pulse rises slowly to a delayed peak (pulsus parvus et tardus). A thrill or anacrotic “shudder” may be palpable over the carotid arteries, more commonly the left. In the elderly, the stiffening of the arterial wall may mask this important physical sign. In many patients, the a wave in the jugular venous pulse is accentuated. This results from the diminished distensibility of the RV cavity caused by the bulging, hypertrophied interventricular septum. The LV impulse is sometimes displaced laterally in the later stages of the disease. A double apical impulse (with a palpable S4) may be appreciated, particularly with the patient in the left lateral recumbent position. A systolic thrill may be present at the base of the heart to the right of the sternum when leaning forward or in the suprasternal notch. Auscultation  An early systolic ejection sound is frequently audi­ ble in children, adolescents, and young adults with congenital BAV disease. This sound usually disappears when the valve becomes calci­ fied and rigid. As AS increases in severity, LV systole may become pro­ longed so that the aortic valve closure sound no longer precedes the pulmonic valve closure sound, and the two components may become synchronous, or aortic valve closure may even follow pulmonic valve closure, causing paradoxical splitting of S2 (Chap. 246). The sound of aortic valve closure can be heard most frequently in patients with AS who have pliable valves; calcification diminishes the intensity of this sound. Frequently, an S4 is audible at the apex and reflects the presence of LV hypertrophy and an elevated LV end-diastolic pressure; an S3 generally occurs late in the course when the LV dilates and its systolic function becomes severely compromised. The murmur of AS is described as an ejection (mid) systolic mur­ mur that commences shortly after the S1, increases in intensity to reach a peak toward the middle of ejection, and ends just before aortic valve closure. It is characteristically low-pitched, rough, and rasping in character, and loudest at the base of the heart, most commonly in the second right intercostal space. It is transmitted upward along the carotid arteries. Occasionally, it is transmitted downward and to the apex, where it may be confused with the systolic murmur of mitral regurgitation (MR) (Gallavardin effect). In almost all patients with severe obstruction and preserved CO, the murmur is at least grade III/ VI. In patients with mild degrees of obstruction or in those with severe stenosis with heart failure and low CO in whom the stroke volume and, therefore, the transvalvular flow rate are reduced, the murmur may be relatively soft and brief. ■ ■LABORATORY EXAMINATION ECG  In most patients with severe AS, there is LV hypertrophy. In advanced cases, ST-segment depression and T-wave inversion (LV “strain”) in standard leads I and aVL and in the left precordial leads are evident. However, there is no close correlation between the ECG

and the hemodynamic severity of obstruction, and the absence of ECG signs of LV hypertrophy does not exclude severe obstruction. Systemic hypertension can coexist and also contribute to the development of hypertrophy.

Echocardiogram  The key findings on transthoracic echocar­ diogram are thickening, calcification, and reduced systolic opening of the aortic valve leaflets and LV hypertrophy. Eccentric closure of the aortic valve cusps is characteristic of congenitally bicuspid valves. Transesophageal echocardiography imaging can display the obstructed orifice extremely well, but it is not routinely required for accurate characterization of AS. The valve gradient and aortic valve area can be estimated by Doppler measurement of the transaortic velocity. Severe AS is defined by a valve area <1 cm2, whereas moder­ ate AS is defined by a valve area of 1–1.5 cm2 and mild AS by a valve area of 1.6–2 cm2. Aortic valve sclerosis, conversely, is accompanied by a jet velocity of <2.5 m/s (peak gradient <25 mmHg). LV dilation and reduced systolic shortening reflect impairment of LV function. There is a robust experience with the use of longitudinal strain to characterize earlier changes in LV systolic function before a decline in EF can be appreciated. Doppler indices of impaired diastolic func­ tion are frequently seen. The frequency with which echocardiography should be repeated during follow-up is dictated by the severity of the stenosis (Table 272-2). PART 6 Disorders of the Cardiovascular System Echocardiography is useful for identifying coexisting valvular abnormalities, differentiating valvular AS from other forms of LV outflow obstruction, and measuring the aortic root and proximal ascending aortic dimensions. These aortic measurements are par­ ticularly important for patients with BAV disease. Dobutamine stress echocardiography can be useful for the evaluation of patients with AS and severe LV systolic dysfunction (low-flow, low-gradient, severe AS with reduced EF), in whom the severity of the AS can often be difficult to judge. Patients with severe AS (i.e., valve area <1 cm2) with a relatively low mean gradient (<40 mmHg) despite a normal EF (low-flow, low-gradient, severe AS with normal EF) are often hyper­ tensive, and efforts to control their systemic blood pressure should be optimized before Doppler echocardiography is repeated. The use of dobutamine stress echocardiography in this setting is not advised. When there is continued uncertainty regarding the severity of AS in patients with reduced CO and reduced or normal LVEF, quantitative analysis of the amount of aortic valve calcium with chest computed tomography (CT) can be helpful. Aortic valve calcium scores that define severe AS differ for men and women, as men tend to have relatively more calcification and women more fibrosis of the valve leaflets. There is increasing use of chest CT angiography to assess aortic valve morphology and function. It has become the imaging method of choice to plan for transcatheter aortic valve implanta­ tion (TAVI). Finally, the use of cardiac magnetic resonance (CMR) imaging to screen for the presence of increased extracellular volume (interstitial fibrosis) and late gadolinium enhancement (replacement fibrosis) in patients with severe AS is an area of active investigation. Future management pathways related to the asymptomatic AS patient are likely to include an integrated assessment of the findings from multimodality imaging studies. Chest X-Ray  The chest x-ray may show no or little overall car­ diac enlargement for many years. Hypertrophy without dilation may produce some rounding of the cardiac apex in the frontal projec­ tion and slight backward displacement in the lateral view. A dilated TABLE 272-2  Frequency of Follow-Up Echocardiography in Aortic Stenosis STAGE OF DISEASE FREQUENCY OF ECHOCARDIOGRAPHY Progressive (stage B) Every 3–5 years (mild severity, Vmax 2.0–2.9 m/s)   Every 1–2 years (moderate severity, Vmax 3.0–3.9 m/s) Severe asymptomatic (stage C1) Every 6–12 months (Vmax >4 m/s)

proximal ascending aorta may be seen along the upper right heart border in the frontal view. Aortic valve calcification may be discern­ ible in the lateral view, but it is usually readily apparent on fluoro­ scopic examination or by echocardiography; the absence of valvular calcification on fluoroscopy in an adult suggests that severe valvular AS is not present. In later stages of the disease, as the LV dilates, there is increasing roentgenographic evidence of LV enlargement, pulmonary congestion, and enlargement of the LA, PA, and rightsided heart chambers. Catheterization  Right- and left-sided heart catheterization for invasive assessment of AS is performed infrequently but can be useful when there is a discrepancy between the clinical and nonin­ vasive findings. Concern has been raised that attempts to cross the aortic valve for measurement of LV pressures are associated with a risk of cerebral embolization. Catheterization can also be useful in three distinct categories of patients: (1) patients with multivalvular disease, in whom the role played by each valvular deformity should be defined to aid in the planning of operative treatment; (2) young, asymptomatic patients with noncalcific congenital AS, to define the severity of obstruction to LV outflow, because operation or percuta­ neous aortic balloon valvuloplasty (PABV) may be indicated in these patients if severe AS is present, even in the absence of symptoms; and (3) patients in whom it is suspected that the obstruction to LV outflow may not be at the level of the aortic valve but rather at the sub- or supravalvular level. Coronary angiography is indicated to screen for CAD in appropriate patients with severe AS who are being considered for surgical or trans­ catheter valve intervention. Angiography can be performed invasively at the time of catheterization for hemodynamic assessment or with noninvasive CT techniques. Decision-making regarding the need for coronary artery revascularization at the time of aortic valve interven­ tion is individualized. ■ ■NATURAL HISTORY Death in patients with severe AS occurs most commonly in the seventh and eighth decades. Based on data obtained at postmortem examina­ tion in patients before surgical treatment became widely available, the average time to death after the onset of various symptoms was as fol­ lows: angina pectoris, 3 years; syncope, 3 years; dyspnea, 2 years; and heart failure, 1.5–2 years. Moreover, in >80% of patients who died with AS, symptoms had existed for <4 years. Among adults dying with val­ vular AS, sudden death, which presumably resulted from an arrhyth­ mia, occurred in 10–20%; however, most sudden deaths occurred in patients who had previously been symptomatic. Sudden death as the first manifestation of severe AS is very uncommon (~1% per year) in asymptomatic adult patients. Calcific AS is a progressive disease, with an annual reduction in valve area averaging 0.1 cm2 and annual increases in peak jet velocity and mean valve gradient averaging 0.3 m/s and 7 mmHg, respectively. TREATMENT Aortic Stenosis (Fig. 272-4) MEDICAL TREATMENT In patients with severe AS (valve area <1 cm2), strenuous physi­ cal activity and competitive sports should be avoided, even in the asymptomatic stage. Care must be taken to avoid dehydra­ tion and hypovolemia to protect against a significant reduction in CO. Medications used for the treatment of hypertension or CAD, including beta blockers and angiotensin-converting enzyme (ACE) inhibitors, are generally safe for asymptomatic patients with preserved LV systolic function. Control of blood pressure is important to attenuate the deleterious pathophysiologic effects of two resistance circuits (valve, arterial circulation) in series. Nitroglycerin is helpful in relieving angina pectoris in patients with CAD. Neither HMG-CoA reductase inhibitors (“statins”) nor

Abnormal aortic valve with reduced systolic opening Symptoms due to AS Severe AS stage D1 • Vmax ≥4 m/s or • ∆Pmean ≥40 mm Hg Vmax ≥4 m/s and AVA ≤1.0 cm2 LV EF <50% Yes No EF <50% Severe AS stage D2 DSE Vmax ≥4 m/s at any flow rate Severe AS stage D3 AVA1 ≤0.6 cm2/m2 and SVI <35 mL/m2 AS most likely cause of symptoms AVR (SAVR or TAVI) (1) AVR (SAVR or TAVI) (1) SAVR (2a) SAVR (2b) FIGURE 272-4  Management strategy for patients with aortic stenosis. Preoperative coronary angiography should be performed routinely as determined by age, symptoms, and coronary risk factors. Cardiac catheterization and angiography may also be helpful when there is a discrepancy between clinical and noninvasive findings. Patients who do not meet criteria for intervention should be monitored with clinical and echocardiographic follow-up. The class designations refer to the American Heart Association/ American College of Cardiology methodology for treatment recommendations. Class I recommendations should be performed or are indicated; Class IIa recommendations are considered reasonable to perform; Class IIb recommendations may be considered. The stages refer to the stages of progression of the disease. At disease stage A, risk factors are present for the development of valve dysfunction; stage B refers to progressive, mild-moderate, asymptomatic valve disease; stage C disease is severe in nature but clinically asymptomatic; stage C1 characterizes asymptomatic patients with severe valve disease but compensated ventricular function; stage C2 refers to asymptomatic, severe disease with ventricular decompensation; stage D refers to severe, symptomatic valve disease. With aortic stenosis, stage D1 refers to symptomatic patients with severe aortic stenosis and a high valve gradient (>40 mmHg mean gradient); stage D2 comprises patients with symptomatic, severe, low-flow, low-gradient aortic stenosis and low left ventricular ejection fraction (LVEF); and stage D3 characterizes patients with symptomatic, severe, low-flow, low-gradient aortic stenosis and preserved LVEF (paradoxical, low-flow, low-gradient severe aortic stenosis). Patients with symptomatic severe AS (left side of the diagram, jet velocity ≥4m/s) should be referred for AVR (SAVR or TAVI). Asymptomatic patients with severe AS (jet velocity ≥4m/s) should be referred for AVR (SAVR or TAVI) for LVEF <50% or when other cardiac surgery is needed (e.g., aneurysm repair). There are several findings for which referral for AVR would be reasonable related to results of exercise testing, the presence of a jet velocity >5 m/s, or elevated B-type natriuretic peptide (BNP), provided the patient is considered low risk for complications related to AVR. AS, aortic stenosis; AVA, aortic valve area; AVR, aortic valve replacement; BP, blood pressure; DSE, dobutamine stress echocardiography; EF, ejection fraction; ETT, exercise treadmill test; ΔPmean, mean pressure gradient; SAVR, surgical AVR; TAVI, transcatheter aortic valve implantation; Vmax, maximum velocity. (Reproduced with permission from CM Otto et al: 2020 AHA/ACC Guideline for management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 143(5):e72, 2021.) inhibitors of the renin-angiotensin-aldosterone system slow the rate of progression of AS. The use of statin medications should be driven by considerations regarding primary and secondary pre­ vention of atherosclerotic cardiovascular disease (ASCVD) events. Studies with agents targeted to Lp(a) are ongoing. The need for endocarditis prophylaxis is restricted to AS patients with a prior history of endocarditis. SURGICAL TREATMENT Asymptomatic patients with calcific AS and severe obstruction should be followed carefully for the development of symptoms and for evidence of deteriorating LV function on serial echocardiogra­ phy. Operation is indicated in patients with severe AS (valve area

CHAPTER 272 No AS symptoms Aortic Stenosis AS stage B (Vmax 3–3.9 m/s) AS stage C (Vmax ≥4 m/s) Other cardiac surgery Other cardiac surgery ETT with ↓BP or ↓ex. capacity Vmax ≥5 m/s or BNP >3x normal or Rapid disease progression ↓ EF to <60% on 3 serial studies Low surgical risk <1 cm2 or 0.6 cm2/m2 body surface area) who are symptomatic, those who exhibit LV systolic dysfunction (EF <50%), and those with AS due to BAV disease and an aneurysmal root or ascending aorta (maximal dimension >5.5 cm). Operation for aneurysm disease is recommended at smaller aortic diameters (4.5–5.0 cm) for patients with a family history of an aortic catastrophe and for patients who exhibit rapid aneurysm growth (>0.5 cm/year). Patients with asymptomatic moder­ ate or severe AS who are referred for coronary artery bypass grafting surgery should also have AVR. The majority (~80%) of patients with symptomatic severe AS referred for surgery are considered low risk for perioperative death or major complication. Operative risk increases as a function of age, comorbidities, and the need for concomitant aortic or other heart valve surgery or coronary artery bypass grafting. A 2023

analysis from the STS Adult Cardiac Surgery Database reported a 5-year survival rate of 95% following isolated surgical AVR (SAVR) in low-risk AS patients of mean age 74 years. The indications for SAVR in the asymptomatic patient have been the subject of intense debate, as surgical outcomes in selected patients have continued to improve. Relative indications for which surgery is reasonable include an abnormal response to treadmill exercise; rapid progres­ sion of AS, especially when urgent access to medical care might be compromised; very severe AS, defined by an aortic valve jet velocity

5 m/s or mean gradient >60 mmHg; excessive LV hypertrophy in the absence of systemic hypertension; and a brain natriuretic pep­ tide level >3 times the upper reference limit, with low surgical risk. Exercise testing can be safely performed in asymptomatic patients, as many as one-third of whom will show signs of functional impair­ ment. In a small randomized controlled trial (RCT) of early surgery versus conservative care for asymptomatic patients with very severe AS (defined by a transaortic valve jet velocity ≥4.5 m/s, mean gradi­ ent ≥50 mmHg, or aortic valve area ≤0.75 cm2), the rate of opera­ tive death or death from cardiovascular causes during follow-up was reduced with early surgery. In the conservative care group, the cumulative incidence of sudden death was 4% at 4 years and 14% at 8 years. In another randomized trial of early surgery versus conser­ vative care for asymptomatic patients with lesser degrees of AS (jet velocity ≥4 m/s, mean gradient ≥40 mmHg, aortic valve areas ≤1.0 cm2) and normal LV systolic function, early surgery resulted in a significant reduction in a composite endpoint of death, MI, stroke, and heart failure hospitalization.

PART 6 Disorders of the Cardiovascular System Operation should be carried out promptly (1–3 months) after symptom onset. Clinical decision-making is straightforward for patients with normal-flow (>35 mL/m2), high-gradient (≥40 mmHg) severe AS. In patients with low-flow, low-gradient severe AS with reduced LVEF, perioperative mortality rates are high (15–20%), and evidence of LV dysfunction usually persists even after a technically successful operation. Long-term postoperative sur­ vival correlates with preoperative LV function. Nonetheless, in view of the even worse prognosis of such patients when they are treated medically, there is usually little choice but to advise valve replacement, especially in patients in whom flow reserve can be demonstrated by dobutamine stress echocardiography (defined by a ≥20% increase in stroke volume after dobutamine challenge). Patients in this high surgical risk group are treated with TAVI whenever feasible (see below), but robust data from RCTs in this subpopulation of severe AS patients are lacking. The management of patients with low-flow, low-gradient severe AS with normal LVEF is also challenging. Outcomes are improved with surgery or TAVI compared with conservative care for symptomatic patients with this type of “paradoxical” low-flow AS, but more research is needed to guide therapeutic decision-making for individual patients. In patients in whom severe AS and CAD coexist, relief of the AS and revascularization may sometimes result in striking clinical and hemodynamic improvement. Because many patients with calcific AS are elderly, particular attention must be directed to the adequacy of hepatic, renal, and pulmonary function before AVR is recommended. Age alone is not a contraindication to SAVR for AS. The perioperative mortality rate depends to a substantial extent on the patient’s preoperative clinical and hemodynamic state. Assessment of frailty is a criti­ cal component of preprocedural evaluation. Treatment decisions for AS patients who are not at low operative risk are made by a multidisciplinary heart team with representation from general car­ diology, interventional cardiology, multimodality imaging, cardiac surgery, and other subspecialties as needed, including geriatrics. The 8-year survival rate of older adult (mean age 74), low surgical risk patients following isolated SAVR is 85–90%. Recommenda­ tions regarding the type of valve prosthesis (biological or mechani­ cal) must weigh the trade-offs between limited bioprosthetic valve durability and the risks of thromboembolism and bleeding with a mechanical valve and are heavily influenced by patient age, expected longevity, and individual preferences. Bioprostheses are

generally favored for patients age >65 years. Shared decisionmaking with younger patients must be individualized, although increasing numbers of patients age <65 now opt for a biological valve replacement. Approximately 10–20% of bioprosthetic valves evidence primary valve failure by 15 years, requiring re-replace­ ment (or valve-in-valve TAVI, see below), and an approximately equal percentage of patients with mechanical prostheses develop hemorrhagic complications as a consequence of treatment with vitamin K antagonists. In a large observational study of patients who underwent SAVR in California between 1996 and 2013, receipt of a biological versus a mechanical prosthesis in patients <55 years old was associated with an excess hazard of death over 15 years of follow-up. Homograft AVR is usually reserved for patients with aortic valve endocarditis. The Ross procedure involves replacement of the diseased aortic valve with the autologous pulmonic valve and implantation of a homograft in the native pulmonic position. It is a technically complex procedure that may be considered in selected young or middle-aged adult patients when surgical and institutional exper­ tise are available. Late postoperative complications include aortic root dilation, AR, and pulmonary homograft stenosis. PERCUTANEOUS AORTIC BALLOON VALVULOPLASTY This procedure is preferable to operation in many children and young adults with congenital, noncalcific AS (Chap. 280). It is not recommended as definitive therapy in adults with severe calcific AS because of a very high restenosis rate (80% within 1 year) and the risk of procedural complications, although on occasion, it has been used successfully as a bridge to operation or TAVI in patients with severe LV dysfunction and shock. It is performed routinely as part of the TAVI procedure (see below). TRANSCATHETER AORTIC VALVE IMPLANTATION TAVI surpassed SAVR for treatment of isolated AS in the United States in 2016 and is now available to symptomatic patients across the entire surgical risk spectrum (prohibitive, high, intermediate, and low) on the basis of the favorable results observed in a series of landmark RCTs reported over the past decade. The results of a randomized trial of TAVI versus conventional care in asymp­ tomatic AS patients will be released around 2024–2025. TAVI is most commonly performed using one of two systems, a balloonexpandable valve (BEV) or a self-expanding valve (SEV), both of which incorporate a pericardial bioprosthesis (Fig. 272-5A, B). TAVI is most frequently undertaken via the transfemoral route, although trans-LV apical, subclavian, carotid, and ascending aor­ tic routes have been used. Nonfemoral access is associated with higher complication rates. Aortic balloon valvuloplasty under rapid RV (or LV) pacing is performed as a first step to create an orifice of sufficient size for the prosthesis. Procedural success rates exceed 95% in appropriately selected patients. Among low surgical risk patients with symptomatic severe AS, random­ ized trials with follow-up through 4–5 years have demonstrated similar valve performance and clinical outcomes for SAVR versus TAVI using either a BEV or SEV platform (Fig. 272-6). Outcomes achieved with TAVI technology have been very favorable and have allowed the extension of AVR to groups of patients previ­ ously considered poor candidates for conventional surgery. Nev­ ertheless, some prohibitive or high surgical risk patients are not candidates for this procedure because their comorbidity profile, frailty, and expected longevity would make its undertaking inap­ propriate. The heart team is specifically charged with making challenging decisions of this nature. The use of these devices for treatment of patients with structural deterioration of biopros­ thetic aortic valves (valve-in-valve TAVI), as an alternative to reoperative valve replacement, has increased sharply over the past 5 years. The technology has also been increasingly applied to selected BAV patients despite the fact that patients with this anatomy were excluded from the landmark RCTs.

B V N A B FIGURE 272-5  Balloon-expandable (A) and self-expanding (B) valves for transcatheter aortic valve replacement (TAVR). B, inflated balloon; N, nose cone; V, valve. (Part A, courtesy of Edwards Lifesciences, Irvine, CA; with permission. NovaFlex+ is a trademark of Edwards Lifesciences Corporation. Part B, © Medtronic, Inc. 2015. Medtronic CoreValve Transcatheter Aortic Valve. CoreValve is a registered trademark of Medtronic, Inc.) Compared with SAVR, transfemoral TAVI results in fewer peri­ procedural deaths and confers lower risks of strokes, major bleed­ ing, and AF. Hospital lengths of stay are significantly shorter and return to normal activity more rapid with TAVI. Rates of perma­ nent pacemaker use, perivalvular AR, bioprosthetic leaflet throm­ bosis, and vascular complications are lower with SAVR. The choice between TAVI versus SAVR for patients with trileaflet AS who

HR = 0.74 (95% CI 0.54–1.00) Log-rank p = 0.05 25% 4 Years SE TAVR SAVR ∆–3.4% All-cause mortality or disabling stroke 2 Years 3 Years 20% CHAPTER 272 ∆–2.0% ∆–2.9% 10.3% 14.1% 15% 10% 1 Year ∆–1.8% 10.7% 4.3% 6.3% 2.5% 4.3% 7.4% 5% 0%

Aortic Stenosis

Months since procedure

SE TAVR SAVR

FIGURE 272-6  Four-year cumulative incidence of all-cause mortality or disabling stroke for low surgical risk aortic stenosis patients assigned to self-expanding transcatheter aortic valve implantation (SE-TAVR; n = 730) or surgical aortic valve replacement (SAVR; n = 684). In this study, TAVR was noninferior to SAVR and marginally superior to SAVR for the combined endpoint. (Reproduced with permission from JK Forrest et al: 4-year outcomes of patients with aortic stenosis in the EVOLUT low risk trial. J Am Coll Cardiol 82:2163, 2023.) prefer a biological prosthesis rests on several clinical, imag­ ing, and technical considerations (Fig. 272-7 and Table 272-3). Because there are scant RCT data on TAVI outcomes in patients <65 years, SAVR is recommended in this age group. Aortic valve/ root anatomy, as well as the extent, severity, and distribution of calcium, and the distance of the coronary arteries from the plane of the annulus, may dictate a surgical approach, as could the need to perform a concomitant procedure such as ascending aortic replacement. Lastly, inability to achieve transfemoral access is a relative impediment to TAVI given the higher complication rates observed when this procedure is undertaken from other vascular access sites. Class 1 Shared decision making Class 2a Bioprosthetic Valve Class 2b Indication for AVR and anatomy suitable for TF TAVI? No Yes Age < 65 Age 65 to 80 Age >80 SAVR (1) SAVR (1) TF TAVI (1) TF TAVI (1) SAVR (2a) FIGURE 272-7  Suggested decision-making algorithm for the elective choice of transcatheter aortic valve implantation (TAVI) versus surgical aortic valve replacement (SAVR) for aortic stenosis patients with an indication for valve intervention. The pathway emphasizes the premium placed on transfemoral (TF) TAVI access and the age-related differences in recommendations. Patients younger than age 65 are recommended to undergo SAVR given the paucity of prospective randomized data on intermediate- and long-term TAVI outcomes for individuals younger than age 70. AVR, aortic valve replacement. (Reproduced and abridged with permission from CM Otto et al: 2020 AHA/ACC Guideline for management of patients with valvular heart disease: A report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. Circulation 143:e72, 2021.)

TABLE 272-3  Factors Favoring SAVR, TAVI, or Palliative Care in Patients with Aortic Stenosis   FAVORS SAVR FAVORS TAVI FAVORS PALLIATION Age/life expectancya Younger age/longer life expectancy Older age/fewer expected remaining years of life Valve anatomy Bicuspid aortic valve Subaortic (LVOT) calcification Rheumatic valve disease Small or large aortic annulusb PART 6 Disorders of the Cardiovascular System Prosthetic valve preference Mechanical or surgical bioprosthetic valve preferred Concern for patient-prosthesis mismatch (annular enlargement might be considered) Concurrent cardiac conditions Aortic dilationc Severe primary MR Severe CAD requiring bypass grafting Septal hypertrophy requiring myectomy Atrial fibrillation Noncardiac conditions   Severe lung, liver, or renal disease Mobility issues (high risk for sternotomy) Frailty Not frail or few frailty measures Frailty likely to improve after TAVI Severe frailty unlikely to improve after TAVI Estimated risk of SAVR or TAVI SAVR risk low TAVI risk high Procedure-specific impediments Valve anatomy, annular size, or low coronary ostial height precludes TAVI Vascular access does not allow transfemoral TAVI Goals of care and patient preferences and values Less uncertainty about valve durability Avoid repeat intervention Lower risk of permanent pacer Life prolongation Symptom relief Improved long-term exercise capacity and QOL Avoid vascular complications Accepts longer hospital stay, pain in recovery period aData on bioprosthetic valve durability are more robust for SAVR valves than for TAVI valves. Mechanical valves are very durable but require lifelong anticoagulation. Choice of prosthesis is a shared decision-making process accounting for individual patient values and preferences. bSurgical root enlargement can be performed at time of SAVR to allow a use of a larger prosthesis and reduce the occurrence of prosthesis-patient mismatch. cAortic root or ascending aortic enlargement may require surgical correction at time of SAVR. Abbreviations: AS, aortic stenosis; CAD, coronary artery disease; LV, left ventricular; LVOT, left ventricular outflow tract; MR, mitral regurgitation; QOL, quality of life; SAVR, surgical aortic valve replacement; TAVI, transcatheter aortic valve implantation. Source: Reproduced with permission from CR Burke et al: Goals of care in patients with severe aortic stenosis. Eur Heart J 41:929, 2020. ■ ■FURTHER READING Banovic M et al: Aortic valve replacement versus conservative treat­ ment in asymptomatic severe aortic stenosis: The AVATAR trial. Circulation 145:648, 2022. Carapetis JR et al: Acute rheumatic fever and rheumatic heart disease. Nat Rev Dis Primers 2:15084, 2016. Forrest JK et al: 4-year outcomes of patients with aortic stenosis in the EVOLUT low risk trial. J Am Coll Cardiol 82:2163, 2023. Kang D-H et al: Early surgery or conservative care for asymptomatic aortic stenosis. N Engl J Med 382:111, 2020. Lindman B et al: Calcific aortic stenosis. Nat Rev Dis Primers 2:16006, 2016. Mack MJ et al: Transcatheter aortic valve replacement in low-risk patients at 5 years. N Engl J Med 389:1949, 2023. Mensah GA et al: Global burden of cardiovascular diseases and risks, 1990-2022. J Am Coll Cardiol 82:2350, 2023. Otto CM et al: 2020 AHA/ACC Guideline for management of patients with valvular heart disease: A report of the American College

Limited life expectancy Calcific trileaflet AS   Bioprosthetic valve preferred Favorable ratio of life expectancy to valve durability TAVI provides larger valve area than same-sized SAVR   Severe calcification of the ascending aorta (“porcelain” aorta) Irreversible severe LV systolic dysfunction Severe MR due to annular calcification Symptoms likely due to noncardiac conditions Severe dementia Moderate to severe involvement of 2 or more other organ systems TAVI risk low to medium SAVR risk high to prohibitive Prohibitive SAVR risk (>15%) or post-TAVI life expectancy <1 year Previous cardiac surgery with at-risk coronary grafts Previous chest irradiation Valve anatomy, annular size, or coronary ostial height precludes TAVI Vascular access does not allow transfemoral TAVI Accepts uncertainty about valve durability and possible repeat intervention Higher risk of permanent pacer Life prolongation Symptom relief Improved exercise capacity and QOL Prefers shorter hospital stay, less postprocedure pain Life prolongation not an important goal Avoid futile or unnecessary diagnostic or therapeutic procedures Avoid procedural stroke risk Avoid possibility of cardiac pacer of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 143:e72, 2021. Siontis GCM et al: Transcatheter aortic valve implantation versus surgical aortic valve replacement for treatment of symptomatic severe aortic stenosis: An updated meta-analysis. Eur Heart J 40:3143, 2019. Thourani VH: Survival after surgical aortic valve replacement in low-risk patients: A contemporary trial benchmark. Ann Thor Surg 117:106, 2024. Tsao CW et al: Heart disease and stroke statistics–2023 update. A report from the American Heart Association. Circulation 147:e93, 2023. Watkins DA et al: Global, regional, and national burden of rheumatic heart disease, 1990-2015. N Engl J Med 377:713, 2017. Zühlke L et al: Clinical outcomes in 3343 children and adults with rheumatic heart disease from 14 low- and middle-income countries: Two-year follow-up of the global Rheumatic Heart Disease Registry (the REMEDY Study). Circulation 134:1456, 2016.

35 - 273 Aortic Regurgitation

273 Aortic Regurgitation

Patrick T. O’Gara, Joseph Loscalzo

Aortic Regurgitation ■ ■ETIOLOGY (Table 273-1) Aortic regurgitation (AR) may be caused by primary valve disease, aortic root disease, or their combination. Primary Valve Disease  Rheumatic disease results in thicken­ ing, deformity, and shortening of the individual aortic valve cusps, changes that prevent their proper opening during systole and closure during diastole. A rheumatic origin is much less common in patients with isolated AR who do not have associated rheumatic mitral valve disease. Patients with congenital bicuspid aortic valve (BAV) disease may develop predominant AR, and ~20% of these patients will require aortic valve surgery between 10 and 40 years of age. Congenital fenes­ trations of the aortic valve occasionally produce mild AR. Membranous subaortic stenosis results in a high-velocity systolic jet that often leads to thickening and scarring of the aortic valve leaflets and secondary AR. Prolapse of an aortic cusp, resulting in progressive chronic AR, occurs in ~15% of patients with ventricular septal defect (Chap. 280), but may also occur as an isolated phenomenon or as a consequence of myxomatous degeneration sometimes associated with mitral and/or tricuspid valve involvement. AR may result from infective endocarditis (IE), which can develop on a valve previously affected by rheumatic disease, a congenitally deformed valve, or on a normal aortic valve, and may lead to perfora­ tion or destruction of one or more leaflets. The aortic valve leaflets may become scarred and retracted during the course of syphilis or ankylos­ ing spondylitis and contribute further to the AR that derives primarily from associated root dilation. Although traumatic rupture or avulsion of an aortic cusp is an uncommon cause of acute AR, it represents the most frequent serious lesion in patients surviving nonpenetrat­ ing cardiac injuries. The coexistence of hemodynamically significant aortic stenosis (AS) with AR usually excludes all the rarer forms of AR because it occurs almost exclusively in patients with rheumatic or congenital AR. In patients with AR due to primary valvular disease, dilation of the aortic annulus may occur secondarily and lead to wors­ ening regurgitation. Primary Aortic Root Disease  AR also may be due entirely to marked aortic annular dilation, i.e., aortic root disease, without pri­ mary involvement of the valve leaflets; widening of the aortic annulus and lack of diastolic coaptation of the aortic leaflets are responsible for the AR (Chap. 291). Medial degeneration of the ascending aorta, TABLE 273-1  Major Causes of Aortic Regurgitation VALVE LESION ETIOLOGIES Aortic regurgitation Valvular   Congenital (bicuspid)   Endocarditis   Rheumatic fever   Myxomatous (prolapse)   Radiation   Trauma   Syphilis   Ankylosing spondylitis Aortic root disease   Aortic dissection   Medial degeneration   Marfan syndrome   Bicuspid aortic valve   Nonsyndromic familial aneurysm   Aortitis   Hypertension

which may or may not be associated with other manifestations of Marfan’s syndrome; idiopathic dilation of the aorta; annuloaortic ectasia; osteogenesis imperfecta; and severe, chronic hypertension may all widen the aortic annulus and lead to progressive AR. Occasionally AR is caused by retrograde dissection of the aorta involving the aortic annulus. Syphilis and ankylosing spondylitis, both of which may also affect the aortic leaflets, may be associated with cellular infiltration and scarring of the media of the thoracic aorta, leading to aortic dilation, aneurysm formation, and severe regurgitation. In syphilis of the aorta (Chap. 187), now a very rare condition, the involvement of the intima may narrow the coronary ostia, which in turn may be responsible for myocardial ischemia. Takayasu’s aortitis and giant cell aortitis can also result in aneurysm formation and secondary AR.

CHAPTER 273 Aortic Regurgitation ■ ■PATHOPHYSIOLOGY The total stroke volume ejected by the left ventricle (LV) (i.e., the sum of the effective forward stroke volume and the volume of blood that regurgitates back into the LV) is increased in patients with AR. In patients with severe AR, the volume of regurgitant flow may equal the effective forward stroke volume. In contrast to MR, in which a portion of the LV stroke volume is delivered into the low-pressure left atrium (LA), in AR, the entire LV stroke volume is ejected into a high-pressure zone, the aorta. An increase in the LV end-diastolic volume (increased preload) constitutes the major hemodynamic compensation for AR. The dilation and eccentric hypertrophy of the LV allow this chamber to eject a larger stroke volume without requiring any increase in the relative shortening of each myofibril. Therefore, severe AR may occur with a normal effective forward stroke volume and a normal LV ejec­ tion fraction (LVEF, total [forward plus regurgitant] stroke volume/ end-diastolic volume), together with an elevated LV end-diastolic pressure and volume. However, through the operation of Laplace’s law, LV dilation increases the LV systolic tension required to develop any given level of systolic pressure. Chronic AR is, thus, a state in which LV preload and afterload are both increased. Ultimately, these adaptive measures fail. As LV function deteriorates, the end-diastolic volume rises further and the forward stroke volume and ejection fraction (EF) decline. Deterioration of LV function often precedes the development of symptoms. Considerable thickening of the LV wall also occurs with chronic AR, and at autopsy, the hearts of these patients may be among the largest encountered, sometimes weighing >1000 g. The reverse diastolic pressure gradient from aorta to LV, which drives the AR flow, decreases progressively during diastole, accounting for the typical decrescendo nature of the diastolic murmur. Equilibration between aortic and LV pressures may occur toward the end of diastole in patients with chronic severe AR, particularly when the heart rate is slow. In patients with acute severe AR, the LV is unprepared for the regurgi­ tant volume load. LV compliance is normal or reduced, and LV diastolic pressures rise rapidly, occasionally to levels >40 mmHg. The LV pressure may exceed the LA pressure toward the end of diastole, and this reversed pressure gradient closes the mitral valve prematurely. In patients with chronic severe AR, the effective forward cardiac output (CO) usually is normal or only slightly reduced at rest, but often it fails to rise normally during exercise. An early sign of LV dysfunction is a reduction in the EF. In advanced stages, there may be considerable elevation of the LA, pulmonary artery (PA) wedge, PA, and right ven­ tricular (RV) pressures and reduced forward CO at rest. Myocardial ischemia may occur in patients with AR because myo­ cardial oxygen requirements are elevated by LV dilation, hypertrophy, and elevated LV systolic tension, and coronary blood flow may be compromised. A large fraction (the majority) of coronary blood flow occurs during diastole, when aortic pressure is low, thereby reducing coronary perfusion or driving pressure. This combination of increased oxygen demand and reduced supply may cause myocardial ischemia, particularly of the subendocardium, even in the absence of epicardial coronary artery disease (CAD). ■ ■HISTORY Approximately three-fourths of patients with pure or predominant val­ vular AR are men; women predominate among patients with primary

valvular AR who have associated rheumatic mitral valve disease. A his­ tory compatible with IE may sometimes be elicited from patients with rheumatic or congenital involvement of the aortic valve, and the infec­ tion often precipitates or seriously aggravates preexisting symptoms.

In patients with acute severe AR, as may occur in IE, aortic dissec­ tion, or trauma, the LV cannot dilate sufficiently to maintain stroke volume, and LV diastolic pressure rises rapidly with associated marked elevations of LA and PA wedge pressures. Pulmonary edema and/or cardiogenic shock may develop rapidly. PART 6 Disorders of the Cardiovascular System Chronic severe AR may have a long latent period, and patients may remain relatively asymptomatic for as long as 10–15 years. Uncomfort­ able awareness of the heartbeat, especially on lying down, may be an early complaint. Sinus tachycardia, during exertion or with emotion, or premature ventricular contractions may produce particularly uncom­ fortable palpitations as well as head pounding. These complaints may persist for many years before the development of exertional dyspnea, usually the first symptom of diminished cardiac reserve. The dyspnea is followed by orthopnea, paroxysmal nocturnal dyspnea, and excessive diaphoresis. Anginal chest pain even in the absence of CAD may occur in patients with severe AR, even in younger patients. Anginal pain may develop at rest as well as during exertion. Nocturnal angina may be a particularly troublesome symptom, and it may be accompanied by marked diaphoresis. The anginal episodes can be prolonged and often do not respond satisfactorily to sublingual nitroglycerin. Systemic fluid accumulation, including congestive hepatomegaly and ankle edema, may develop late in the course of the disease. ■ ■PHYSICAL FINDINGS In chronic severe AR, the jarring of the entire body and the bobbing motion of the head with each systole can be appreciated, and the abrupt distention and collapse of the larger arteries are easily visible. The examination should be directed toward the detection of conditions predisposing to AR, such as bicuspid valve, IE, Marfan’s syndrome, or ankylosing spondylitis. Arterial Pulse  A rapidly rising “water-hammer” pulse, which col­ lapses suddenly as arterial pressure falls rapidly during late systole and diastole (Corrigan’s pulse), and capillary pulsations, an alternate flushing and paling of the skin at the root of the nail while pressure is applied to the tip of the nail (Quincke’s pulse), are characteristic of chronic severe AR. A booming “pistol-shot” sound can be heard over the femoral arter­ ies (Traube’s sign), and a to-and-fro murmur (Duroziez’s sign) is audible if the femoral artery is lightly compressed with a stethoscope. The arterial pulse pressure is widened as a result of both systolic hypertension and a lowering of the diastolic pressure. The measure­ ment of arterial diastolic pressure with a sphygmomanometer may be complicated by the fact that systolic sounds are frequently heard with the cuff completely deflated. However, the level of cuff pressure at the time of muffling of the Korotkoff sounds (phase IV) generally corre­ sponds fairly closely to the true intra-arterial diastolic pressure. As the disease progresses and the LV end-diastolic pressure rises, the arterial diastolic pressure may actually rise as well, because the aortic diastolic pressure cannot fall below the LV end-diastolic pressure. For the same reason, acute severe AR may also be accompanied by only a slight wid­ ening of the pulse pressure. Such patients are invariably tachycardic as the heart rate increases in an attempt to preserve the CO. Palpation  In patients with chronic severe AR, the LV impulse is heaving and displaced laterally and inferiorly. The systolic expansion and diastolic retraction of the apex are prominent. A diastolic thrill may be palpable along the left sternal border in thin-chested individu­ als, and a prominent systolic thrill may be palpable in the suprasternal notch and transmitted upward along the carotid arteries. This systolic thrill and the accompanying murmur do not necessarily signify the coexistence of AS. In some patients with AR or with combined AS and AR, the carotid arterial pulse may be bisferiens, i.e., with two systolic waves separated by a trough (see Fig. 246-2C). Auscultation  In patients with severe AR, the aortic valve closure sound (A2) is usually absent. A systolic ejection sound is audible in

patients with BAV disease, and occasionally an S4 also may be heard. The murmur of chronic AR is typically a high-pitched, blowing, decre­ scendo diastolic murmur, heard best in the third intercostal space along the left sternal border (see Fig. 246-5B). In patients with mild AR, this murmur is brief, but as the severity increases, it generally becomes louder and longer, indeed holodiastolic. When the murmur is soft, it can be heard best with the diaphragm of the stethoscope and with the patient sitting up, leaning forward, and with the breath held in forced expiration. In patients in whom the AR is caused by primary valvular disease, the diastolic murmur is usually louder along the left than the right sternal border. However, when the murmur is louder along the right sternal border, it suggests that the AR is caused by aneurysmal dilation of the aortic root. “Cooing” or musical diastolic murmurs suggest eversion of an aortic cusp vibrating in the regurgitant stream. A mid-systolic ejection murmur is frequently audible in isolated AR. It is generally heard best at the base of the heart and is transmitted along the carotid arteries. This murmur may be quite loud without sig­ nifying aortic valve obstruction. A third murmur sometimes heard in patients with severe AR is the Austin Flint murmur, a soft, low-pitched, rumbling mid-to-late diastolic murmur. It is probably produced by the diastolic displacement of the anterior leaflet of the mitral valve by the AR stream and is not associated with hemodynamically significant mitral valve obstruction. The auscultatory features of AR are intensi­ fied by strenuous and sustained handgrip, which augments systemic vascular resistance and increases LV afterload. In acute severe AR, the elevation of LV end-diastolic pressure may lead to early closure of the mitral valve, a soft S1, a pulse pressure that is not particularly wide, and a soft, short, early diastolic murmur of AR. ■ ■LABORATORY EXAMINATION ECG  In patients with chronic severe AR, ECG signs of LV hyper­ trophy are common (Chap. 247). In addition, these patients frequently exhibit ST-segment depression and T-wave inversion in leads I, aVL, V5, and V6 (“LV strain”). Left axis deviation and/or QRS prolongation may also be present. Echocardiogram (Fig. 273-1)  LV size is increased in chronic AR, and systolic function is normal or even supernormal until myocar­ dial contractility declines, as signaled by a decrease in EF or increase in the end-systolic dimension. A rapid, high-frequency diastolic fluttering of the anterior mitral leaflet produced by the impact of the regurgi­ tant jet is a characteristic finding. The echocardiogram is also useful in determining the cause of AR, by detecting dilation of the aortic annulus and root, aortic dissection or primary leaflet pathology. With severe AR, the central jet width assessed by color flow Doppler imag­ ing exceeds 65% of the width of the LV outflow tract, the regurgitant volume is ≥60 mL/beat, the regurgitant fraction is ≥50%, and there is diastolic flow reversal in the proximal portion of the descending tho­ racic aorta. The continuous-wave Doppler profile of the AR jet shows a rapid deceleration time in patients with acute severe AR, due to the rapid increase in LV diastolic pressure. Surveillance transthoracic echocardiography (TTE) forms the cornerstone of longitudinal followup and allows for the early detection of changes in LV size and/or function. Assessment of LV global longitudinal strain (GLS; a measure of myocardial thickening in systole) with speckle track imaging may demonstrate changes in LV systolic function that precede a fall in EF. There is increasing experience with the use of three-dimensional echo­ cardiography to measure LV volumes. Transesophageal echocardiogra­ phy (TEE) can provide detailed anatomic assessment of the valve, root, and portions of the aorta. For patients in whom TTE is limited by poor acoustical windows or inadequate characterization of LV function or the cause or severity of the regurgitation, cardiac magnetic resonance (CMR) imaging can be performed. This modality also allows for accu­ rate assessment of LV volumes, as well as aortic size and contour. It can also be utilized to screen for increased LV interstitial (extracellular volume fraction) and replacement fibrosis (late gadolinium enhance­ ment). Both CMR imaging and cardiac computed tomography (CT) can also provide detailed assessment of aortic valve, root, and thoracic aortic anatomy.

A B FIGURE 273-1  Echocardiographic and Doppler depiction of severe aortic regurgitation. (A) Color flow transesophageal echocardiographic long axis image in diastole shows a broad jet of severe aortic regurgitation (AR, yellow arrow) directed into the left ventricle. ECG rhythm strip below. Ao, aorta; BPM, beats per minute; HR, heart rate; LV, left ventricle. (B) Continuous wave Doppler tracing (middle image) obtained from the suprasternal window (top image) during transthoracic echocardiography shows dense, holodiastolic flow reversal in the descending thoracic aorta (yellow arrow) indicative of severe AR. ECG rhythm strip below. Chest X-Ray  In chronic severe AR, the apex is displaced down­ ward and to the left in the frontal projection. In the left anterior oblique and lateral projections, the LV is displaced posteriorly and encroaches on the spine. When AR is caused by primary disease of the aortic root, aneurysmal dilation of the aorta may be noted, and the aorta may fill the retrosternal space in the lateral view. Echocar­ diography, CMR imaging, and chest CT angiography are more sensi­ tive than a chest x-ray for the detection of root and ascending aortic enlargement. Cardiac Catheterization and Angiography  When needed, right and left heart catheterization with contrast aortography can pro­ vide confirmation of the magnitude of regurgitation and the status of LV function. Coronary angiography is performed routinely in patients at risk of coronary artery disease prior to surgery, although this ana­ tomic information can also be obtained in many patients with coronary CT angiography. TREATMENT Aortic Regurgitation ACUTE AORTIC REGURGITATION (FIG. 273-2) Patients with acute severe AR may respond to intravenous diuretics and vasodilators (such as sodium nitroprusside), but stabilization is usually short-lived and operation is indicated urgently. Intra-aortic balloon counterpulsation is contraindicated. Beta blockers are best avoided so as not to reduce the CO further or slow the heart rate, thus allowing more time for diastolic filling of the LV. Surgery is the treatment of choice and is usually necessary within 24 h of diagnosis. CHRONIC AORTIC REGURGITATION The onset of symptoms, or LV systolic dysfunction, is an indica­ tion for surgery. Medical treatment with diuretics and vasodilators (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers [ARBs], dihydropyridine calcium channel blockers, or hydralazine) may be useful as a temporizing measure. Surgery

CHAPTER 273 Aortic Regurgitation can then be performed in a more controlled setting. The use of vasodilators to extend the compensated phase of chronic severe AR in asymptomatic patients before the onset of symptoms or the development of LV dysfunction is not useful, although these agents should be employed to treat hypertension (systolic blood pressure

140 mmHg). It is often difficult to achieve adequate blood pres­ sure control because of the increased stroke volume and enhanced LV ejection that accompany severe AR. Cardiac arrhythmias and systemic infections are poorly tolerated in patients with severe AR and must be treated promptly and vigorously. Although nitroglyc­ erin and long-acting nitrates are not as helpful in relieving anginal pain as they are in patients with coronary heart disease, they are worth a trial. Patients with syphilitic aortitis should receive a full course of penicillin therapy (Chap. 187). Beta blockers and the ARB losartan may be useful to retard the rate of aortic root enlarge­ ment in young patients with Marfan’s syndrome and aortic root dilation. A randomized controlled trial showed no difference in efficacy between atenolol and losartan for this indication. Whether beta blockers or ARBs are useful in retarding the rate of growth of aortic aneurysms in other patient subsets (e.g., BAV disease with aortopathy, Takayasu’s disease) has not been demonstrated. Beta blockers in patients with valvular AR were previously considered relatively contraindicated due to concern that slowing of the heart rate would allow more time for diastolic regurgitation and LV filling. Observational reports, however, have suggested that beta blockers may provide functional benefit in some patients with chronic AR. Beta blockers can sometimes provide incremental blood pressure lowering in patients with chronic AR and hypertension. They can also lessen the sense of forceful heart action that many patients find uncomfortable. Patients with severe AR, particularly those with an associated aortopathy, should avoid isometric exercises. SURGICAL TREATMENT In deciding on the advisability and proper timing of surgical treat­ ment, two points should be kept in mind: (1) patients with chronic severe AR usually do not become symptomatic until after the devel­ opment of myocardial dysfunction; and (2) when delayed too long

PART 6 Disorders of the Cardiovascular System Severe AR (VC >0.6 cm, holodiastolic aortic flow reversal, RVol ≥60 mL, RF ≥50%, ERO ≥0.3 cm2) Symptomatic (Stage D) Asymptomatic (Stage C) Other cardiac surgery EF ≤55% (Stage C2) EF ≥55% LVESD >50 mm and LVESD >25 mm/m2 AVR (1) AVR (2a) AVR (2a) AVR (2b) FIGURE 273-2  Management of patients with aortic regurgitation. See legend for Fig. 272-4 for explanation of treatment recommendations (Class I, IIa, and IIb) and disease stages (B, C1, C2, and D). Preoperative coronary angiography should be performed routinely as determined by age, symptoms, and coronary risk factors. Cardiac catheterization and angiography may also be helpful when there is a discrepancy between clinical and noninvasive findings. Surgery is indicated for patients with severe AR and symptoms, LV dysfunction, or other indications for operation (e.g., aneurysm disease). Surgery is also reasonable once the LV indexed end-systolic dimension reaches or exceeds 25 mm/m2. Patients who do not meet criteria for intervention should be monitored periodically with clinical and echocardiographic follow-up. AR, aortic regurgitation; AVR, aortic valve replacement (valve repair may be appropriate in selected patients); EDD, end-diastolic dimension; EF, ejection fraction; ERO, effective regurgitant orifice; LV, left ventricular; LVEDD, left ventricular end-diastolic dimension; LVEF, left ventricular ejection fraction; LVESD, left ventricular end-systolic dimension; RF, regurgitant fraction; RVol, regurgitant volume; VC, vena contracta. (Reproduced with permission from CM Otto et al: 2020 AHA/ACC Guideline for management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2021;143(5):e72.) (defined as >1 year from onset of symptoms or LV dysfunction), surgical treatment often does not restore normal LV size and func­ tion. Therefore, in patients with chronic severe AR, careful clinical follow-up and noninvasive testing with echocardiography at ~6- to 12-month intervals are necessary if operation is to be undertaken at the optimal time, i.e., coincident with or after the onset of LV dysfunction but prior to the development of symptoms. Exercise testing may be helpful to assess effort tolerance more objectively and should be employed whenever questions about symptoms arise. Operation can be deferred as long as the patient both remains asymptomatic and retains normal LV function without severe or progressive chamber dilation. Aortic valve replacement (AVR) is indicated for the treatment of severe AR in symptomatic patients irrespective of LV function. In general, the operation should be carried out in asymptomatic patients with severe AR and progressive LV dysfunction defined by an LVEF <55% on serial studies, an LV end-systolic dimension

50 mm (>25 mm/m2), or an LV diastolic dimension >65 mm. Smaller dimensions may be appropriate thresholds in individuals of smaller stature or when there is evidence of progressively decreasing LV function or increasing LV size on serial studies and the anticipated risks for surgical morbidity and mortality are low. Two case series

Aortic regurgitation Moderate AR Other cardiac surgery Progressive changes (≥3 studies) EF 55–60% EDD >65 mm Low surgical risk from surgical referral centers have suggested that surgery should be performed at an even lower threshold for LV end-systolic dimension index (≥20 mm/m2), but data from randomized con­ trolled trials are lacking. Abnormal LV GLS (≥ –18%) has been associated with an excess hazard for death in single-center studies. Observational studies using either three-dimensional echocar­ diography or CMR imaging have also suggested that event-free survival is reduced in asymptomatic patients with an LV endsystolic volume index ≥45 mL/m2, compared with patients with an LV end-systolic volume index <45 mL/m2. Patients with severe AR without indications for operation should be followed by clinical and echocardiographic examination every 6–12 months. Trans­ catheter aortic valve implantation (TAVI) is not recommended for patients with severe AR who are surgical candidates. Technical success with TAVI in patients with chronic AR is limited by the degree of aortic annular dilation and the relative paucity of valvu­ lar and annular calcium. Surgical options for management of aortic valve and root disease have expanded considerably over the past decade. AVR with a suit­ able mechanical or tissue (biological) prosthesis is generally necessary in patients with rheumatic AR and in many patients with other causes of valvular AR. Rarely, when a leaflet has been perforated during IE

B A D FIGURE 273-3  Valve-sparing aortic root reconstruction (David procedure). Aortic root and proximal ascending aorta (A) are resected (B) with sinuses of Valsalva and mobilized coronary artery buttons remaining. Subannular sutures (C) are placed, commissural posts are drawn up inside the valve, and the annular sutures are passed through the proximal end of the graft. The annular sutures are tied (D), the valve is reimplanted inside the graft, aortic continuity is reestablished with another graft of appropriate size, and the coronary buttons are attached to the side of the graft. (From P Steltzer et al [eds]: Valvular Heart Disease: A Companion to Braunwald’s Heart Disease, 3rd ed, Fig. 12-27, p. 200.) or torn from its attachments to the aortic annulus by thoracic trauma, primary surgical repair may be possible. When AR is due to aneurys­ mal dilation of the root or proximal ascending aorta rather than to primary valve involvement, it may be possible to reduce or eliminate the regurgitation by narrowing the annulus or by excising a portion of the aortic root without replacing the valve. Elective, valve-sparing aortic root reconstruction generally involves reimplantation of the valve in a contoured graft with reattachment of the coronary artery buttons into the side of the graft and is best undertaken in specialized surgical centers by experienced operators (Fig. 273-3). Resuspension of the native aortic valve leaflets is possible in ~50% of patients with acute AR in the setting of type A aortic dissection. In other condi­ tions, however, AR can be effectively eliminated only by replacing the aortic valve, as well as the dilated or aneurysmal ascending aorta responsible for the regurgitation, often using a composite prosthetic valve-graft conduit. Pure AR is not by itself a contraindication to the Ross procedure, although the presence of aortic annular dilation and/ or an associated aortopathy would eliminate this option. As is true in patients with other valvular heart disease, both operative and late mortality risks are largely dependent on the stage of the disease and myocardial function at the time of operation. The overall operative mortality rate for isolated AVR performed for pure AR is ~1–2%. The mortality risk doubles when aortic surgery is added to the operation. Patients with AR, marked cardiac enlarge­ ment, and established LV dysfunction experience an operative mortality rate of ~5–10% and a late mortality rate of ~3–5% per

CHAPTER 273 Aortic Regurgitation C year due to LV failure despite a technically satisfactory operation. Nonetheless, because of the very poor prognosis with medical management, even patients with advanced LV systolic dysfunction should be considered for operation. Patients with acute severe AR require prompt (24–48 h) surgical treatment, which may be lifesaving. ■ ■FURTHER READING Hashimoto G et al: Association of left ventricular remodeling assess­ ment by cardiac magnetic resonance with outcomes in patients with chronic aortic regurgitation. JAMA Cardiol 7:924, 2022. Lacro RV et al: Atenolol versus losartan in children and young adults with Marfan’s syndrome. N Engl J Med 371:2061, 2014. Malaisrie SC, McCarthy PM: Surgical approach to disease of the aortic valve and the aortic root, in Valvular Heart Disease: A Compan­ ion to Braunwald’s Heart Disease, 5th ed. CM Otto, RO Bonow (eds). Philadelphia, Elsevier Saunders, 2020, pp 267–288. Otto CM et al: 2020 ACC/AHA guideline for the management of patients with valvular heart disease: A report of the American Col­ lege of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 143:e72, 2021. Yang L-T et al: Association of echocardiographic left ventricular endsystolic volume and volume-derived ejection fraction with outcome in asymptomatic chronic aortic regurgitation. JAMA Cardiol 6:189, 2021.

36 - 274 Mitral Stenosis

274 Mitral Stenosis

Patrick T. O’Gara, Joseph Loscalzo

Mitral Stenosis PART 6 Disorders of the Cardiovascular System The role of the physical examination in the evaluation of patients with valvular heart disease is also considered in Chaps. 44 and 246; of elec­ trocardiography (ECG) in Chap. 247; of echocardiography and other noninvasive imaging techniques in Chap. 248; and of cardiac catheter­ ization and angiography in Chap. 249. MITRAL STENOSIS ■ ■ETIOLOGY AND PATHOLOGY Rheumatic fever is the leading cause of mitral stenosis (MS) (Table 274-1; see also Chap. 371). Other less common etiologies of obstruction to left ventricular inflow include congenital mitral valve stenosis, cor triatriatum, mitral annular calcification with extension onto the leaflets, systemic lupus erythematosus, rheumatoid arthritis, left atrial myxoma, and infective endocarditis with large vegetations. Pure or predominant MS occurs in ~40% of all patients with rheumatic heart disease and a history of rheumatic fever (Chap. 371). In other patients with rheumatic heart disease, lesser degrees of MS may accompany mitral regurgitation (MR) and aortic valve disease. With reductions in the incidence of acute rheumatic fever, particularly in temperate climates and middle- to high-income countries, the incidence of MS has declined considerably over the past several decades. However, it remains a major problem in low-income countries, especially in subSaharan Africa, India, Southeast Asia, and Oceania (Chap. 272). In rheumatic MS, chronic inflammation leads to diffuse thicken­ ing of the valve leaflets with formation of fibrous tissue often with calcific deposits. The mitral commissures fuse, the chordae tendineae fuse and shorten, the valvular cusps become rigid, and the pathologic process eventually leads to narrowing at the apex of the funnel-shaped (“fish-mouth”) valve. Although the initial insult to the mitral valve is rheumatic, later changes may be exacerbated by inflammation, fibrosis, and trauma due to altered flow patterns. Calcification of the stenotic mitral valve immobilizes the leaflets and narrows the orifice further. Thrombus formation and arterial embolization may arise from the calcific valve itself, but in patients with atrial fibrillation (AF), thrombi arise more frequently from the dilated left atrium (LA), particularly from within the LA appendage. ■ ■PATHOPHYSIOLOGY In normal adults, the area of the mitral valve orifice is 4–6 cm2. In the presence of significant obstruction, i.e., when the orifice area is reduced to <~2 cm2, blood can flow from the LA to the left ventricle (LV) only if propelled by an abnormally elevated left atrioventricular pressure gradient, the hemodynamic hallmark of MS. When the mitral valve opening is reduced to <1.5 cm2, referred to as “severe” MS, an LA pressure of ~25 mmHg is required to maintain a normal cardiac output (CO). The elevated pulmonary venous and pulmonary arterial (PA) wedge pressures reduce pulmonary compliance, contributing to exertional dyspnea. The first bouts of dyspnea are usually precipitated TABLE 274-1  Major Causes of Mitral Stenosis Etiologies Rheumatic fever Congenital (parachute valve, cor triatriatum) Severe mitral annular calcification with leaflet involvement SLE, RA Myxoma IE with large vegetations Abbreviations: IE, infective endocarditis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus.

by clinical events that increase the rate of blood flow across the mitral orifice, resulting in further elevation of the LA pressure (see below). To assess the severity of obstruction hemodynamically, both the transvalvular pressure gradient and the flow rate must be measured (Chap. 249). The latter depends not only on the CO but on the heart rate, as well. An increase in heart rate shortens diastole proportionately more than systole and diminishes the time available for flow across the mitral valve. Therefore, at any given level of CO, tachycardia, includ­ ing that associated with rapid AF, augments the transvalvular pressure gradient and elevates further the LA pressure. Similar considerations apply to the pathophysiology of tricuspid stenosis (TS). The LV diastolic pressure and ejection fraction (EF) are normal in isolated MS. In MS and sinus rhythm, the elevated LA and PA wedge pressures exhibit a prominent atrial contraction pattern (a wave) and a gradual pressure decline after the v wave and mitral valve opening (y descent). In severe MS and whenever pulmonary vascular resistance is significantly increased, the PA pressure (PAP) is elevated at rest and rises further during exercise, often causing secondary elevations of right ventricular (RV) end-diastolic pressure and volume. Cardiac Output  In patients with severe MS (mitral valve orifice 1–1.5 cm2), the CO is normal or almost so at rest, but rises subnormally during exertion. In patients with very severe MS (valve area <1 cm2), particularly those in whom pulmonary vascular resistance is markedly elevated, the CO is subnormal at rest and may fail to rise or may even decline during activity. Pulmonary Hypertension  The clinical and hemodynamic fea­ tures of MS are influenced importantly by the level of the PAP. Pul­ monary hypertension results from (1) passive backward transmission of the elevated LA pressure; (2) pulmonary arteriolar constriction (the so-called “second stenosis”), which presumably is triggered by LA and pulmonary venous hypertension (reactive pulmonary hypertension); (3) interstitial edema in the walls of the small pulmonary vessels; and (4) at end stage, organic obliterative changes in the pulmonary vascular bed. Severe pulmonary hypertension results in RV enlargement, secondary tricuspid regurgitation (TR), and pulmonic regurgitation (PR), as well as right-sided heart failure. ■ ■SYMPTOMS In temperate climates, the latent period between the initial attack of rheumatic carditis (in the increasingly rare circumstances in which a history of one can be elicited) and the development of symptoms due to MS is generally about two decades; most patients begin to experience disability in the fourth decade of life. Studies carried out before the development of surgical mitral valvotomy revealed that once a patient with MS became seriously symptomatic, the disease progressed inexo­ rably to death within 2–5 years. In patients whose mitral orifices are large enough to accommodate a normal blood flow with only mild elevations of LA pressure, marked elevations of this pressure leading to dyspnea and cough may be precip­ itated by sudden changes in the heart rate, volume status, or CO, as, for example, with severe exertion, excitement, fever, severe anemia, parox­ ysmal AF and other tachycardias, sexual intercourse, pregnancy, and thyrotoxicosis. As MS progresses, lesser degrees of stress precipitate dyspnea, the patient becomes limited in daily activities, and orthop­ nea and paroxysmal nocturnal dyspnea develop. The development of persistent AF often marks a turning point in the patient’s course and is generally associated with acceleration of the rate at which symptoms progress. Hemoptysis (Chap. 41) results from rupture of pulmonarybronchial venous connections secondary to pulmonary venous hyper­ tension. It occurs most frequently in patients who have elevated LA pressures without markedly elevated pulmonary vascular resistances and is rarely fatal. Recurrent pulmonary emboli (Chap. 290), sometimes with infarction, are an important cause of morbidity and mortality late in the course of MS and often arise from right atrial mural thrombus. Pulmonary infections, i.e., bronchitis, bronchopneumonia, and lobar pneumonia, commonly complicate untreated MS, especially during the winter months. In patients with significant left atrial enlargement,

cardiovocal syndrome (Ortner’s syndrome) may develop with hoarse­ ness secondary to left recurrent laryngeal nerve compression. Pulmonary Changes  In addition to the aforementioned changes in the pulmonary vascular bed, fibrous thickening of the walls of the alveoli and pulmonary capillaries occurs commonly in MS. The vital capacity, total lung capacity, maximal breathing capacity, and oxygen uptake per unit of ventilation are reduced (Chap. 296). Pulmonary compliance falls further as pulmonary capillary pressure rises during exercise. Thrombi and Emboli  Thrombi may form in the left atria, par­ ticularly within the enlarged atrial appendages of patients with MS. Systemic embolization, the incidence of which is 10–20%, occurs more frequently in patients with AF, in patients >65 years of age, and in those with a reduced CO. However, systemic embolization may be the pre­ senting feature in otherwise asymptomatic patients with only mild MS. ■ ■PHYSICAL FINDINGS (See also Chaps. 44 and 246). Inspection and Palpation  In patients with severe MS, there may be a malar flush with pinched and blue facies. In patients with sinus rhythm and severe pulmonary hypertension or associated TS, the jugu­ lar venous pulse reveals prominent a waves due to vigorous right atrial systole. The systemic arterial pressure is usually normal or slightly low. A parasternal lift signifies an enlarged RV. A diastolic thrill may very rarely be present at the cardiac apex, with the patient in the left lateral recumbent position. Auscultation  The first heart sound (S1) is usually accentuated in the early stages of the disease and slightly delayed. The pulmonic component of the second heart sound (P2) also is often accentuated with elevated PAPs, and the two components of the second heart sound (S2) are closely split. The opening snap (OS) of the mitral valve is most readily audible in expiration at, or just medial to, the cardiac apex. This sound generally follows the sound of aortic valve closure (A2) by 0.05–0.12 s. The time interval between A2 and OS varies inversely with the severity of the MS. The OS is followed by a low-pitched, rumbling, diastolic murmur, heard best at the apex with the patient in the left lateral recumbent position (see Fig. 246-5); it is accentuated by mild exercise (e.g., a few rapid sit-ups) carried out just before auscultation. In general, the duration of this murmur correlates with the severity of the stenosis in patients with preserved CO. In patients with sinus rhythm, the murmur often reappears or becomes louder during atrial systole (presystolic accentuation). Soft, grade I or II/VI systolic mur­ murs may be heard at or medial to the apex and may signify mixed mitral valve disease with regurgitation. Hepatomegaly, ankle edema, ascites, and pleural effusion, particularly in the right pleural cavity, may occur in patients with MS and RV failure. Associated Lesions  With severe pulmonary hypertension, a pan­ systolic murmur produced by functional TR may be audible along the left sternal border. This murmur is usually louder during inspiration and diminishes during forced expiration (Carvallo’s sign). When the CO is markedly reduced in MS, the typical auscultatory findings, including the diastolic rumbling murmur, may not be detectable (silent MS), but they may reappear as compensation is restored. The Graham Steell murmur of PR, a high-pitched, diastolic, decrescendo blowing murmur along the left sternal border, results from dilation of the pul­ monary valve ring and occurs in patients with mitral valve disease and severe pulmonary hypertension. This murmur may be indistinguish­ able from the more common murmur produced by aortic regurgita­ tion (AR), although it may increase in intensity with inspiration and is accompanied by a loud and often palpable P2. ■ ■LABORATORY EXAMINATION ECG  In MS and sinus rhythm, the P wave usually suggests LA enlargement (see Fig. 247-8). It may become tall and peaked in lead II and upright in lead V1 when severe pulmonary hypertension or TS

CHAPTER 274 Mitral Stenosis FIGURE 274-1  Continuous wave Doppler interrogation of transmitral valve velocities in a patient with severe rheumatic mitral stenosis. Electrocardiogram on top. Vertical scale in meters/second. Horizontal scale in seconds at sweep speed of 75 mm/se. Velocity is converted to pressure using the Bernoulli equation. In this example, the mean mitral valve gradient (area under the green tracing) is calculated to 38 mmHg and mitral valve area to 0.7 cm2. complicates MS and right atrial (RA) enlargement develops. The QRS complex is usually normal. However, with severe pulmonary hyperten­ sion, right axis deviation and RV hypertrophy are often present. Echocardiogram (See also Chap. 248)  Transthoracic echo­ cardiography (TTE) with color flow and spectral Doppler imaging provides critical information, including measurements of mitral inflow velocity during early (E wave) and late (A wave in patients in sinus rhythm) diastolic filling, estimates of the transvalvular peak and mean gradients and mitral orifice area (Fig. 274-1), the presence and severity of any associated MR, the extent of leaflet calcification and restriction, the degree of distortion of the subvalvular apparatus, and the anatomic suitability for percutaneous mitral balloon commissurotomy (PMBC; see below). In addition, TTE provides an assessment of LV and RV function, chamber sizes, an estimation of the PA systolic pressure based on the tricuspid regurgitant jet velocity, and an indication of the presence and severity of any associated valvular lesions, such as aortic stenosis (AS) and/or regurgitation. Transesophageal echocardiogra­ phy (TEE) provides superior images and should be used when TTE is inadequate for guiding management decisions. TEE is especially indicated to exclude the presence of LA thrombus prior to PMBC. The performance of TTE with exercise to evaluate the mean mitral diastolic gradient, PAPs, and RV function can be very helpful in the evaluation of patients with MS when there is a discrepancy between the clinical findings and the resting hemodynamics. Chest X-Ray  The earliest changes are straightening of the upper left border of the cardiac silhouette, prominence of the main PAs, dilation of the upper lobe pulmonary veins, and posterior displacement of the esophagus by an enlarged LA. Kerley B lines are fine, dense, opaque, horizontal lines that are most prominent in the lower and mid-lung fields that result from distention of interlobular septae and lymphatics with edema when the resting mean LA pressure exceeds ~20 mmHg. ■ ■DIFFERENTIAL DIAGNOSIS Like MS, significant MR may also be associated with a prominent dia­ stolic murmur at the apex due to increased antegrade transmitral flow, but in patients with isolated MR, this diastolic murmur commences slightly later than in patients with MS, and there is often clear-cut evidence of LV enlargement. An OS and increased P2 are absent, and S1 is soft or absent. An apical pansystolic murmur of at least grade III/VI intensity as well as an S3 suggests significant MR. Similarly, the apical mid-diastolic murmur associated with severe AR (Austin Flint murmur) may be mistaken for MS but can be differentiated from it because it is not intensified in pre-systole and becomes softer with administra­ tion of amyl nitrite or other arterial vasodilators. TS, which occurs rarely in the absence of MS, may mask many of the clinical features of MS or be clinically silent; when present, the diastolic murmur of

TS increases with inspiration and the y descent in the jugular venous pulse is delayed.

Atrial septal defect (Chap. 280) may be mistaken for MS; in both conditions, there is often clinical, ECG, and chest x-ray evidence of RV enlargement and accentuation of pulmonary vascularity. However, the absence of LA enlargement and of Kerley B lines and the demonstra­ tion of fixed splitting of S2 with a grade II or III mid-systolic murmur at the mid to upper left sternal border all favor atrial septal defect over MS. Atrial septal defects with large left-to-right shunts may result in functional TS because of the enhanced diastolic flow. An incomplete right bundle branch block pattern on ECG is often present. PART 6 Disorders of the Cardiovascular System Left atrial myxoma (Chap. 282) may obstruct LA emptying, causing dyspnea, a diastolic murmur, and hemodynamic changes resembling those of MS. However, patients with an LA myxoma often have features suggestive of a systemic disease, such as weight loss, fever, anemia, systemic emboli, and elevated serum IgG and interleukin 6 (IL-6) con­ centrations. The auscultatory findings may change markedly with body position. The diagnosis can be established by the demonstration of a characteristic echo-producing mass in the LA with TTE. ■ ■CARDIAC CATHETERIZATION Left and right heart catheterization can be useful when there is a discrepancy between the clinical and noninvasive findings, includ­ ing those from TEE and exercise echocardiographic testing when appropriate. Catheterization can also be helpful in assessing associated lesions, such as AS and AR, and in patients with recurring or worsening symptoms late after mitral valve intervention. Computed tomographic coronary angiography is increasingly used to screen preoperatively for Severe MS MVA ≤1.5 cm2 Symptomatic Stage D Severe symptoms NYHA III–IV No Pliable valve No clot <2+ MR Surgical candidate Yes Yes No PMBC at CVC (1) MV surgery (1) FIGURE 274-2  Management of rheumatic mitral stenosis. See legend for Fig. 272-4 for explanation of treatment recommendations (Class I, IIa, IIb) and disease stages (C, D). Preoperative coronary angiography should be performed routinely as determined by age, symptoms, and coronary risk factors. Cardiac catheterization and angiography may also be helpful when there is a discrepancy between clinical and noninvasive findings. AF, atrial fibrillation; CVC, comprehensive valve center; MR, mitral regurgitation; MS, mitral stenosis; MV, mitral valve; MVA, mitral valve area; MVR, mitral valve surgery (repair or replacement); NYHA, New York Heart Association; PASP, pulmonary arterial systolic pressure; PMBC, percutaneous mitral balloon commissurotomy. (Reproduced with permission from CM Otto et al: ACC/AHA guideline for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 143:e72, 2021.)

the presence of coronary artery disease in appropriate patients prior to heart valve surgery or transcatheter treatment. TREATMENT Mitral Stenosis (Fig. 274-2) Penicillin prophylaxis of group A β-hemolytic streptococcal infec­ tions (Chap. 371) for secondary prevention of rheumatic fever is important for at-risk patients with rheumatic MS. Recommenda­ tions for infective endocarditis prophylaxis are similar to those for other valve lesions and are restricted to patients at high risk for complications from infection, including patients with a his­ tory of endocarditis. In symptomatic patients, some improvement usually occurs with restriction of sodium intake and small doses of oral diuretics. Beta blockers, nondihydropyridine calcium chan­ nel blockers (e.g., verapamil or diltiazem), and digitalis glycosides are useful in slowing the ventricular rate of patients with AF. Vitamin K antagonist therapy (such as warfarin) targeted to an international normalized ratio (INR) of 2–3 should be adminis­ tered indefinitely to patients with MS who have AF, a history of thromboembolism, or demonstrated LA thrombus. The routine use of a vitamin K antagonist in patients in sinus rhythm with LA enlargement (maximal dimension >5.5 cm) with or without spon­ taneous echo contrast is more controversial. In a randomized trial of patients with rheumatic MS and AF, there was a significantly higher incidence of death among patients treated with rivaroxaban than with vitamin K antagonist therapy. A vitamin K antagonist is Rheumatic mitral stenosis Progressive MS MVA >1.5 cm2 Asymptomatic Stage C Exertional symptoms Pliable valve No clot <2+ MR Stress test Hemodynamically significant MS New AF PASP

50 mmHg Pliable valve No clot <2+ MR PMBC at CVC (2b) PMBC at CVC (2b) PMBC at CVC (2a)

1 year, conditions that favor the development of an LA myopathy. MITRAL COMMISSUROTOMY Unless there is a contraindication, mitral commissurotomy is indi­ cated in symptomatic (New York Heart Association [NYHA] func­ tional class II–IV) patients with isolated severe MS, whose effective orifice (valve area) is <~1 cm2/m2 body surface area or <1.5 cm2 in normal-sized adults. Mitral commissurotomy can be carried out either percutaneously or surgically. In PMBC (Figs. 274-3 and 274-4), a catheter is directed into the LA after transseptal punc­ ture, and a single balloon is directed across the valve and inflated in the valvular orifice. Ideal patients have relatively pliable leaflets with little or no commissural calcium. In addition, the subvalvular structures should not be significantly scarred or thickened, and there should be no LA thrombus. Any associated MR should be of ≤2+/4+ severity. The short- and long-term results of this procedure in appropriate patients are similar to those of surgical commissur­ otomy, but with less morbidity and a lower periprocedural mortality rate. Event-free survival in younger (<45 years) patients with pliable valves is excellent, with rates as high as 80–90% over 3–7 years. Therefore, PMBC is the procedure of choice for such patients when it can be performed by a skilled operator in a high-volume center. Guide wire Stiffening cannula B A D C FIGURE 274-3  Inoue balloon technique for percutaneous mitral balloon commissurotomy. A. After transseptal puncture, the deflated balloon catheter is advanced across the interatrial septum, then across the mitral valve and into the left ventricle. B–D. The balloon is inflated stepwise within the mitral orifice.

PREDILATATION POSTDILATATION ECG ECG CHAPTER 274 LV LV

Pressure (mmHg) Mitral Stenosis LA LA

Mean mitral gradient 3 mmHg Cardiac output 3.8 L/min Mitral valve area 1.8 cm2 Mean mitral gradient 15 mmHg Cardiac output 3 L/min Mitral valve area 0.6 cm2 FIGURE 274-4  Simultaneous left atrial (LA) and left ventricular (LV) pressure before and after percutaneous mitral balloon commissurotomy (PMBC) in a patient with severe mitral stenosis. ECG, electrocardiogram. (Courtesy of Raymond G. McKay, MD.) TTE is helpful in identifying patients for the percutaneous pro­ cedure; TEE is performed routinely to exclude LA thrombus and to assess the degree of MR at the time of the scheduled procedure. An “echo score” has been developed to help guide decision-making. The score accounts for the degree of leaflet thickening, calcification, and mobility, and for the extent of subvalvular thickening. A lower score predicts a higher likelihood of successful PMBC. In patients in whom PMBC is not possible or unsuccessful, or in many patients with restenosis after previous surgery, an “open” surgical commissurotomy using cardiopulmonary bypass is neces­ sary. In addition to opening the valve commissures, it is important to loosen any subvalvular fusion of papillary muscles and chordae tendineae; to remove large deposits of calcium, thereby improving valvular function; and to remove atrial thrombi. The perioperative mortality rate for this type of mitral valve repair procedure is ~2%. Successful commissurotomy is defined by a 50% reduction in the mean mitral valve gradient and a doubling of the mitral valve area. Successful commissurotomy, whether balloon or surgical, usually results in striking symptomatic and hemodynamic improvement and prolongs survival. However, there is no evidence that the proce­ dure improves the prognosis of patients with slight or no functional impairment. Therefore, unless recurrent systemic embolization or severe pulmonary hypertension has occurred (PA systolic pressures

50 mmHg at rest or >60 mmHg with exercise), commissurotomy is not recommended for patients who are asymptomatic and/or who have mild or moderate stenosis (mitral valve area >1.5 cm2). When there is little symptomatic improvement after commissurotomy, it is likely that the procedure was ineffective, that it induced MR, or that associated valvular or myocardial disease was present. About half of all patients undergoing surgical mitral commissurotomy require reoperation by 10 years. In the pregnant patient with MS, commissurotomy should be carried out if pulmonary congestion occurs despite intensive medical treatment. PMBC is the preferred strategy in this setting and is performed with TEE and no or mini­ mal x-ray exposure. Mitral valve replacement (MVR) is necessary in patients with MS and significant associated MR, those in whom the valve has been severely distorted by previous transcatheter or operative manipulation, or those in whom the surgeon does not find it pos­ sible to improve valve function significantly with commissurotomy. MVR is now routinely performed with preservation of the chordal attachments to optimize LV functional recovery. Perioperative mor­ tality rates with MVR vary with age, LV function, the presence of CAD, and associated comorbidities. They average 2–5% overall but

37 - 275 Mitral Regurgitation

275 Mitral Regurgitation

are lower in young patients and may be twice as high in patients

65 years of age with significant comorbidities. Because there are also long-term complications of valve replacement, patients in whom preoperative evaluation suggests the possibility that MVR may be required should be operated on only if they have severe MS—i.e., an orifice area ≤1.5 cm2—and are in NYHA class III, i.e., symptomatic with ordinary activity despite optimal medical therapy. The overall 10-year survival of surgical survivors is ~70%. Long-term prognosis is worse in patients >65 years of age and those with marked disability and marked depression of the CO preopera­ tively. Pulmonary hypertension and RV dysfunction are additional risk factors for poor outcome.

PART 6 Disorders of the Cardiovascular System ■ ■FURTHER READING Connolly SJ et al: Rivaroxaban in rheumatic heart disease-associated atrial fibrillation. N Engl J Med 387:978, 2022. Nishimura RA et al: Mitral valve disease: Current management and future challenges. Lancet 387:1324, 2016. Otto CM et al: 2020 ACC/AHA guideline for the management of patients with valvular heart disease: A report of the American Col­ lege of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 143:e72, 2021. Patrick T. O’Gara, Joseph Loscalzo

Mitral Regurgitation The role of the physical examination in the evaluation of patients with valvular heart disease is also considered in Chaps. 44 and 246; of elec­ trocardiography (ECG) in Chap. 247; of echocardiography and other noninvasive imaging techniques in Chap. 248; and of cardiac catheter­ ization and angiography in Chap. 249. ■ ■ETIOLOGY Mitral regurgitation (MR) may result from an abnormality or disease process that affects any one or more of the five functional components of the mitral valve apparatus (leaflets, annulus, chordae tendineae, pap­ illary muscles, and subjacent myocardium) (Table 275-1). Acute MR can occur in the setting of acute myocardial infarction (MI) with pap­ illary muscle rupture (Chap. 286), following blunt chest wall trauma, or during the course of infective endocarditis (IE) owing to leaflet perforation or destruction. With acute MI, the posteromedial papil­ lary muscle is involved much more frequently than the anterolateral papillary muscle because of its singular blood supply. Transient, acute MR can occur during periods of active ischemia and bouts of angina pectoris. Rupture of chordae tendineae can result in “acute-on-chronic MR” in patients with myxomatous degeneration of the valve apparatus. Chronic MR can result from several disease processes (Table 275-1). Distinction should be drawn between primary (degenerative) MR, in which the leaflets and/or chordae tendineae are primarily respon­ sible for abnormal valve function, and secondary (functional) MR, in which the leaflets and chordae tendineae are usually normal but the regurgitation is caused by left ventricular (LV) and/or left atrial remodeling, annular dilation, papillary muscle displacement, dys­ synchrony, leaflet tethering, or their combination. Patient assessment, treatment approach, and long-term prognosis differ significantly between primary and secondary MR. Mitral valve prolapse (MVP) is discussed more extensively in Chap. 276. The rheumatic process produces rigidity, deformity, and retraction of the valve cusps and com­ missural fusion, as well as shortening, contraction, and fusion of the chordae tendineae. MR can persist after resolution of the acute phase

TABLE 275-1  Major Causes of Mitral Regurgitation (MR) Etiologies Acute   IE   Papillary muscle rupture (post-MI)   Chordal rupture/leaflet flail (MVP, IE)   Blunt trauma Chronic   Primary (affecting leaflets, chordae)     Myxomatous (MVP, Barlow’s, forme fruste)     Rheumatic fever     IE (healed)     Congenital (cleft, AV canal)     Radiation   Secondary (leaflets, chordae are “innocent bystanders”)     Ischemic cardiomyopathy     Dilated cardiomyopathy     HOCM (with SAM)     AF with LA enlargement and annular dilation (atrial functional MR)   Mitral annular calcificationa aMitral annular calcification may include elements of both primary and secondary MR (mixed) as the disease process may encroach on the leaflets, impair the normal sphincteric function of the annulus, or both. There are additional examples of “mixed” secondary MR such as the coexistence of MVP with an ischemic cardiomyopathy. Abbreviations: AF, atrial fibrillation; AV, atrioventricular; HOCM, hypertrophic obstructive cardiomyopathy; IE, infective endocarditis; LA, left atrial; LV, left ventricular; MI, myocardial infarction; MVP, mitral valve prolapse; SAM, systolic anterior motion. of infection and inflammation. MR may occur as a congenital anomaly (Chap. 280), most commonly as a defect of the endocardial cushions (atrioventricular cushion defects). A cleft anterior mitral valve leaflet accompanies ostium primum atrial septal defect. Radiation can result in leaflet thickening, retraction, and calcification, often in association with annular and chordal involvement and some degree of mitral ste­ nosis. Chronic MR occurs frequently after prior MI(s) associated with changes in LV size, shape, and function. Similar mechanisms of annular dilation and ventricular remodeling contribute to the MR that occurs among patients with nonischemic forms of dilated cardiomyopathy once the LV end-diastolic dimension reaches 6 cm. The MR associated with hypertrophic obstructive cardiomyopathy (HOCM) is usually dynamic in nature and dependent on systolic anterior motion of the anterior mitral valve leaflet into a narrowed LV outflow tract. Patients with chronic persistent atrial fibrillation (AF) may develop atrial remodeling and annular dilation with inadequate leaflet lengthening and MR (atrial functional MR). Secondary MR due to LV remodeling is more frequently encountered in the community than secondary MR that occurs in association with AF and annular dilation. Annular calci­ fication can result in MR when it encroaches on the leaflets or results in decreased sphincteric function, is especially prevalent among patients with advanced renal disease, and is commonly observed in women

65 years of age with hypertension and diabetes mellitus. Irrespective of cause, chronic severe MR is often progressive because enlargement of the left atrium (LA) places tension on the posterior mitral leaflet, pulling it further away from the mitral orifice and thereby aggravating the valvular dysfunction. Similarly, LV dilation increases the regurgi­ tation, which, in turn, enlarges the LA and LV further, resulting in a vicious cycle; hence the aphorism, “MR begets MR.” ■ ■PATHOPHYSIOLOGY The resistance to LV emptying (LV afterload) is reduced in patients with MR. As a consequence, the LV is decompressed into the LA during ejec­ tion, and with the reduction in LV size during systole, there is a rapid decline in LV tension. The initial compensation to MR is more com­ plete LV emptying. However, LV volume increases progressively with time as the severity of the regurgitation increases and as LV contractile function deteriorates. This increase in LV volume is often accompanied

by a reduced forward cardiac output (CO). LV compliance is often increased, and thus, LV diastolic pressure does not increase until late in the course. The regurgitant volume varies directly with the LV systolic pressure and the size of the regurgitant orifice; the latter, in turn, is influenced by the extent of LV and mitral annular dilation, as well as by leaflet morphology. Because ejection fraction (EF) rises in severe MR in the presence of normal LV function, even a modest reduction in this parameter (<60%) reflects significant contractile dysfunction. During early diastole, as the distended LA empties, there is a par­ ticularly rapid y descent in the absence of accompanying MS. A brief, early diastolic LA-LV pressure gradient (often generating a rapid filling sound [S3] and mid-diastolic murmur masquerading as MS) may occur in patients with pure, severe MR as a result of the very rapid flow of blood across a normal-sized mitral orifice. Measurements of LV ejection fraction (LVEF), CO, pulmonary arterial (PA) systolic pressure, regurgitant volume, regurgitant fraction (RF), and the effective regurgitant orifice area can be obtained during a careful Doppler echocardiographic examination. These measure­ ments can also be obtained accurately with cardiac magnetic resonance (CMR) imaging, although this technology is not widely available. Left and right heart catheterization with contrast ventriculography is used less frequently. Chronic, severe MR is defined by a regurgitant volume ≥60 mL/beat, RF ≥50%, and effective regurgitant orifice area ≥0.40 cm2. In patients with secondary MR, in whom the severity of MR can be underappreciated using echocardiographic/Doppler techniques, lesser degrees of regurgitation may carry relatively greater prognostic weight. The adverse prognosis in secondary MR related to adverse LV remod­ eling is intimately related to the degree of myocardial dysfunction. LA Compliance  In acute severe MR, the regurgitant volume is delivered into a normal-sized LA having normal or reduced compli­ ance. As a result, LA pressures rise markedly for any increase in LA volume. The v wave in the LA pressure pulse is usually prominent, LA and pulmonary venous pressures are markedly elevated, and pul­ monary edema is common. Because of the rapid rise in LA pressures during ventricular systole, the murmur of acute MR is early in timing and decrescendo in configuration ending well before S2, as a reflection of the progressive diminution in the LV-LA pressure gradient. LV sys­ tolic function in acute MR may be normal, hyperdynamic, or reduced, depending on the clinical context. Patients with chronic severe MR, on the other hand, develop marked LA enlargement and increased LA compliance with little if any increase in LA and pulmonary venous pressures for any increase in LA volume. The LA v wave is relatively less prominent. The murmur of chronic MR is classically holosystolic in timing and plateau in configuration, as a reflection of the near-constant LV-LA pressure gradient. These patients usually complain of severe fatigue and exhaustion secondary to a low forward CO, whereas symptoms resulting from pulmonary congestion are less prominent initially; AF is almost invariably present once the LA dilates significantly. ■ ■SYMPTOMS Patients with chronic mild-to-moderate, isolated MR are usually asymptomatic. This form of LV volume overload is well tolerated. Fatigue, exertional dyspnea, and orthopnea are the most prominent complaints in patients with chronic severe MR. Palpitations are com­ mon and may signify the onset of AF. Late-onset right-sided heart failure, with painful hepatic congestion, ankle edema, distended neck veins, ascites, and secondary tricuspid regurgitation (TR), occurs in patients with MR who have associated pulmonary vascular disease and pulmonary hypertension. Acute pulmonary edema is common in patients with acute severe MR. ■ ■PHYSICAL FINDINGS In patients with chronic severe MR, the arterial pressure is usually nor­ mal, although the carotid arterial pulse may show a sharp, low-volume upstroke owing to the reduced forward CO. A systolic thrill is often palpable at the cardiac apex, the LV is hyperdynamic with a brisk sys­ tolic impulse and a palpable rapid-filling wave (S3), and the apex beat is often displaced laterally.

In patients with acute severe MR, the arterial pressure may be reduced with a narrow pulse pressure, the jugular venous pressure and waveforms may be normal or increased and exaggerated, the api­ cal impulse is not displaced, and signs of pulmonary congestion are prominent.

CHAPTER 275 Auscultation  S1 is generally absent, soft, or buried in the holosys­ tolic murmur of chronic, severe MR. In patients with severe MR, the aortic valve may close prematurely (due to the reduced forward cardiac output), resulting in wide but physiologic splitting of S2. A low-pitched S3 occurring 0.12–0.17 s after the aortic valve closure sound, i.e., at the completion of the rapid-filling phase of the LV, is believed to be caused by the sudden tensing of the papillary muscles, chordae tendineae, and valve leaflets. It may be followed by a short, rumbling, mid-diastolic murmur, even in the absence of structural MS. In patients with isch­ emic or dilated cardiomyopathy, however, a third sound (S3) may also signify ventricular dysfunction. A fourth heart sound is often audible in patients with acute severe MR who are in sinus rhythm. A presystolic murmur is not ordinarily heard with isolated MR. Mitral Regurgitation A systolic murmur of at least grade III/VI intensity is the most char­ acteristic auscultatory finding in chronic severe MR. It is usually holo­ systolic (see Fig. 246-5A), but as previously noted, it is decrescendo and ceases in mid-to-late systole in patients with acute severe MR. The systolic murmur of chronic MR is usually most prominent at the apex and radiates to the axilla. However, in patients with ruptured chordae tendineae or primary involvement of the posterior mitral leaflet with prolapse or flail, the regurgitant jet is eccentric, directed anteriorly, and strikes the LA wall adjacent to the aortic root. In this situation, the systolic murmur is transmitted to the base of the heart and, therefore, may be confused with the murmur of AS. The murmur associated with anterior leaflet prolapse or flail is directed to the axilla. In patients with ruptured chordae tendineae, the systolic murmur may have a cooing or “seagull” quality, whereas a flail leaflet may produce a murmur with a musical quality. The systolic murmur of chronic MR not due to MVP is intensified by isometric exercise (handgrip) but is reduced during the strain phase of the Valsalva maneuver because of the associated decrease in LV preload. ■ ■LABORATORY EXAMINATION ECG  In patients with sinus rhythm, there is evidence of LA enlarge­ ment, but right atrial (RA) enlargement also may be present when pul­ monary hypertension is significant and affects right ventricular function and size. Chronic severe MR is frequently associated with AF. In many patients, there is no clear-cut ECG evidence of enlargement of either ven­ tricle. In others, the signs of eccentric LV hypertrophy are present. Echocardiogram (Fig. 275-1)  Transthoracic echocardiography (TTE) is indicated to assess the mechanism of the MR and its hemo­ dynamic severity. LV function can be assessed from LV end-diastolic and end-systolic volumes and EF. Observations can be made regarding leaflet structure and function, chordal integrity, LA and LV size, annu­ lar calcification, and regional and global LV systolic function. Doppler imaging should demonstrate the width or area of the color flow MR jet within the LA, the duration and intensity of the continuous wave Dop­ pler signal, the pulmonary venous flow contour, the early peak mitral inflow velocity, and quantitative measures of regurgitant volume, RF, and effective regurgitant orifice area. In addition, the PA pressures (PAPs) can be estimated from the TR jet velocity. TTE is also indicated to follow the course of patients with chronic MR and to provide rapid assessment for any clinical change. Transesophageal echocardiography (TEE) provides greater anatomic detail than TTE (see Fig. 248-5). Exercise testing with TTE can be useful to assess exercise capacity as well as any dynamic change in MR severity, PA systolic pressures, and biventricular function, for patients in whom there is a discrepancy between clinical findings and the results of other noninvasive testing. Chest X-Ray  The LA and LV are the dominant chambers in chronic MR. Late in the course of the disease, the LA may be mas­ sively enlarged and forms the right border of the cardiac silhouette. Pulmonary venous congestion, interstitial edema, and Kerley B lines

PART 6 Disorders of the Cardiovascular System FIGURE 275-1  Mitral regurgitation. Apical two-chamber transthoracic color flow Doppler echocardiographic display of a broad systolic jet of severe mitral regurgitation (yellow stream between the two white arrows) from the left ventricle directed posteriorly into the left atrium. LA, left atrium; LV, left ventricle; MV, anterior leaflet of the mitral valve. are sometimes noted. Marked calcification of the mitral leaflets occurs commonly in patients with long-standing, combined rheumatic MR and MS, as well as in patients with radiation-induced mitral valve dis­ ease. Calcification of the mitral annulus may be visualized, particularly Symptoms due to MR (Stage D) (regardless of LV function) LV systolic dysfunction (Stage C2) (LVEF ≤60% or ESD ≥40 mm) High or prohibitive surgical risk with anatomy favorable for transcatheter approach and life expectancy >1 y MV surgery (1) Degenerative MV disease Rheumatic MV disease Successful and durable repair possible Successful and durable repair possible MV surgery at primary or CVC (1) MV repair at primary or CVC (2a) Transcatheter edge-toedge MV repair (2a) MV repair or replacement (2b) MV repair at CVC (2b) FIGURE 275-2  Management of primary mitral regurgitation (MR). See legend for Fig. 272-4 for explanation of treatment recommendations (Class I, IIa, IIb) and disease stages (B, C1, C2, D). Preoperative coronary angiography should be performed routinely as determined by age, symptoms, and coronary risk factors. Cardiac catheterization and angiography may also be helpful when there is a discrepancy between clinical and noninvasive findings. Mitral valve repair is strongly preferred over valve replacement whenever feasible for surgical treatment of primary MR. Transcatheter edge-to-edge repair (TEER) is reserved for high or prohibitive surgical risk patients with appropriate anatomy on transesophageal imaging. CVC, comprehensive valve center; EF, ejection fraction; ERO, effective regurgitant orifice; ESD, end-systolic dimension; LV, left ventricular; MV, mitral valve; RF, regurgitant fraction; RVol, regurgitant volume; VC, vena contracta. (Reproduced with permission from CM Otto et al: ACC/AHA guideline for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2021; 143(5):e72.)

on the lateral view of the chest. Patients with acute severe MR may have asymmetric pulmonary edema if the regurgitant jet is directed predominantly to the orifice of an upper lobe pulmonary vein. TREATMENT (FIGS. 275-2 AND 275-3) Mitral Regurgitation MEDICAL TREATMENT The management of chronic severe MR depends to some degree on its cause. Anticoagulation with either warfarin or a direct oral agent (e.g., apixaban, rivaroxaban) should be provided if AF inter­ venes, as guided by the CHA2DS2-VASc risk score. The direct oral anticoagulants should not be used if moderate or severe rheumatic mitral stenosis is also present (Ch. 274); they are also not approved for use in patients with mechanical prosthetic heart valves. Cardio­ version should be considered depending on the clinical context, AF chronicity, and LA size. In contrast to the acute setting, there are no large, long-term prospective studies to substantiate the use of vasodilators for the treatment of chronic, isolated severe primary MR with preserved LV systolic function in the absence of systemic hypertension. However, the severity of secondary MR in the setting of an ischemic or dilated cardiomyopathy may dimin­ ish with aggressive guideline-directed medical therapy (GDMT) of heart failure including the use of diuretics for decongestion, beta blockers, angiotensin-converting enzyme (ACE) inhibitors/angio­ tensin receptor blockers, angiotensin-neprilysin inhibitors, min­ eralocorticoid receptor antagonists, sodium-glucose cotransporter Primary mitral regurgitation Severe MR (VC ≥0.7 cm, RVol ≥60 mL, RF ≥50%, ERO ≥0.40 cm2) No symptoms due to MR (Stage C) Normal LV systolic function (Stage C1) (LVEF >60% or ESD <40 mm) Expected surgical mortality <1% with

95% likelihood of successful and durable repair without residual MR Progressive increase in LV size or decrease in LVEF on at least 3 studies No Yes

2 inhibitors, and biventricular pacing (cardiac resynchronization therapy [CRT]) when indicated. Antibiotic prophylaxis for pre­ vention of IE is indicated for MR patients with a prior history of IE. Asymptomatic patients with severe MR in sinus rhythm with normal LV size and systolic function should avoid isometric forms of exercise. Patients with acute severe MR require urgent stabilization and preparation for surgery. Diuretics, intravenous vasodilators (par­ ticularly sodium nitroprusside), and even mechanical circulatory support may be needed for patients with post-MI papillary muscle rupture or other forms of acute severe MR. SURGICAL TREATMENT In the selection of patients with chronic, severe, primary MR for surgical treatment, the often slowly progressive nature of the condition must be balanced against the immediate and longterm risks associated with operation. These risks are signifi­ cantly lower for primary valve repair than for valve replacement

(Table 275-2). In a 2023 analysis of outcomes reported to the Soci­ ety of Thoracic Surgeons Adult Cardiac Surgical Database, investi­ gators reported a mean perioperative mortality risk of 1.16% (<0.5% for patients <65 years of age) for repair of primary MR. Repair usu­ ally consists of valve reconstruction using a variety of valvuloplasty techniques and insertion of an annuloplasty ring. Repair spares the patient the long-term adverse consequences of valve replacement, including thromboembolic and hemorrhagic complications in the case of mechanical prostheses and late valve failure necessitating repeat valve replacement in the case of bioprostheses. In addition, Secondary mitral regurgitation GDMT supervised by a HF specialist (1) Severe MR Stage D RVol ≥60 mL, RF ≥50%, ERO ≥0.40 cm2) LV EF <50% LV EF ≥50% Persistent symptoms on optimal GDMT and AF Rx Persistent symptoms on optimal GDMT Mitral anatomy favorable LV EF 20–50% LV ESD ≤70 mm PASP ≤70 mm Hg MV surgery (2b) MV surgery* (2a) Transcatheter edge-toedge MV repair (2a) FIGURE 275-3  Management of secondary mitral regurgitation. See legend for Fig. 272-4 for explanation of treatment recommendations (Class I, IIa, IIb) and disease stages (B, C1, C2, D). Preoperative coronary angiography should be performed routinely as determined by age, symptoms, and coronary risk factors. Cardiac catheterization and angiography may also be helpful when there is a discrepancy between clinical and noninvasive findings. Surgery is recommended for patients with left ventricular ejection fraction (LVEF) >50%. Transcatheter edge-to-edge repair (TEER) is reasonable in selected patients after guideline-directed management and therapy (GDMT) has been optimized. *MV replacement may be preferred over MV repair for ischemic MR; AF, atrial fibrillation; CABG, coronary artery bypass grafting; EF, ejection fraction; ERO, effective regurgitant orifice; ESD, end-systolic dimension; HF, heart failure; LV, left ventricular; MR, mitral regurgitation, MV, mitral valve; PASP, pulmonary artery systolic pressure; RF, regurgitant fraction; RVol, regurgitant volume; Rx, treatment. (Reproduced with permission from CM Otto et al: ACC/AHA guideline for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2021; 143(5):e72.)

TABLE 275-2  Mortality Rates After Mitral Valve Surgerya UNADJUSTED OPERATIVE MORTALITY (%) OPERATION NUMBER MVR (isolated) 10,699 4.5 CHAPTER 275 MVR + CAB

9.6 MVRp 12,424 1.2 MVRp + CAB

5.4 aData are for calendar year 2018 during which 1088 participant groups reported a total of 287,872 procedures. Surgical mitral valve commissurotomy cases are included in the mitral valve repair procedures. Abbreviations: CAB, coronary artery bypass; MVR, mitral valve replacement; MVRp, mitral valve repair. Source: Adapted from ME Bowdish et al: Ann Thorac Surg 109:1646, 2020. Mitral Regurgitation by preserving the integrity of the papillary muscles, subvalvular apparatus, and chordae tendineae, mitral repair and valvuloplasty maintain LV function to a relatively greater degree than does valve replacement. Surgery for chronic severe primary MR is indicated once symp­ toms occur, especially if valve repair is feasible (Fig. 275-2). Surgery should also be recommended for asymptomatic patients with LV dysfunction characterized by an EF ≤60% or an LV end-systolic dimension (LV ESD) ≥40 mm. Other indications for early con­ sideration of mitral valve repair in asymptomatic patients include a progressive decrease in LVEF or increase in LV ESD on serial imaging as well as mitral valve anatomy that would predict a >95% of a successful and durable repair in a low surgical risk patient. Undergoing CABG MV surgery (2b)

These aggressive recommendations for surgery are predicated on the adverse long-term consequences of waiting for LV function to decline further as well as the outstanding results achievable with mitral valve repair by reference surgeons at high-volume centers. Indeed, the majority of patients <75 years of age with degenerative MR, normal LV systolic function, and no coronary artery disease (CAD) can now undergo successful and durable repair of degenera­ tive MR (e.g., prolapse, flail) by an experienced surgeon at very low risk for perioperative death or major complication. Repair is feasible in up to 95% of patients with degenerative disease operated on by a high-volume surgeon in a referral center of excellence. Repair tech­ niques include chordal transfer, creation of neochords, limited leaflet resection, and insertion of an annuloplasty band. Long-term durabil­ ity is excellent; the incidence of reoperative surgery for failed primary repair is ~1% per year for the first 10 years after surgery. For patients with paroxysmal or persistent AF, left or biatrial maze surgery, or radiofrequency or cryoablative isolation of the pulmonary veins, along with left atrial appendage amputation, is performed to reduce the risk of recurrent postoperative AF and associated thrombus formation.

PART 6 Disorders of the Cardiovascular System The surgical management of patients with secondary MR is more complicated. Surgery for patients with ischemic MR most often involves simultaneous coronary artery revascularization. Current surgical practice includes either annuloplasty repair with an under­ sized, rigid ring or chord-sparing valve replacement for patients with moderate or greater degrees of MR. Valve repair for ischemic MR is associated with lower perioperative mortality rates than valve replacement but significantly higher rates of recurrent MR over time. Thus, replacement may be preferred over repair in this context. In patients with ischemic MR and significantly impaired LV systolic function (EF <30%), the risk of surgery is higher, recov­ ery of LV performance is incomplete, and long-term survival is reduced. Referral for surgery must be individualized and made only A B C D E F G4 NT G4 NTW G4 XT G4 XTW G4 NT AND NTW G4 XT AND XTW 4 mm 6 mm 4 mm 6 mm A PASCAL PASCAL Ace Retention elements Spacer Paddles Independent clasps B FIGURE 275-4  Clip devices used to grasp the free edges of the anterior and posterior leaflets in their midsections during transcatheter mitral valve repair of selected patients with mitral regurgitation. A. Fourth-generation of the first approved edge-to-edge repair device. B. System approved in 2022 includes a central spacer device and two paddles. The spacer is designed to reduce stress on the leaflets and preserve mitral valve area. (MitraClip is a trademark of Abbott or its related companies. PASCAL is an Edwards Lifesciences tradename.)

after aggressive attempts to improve symptoms with GDMT and CRT, when indicated. The routine performance of surgical valve repair in patients with significant secondary MR due to a dilated cardiomyopathy has not been shown to improve long-term survival compared with optimal GDMT, especially in the era of quadruple medical therapy for heart failure with reduced EF. Patients with acute severe MR can often be stabilized temporarily with appro­ priate medical therapy, but surgical correction will be necessary emergently in the case of papillary muscle rupture and within days in most other settings. When surgical treatment is contemplated, left and right heart catheterization and left ventriculography may be helpful in con­ firming the presence of severe MR in patients in whom there is a discrepancy between the clinical and TTE findings that cannot be resolved with TEE or CMR. Coronary angiography identifies patients who require concomitant coronary revascularization. TRANSCATHETER MITRAL VALVE REPAIR AND REPLACEMENT A transcatheter approach to the treatment of either primary or secondary MR may be feasible in selected patients with appropri­ ate mitral valve anatomy. One approach involves the deployment of a clip delivered via transseptal puncture that grasps the leading edges of the mitral leaflets in their mid-portion (anterior scallop to posterior scallop). The length and width of the gap between the leading edges of the leaflets, as well as other considerations such as leaflet thickening and calcification, dictate patient eligi­ bility. There are two commercially available transcatheter systems employing clip technology for the treatment of degenerative MR in symptomatic patients considered to be at high or prohibitive surgical risk (Fig. 275-4). Randomized trials of transcatheter 12 mm 9 mm 17 mm at 120° 22 mm at 120° Independent clasps

38 - 276 Mitral Valve Prolapse

276 Mitral Valve Prolapse

edge-to-edge repair (TEER) versus surgical repair are ongo­ ing to determine if the extension of clip technology to low- and intermediate-risk surgical patients with significant degenerative MR is appropriate. The TEER system is also approved for the treatment of heart failure patients with secondary MR. The results of transthoracic and transesophageal echocardiographic imaging are critical to patient selection, along with an assessment of the adequacy of GDMT for heart failure. The use of TEER with a clip device in addition to medical therapy was shown to be superior to medical therapy alone in a trial involving symptomatic heart failure patients with reduced EF and at least moderately severe secondary MR followed through 5 years. Patients treated with the clip device had significantly lower rates of heart failure hos­ pitalizations and all-cause mortality than those treated medically. This was the first randomized trial to show a survival benefit in patients with heart failure and secondary MR. There has been a rapid expansion over the past 5 years in both the number of sites offering mitral valve TEER and the number of cases reported to the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. Other transcatheter approaches to mitral valve repair have included the deployment of a device within the coronary sinus that can be adjusted to reduce mitral annular circumference and the effective orifice area of the valve much like a surgically implanted ring. Variations in the anatomic relationship of the coronary sinus to the mitral annulus and circumflex coronary artery have limited the applicability of this technique. Attempts to reduce the septal-lateral dimension of a dilated annulus using adjustable cords placed across the LV in a subvalvular location have been investigated. Construction of neochords to the mitral leaflets under TEE guidance using a system delivered via the cardiac apex has also been studied. Investigational experience with transcatheter mitral valve replacement systems remains in early clinical stages, although the field is evolving rapidly. Many high surgical risk patients are not candidates for transcatheter mitral valve repair, and thus, there is keen interest in refining this technology. Challenges with transseptal delivery and LV outflow tract obstruction from the devices used have prompted iterative changes in the systems utilized in early feasibility studies. ■ ■FURTHER READING Badhwar V et al: Risk of mitral valve repair for primary mitral regur­ gitation. J Am Coll Cardiol 81:636, 2023. Bonow RO et al: 2020 focused update of the 2017 expert consensus decision pathway on the management of mitral regurgitation. J Am Coll Cardiol 75:2236, 2020. Lim DS et al: Randomized comparison of transcatheter edge-to-edge repair for degenerative mitral regurgitation in prohibitive surgical risk patients. J Am Coll Cardiol Interv 15:2523, 2022. Otto CM et al: 2020 ACC/AHA guideline for the management of patients with valvular heart disease: A report of the American Col­ lege of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 143:e72, 2021. Stone GW et al: Five-year follow-up after transcatheter repair of sec­ ondary mitral regurgitation. N Engl J Med 388:2037, 2023. von Bardeleben RS et al: 1-year outcomes with fourth generation mitral valve transcatheter edge-to-edge repair from the EXPAND G4 study. J Am Coll Cardiol Interv 16:2600, 2023. Zahr F et al: 1-year outcomes following transfemoral transseptal transcatheter mitral valve replacement: Intrepid TMVR early feasibil­ ity study results. J Am Coll Cardiol Interv 16:2868, 2023.

Patrick T. O’Gara, Joseph Loscalzo

Mitral Valve Prolapse Mitral Valve Prolapse CHAPTER 276 The role of the physical examination in the evaluation of patients with valvular heart disease is also considered in Chaps. 44 and 246; of elec­ trocardiography (ECG) in Chap. 247; of echocardiography and other noninvasive imaging techniques in Chap. 241; and of cardiac catheter­ ization and angiography in Chap. 249. MITRAL VALVE PROLAPSE Mitral valve prolapse (MVP), also variously termed the systolic clickmurmur syndrome, Barlow’s syndrome (Fig. 276-1), floppy-valve syndrome, and billowing mitral leaflet syndrome, is a relatively common but highly variable clinical syndrome resulting from diverse pathologic mecha­ nisms affecting the mitral valve apparatus. Among these are excessive or redundant mitral leaflet tissue, which is commonly associated with myxomatous degeneration and greatly increased concentrations of certain glycosaminoglycans. MVP is the most common abnormality leading to primary mitral regurgitation (MR) and mitral valve repair surgery (see Chap. 275). In most patients with MVP, the cause is unknown, but in some, it appears to be genetically determined. A reduction in the production of type III collagen has been implicated, and electron microscopy has revealed fragmentation of collagen fibrils. A meta-analysis of six B A C FIGURE 276-1  Mitral valve prolapse. Myxomatous thickening and prolapse of the mitral valve can occur in isolation in 2–3% of the general population or may be associated with heritable connective tissue disorders, such as Marfan syndrome. Myxomatous degeneration of the valve predisposes to severe regurgitation and chordal rupture and is a frequent indication for mitral valve repair or replacement. Prolapse can affect one or both leaflets, to varying degrees. A. Three-dimensional transesophageal echocardiogram showing a myxomatous mitral valve from the left atrial en face aspect. There is billowing and prolapse of the entire middle scallop of the posterior leaflet (asterisk). (Figure courtesy of Douglas C. Shook, MD, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital.) B. The posterior leaflet of the mitral valve demonstrates marked prolapse and hooding in all segments and severe redundancy in this postmortem photograph taken from the vantage point of the left atrium. C. Opening the left heart reveals prominent mitral leaflet hooding (arrows). The chordae are focally thickened but are not fused as would be the case in rheumatic valve disease. (Used with permission from JC Wu, RF Padera: Clinicopathologic correlates, in Atlas of Echocardiography, 2nd ed, SD Solomon [ed], E Braunwald [series ed]. Philadelphia, Current Medicine Group LLC, 2008. p 363.)

PART 6 Disorders of the Cardiovascular System genome-wide association studies and 4884 MVP cases identified 14 genetic loci associated with MVP. Candidate genes included LMCD1, SPTBN1, LTBP2, TGFB2, NMB, and ALPK3. A polygenic risk score improved the performance of a clinical risk prediction model for the development of MVP, although overall performance was modest. Other work has identified genetic associations with LMNA, FLNC, and FLNA, which are often expressed as cardiomyopathies. MVP is a frequent finding in patients with heritable disorders of connective tissue, including Marfan syndrome (Chap. 425), osteogen­ esis imperfecta, and Ehlers-Danlos syndrome. MVP may be associated with thoracic skeletal deformities similar to but not as severe as those in Marfan syndrome, such as a high-arched palate and alterations of the chest and thoracic spine, including kyphosis and the so-called straight back syndrome. Other associated features can include a his­ tory of inguinal hernias, joint dislocations, meniscal tears, and easy bruisability. In most patients with MVP, myxomatous degeneration is confined to the mitral valve, although the tricuspid and aortic valves may also be affected. Prolapse can affect one or both leaflets. The posterior mitral leaflet is usually more affected than the anterior, and the mitral valve annulus is often dilated. In many patients, elongated, redundant, or ruptured chordae tendineae cause or contribute to the regurgitation. MVP also may occur rarely as a sequel to acute rheumatic fever, in ischemic heart disease, and in various cardiomyopathies (see above), as well as in 20% of patients with ostium secundum atrial septal defect. MVP may lead to excessive stress on the papillary muscles, leading to localized ischemia, infarction, and replacement fibrosis. The latter, which may be a nidus for ventricular arrhythmias, may be visible on cardiac magnetic resonance imaging as late gadolinium enhancement and occurs in the absence of coronary artery disease. Rupture of chordae tendineae and progressive annular dilation and calcification contribute to valvular regurgitation, which then places more stress on the diseased mitral valve apparatus, thereby creating a vicious cycle. ■ ■CLINICAL FEATURES MVP is more common in women than men and occurs most fre­ quently between the ages of 15 and 30 years; the clinical course is most often benign. MVP may also be observed in older (>50 years) patients, often men, in whom MR is often more severe because of chordal rupture and requires surgical treatment. There is an increased familial incidence for some patients, suggesting an autosomal dominant form of inheritance with incomplete penetrance. MVP varies in its clinical expression, ranging from only a systolic click and murmur with mild prolapse of the posterior leaflet to severe MR due to chordal rupture and leaflet flail. The degree of myxomatous change of the leaflets can also vary widely. In many patients, the condition progresses over years or decades; in others, it worsens rapidly as a result of chordal rupture or endocarditis. Most patients are asymptomatic and remain so for their entire lives. However, in North America, MVP is now the most com­ mon cause of isolated severe MR requiring surgical treatment. Arrhythmias, most commonly ventricular premature contractions and paroxysmal supraventricular and ventricular tachycardia, as well as atrial fibrillation (AF), have been reported and may cause palpitations, light-headedness, and syncope. Sudden death is a very rare complication and occurs most often in patients with severe MR and depressed left ventricle (LV) systolic function, although it can occur in individuals with normal LV size and function. A small subset of MVP patients with high-grade ventricular ectopy has been identified with phenotypic features including electrocardiographic inferior-apical T-wave abnormalities, high-density premature ven­ tricular complexes at rest, mitral annular disjunction (defined as abnormal atrial displacement of the mitral valve leaflet hinge point), and papillary muscle fibrosis on cardiac magnetic resonance imaging (see above). In addition, there may be an excess risk of sudden death among patients with a flail leaflet. Most of these patients have severe MR. Many patients with MVP have chest pain that can be difficult to evaluate; it is often substernal, prolonged, and not related to exertion, FIGURE 276-2  Barlow’s valve with classic mitral valve prolapse, as seen on transthoracic echocardiogram in parasternal long-axis windows. Left: parasternal long-axis window, showing both myxomatous leaflets (arrows) billowing into the left atrium in late systole. Right: same window with color Doppler showing significant mitral regurgitation (arrow) in systole. (Courtesy of Justina Wu, MD, PhD.) but may rarely resemble angina pectoris. Transient cerebral ischemic attacks secondary to emboli from the mitral valve due to endothelial disruption have been reported. Infective endocarditis may occur in patients with MR and/or leaflet thickening. Auscultation  A frequent finding is the mid- or late (nonejection) systolic click, which occurs 0.14 s or more after S1 and is thought to be generated by the sudden tensing of slack, elongated chordae ten­ dineae or by the prolapsing mitral leaflet when it reaches its maximal excursion. Systolic clicks may be multiple and may be followed by a high-pitched, mid-late systolic crescendo–decrescendo murmur, which occasionally is “whooping” or “honking” and is heard best at the apex. Radiation of the murmur will depend on the involved leaf­ let. With posterior leaflet prolapse, the jet of MR is directed anteriorly and the murmur will radiate to the base of the heart. With anterior leaflet involvement, the jet of MR is directed posteriorly and the mur­ mur will radiate to the axilla and back. The click and murmur occur earlier with standing, during the strain phase of the Valsalva maneu­ ver and with any intervention that decreases LV volume (preload), exaggerating the propensity of the leaflet to prolapse. Conversely, squatting and isometric exercises, which increase LV volume, dimin­ ish MVP; the click-murmur complex is delayed, moves away from S1, and may even disappear. Some patients have a mid-systolic click without a murmur; others have a murmur without a click. Still others have both sounds at different times. LABORATORY EXAMINATION The ECG most commonly is normal but may show biphasic or inverted T waves in leads II, III, and aVF and, occasionally, supra­ ventricular or ventricular premature beats. Transthoracic echocar­ diography (TTE) is particularly effective in identifying the abnormal position and prolapse of the mitral valve leaflets. A useful echocar­ diographic definition of MVP is systolic displacement (in the para­ sternal long axis view) of the belly of the mitral valve leaflets by at least 2 mm into the left atrium (LA) superior to the plane of the mitral annulus. There can be prolapse of one or both leaflets (Fig. 276-2). Color flow and continuous wave Doppler imaging is helpful to evaluate the associated MR and provide estimates of severity. The jet lesion of MR due to MVP is most often eccentric, and assessment of the effective regurgitant orifice area and regurgitant volume can be difficult with standard techniques. Both three-dimensional echocardiography and cardiac magnetic resonance imaging can provide more precise deter­ minations of LV volumes. Transesophageal echocardiography (TEE) is indicated when more accurate anatomic information is required and is performed routinely for intraoperative guidance during surgi­ cal or transcatheter valve repair. Exercise testing can be performed when there is uncertainty regarding functional capacity. It is often combined with rest and immediate poststress TTE to assess LV and right ventricular (RV) function and the dynamic nature of MR and pulmonary artery pressures. Left ventriculography done at the time

39 - 277 Tricuspid Valve Disease

277 Tricuspid Valve Disease

of right and left heart catheterization is rarely necessary but can also show prolapse of the posterior and sometimes of both mitral valve leaflets. TREATMENT Mitral Valve Prolapse Infective endocarditis prophylaxis is indicated for patients with a prior history of endocarditis. Beta blockers sometimes relieve chest pain and control palpitations. Decisions regarding anticoagulation for stroke prevention in AF should be based on the CHA2DS2-VASc score and an assessment of bleeding risk. If the patient is symptom­ atic from severe MR, mitral valve repair is indicated (see Fig. 275-2). Other indications for surgery for MVP with severe primary MR include findings of established or progressive LV systolic dysfunc­ tion. Surgery can also be considered for low-risk asymptomatic patients in whom a successful and durable repair can be achieved with at least 95% likelihood by an expert surgeon. Mitral valve repair is preferred over replacement in patients with MVP or flail mitral leaflet (see Table 275-2); technical success is dependent not only on the anatomic findings but also on the skill and experience of the surgeon. Repair of isolated posterior leaflet prolapse is usu­ ally straightforward, but increasingly more complex pathologies (e.g., anterior leaflet prolapse, bileaflet prolapse, Barlow’s defor­ mity) require advanced skills. Careful pre- and intraoperative TEE imaging is an important component of patient evaluation and surgical planning. Transcatheter edge-to-edge repair (TEER) using one of two commercially available systems to grasp the anterior and posterior leaflets together can be considered for treatment of symptomatic patients at prohibitive or high surgical risk with severe primary MR due to MVP (see Chap. 275 and Fig. 275-4). Most often, the MR will be reduced in severity but not eliminated. Nevertheless, symptom status and indices of LV size and function can be improved with this approach, which is now offered at >540 specialized sites in the United States. Reported hospital mortality rates following the procedure are <2%. Transcatheter replacement devices remain under active investigation but are not yet approved for use in the United States (see Chap. 275). ■ ■FURTHER READING Essayagh B et al: Arrhythmic mitral valve prolapse and mitral annular disjunction: Pathophysiology, risk stratification, and management. Eur Heart J 44:3121, 2023. Otto CM et al: 2020 ACC/AHA guideline for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 143:e72, 2021. Roselli C et al: Genome-wide association study identifies novel genetic loci: A new polygenic risk score for mitral valve prolapse. Eur Heart J 43:1668, 2022. Patrick T. O’Gara, Joseph Loscalzo

Tricuspid Valve Disease TRICUSPID STENOSIS Tricuspid stenosis (TS), which is much less prevalent than mitral steno­ sis (MS) in North America and Western Europe, is generally rheumatic in origin and is more common in women than men (Table 277-1). It does not occur as an isolated lesion and is usually associated with MS.

TABLE 277-1  Causes of Tricuspid Valve Diseases VALVE LESION ETIOLOGIES Tricuspid stenosis Rheumatic Congenital CHAPTER 277 Tricuspid regurgitation Primary (organic, leaflet, or chordal related) Rheumatic Endocarditis Myxomatous (TVP) Carcinoid Radiation Congenital (Ebstein’s) Trauma (including that due to RV endomyocardial biopsy) Secondary (functional, atrial, and/or ventricular) RV and/or tricuspid annular dilation due to multiple causes (e.g., long-standing pulmonary HTN, remodeling post-RV MI, left-sided heart disease, cardiomyopathy, AF (atrial functional tricuspid regurgitation) CIED related Leaflet impingement, adherence, laceration, perforation, avulsion; chordal entrapment Tricuspid Valve Disease Abbreviations: AF, atrial fibrillation; CIED, cardiac implanted electronic device; HTN, hypertension; MI, myocardial infarction; RV, right ventricular; TVP, tricuspid valve prolapse. Hemodynamically significant TS occurs in 5–10% of patients with severe MS; rheumatic TS is commonly associated with some degree of tricuspid regurgitation (TR). Nonrheumatic causes of TS are rare. ■ ■PATHOPHYSIOLOGY A diastolic pressure gradient between the right atrium (RA) and right ventricle (RV) defines TS. It is augmented when the transvalvular blood flow increases during inspiration and declines during expiration. A mean diastolic pressure gradient of 4 mmHg is usually sufficient to elevate the mean RA pressure to levels that result in systemic venous congestion. Unless sodium intake has been restricted and diuretics administered, this venous congestion is associated with hepatomegaly, ascites, and edema, sometimes severe. In patients with sinus rhythm, the RA a wave may be extremely tall and may even approach the level of the RV systolic pressure. The y descent is prolonged. The cardiac output (CO) at rest is usually depressed, and it fails to rise during exercise. The low CO is responsible for the normal or only slightly elevated left atrial (LA), pulmonary artery (PA), and RV systolic pres­ sures despite the presence of MS. Thus, the presence of TS can mask the hemodynamic and clinical features of any associated MS. ■ ■SYMPTOMS Because the development of MS generally precedes that of TS, many patients initially have symptoms of pulmonary congestion and fatigue. Characteristically, patients with severe TS complain of relatively little dyspnea for the degree of hepatomegaly, ascites, and edema that they have. However, fatigue secondary to a low CO and discomfort due to signs of right-sided congestion such as hepatomegaly and ascites are common in patients with advanced TS and/or TR. In some patients, TS may be suspected for the first time when symptoms of right-sided failure persist after an adequate mitral commissurotomy. ■ ■PHYSICAL FINDINGS Because TS usually occurs in the presence of other obvious valvular disease, the diagnosis may be missed unless it is considered. Severe TS is associated with marked hepatic congestion, often resulting in cirrhosis, jaundice, serious malnutrition, anasarca, and ascites. Con­ gestive hepatomegaly and, in cases of severe tricuspid valve disease, splenomegaly are present. The jugular veins are distended, and in patients with sinus rhythm, there may be giant a waves. The v waves are less conspicuous, and because tricuspid obstruction impedes RA emptying during diastole, there is a slow y descent. In patients with sinus rhythm, there may be prominent presystolic pulsations of the enlarged liver as well.

PART 6 Disorders of the Cardiovascular System On auscultation, an opening snap (OS) of the tricuspid valve may rarely be heard ~0.06 s after pulmonic valve closure. The diastolic murmur of TS has many of the qualities of the diastolic murmur of MS, and because TS almost always occurs in the presence of MS, it may be missed. However, the tricuspid murmur is generally heard best along the left lower sternal border and over the xiphoid pro­ cess and is most prominent during presystole in patients with sinus rhythm. The murmur of TS is augmented during inspiration, and it is reduced during expiration and particularly during the strain phase of the Valsalva maneuver, when tricuspid transvalvular flow is reduced. ■ ■LABORATORY EXAMINATION The electrocardiogram (ECG) features of RA enlargement (see Fig. 247-8) include tall, peaked P waves in lead II, as well as promi­ nent, upright P waves in lead V1. The absence of ECG evidence of RV hypertrophy (RVH) in a patient with right-sided heart failure who is believed to have MS should suggest associated tricuspid valve disease. The chest x-ray in patients with combined TS and MS shows par­ ticular prominence of the RA and superior vena cava without much enlargement of the PA and with less evidence of pulmonary vascular congestion than occurs in patients with isolated MS; engorgement of the azygos vein can often be appreciated. On transthoracic echo­ cardiographic (TTE) examination, the tricuspid valve is usually thickened and domes in diastole; the transvalvular gradient can be estimated by continuous wave Doppler echocardiography. Severe TS is characterized by a valve area ≤1 cm2 or pressure half-time of ≥190 ms. The RA and inferior vena cava (IVC) are enlarged. TTE provides additional information regarding the severity of any associated TR, mitral valve structure and function, left ventricular (LV) and RV size and function, and PA pressure. Cardiac catheterization is not rou­ tinely necessary for assessment of TS. TREATMENT Tricuspid Stenosis Patients with TS generally exhibit marked systemic venous conges­ tion; salt restriction, bed rest, and diuretic therapy are required during the preoperative period. Such a preparatory period may diminish hepatic congestion and thereby improve hepatic function sufficiently so that the risks of operation, particularly bleeding, are diminished. Surgical relief of the TS should be carried out, preferably at the time of surgical mitral commissurotomy or mitral valve replacement (MVR) for mitral valve disease, in patients with moderate or severe TS who have mean diastolic pressure gradients exceeding ~4 mmHg and tricuspid orifice areas <1.5–2 cm2. TS is almost always accompanied by significant TR. Operative repair may permit substantial improvement of tricuspid valve function. If repair cannot be accomplished, the tricuspid valve may have to be replaced. Meta-analysis has shown no difference in overall survival between mechanical and tissue valve replacement. Mechanical valves in the tricuspid position are more prone to thromboembolic complications than in other positions. Percutaneous tricuspid bal­ loon commissurotomy for isolated severe TS without significant TR is very rarely performed. TRICUSPID REGURGITATION More than 85% of TR cases encountered in clinical practice are second­ ary (functional) in nature and related to tricuspid annular dilation and leaflet tethering in the setting of RV remodeling caused by pressure or volume overload (or both), myocardial infarction (MI), or trauma (Table 277-1). Secondary TR is commonly seen in the late stages of heart failure due to rheumatic or congenital heart disease with severe PA hypertension (PA systolic pressure >55 mmHg), as well as in other types of left-sided valvular (e.g., mitral regurgitation) or myocardial diseases (e.g., ischemic and idiopathic dilated cardiomyopathies). TR can often emerge in the setting of new-onset atrial fibrillation (AF), particularly in older patients (atrial functional TR). Rheumatic fever may produce primary TR, often associated with TS. Tricuspid valve prolapse, carcinoid heart disease, endomyocardial fibrosis, radiation, infective endocarditis, and leaflet trauma can also produce primary TR. Less commonly, primary TR results from congenitally deformed tricuspid valves and can occur with defects of the atrioventricular canal, as well as with Ebstein’s malformation of the tricuspid valve (Chap. 280). A third category of TR is that associated with cardiac implantable electronic device (CIED) leads from pacemakers or defi­ brillators. When placed across the tricuspid valve, the leads can result A B FIGURE 277-1  Tricuspid regurgitation. A. Transthoracic apical two-chamber view showing right atrium on bottom and right ventricle on top. There is a pacemaker lead (white arrows) traversing the tricuspid valve. The plane of tricuspid valve closure is shown by the dotted yellow line. B. Corresponding color flow Doppler image in systole shows a broad jet of severe tricuspid regurgitation (between the yellow arrows) refluxing into the right atrium. RA, right atrium; RV right ventricle.

Severe TR (Stages C and D) At time of leftsided valve surgery At time of leftsided valve surgery Right heart failure Stage D Prior left-sided valve surgery Secondary TR Primary TR Poorly responsive to GDMT Annular dilation without ↑PAP or leftsided disease TV surgery (2a) TV surgery (2a) TV surgery (2a) TV surgery (1) FIGURE 277-2  Management of tricuspid regurgitation. See legend for Fig. 272-4 for explanation of treatment recommendations (Class I, IIa, IIb) and disease stages (B, C, D). Preoperative coronary angiography should be performed routinely as determined by age, symptoms, and coronary risk factors. Cardiac catheterization and angiography may also be helpful when there is a discrepancy between clinical and noninvasive findings. GDMT, guideline-directed management and therapy; HF, heart failure; PAP, pulmonary artery pressure; PH, pulmonary hypertension; RV, right ventricular; TR, tricuspid regurgitation; TV, tricuspid valve. Annular dilation is defined by >40 mm on transthoracic echocardiography (>21 mm/m2) or >70 mm on direct intraoperative measurement. (Reproduced with permission from CM Otto et al: 2020 AHA/ACC Guideline for management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 143:e72, 2021.) in leaflet entrapment or perforation. In addition, pacing from the right ventricular apex can result in dyssynchronous ventricular contraction and functional TR. ■ ■PATHOPHYSIOLOGY The incompetent tricuspid valve allows blood to flow backward from the RV into the RA, the volume of which is dependent on the driv­ ing pressure (i.e., RV systolic pressure) and the size of the regurgitant orifice. The severity and physical signs of TR can vary as a function of PA systolic pressure (in the absence of RV outflow tract stenosis), the dimensions of the tricuspid valve annulus, the respiratory cycledependent changes in RV preload, and RA compliance. RV filling is increased during inspiration. With TR, forward CO is reduced and does not augment with exercise. Significant degrees of TR will lead to RA enlargement and elevation of the RA and jugular venous pressures with prominent c-v waves in the pulse tracings. Progressively severe TR can lead to “ventricularization” of the RA wave form (see Fig. 246-1B). Severe TR is also characterized by RV dilation (RV volume overload) and eventual systolic dysfunction, the progression of which can be accelerated by a concomitant pressure load from PA hypertension or by myocardial fibrosis from previous injury. ■ ■SYMPTOMS Mild or moderate degrees of TR are usually well tolerated in the absence of other hemodynamic disturbances. Because TR often coexists with left-sided valve lesions, LV dysfunction, and/or PA

Tricuspid regurgitation CHAPTER 277 Progressive TR (Stage B) Tricuspid Valve Disease Asymptomatic Stage C Primary TR with progressive RV dilation or systolic dysfunction Annular dilation

4.0 cm or prior right HF Absences of severe PH or RV systolic dysfunction TV surgery (2b) TV surgery (2b) hypertension, symptoms related to these lesions may dominate the clinical picture. Atrial functional TR due to atrial fibrillation is usually accompanied by palpitations. Fatigue and exertional dyspnea owing to reduced forward CO are early symptoms of isolated, severe TR. As the disease progresses and RV function declines, patients may report cervical pulsations, abdominal fullness/bloating, diminished appetite, and muscle wasting, although with progressive weight gain and painful swelling of the lower extremities. ■ ■PHYSICAL FINDINGS The neck veins in patients with severe TR are distended with promi­ nent c-v waves and rapid y descents (in the absence of TS). TR is more often diagnosed by examination of the neck veins than by auscultation of the heart sounds. Other findings may include marked hepatomegaly with systolic pulsations, ascites, pleural effusions, edema, and a posi­ tive hepatojugular reflux sign. A prominent RV pulsation in the left parasternal region and a blowing holosystolic murmur along the lower left sternal margin, which may be intensified during inspiration (Carvallo’s sign) and reduced during expiration or the strain phase of the Valsalva maneuver, are characteristic findings. The murmur of TR may sometimes be confused with that of mitral regurgitation (MR) unless attention is paid to its variation during the respiratory cycle and the extent of RV enlargement is appreciated. AF may be the driver of TR or may emerge later in the disease with ventricular and atrial remodeling.

PART 6 Disorders of the Cardiovascular System A B FIGURE 277-3  Transcatheter tricuspid valve (TV) repair and replacement. A. Shown is a clip device that can be used to grasp the leading edges of the TV leaflets to reduce the severity of tricuspid regurgitation (TR) by decreasing the effective orifice area of the valve. (TriClip is a trademark of Abbott or its related companies.) B. Bioprosthetic heart valve replacement approved for percutaneous treatment of severe TR is selected for high or prohibitive surgical risk patients. (EVOQUE is a trademark of Edwards Lifesciences.) ■ ■LABORATORY EXAMINATION The ECG may show changes characteristic of the lesion responsible for the TR, e.g., an inferior Q-wave MI suggestive of a prior RV MI, RVH, or a bizarre right bundle branch block–type pattern with preexcita­ tion in patients with Ebstein’s anomaly. ECG signs of RA enlargement may be present in patients with sinus rhythm; AF is frequently noted. The chest x-ray may show RA and RV enlargement, depending on the chronicity and severity of TR. TTE is usually definitive with demon­ stration of RA dilation and RV volume overload and prolapsing, flail, scarred, or displaced/tethered tricuspid leaflets with annular dilata­ tion; the diagnosis and assessment of TR can be made by color flow Doppler imaging (see Figs. 248-8 and 277-1). Severe TR is accompa­ nied by hepatic vein systolic flow reversal. Continuous wave Doppler of the TR velocity profile is useful in estimating PA systolic pressure, except when the TR is very severe and the jet velocity is blunted by rapidly increasing RA pressure. Accurate assessment of TR severity, PA pressures, and RV size and systolic function with TTE can be quite challenging in many patients. Real-time three-dimensional echocardiography and cardiac magnetic resonance (CMR) imaging provide alternative imaging modalities to aid in the assessment of TR severity, although they are not widely available. In patients with severe TR, the CO is usually markedly reduced, and the RA pressure pulse may not exhibit an x descent during early systole but rather show a prominent c-v wave with a rapid y descent. The mean RA and RV end-diastolic pressures are often elevated. Exercise testing can be used to assess functional capacity in patients with asymp­ tomatic severe TR. The prognostic significance of exercise-induced changes in TR severity and RV function has not been well studied.

(See Fig. 277-1.) TREATMENT Tricuspid Regurgitation (Fig. 277-2) Diuretics can be useful for patients with severe TR and signs of right heart failure. An aldosterone antagonist may be particularly helpful because many patients have secondary hyperaldosteronism from marked hepatic congestion. Therapies to reduce elevated PA pressures and/or pulmonary vascular resistance, including those targeted at left-sided heart disease, can also be considered for patients with PA hypertension and severe secondary TR. Tricuspid valve surgery is recommended for patients with severe TR who are undergoing left-sided valve surgery and is also undertaken fre­ quently for treatment of even moderate TR in patients undergoing left-sided valve surgery especially those with tricuspid annular dila­ tion (>40 mm), a history of right heart failure, or PA hypertension.

Operation most often comprises repair rather than replacement in these settings and has become more routine in many surgical cen­ ters. In a randomized trial of tricuspid valve annuloplasty surgery at the time of mitral valve surgery for degenerative MR in patients with moderate TR or mild TR with annular dilation, there was a significant reduction in the 2-year incidence of a composite end­ point of reoperation, progression of TR, or all-cause death among those who underwent tricuspid surgery versus those who had mitral valve surgery alone. The composite endpoint was driven by a reduction in the progression of TR. Surgery may also infrequently be required for treatment of severe, primary TR with right heart failure not responsive to standard medical therapy or because of progressively declining RV systolic function. Reported periopera­ tive mortality rates for isolated tricuspid valve surgery (repair and replacement) are high (~8–9%) and likely are influenced by the hazards encountered during reoperation on patients who have undergone previous left-sided valve surgery and have reduced RV function. There have been several recent advances in the application of transcatheter tricuspid valve repair and replacement tech­ niques in patients with severe TR and high or prohibitive sur­ gical risk. In a randomized trial of percutaneous transcatheter edge-to-edge repair versus medical therapy, clip repair resulted in a significant reduction in TR severity and improvement in quality-of-life scores, but no differences in all-cause mortal­ ity or hospitalization for heart failure over 1-year follow-up. The U.S. Food and Drug Administration approved the use of a transcatheter tricuspid valve replacement system in early 2024 based on favorable hemodynamic, echocardiographic, clinical, and quality-of-life results from prospective single-arm studies.

(See Figure 277-3.) ■ ■FURTHER READING Hahn RT et al: Tricuspid regurgitation management for heart failure. J Am Coll Cardiol HF 11:1084, 2023. Kadri AN et al: Outcomes of patients with severe tricuspid regurgita­ tion and congestive heart failure. Heart 105:1813, 2019. Kodali S et al: Transfemoral tricuspid valve replacement and one-year outcomes: The TRISCEND study. Eur Heart J 44:4862, 2023. Otto CM et al: 2020 ACC/AHA guideline for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 143:e72, 2021. Sorajja P et al: Transcatheter repair for patients with tricuspid regur­ gitation. N Engl J Med 388:1833, 2023.

40 - 278 Pulmonic Valve Disease

278 Pulmonic Valve Disease

Patrick T. O’Gara, Joseph Loscalzo

Pulmonic Valve Disease PULMONIC STENOSIS Pulmonic valve stenosis (PS) is essentially a congenital disorder (Table 278-1). With isolated PS, the valve is typically domed. Dys­ plastic pulmonic valves are seen as part of the Noonan syndrome (Chap. 292), which maps to chromosome 12. Mutations in the PTPN1 gene are associated with about half of all cases of Noonan syndrome. Much less common etiologies include carcinoid and obstructing tumors or bulky vegetations. The pulmonic valve is only very rarely affected by the rheumatic process. ■ ■PATHOPHYSIOLOGY PS is defined hemodynamically by a systolic pressure gradient between the right ventricle (RV) and the main pulmonary artery (PA). RV hypertrophy (RVH) develops as a consequence of sustained obstruc­ tion to RV outflow, and systolic ejection is prolonged. Compared with the ability of the LV to compensate for the pressure overload imposed by aortic stenosis (AS), RV dysfunction from afterload mismatch occurs earlier in the course of PS and at lower peak systolic pressures, because the RV adapts less well to this type of hemodynamic burden. With nor­ mal systolic function and cardiac output (CO), severe PS is defined by a peak systolic gradient across the pulmonic valve of >64 mmHg (mean gradient >35 mmHg, Doppler jet velocity >4 m/s); moderate PS corre­ lates with a peak gradient of 36–64 mmHg (Doppler jet velocity 3–4 m/s). Mild PS is characterized by a jet velocity <3 m/s (peak gradient <36 mmHg). PS rarely progresses in patients with mild PS but may worsen with age in those with moderate disease due to valve thickening and calcification. The right atrial (RA) a wave elevates in relation to the higher pressures needed to fill a noncompliant, hypertrophied RV. A prominent RA v wave signifies functional tricuspid regurgitation (TR) from RV and annular dilation. The CO is maintained until late in the course of the disease. ■ ■SYMPTOMS Patients with mild or even moderate PS are usually asymptomatic and first come to medical attention because of a heart murmur (or early systolic click) that leads to echocardiography. With severe PS, patients may report exertional dyspnea or early-onset fatigue. Anginal chest pain from RV oxygen supply-demand mismatch and syncope may occur with very severe forms of obstruction, particularly in the pres­ ence of a destabilizing trigger such as atrial fibrillation, fever, infection, anemia, or pregnancy. ■ ■PHYSICAL FINDINGS The murmur of mild or moderate PS is mid-systolic in timing, cre­ scendo–decrescendo in configuration, heard best in the left second interspace, and usually introduced by an ejection sound (click) in younger adults whose valves are still pliable. The ejection sound is the only right-sided acoustic event that decreases in intensity with inspiration. This phenomenon reflects premature opening of the pulmonic valve by the elevated RV end-diastolic (post-atrial a wave) pressure. The systolic murmur increases in intensity during inspira­ tion. With progressively severe PS, the ejection sound moves closer to the first heart sound and eventually becomes inaudible. A right-sided fourth heart sound may emerge. The systolic murmur peaks later and may persist through the aortic component of the second heart sound (A2). Pulmonic valve closure is delayed, and the pulmonic component of the second heart sound (P2) is reduced or absent. A prominent a wave, indicative of the higher atrial pressure necessary to fill the noncompliant RV, may be seen in the jugular venous pulse. A parasternal or RV lift can be felt with significant pressure overload. Signs of right heart failure due to RV systolic dysfunction, such as

TABLE 278-1  Causes of Pulmonic Valve Disease VALVE LESION ETIOLOGIES Pulmonic stenosis Congenital Carcinoid Tumor Endocarditis CHAPTER 278 Pulmonic regurgitation Primary valve disease   Congenital   Post-valvotomy   Endocarditis   Carcinoid Annular enlargement   Pulmonary hypertension   Idiopathic dilation   Marfan syndrome Pulmonic Valve Disease hepatomegaly, ascites, and edema, are uncommon but may appear very late in the disease. ■ ■LABORATORY EXAMINATION The electrocardiogram (ECG) will show right axis deviation, RVH, and RA enlargement in adult patients with severe PS. Chest x-ray find­ ings include poststenotic dilation of the main PA in the frontal plane projection and filling of the retrosternal airspace due to RV enlarge­ ment on the lateral film. In some patients with RVH, the cardiac apex appears to be lifted off the left hemidiaphragm. The RA may also be enlarged. Transthoracic echocardiography (TTE) allows definitive diagnosis and characterization in most cases, with depiction of the valve and assessment of the jet velocity, gradient, RV function, PA pressures (which should be low), and any associated cardiac lesions. Transesophageal echocardiography (TEE) may be useful in some patients for improved delineation of the RV outflow tract (RVOT) and assessment of infundibular hypertrophy. Cardiac catheterization is not usually necessary for diagnostic purposes, but if performed, pressures should be obtained from just below and above the pulmonic valve with attention to the possibility that a dynamic component to the gradient may exist. The correlation between Doppler assessment of peak instantaneous gradient and catheterization-measured peak-topeak gradient is weak. The latter may correlate better with the Doppler mean gradient. TREATMENT Pulmonic Stenosis Diuretics can be used to treat symptoms and signs of right heart failure. Provided there is less than moderate pulmonic regurgita­ tion (PR), percutaneous pulmonic balloon valvuloplasty is recom­ mended for symptomatic patients with moderate or severe PS and for asymptomatic patients with a peak gradient >64 mmHg (or mean gradient >35 mmHg). Surgery may be required when the valve is dysplastic (as seen in patients with Noonan’s syndrome and other disorders). A multidisciplinary heart team is best positioned to make treatment decisions of this nature. PULMONIC REGURGITATION PR may develop as a consequence of primary valve pathology, annu­ lar enlargement, or their combination; after surgical treatment of RVOT obstruction in children with such disorders as tetralogy of Fal­ lot; or after percutaneous pulmonic balloon valvotomy (Table 278-1). Carcinoid usually causes mixed pulmonic valve disease with PR and PS. Long-standing severe PA hypertension from any cause can result in dilation of the pulmonic valve ring and PR. Trace or mild PR of no hemodynamic or clinical consequence is frequently observed on TTE in the absence of structural pulmonic valve disease (Fig. 278-1).

PART 6 Disorders of the Cardiovascular System A B FIGURE 278-1  Pulmonic regurgitation. A. Transthoracic short axis window at the level of the aortic valve (AoV). The pulmonic valve (PV) is shown with the yellow arrow. Tricuspid valve (TV) leaflets are partially visualized (white arrows). B. Color flow Doppler image shows moderate pulmonic regurgitation (PR, white arrow). ■ ■PATHOPHYSIOLOGY Severe PR results in RV chamber enlargement and eccentric hyper­ trophy. As is the case for aortic regurgitation (AR), PR is a state of increased preload and afterload. The diastolic pressure gradient between the PA to the RV, which drives the PR, progressively decreases throughout diastole and accounts for the decrescendo nature of the murmur. As RV diastolic pressure increases, the murmur becomes shorter in duration. The forward CO is preserved during the early stages of the disease but may not increase normally with exercise and declines over time. A reduction in RV ejection fraction may be an early indicator of hemodynamic compromise. In advanced stages, there is significant enlargement of the RV and RA with marked elevation of the jugular venous pressure. ■ ■SYMPTOMS Mild or moderate degrees of PR do not, by themselves, result in symp­ toms. Other issues, such as PA hypertension, may dominate the clini­ cal picture. With progressively severe PR and RV dysfunction, fatigue, exertional dyspnea, abdominal fullness/bloating, and lower extremity swelling may be reported. ■ ■PHYSICAL FINDINGS The physical examination hallmark of PR is a high-pitched, decre­ scendo diastolic murmur (Graham Steell murmur) heard along the left sternal border that can be difficult to distinguish from the more frequently appreciated murmur of AR. The Graham Steell murmur may become louder with inspiration and is usually associated with a loud and sometimes palpable P2 and an RV lift, as would be expected in patients with significant PA hypertension of any cause. Survivors of childhood surgery for tetralogy of Fallot or PS/pulmonary atresia may have an RV-PA conduit that is freely regurgitant because it does not contain a valve. PA pressures in these individuals are not elevated, and the diastolic murmur can be misleadingly low pitched and of short duration despite significant degrees of PR and RV volume overload. ■ ■LABORATORY EXAMINATION Depending on both the etiology and severity of PR, the ECG may show findings of RVH and RA enlargement. On chest x-ray, the RV and RA

may be enlarged. Pulmonic valve morphology and function can be assessed with transthoracic Doppler echocardiography. RV systolic pressure can be estimated from the tricuspid valve systolic jet veloc­ ity. Cardiac magnetic resonance (CMR) imaging can provide greater anatomic detail, particularly in patients with repaired congenital heart disease, and more precise assessment of RV volumes and function. Car­ diac catheterization is not routinely necessary but would be performed as part of a planned transcatheter PV procedure. TREATMENT Pulmonic Regurgitation In patients with significant functional PR due to PA hyperten­ sion and annular dilation, efforts to reduce pulmonary vascu­ lar resistance and pressure should be pursued. Such efforts may include pharmacologic/vasodilator and/or surgical/interventional strategies, depending on the cause of the PA hypertension (e.g., idiopathic PA hypertension, left-sided heart valve disease). Diuret­ ics can be used to treat the manifestations of right heart failure. Surgical valve replacement for primary, severe, pulmonic valve disease, such as carcinoid or endocarditis, is rarely undertaken. Transcatheter pulmonic valve replacement has been successfully performed in many patients with severe PR after childhood repair of tetralogy of Fallot or pulmonic valve stenosis or atresia. This procedure was introduced clinically prior to transcatheter aortic valve replacement. Earlier concerns regarding an excess hazard of infective endocarditis with first-generation valves have led to pro­ cedural modifications. ■ ■FURTHER READING Otto CM et al: 2020 AHA/ACC guideline for the management of patients with valvular heart disease. A report of the American Col­ lege of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 143:e72, 2021. Stout KK et al: 2018 ACC/AHA guidelines for the management of adults with congenital heart disease. J Am Coll Cardiol 73:e81, 2019.

41 - 279 Multiple and Mixed Valvular Heart Disease

279 Multiple and Mixed Valvular Heart Disease

Patrick T. O’Gara, Joseph Loscalzo

Multiple and Mixed

Valvular Heart Disease Many acquired and congenital cardiac lesions may result in stenosis and/or regurgitation of one or more heart valves. For example, rheu­ matic heart disease can involve the mitral (mitral stenosis [MS], mitral regurgitation [MR], or MS and MR), aortic (aortic stenosis [AS], aortic regurgitation [AR], or AS and AR), and tricuspid (tricuspid stenosis [TS], tricuspid regurgitation [TR], or TS and TR) valve, alone or in combination. The common association of functional TR with sig­ nificant mitral valve disease is discussed in Chap. 277. Severe mitral annular calcification can result in regurgitation (due to decreased annular shortening during systole) and mild or moderate stenosis (caused by extension of the calcification onto the leaflets resulting in restricted valve opening). Patients with severe AS and left ventricular (LV) remodeling may develop functional MR that may not improve after isolated aortic valve replacement (AVR). Primary MR due to mitral valve prolapse or chordal rupture has been noted in patients with severe AS. Aortic valve infective endocarditis (IE) may second­ arily involve the mitral apparatus either by abscess formation and contiguous spread via the intervalvular fibrosa or by “drop metastases” from the aortic leaflets onto the anterior leaflet of the mitral valve. Mediastinal radiation may result in aortic, mitral, and even tricus­ pid valve disease, most often with mixed stenosis and regurgitation. Carcinoid heart disease may cause mixed lesions of either or both the tricuspid and pulmonic valves. Ergotamines, and the previously used combination of fenfluramine and phentermine, can rarely result in mixed lesions of the aortic and/or mitral valve. Patients with Marfan syndrome may have both AR from aortic root dilation and MR due to mitral valve prolapse (MVP). Myxomatous degeneration causing pro­ lapse of multiple valves (mitral, aortic, tricuspid) can also occur in the absence of an identifiable connective tissue disorder. Bicuspid aortic or pulmonic valve disease can result in mixed stenosis and regurgita­ tion. The former is also associated with aortic aneurysm disease and a predisposition to aortic dissection. ■ ■PATHOPHYSIOLOGY In patients with multivalvular heart disease, the pathophysiologic derangements associated with the more proximal valve disease can mask the full expression of the attributes of the more distal valve lesion. For example, in patients with rheumatic mitral and aortic valve disease, the reduction in cardiac output (CO) imposed by the mitral valve dis­ ease will decrease the magnitude of the hemodynamic derangements related to the severity of the aortic valve lesion (stenotic, regurgitant, or both). Alternatively, the development of atrial fibrillation (AF) dur­ ing the course of MS can lead to sudden worsening in a patient whose aortic valve disease was not previously felt to be significant. The devel­ opment of reactive pulmonary vascular disease, sometimes referred to as a “secondary obstructive lesion in series,” can impose an additional challenge in these settings. As CO falls with progressive tricuspid valve disease, the severity of any associated mitral or aortic disease can be underestimated. One of the most common examples of multivalve disease is that of functional TR in the setting of significant mitral valve disease. Func­ tional TR occurs as a consequence of right ventricular and annular dilation; pulmonary artery (PA) hypertension may be present. The tricuspid leaflets are morphologically normal. Progressive degrees of TR lead to right ventricular volume overload and continued chamber and annular dilation. The TR is usually central in origin; reflux into the right atrium (RA) is expressed as large, systolic c-v waves in the RA pressure pulse. The height of the c-v wave is dependent on RA compliance and the volume of regurgitant flow. The RA waveform may become “ventricularized” in advanced stages of chronic, severe TR. CO falls and the severity of the associated mitral valve disease may become

more difficult to appreciate. Findings related to advanced right heart failure (e.g., ascites, edema) predominate. Primary rheumatic tricus­ pid valve disease may occur with rheumatic mitral disease and cause hemodynamic changes reflective of TR, TS, or their combination. With TS, the y descent in the RA pressure pulse is prolonged. Typically, however, findings related to the mitral valve disease predominate over those related to the tricuspid valve disease.

CHAPTER 279 Another example of rheumatic, multivalve disease involves the com­ bination of mitral and aortic valve pathology, frequently characterized by MS and AR. In isolated MS, LV preload and diastolic pressure are reduced as a function of the severity of inflow obstruction. With con­ comitant AR, however, LV filling is enhanced and diastolic pressure may rise depending on the compliance characteristics of the chamber. Because the CO falls with progressive degrees of MS, transaortic valve flows will decline, masking the potential severity of the aortic valve lesion (AR, AS, or its combination). As noted above, onset of AF in such patients can be especially deleterious. The loss of atrial systole with AF may result in a critical reduction in CO, a rise in left atrial (LA) and LV diastolic pressures, and a further deleterious increase in heart rate. Multiple and Mixed Valvular Heart Disease Secondary (functional) MR may complicate the course of some patients with severe AS. The mitral valve leaflets and chordae tendineae are usually normal. Incompetence is related to changes in LV geometry (remodeling) and abnormal systolic tethering of the leaflets in the context of markedly elevated LV systolic pressures. Relief of the excess afterload with surgical or transcatheter AVR may result in reduction of the secondary MR. Persistence of significant, secondary MR following AVR is associated with impaired functional outcomes and reduced sur­ vival. Identification of patients who would benefit from concomitant treatment of their secondary MR at time of AVR is quite challenging. Most surgeons perform mitral valve repair of moderate-to-severe or severe secondary MR at time of surgical AVR. Significant primary MR may also coexist with AS and is routinely managed with repair (or replacement) at the time of AVR. There is increasing experience with the combination of transcatheter aortic valve implantation (TAVI) and transcatheter edge-to-edge mitral valve repair (TEER) in high surgical risk patients with severe AS and moderate-severe primary or secondary MR. Decision-making regarding the need for mitral valve intervention can be challenging. In patients with mixed AS and AR, assessment of valve stenosis can be influenced by the magnitude of the regurgitant valve flow. Because transvalvular systolic flow velocities are augmented in patients with AR and preserved LV systolic function, the LV-aortic Dopplerderived pressure gradient and the intensity of the systolic murmur will be elevated to values higher than expected for the true systolic valve orifice size as measured by planimetry. Uncorrected, the Gorlin formula, which relies on forward CO (systolic transvalvular flow) and the mean pressure gradient for calculation of valve area, is not accurate in the setting of mixed aortic valve disease. Similar considerations apply to patients with mixed mitral valve disease. The peak mitral valve Doppler E wave velocity (v0) is increased in the setting of severe MR because of enhanced early diastolic flow and may not accurately reflect the contribution to LA hypertension from any associated MS. When either AR or MR is the dominant lesion in patients with mixed aortic or mitral valve disease, respectively, the LV is dilated. When AS or MS predominates, LV chamber size will be normal or small. It can sometimes be difficult to ascertain whether stenosis or regurgitation is the dominant lesion in patients with mixed valve disease, although an integrated clinical and noninvasive assessment can usually provide clarification for purposes of patient management. For patients with moderate, mixed AS and AR in whom stenosis is the dominant lesion, the natural history tends to parallel what might be expected for isolated severe AS, and the treatment approach should be accordingly aligned. Patients with significant AS, a nondilated LV chamber, and concen­ tric hypertrophy will poorly tolerate the abrupt development of aortic regurgitation, as may occur, for example, with IE or after surgical AVR or TAVI complicated by paravalvular leakage. The noncompliant LV is not prepared to accommodate the sudden volume load, and as a result, LV diastolic pressure rises rapidly and severe heart failure develops.

Indeed, significant paravalvular regurgitation is a significant risk fac­ tor for short- to intermediate-term death following transcatheter AVR. Conditions in which the LV may not be able to dilate in response to chronic AR (or MR) include radiation heart disease, cardiac amyloid, and, in some patients, the cardiomyopathy associated with obesity and diabetes. Noncompliant ventricles of small chamber size predispose to earlier onset diastolic dysfunction and heart failure in response to any further perturbation in valve function.

PART 6 Disorders of the Cardiovascular System ■ ■SYMPTOMS Compared with patients with isolated, single-lesion valve disease, patients with multiple or mixed valve disease may develop symptoms at a relatively earlier stage in the natural history of their disease. Symptoms such as exertional dyspnea and fatigue are usually related to elevated filling pressures, reduced CO, or their combination. Palpitations may signify AF and identify mitral valve disease as an important component of the clinical presentation, even when not previously suspected. Chest pain compatible with angina could reflect left or right ventricular oxy­ gen supply/demand mismatch on a substrate of hypertrophy and pres­ sure/volume overload with or without superimposed coronary artery disease. Symptoms related to right heart failure (abdominal fullness/ bloating, edema) are late manifestations of advanced disease. ■ ■PHYSICAL FINDINGS Mixed disease of a single valve is most often manifested by systolic and diastolic murmurs, each with the attributes expected for the valve in question. Thus, patients with AS and AR will have characteristic midsystolic, crescendo-decrescendo and blowing, decrescendo diastolic murmurs at the base of the heart in the second right interspace and along the left sternal edge, respectively. Many patients with significant AR have mid-systolic outflow murmurs even in the absence of valve sclerosis/stenosis, and other findings of AS must be sought. The sepa­ rate murmurs of AS and AR can occasionally be difficult to distinguish from the continuous murmurs associated with either a patent ductus arteriosus (PDA) or ruptured sinus of Valsalva aneurysm. With mixed aortic valve disease, the systolic murmur should end before, and not envelope or extend through, the second heart sound (S2). The murmur associated with a PDA is heard best to the left of the upper sternum. The continuous murmur heard with a ruptured sinus of Valsalva aneu­ rysm is often first appreciated after an episode of acute chest pain. An early ejection click, which usually defines bicuspid aortic valve disease in young adults, is often not present in patients with congenital mixed AS and AR. As noted above, both the intensity and duration of these separate murmurs can be influenced by a reduction in CO and trans­ valvular flow due to coexistent mitral valve disease or AF. In patients with isolated MS and MR, expected findings would include a blowing, holosystolic murmur and a mid-diastolic rumble (with or without an opening snap) best heard at the cardiac apex. An irregularly irregular heart rhythm in such patients would likely signify AF. Findings with TS and TR would mimic those of left-sided MS and MR, save for the expected changes in the murmurs with respiration. The murmurs of pulmonic stenosis and regurgitation behave in a fashion directionally similar to AS and AR; dynamic changes during respiration should be noted. Specific attributes of these cardiac murmurs are reviewed in Chaps. 44 and 277. ■ ■LABORATORY EXAMINATION The electrocardiogram (ECG) may show evidence of ventricular hypertrophy and/or atrial enlargement. ECG signs indicative of rightsided cardiac abnormalities in patients with left-sided valve lesions should prompt additional assessment for PA hypertension and/or right-sided valve disease. The presence of AF in patients with aortic valve disease may be a clue to the presence of previously unsuspected mitral valve disease in the appropriate context. The chest x-ray can be reviewed for evidence of cardiac chamber enlargement, valve and/ or annular calcification, and any abnormalities in the appearance of the pulmonary vasculature. The latter could include enlargement of the main and proximal pulmonary arteries with PA hypertension and

pulmonary venous redistribution/engorgement or Kerley B lines with increasing degrees of LA and pulmonary venous hypertension. An enlarged azygos vein in the frontal projection indicates RA hyperten­ sion. Roentgenographic findings not expected based on a single or mixed valve lesion may reflect other valve disease. Transthoracic echocardiography (TTE) is the most commonly used imaging modality for the diagnosis and characterization of multiple and/or mixed valvular heart disease and may often demonstrate find­ ings not clinically suspected. Transesophageal echocardiography (TEE) may sometimes be required for more accurate assessment of valve anatomy (specifically, the mitral valve) and when IE is considered responsible for the clinical presentation. TTE findings of particular interest include those related to valve morphology and function, cal­ cification, chamber size, ventricular wall thickness, biventricular func­ tion, estimated PA systolic pressure, and the dimensions of the great vessels, including the root and ascending aorta, PA, and inferior vena cava. Exercise testing (with or without echocardiography) can be use­ ful when the degree of functional limitation reported by the patient is not adequately explained by the findings on TTE performed at rest. An integrated assessment of the clinical and TTE findings is needed to help determine the dominant valve lesion(s) and establish an appropriate plan for treatment and follow-up. Natural history is usually influenced to a relatively greater degree by the dominant lesion. Cardiac magnetic resonance (CMR) imaging can be used to provide additional anatomic and physiologic information when echocardiog­ raphy proves suboptimal but is less well suited to the evaluation of valve morphology. Cardiac computed tomography (CT) has been used to assess intracardiac structures in patients with complicated IE. It is invaluable in planning for transcatheter valve implantation. Coronary CT angiography provides a noninvasive alternative for the assess­ ment of coronary artery anatomy prior to surgery or transcatheter intervention. Invasive hemodynamic evaluation with right and left heart cath­ eterization may be required to characterize more completely the individual contributions of each lesion in patients with either multiple or mixed valvular heart disease. It is strongly recommended when there is a discrepancy between the clinical and noninvasive find­ ings in a symptomatic patient. Measurement of PA pressures and calculation of pulmonary vascular resistance (PVR) can help inform clinical decision-making in certain patient subsets, such as those with advanced mitral and tricuspid valve disease. It is important to identify any potential contribution to the clinical picture from pulmonary vas­ cular disease. Attention to the accurate assessment of CO is essential. Coronary angiography (if indicated) can be performed as part of the procedure. Contrast ventriculography and great vessel angiography are performed infrequently. TREATMENT Multiple and Mixed Valve Disease Management of patients with multiple or mixed valve disease can be challenging. As noted above, it is helpful to determine the dominant valve lesion and proceed according to the treatment and follow-up recommendations for it (Chaps. 272–278), being mind­ ful of deviations from the expected course due to the contributions of more than one valve lesion. For example, AF that emerges in the course of moderate mitral valve disease may precipitate heart failure in patients with concomitant, severe aortic valve disease that was previously asymptomatic. Medical therapies are limited and include diuretics when indicated for relief of congestion and anticoagulation to prevent stroke and thromboembolism in patients with AF. Blood pressure– lowering medications may be needed to treat systemic hyperten­ sion, which may aggravate left-sided regurgitant valve lesions, but should be initiated and titrated carefully. Pulmonary vasodilators to lower PVR are not generally effective in this context.

42 - 280 Congenital Heart Disease in the Adult

280 Congenital Heart Disease in the Adult

There is a paucity of evidence to inform practice guidelines for surgical and/or transcatheter valve intervention in patients with multiple or mixed valve disease. When there is a clear, dominant lesion, as for example in a patient with severe AS and mild AR, indications for intervention are straightforward and follow those recommended for patients with AS (Chap. 272). In other patients, however, there is less clarity, and decisions regarding intervention should be based on several considerations, including those related to lesion severity, ventricular remodeling, functional capacity, and PA pressures. In this regard, it is important to realize that patients with multiple and/or mixed valve disease may develop limiting symptoms or signs of physiologic impairment even with moderate valve lesions. Concomitant aortic and mitral valve replacement surgery is associated with a significantly higher perioperative mortality risk than replacement of either valve alone; therefore, operation should be carefully considered. Double valve replacement surgery is usu­ ally performed for treatment of severe (unrepairable) valve disease at both locations and for the combination of severe disease at one location with moderate disease at the other to avoid the hazards of reoperation in the intermediate to late term for progressive disease of the unoperated valve. In addition, the presence of a prosthesis in the aortic position significantly restricts surgical exposure of the native mitral valve. The need for double valve replacement may also impact the decision regarding the type of prosthesis (i.e., mechani­ cal vs tissue). In selected patients, TAVI for severe AS followed by edge-to-edge clip repair for severe MR can be accomplished during the same procedure. Tricuspid valve repair for moderate or severe secondary (func­ tional) TR at the time of left-sided valve surgery is now common­ place, particularly if there is dilation of the tricuspid annulus (>40 mm). The addition of tricuspid valve repair, consisting usu­ ally of insertion of an annuloplasty ring, adds little time or com­ plexity to the procedure and is well tolerated, but may be associated with an excess risk of heart block and the need for a permanent pacemaker. Reoperation for repair (or replacement) of progres­ sive TR years after initial surgery for left-sided valve disease, on the other hand, is associated with a relatively high perioperative mortality risk. Mitral valve repair or replacement for moderate or severe secondary MR at time of AVR for AS can usually be undertaken with acceptable risk for perioperative death or major complication. The presence of moderate or severe MR in patients with rheu­ matic MS is a contraindication to percutaneous mitral balloon commissurotomy (PMBC). TAVI can be performed for mixed AS and AR when the anatomic findings related to annulus size, coro­ nary height, and the distribution of calcium are favorable. Trans­ catheter management of both severe AS and severe primary or secondary MR (with deployment of an edge-to-edge clip) has been undertaken with increasing frequency in appropriately selected patients with prohibitive or high surgical risk. Further advances in transcatheter treatments for multiple and mixed valve disease are anticipated. ■ ■FURTHER READING Alaour B et al: Combined significant aortic stenosis and mitral regur­ gitation: Challenges in timing and type of intervention. Can J Cardiol 40:235, 2024. Egbe AC et al: Outcomes in moderate mixed aortic valve disease: Is it time for a paradigm shift? J Am Coll Cardiol 67:2321, 2016. Gammie JS et al: Concomitant tricuspid repair in patients with degenerative mitral regurgitation. N Engl J Med 286:327,

Otto CM et al: 2020 AHA/ACC guidelines for management of patients with valvular heart disease. A report of the American Heart Association Joint Commission on Clinical Practice Guidelines. Circulation 143:e72, 2021.

Anne Marie Valente, Michael J. Landzberg

Congenital Heart Disease

in the Adult CHAPTER 280 ■ ■PREVALENCE The number of adults with congenital heart disease (CHD) living in the United States is estimated to be at least 1.4 million. It is now projected that >10% of adults living with CHD in Europe will be over 60 years old by 2030. The majority of adults with CHD were diagnosed in childhood, although a substantial percentage may have CHD first recognized as adults. Lifelong follow-up in coordination with, or directly by, clinicians with expertise in adult congenital heart disease (ACHD) is recommended. In this chapter, we will review the cur­ rent field of ACHD, with an introduction to CHD nomenclature and cardiac development. This is followed by a summary of the more com­ mon CHD lesions that may be diagnosed in adulthood. Lastly, some of the common repaired CHD lesions that are encountered in adults are discussed. Throughout the chapter, to aid in the understanding of con­ genital cardiac anatomy and physiology, we include figures displaying the passage of blood flow between blood vessels and cardiac chambers in various disorders (Fig. 280-1). Congenital Heart Disease in the Adult ■ ■THE CHANGING LANDSCAPE OF ADULT CHD A Relatively New Subspecialty in Cardiovascular Disease 

Over the past two decades, the field of caring for adults with CHD has blossomed, and several nationwide initiatives have been initiated to standardize care. The American College of Cardiology and American Heart Association developed guidelines for the care of adults with CHD, first published in 2008 and revised in 2018, which emphasize the need for collaboration among primary care practitioners, cardiologists, and ACHD subspecialty cardiologists. The body of medical knowledge and competencies attendant with ACHD combined with skill acquisition in coordination of complex care over a patient’s medical lifetime led in 2015 to ACHD board certification examinations by the American Board of Medical Subspecialties, as well as the establishment of requirements for advanced fellowship training in ACHD care by the Accreditation Coun­ cil for Graduate Medical Education. In temporal association, the Adult Congenital Heart Association (ACHA) developed a process for ACHD care program accreditation based on standardization of infrastructural components felt requisite to achieve quality outcomes for ACHD. ■ ■SPECIAL CONSIDERATIONS FOR THE ACHD PATIENT Due to the need for lifelong care, it is essential that pediatric cardiology programs partner with ACHD programs to provide successful transi­ tion of patients. However, gaps in care are common during transition, much of which may be due to disparities in social determinants of health, such as race, ethnicity, socioeconomic status, access to insur­ ance, and residence in geographically remote locations. Additionally, adults with CHD may not recognize subtle changes in their exercise capacity, some of which are associated with worse survival; by the time symptoms are recognized, irreversible physiologic changes may have occurred. ACHD patients are, therefore, advised to undergo regular evaluations for surveillance of anatomic, hemodynamic, and electro­ physiologic sequelae that may be present. In addition, specific situa­ tions may arise in which it is prudent to review care in consultation with an ACHD specialist, several of which are outlined below. Noncardiac Surgery  Nearly all adults with CHD can be classi­ fied with stage A (harboring risk) or greater degrees of heart failure. As such, adults with CHD may demonstrate limited hemodynamic reserve to altered myocardial perfusion or loading conditions and may have subclinical organ dysfunction that is not recognized by standard laboratory assessment. Comprehensive, multispecialty assessment and care strategy review are recommended in advance of invasive or

Normal Heart Pulmonary artery PART 6 Disorders of the Cardiovascular System Aorta Right pulmonary veins Left pulmonary veins Left atrium Superior vena cava Right atrium Mitral valve Pulmonary valve Left ventricle Right ventricle Inferior vena cava Aortic valve Tricuspid valve FIGURE 280-1  Normal heart. Understanding of congenital cardiac anatomy and physiology is facilitated by use of box diagrams, displaying passage of blood flow between blood vessels and cardiac chambers. Labeling (e.g., structure names, arrows to denote direction of flow, coloring to represent oxygen saturation, connections or obstructions, chamber or vascular pressures, oxygen saturations) can aid in representation. Ao, aorta; IVC, inferior vena cava; LA, left atrium; LV, left ventricle; PA, pulmonary artery; PV, pulmonary veins; RA, right atrium; RV, right ventricle; SVC, superior vena cava. operative procedures for adults with CHD. Figure 280-2 illustrates the multiorgan considerations that should be considered in adults with CHD during perioperative resuscitation and convalescence. Anesthetic management requires knowledge of anatomy, physiologic consequence of underlying defects, myocardial and vascular performance, presence and nature of previous palliative procedures and residual shunts, altera­ tion of venous or arterial pathways within the circulation, and status of noncardiovascular organ physiology. Pregnancy  Women with CHD should receive counseling regard­ ing both maternal and fetal risks prior to conceiving a pregnancy and should be cared for in institutions with experience in treating CHD during pregnancy. Preconception evaluation includes detailed medical history, with particular attention to the women’s functional capacity, which is closely linked to maternal and fetal outcomes. Table 280-1 lists the World Health Organization classification of risk during preg­ nancy in women with heart disease; women at risk should be strongly counseled about the significant risks of morbidity and mortality during pregnancy and the postpartum period. Normal physiologic hemody­ namic changes of pregnancy are significant, occur over a relatively Hepatic Neurologic Congestive hepatopathy Neurocognitive dysfunction Hepatic fibrosis Stroke Renal Mood disorders (anxiety, depression) Chronic kidney disease Malignancy Endocrine Long-term exposure to ionizing radiation Hepatocellular carcinoma Diabetes Hypercholesterolaemia Obesity Immune/Infection Calcium metabolism and bone density SBE Abnormal immune function Thyroid disorders FIGURE 280-2  Noncardiac considerations in adults with congenital heart disease (CHD). SBE, subacute bacterial endocarditis. (Modified from J Buber et al: Common congenital heart problems in acute and intensive care. Eur Heart J Acute Cardiovasc Care 12:267, 2023.)

condensed period of time, and may be compounded in adults with CHD. Silversides and colleagues have devel­ oped a weighted-risk score for pregnant women with heart disease, based on a large registry known as CARPREG  2. The highest-weighted risk factors (weight of 3 points) include a prior his­ tory of cardiac events or arrhythmias, decreased functional status (New York Heart Association class ≥III), and pres­ ence of a mechanical heart valve. Risk factors that account for 2 points include ventricular dysfunction, high-risk leftsided valve disease/left ventricular outflow tract obstruction, pulmonary hypertension, coronary artery disease, and high-risk aortopathy. One point is assigned for late pregnancy assessment or no prior cardiac intervention. In this cohort, 16% of women experienced an adverse cardiac outcome, primarily heart failure and arrhythmia related. The predicted risks for cardiac events stratified according to point score were as follows: ≤1 point, 5%; 2 points, 10%; 3 points, 15%; 4 points, 22%; and >4 points, 41%. PV SVC IVC RA LA Mitral valve Tricuspid valve RV LV Pulmonary valve Aortic valve PA Ao Prepregnancy medications should be reviewed to ensure their safety in pregnancy. Alternatives to angiotensinconverting enzyme (ACE) inhibitors, angiotensin receptor blockers, direct oral anticoagulants, and endothelin receptor blockers should be considered, as these agents are teratogenic and contraindicated during pregnancy and should be discontinued. Women requiring anticoagula­ tion must be advised of the challenges of managing anticoagulation during pregnancy, and individualized strategies should be developed. A fetal echocardiogram between 18 and 22 weeks of gestation is advised for patients with CHD. Additionally, both men and women with CHD should be counseled regarding the risk of CHD in their offspring. ■ ■CONGENITAL TERMINOLOGY, DEVELOPMENT, AND GENETICS Congenital Nomenclature  One of the challenges in caring for adults with CHD is the inconsistent terminology used to describe the congenital heart lesions. Several classification systems have been pro­ posed, from the initial descriptions by Maude Abbott, Maurice Lev, and Jesse Edwards, to the extensive characterizations by Stella and Richard Van Praagh and Robert Anderson. In this chapter, we follow a seg­ mental approach. The heart is composed of several segments that are Genetic Gastrointestinal Malnutrition Specific genetic syndromes associated with CHD Malabsorption Haematologic Airway Anaemia Thrombosis Congenital anomalies Small airways disease Coagulopathy Bleeding diathesis Pulmonary Frailty Restrictive lung disease Sarcopenia Obstructive sleep apnoea Deconditioning Pulmonary hypertension

TABLE 280-1  Modified World Health Organization (mWHO) Classification of Heart Disease in Pregnancy   mWHO I mWHO II mWHO II–III mWHO III mWHO IV Small or mild Pulmonary stenosis Patent ductus arteriosus Mitral valve prolapse Successfully repaired simple lesions (atrial or ventricular septal defect, patent ductus arteriosus, anomalous pulmonary venous drainage) Atrial or ventricular ectopic beats, isolated Unoperated atrial or ventricular septal defect Repaired tetralogy of Fallot Most arrythmias (supraventricular arrhythmias) Turner syndrome without aortic dilatation Diagnosis (if otherwise well and uncomplicated) Risk No detectable increased risk of maternal mortality and no/mild increased risk in morbidity Small increased risk of maternal mortality or moderate increase in morbidity Abbreviations: ASI, aortic size index; EF, ejection fraction; HTAD, heritable thoracic aortic disease. analyzed separately before formulating a comprehensive diagnosis. The principal segments are the atria, the ventricles, and the great arteries, which are joined together by the atrioventricular canal and the conus (infundibulum). In the normal heart, the right ventricle (RV) is rightsided and organized inflow-to-outflow from right to left, while the left ventricle (LV) is left-sided and organized inflow-to-outflow from left to right. It is important to determine the segmental alignments, that is, what drains into what. For example, in the normal heart, the right atrium (RA) is aligned with the RV and the LV with the aorta. Finally, the segmental connections, the way in which adjacent segments are physically linked to each other, are described. For example, in the normal heart, the pulmonary artery (PA) is connected to the RV by a complete muscular conus (infundibulum), while the aorta is connected to the LV by aortic-mitral fibrous continuity (without a complete conus). Alignment and connection are different concepts, and both are important, especially in complex defects. Cardiac Development  The heart starts to form in the third week of gestation and is nearly fully formed by 8 weeks’ gestation. Mesoder­ mal precardiac cells migrate to form the cardiac crescents (primary heart fields) in anterior lateral plate mesoderm, which are then brought together to form a primary linear heart tube by ventral closure of the embryo. Cells of the second heart field continue to proliferate outside the heart and are added to the heart tube over the course of embryo­ genesis, contributing to the atria, the RV, and outflow tract. Addition­ ally, cardiac neural crest cells migrate into the developing heart in the 5th–6th weeks and are essential for septation of the outflow, formation of the semilunar valves, and patterning of the aortic arches. Once formed, the heart tube grows and elongates by addition of cells from the second heart field. The ends of the heart tube are relatively fixed by the pericardial sac so that as it elongates it must loop (bend), and in the vast majority of hearts, the loop falls to the right (D-loop). Fur­ ther elongation pushes the mid-portion of the tube (future ventricles)

Mild left ventricular impairment (EF >45%) Hypertrophic cardiomyopathy Native or tissue valve disease not considered WHO I or IV (mild mitral stenosis, moderate aortic stenosis) Marfan or other HTAD syndrome without aortic dilatation Aorta <45 mm in bicuspid aortic valve pathology Repaired coarctation Atrioventricular septal defect Moderate left ventricular impairment (EF 30–45%) Previous peripartum cardiomyopathy without any residual left ventricular impairment Mechanical valve Systemic right ventricle with good or mildly decreased ventricular function Fontan circulation Fontan circulation with good clinical course and without associated comorbidities Unrepaired cyanotic heart disease Other complex heart disease Moderate mitral stenosis Severe asymptomatic aortic stenosis Moderate aortic dilatation

(40–45 mm in Marfan syndrome or other HTAD; 45–50 mm in bicuspid aortic valve, Turner syndrome ASI 20–25 mm/m2, tetralogy of Fallot <50 mm) Ventricular tachycardia Pulmonary arterial hypertension Severe systemic ventricular dysfunction (EF <30% or NYHA class III–IV) Previous peripartum cardiomyopathy with any residual left ventricular impairment Severe mitral stenosis Severe symptomatic aortic stenosis Systemic right ventricle with moderate or severely decreased ventricular function Severe aortic dilatation (>45 mm in Marfan syndrome or other HTAD,

50 mm in bicuspid aortic valve, Turner syndrome ASI >25 mm/m2, tetralogy of Fallot >50 mm) Vascular Ehlers-Danlos Severe (re)coarctation Fontan with any complication CHAPTER 280 Congenital Heart Disease in the Adult Intermediate increased risk of maternal mortality or moderate to severe increase in morbidity Significantly increased risk of maternal mortality or severe morbidity Extremely high risk of maternal mortality or severe morbidity inferior or caudal to the inflow, resulting in the normal relationship between the atria and ventricles. Further growth pushes the outflow medially and is associated with outflow rotation, both processes essen­ tial for normal alignment of the outflow. Finally, the proximal part of the outflow is incorporated in the RV, shortening the outflow in asso­ ciation with further rotation. While this remodeling is occurring, the outflow is undergoing septation under the influence of cardiac neural crest cells. Septation proceeds from distal to proximal, culminating in formation and muscularization of the infundibular, or muscular, outflow septum, which inserts onto the superior endocardial cushion at the rightward rim of the outflow foramen, walling the aorta into the LV via the outflow foramen and the PA directly into the RV. Genetic Considerations  CHD is the most commonly occur­ ring birth defect; etiologic contributors are increasingly recognized, although often speculated to be multifactorial. Children born with trisomy 21 have a 50% chance of having CHD, most commonly defects in the atrioventricular canal. Conotruncal defects are associated with several chromosomal abnormalities, most notably a deletion at chro­ mosome 22q11 (DiGeorge syndrome). Echocardiographic clues to this association in patients with a conotruncal defect include an associated right aortic arch or aberrant subclavian artery. Many adults currently living with conotruncal defects may not have undergone testing for DiGeorge syndrome. This condition is important to recognize because a variety of psychiatric disorders and disabilities in cognitive function may be present and go untreated. Patients with Noonan syndrome commonly have a dysplastic pulmonary valve and have facial and lymphatic abnormalities. Several defects in specific genes have been associated with Noonan syndrome, most notably PTPN11. Adults with Williams syndrome (7q11.23 deletion) commonly have supravalvar aortic stenosis and diffuse arteriopathy, with a “cocktail-like” personal­ ity and hypercalcemia. There is a growing importance of genome-wide analyses in subjects with CHD.

TABLE 280-2  Congenital Etiologies of Right Heart Dilation Congenital tricuspid valve disease   Tricuspid valve dysplasia with regurgitation   Ebstein anomaly Congenital pulmonary valve regurgitation Pulmonary arterial hypertension Myocardial abnormalities   Arrhythmogenic RV cardiomyopathy   Uhl’s anomaly Shunt lesions   Partial anomalous pulmonary venous return   Primum ASD   Secundum ASD   Sinus venosus defect   Coronary sinus septal defect   Gerbode defect (LV-RA shunt)   Coronary artery fistula to the RA, CS   Postoperative residual shunts PART 6 Disorders of the Cardiovascular System Abbreviations: ASD, atrial septal defect; CS, coronary sinum; LV, left ventricle; RA, right atrium; RV, right ventricle. ■ ■SPECIFIC CHD LESIONS Dilated Right Heart  There are many congenital etiologies for right heart dilation (Table 280-2). These include congenital valvular anomalies (such as Ebstein anomaly or pulmonary regurgitation), intrinsic RV myocardial anomalies (arrhythmogenic RV dysplasia, Uhl’s anomaly), or shunt lesions occurring proximal to the tricuspid valve (atrial septal defects or partial anomalous pulmonary veins). Cardiac imaging is critical in determining the etiology of right heart dilation, and knowledge of the anatomy and physiology of various shunt lesions is essential. Atrial Septal Defect  One of the most common etiologies of right heart dilation is presence of an atrial septal defect (ASD; Fig. 280-3A). Intracardiac communications allow blood transmission between chambers or spaces based on relative resistance, propulsion, and flow patterns. Patients with large ASDs often present in child­ hood; however, many ASDs are not discovered until adult life. The physiology of an ASD is predominantly that of a “left-to-right” shunt Atrial Septal Defect SVC IVC x x+y PA Ao Right PVs SVC x Left PVs x x+y ASD y LA x RA x+y x LV x+y RV IVC A FIGURE 280-3  A. Atrial septal defect. In the presence of an atrial septal defect, the difference in compliance between the (RA + RV) as compared to the (LA + LV), combined with the size of the defect itself, allows for a “shunt” of flow (“y”) of “red” (oxygenated) blood from the left side of the heart to the right side (deoxygenated). Systemic venous return of pure deoxygenated blood (“x”) is increased by the oxygenated shunted blood (“y”) to increase volume of blood (“x + y”) in the RA, RV, and total blood flow to the lungs. If the volume or the sequelae of the shunted blood are sufficient, RA and RV can dilate (hashed lines), and arrhythmias or shortness of breath (and occasionally pulmonary hypertension) can ensue. Ao, aorta; ASD, atrial septal defect; IVC, inferior vena cava; LA, left atrium; LV, left ventricle; PA, pulmonary artery; PV, pulmonary veins; RA, right atrium; RV, right ventricle; SVC, superior vena cava. B. Diagrammatic representation of the location of various atrial septal defects. ASD 1, primum atrial septal defect; ASD 2, secundum atrial septal defect. (Part B used with permission from Emily Flynn McIntosh, illustrator.)

(flow of pulmonary venous, or oxygenated, blood toward systemic venous, or deoxygenated, chambers or vessels). The degree of left-toright shunting determines the amount of right heart volume loading and is dictated by the size of the defect as well as the diastolic prop­ erties of the heart. As patients age, several factors, such as diabetes mellitus, systemic hypertension, and atherosclerosis, may contribute to decreased compliance of the left-sided cardiac chambers and contribute to increased left-to-right shunting and symptomatology. The classic physical examination finding is a wide, fixed splitting of the second heart sound, which is due to prolonged RV ejection and increased PA capacitance, which, in turn, delay pulmonary valve closure. The surface electrocardiogram (ECG) commonly displays an incomplete right bundle branch block. Symptoms, when they occur, most commonly include exercise intolerance, arrhythmia, and dyspnea with exertion. It is not uncommon for adults to have incidentally noted asymptomatic ASD during evaluation of other comorbid issues. Right heart dilation, without additional etiology for such, in the setting of unrepaired ASD is considered a risk for pro­ gression toward symptomatic right heart failure, atrial arrhythmias, and potential development of pulmonary arterial hypertension (if such is not already present). Therefore, a patient with an ASD and right heart dilation, particularly with symptoms attributable to such, should be offered ASD closure. Pulmonary vascular disease leading to pulmonary hypertension develops in up to 10% of patients with unrepaired ASD, and Eisenmenger syndrome (ES) is a rare complica­ tion (see below). Management of patients with concomitant ASD and pulmonary hypertension should be coordinated with both ACHD and pulmonary hypertension experts. Figure 280-3B illustrates the locations of various ASDs. The most common type of an ASD is a secundum ASD, which is a defect, or true deficiency in the atrial septum, in the region of the fossa ovalis. This should be differentiated from a patent foramen ovale (PFO), which is persistence of patency of the flap valve of the fossa ovalis (not associ­ ated with right-sided cardiac dilation) and persists in up to 25% of adults. Secundum ASDs can often be closed with occluder devices placed percutaneously. However, certain anatomic determinants make percutaneous closure less favorable, including large defects, inade­ quate tissue rims surrounding the defect, and concomitance of anom­ alous draining pulmonary veins. A primum ASD is a deficiency of the atrioventricular (AV) canal portion of the atrial septum; primum ASD is always associated with abnormal development of the AV valves, PV ASD y RA LA x+y x Sinus venosus defect ASD 1° RV LV x+y x x+y x PA Ao ASD 2° B

most commonly resulting in a cleft in the mitral valve. A coronary sinus defect is rare and involves an opening between the coronary sinus and the left atrium. A sinus venosus defect is not a defect in the atrial septum but, rather, a defect between either the right superior vena caval–atrial junc­ tion and the right upper pulmonary vein(s) or, less commonly, the inferior vena caval–atrial junction and the right lower pulmonary veins. Surgical closure is required for primum ASDs, sinus venosus defects, and coronary sinus septal defects. APV APV Right PVs Partial Anomalous Pulmonary Venous Return  Partial anomalous pulmonary venous return (PAPVR) is occasionally discovered in adults with right heart dilation or incidentally on cross-sectional imaging (Fig. 280-4). There are several possible anomalous connections, with the most common being a left upper pulmonary vein to an ascending vertical vein into the innominate vein or the right upper pulmonary vein draining to the superior vena cava. In the latter case, care­ ful attention should be paid to ensure that there is not an associated sinus venosus defect. Con­ comitant pulmonary hypertension can occur but is uncommon. Symptomatology may be absent, and a decision to repair isolated PAPVR should include variance in anatomy, lung ventilation and perfusion, hemodynamic response to shunt, symptoms, and surgical experience. FIGURE 280-4  Partial anomalous pulmonary venous return. In the presence of an anomalously draining pulmonary vein (typically to a systemic vein such as the left innominate vein, SVC, or rarely IVC), an obligate “shunt” of flow (“y”) of “red” (oxygenated) blood from the affected pulmonary vein to the right heart (deoxygenated) ensues. Systemic venous return of pure deoxygenated blood (“x”) is increased by the oxygenated shunted blood (“y”) to increase volume of blood (“x + y”) in the SVC, RA, RV, and total blood flow to the lungs. If the volume or the sequelae of the shunted blood are sufficient, RA and RV can dilate (hashed lines), or shortness of breath can ensue. Ao, aorta; APV, anomalous pulmonary vein; IVC, inferior vena cava; LA, left atrium; LV, left ventricle; PA, pulmonary arteries; PV, pulmonary veins; RA, right atrium; RV, right ventricle; SVC, superior vena cava. Ebstein Anomaly  Ebstein anomaly (Fig. 280-5) is the result of embryologic failure of delamination, or “peeling away,” of the tricuspid valve leaflets from the ventricular myocardium, resulting in adher­ ence of the valve leaflets to the underlying myocardium. This results in a wide variety of abnormalities, including apical and posterior Ebstein Malformation SVC IVC PA Ao Right PVs x+y x+z x+z x SVC Left PVs x LA PFO x+z z RA x+y x+z y LV RV x+y IVC FIGURE 280-5  Ebstein malformation. In the presence of Ebstein anomaly, the tricuspid valve leaflets can be redundant, fenestrated, and sail-like (typically seen in the anterior leaflet*) or adherent to the underlying myocardium with apical displacement of the nonadherent components (typically the septal and posterior leaflets). Location and degree of leaflet coaptation are variable and account for varying degrees of tricuspid regurgitation, shift of the functional tricuspid valve anterior from the anatomic annulus into the right ventricle, “atrialization” of the right ventricle, and most commonly angulation of the tricuspid valve into the RV outflow tract. RA and RV dilation (hashed lines) can occur due to the effects of combined volume from systemic venous return (“x”) and tricuspid regurgitant flow (“y”). PFO is frequent; worsening compliance and elevation of pressure in the RA as compared to the LA can lead to increasing “right-to-left” (deoxygenated to oxygenated) shunt and cyanosis. RV myocardial function may be abnormal. Ao, aorta; IVC, inferior vena cava; LA, left atrium; LV, left ventricle; PA, pulmonary arteries; PFO, patent foramen ovale; PV, pulmonary veins; RA, right atrium; RV, right ventricle; SVC, superior vena cava; *, anterior tricuspid valve leaflet.

Partial Anomalous Pulmonary Venous Return PV SVC CHAPTER 280 y x IVC x x+y y RA LA PA Ao x+y x x x+y Left PVs SVC Congenital Heart Disease in the Adult LA RV LV x x+y x RA x+y x x+y x x+y LV PA Ao RV IVC displacement of the dilated tricuspid valve annulus, dilation of the “atrialized” portion of the RV, and fenestrations, redundancy, and tethering typically of the anterior leaflet of the tricuspid valve. The malformed tricuspid valve is usually regurgitant but may occasionally be stenotic. The clinical presentation of Ebstein anomaly in the adult depends on several factors, including the extent of tricuspid valve leaflet distortion, degree of tricuspid regurgitation (TR), right atrial pressure, and presence of an atrial level shunt. The physical examination of a patient with Ebstein anomaly may vary depending on the severity of disease. In more severe cases, the first heart sound may be split and the second component of the first heart sound may have a distinctive snapping quality (known as the sail sign, due to the redundancy of the anterior tricuspid valve leaflet). Patients with significant TR may have prominent “v” waves of the jugular venous pulsations; however, this find­ ing is often absent due to abnormal right atrial compliance. The ECG is often abnormal, with right atrial and ventricular enlargement. Up to 20% of patients have evidence of ventricular pre­ excitation (Wolff-Parkinson-White pattern). Sur­ gical treatment includes a tricuspid valve repair or replacement, closure of any atrial level defects, and arrhythmia ablative procedures. PV PFO x x z RA LA y * RV LV x+z x+y x+z x PA Ao Shunt Lesions Causing Left Heart Dilation  Intracardiac shunts or intravascu­ lar passages that occur below the level of the tricuspid valve result in left heart dilation. The two major types of congenital shunts that result in left heart dilation are a ventricular septal defect (VSD; Fig. 280-6A) and patent ductus arteriosus (PDA; Fig. 280-7). Ventricular Septal Defects  VSDs are the most common congenital anomaly recognized at

Ventricular Septal Defect SVC IVC x x+y PART 6 Disorders of the Cardiovascular System PA Ao Right PVs SVC x x x+y Left PVs LA x+y RA x y x+y LV RV x IVC A FIGURE 280-6  A. Ventricular septal defect. In the presence of a ventricular septal defect, the difference in pressure and outflow resistance in systole (and the difference in compliance in diastole) between the RV and LV, combined with the size of the defect itself, allow for a “shunt” of flow (“y”) of “red” (oxygenated) blood from the left side of the heart to the right side (deoxygenated). Systemic venous return of pure deoxygenated blood (“x”) is increased by the oxygenated shunted blood (“y”) to increase volume of blood (“x + y”) through the outflow of the RV into the lungs, and in the left atrium and left ventricle. If the volume or the sequelae of the shunted blood are sufficient, LA and LV can dilate (hashed lines), and arrhythmias or shortness of breath (and occasionally pulmonary hypertension) can ensue. Ao, aorta; IVC, inferior vena cava; LA, left atrium; LV, left ventricle; PA, pulmonary arteries; PV, pulmonary veins; RA, right atrium; RV, right ventricle; SVC, superior vena cava; VSD, ventricular septal defect. B. Diagrammatic representation of the location of various ventricular septal defects. AV, atrioventricular. (Part B used with permission from Emily Flynn McIntosh, illustrator.) birth; however, they account for only ~10% of CHD in the adult, due to the high rate of spontaneous closure of small VSDs during the early years of life. Large VSDs usually cause symptoms of heart failure and poor somatic growth and are most often surgically closed before adult­ hood. Several classification systems for VSDs exist. Figure 280-6B illustrates various locations of VSDs; the most common location is in the membranous septum (also referred to as perimembranous or outlet defects). Muscular defects that persist into adult life are often pressure and flow restricted, resulting in no significant hemodynamic conse­ quence. AV canal defects, also referred to as inlet defects, are located in the crux of the heart and are associated with abnormalities of the AV valve leaflets. Subpulmonary defects, also known as conal septal defects, are commonly associated with prolapse of the right coronary Patent Ductus Arteriosus y Ao PA Right PVs x SVC x LA x+y RA x x+y x LV RV IVC FIGURE 280-7  Patent ductus arteriosus. In the presence of a patent ductus arteriosus, the difference in pressure and resistance in both systole and diastole between the pulmonary arteries and the aorta, combined with the size of the ductus itself, allow for a “shunt” of flow (“y”) of “red” (oxygenated) blood from the aorta to the pulmonary arteries (deoxygenated). Systemic venous return of pure deoxygenated blood (“x”) is increased by the oxygenated shunted blood (“y”) to increase volume of blood (“x + y”) in the lungs, the left atrium, the left ventricle, and out the aortic valve. If the volume or the sequelae of the shunted blood are sufficient, LA and LV can dilate (hashed lines), and arrhythmias or shortness of breath (and occasionally pulmonary hypertension) can ensue. Ao, aorta; IVC, inferior vena cava; LA, left atrium; LV, left ventricle; PA, pulmonary arteries; PDA, patent ductus arteriosus; PV, pulmonary veins; RA, right atrium; RV, right ventricle; SVC, superior vena cava.

PV RA LA x x+y Subpulmonary RV LV Membranous x+y y x VSD x x+y AV canal type PA Ao Muscular B cusp and aortic insufficiency. The outcome for adults with small VSDs without evidence of ventricular dilation or pulmonary hypertension is generally excellent. Patent Ductus Arteriosus  A PDA courses between the aortic isthmus and the origin of one of the branch PAs. Small PDAs are often silent to auscultation and do not cause hemodynamic changes. The classic murmur is heard best just below the left clavicle and typically extends from systole past the second heart sound into diastole, reflect­ ing flow turbulence and gradient between the aorta and the PAs (result­ ing in left-to-right shunting). Large PDAs will lead to left heart dilation and may lead to chronically elevated pulmonary vascular resistance, including the potential for ES. PV SVC PDA IVC x x+y RA LA x x+y Left PVs RV LV x x+y x x+y y PDA x x+y PA Ao

■ ■MODERATE AND COMPLEX CHD Tetralogy of Fallot  Tetralogy of Fallot (TOF) is the most common form of cyanotic CHD, occurring in 0.5 per 1000 live births. It involves anterior deviation of the conal septum, resulting in RV outflow tract (RVOT) obstruction, a VSD, RV hypertrophy, and an overriding aorta (Fig. 280-8A, B). There is a large spectrum of severity of disease in TOF, from patients who have only mild pulmonary stenosis to those with complete pulmonary atresia (TOF/PA). Current surgical strategies involve primary repair in infancy (Fig. 280-8C); however, many adults Tetralogy of Fallot (unrepaired) PV SVC IVC x x-y RA LA x x-y Right PVs

SVC RV LV x x-y x y RVH

VSD RA x x-y x x PA Ao IVC A Tetralogy of Fallot (repaired) PA Ao Right PVs x SVC x x x x+y RA y x x+y LV RV IVC C FIGURE 280-8  A. Tetralogy of Fallot involves anterior and superior malalignment of a bar of tissue (conal septum) (see *in part B, which presents a cut-away view through the anterior surface of the RV, into the RV outflow), partially obstructing the right ventricular outflow (under the pulmonary valve, i.e., “subpulmonary stenosis”; labeled as 1), and leaving a gap in the interventricular septum (VSD). The pulmonary valve annulus is typically hypoplastic. Outflow obstruction prevents regression of right ventricular hypertrophy (#), which was present in utero. The difference in pressure and outflow resistance in systole (and the difference in compliance in diastole) between the obstructed RV and the LV allows for a “shunt” of flow (“y”) of “blue” (deoxygenated) blood from the right side of the heart to the left side (oxygenated). Systemic venous return of pure deoxygenated blood (“x”) is decreased by the shunted blood (“y”), leading to a total decrease in the volume of blood (“x – y”) passing beyond into the lungs. The deoxygenated shunted blood (“y”) mixes with fully oxygenated blood in the LV, contributing to systemic arterial cyanosis. C. Tetralogy of Fallot—repaired. After modern repair of tetralogy of Fallot, VSD has been patched closed, and outflow tract obstruction has been surgically removed, frequently at the expense of a patch enlarging the pulmonary valve annulus at the expense of sacrificing the integrity of the pulmonary valve (causing pulmonary regurgitation). The pulmonary regurgitant volume (“y”) is added to systemic venous return (“x”), contributing to RV chamber enlargement (hashed lines) and may be associated with tricuspid annular dilation and valve regurgitation, resulting in RA enlargement. Ao, aorta; IVC, inferior vena cava; LA, left atrium; LV, left ventricle; PA, pulmonary arteries; PV, pulmonary veins; RA, right atrium; RV, right ventricle; RVH, right ventricular hypertrophy; SVC, superior vena cava; VSD, ventricular septal defect.

may have first undergone palliative procedures (Blalock-Taussig, Potts, Waterston shunts) prior to a complete repair. The goal of surgical repair is to alleviate the pulmonary stenosis and close the VSD. Up to 10% of patients with TOF have an anomalous coronary artery, most com­ monly, an anomalous left anterior descending coronary artery from the right coronary cusp. Patients with an anomalous coronary as well as those with TOF/PA may require an RV-to-PA conduit.

CHAPTER 280 Adults with repaired TOF often have hemodynamic sequelae that may require reintervention in adulthood (Table 280-3). Pulmonary Congenital Heart Disease in the Adult Conal Anatomy PA Ao x-y Left PVs LA * x-y VSD *

x-y

LV y x-y RV x

B PV SVC IVC x x RA LA x+y x Left PVs RV LV x+y x LA x VSD patch VSD patch x+y x x PA Ao

TABLE 280-3  Potential Sequelae of Repaired Tetralogy of Fallot Right atrial dilation Right ventricular dilation Right ventricular dysfunction Right ventricular outflow tract obstruction Pulmonary regurgitation Branch pulmonary artery stenosis Tricuspid regurgitation Residual ventricular septal defect Left ventricular dysfunction Aortic root dilation Atrial arrhythmias Ventricular arrhythmias Sudden cardiac death PART 6 Disorders of the Cardiovascular System regurgitation is common following TOF repair and is usually associ­ ated with RV dilation. Accurate quantification of RV size, function, and mass is particularly important in adults after repair of TOF, as RV dilation, dysfunction, and hypertrophy are associated with adverse out­ comes in these patients. Patients may also have residual RVOT obstruc­ tion, which may occur beneath the pulmonary valve, at the valve level, above the valve, or in the branch PAs. Cardiac magnetic resonance imaging is routinely used in the surveillance of these patients. Left ven­ tricular dysfunction is present in at least 20% of adults with repaired TOF, particularly those who were repaired later in life, had prior pal­ liative shunts, or have concomitant RV dysfunction. As patients age with repaired TOF, both atrial and ventricular arrhythmias occur with increasing frequency. A QRS duration on a D-loop Transposition PA Ao Right PVs SVC LA RA RV IVC A FIGURE 280-9  A. Transposition of the great arteries. When the great arteries are transposed, the aorta arises from the RV, and the pulmonary artery arises from the LV, leaving deoxygenated blood circulating from systemic veins to systemic arteries in separated fashion from oxygenated blood, which circulates from pulmonary veins to pulmonary arteries. Without interchamber or intravascular communications, this circulation is incompatible with life. Presence of an atrial septal defect (ASD), depicted here, ventricular septal defect (VSD), or patent ductus arteriosus (PDA) allows for some interchamber or intravascular mixing and, at best, partial relief of cyanosis and sustenance of life, at the expense of increased pulmonary blood flow. B. Atrial switch. Atrial level switch procedures (Mustard and Senning) were the first standardized surgeries to alter the natural course of complex congenital heart disease, utilizing intracardiac rerouting via a “baffle” to redirect blood flow. The atrial switch simulates inverted trousers, with each “pants leg” () attaching to either the SVC or the IVC, transporting deoxygenated blood through the interior of the trousers to the “waist of the trousers” and directing blood through the mitral valve to the LV and out the PA. Surgical removal of the atrial septum allows pulmonary venous return to traverse from posterior left atrium through the space between the pants legs of the baffle, through the tricuspid valve to the RV (serving as the “systemic ventricle,” i.e., that pumps to the systemic arterial circulation), through the aorta. Non-infrequent sequelae include sinus node dysfunction, atrial arrhythmias, systolic dysfunction of the RV, tricuspid regurgitation (from RV to LA), leaks in the baffle material allowing shunting of blood, and obstruction of the systemic or pulmonary venous baffles. C. Arterial switch. The arterial switch operation allowed both anatomic and physiologic correction for D-loop transposition of the great arteries. Successful surgical switching of the PA and the Ao above the level of the native roots (hashed lines) necessitated ability to transfer coronary artery origins contained within a button of tissue () back to the neo-aorta (now supported by the LV). Deoxygenated blood flow from SVC and IVC passes from RA to RV to PA, and oxygenated blood passes from PV to LA to LV to Ao. Uncommon sequelae include obstruction at any of the surgical sites (supravalvar PA or Ao stenosis, coronary orifice obstruction) or more distal obstructions due to tension placed on the PA, Ao, or coronary arteries. Ao, aorta; IVC, inferior vena cava; LA, left atrium; LV, left ventricle; PA, pulmonary arteries; PV, pulmonary veins; RA, right atrium; RV, right ventricle; SVC, superior vena cava.

resting ECG of 180 ms or more has been associated with increased risk of ventricular tachycardia and sudden death in this patient popula­ tion. In one prospective follow-up study of 144 adults with repaired TOF, there was a 72% survival at 40 years, but only a 25% cumula­ tive event-free survival. These events include need for reintervention (most commonly pulmonary valve replacement [PVR]), symptomatic arrhythmias, and heart failure. The most common reintervention in a repaired TOF patient is a PVR. However, optimal timing of PVR in asymptomatic patients with repaired TOF remains unclear. Traditionally, PVR has been accomplished with a surgical procedure; however, percutaneous implantation of pulmonary valves is becoming increasingly utilized in clinical practice. Patients with repaired TOF may also undergo interventions includ­ ing closure of residual VSDs, dilation and/or stenting of the RVOT or branch PAs, and tricuspid valve repair. Patients with clinically signifi­ cant arrhythmias may benefit from catheter ablation. Transposition of the Great Arteries  Transposition of the great arteries (TGA) is defined by the great arteries arising from the opposite side of the ventricular septum than normal; as such, the aorta arises from the RV and the PA from the LV. The more common form of TGA, known as D-loop TGA, involves AV concordance and ventriculararterial discordance, resulting in a physiology that allows two circuits to be in parallel rather than in series (Fig. 280-9A) and intense cyano­ sis shortly after birth. This physiology is not compatible with long-term survival without surgical intervention. Patients with TGA may be born with additional congenital defects (most commonly a VSD). The surgical repairs for D-loop TGA have evolved over time. In the late 1950s through the 1970s, the atrial switch procedure (Mustard, Senning procedures) was performed (Fig. 280-9B). These atrial switch PV SVC ASD IVC RA LA Left PVs RV LV Ao PA LV

Atrial Switch PA Ao Right PVs SVC RA RV IVC B Arterial Switch neo Ao Right PVs neo PA LA SVC oo oo * * RA RV IVC C FIGURE 280-9  (Continued) procedures relieved the cyanosis but left the patient with a systemic RV. Despite moderate-term survival over decades, there are multiple longterm sequelae that may present following the atrial switch procedure. The most worrisome complication is that of systemic RV dysfunc­ tion. The prevalence of RV dysfunction in this population is not well defined. Limited study has failed to reveal medical therapies effective for systemic RV dysfunction. A subset of patients with D-loop TGA, VSD, and PS may have undergone a Rastelli procedure. This intervention involves placing an RV-to-PA conduit and routing the LV to the aorta through the VSD, which results in relief of cyanosis and the benefit of a systemic LV. In the 1980s, the arterial switch operation (ASO; Fig. 280-9C) became the surgical procedure of choice for D-loop TGA. This pro­ cedure involves transecting the great arteries above the sinuses and placing the PAs anteriorly to come into alignment with the RV, result­ ing in draping of the branch PAs over the ascending aorta. A coronary artery translocation is performed. The ASO has resulted in substantial long-term survival. The potential long-term sequelae of the various surgical procedures for D-loop TGA are listed in Table 280-4.

PV LA CHAPTER 280 SVC IVC Left PVs RV LV LA Congenital Heart Disease in the Adult Ao PA LV PV SVC IVC RA LA Left PVs RV LV neo PA neo Ao LV The less common form of TGA, known as L-loop TGA (physiologi­ cally corrected or “congenitally corrected” TGA; Fig. 280-10), may not require surgical intervention but is presented here in relation to other forms of TGA. L-loop TGA involves both AV discordance (RA allow­ ing passage of deoxygenated systemic venous return to the LV, and TABLE 280-4  Long-Term Sequelae of D-Loop TGA Surgery ATRIAL SWITCH ARTERIAL SWITCH RASTELLI PROCEDURE Systemic venous baffle Arterial anastomosis stenosis Subaortic stenosis Pulmonary venous baffle Branch PA stenosis RV-PA conduit obstruction RV (systemic) dysfunction Neo-aortic root dilation Pulmonary regurgitation Tricuspid regurgitation Neo-aortic regurgitation Ventricular dysfunction Baffle leaks Coronary artery stenosis   LVOT obstruction (PS) LV dysfunction   Abbreviations: LV, left ventricle; LVOT, left ventricular outflow tract; PA, pulmonary artery; PS, pulmonary stenosis; RV, right ventricle; TGA, transposition of the great arteries.

Congenitally (L-loop transposition) Corrected TGA PART 6 Disorders of the Cardiovascular System PA Ao Right PVs SVC LA RA LV IVC FIGURE 280-10  Congenitally corrected transposition of the great arteries. Physiologically corrected transposition of the great arteries (also known as congenitally corrected transposition of the great arteries) is characterized by atrioventricular discordance and ventriculoarterial discordance. Systemic venous blood passes from the right atrium (RA) through the mitral valve into the morphologic left ventricle (LV) to the pulmonary artery (PA). Oxygenated blood then returns to the lungs to the left atrium (LA) through the tricuspid valve into the morphologic right ventricle (RV) and then out the aorta (Ao). IVC, inferior vena cava; PV, pulmonary veins; SVC, superior vena cava. conversely, the left atrium conducting oxygenated pulmonary venous blood to the RV) as well as ventriculoarterial discordance (connections of LV to PA, RV to aorta). This results in normal arterial oxygen satu­ ration, yet an RV associated with the aorta. Patients with L-loop TGA commonly have associated congenital anomalies, including dextrocar­ dia, ASDs, a dysplastic tricuspid valve, and pulmonary stenosis. Con­ duction disturbances are common, and complete heart block occurs in up to 30% of patients. Those patients without associated defects may not present until later in life, most commonly with heart failure, TR, or newly recognized conduction disease. Coarctation of the Aorta  Adults with coarctation of the aorta (Fig. 280-11) typically have a shelf-like obstruction at the level of the descending aorta that passes just posterior to the junction of the main and left PA; obstruction less commonly involves the transverse aortic arch. On physical examination, the lower extremity blood pres­ sure and pulses are lower than (and delayed in timing, in contrast to) the upper extremity values, unless significant aortic collaterals have developed. A continuous murmur over the scapula may be present due to the collateral blood flow. Significant coarctation increases afterload to all proximal structures in the path of oxygenated blood, from LV and coronary arteries to ascending and transverse aorta, to cerebral and arm vessels and proximal descending aorta. Bicuspid aortic valve (typically with right-left commissural fusion) is a common association. In women with short stature, webbed neck, lymphedema, and primary amenorrhea, a concomitant diagnosis of Turner syndrome should be considered, the presence of which indicates greater degree of, and risks from, sequelae from seemingly similar anatomy and physiology. Patients who have undergone surgical repair in general have a good prognosis; however, they remain at risk for systemic hypertension, premature atherosclerosis, LV failure, and aortic aneurysm, dissection, and recurrent coarctation. Single Ventricle  The term single ventricle heart disease is impre­ cise but useful in some settings, as it refers to congenital heart condi­ tions in which one ventricle or its valves preclude surgical creation of a biventricular circulation. Common congenital diagnoses in this category include tricuspid atresia, double inlet LV, and hypoplastic left heart syndrome. Most patients with single ventricle physiology undergo a series of surgeries culminating in a Fontan procedure (Fig. 280-12A, B). Since its initial use for tricuspid valve atresia in

PV SVC IVC RA LA Left PVs LV RV PA Ao RV 1971, multiple modifications of this procedure have occurred, with common features of near complete separation of the pulmonary and systemic circulations. The Fontan procedure utilizes the single ventri­ cle to pump pulmonary venous (oxygenated) blood through the aorta to the body and allows for “passive” flow of systemic venous return of deoxygenated blood through surgically created connections to the lungs. Patients who have undergone a Fontan procedure are at risk for multiple comorbidities in adulthood, including atrial arrhythmias, heart failure, renal and hepatic dysfunction, and both venous and arte­ rial thrombosis and embolism. Coarctation of the Aorta: Sequelae/Associations

PA *

LA Ao

RA

LV

RV FIGURE 280-11  Aortic coarctation (*). Bicuspid aortic valve (1) is most common concomitant lesion. Sequelae from aortic coarctation (unrepaired or repaired) include systemic arterial hypertension, ascending (2) or descending (3) aortic enlargement or aneurysm formation, left ventricular (LV) hypertrophy (4), LV diastolic and systolic heart failure, accelerated coronary (5) or cerebral (6) atherosclerosis, cerebral aneurysm formation, and recurrence of coarctation after repair. Ao, aorta; PA, pulmonary arteries.

Fontan PA Ao RA LA SVC RA * LV RV IVC A Atriopulmonary Fontan Classic Fontan Extracardiac Fontan Lateral tunnel Fontan B FIGURE 280-12  A. Fontan surgery creates a unique circulation in which deoxygenated blood is directed to the PAs from the SVC and IVC in a fashion that bypasses any pumping chamber. The SVC and IVC are connected (*) via either an internal “tunnel” or an extracardiac conduit that guides flow to the PA. Pulmonary venous (oxygenated) return courses from PV to LA to LV to aorta. In contrast to physiology in normal adults (where pressure is generated by an RV to propel blood flow from a lower pressure RA to a higher pressure LA), in Fontan circulation, by definition, due to the absence of a pumping chamber to the PA, RA pressure is greater than LA pressure, permitting flow through the lungs. Ao, aorta; IVC, inferior vena cava; LA, left atrium; LV, left ventricle; PA, pulmonary arteries; PV, pulmonary veins; SVC, superior vena cava; *, Fontan baffle. B. Diagrammatic representation of the location of various types of Fontan operations. (Part B used with permission from Emily Flynn McIntosh, illustrator.)

PV SVC Extracardiac conduit CHAPTER 280 IVC LA * * LV Congenital Heart Disease in the Adult PA Ao

43 - 281 Pericardial Disease

281 Pericardial Disease

■ ■UNREPAIRED CYANOTIC CHD

Eisenmenger Syndrome  ES is felt to be the consequence of a long-standing high-volume or pressurized left-to-right shunt in which excessive blood flow to the pulmonary vasculature leads to severely increased pulmonary vascular resistance that eventually results in reversal of the shunt, creating bidirectional or right-to-left flow. ES is a multiple-organ condition and may occur with any CHD with an initial left-to-right shunt. The natural history of ES is variable, and although there is significant morbidity, in general, adults with ES appear to survive longer than those with other forms of pulmonary arterial hypertension. Medical care recommendations have included sustain­ ing adequate hydration, avoiding, and treating anemia including iron supplementation when appropriate, and anticoagulation (although this remains controversial due to predisposition to bleeding and occur­ rence of clinical hemoptysis, which has frequently been associated with pulmonary vascular thrombosis). Elevation of hematocrit above that considered appropriate for the degree of cyanosis can be managed in symptomatic patients by hydration alone or, on occasion, by perform­ ing phlebotomy with isovolumic replenishment. Routine phlebotomy in the asymptomatic adult with ES is contraindicated. Appropriate optimization of iron stores has been demonstrated to improve qual­ ity of life and functional performance in iron-deficient adults with ES. Contraception for women with ES who are of childbearing age is strongly recommended, avoiding use of estrogen, which may be throm­ bogenic. Pregnancy is contraindicated in these women due to the high risk of maternal mortality. PART 6 Disorders of the Cardiovascular System Selective pulmonary vasodilators, such as bosentan or sildenafil, are efficacious in ES. Select patients may be candidates for combined heart–lung transplantation or preferably lung transplantation with concomitant repair of the intracardiac defect, if feasible. The Role of Palliative Care in ACHD  In aggregate, adults with CHD demonstrate both quality-of-life–limiting comorbidities and premature mortality far in excess of age-matched controls. The reported prevalence of pain, anxiety, depression, dyspnea, and fatigue appears similar to that reported for adults who are decades older and engaged in palliative care for acquired cardiovascular disease at end of life (EOL). Similarly, at EOL with ACHD, frequencies of hospital­ ization, intensive care admission, 30-day readmission, and increased length of hospital stay appear greater (despite younger age) than for adults with cancer. In a retrospective study of ACHD patients who died during a hospital admission, only a minority had engaged in EOL discussions with their providers. Surveys of both adults with CHD and their providers suggest that the overwhelming majority of patients wish to participate in advanced care planning and discussion of palliative care; this contrasts with statements from ACHD care providers noting their uncertainties regarding EOL prognostication and concerns over discussion about EOL. Palliative care specialists who are embedded within or aligned with ACHD care teams can play an important and iterative role in defining and addressing alignment of patient and clini­ cian goals within the boundaries of frequently complex care decisions over the adult life span. Global Considerations  As survival patterns improve for all medically complex patients, the internist and general practitioner are faced with particular challenges and dilemmas; foremost is accrual of sufficient knowledge and competency so as to be able both to engage in patient care provision as well as to seek greater expertise, guidance, and support, when such is appropriate. Across the globe, lifelong care for adults with CHD typifies this growing demand. Care for adults with CHD within medical care centers that contain an ACHD specialty care program has been associated with improved overall survival. However, current analyses suggest that the majority of adults with CHD seek and receive their medical care outside of such ACHD specialty care centers and within the hands of the general practitioner, internist, and cardiologist. Under a surface of adaptability and determination, adults with CHD present a wide spectrum of cognitive and functional perfor­ mance, multiple organ system comorbidities, abnormalities of systemic and pulmonary vasculature, and a near universal presence of heart

failure of one stage or another, all over a lifetime. It appears incumbent on the ACHD specialist and ACHD specialty care centers to serve as a hub for partnering practitioners, encouraging engagement to the level of highest competencies, and providing education, oversight, and sup­ port, so as to achieve optimal outcomes. ■ ■FURTHER READING Gilboa SM et al: Congenital heart defects in the United States: Esti­ mating the magnitude of the affected population in 2010. Circulation 134:101, 2016. Gurvitz M et al: Emerging research directions in adult congenital heart disease: A report from an NHLBI/ACHA Working Group. J Am Coll Cardiol 67:1956, 2016. Holzer R et al: PICS/AEPC/APPCS/CSANZ/SCAI/SOLACI: Expert consensus statement on cardiac catheterization for pediatric patients and adults with congenital heart disease. JACC Cardiovasc Interv 17:115, 2024. Regitz-Zagrosek V et al: 2018 ESC guidelines for the management of cardiovascular diseases during pregnancy. Eur Heart J 39:3165, 2018. Sachdeva R et al: ACC/AHA/ASE/HRS/ISACHD/SCAI/SCCT/ SCMR/SOPE 2020 Appropriate Use Criteria for non-invasive mul­ timodality imaging during the follow-up care of patients with con­ genital heart disease: A report of the American College of Cardiology Solution Set Oversight Committee and Appropriate Use Criteria Task Force, American Heart Association, American Society of Echo­ cardiography, Heart Rhythm Society, International Society for Adult Congenital Heart Disease, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomogra­ phy, Society for Cardiovascular Magnetic Resonance, and Society of Pediatric Echocardiography. J Am Coll Cardiol 75:657, 2020. Silversides CK et al: Pregnancy outcomes in women with heart dis­ ease: The CARPREG II Study. J Am Coll Cardiol 71:2419, 2018. Stout KK et al: 2018 AHA/ACC guidelines for the management of adults with congenital heart disease: A report of the American Col­ lege of Cardiology/American Heart Association Task Force on Clini­ cal Practice Guidelines. Circulation 139:e698, 2019. Joseph Loscalzo

Pericardial Disease ■ ■NORMAL FUNCTIONS OF THE PERICARDIUM The normal pericardium is a double-layered sac of the visceral pericar­ dium and parietal pericardium. The visceral pericardium is a serous membrane that is separated from the fibrous parietal pericardium by a small quantity (15–50 mL) of fluid, an ultrafiltrate of plasma. The nor­ mal pericardium, by exerting a restraining force, prevents sudden dila­ tion of the cardiac chambers, especially the right atrium and ventricle, e.g., during exercise. It also restricts the anatomic position of the heart and likely retards the spread of infections from the lungs and pleural cavities to the heart. Nevertheless, total absence of the pericardium, either congenital or after surgery, does not produce obvious clinical disease. In partial left pericardial defects, the main pulmonary artery and left atrium may bulge through the defect; very rarely, herniation and subsequent strangulation of the left atrium may cause sudden death. ACUTE PERICARDITIS Acute pericarditis, by far the most common pathologic process involving the pericardium (Table 281-1), has four principal diagnostic features:

  1. Chest pain is usually present in acute infectious pericarditis and in many of the forms presumed to be related to hypersensitivity,

TABLE 281-1  Classification of Pericarditis Clinical Classification I. Acute pericarditis (<6 weeks)

A. Fibrinous

B. Effusive (serous or sanguineous) II. Subacute pericarditis (6 weeks to 6 months) A. Effusive-constrictive B. Constrictive III. Chronic pericarditis (>6 months) A. Constrictive B. Adhesive (nonconstrictive) Etiologic Classification I. Infectious pericarditis A. Viral (coxsackievirus A and B, echovirus, herpesviruses, mumps, adenovirus, hepatitis, HIV, post-acute COVID, mpox) B. Pyogenic (pneumococcus, Streptococcus, Staphylococcus, Neisseria, Legionella, Chlamydia) C. Tuberculous D. Fungal (histoplasmosis, coccidioidomycosis, Candida, blastomycosis) E. Other infections (syphilitic, protozoal, parasitic) II. Noninfectious pericarditis A. Acute idiopathic B. Renal failure C. Neoplasia

  1. Primary tumors (benign or malignant, mesothelioma)
  2. Tumors metastatic to pericardium (lung and breast cancer, lymphoma, leukemia) D. Trauma (penetrating chest wall, nonpenetrating) E. Aortic dissection (with leakage into pericardial sac) F. Acute myocardial infarction G. Postirradiation H. Familial Mediterranean fever and other autoinflammatory syndromes I. Familial pericarditis
  3. Mulibrey nanisma J. Metabolic (myxedema, cholesterol) III. Pericarditis presumably related to autoimmunity A. Rheumatic fever B. Collagen vascular disease (systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, scleroderma, acute rheumatic fever, granulomatosis with polyangiitis, IgG4 disease) C. Drug-induced (e.g., procainamide, hydralazine, phenytoin, isoniazid, minoxidil, anticoagulants, methysergide) D. Postcardiac injury
  4. Postpericardiotomy
  5. Posttraumatic
  6. Postmyocardial infarction (Dressler’s syndrome) aAn autosomal recessive syndrome characterized by growth failure, muscle hypotonia, hepatomegaly, ocular changes, enlarged cerebral ventricles, intellectual disability, ventricular hypertrophy, and chronic constrictive pericarditis. Abbreviation: COVID, coronavirus disease. autoimmunity, or of unknown cause (idiopathic). The pain of acute pericarditis is often severe, retrosternal and/or left precordial, and referred to the neck, arms, or left shoulder. Frequently the pain is pleuritic, consequent to accompanying pleural inflammation (i.e., sharp and aggravated by inspiration and coughing); however, at times, it is steady, radiates to the trapezius ridge or into either arm, and resembles that of myocardial ischemia. For this reason, confu­ sion with acute myocardial infarction (AMI) is common. Charac­ teristically, pericardial pain may be intensified by lying supine and relieved by sitting up and leaning forward (Chap. 15). Pain is often absent in slowly developing tuberculous, postirradiation, neoplastic, and uremic pericarditis. The differentiation of AMI from acute pericarditis may be chal­ lenging when, with the latter, serum biomarkers of myocardial damage rise, presumably because of concomitant involvement of the

epicardium in the inflammatory process (an epi-myocarditis) with resulting myocyte necrosis. If they occur, however, these elevations are quite modest compared to those in AMI, given the superficial (sub-)epicardial injury despite often extensive electrocardiographic ST-segment elevation in pericarditis. This dissociation is useful in differentiating between these conditions. 2. A pericardial friction rub is audible at some point in the illness in

CHAPTER 281 approximately 85% of patients with acute pericarditis. The rub may have up to three components per cardiac cycle and is described as rasping, scratching, or grating (Chap. 246); it is heard most frequently at end expiration with the patient upright and leaning forward. 3. The electrocardiogram (ECG) in acute pericarditis without massive Pericardial Disease effusion usually displays changes secondary to acute subepicardial inflammation (Fig. 281-1A), and typically evolves through four stages. In stage 1, there is widespread elevation of the ST segments, often with upward concavity, involving two or three standard limb leads and V2–V6, with reciprocal depressions only in aVR and occasionally V1. In addition, there is depression of the PR segment below the TP segment, reflecting atrial involvement, an early change that may occur prior to ST segment elevation. Usually there are no significant changes in QRS complexes unless a large pericardial effu­ sion develops (see below). After several days, the ST segments return to normal (stage 2), and only then, or even later, do the T waves become inverted (stage 3). Weeks or months after the onset of acute pericarditis, the ECG returns to normal (stage 4). In contrast, in AMI, ST elevations are upwardly convex, and reciprocal depression is usually more prominent; these changes may return to normal within a day or two (Chaps. 285 and 286). 4. Pericardial effusion is usually associated with pain and/or the ECG changes mentioned above and, if the effusion is large, with electrical alternans (Fig. 281-1B). Pericardial effusion is especially important clinically when it develops within a relatively short time because it may lead to cardiac tamponade (see below). Differentiation from cardiac enlargement on physical examination may be difficult, but heart sounds may be fainter with large pericardial effusion. The fric­ tion rub and the apex impulse may disappear. The base of the left lung may be compressed by pericardial fluid, producing Ewart’s sign, a patch of dullness, increased fremitus, and egophony beneath the angle of the left scapula. The chest x-ray may show enlargement of the cardiac silhouette, with a “water bottle” configuration, but may be normal in patients with small effusions. Diagnosis  Echocardiography (Chap. 248) is the most widely used imaging technique. It is sensitive, specific, simple, and noninvasive; may be performed at the bedside; and allows localization and estima­ tion of the quantity of pericardial fluid. The presence of pericardial fluid is recorded by two-dimensional transthoracic echocardiography as a relatively echo-free space between the posterior pericardium and left ventricular epicardium and/or as a space between the anterior right ventricle and the parietal pericardium just beneath the anterior chest wall (Fig. 281-2). The diagnosis of pericardial fluid or thickening may be confirmed by computed tomography (CT) or magnetic resonance imaging (MRI). These techniques may be superior to echocardiography in detecting loculated pericardial effusions and pericardial thickening, and in the identification of pericardial masses. MRI is also helpful in detecting pericardial inflammation (Fig. 281-3). TREATMENT Acute Pericarditis There is no specific therapy for acute idiopathic pericarditis, but bed rest may be recommended, and anti-inflammatory treat­ ment with aspirin (2–4 g/d) or nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen (600–800 mg tid) or indo­ methacin (25–50 mg tid), should be administered along with gastric protection (e.g., omeprazole 20 mg/d). In responsive

I aVR PR ST PART 6 Disorders of the Cardiovascular System II aVL III aVF A aVR V1 V4 I aVL V2 V5 II aVF V3 V6 III II B FIGURE 281-1  A. Acute pericarditis. There are diffuse ST-segment elevations in leads I, II, aVF, and V2–V6). There is PR-segment depression due to a concomitant atrial injury current. B. Electrical alternans. This tracing was obtained from a patient with a large pericardial effusion with cardiac tamponade. patients, these doses should be continued for 1–2 weeks and then tapered over several weeks. In addition, colchicine (0.5 to 0.6 mg qd [<70 kg] or 0.5 to 0.6 mg bid [>70 kg]) should be adminis­ tered for 3 months. Colchicine enhances the response to NSAIDs FIGURE 281-2  Two-dimensional echocardiogram in lateral view in a patient with a large pericardial effusion. Ao, aorta; LA, left atrium; LV, left ventricle; pe, pericardial effusion; RV, right ventricle. (Reproduced with permission from Imazio M: Contemporary management of pericardial diseases. Curr Opin Cardiol 27:308, 2012.)

V1 V4 ST PR V2 V5 V3 V6 and also aids in reducing the risk of recurrent pericarditis. This drug is concentrated in and interferes with the migration of neutrophils, may cause diarrhea and other gastrointestinal side effects, and is contraindicated in patients with hepatic or renal dysfunction. Glucocorticoids (e.g., prednisone 1 mg/kg per day) usually suppress the clinical manifestations of acute pericardi­ tis in patients who have failed therapy with or do not tolerate NSAIDs and colchicine. However, since they increase the risk of subsequent recurrence, full-dose corticosteroids should be given for only 2–4 days and then tapered. Anticoagulants should be avoided because their use could cause bleeding into the pericar­ dial cavity and tamponade. In patients with multiple, frequent, and disabling recurrences that continue for >2 years, are not prevented by continuing colchi­ cine and other NSAIDs, and are not controlled by glucocorticoids, treatment with azathioprine or anakinra (an interleukin 1β receptor antagonist) has been reported to be of benefit. Rarely, pericardial stripping may be necessary; however, this procedure may not always terminate the recurrences. The majority of patients with acute pericarditis can be man­ aged as outpatients with careful follow-up. However, when specific causes (tuberculosis, neoplastic disease, bacterial infection) are sus­ pected, or if any of the predictors of poor prognosis (fever >38°C, subacute onset, large pericardial effusion, immunosuppression, or evidence of pericardial tamponade) are present, hospitalization is advisable.

RV LV LV A B FIGURE 281-3  Pericardial inflammation by cardiac magnetic resonance imaging. A. Short axis view. The pericardium is thickened and enhanced on T2 magnetic images. Note thickened white line denoted by arrow. B. Long axis view. Late gadolinium enhancement of thickened, inflamed pericardium. AO, aorta; LA, left atrium; LV, left ventricle; RV, right ventricle. (From RY Kwong: Cardiovascular magnetic resonance imaging, in Braunwald’s Heart Disease, 10th ed, Mann DL et al [eds]. Philadelphia: Elsevier, 2015, pp 320–40.) ■ ■CARDIAC TAMPONADE The accumulation of fluid in the pericardial space in a quantity suf­ ficient to cause serious obstruction of the inflow of blood into the ventricles results in cardiac tamponade. This complication may be fatal if it is not recognized and treated promptly. The most common causes of tamponade are idiopathic pericarditis and pericarditis secondary to neoplastic disease, tuberculosis, or bleeding into the pericardial space after leakage from an aortic dissection, cardiac operation, trauma, or treatment with anticoagulants. The three principal features of tamponade (Beck’s triad) are hypo­ tension, soft or absent heart sounds, and jugular venous distention with a prominent x (early systolic) descent but an absent y (early diastolic) descent. The limitations to ventricular filling are responsible for reduc­ tions of cardiac output and arterial pressure. The quantity of fluid necessary to produce cardiac tamponade may be as small as 200 mL when the fluid develops rapidly or be as much as >2000 mL in slowly developing effusions when the pericardium has had the opportunity to stretch and adapt to an increasing volume. TABLE 281-2  Features That Distinguish Cardiac Tamponade from Constrictive Pericarditis and Similar Clinical Disorders CONSTRICTIVE PERICARDITIS CHARACTERISTIC TAMPONADE Clinical Pulsus paradoxus +++ + + + +++ Jugular veins   Prominent y descent – ++ + + –   Prominent x descent +++ ++ +++ + +++   Kussmaul’s sign – +++ + +++ ++ Third heart sound – – + + + Pericardial knock – ++ – – – Electrocardiogram Low ECG voltage ++ ++ + – + Electrical alternans ++ – – – + Echocardiogram Thickened pericardium – +++ – – ++ Pericardial calcification – ++ – – _ Pericardial effusion +++ – – – ++ RV size Usually small Usually normal Usually normal Enlarged Usually normal Exaggerated respiratory variation in flow velocity +++ +++ – +++ + CT/MRI Thickened pericardium – +++ – ++ Equalization of diastolic pressures +++ +++ – ++ ++ Abbreviations: +++, always present; ++, usually present; +, rare; –, absent; CT, computed tomography; ECG, electrocardiogram; MRI, magnetic resonance imaging; RV, right ventricle. Source: Reproduced with permission from GM Brockington et al: Constrictive pericarditis. Cardiol Clin 8:645, 1990.

LA AO CHAPTER 281 * * Pericardial Disease * A high index of suspicion for cardiac tamponade is required because in many instances no obvious cause for pericardial disease is apparent. This diagnosis should be considered in any patient with otherwise unexplained sudden enlargement of the cardiac silhouette, hypoten­ sion, and elevation of jugular venous pressure. Reductions in amplitude of the QRS complexes and electrical alternans of the P, QRS, or T waves should also raise the suspicion of cardiac tamponade (Fig. 281-1). Table 281-2 lists the features that distinguish acute cardiac tamponade from constrictive pericarditis. Paradoxical Pulse  This important clue to the presence of cardiac tamponade consists of a greater than normal (10 mmHg) inspiratory decline in systolic arterial pressure. When severe, it may be detected by palpating weakness or even disappearance of the arterial pulse during inspiration, but usually sphygmomanometric measurement of systolic pressure during slow respiration is required. Because both ventricles share a tight incompressible covering, i.e., the pericardial sac, the inspiratory enlargement of the right ventricle RIGHT VENTRICULAR MYOCARDIAL INFARCTION RESTRICTIVE CARDIOMYOPATHY EFFUSIVE CONSTRICTIVE PERICARDITIS

Inspiration Expiration Septum E Septum E A A TV TV MV MV LV RV PART 6 Disorders of the Cardiovascular System Doppler transvalvular inflow patterns Thickened pericardium RA Pulmonary vein LA DIASTOLE DIASTOLE IVC and hepatic veins Apical 4-chamber views FIGURE 281-4  Constrictive pericarditis. Doppler schema of respirophasic changes in mitral and tricuspid inflow. Reciprocal patterns of ventricular filling are assessed on pulsed Doppler examination of mitral valve (MV) and tricuspid valve (TV) inflow. IVC, inferior vena cava; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. (Courtesy of Bernard E. Bulwer, MD.) causes leftward bulging of the interventricular septum, reducing left ventricular volume, stroke volume, and arterial systolic pressure. Para­ doxical pulse also occurs in approximately one-third of patients with constrictive pericarditis (see below), and in some cases of hypovolemic shock, acute and chronic obstructive airway disease, and pulmonary embolism. Right ventricular infarction (Chap. 286) may resemble cardiac tamponade with hypotension, elevated jugular venous pres­ sure, a slow y descent in the jugular venous pulse, and, occasionally, a paradoxical pulse (Table 281-2). Diagnosis  Because immediate treatment of cardiac tamponade may be lifesaving, prompt establishment of the diagnosis, usually by echocardiography, should be undertaken. When pericardial effusion causes tamponade, Doppler ultrasound shows that tricuspid and pulmonic valve flow velocities increase markedly during inspiration, whereas pulmonic vein, mitral, and aortic flow velocities decrease (as in constrictive pericarditis, see below) (Fig. 281-4). In tamponade, there is late diastolic inward motion (collapse) of the right ventricular free wall and the right atrium. Transesophageal echocardiography, CT, or cardiac MRI may be necessary to diagnose a loculated effusion responsible for cardiac tamponade. TREATMENT Cardiac Tamponade Patients with acute pericarditis should be observed frequently for the development of an effusion. If a large effusion is present, peri­ cardiocentesis should be performed or the patient watched closely for signs of tamponade with serial echocardiography and monitor­ ing of arterial and venous pressures. PERICARDIOCENTESIS If manifestations of tamponade appear, pericardiocentesis using an apical, parasternal, or, most commonly, subxiphoid approach must be carried out at once because if left untreated, tamponade may be rapidly fatal. Whenever possible, this procedure should be carried out under echocardiographic guidance. Intravenous saline may be administered as the patient is being readied for the procedure, but the pericardiocentesis must not be delayed. If possible, intraperi­ cardial pressure should be measured before fluid is withdrawn, and the pericardial cavity should be drained as completely as possible. A small, multiholed catheter may be advanced over the needle inserted into the pericardial cavity and left in place to allow drain­ ing of the pericardial space if fluid reaccumulates. Surgical drainage through a limited (subxiphoid) thoracotomy may be required in recurrent tamponade to remove loculated effusions and/or when it is necessary to obtain tissue for diagnosis.

Pericardial fluid obtained from an effusion may have the physical characteristics of an exudate. In developed nations, bloody fluid is most commonly due to neoplasm, renal failure, or cardiac trauma. In developing nations, tuberculosis may also cause exudative and/ or bloody effusion. The pericardial fluid should be analyzed for red and white blood cells and cytology for neoplastic cells. Cultures should be obtained. The presence of DNA of Mycobacterium tuberculosis determined by the polymerase chain reaction and/or of an elevated adenosine deaminase strongly supports the diagnosis of tuberculous pericar­ ditis; however, it is often necessary to obtain pericardial tissue to make this diagnosis (Chap. 183). ■ ■VIRAL OR IDIOPATHIC ACUTE PERICARDITIS In many instances, acute pericarditis occurs in association with or following illnesses of known or presumed viral origin and probably is caused by the same agent. There may be an antecedent infection of the respiratory tract, but viral isolation and serologic studies are usually negative. In some cases, coxsackievirus A or B or the virus of influenza, echovirus, mumps, herpes simplex, varicella-zoster, adeno­ virus, or cytomegalovirus has been isolated from pericardial fluid, and/ or appropriate elevations in viral antibody titers have been observed. Frequently, a viral cause cannot be established, and the term idiopathic acute pericarditis is appropriate. Viral or idiopathic acute pericarditis occurs at all ages but is most common in young adult males and is often associated with pleural effu­ sion and pneumonitis. The almost simultaneous development of fever and precordial pain, often 10–12 days after a presumed viral illness, constitutes an important feature in the differentiation of acute pericar­ ditis from AMI, in which chest pain precedes fever. The constitutional symptoms are usually mild to moderate, and a pericardial friction rub is often audible. The disease ordinarily runs its course in a few days to 4 weeks. Elevations of C-reactive protein and of the white blood cell count are common. The ST-segment alterations in the ECG usually dis­ appear after 1 or more weeks, but the abnormal T waves may persist for as long as several years and be a source of confusion in persons without a clear history of pericarditis. Accumulation of some pericardial fluid is common, and both tamponade and constrictive pericarditis are pos­ sible, but infrequent, complications. The most frequent complication is recurrent (relapsing) pericardi­ tis, which occurs in approximately one-fourth of patients with acute idiopathic pericarditis. A smaller number of individuals have multiple recurrences. Postcardiac Injury Syndrome  Acute pericarditis may appear in a variety of circumstances that have one common feature—previous injury to the myocardium with blood in the pericardial cavity. The syndrome may develop after a cardiac operation (postpericardiotomy syndrome), after blunt or penetrating cardiac trauma (Chap. 283), or after perforation of the heart with a catheter; rarely, it follows AMI. The clinical picture mimics acute viral or idiopathic pericarditis. The principal symptom is the pain of acute pericarditis, which usually develops 1–4 weeks after the cardiac injury. Recurrences are common and may occur up to 2 years or more following the injury. Fever, pleuri­ tis, and pneumonitis are accompanying features, and the illness usually subsides in 1 or 2 weeks. The pericarditis may be of the fibrinous vari­ ety, or it may be a pericardial effusion, which is often serosanguinous and rarely causes tamponade. ECG changes typical of acute pericarditis may also occur. This syndrome is probably the result of a hypersensitiv­ ity (or autoimmune) reaction to antigen(s) that originate from injured myocardial tissue and/or pericardium. Often no treatment is necessary aside from aspirin and analgesics. When the illness is severe or followed by a series of disabling recur­ rences, therapy with another NSAID, colchicine, or a glucocorticoid, such as described for treatment of acute pericarditis, is usually effective. ■ ■DIFFERENTIAL DIAGNOSIS Because there is no specific test for acute idiopathic pericarditis, the diagnosis is one of exclusion. Consequently, all other disorders that

may be associated with acute fibrinous pericarditis must be considered. A common diagnostic error is mistaking acute viral or idiopathic peri­ carditis for AMI and vice versa. Pericarditis secondary to postcardiac injury is differentiated from acute idiopathic pericarditis chiefly by timing. If it occurs within a few days or weeks of a chest blow, a cardiac perforation, a cardiac opera­ tion, or an AMI, the two are probably related. It is important to distinguish pericarditis due to collagen vascular disease from acute idiopathic pericarditis. Most important in the dif­ ferential diagnosis is the pericarditis due to systemic lupus erythemato­ sus (SLE; Chap. 368) or drug-induced (hydralazine or procainamide) lupus. When pericarditis occurs in the absence of any obvious under­ lying disorder, the diagnosis of SLE may be suggested by a rise in the titer of antinuclear antibodies. Acute pericarditis is an occasional com­ plication of rheumatoid arthritis, scleroderma, and polyarteritis nodosa, and other evidence of these diseases is usually obvious at the time of presentation with acute pericarditis. Pyogenic (purulent) pericarditis is usually secondary to cardiotho­ racic operations, by extension of infection from the lungs or pleural cavities, from rupture of the esophagus into the pericardial sac, or from rupture of a valvular ring abscess in a patient with infective endocardi­ tis. It may also complicate the viral, bacterial, mycobacterial, and fungal infections that occur with HIV infection. It is generally accompanied by fever, chills, septicemia, and evidence of infection elsewhere, and generally has a poor prognosis. The diagnosis is made by examination of the pericardial fluid. It requires immediate drainage as well as vigor­ ous antibiotic treatment. Pericarditis of renal failure (uremic pericarditis) occurs in up to one-third of patients with severe renal dysfunction and is also seen in patients undergoing chronic dialysis who have normal levels of blood urea nitrogen (dialysis-associated pericarditis). These two forms of pericarditis may be fibrinous and are generally associated with serosanguinous effusions; frank hemorrhagic effusions may be seen in some cases of uremic pericarditis prior to the onset of dialysis. A pericardial friction rub is common, but pain is usually absent or mild. Treatment with an NSAID and intensification of dialysis are usually adequate. Occasionally, tamponade occurs and pericardiocentesis is required. When the pericarditis of renal failure is recurrent or persis­ tent, a pericardial window should be created or pericardiectomy may be necessary. Pericarditis due to neoplastic diseases results from extension or invasion of metastatic tumors (most commonly carcinoma of the lung and breast, malignant melanoma, lymphoma, and leukemia) to the pericardium. The pain of pericarditis, tamponade, and atrial arrhythmias are complications that occur occasionally. Diagnosis is made by pericardial fluid cytology or pericardial biopsy. Mediastinal irradiation for neoplasm may cause acute pericarditis and/or chronic constrictive pericarditis. Unusual causes of acute pericarditis include syphilis, fungal infection (histoplasmosis, blastomycosis, aspergillosis, and candidiasis), and parasitic infestation (amebiasis, toxoplasmosis, echinococcosis, and trichinosis) (Table 281-1). ■ ■CHRONIC PERICARDIAL EFFUSIONS Chronic pericardial effusions are sometimes encountered in patients without an antecedent history of acute pericarditis. They may cause few symptoms per se, and their presence may be detected by finding an enlarged cardiac silhouette on a chest roentgenogram. Tuberculosis and myxedema may be causal. Neoplasms, SLE, rheumatoid arthritis, mycotic infections, radiation therapy to the chest, and chyloperi­ cardium may also cause chronic pericardial effusion and should be considered and specifically sought in such patients. Aspiration and analysis of the pericardial fluid are often helpful in diagnosis. Pericar­ dial fluid should be analyzed as described under pericardiocentesis. Grossly sanguineous pericardial fluid results most commonly from a neoplasm, tuberculosis, renal failure, or slow leakage from an aortic dissection. Pericardiocentesis may resolve large effusions, but pericar­ diectomy may be required in patients with recurrence. Intrapericardial instillation of sclerosing agents may be used to prevent reaccumula­ tion of fluid, most commonly in recurrent neoplastic effusions.

CHRONIC CONSTRICTIVE PERICARDITIS This disorder results when the healing of an acute fibrinous or serofi­ brinous pericarditis or the resorption of a chronic pericardial effusion is followed by obliteration of the pericardial cavity with the formation of granulation tissue. The latter gradually contracts and forms a firm scar encasing the heart, which may become calcified. In developing nations, a high percentage of cases are of tuberculous origin, but this is now an uncommon cause in North America or Western Europe. Chronic constrictive pericarditis may follow acute or relapsing viral or idiopathic pericarditis, trauma with organized blood clot, or cardiac surgery of any type, or results from mediastinal irradiation, purulent infection, histoplasmosis, neoplastic disease (especially breast cancer, lung cancer, and lymphoma), rheumatoid arthritis, SLE, or chronic renal failure treated by chronic dialysis. In many patients, the cause of the pericardial disease is undetermined, and in these patients, an asymptomatic or forgotten bout of viral pericarditis, idiopathic or acute, may have been the inciting event.

CHAPTER 281 Pericardial Disease The basic physiologic abnormality in patients with chronic constric­ tive pericarditis is the inability of the ventricles to fill owing to the limitations imposed by the rigid, thickened pericardium. Ventricular filling is unimpeded during early diastole but is reduced abruptly when the elastic limit of the pericardium is reached, whereas in cardiac tamponade, ventricular filling is impeded throughout diastole. In both conditions, ventricular end-diastolic and stroke volumes are reduced and the end-diastolic pressures in both ventricles and the mean pres­ sures in the atria, pulmonary veins, and systemic veins are all elevated to similar levels (i.e., within 5 mmHg of one another). Despite these hemodynamic changes, systolic function may be normal or only slightly impaired at rest. However, in advanced cases, the fibrotic pro­ cess may extend into the myocardium and cause myocardial scarring and atrophy, and venous congestion may then be due to the combined effects of the pericardial and myocardial lesions. In constrictive pericarditis, the right and left atrial pressure pulses display an M-shaped contour, with prominent x and y descents. The y descent, which is absent or diminished in cardiac tamponade, is the most prominent deflection in constrictive pericarditis; it reflects rapid early filling of the ventricles. The y descent is interrupted by a rapid rise in atrial pressure during early diastole, when ventricular filling is impeded by the constricting pericardium. These characteristic changes are transmitted to the jugular veins where they may be recognized by inspection. In constrictive pericarditis, the ventricular pressure pulses in both ventricles exhibit the characteristic “square root” sign during diastole. These hemodynamic changes, although characteristic, are not pathognomonic of constrictive pericarditis and may also be observed in restrictive cardiomyopathies (Chaps. 266–270, Table 266-1). ■ ■CLINICAL AND LABORATORY FINDINGS Weakness, fatigue, weight gain, increased abdominal girth, abdominal discomfort, and edema are common. The patient often appears chroni­ cally ill, and in advanced cases, anasarca, skeletal muscle wasting, and cachexia may be present. Exertional dyspnea is common, and orthop­ nea may occur, although it is usually not severe. The neck veins are distended and may remain so even after intensive diuretic treatment, and venous pressure may fail to decline during inspiration (Kussmaul’s sign). The latter is common in chronic pericarditis but may also occur in tricuspid stenosis, right ventricular infarction, and restrictive cardiomyopathy. The pulse pressure is normal or reduced. A paradoxical pulse can be detected in about one-third of cases. Congestive hepatomegaly is pronounced, may impair hepatic function, and may cause jaundice; ascites is common and is usually more prominent than dependent edema. Pleural effusions and splenomegaly may also be present. The apical pulse is reduced and may retract in systole (Broadbent’s sign). The heart sounds may be distant; an early third heart sound (i.e., a pericardial knock) occurring at the cardiac apex with the abrupt cessa­ tion of ventricular filling is often conspicuous. The ECG frequently displays low voltage of the QRS complexes and diffuse flattening or inversion of the T waves. Atrial fibrillation is present in about one-third of patients. The chest roentgenogram shows

44 - 282 Atrial Myxoma and Other Cardiac Tumors

282 Atrial Myxoma and Other Cardiac Tumors

a normal or slightly enlarged heart. Pericardial calcification is most common in tuberculous pericarditis. Pericardial calcification may, however, occur in the absence of constriction, and constriction may occur without calcification.

Inasmuch as the common physical signs of cardiac disease (mur­ murs, cardiac enlargement) may be inconspicuous or absent in chronic constrictive pericarditis, hepatic enlargement and dysfunction asso­ ciated with jaundice and intractable ascites may lead to a mistaken diagnosis of hepatic cirrhosis. This error can be avoided if the neck veins are inspected and found to be distended with the characteristic waveform features. PART 6 Disorders of the Cardiovascular System The transthoracic echocardiogram often shows pericardial thicken­ ing, dilation of the inferior vena cava and hepatic veins, and a sharp halt to rapid left ventricular filling in early diastole, with normal ventricular systolic function and flattening of the left ventricular posterior wall. There is a distinctive pattern of transvalvular flow velocity on Doppler echocardiography (Fig. 281-4). During inspiration, there is an exagger­ ated reduction in blood flow velocity in the pulmonary veins and across the mitral valve, and a leftward shift of the ventricular septum; the opposite occurs during expiration. Diastolic flow velocity in the inferior vena cava into the right atrium and across the tricuspid valve increases in an exaggerated manner during inspiration and declines during expiration. However, echocardiography cannot definitively establish or exclude the diagnosis of constrictive pericarditis; CT and MRI are more accurate, with the latter useful in evaluating myocardial involvement. ■ ■DIFFERENTIAL DIAGNOSIS As with chronic constrictive pericarditis, cor pulmonale (Chap. 264) may be associated with marked systemic venous hypertension, little pulmonary congestion, a (left) heart that is not enlarged, and a para­ doxical pulse. However, in cor pulmonale, advanced parenchymal pulmonary disease is usually apparent and venous pressure falls dur­ ing inspiration (i.e., Kussmaul’s sign is negative). Tricuspid stenosis (Chap. 277) may also simulate chronic constrictive pericarditis with congestive hepatomegaly, splenomegaly, ascites, and venous distention. However, the characteristic murmur and that of accompanying mitral stenosis are usually present. Because it can be corrected surgically, it is important to distin­ guish chronic constrictive pericarditis from restrictive cardiomyopathy (Chap. 266), which has a similar pathophysiologic underpinning (i.e., restriction of ventricular filling). The differentiating features are sum­ marized in Table 281-2. When a patient has progressive, disabling, and unresponsive congestive heart failure and displays any of the features of constrictive heart disease, Doppler echocardiography to record respira­ tory effects on transvalvular flow (Fig. 281-4) should be performed and an MRI or CT scan should be obtained to detect or exclude constrictive pericarditis because the latter is usually correctable. TREATMENT Constrictive Pericarditis Pericardial resection is the only definitive treatment of constric­ tive pericarditis and should be as complete as possible. Coronary arteriography should be carried out preoperatively in patients aged

50 years to exclude accompanying coronary artery disease. The benefits derived from cardiac decortication are usually progressive over a period of months. The risk of this operation depends on the extent of penetration of the myocardium by the fibrotic and calcific process, the severity of myocardial atrophy, the extent of second­ ary impairment of hepatic and/or renal function, and the patient’s general condition. Operative mortality is in the range of 5–10% even in experienced centers; the patients with the most severe dis­ ease, especially secondary to radiation therapy, are at highest risk. Therefore, surgical treatment should, if possible, be carried out as early as possible. Subacute Effusive-Constrictive Pericarditis  This form of pericardial disease is characterized by the combination of a tense effu­ sion in the pericardial space and constriction of the heart by thickened

pericardium. As such, it shares a number of features with both chronic pericardial effusion producing cardiac compression and with pericar­ dial constriction. It may be caused by tuberculosis (see below), multiple attacks of acute idiopathic pericarditis, radiation, traumatic pericardi­ tis, renal failure, scleroderma, and neoplasms. The heart is generally enlarged, and a paradoxical pulse is usually present. After pericardio­ centesis, the physiologic findings may change from those of cardiac tamponade to those of pericardial constriction. Furthermore, the intra­ pericardial pressure and the central venous pressure may decline, but not to normal. The diagnosis can be established by pericardiocentesis followed by pericardial biopsy. Wide excision of both the visceral and parietal pericardium is usually effective therapy. Tuberculous Pericardial Disease  This chronic infection is a common cause of chronic pericardial effusion, especially in the developing world where active tuberculosis and HIV are endemic. Tuberculous pericarditis may present as pericardial effusion, chronic constrictive pericarditis, or subacute effusive-constrictive pericarditis (see above). The clinical picture is that of a chronic, systemic illness in a patient with pericardial effusion. It is important to consider this diagnosis in a patient with known tuberculosis, with HIV, and with fever, chest pain, weight loss, and enlargement of the cardiac silhouette of undetermined origin. If the etiology of chronic pericardial effusion remains obscure despite detailed analysis including culture of the peri­ cardial fluid, a pericardial biopsy, preferably by a limited thoracotomy, should be performed. If definitive evidence is still lacking but the speci­ men shows granulomas with caseation, antituberculous chemotherapy (Chap. 183) is indicated. If the biopsy specimen shows a thickened pericardium after 2–4 weeks of antituberculous therapy, pericardiectomy should be per­ formed to prevent the development of constriction. Tubercular cardiac constriction should be treated surgically while the patient is receiving antituberculous chemotherapy. ■ ■FURTHER READING Arula S, Madsen N: Management of acute pericarditis. Curr Opin Caradiol 38:364, 2023. Bayes-Coenis A et al: Colchicine in pericarditis. Eur Heart J 38:1706, 2017. Garcia MJ: Constrictive pericarditis versus restrictive cardiomyopa­ thy? J Am Coll Cardiol 67:2061, 2016. Imazio M et al: New developments in the management of recurrent pericarditis. Can J Cardiol 2023. Janus SE, Hoit BD: Effusive-constrictive pericarditis in the spectrum of pericardial comprehensive syndromes. Heart 15:heartjnl-2020-316664, 2021. LeWinter MM: Acute pericarditis. N Engl J Med 371:2410, 2014. Mircanda WR, Oh JK: Effusive-constrictive pericarditis. Cardiol Clin 3:551, 2017. Vistarini N et al: Pericardiectomy for constrictive pericarditis. Ann Thorac Surg 100:107, 2015. Welch TD: Constrictive pericarditis: Diagnosis, management, and clinical outcomes. Heart 104:725, 2018. Stephen Tsaur, Eric H. Awtry

Atrial Myxoma and

Other Cardiac Tumors Cardiac tumors can be broadly classified into those that arise primar­ ily in the heart and those that reflect metastatic disease from a distant primary source. Primary cardiac tumors can be further divided into those that are pathologically benign and those that are malignant.

TABLE 282-1  Imaging Modalities and Their Utility in the Evaluation of Cardiac Tumors MODALITY UTILITY IN CARDIAC TUMOR EVALUATION Transthoracic

echocardiography (TTE) (including two-dimensional, three-dimensional, and contrast) Assessment of tumor location and size and its impact on adjacent structures (e.g., valves, pericardium). Transesophageal echocardiography (TEE) Improved tumor characterization and spatial resolution compared with TTE. May aid in determining surgical approach. Cardiac magnetic resonance imaging (MRI) with gadolinium contrast Improved tissue characterization, definition of tumor size, and identification of local invasion when compared with TTE or TEE. May differentiate tumor from thrombus. Gated cardiac computed tomography (CT) Provides anatomic assessment and tissue characterization of the tumor. Useful when patients cannot tolerate MRI or when MRI is not feasible (e.g., patients with implantable cardiac devices). Allows for better assessment of calcified lesions and evaluation of extracardiac tumor involvement. Nuclear imaging (including 18F-fluorodeoxyglucose positron emission tomography [FDG-PET]) Definition of extracardiac disease. May be useful in diagnosis of certain cardiac tumors (e.g., neuroendocrine tumors), but assessment of smaller tumors may be limited by surrounding myocardial FDG uptake. Overall, primary cardiac tumors are relatively uncommon, whereas secondary involvement of the heart or pericardium occurs in as many as 20% of patients with end-stage metastatic cancer. While patients with cardiac tumors may present with a variety of symptoms, many patients are asymptomatic at the time of diagnosis, with the tumor being identified incidentally on imaging studies performed for other reasons. Cardiac tumors need to be differentiated from other cardiac masses such as vegetation, thrombus, inflammatory myofibroblastic tumors, or myocardial hypertrophy. Echocardiography is usually the initial imaging modality used to evaluate cardiac tumors; however, a variety of imaging modalities are now available, and a multimodality approach is often necessary for accurate diagnosis and clarification of treatment options (Table 282-1). When diagnosis is uncertain after echocardiography, cardiac magnetic resonance imaging (MRI) is often useful to help further differentiate lesions. Imaging characteristics, including size, location, presence of myocardial infiltration, and first pass perfusion of gadolinium contrast agents, can help differentiate benign from malignant tumors. However, tissue histology remains the gold standard for diagnosis of cardiac tumors. ■ ■PRIMARY TUMORS Primary tumors of the heart are rare, occurring in ~1 in 2000 patients in autopsy series. Approximately three-quarters are histologically benign, the majority of which are myxomas. Malignant tumors, almost all of which are sarcomas, account for 25% of primary cardiac tumors. All cardiac tumors, regardless of pathologic type, have the potential to cause life-threatening complications. Many tumors are now surgically curable; thus, early diagnosis is imperative. Clinical Presentation   Cardiac tumors may present with a wide array of cardiac and noncardiac manifestations. These manifestations, which depend in large part on the location and size of the tumor as well as its impact on surrounding cardiac structures, are often nonspecific features of more common forms of heart disease, and include chest pain, syncope, congestive heart failure (CHF), murmurs, arrhythmias, conduction disturbances, pericardial effusion, and pericardial tampon­ ade. Additionally, embolic phenomena and constitutional symptoms may occur. Myxoma   Myxomas are the most common type of primary cardiac tumor in adults, accounting for one-third to one-half of all cases at postmortem examination, and approximately three-quarters of the tumors treated surgically. They occur at all ages most commonly in the

third through sixth decades, with a female predilection. Approximately 90% of myxomas are sporadic; the remainder are familial with autoso­ mal dominant transmission. The familial variety often occurs as part of a syndrome complex (Carney complex) that includes (1) myxomas (cardiac, skin, and/or breast), (2) lentigines and/or pigmented nevi, and (3) endocrine overactivity (primary nodular adrenal cortical dis­ ease with or without Cushing’s syndrome, testicular tumors, and/or pituitary adenomas with gigantism or acromegaly). The genetic basis of this complex has not been elucidated completely; however, inactivating mutations in the tumor-suppressor gene PRKAR1A, which encodes the protein kinase A type I-α regulatory subunit, have been identified in ~70% of patients with Carney complex.

CHAPTER 282 Atrial Myxoma and Other Cardiac Tumors Pathologically, myxomas are gelatinous structures that consist of myxoma cells embedded in a stroma rich in glycosaminoglycans. Most sporadic tumors are solitary, arise from the interatrial septum in the vicinity of the fossa ovalis (particularly in the left atrium), and are often pedunculated on a fibrovascular stalk. In contrast, familial or syndromic tumors tend to occur in younger individuals, are often multiple, may be ventricular in location, and are more likely to recur after initial resection. Myxomas commonly present with obstructive signs and symptoms. The most common clinical presentation mimics that of mitral valve dis­ ease: either stenosis owing to tumor prolapse into the mitral orifice or regurgitation resulting from tumor-induced valvular trauma or distor­ tion. Ventricular myxomas may cause outflow tract obstruction similar to that caused by subaortic or subpulmonic stenosis. The symptoms and signs of myxoma may be sudden in onset or positional in nature, owing to the effects of gravity on tumor position. A characteristic lowpitched sound, a “tumor plop,” may be appreciated on auscultation during early or mid-diastole and is thought to result from the impact of the tumor against the mitral valve or ventricular wall. Myxomas also may present with peripheral or pulmonary embolic phenomenon (resulting from embolization of tumor fragments or tumor-associated thrombus) or with constitutional signs and symptoms, including fever, weight loss, cachexia, malaise, arthralgias, rash, digital clubbing, and Raynaud’s phenomenon. These constitutional symptoms are likely the result of cytokines (e.g., interleukin 6) secreted by the myxoma. Labo­ ratory abnormalities, such as hypergammaglobulinemia, anemia, poly­ cythemia, leukocytosis, thrombocytopenia or thrombocytosis, elevated erythrocyte sedimentation rate, and elevated C-reactive protein level are often present. These features account for the frequent misdiagnosis of patients with myxomas as having endocarditis, collagen vascular disease, or a paraneoplastic syndrome. Two-dimensional and three-dimensional transthoracic and/or transesophageal echocardiography are useful in the diagnosis of cardiac myxoma and allow for assessment of tumor size and deter­ mination of the site of tumor attachment, both of which are impor­ tant considerations in the planning of surgical excision (Fig. 282-1). A B FIGURE 282-1  Transthoracic echocardiogram demonstrating a large atrial myxoma. The myxoma (Myx) fills the entire left atrium in systole (A) and prolapses across the mitral valve and into the left ventricle (LV) during diastole (B). RA, right atrium; RV, right ventricle. (Courtesy of Dr. Michael Tsang; with permission.)

PART 6 Disorders of the Cardiovascular System FIGURE 282-2  Cardiac magnetic resonance imaging demonstrating a rounded mass (M) within the left atrium (LA). Pathologic evaluation at the time of surgery revealed it to be an atrial myxoma. LV, left ventricle; RA, right atrium; RV, right ventricle. Computed tomography (CT) and MRI may provide important addi­ tional information regarding size, shape, composition, and surface characteristics of the tumor (Fig. 282-2). Although cardiac catheterization and angiography were previously performed routinely before tumor resection, they no longer are con­ sidered mandatory when adequate noninvasive information is avail­ able and other cardiac disorders (e.g., coronary artery disease) are not considered likely. Additionally, catheterization of the chamber from which the tumor arises carries the risk of tumor embolization. Because myxomas may be familial, echocardiographic screening of first-degree relatives is appropriate, particularly if the patient is young and has multiple tumors or features of a myxoma syndrome. TREATMENT Myxoma Surgical excision using cardiopulmonary bypass is indicated regard­ less of tumor size and is generally curative. Myxomas recur in 12–22% of familial cases but in only 1–2% of sporadic cases. Tumor recurrence most likely results from multifocal lesions in the former setting and incomplete tumor resection in the latter. Other Benign Tumors   Cardiac lipomas, although relatively com­ mon, are usually incidental findings at postmortem examination; however, they may grow as large as 15 cm, may present as an abnor­ mality of the cardiac silhouette on chest x-ray, and should be resected if they produce symptoms owing to mechanical interference with cardiac function, arrhythmias, or conduction disturbances. Papillary fibroelastomas are friable tumors with frond-like projections that are usually solitary and are the most common tumors of the cardiac valves. Although usually clinically silent, they can cause valve dysfunction and may embolize distally, resulting in transient ischemic attacks, stroke, or myocardial infarction. In general, these tumors should be resected even when asymptomatic, although a more conservative approach may be considered for small, right-sided lesions. Rhabdomyomas and fibro­ mas are the most common cardiac tumors in infants and children and usually occur in the ventricles, where they may produce mechanical obstruction to blood flow, thereby mimicking valvular stenosis, CHF, restrictive or hypertrophic cardiomyopathy, or pericardial constriction. Rhabdomyomas are probably hamartomatous growths, are multiple in

RA RV T T LV T T FIGURE 282-3  Transthoracic echocardiogram revealing multiple tumors (T) consistent with rhabdomyomas in a 1-day-old infant. The largest tumor (arrows) was located in the left antrioventricular groove and measured 2 cm × 2 cm. LV, left ventricle; RA, right atrium; RV, right ventricle. 90% of cases, occur in ~50% of children with tuberous sclerosis, and are associated with mutations in the tumor-suppressor genes TSC1 and TSC2 (Fig. 282-3). These tumors have a tendency to regress completely or partially; only tumors that cause obstruction require surgical resec­ tion. Fibromas are usually single, universally ventricular in location, often calcified, and may be associated with mutations in the tumorsuppressor gene PTCH1. Fibromas tend to grow and cause arrhythmias and obstructive symptoms and should be completely resected when possible. Paragangliomas are rare chromaffin cell tumors that represent extra-adrenal pheochromocytomas. Most are located in the roof of the left atrium and can be identified on cardiac CT or MRI or with nuclear scanning using 131I-metaiodobenzylguanidine. They are highly vascu­ lar and may be hormonally active, resulting in uncontrolled hyperten­ sion. Extensive surgical resection is usually required. Hemangiomas and mesotheliomas are generally small tumors, most often intramyo­ cardial in location, and may cause atrioventricular (AV) conduction disturbances and even sudden death as a result of their propensity to develop in the region of the AV node. Other benign tumors arising from the heart include teratoma, chemodectoma, neurilemoma, and granular cell myoblastoma. Malignant Tumors   Almost all malignant primary cardiac tumors are sarcomas, which may be of several histologic types; angiosarcomas are the most common type in adults, whereas rhabdomyosarcomas are the most common type in children. In general, sarcomas are characterized by rapid progression that culminates in the patient’s death within weeks to months from the time of presentation as a result of hemodynamic compromise, local invasion, or distant metastases. Almost one-third are metastatic at the time of initial diagnosis, usually involving the lungs. Sarcomas commonly involve the right side of the heart, are rap­ idly growing, frequently invade the pericardial space, and may obstruct the cardiac chambers or venae cavae. Sarcomas also may occur on the left side of the heart and may be mistaken for myxomas. Isolated cardiac lymphomas have been rarely described but more commonly occur in the context of systemic disease. They are more common in men and in the elderly; usually involve the right heart; may present with arrhythmias, syncope, CHF, or constitutional symptoms; and are usually of the large B-cell type. TREATMENT Malignant Tumors The optimal therapy for cardiac sarcoma is complete resection, often with neoadjuvant and postoperative chemotherapy; however, at the time of presentation, many of these tumors have spread too extensively to allow for surgical excision. Although there are

45 - 283 Cardiac Trauma

283 Cardiac Trauma

scattered reports of palliation with radiotherapy and/or chemother­ apy, the response of cardiac sarcomas to these therapies is generally poor. The one exception appears to be cardiac lymphosarcomas, which may respond to a combination of chemo- and radiotherapy. Primary cardiac lymphoma is the most chemotherapy-sensitive primary cardiac malignancy, with long-term survival achieved in ~40% of treated individuals. ■ ■TUMORS METASTATIC TO THE HEART Metastatic cardiac tumors are much more common than primary cardiac tumors, and their incidence is likely to increase as the life expectancy of patients with various forms of malignant neoplasms is extended by more effective therapy and improved imaging modalities allow earlier identification of metastatic disease. Although cardiac metastases may occur with any tumor type, the relative incidence is especially high in malignant melanoma and, to a somewhat lesser extent, leukemia and lymphoma (Fig. 282-4). In absolute terms, the most common primary sites from which cardiac metastases originate are carcinoma of the breast and lung, reflecting the high incidence of these malignancies. Cardiac metastases almost always occur in the set­ ting of widespread primary disease; most often, there is either primary or metastatic disease elsewhere in the thoracic cavity. Cardiac metastases may occur via hematogenous or lymphangitic spread or by direct tumor invasion. While they generally manifest as small, firm nodules, diffuse infiltration also may occur, especially with sarcomas or hematologic neoplasms. The pericardium is most often involved, followed by myocardial involvement of any chamber and, rarely, by involvement of the endocardium or cardiac valves. Cardiac metastases are clinically apparent only ~10% of the time, are usually not the cause of the patient’s presentation, and rarely are the cause of death. The vast majority occur in the setting of a previously recognized malignant neoplasm. As with primary cardiac tumors, the clinical presentation reflects more the location and size of the tumor than its histologic type. When symptomatic, cardiac metastases may result in a variety of clinical features, including dyspnea, acute pericar­ ditis, cardiac tamponade, ectopic tachyarrhythmias, heart block, and CHF. Importantly, many of these signs and symptoms may also result from myocarditis, pericarditis, or cardiomyopathy induced by radio­ therapy or chemotherapy, and a high index of suspicion for cardiac involvement should be maintained for patients with malignant disease who develop these symptoms. Electrocardiographic (ECG) findings are nonspecific but may reveal features consistent with pericarditis or may demonstrate low QRS volt­ age and electrical alternans in the setting of a large pericardial effusion. On chest x-ray, the cardiac silhouette is most often normal but may be enlarged or exhibit a bizarre contour. Echocardiography is useful for Met RV LV LA FIGURE 282-4  Large metastatic lesion (Met) in the left ventricle (LV) of a patient with diffusely metastatic bladder cancer. The mass arose from the interventricular septum and prolapsed into the aortic outflow tract during systole.

identifying and assessing the significance of pericardial effusions and visualizing larger metastases, although CT and radionuclide imaging may define the tumor burden more clearly. Cardiac MRI offers superb image quality and plays a central role in the diagnostic evaluation of cardiac metastases and cardiac tumors in general. Pericardiocentesis may allow for a specific cytologic diagnosis in patients with malignant pericardial effusions with a reported sensitivity of 67–92%. Angiogra­ phy is rarely necessary but may help to delineate discrete myocardial lesions.

CHAPTER 283 Cardiac Trauma TREATMENT Tumors Metastatic to the Heart Most patients with cardiac metastases have advanced malignant disease; thus, therapy is generally palliative and consists of control­ ling symptoms and treatment of the primary tumor. Symptomatic malignant pericardial effusions should be drained by pericardiocen­ tesis. For patients with refractory or recurrent malignant pericardial effusion, the surgical creation of a pericardial window allowing for drainage of the effusion to the adjacent pleural or peritoneal space may prevent recurrent pericardial tamponade. Prolonged drainage (3–5 days) and concomitant instillation of a sclerosing agent (e.g., bleomycin) can be considered as a palliative measure in terminally ill patients. Given the overall poor prognosis of these patients, dis­ cussions regarding goals of care and involvement of palliative care services are often appropriate. ■ ■FURTHER READING Bussani R et al: Cardiac tumors: Diagnosis, prognosis and treatment. Curr Cardiol Rep 22:169, 2020. Mousavi N et al: Assessment of cardiac masses by cardiac magnetic resonance imaging: Histological correlation and clinical outcomes. J Am Heart Assoc 8:e007829, 2019. Shapira O et al: Tumors of the heart, in Sabiston and Spenser Surgery of the Chest, 9th ed, FW Sellke et al (eds). Philadelphia, Elsevier, 2016, pp 1849–1857. Tamin SS et al: Prognostic and bioepidemiologic implications of papil­ lary fibroelastomas. J Am Coll Cardiol 65:2420, 2015. Young PM et al: Computed tomography imaging of cardiac masses. Radiol Clin N Am 57:75, 2019. Alexandra R. Pipilas, Eric H. Awtry

Cardiac Trauma ■ ■CARDIAC TRAUMA Traumatic cardiac injury may be caused by either penetrating or nonpenetrating trauma; the latter is often referred to as blunt cardiac injury (BCI). Penetrating injuries most often result from gunshot or knife wounds, and the site of entry is usually obvious. Blunt cardiac injuries most often occur during motor vehicle accidents, either from rapid deceleration or from impact of the chest, but can also result from falls from heights, crush injuries, blast injuries, violent assault, or significant physical contact during sporting events. Importantly, rapid deceleration following motor vehicle accidents may be associated with significant cardiac injury even in the absence of external signs of thoracic trauma. ■ ■BLUNT CARDIAC INJURY Myocardial contusion is a nonspecific term that has been used to describe a broad spectrum of nonpenetrating cardiac injuries that

TABLE 283-1  Spectrum of Cardiac Abnormalities Following Blunt Cardiac Injury ABNORMALITY COMMENTS ECG abnormalities Sinus tachycardia, RBBB, heart block, ST-T wave abnormalities, atrial and ventricular arrhythmias PART 6 Disorders of the Cardiovascular System Elevated cardiac biomarkers Troponin I or T are most specific Focal wall motion abnormality or hematoma Most commonly involving RV free wall, LV apex, and interventricular septum Valvular insufficiency Most commonly involving mitral and tricuspid valves and occasionally the aortic valve Myocardial rupture Ventricular septal defect or free wall rupture Coronary artery injury Most commonly involving the LAD; usually presents as STEMI Pericardial effusion and tamponade Resulting from free wall rupture or coronary artery laceration Abbreviations: ECG, electrocardiogram; LAD, left anterior descending coronary artery; LV, left ventricle; RBBB, right bundle branch block; RV, right ventricle; STEMI, ST-segment elevation myocardial infarction. result in abnormalities on electrocardiogram (ECG), elevation in cardiac biomarkers, and acute structural cardiac abnormalities (Table 283-1). Importantly, the cardiac injury may initially be overlooked in trauma patients as the clinical focus is directed toward other, more obvious injuries. Unfortunately, there is no one sign or symptom that confirms the diagnosis of BCI, and clinical, laboratory, and radiographic find­ ings may be nonspecific in the setting of significant trauma. The physi­ cal examination may be challenging in the setting of chest wall injury; however, patients should be carefully examined to detect pericardial rubs, cardiac murmurs, and evidence of pericardial tamponade (Chap. 281). The mechanism of injury and the presence of other chest trauma should be considered when determining the index of suspicion for BCI; however, there is no proven association between sternal or rib fractures and the presence of BCI, and significant cardiac injury may be present in the absence of chest wall abnormalities. Chest pain is common following thoracic trauma, and while it can indicate cardiac ischemia or pericardial injury, it often reflects mus­ culoskeletal trauma. Nonetheless, myocardial necrosis may occur as a direct result of the blunt injury or as a result of traumatic coronary laceration, dissection, or thrombosis. The injured myocardium is pathologically similar to infarcted myocardium and may be associ­ ated with atrial or ventricular arrhythmias, conduction disturbances including bundle branch and atrioventricular (AV) nodal block, or abnormalities on ECG resembling those of infarction or pericarditis. Thus, it is important to obtain an ECG in all patients presenting with chest trauma. Serum creatine kinase, myocardial band (CK-MB) isoenzyme levels are increased in ~20% of patients who experience blunt chest trauma but may be falsely elevated in the presence of massive skeletal muscle injury and should not be relied upon to confirm the diagnosis of BCI in the setting of trauma. Cardiac troponin levels are more specific for identifying cardiac damage; patients with normal serial troponin levels after chest trauma are very unlikely to have sustained cardiac injury. When combined with a normal ECG, a normal troponin level at 6–8 h after chest trauma essentially excludes BCI. Echocardiography is the most useful modality for the detection of structural and functional sequelae of BCI, including regional wall motion abnormalities (most commonly involving the right ventricle, interventricular septum, or left ventricular apex), pericardial effusion, valvular dysfunction, and ventricular or ventricular septal rupture. A transthoracic echocardio­ gram (TTE) should be performed in all patients with suspected BCI, especially in those with an abnormal ECG, elevated troponin, or hemo­ dynamic instability; transesophageal echocardiography should be con­ sidered for patients in whom adequate TTE images cannot be obtained. Traumatic rupture of the cardiac valves or their supporting struc­ tures, most commonly of the tricuspid or aortic valves, leads to acute valvular incompetence. This complication is usually heralded by the development of a loud murmur, may be associated with rapidly

progressive heart failure, and can be diagnosed by either TTE or trans­ esophageal echocardiography. BCI may also result in dissection, occlu­ sion, or laceration of the coronary arteries. ST elevation may be seen on the ECG, and prompt intervention is often required. The most serious consequence of nonpenetrating cardiac injury is myocardial rupture. Free wall rupture may result in hemopericar­ dium and tamponade while a ventricular septal rupture can result in significant intracardiac shunting. Although generally fatal, up to 40% of patients with cardiac rupture have been reported to survive long enough to reach a specialized trauma center. Hemopericardium also may result from traumatic rupture of a pericardial vessel or a coro­ nary artery. Additionally, pericarditis and/or pericardial effusion may develop weeks or even months after blunt chest trauma as a manifesta­ tion of the post–cardiac injury syndrome, an inflammatory condition that resembles the postpericardiotomy syndrome (Chap. 281). Blunt, nonpenetrating, often innocent-appearing injuries to the chest may trigger ventricular fibrillation even in the absence of struc­ tural myocardial damage. This syndrome, referred to as commotio cordis, occurs most often in adolescents during sporting events (e.g., baseball, hockey, football, and lacrosse) and is an electrical phenom­ enon that probably results from an impact to the chest wall overlying the heart during the susceptible phase of repolarization (just before the peak of the T wave). Survival depends on prompt defibrillation. Sudden emotional or physical trauma, even in the absence of direct cardiac trauma, may precipitate a transient catecholamine-mediated cardiomyopathy referred to as takotsubo syndrome or apical ballooning syndrome (Chaps. 266–270). Rupture or transection of the aorta, usually just above the aortic valve or at the site of the tethering ligamentum arteriosum, is a com­ mon consequence of nonpenetrating chest trauma and is the most common vascular deceleration injury. The clinical presentation may be similar to that of aortic dissection (Chap. 291); the arterial pressure and pulse amplitude may be increased in the upper extremities and decreased in the lower extremities, and chest x-ray may reveal medi­ astinal widening. Aortic rupture into the left thoracic space is almost universally fatal; however, the rupture may occasionally be contained by the aortic adventitia, resulting in a false, or pseudo-, aneurysm that may be discovered months or years after the initial injury. TREATMENT Blunt Cardiac Injury The treatment of BCI depends on the specific injury sustained. Hemodynamically stable patients with a normal ECG and normal serial troponin levels are at low risk for BCI and usually do not require hospital admission for cardiac issues. Patients with an abnormal ECG, including those with conduction disturbances, and/ or elevated troponin but normal echocardiogram usually warrant 24–48 h of telemetry monitoring; however, other specific cardiac treatment is not usually required in the absence of the development of arrhythmias, as conduction disturbances are often transient. Patients with mechanical complications (acute valvular insuffi­ ciency, myocardial rupture) require urgent operative correction. ■ ■PENETRATING CARDIAC INJURY Penetrating injuries of the heart produced by knife or bullet wounds usually result in rapid clinical deterioration and frequently in death as a result of hemopericardium/pericardial tamponade or massive hemorrhage. Nonetheless, up to half of such patients may survive long enough to reach a specialized trauma center if immediate resuscitation is performed. Prognosis in these patients relates to the mechanism of injury, the specific cardiac chamber(s) involved, and their clinical con­ dition at presentation. In general, gunshot wounds are associated with a higher mortality than are knife wounds. Twenty percent of shooting victims survive versus up to 65% of stabbing victims. This is likely in part because ballistic wounds are more frequently associated with mul­ tichamber cardiac injury. As a result of its anterior position in the chest, the right ventricle (RV) is the most frequently injured cardiac chamber,

RV LV A B FIGURE 283-1  Transthoracic echocardiogram demonstrating a traumatic ventricular septal defect. The patient underwent emergent repair of the right ventricle following a self-inflicted stab wound to the chest. Subsequent two-dimensional imaging (A) revealed a laceration of the interventricular septum (arrow) with color flow Doppler (B) demonstrating prominent left-to-right shunting across the defect. LV, left ventricle; RV, right ventricle. followed by the left ventricle (LV); isolated atrial injury is uncommon. Some studies suggest that RV injuries may be associated with a better prognosis than LV injuries, and most reports indicate that multicham­ ber involvement carries a worse prognosis than single-chamber injury. Patients who are in hemodynamic collapse at presentation to the emer­ gency department have a particularly poor prognosis with a mortality rate approaching 90%, whereas ~75% of patients who are stable enough to be brought to the operating room will survive. Cardiac perforation of the right atrium, the RV free wall, or the interventricular septum may occur as a complication of cardiac pro­ cedures including placement of central venous/intracardiac catheters, insertion of pacemaker/defibrillator leads, or performance of RV endo­ myocardial biopsies; and coronary arterial perforation can occur dur­ ing deployment of intracoronary stents. These iatrogenic injuries are associated with a better prognosis than are other forms of penetrating cardiac trauma, likely related to a more limited degree of cardiac injury and the rapid availability of corrective therapies. Traumatic rupture of a great vessel from penetrating injury is usually associated with hemothorax and, less often, hemopericardium, both of which are associated with significant mortality. Local hematoma formation may compress adjacent vessels and produce ischemic symp­ toms, and arteriovenous fistulas may develop, occasionally resulting in high-output heart failure. Some patients with penetrating chest injuries are hemodynamically stable at presentation and without symptoms to suggest cardiac injury; however, as many as 20% of these patients will have occult penetrating cardiac trauma. As a result, there should always be a high index of sus­ picion for cardiac injury in any patient with penetrating chest trauma, irrespective of clinical stability. TTE should be performed in all of these patients to assess for the presence of pericardial effusion or hematoma. Occasionally, patients who survive penetrating cardiac injuries may subsequently present days or weeks later with a new cardiac murmur or heart failure as a result of mitral or tricuspid regurgitation or an intracardiac shunt (i.e., ventricular or atrial septal defect, aortopulmo­ nary fistula, or coronary arteriovenous fistula) that was undetected at the time of the initial injury or developed subsequently (Fig. 283-1). Therefore, trauma patients should be examined carefully several weeks after the injury. If a mechanical complication is suspected, it can be confirmed by echocardiography or cardiac catheterization.

CHAPTER 283 Cardiac Trauma TREATMENT Penetrating Cardiac Injury Penetrating cardiac injury associated with hemodynamic insta­ bility is a surgical emergency and requires immediate resuscita­ tive measures including endotracheal intubation, establishment of large-bore intravenous access to facilitate massive volume resuscita­ tion, and immediate thoracotomy to allow for pericardial drainage and repair of cardiac injuries. Occasionally, cross-clamping of the descending aorta is required to perfuse the heart and brain pref­ erentially until hemodynamic stability can be achieved. Hemody­ namically stable patients in whom echocardiography reveals even a small pericardial effusion require urgent surgical exploration to evaluate for occult cardiac perforation. Pericardiocentesis may be lifesaving in patients with tamponade but is usually only a tempo­ rizing measure while awaiting definitive surgical therapy. In some survivors of penetrating cardiac injury, the pericardial hemorrhage predisposes to the development of constriction (Chap. 281), which may require surgical decortication. ■ ■FURTHER READING Ali H et al: Clinical and electrocardiographic features of complete heart block after blunt cardiac injury: A systematic review of the literature. Heart Rhythm 14:1561, 2017. Biffl WL et at: Diagnosis and management of blunt cardiac injury: What you need to know. J Trauma Acute Care Surg 96:685, 2024. Crawford T et al: Thoracic trauma, in Sabiston and Spencer Surgery of the Chest, 9th ed, FW Sellke et al (eds). Philadelphia, Elsevier, 2016, pp 100–130. Ismailov RM et al: Trauma associated with cardiac dysrhythmias: Results from a large, matched case-control study. J Trauma 62:1186, 2007. Morse BC et al: Penetrating cardiac injuries: A 36-year perspective at an urban level 1 trauma center. J Trauma Acute Care Surg 81:623, 2016. Wu Y et al: Imaging of cardiac trauma. Radiol Clin N Am 57:795, 2019. Yousef R, Carr JA: Blunt cardiac trauma: A review of the current knowledge and management. Ann Thorac Surg 98:1134, 2014.

46 - SECTION 5 Coronary and Peripheral Vascular Disease

SECTION 5 Coronary and Peripheral Vascular Disease

PART 6 Disorders of the Cardiovascular System Ischemic Heart Disease Robert P. Giugliano, Elliott M. Antman, Joseph Loscalzo

Ischemic heart disease (IHD) is a condition in which there is an inad­ equate supply of blood and oxygen to a portion of the myocardium; it typically occurs when there is an imbalance between myocardial oxygen supply and demand. The most common cause of myocardial ischemia is atherosclerotic disease of an epicardial coronary artery (or arteries) sufficient to cause a regional reduction in myocardial blood flow and inadequate perfusion of the myocardium supplied by the involved coronary artery. This chapter focuses on the chronic manifestations and treatment of IHD (sometimes referred to as chronic coronary disease or chronic coronary syndrome), while the subsequent chapters address the acute phases of IHD. ■ ■EPIDEMIOLOGY AND GLOBAL TRENDS IHD causes more deaths and disability and incurs greater economic costs than any other illness in the developed world. IHD is the most common, serious, chronic, life-threatening illness in the United States, where 20.5 million persons have IHD. Although there is regional variation, ~3–4% of the population has sustained a myocardial infarc­ tion. Genetic factors, a high-fat and energy-rich diet, smoking, and a sedentary lifestyle are associated with the emergence of IHD. In the United States and Western Europe, IHD is growing among low-income groups, but primary prevention has delayed the disease to later in life across socioeconomic groups. Despite these sobering statistics, it is worth noting that epidemiologic data show a decline in the rate of deaths due to IHD, about half of which is attributable to treatments and half to prevention by risk factor modification. Obesity, insulin resistance, and type 2 diabetes mellitus are increas­ ing and are powerful risk factors for IHD. These trends are occurring in the general context of population growth and as a result of the increase in the average age of the world’s population. With urbanization in countries with emerging economies and a growing middle class, ele­ ments of the energy-rich Western diet are being adopted. As a result, the prevalence of risk factors for IHD and the prevalence of IHD itself are both increasing rapidly, so that in analyses of the global burden of disease, there is a shift from communicable to noncommunicable diseases, and it is estimated that globally over 200 million people live with IHD. Population subgroups that appear to be particularly affected are men in South Asian countries, especially India and the Middle East. IHD is a major contributor to the number of disability-adjusted lifeyears (DALYs) experienced globally. ■ ■PATHOPHYSIOLOGY Central to an understanding of the pathophysiology of myocardial ischemia is the concept of myocardial supply and demand. In normal conditions, for any given level of a demand for oxygen, the myocar­ dium will control the supply of oxygen-rich blood to prevent under­ perfusion of myocytes and the subsequent development of ischemia and infarction. The major determinants of myocardial oxygen demand (MVO2) are heart rate, myocardial contractility, and myocardial wall tension (stress). An adequate supply of oxygen to the myocardium requires a satisfactory level of oxygen-carrying capacity of the blood (determined by the inspired level of oxygen, pulmonary function, and hemoglobin concentration and function) and an adequate level of coronary blood flow. Blood flows through the coronary arteries in a phasic fashion, with the majority occurring during diastole. About 75% of the total coronary resistance to flow occurs across three sets of arteries: (1) large epicardial arteries (Resistance 1 = R1), (2) prear­ teriolar vessels (R2), and (3) arteriolar and intramyocardial capillary vessels (R3). In the absence of significant flow-limiting atheroscle­ rotic obstructions, R1 is trivial; the major determinant of coronary resistance is found in R2 and R3 (Fig. 284-1). The normal coronary circulation is dominated and controlled by the heart’s requirements for oxygen. This need is met by the ability of the coronary vascular bed to vary its resistance (and, therefore, blood flow) considerably while the myocardium extracts a high and relatively fixed percentage of oxygen. Normally, intramyocardial resistance vessels demonstrate a great capacity for dilation (R2 and R3 decrease). The changing oxygen needs of the heart with exercise and emotional stress affect coronary Section 5 Coronary and Peripheral Vascular Disease Segment and size Macrocirculation Microcirculation Main stimulus for vasomotion Metabolites Pressure Flow Exchange Regulation Transport Main function Percentage of total resistance to flow Epicardial arteries >400 µm Small arteries <400 µm Arterioles <100 µm Capillaries <10 µm FIGURE 284-1  Macrocirculation and microcirculation across segments and sizes of the arteries. The location and size of the arteries supplying blood to the heart is shown at the top. Vasomotion of the arterial segments occurs in response to the stimuli shown. The main function of each of the arterial segments is shown next, followed by a depiction of the relative resistance to antegrade flow. (Adapted from J Knuuti et al: 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 41:407, 2020/.)

47 - 284 Ischemic Heart Disease

284 Ischemic Heart Disease

PART 6 Disorders of the Cardiovascular System Ischemic Heart Disease Robert P. Giugliano, Elliott M. Antman, Joseph Loscalzo

Ischemic heart disease (IHD) is a condition in which there is an inad­ equate supply of blood and oxygen to a portion of the myocardium; it typically occurs when there is an imbalance between myocardial oxygen supply and demand. The most common cause of myocardial ischemia is atherosclerotic disease of an epicardial coronary artery (or arteries) sufficient to cause a regional reduction in myocardial blood flow and inadequate perfusion of the myocardium supplied by the involved coronary artery. This chapter focuses on the chronic manifestations and treatment of IHD (sometimes referred to as chronic coronary disease or chronic coronary syndrome), while the subsequent chapters address the acute phases of IHD. ■ ■EPIDEMIOLOGY AND GLOBAL TRENDS IHD causes more deaths and disability and incurs greater economic costs than any other illness in the developed world. IHD is the most common, serious, chronic, life-threatening illness in the United States, where 20.5 million persons have IHD. Although there is regional variation, ~3–4% of the population has sustained a myocardial infarc­ tion. Genetic factors, a high-fat and energy-rich diet, smoking, and a sedentary lifestyle are associated with the emergence of IHD. In the United States and Western Europe, IHD is growing among low-income groups, but primary prevention has delayed the disease to later in life across socioeconomic groups. Despite these sobering statistics, it is worth noting that epidemiologic data show a decline in the rate of deaths due to IHD, about half of which is attributable to treatments and half to prevention by risk factor modification. Obesity, insulin resistance, and type 2 diabetes mellitus are increas­ ing and are powerful risk factors for IHD. These trends are occurring in the general context of population growth and as a result of the increase in the average age of the world’s population. With urbanization in countries with emerging economies and a growing middle class, ele­ ments of the energy-rich Western diet are being adopted. As a result, the prevalence of risk factors for IHD and the prevalence of IHD itself are both increasing rapidly, so that in analyses of the global burden of disease, there is a shift from communicable to noncommunicable diseases, and it is estimated that globally over 200 million people live with IHD. Population subgroups that appear to be particularly affected are men in South Asian countries, especially India and the Middle East. IHD is a major contributor to the number of disability-adjusted lifeyears (DALYs) experienced globally. ■ ■PATHOPHYSIOLOGY Central to an understanding of the pathophysiology of myocardial ischemia is the concept of myocardial supply and demand. In normal conditions, for any given level of a demand for oxygen, the myocar­ dium will control the supply of oxygen-rich blood to prevent under­ perfusion of myocytes and the subsequent development of ischemia and infarction. The major determinants of myocardial oxygen demand (MVO2) are heart rate, myocardial contractility, and myocardial wall tension (stress). An adequate supply of oxygen to the myocardium requires a satisfactory level of oxygen-carrying capacity of the blood (determined by the inspired level of oxygen, pulmonary function, and hemoglobin concentration and function) and an adequate level of coronary blood flow. Blood flows through the coronary arteries in a phasic fashion, with the majority occurring during diastole. About 75% of the total coronary resistance to flow occurs across three sets of arteries: (1) large epicardial arteries (Resistance 1 = R1), (2) prear­ teriolar vessels (R2), and (3) arteriolar and intramyocardial capillary vessels (R3). In the absence of significant flow-limiting atheroscle­ rotic obstructions, R1 is trivial; the major determinant of coronary resistance is found in R2 and R3 (Fig. 284-1). The normal coronary circulation is dominated and controlled by the heart’s requirements for oxygen. This need is met by the ability of the coronary vascular bed to vary its resistance (and, therefore, blood flow) considerably while the myocardium extracts a high and relatively fixed percentage of oxygen. Normally, intramyocardial resistance vessels demonstrate a great capacity for dilation (R2 and R3 decrease). The changing oxygen needs of the heart with exercise and emotional stress affect coronary Section 5 Coronary and Peripheral Vascular Disease Segment and size Macrocirculation Microcirculation Main stimulus for vasomotion Metabolites Pressure Flow Exchange Regulation Transport Main function Percentage of total resistance to flow Epicardial arteries >400 µm Small arteries <400 µm Arterioles <100 µm Capillaries <10 µm FIGURE 284-1  Macrocirculation and microcirculation across segments and sizes of the arteries. The location and size of the arteries supplying blood to the heart is shown at the top. Vasomotion of the arterial segments occurs in response to the stimuli shown. The main function of each of the arterial segments is shown next, followed by a depiction of the relative resistance to antegrade flow. (Adapted from J Knuuti et al: 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 41:407, 2020/.)

vascular resistance and, in this manner, regulate the supply of oxygen and substrate to the myocardium (metabolic regulation). The coronary resistance vessels also adapt to physiologic alterations in blood pres­ sure to maintain coronary blood flow at levels appropriate to myocar­ dial needs (autoregulation). By reducing the lumen of the coronary arteries, atherosclerosis limits appropriate increases in perfusion when the demand for more coronary flow occurs. When the luminal reduction is severe, myocar­ dial perfusion in the basal state is reduced. Coronary blood flow also can be limited by spasm (see vasospastic angina in Chap. 285), arterial thrombi, and, rarely, coronary emboli as well as by ostial narrowing due to aortitis. Congenital abnormalities such as the origin of the left anterior descending coronary artery from the pulmonary artery may cause myocardial ischemia and infarction in infancy, but this cause is very rare in adults. Myocardial ischemia also can occur if myocardial oxygen demands are markedly increased and particularly when coronary blood flow may be limited, as occurs in severe left ventricular hypertrophy (LVH) due to aortic stenosis. The latter can present with angina that is indis­ tinguishable from that caused by coronary atherosclerosis largely owing to subendocardial ischemia (Chap. 272). A reduction in the oxygen-carrying capacity of the blood, as in extremely severe anemia or in the presence of carboxyhemoglobin, rarely causes myocardial ischemia by itself but may lower the threshold for ischemia in patients with moderate coronary obstruction. Not infrequently, two or more causes of ischemia coexist in a patient, such as an increase in oxygen demand due to LVH second­ ary to hypertension and a reduction in oxygen supply secondary to coronary atherosclerosis and anemia. Abnormal constriction or failure of normal dilation of the coronary resistance vessels also can cause ischemia. When it causes angina, this condition is referred to as micro­ vascular angina. CORONARY ATHEROSCLEROSIS Epicardial coronary arteries are the major site of atherosclerotic dis­ ease. The major risk factors for atherosclerosis (high levels of plasma low-density lipoprotein [LDL], cigarette smoking, hypertension, and diabetes mellitus) vary in their relative impact on disturbing the nor­ mal functions of the vascular endothelium. These functions include local control of vascular tone, maintenance of an antithrombotic surface, and control of inflammatory cell adhesion and diapedesis. The loss of these defenses leads to inappropriate constriction, luminal thrombus formation, and abnormal interactions between blood cells, especially monocytes and platelets, and the activated vascular endo­ thelium. Functional changes in the vascular milieu ultimately result in the subintimal collections of fat, smooth muscle cells, fibroblasts, and intercellular matrix that define the atherosclerotic plaque. Rather than viewing atherosclerosis strictly as a vascular problem, it is useful to consider it in the context of alterations in the nature of the circulating blood (hyperglycemia; increased concentrations of LDL cholesterol, tissue factor, fibrinogen, von Willebrand factor, coagulation factor VII, and platelet microparticles). The combination of a “vulnerable vessel” in a patient with “vulnerable blood” promotes a state of hyper­ coagulability and hypofibrinolysis. This is especially true in patients with diabetes mellitus. Atherosclerosis develops at irregular rates in different segments of the epicardial coronary tree and leads eventually to segmental reduc­ tions in cross-sectional area, i.e., plaque formation. There is also a predilection for atherosclerotic plaques to develop at sites of increased turbulence in coronary flow, such as at branch points in the epicardial arteries. When a stenosis reduces the diameter of an epicardial artery by 50%, there is a limitation of the ability to increase flow to meet increased myocardial demand. When the diameter is reduced by ~80%, blood flow at rest may be reduced, and further minor decreases in the stenotic orifice area can reduce coronary flow dramatically to cause myocardial ischemia at rest or with minimal stress. Segmental atherosclerotic narrowing of epicardial coronary arter­ ies is caused most commonly by the formation of a plaque, which is subject to rupture or erosion of the cap separating the plaque from

the bloodstream. Upon exposure of the plaque contents to blood, two important and interrelated processes are set in motion: (1) platelets are activated and aggregate, and (2) the coagulation cascade is acti­ vated, leading to deposition of fibrin strands. A thrombus composed of platelet aggregates and fibrin strands traps red blood cells and can reduce coronary blood flow, leading to the clinical manifestations of myocardial ischemia.

CHAPTER 284 The location of the obstruction influences the quantity of myo­ cardium rendered ischemic and determines the severity of the clini­ cal manifestations. Thus, critical obstructions in vessels, such as the left main coronary artery and the proximal left anterior descending coronary artery, are particularly hazardous. Chronic severe coronary narrowing and myocardial ischemia frequently are accompanied by the development of collateral vessels, especially when the narrowing devel­ ops gradually. When well developed, such vessels can by themselves provide sufficient blood flow to sustain the viability of the myocardium at rest but not during conditions of increased demand. Ischemic Heart Disease With progressive worsening of a stenosis in a proximal epicardial artery, the distal resistance vessels (when they function normally) dilate to reduce vascular resistance and maintain coronary blood flow. A pressure gradient develops across the proximal stenosis, and poststenotic pressure falls. When the resistance vessels are maximally dilated, myocardial blood flow becomes dependent on the pressure in the coronary artery distal to the obstruction. In these circumstances, ischemia, manifest clinically by angina or electrocardiographically by ST-segment deviation, can be precipitated by increases in myocardial oxygen demand caused by physical activity, emotional stress, and/or tachycardia. Changes in the caliber of the stenosed coronary artery resulting from physiologic vasomotion, loss of endothelial control of dilation (as occurs in atherosclerosis), pathologic spasm (vasospastic angina), or small platelet-rich plugs also can upset the critical balance between oxygen supply and demand and thereby precipitate myocar­ dial ischemia. ■ ■EFFECTS OF ISCHEMIA During episodes of inadequate perfusion caused by coronary ath­ erosclerosis, myocardial tissue oxygen tension falls and may cause transient disturbances of the mechanical, biochemical, and electrical functions of the myocardium (Fig. 284-2). Coronary atherosclerosis is a focal process that usually causes nonuniform ischemia. During isch­ emia, regional disturbances of ventricular contractility cause segmental hypokinesia, akinesia, or, in severe cases, bulging (dyskinesia), which can reduce myocardial pump function. The abrupt development of severe ischemia, as occurs with total or subtotal coronary occlusion, is associated with near instantaneous fail­ ure of normal muscle relaxation and then diminished contraction. The relatively poor perfusion of the subendocardium causes more intense ischemia of this portion of the wall (compared with the subepicardial region). Ischemia of large portions of the ventricle causes transient left ventricular (LV) failure, and if the papillary muscle apparatus is involved, mitral regurgitation can occur. When ischemia is transient, it may be associated with angina pectoris; when it is prolonged, it can lead to myocardial necrosis and scarring with or without the clinical picture of acute myocardial infarction (Chap. 286). A wide range of abnormalities in cell metabolism, function, and structure underlie these mechanical disturbances during ischemia. The normal myocardium metabolizes fatty acids and glucose to carbon dioxide and water. With severe oxygen deprivation, fatty acids cannot be oxidized, and glucose is converted to lactate; intracellular pH is reduced, as are the myocardial stores of high-energy phosphates, i.e., ATP and creatine phosphate. Impaired cell membrane function leads to the leakage of potassium and the uptake of sodium by myocytes as well as an increase in cytosolic calcium. The severity and duration of the imbalance between myocardial oxygen supply and demand deter­ mine whether the damage is reversible (≤20 min for total occlusion in the absence of collaterals) or permanent, with subsequent myocardial necrosis (>20 min). Ischemia also causes characteristic changes in the electrocardiogram (ECG) such as repolarization abnormalities, as evidenced by inversion

Repetitive/progressive manifestations of ischemia Regional wall motion PART 6 Disorders of the Cardiovascular System Decreased segmental perfusion Diastolic dysfunction Micro-infarction/myocardial fibrosis Altered metabolism/abnormal ST segment Decreased subendocardial perfusion Endothelial and microvascular dysfunction Near term Exposure time of mismatch in myocardial oxygen supply/demand FIGURE 284-2  Cascade of mechanisms and manifestations of ischemia. (Reproduced with permission from LJ Shaw et al: Women and ischemic heart disease: Evolving knowledge. J Am Coll Cardiol 54:1561, 2009.) of T waves and, when more severe, displacement of ST segments (Chap. 247). Transient T-wave inversion probably reflects nontrans­ mural, intramyocardial ischemia; transient ST-segment depression often reflects patchy subendocardial ischemia; and ST-segment eleva­ tion is thought to be caused by more severe transmural ischemia. Another important consequence of myocardial ischemia is electrical instability, which may lead to isolated ventricular premature beats or even ventricular tachycardia or ventricular fibrillation (Chaps. 261 and 262). Most patients who die suddenly from IHD do so as a result of ischemia-induced ventricular tachyarrhythmias (Chap. 317). ■ ■ASYMPTOMATIC VERSUS SYMPTOMATIC IHD Although the prevalence is decreasing, postmortem studies of acci­ dent victims and military casualties in Western countries show that coronary atherosclerosis can begin before age 20 and is present among adults who were asymptomatic during life. Exercise stress tests in asymptomatic persons may show evidence of silent myocardial isch­ emia, i.e., exercise-induced ECG changes not accompanied by angina pectoris; coronary angiographic studies of such persons may reveal coronary artery plaques and previously unrecognized obstructions (Chap. 249). Coronary artery calcifications (CACs) may be seen on computed tomography (CT) images of the heart, can be quantified in a CAC score, and may be used as adjunctive information to support a diagnosis of IHD. However, they should not be used as the primary screening modality or as the isolated basis on which to formulate thera­ peutic decisions. (See further discussion below.) Postmortem examina­ tion of patients with such obstructions without a history of clinical manifestations of myocardial ischemia often shows macroscopic scars secondary to myocardial infarction in regions supplied by diseased coronary arteries, with or without collateral circulation. According to population studies, ~25% of patients who survive acute myocardial infarction may not come to medical attention, and these patients have the same adverse prognosis as do those who present with the classic clinical picture of acute myocardial infarction (Chap. 286). Sudden death may be unheralded and is a common presenting manifestation of IHD (Chap. 317). Patients with IHD also can present with cardiomegaly and heart failure secondary to ischemic damage of the LV myocardium that may have caused no symptoms before the development of heart failure; this condition is referred to as ischemic cardiomyopathy. In contrast to the asymptomatic phase of IHD, the symptomatic phase is characterized

Systolic dysfunction Prolonged by chest discomfort due to either angina pectoris or acute myocardial infarction (Chap. 286). Having entered the symptomatic phase, the patient may exhibit a stable or progressive course, revert to the asymp­ tomatic stage, or die suddenly. STABLE ANGINA PECTORIS This episodic clinical syndrome is a result of transient myocardial isch­ emia. Various diseases that cause myocardial ischemia and the numer­ ous forms of discomfort with which it may be confused are discussed in Chap. 15. Males constitute ~70% of all patients with angina pectoris and an even greater proportion of those aged <50 years. It is, however, important to note that descriptions of angina pectoris in women may be different from that in men. ■ ■HISTORY The typical patient with angina is a man >50 years or a woman

60 years of age who complains of episodes of chest discomfort, usually described as heaviness, pressure, squeezing, smothering, or choking and only rarely as frank pain. When the patient is asked to localize the sensation, they typically place a hand over the sternum, sometimes with a clenched fist, to indicate a squeezing, central, substernal discomfort (Levine’s sign). Angina is usually crescendodecrescendo in nature (typically with the severity of the discomfort not at its most intense level at the outset of symptoms), typically lasts 2–5 min, and can radiate to either shoulder and to both arms (espe­ cially the ulnar aspects of the forearm and hand). It also can arise in or radiate to the back, interscapular region, root of the neck, jaw, teeth, and epigastrium. Angina is rarely localized below the umbilicus or above the mandible. A useful finding in assessing a patient with chest discomfort is the fact that myocardial ischemic discomfort does not radiate to the trapezius muscles; that radiation pattern is more typical of pericarditis. Although episodes of angina typically are caused by exertion (e.g., exercise, hurrying, or sexual activity) or emotion (e.g., stress, anger, fright, or frustration) and are relieved by rest, they also may occur at rest and while the patient is recumbent (angina decubitus). The patient may be awakened at night by typical chest discomfort and dyspnea. Nocturnal angina may be due to episodic tachycardia, diminished oxygenation as the respiratory pattern changes during sleep, or expan­ sion of the intrathoracic blood volume that occurs with recumbency; the latter causes an increase in cardiac size (end-diastolic volume), wall

tension, and myocardial oxygen demand that can lead to ischemia and transient LV failure. The threshold for the development of angina pectoris may vary by time of day and emotional state. Many patients report a fixed threshold for angina, occurring predictably at a certain level of activity, such as climbing two flights of stairs at a normal pace. In these patients, coro­ nary stenosis and myocardial oxygen supply are fixed, and ischemia is precipitated by an increase in myocardial oxygen demand; they are said to have stable exertional angina. In other patients, the threshold for angina may vary considerably within any particular day and from day to day. In such patients, variations in myocardial oxygen supply, most likely due to changes in coronary vasomotor tone, may play an important role in defining the pattern of angina. A patient may report symptoms upon minor exertion in the morning yet by midday be capable of much greater effort without symptoms. Angina may also be precipitated by unfamiliar circumstances, a heavy meal, exposure to cold, or a combination of these factors. Exertional angina typically is relieved in 1–5 min by slowing or ceas­ ing activities and even more rapidly by rest and sublingual nitroglyc­ erin (see below). Indeed, the diagnosis of angina should be suspect if it does not respond to the combination of these measures. The severity of angina can be conveniently summarized by the Canadian Cardiac Soci­ ety functional classification (Table 284-1). Its impact on the patient’s functional capacity can be described by using the New York Heart Association functional classification (Table 284-1). Sharp, fleeting chest pain or a prolonged, dull ache localized to the left submammary area is rarely due to myocardial ischemia. However, especially in women and patients with diabetes mellitus, angina pec­ toris may be atypical in location and not strictly related to provoking factors. In addition, this symptom may exacerbate and remit over days, weeks, or months. Its occurrence can be seasonal, occurring more TABLE 284-1  Cardiovascular Disease Classification Chart CANADIAN CARDIOVASCULAR SOCIETY FUNCTIONAL CLASSIFICATION NEW YORK HEART ASSOCIATION FUNCTIONAL CLASSIFICATION CLASS I Patients have cardiac disease but without the resulting limitations of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain. Ordinary physical activity, such as walking and climbing stairs, does not cause angina. Angina present with strenuous or rapid or prolonged exertion at work or recreation. II Patients have cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain. Slight limitation of ordinary activity. Walking or climbing stairs rapidly, walking uphill, walking or stair climbing after meals, in cold, or when under emotional stress or only during the few hours after awakening. Walking more than two blocks on the level and climbing more than one flight of stairs at a normal pace and in normal conditions. III Patients have cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnea, or anginal pain. Marked limitation of ordinary physical activity. Walking one to two blocks on the level and climbing one flight of stairs at normal pace. IV Patients have cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased. Inability to carry on any physical activity without discomfort— anginal syndrome may be present at rest. Source: Reproduced with permission from L Goldman et al: Comparative reproducibility and validity of systems for assessing cardiovascular functional class: Advantages of a new specific activity scale. Circulation 64:1227, 1981.

frequently in the winter in temperate climates. Anginal “equivalents” are symptoms of myocardial ischemia other than angina. They include dyspnea, nausea, fatigue, and faintness and are more common in the elderly and in patients with diabetes mellitus.

Systematic questioning of a patient with suspected IHD is impor­ tant to uncover the features of an unstable syndrome associated with increased risk, such as angina occurring with less exertion than in the past, occurring at rest, or awakening the patient from sleep. Since coro­ nary atherosclerosis often is accompanied by similar lesions in other arteries, a patient with angina should be questioned and examined for peripheral arterial disease (intermittent claudication [Chap. 292]), stroke, or transient ischemic attacks (Chap. 437). It is also important to uncover a family history of premature IHD (<55 years in first-degree male relatives and <65 years in female relatives) and the presence of diabetes mellitus, hyperlipidemia, hypertension, cigarette smoking, and other risk factors for coronary atherosclerosis. CHAPTER 284 Ischemic Heart Disease The history of typical angina pectoris establishes the diagnosis of IHD until proven otherwise. Given the importance of the his­ tory, clinicians should move beyond unstructured interviews with the patient and consider using a validated questionnaire (e.g., Seattle Angina Questionnaire) to establish the presence and severity of IHD. The coexistence of advanced age, male sex, the postmenopausal state, and risk factors for atherosclerosis increases the likelihood of hemo­ dynamically significant coronary disease. A particularly challenging problem is the evaluation and management of patients with persistent ischemic-type chest discomfort but no flow-limiting obstructions in their epicardial coronary arteries. This situation arises more often in women than in men. Potential etiologies include microvascular coronary disease (detectable on coronary reactivity testing in response to vasoactive agents such as intracoronary adenosine, acetylcholine, and nitroglycerin) and abnormal cardiac nociception. Treatment of microvascular coronary disease should focus on efforts to improve endothelial function, including nitrates, beta blockers, calcium antago­ nists, statins, and angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Abnormal cardiac nociception is more difficult to manage and may be ameliorated in some cases by imipramine. ■ ■PHYSICAL EXAMINATION The physical examination is often normal in patients with stable angina when they are asymptomatic. However, because of the increased likelihood of IHD in patients with diabetes and/or peripheral or cere­ brovascular arterial disease, clinicians should search for evidence of atherosclerotic disease at other sites, such as an abdominal aortic aneu­ rysm, carotid arterial bruits, and diminished arterial pulses in the lower extremities. The physical examination also should include a search for evidence of risk factors for atherosclerosis such as xanthelasmas and xanthomas. Evidence for peripheral and cerebrovascular arterial dis­ ease should be sought by evaluating the pulse contour at multiple loca­ tions and comparing the blood pressure between the arms and between the arms and the legs (ankle-brachial index). Examination of the fundi may reveal an increased light reflex and arteriovenous nicking as evidence of hypertension. There also may be signs of anemia, thyroid disease, and nicotine stains on the fingertips from cigarette smoking. Palpation may reveal cardiac enlargement and abnormal contrac­ tion of the cardiac impulse (LV dyskinesia). Auscultation can uncover arterial bruits, a third and/or fourth heart sound, and, if acute ischemia or previous infarction has impaired papillary muscle function, an api­ cal systolic murmur due to mitral regurgitation. These auscultatory signs are best appreciated with the patient in the left lateral decubitus position. Aortic stenosis, aortic regurgitation (Chap. 272), pulmo­ nary hypertension (Chap. 294), and hypertrophic cardiomyopathy (Chaps. 266–270) must be excluded, since these disorders may cause angina in the absence of coronary atherosclerosis. Examination during an anginal attack is useful, since ischemia can cause transient LV failure with the appearance of a third and/or fourth heart sound, a dyskinetic cardiac apex, mitral regurgitation, and even pulmonary edema. Ten­ derness of the chest wall, localization of the discomfort with a single fingertip on the chest, or reproduction of the pain with palpation of the

chest makes it unlikely that the pain is caused by myocardial ischemia. A protuberant abdomen may indicate that the patient has the meta­ bolic syndrome and is at increased risk for atherosclerosis.

■ ■LABORATORY EXAMINATION Although the diagnosis of IHD can be made with a high degree of confidence from the history and physical examination, a number of simple laboratory tests can be helpful. The urine should be examined for evidence of diabetes mellitus and renal disease (including microal­ buminuria) since these conditions accelerate atherosclerosis. Similarly, examination of the blood should include measurements of lipids (cho­ lesterol—total, LDL, high-density lipoprotein [HDL]—triglycerides, and lipoprotein (a)), glucose (hemoglobin A1C), creatinine, hematocrit, and, if indicated based on the physical examination, thyroid function. A chest x-ray may be helpful in demonstrating the consequences of IHD, i.e., cardiac enlargement, ventricular aneurysm, or signs of heart failure. These signs can support the diagnosis of IHD and are impor­ tant in assessing the degree of cardiac damage. Evidence exists that an elevated level of high-sensitivity C-reactive protein (CRP) (specifically, between 1 and 3 mg/L) is an independent risk factor for IHD and may be useful in therapeutic decision-making about the initiation of hypolipidemic treatment. The major benefit of high-sensitivity CRP is in reclassifying the risk of IHD in patients in the “intermediate” risk category on the basis of traditional risk factors. PART 6 Disorders of the Cardiovascular System ■ ■ELECTROCARDIOGRAM A 12-lead ECG recorded at rest may be normal in patients with typi­ cal angina pectoris, but there may also be signs of an old myocardial infarction (Chap. 247). Although repolarization abnormalities, i.e., ST-segment and T-wave changes, as well as LVH and disturbances of cardiac rhythm or intraventricular conduction, are suggestive of IHD, they are nonspecific, since they also can occur in pericardial, myocar­ dial, and valvular heart disease or, in the case of the former, transiently with anxiety, changes in posture, drugs, or esophageal disease. The presence of LVH is a significant indication of increased risk of adverse outcomes from IHD. Of note, even though LVH and cardiac rhythm disturbances are nonspecific indicators of the development of IHD, they may be contributing factors to episodes of angina in patients in whom IHD has developed as a consequence of conventional risk factors. Dynamic ST-segment and T-wave changes that accompany episodes of angina pectoris and disappear thereafter are more specific. ■ ■STRESS TESTING Electrocardiographic  The most widely used test for both the diagnosis of IHD and the estimation of risk and prognosis involves recording of the 12-lead ECG before, during, and after exercise, usually on a treadmill (Fig. 284-3). The test consists of a standardized incre­ mental increase in external workload (Table 284-2) while symptoms, the ECG, and arm blood pressure are monitored. Exercise duration is usually symptom-limited, and the test is discontinued upon evidence of chest discomfort, severe shortness of breath, dizziness, severe fatigue, ST-segment depression >0.2 mV (2 mm), a fall in systolic blood pressure >10 mmHg, or the development of a ventricular tachyarrhyth­ mia. This test is used to discover any limitation in exercise performance, detect typical ECG signs of myocardial ischemia, and establish their relationship to chest discomfort. The ischemic ST-segment response generally is defined as flat or downsloping depression of the ST segment >0.1 mV below baseline (i.e., the PR segment) and lasting longer than 0.08 s (Fig. 284-2). Upsloping or junctional ST-segment changes are not considered characteristic of ischemia and do not constitute a positive test. Although T-wave abnormalities, conduction disturbances, and ventricular arrhythmias that develop during exercise should be noted, they are also not diagnostic. Negative exercise tests in which the target heart rate (85% of maximal predicted heart rate for age and sex) is not achieved are considered nondiagnostic. In interpreting ECG stress tests, the probability that coronary artery disease (CAD) exists in the patient or population under study (i.e., pretest probability) should be considered. A positive result on exer­ cise indicates that the likelihood of CAD is 98% in males who are

50 years with a history of typical angina pectoris and who develop chest discomfort during the test. The likelihood decreases if the patient has atypical or no chest pain by history and/or during the test. The incidence of false-positive tests is significantly increased in patients with low probabilities of IHD, such as asymptomatic men age <40 or premenopausal women with no risk factors for premature athero­ sclerosis. It is also increased in patients taking cardioactive drugs, such as digitalis and antiarrhythmic agents, and in those with intraventricular conduction disturbances, resting ST-segment and T-wave abnormalities, ventricular hypertrophy, or abnormal serum potassium levels. Obstruc­ tive disease limited to the circumflex coronary artery may result in a false-negative stress test since the posterolateral portion of the heart that this vessel supplies is not well represented on the surface 12-lead ECG. Since the overall sensitivity of an exercise stress ECG is only ~75%, a negative result does not exclude CAD, although it makes the likelihood of three-vessel or left main CAD extremely unlikely. A medical professional should be present throughout the exercise test. It is important to measure total duration of exercise, the times to the onset of ischemic ST-segment change and chest discomfort, the external work performed (generally expressed as the stage of exercise), and the internal cardiac work performed, i.e., by the heart rate–blood pressure product. The depth of the ST-segment depres­ sion and the time needed for recovery of these ECG changes are also important. Because the risks of exercise testing are small but real— estimated at one fatality and two nonfatal complications per 10,000 tests—equipment for resuscitation should be available. Modified (heart rate–limited rather than symptom-limited) exercise tests can be performed safely in patients as early as 6 days after uncomplicated myocardial infarction (Table 284-2). Contraindications to exercise stress testing include rest angina within 48 h, unstable rhythm, severe aortic stenosis, acute myocarditis, uncontrolled heart failure, severe pulmonary hypertension, and active infective endocarditis. The normal response to graded exercise includes progressive increases in heart rate and blood pressure. Failure of the blood pres­ sure to increase or an actual decrease with signs of ischemia during the test is an important adverse prognostic sign, since it may reflect ischemia-induced global LV dysfunction. The development of angina and/or severe (>0.2 mV) ST-segment depression at a low workload, i.e., before completion of stage II of the Bruce protocol, and/or ST-segment depression that persists >5 min after the termination of exercise increases the specificity of the test and suggests severe IHD and a high risk of future adverse events. Cardiac Imaging  (See also Chap. 248) When the resting ECG is abnormal (e.g., preexcitation syndrome, >1 mm of resting ST-segment depression, left bundle branch block, paced ventricular rhythm), information gained from an exercise test can be enhanced by stress myocardial radionuclide perfusion imaging after the intravenous administration of thallium-201 or 99m-technetium sestamibi during exercise (or with pharmacologic) stress. Contemporary data also sug­ gest positron emission tomography (PET) imaging (with exercise or pharmacologic stress) using N-13 ammonia or rubidium-82 as another technique for assessing perfusion. Images obtained immediately after cessation of exercise to detect regional ischemia are compared with those obtained at rest to confirm reversible ischemia and regions of persistently absent uptake that signify infarction. A sizable fraction of patients who need noninvasive stress testing to identify myocardial ischemia and increased risk of coronary events cannot exercise because of peripheral vascular or musculoskeletal disease, exertional dyspnea, or deconditioning. In these circum­ stances, an intravenous pharmacologic challenge is used in place of exercise. For example, adenosine can be given to create a coronary “steal” by temporarily increasing flow in nondiseased segments of the coronary vasculature at the expense of diseased segments. Alternatively, a graded incremental infusion of dobutamine may be administered to increase MVO2. A variety of imaging options are available to accompany these pharmacologic stressors (Fig. 284-3). The development of a transient perfusion defect with a tracer such as thallium-201 or 99m-technetium sestamibi is used to detect myo­ cardial ischemia.

Echocardiography is used to assess LV function in patients with chronic stable angina and patients with a history of a prior myocardial infarction, pathologic Q waves, or clinical evidence of heart failure. Twodimensional echocardiography can assess both global and regional wall motion abnormalities of the left ventricle that are transient when due to ischemia. Stress (exercise or dobutamine) echocardiography may cause the emergence of regions of akinesis or dyskinesis that are not present at rest. Stress echocardiography, like stress myocardial perfusion imaging, is more sensitive than exercise electrocardiography No diagnostic testing mandated Choice of the test based on clinical likelihood, patient characteristics and preference, availability, as well as local expertise Coronary CTA Very high Very low Clinical likelihood of obstructive CAD A FIGURE 284-3  Selecting appropriate testing patients with angina and suspected coronary artery disease (CAD). On the left of the figure is an algorithm for selecting from among testing options. In patients who are at low risk, in whom prior testing was equivocal, or in whom the diagnosis of is CAD uncertain, noninvasive functional stress testing with imaging for myocardial ischemia or computed tomography angiography (CTA) is reasonable to establish the diagnosis of CAD prior to initiation of treatment. Patients with a high clinical likelihood of CAD, patients with symptoms despite antianginal therapy or with low-level activities, and patients with high-risk features based on the initial clinical evaluation may proceed directly to invasive coronary angiography without further diagnostic testing. (Adapted from J Knuuti et al: 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 41:407, 2020.) Panels A–F are examples of the data obtained with electrocardiogram (ECG) monitoring and specialized imaging procedures. CMR, cardiac magnetic resonance; EBCT, electron beam computed tomography; ECHO, echocardiography; FFR, fractional flow reserve; IHD, ischemic heart disease; iwFR, instantaneous wave-free ration; MIBI, methoxyisobutyl isonitrite; MR, magnetic resonance; PET, positron emission tomography. A. Lead V4 at rest (top panel) and after 4.5 min of exercise (bottom panel). There is 3 mm (0.3 mV) of horizontal ST-segment depression, indicating a positive test for ischemia. (Adapted from BR Chaitman, in E Braunwald et al [eds]: Heart Disease, 8th ed, Philadelphia, Saunders, 2008.) B. A 45-year-old avid jogger who began experiencing classic substernal chest pressure underwent an exercise echo study. With exercise, the patient’s heart rate increased from 52 to 153 beats/min. The left ventricular chamber dilated with exercise, and the septal and apical portions became akinetic to dyskinetic (red arrow). These findings are strongly suggestive of a significant flow-limiting stenosis in the proximal left anterior descending artery, which was confirmed at coronary angiography. (Modified from SD Solomon, in E Braunwald et al [eds]: Primary Cardiology, 2nd ed, Philadelphia, Saunders, 2003.) C. Stress and rest myocardial perfusion single-photon emission computed tomography images obtained with 99m-technetium sestamibi in a patient with chest pain and dyspnea on exertion. The images demonstrate a medium-size and severe stress perfusion defect involving the inferolateral and basal inferior walls, showing nearly complete reversibility, consistent with moderate ischemia in the right coronary artery territory (red arrows). (Images provided by Dr. Marcello Di Carli, Nuclear Medicine Division, Brigham and Women’s Hospital, Boston, MA.) D. A patient with a prior myocardial infarction presented with recurrent chest discomfort. On cardiac magnetic resonance (CMR) cine imaging, a large area of anterior akinesia was noted (marked by the arrows in the top left and right images, systolic frame only). This area of akinesia was matched by a larger extent of late gadolinium-DTPA enhancements consistent with a large transmural myocardial infarction (marked by arrows in the middle left and right images). Resting (bottom left) and adenosine vasodilating stress (bottom right) first-pass perfusion images revealed reversible perfusion abnormality that extended to the inferior septum. This patient was found to have an occluded proximal left anterior descending coronary artery with extensive collateral formation. This case illustrates the utility of different modalities in a CMR examination in characterizing ischemic and infarcted myocardium. DTPA, diethylenetriamine penta-acetic acid. (Images provided by Dr. Raymond Kwong, Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA.) E. Stress and rest myocardial perfusion PET images obtained with rubidium-82 in a patient with chest pain on exertion. The images demonstrate a large and severe stress perfusion defect involving the mid and apical anterior, anterolateral, and anteroseptal walls and the left ventricular apex, showing complete reversibility, consistent with extensive and severe ischemia in the mid-left anterior descending coronary artery territory (red arrows). (Images provided by Dr. Marcello Di Carli, Nuclear Medicine Division, Brigham and Women’s Hospital, Boston, MA.) F. A 58-year-old woman with psoriasis presented with chest discomfort and underwent coronary CT angiography (CCTA) for further evaluation. There was a large amount of mostly noncalcified plaque resulting in severe (>70%) stenosis of the mid left anterior descending artery (LAD) and the mid-right coronary artery (RCA). There was minimal plaque in the left circumflex (LCx). CCTA data can be used to reconstruct three-dimensional images to aid visualization. In addition, each coronary artery can be visualized en face by creating a short axis along the length of the coronary segment being visualized. In this case, the stenosis of the LAD is seen in the red box (corresponding to the level of the dashed red line) and compared with the proximal normal segment in the green box (corresponding to the level of the dashed green line). (Images provided by Dr. Ron Blankstein, Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA.)

in the diagnosis of IHD. Cardiac magnetic resonance (CMR) stress testing is also evolving as an alternative to radionuclide, PET, or echocardiographic stress imaging. CMR stress testing performed with dobutamine infusion can be used to assess wall motion abnormalities accompanying ischemia, as well as myocardial perfusion. CMR can be used to provide more complete ventricular evaluation using multislice magnetic resonance imaging (MRI) studies.

CHAPTER 284 Atherosclerotic plaques become progressively calcified over time, and coronary calcification in general increases with age. For this Ischemic Heart Disease Invasive angiography (with iwFR/FFR) Testing for ischemia (imaging testing preferred)

PART 6 Disorders of the Cardiovascular System FIGURE 284-3­  (Continued)

F FIGURE 284-3­  (Continued) reason, methods for detecting coronary calcium have been developed as a measure of the presence of coronary atherosclerosis. These meth­ ods involve CT applications that achieve rapid acquisition of images (electron beam [EBCT] and multidetector [MDCT] detection). Coro­ nary calcium detected by these imaging techniques most commonly is quantified by using the Agatston score, which is based on the area and density of calcification. Coronary CT angiography (CCTA) (Fig. 284-3) is helpful in diag­ nosing the extent and severity of nonobstructive and obstructive IHD, as well as assessing plaque composition. Thus, CCTA is an attractive option when the pretest likelihood of IHD is intermediate in a young patient (< 65 years) with chest pain or less obstructive IHD is sus­ pected. Stress imaging is the preferred diagnostic test when the goal is assessing the adequacy of ischemia-guided management. ■ ■CORONARY ARTERIOGRAPHY (See also Chap. 249) This diagnostic method outlines the lumina of the coronary arteries and can be used to detect or exclude serious coronary obstruction. However, coronary arteriography provides no TABLE 284-2  Relation of Metabolic Equivalent Tasks (METs) to Stages in Various Testing Protocols FUNCTIONAL CLASS CLINICAL STATUS             BRUCE Modified 3 min Stages BRUCE 3 min Stages HEALTHY, DEPENDENT ON AGE, ACTIVITY NORMAL AND I SEDENTARY HEALTHY II   LIMITED SYMPTOMATIC III   10.5

1.7

IV   3.5

Note: The standard Bruce treadmill protocol (right-hand column) begins at 1.7 MPH and 10% gradient (GR) and progresses every 3 min to a higher speed and elevation. The corresponding oxygen consumption and clinical status of the patient are shown in the center and left-hand columns. Abbreviations: GR, grade; MPH, miles per hour. Source: Reproduced with permission from GF Fletcher et al: Exercise standards for testing and training. Circulation 104:1694, 2001.

CHAPTER 284 Ischemic Heart Disease information about the arterial wall, and severe atherosclerosis that does not encroach on the lumen may go undetected. Of note, atherosclerotic plaques characteristically are scattered throughout the coronary tree, tend to occur more frequently at branch points, and grow progressively in the intima and media of an epicardial coronary artery at first without encroaching on the lumen, causing an outward bulging of the artery—a process referred to as remodeling. Later in the course of the disease, further growth causes luminal narrowing. Indications  The ISCHEMIA trial informs decision-making about referral for coronary arteriography (with intent to perform revascular­ ization) in patients with stable IHD and an ejection fraction >35% even in the presence of moderate-severe ischemia on noninvasive functional testing. Over the course of 4 years of follow-up, early referral for an invasive strategy was not associated with a reduction in the risk of myocardial infarction or death but was more effective than an initial conservative, medical strategy in relieving angina. Thus, coronary arteriography is indicated in (1) patients with chronic stable angina pectoris who are severely symptomatic despite medical therapy and are O2 COST

mL/Kg/min METs TREADMILL PROTOCOLS MPH %GR MPH %GR 6.0

6.0

5.5

5.2

5.0

5.0

56.0

52.5

49.0

45.5

4.2

4.2

42.0

38.5

3.4

3.4

35.0

31.5

28.0

24.5

2.5

2.5

21.0

17.5

1.7

1.7

14.0

7.0

1.7

being considered for revascularization, i.e., a percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG); (2) patients with troublesome symptoms that present diagnostic difficul­ ties in whom there is a need to confirm or rule out the diagnosis of IHD; (3) patients with known or possible angina pectoris who have survived cardiac arrest; and (4) patients with angina or evidence of ischemia on noninvasive testing with clinical or laboratory evidence of ventricular dysfunction.

PART 6 Disorders of the Cardiovascular System Examples of other indications for coronary arteriography include the following:

  1. Patients with chest discomfort suggestive of angina pectoris but a negative or nondiagnostic stress test who require a definitive diag­ nosis for guiding medical management, alleviating psychological stress, career or family planning, or insurance purposes.
  2. Patients who have been admitted repeatedly to the hospital for a suspected acute coronary syndrome (Chaps. 285 and 286), but in whom this diagnosis has not been established and in whom it is considered clinically important to determine the presence or absence of CAD.
  3. Patients with careers that involve the safety of others (e.g., pilots, firefighters, police) who have questionable symptoms or suspicious or positive noninvasive tests and in whom there are reasonable doubts about the state of the coronary arteries.
  4. Patients with aortic stenosis or hypertrophic cardiomyopathy and angina in whom the chest pain could be due to IHD.
  5. Male patients >45 years and females >55 years who are to undergo a cardiac operation such as valve replacement or repair and who may or may not have clinical evidence of myocardial ischemia.
  6. Patients after myocardial infarction, especially those who are at high risk after myocardial infarction because of the recurrence of angina or the presence of heart failure, frequent ventricular premature con­ tractions, or signs of ischemia on the stress test.
  7. Patients in whom coronary spasm or another nonatherosclerotic cause of myocardial ischemia (e.g., coronary artery anomaly, Kawa­ saki disease) is suspected. Noninvasive alternatives to diagnostic coronary arteriography include CT angiography and CMR angiography (Chap. 248). Important aspects of their use that should be noted include the substantially higher radia­ tion exposure with CT angiography compared to conventional diag­ nostic arteriography and the limitations on CMR imposed by cardiac movement during the cardiac cycle, especially at high heart rates. ■ ■PROGNOSIS The principal prognostic indicators in patients known to have IHD are age, the functional state of the left ventricle, the location(s) and severity of coronary artery narrowing, and the severity or activity of myocardial ischemia. Angina pectoris of recent onset, unstable angina (Chap. 285), early postmyocardial infarction angina, angina that is unresponsive or poorly responsive to medical therapy, and angina accompanied by symptoms of congestive heart failure all indicate an increased risk for adverse coronary events. The same is true for the physical signs of heart failure, episodes of pulmonary edema, transient third heart sounds, and mitral regurgitation and for echocardiographic or radioisotopic (or roentgenographic) evidence of cardiac enlarge­ ment and reduced (<0.40) ejection fraction. Most important, any of the following signs during noninvasive test­ ing indicates a high risk for coronary events: inability to exercise for 6 min, i.e., stage II (Bruce protocol) of the exercise test; a strongly posi­ tive exercise test showing onset of myocardial ischemia at low work­ loads (≥0.1 mV ST-segment depression before completion of stage II, ≥0.2 mV ST-segment depression at any stage, ST-segment depression for >5 min after the cessation of exercise, a decline in systolic pressure

10 mmHg during exercise, or the development of ventricular tachyar­ rhythmias during exercise); the development of large or multiple perfusion defects or increased lung uptake during stress radioisotope perfusion imaging; and a decrease in LV ejection fraction during exer­ cise on radionuclide ventriculography or during stress echocardiog­ raphy. Conversely, patients who can complete stage III of the Bruce

exercise protocol and have a normal stress perfusion scan or negative stress echocardiographic evaluation are at very low risk for future coro­ nary events. The finding of frequent episodes of ST-segment deviation on ambulatory ECG monitoring (even in the absence of symptoms) is also an adverse prognostic finding. On cardiac catheterization, elevations of LV end-diastolic pressure and ventricular volume and reduced ejection fraction are the most important signs of LV dysfunction and are associated with a poor prog­ nosis. Patients with chest discomfort but normal LV function and normal coronary arteries have an excellent prognosis. Obstructive lesions of the left main (>50% luminal diameter) or left anterior descending coronary artery proximal to the origin of the first septal artery are associated with a greater risk than are lesions of the right or left circumflex coronary artery because of the greater quantity of myocardium at risk. Athero­ sclerotic plaques in epicardial arteries with fissuring or filling defects indicate increased risk. These lesions go through phases of inflammatory cellular activity, degeneration, endothelial dysfunction, abnormal vaso­ motion, platelet aggregation, and fissuring or hemorrhage. These factors can temporarily worsen the stenosis and cause thrombosis and/or abnor­ mal reactivity of the vessel wall, thus exacerbating the manifestations of ischemia. The recent onset of symptoms, the development of severe ischemia during stress testing (see above), and unstable angina pectoris (Chap. 285) all reflect episodes of rapid progression in coronary lesions. With any degree of obstructive CAD, mortality is greatly increased when LV function is impaired; conversely, at any level of LV function, the prognosis is influenced importantly by the quantity of myocardium perfused by critically obstructed vessels. Therefore, it is essential to col­ lect all the evidence substantiating past myocardial damage (evidence of myocardial infarction on ECG, echocardiography, radioisotope imaging, or left ventriculography), residual LV function (ejection frac­ tion and wall motion), and risk of future damage from coronary events (extent of coronary disease and severity of ischemia defined by nonin­ vasive stress testing). The larger the quantity of established myocardial necrosis is, the less the heart is able to withstand additional damage and the poorer the prognosis. Risk estimation must include age, presenting symptoms, all risk factors, signs of arterial disease, existing cardiac damage, and signs of impending damage (i.e., ischemia). The greater the number and severity of risk factors for coronary atherosclerosis (advanced age [>75 years], hypertension, dyslipidemia, diabetes, morbid obesity, accompanying peripheral and/or cerebrovas­ cular disease, previous myocardial infarction), the worse the prognosis of an angina patient. Evidence exists that elevated levels of CRP in the plasma, extensive coronary calcification on EBCT (see above), and increased carotid intimal thickening on ultrasound examination also indicate an increased risk of coronary events. TREATMENT Stable Angina Pectoris Once the diagnosis of IHD has been made, each patient must be evaluated individually with respect to their level of understanding, expectations and goals, control of symptoms, and prevention of adverse clinical outcomes such as myocardial infarction and prema­ ture death. The degree of disability and the physical and emotional stress that precipitates angina must be recorded carefully to set treatment goals. The management plan should include the following components: (1) explanation of the problem and reassurance about the ability to formulate a treatment plan, (2) identification and treat­ ment of aggravating conditions, (3) recommendations for adaptation of activity as needed, (4) treatment of risk factors that will decrease the occurrence of adverse coronary outcomes, (5) drug therapy for angina, and (6) consideration of revascularization. Emphasis should be placed on a patient-centric, team-based approach to care, with recognition of the importance of social determinants of health. EXPLANATION AND REASSURANCE Patients with IHD need to understand their condition and realize that a long and productive life is possible even though they have angina pectoris or have experienced and recovered from an acute

myocardial infarction. Offering results of clinical trials showing improved outcomes can be of great value in encouraging patients to resume or maintain activity and return to work. A planned program of rehabilitation can encourage patients to lose weight, improve exercise tolerance, and control risk factors with more confidence. IDENTIFICATION AND TREATMENT OF AGGRAVATING CONDITIONS A number of conditions may increase oxygen demand or decrease oxygen supply to the myocardium and may precipitate or exacer­ bate angina in patients with IHD. LVH, aortic valve disease, and hypertrophic cardiomyopathy may cause or contribute to angina and should be excluded or treated. Obesity, hypertension, and hyperthyroidism should be treated aggressively to reduce the fre­ quency and severity of anginal episodes. Decreased myocardial oxy­ gen supply may be due to reduced oxygenation of the arterial blood (e.g., in pulmonary disease or, when carboxyhemoglobin is present, due to cigarette or cigar smoking) or decreased oxygen-carrying capacity (e.g., in anemia). Correction of these abnormalities, if pres­ ent, may reduce or even eliminate angina pectoris. ADAPTATION OF ACTIVITY Myocardial ischemia is caused by a discrepancy between the demand of the heart muscle for oxygen and the ability of the coro­ nary circulation to meet that demand. Most patients can be helped to understand this concept and utilize it in the rational programming of activity. Many tasks that ordinarily evoke angina may be accom­ plished without symptoms simply by reducing the speed at which they are performed. Patients must appreciate the diurnal variation in their tolerance of certain activities and reducing their energy requirements in the morning, immediately after meals, and in cold or inclement weather. On occasion, it may be necessary to recom­ mend a change in employment or residence to avoid physical stress. Physical conditioning usually improves the exercise tolerance of patients with angina and has substantial psychological benefits. A regular program of isotonic exercise that is within the limits of TABLE 284-3  Energy Requirements for Some Common Activities LESS THAN 3 METs 3–5 METs 5–7 METs 7–9 METs MORE THAN 9 METs Self-Care Washing/shaving Cleaning windows Easy digging in garden Heavy shoveling Carrying loads upstairs (objects >90 lb) Dressing Raking Level hand lawn mowing Carrying objects (60–90 lb) Climbing stairs (quickly) Light housekeeping Power lawn mowing Carrying objects (30–60 lb)   Shoveling heavy snow Desk work Bed making/stripping       Driving auto Carrying objects (15–30 lb) Occupational Sitting (clerical/assembly) Stocking shelves (light objects) Carpentry (exterior) Digging ditches (pick and shovel) Desk work Light welding/carpentry Shoveling dirt Standing (store clerk) Sawing wood Recreational Golf (cart) Dancing (social) Tennis (singles) Canoeing Squash Knitting Golf (walking) Snow skiing (downhill) Mountain climbing Ski touring Sailing Light backpacking Vigorous basketball Tennis (doubles) Basketball Stream fishing Physical Conditioning Walking (2 mph) Level walking (3–4 mph) Level walking (4.5–5.0 mph) Level jogging (5 mph) Running more than 6 mph Stationary bike Level biking (6–8 mph) Bicycling (9–10 mph) Swimming (crawl stroke) Bicycling (more than 13 mph) Very light calisthenics Light calisthenics Swimming, breast stroke Rowing machine Rope jumping Abbreviation: METs, metabolic equivalent tasks. Source: Modified from WL Haskell: Rehabilitation of the coronary patient, in NK Wenger, HK Hellerstein (eds): Design and Implementation of Cardiac Conditioning Program. New York, Churchill Livingstone, 1978.

the individual patient’s threshold for the development of angina pectoris and that does not exceed 80% of the heart rate associated with ischemia on exercise testing should be strongly encouraged. Based on the results of an exercise test, the number of metabolic equivalent tasks (METs) performed at the onset of ischemia can be estimated (Table 284-2) and a practical exercise prescription can be formulated to permit daily activities that will fall below the ischemic threshold (Table 284-3).

CHAPTER 284 TREATMENT OF RISK FACTORS A family history of premature IHD is an important indicator of increased risk and should trigger a search for treatable risk fac­ tors such as hyperlipidemia, hypertension, and diabetes mellitus. Obesity impairs the treatment of other risk factors and increases the risk of adverse coronary events. In addition, obesity often is accompanied by three other risk factors: diabetes mellitus, hyper­ tension, and hyperlipidemia. The treatment of obesity and these accompanying risk factors is an important component of any management plan. A diet low in saturated and trans-unsaturated fatty acids and a reduced caloric intake to achieve optimal body weight are a cornerstone in the management of chronic IHD. It is especially important to emphasize weight loss and regular exer­ cise in patients with the metabolic syndrome or overt diabetes mellitus. Ischemic Heart Disease Cigarette smoking accelerates coronary atherosclerosis in both sexes and at all ages and increases the risk of thrombosis, plaque instability, myocardial infarction, and death. In addition, by increasing myocardial oxygen needs and reducing oxygen supply, it aggravates angina. Smoking cessation studies have demonstrated important benefits with a significant decline in the occurrence of these adverse outcomes. Noncombustible tobacco in the form of electronic cigarettes (nicotine delivery systems) may also increase the frequency of anginal episodes. The physician’s message must be clear and strong and supported by programs that achieve and monitor abstinence from all tobacco product use (Chap. 465). Heavy labor Heavy calisthenics Walking uphill (5 mph) Bicycling (12 mph)

Hypertension (Chap. 288) may coexist with other risk factors for IHD and is associated with an increased risk of adverse clinical events from coronary atherosclerosis as well as stroke. In addition, the LVH that results from sustained hypertension aggravates ischemia. There is evidence that long-term effective treatment of hypertension can decrease the occurrence of adverse coronary events (Chap. 288).

PART 6 Disorders of the Cardiovascular System Diabetes mellitus (Chap. 415) accelerates coronary, cerebrovas­ cular, and peripheral atherosclerosis and is frequently associated with dyslipidemia and increases in the risk of angina, myocardial infarction, and sudden coronary death. Aggressive control of the dyslipidemia (target LDL cholesterol <70 mg/dL) and hyperten­ sion (blood pressure <130/80 mmHg), that are frequently found in patients with diabetes mellitus, is highly effective and there­ fore essential, as described below. Use of either a sodium-glucose cotransporter 2 (SGLT-2) inhibitor or glucagon-like peptide 1 (GLP-1) receptor agonist in patients with IHD and type 2 diabetes is recommended in current guidelines to reduce the risk of major adverse cardiovascular events. DYSLIPIDEMIA The treatment of dyslipidemia is central in aiming for long-term relief from angina, reduced need for revascularization, and reduc­ tion in myocardial infarction and death. The control of lipids can be achieved by the combination of a diet low in saturated and trans-unsaturated fatty acids, exercise, and weight loss. Nearly always, HMG-CoA reductase inhibitors (statins) are required and can lower LDL cholesterol (25–50%), raise HDL cholesterol (5–9%), and lower triglycerides (5–30%). A powerful treatment effect of statins on atherosclerosis, IHD, and outcomes is seen regardless of the pretreatment LDL cholesterol level. In patients with IHD on a maximally tolerated statin with an LDL cholesterol ≥70 mg/dL, addition of ezetimibe is recommended as the next step, followed by a PCSK9 inhibitor (in patients at very high risk) should the LDL cholesterol goal not be achieved. When these therapies are not sufficient or tolerated, bempedoic acid may be considered for further LDL cholesterol reduction. Icosapent ethyl (purified eicos­ apentaenoic acid), fibrates, and resin-binding agents can be used to lower triglycerides (Chap. 419), but only icosapent ethyl has been shown to reduce cardiovascular risk in the statin era. Controlled trials with lipid-regulating regimens have shown equal propor­ tional benefit for men, women, the elderly, patients with diabetes mellitus, and smokers. Evidence exists that a high rate of control of LDL over time is associated with a lower cumulative LDL exposure and lower rate of major adverse cardiovascular events. Compliance with the health-promoting behaviors listed above is generally very poor, and a conscientious physician must not under­ estimate the major effort required to meet this challenge. Many patients who are discharged from the hospital with proven coronary disease do not receive adequate treatment for dyslipidemia. In light of the proof that treating dyslipidemia brings major benefits, physi­ cians need to establish treatment pathways, monitor compliance, and follow up regularly. RISK REDUCTION IN WOMEN WITH IHD The incidence of clinical IHD in premenopausal women is very low; however, after menopause, the atherogenic risk factors increase (e.g., increased LDL) and the rate of clinical coronary events accelerates to the levels observed in men. Diabetes mellitus, which is more com­ mon in women, greatly increases the occurrence of clinical IHD and amplifies the deleterious effects of hypertension, hyperlipidemia, and smoking. Cardiac catheterization and coronary revascularization are underused in women and are performed at a later and more severe stage of the disease than in men. When cholesterol lowering, beta blockers after myocardial infarction, and CABG are applied in the appropriate patient groups, women benefit to the same degree as men. DRUG THERAPY The commonly used drugs for the treatment of angina pectoris are summarized in Tables 284-4 through 284-6. Pharmacotherapy for IHD is designed to reduce the frequency of anginal episodes,

TABLE 284-4  Nitrate Therapy in Patients with Ischemic Heart Disease PREPARATION OF AGENT DOSE SCHEDULE Nitroglycerina       Ointment 0.5–2 in. Two or three times daily   Transdermal patch 0.2–0.8 mg/h Every 24 h; remove at bedtime for 12–14 h   Sublingual tablet 0.3–0.6 mg As needed, up to three doses

5 min apart   Spray One or two sprays As needed, up to three doses

5 min apart Isosorbide dinitratea       Oral 10–40 mg Two or three times daily   Oral sustained release 80–120 mg Once or twice daily (eccentric schedules) Isosorbide 5-mononitrate       Oral 20 mg Twice daily (given 7–8 h apart)   Oral sustained release 30–240 mg Once daily aA 10- to 12-h nitrate-free interval is recommended. Source: Reproduced with permission from DA Morrow, WE Boden: Stable ischemic heart disease. In RO Bonow et al (eds): Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine, 9th ed. Philadelphia, Saunders, 2012. myocardial infarction, and coronary death. Trial data emphasize how important medical management is when added to the healthpromoting behaviors discussed above. To achieve maximum benefit from medical therapy for IHD, it is frequently necessary to com­ bine agents from different classes and titrate the doses as guided by the individual profile of risk factors, symptoms, hemodynamic responses, and side effects. NITRATES The organic nitrates are a valuable class of drugs in the manage­ ment of angina pectoris (Table 284-4). Their major mechanisms of action include systemic venodilation with concomitant reduc­ tion in LV end-diastolic volume and pressure, thereby reducing myocardial wall tension and oxygen requirements; dilation of epicardial coronary vessels; and increased blood flow in collateral vessels. When metabolized, organic nitrates release nitric oxide (NO) that binds to guanylyl cyclase in vascular smooth muscle TABLE 284-5  Properties of Beta Blockers in Clinical Use for Ischemic Heart Disease PARTIAL AGONIST ACTIVITY USUAL DOSE FOR ANGINA DRUGS SELECTIVITY Acebutolol β1 Yes 200–600 mg twice daily Atenolol β1 No 50–200 mg/d Betaxolol β1 No 10–20 mg/d Bisoprolol β1 No 10 mg/d Esmolol (intravenous)a β1 No 50–300 μg/kg/min Labetalolb None Yes 200–600 mg twice daily Metoprolol β1 No 50–200 mg twice daily Nadolol None No 40–80 mg/d Nebivolol β1 (at low doses) No 5–40 mg/d Pindolol None Yes 2.5–7.5 mg 3 times daily Propranolol None No 80–120 mg twice daily Timolol None No 10 mg twice daily aEsmolol is an ultra-short-acting beta blocker that is administered as a continuous intravenous infusion. Its rapid offset of action makes esmolol an attractive agent to use in patients with relative contraindications to beta blockade. bLabetolol is a combined alpha and beta blocker. Note: This list of beta blockers that may be used to treat patients with angina pectoris is arranged alphabetically. It is preferable to use a sustained-release formulation that may be taken once daily to improve the patient’s compliance with the regimen. Source: Data from RJ Gibbons et al: J Am Coll Cardiol 41:159, 2003.

TABLE 284-6  Calcium Channel Blockers in Clinical Use for Ischemic Heart Disease DURATION OF ACTION SIDE EFFECTS DRUGS USUAL DOSE Dihydropyridines Amlodipine 5–10 mg qd Long Headache, edema Felodipine 5–10 mg qd Long Headache, edema Isradipine 2.5–10 mg bid Medium Headache, fatigue Nicardipine 20–40 mg tid Short Headache, dizziness, flushing, edema Nifedipine Immediate release:a 30–90 mg daily orally Slow release:

30–180 mg orally Short Hypotension, dizziness, flushing, nausea, constipation, edema Nisoldipine 20–40 mg qd Short Similar to nifedipine Nondihydropyridines Diltiazem Immediate release: 30–80 mg 4 times daily Short Hypotension, dizziness, flushing, bradycardia, edema Slow release:

120–320 mg qd Long   Verapamil Immediate release: 80–160 mg tid Short Hypotension, myocardial depression, Slow release: 120–480 mg qd Long heart failure, edema, bradycardia aMay be associated with increased risk of mortality if administered during acute myocardial infarction. Note: This list of calcium channel blockers that may be used to treat patients with angina pectoris is divided into two broad classes, dihydropyridines and nondihydropyridines, and arranged alphabetically within each class. Among the dihydropyridines, the greatest clinical experience has been obtained with amlodipine and nifedipine. After the initial period of dose titration with a shortacting formulation, it is preferable to switch to a sustained-release formulation that may be taken once daily to improve patient compliance with the regimen. Source: Data from RJ Gibbons et al: J Am Coll Cardiol 41:159, 2003. cells, leading to an increase in cyclic guanosine monophosphate, which causes relaxation of vascular smooth muscle. Nitrates also exert antithrombotic activity by NO-dependent activation of plate­ let guanylyl cyclase, impairment of intraplatelet calcium flux, and platelet activation. The absorption of these agents is rapid and complete through mucous membranes. For this reason, nitroglycerin is most com­ monly administered sublingually in tablets of 0.4 or 0.6 mg. Patients with angina should be instructed to take the medication both to relieve angina and also ~5 min before activities that are likely to induce an episode. Nitrates improve exercise tolerance in patients with chronic angina and relieve ischemia in patients with unstable angina as well as patients with vasospastic variant angina (Chap. 285). A diary of angina and nitroglycerin use may be valuable for detecting changes in the frequency, severity, or threshold for discomfort that may sig­ nify the development of unstable angina pectoris and/or herald an impending myocardial infarction. Long-Acting Nitrates  None of the long-acting nitrates is as effec­ tive as sublingual nitroglycerin for the acute relief of angina. These organic nitrate preparations can be swallowed, chewed, or admin­ istered as a patch or paste by the transdermal route (Table 284-4). They provide effective plasma levels for up to 24 h, but the thera­ peutic response is highly variable. Different preparations and/or administration during the daytime should be tried only to prevent discomfort while avoiding side effects such as headache and dizzi­ ness. Individual dose titration is important to prevent side effects. To minimize the effects of nitrate tolerance, the minimum effective dose should be used and a minimum of 8 h each day kept free of the drug to restore any useful response(s).

Beta-Adrenergic Blockers  These drugs represent an important component of the pharmacologic treatment of angina pectoris (Table 284-5). They reduce myocardial oxygen demand by inhib­ iting the increases in heart rate, arterial pressure, and myocardial contractility caused by adrenergic activation. Beta blockade reduces these variables most strikingly during exercise but causes only small reductions at rest. Long-acting beta-blocking drugs or sustained-release formulations offer the advantage of oncedaily dosing (Table 284-5). The therapeutic aims include relief of angina and ischemia. These drugs also can reduce mortality and reinfarction rates in patients after myocardial infarction and are moderately effective antihypertensive agents. Use of beta block­ ers beyond 1 year after myocardial infarction may be reassessed in the absence of LV systolic dysfunction, angina, arrhythmias, or uncontrolled hypertension, as their long-term benefit in such patients is unclear.

CHAPTER 284 Ischemic Heart Disease Relative contraindications include asthma and reversible air­ way obstruction in patients with chronic lung disease, atrioven­ tricular conduction disturbances, severe bradycardia, Raynaud’s phenomenon, and a history of mental depression. Side effects include fatigue, reduced exercise tolerance, nightmares, impo­ tence, cold extremities, intermittent claudication, bradycardia (sometimes severe), impaired atrioventricular conduction, LV failure, bronchial asthma, worsening claudication, and inten­ sification of the hypoglycemia produced by oral hypoglycemic agents and insulin. Reducing the dose or even discontinuation may be necessary if these side effects develop and persist. Since sudden discontinuation can intensify ischemia, the doses should be tapered over 2 weeks. Beta blockers with relative β1-receptor specificity such as metoprolol and atenolol may be preferable in patients with mild bronchial obstruction and insulin-requiring diabetes mellitus. Calcium Channel Blockers  Calcium channel blockers (Table 284-6) are coronary vasodilators that produce variable and dose-dependent reductions in myocardial oxygen demand, contractility, and arterial pressure. These combined pharmacologic effects are advantageous and make these agents as effective as beta block­ ers in the treatment of angina pectoris. They are indicated when beta blockers are contraindicated, poorly tolerated, or ineffective. Because of differences in the dose-response relationship on car­ diac electrical activity between the dihydropyridine and nondi­ hydropyridine calcium channel blockers, verapamil and diltiazem may produce symptomatic disturbances in cardiac conduction and bradyarrhythmias. They also exert negative inotropic actions and are more likely to aggravate LV failure, particularly when used in patients with LV dysfunction, especially if the patients are also receiving beta blockers. Although useful effects usually are achieved when calcium channel blockers are combined with beta blockers and nitrates, individual titration of the doses is essential with these combinations. Vasospastic angina responds particu­ larly well to calcium channel blockers (especially members of the dihydropyridine class), supplemented when necessary by nitrates (Chap. 285). Verapamil ordinarily should not be combined with beta block­ ers because of the combined adverse effects on heart rate and contractility. Diltiazem can be combined with beta blockers in patients with normal ventricular function and no conduction disturbances. Amlodipine and beta blockers have complemen­ tary actions on coronary blood supply and myocardial oxygen demands. Whereas the former decreases blood pressure and dilates coronary arteries, the latter slows heart rate and decreases contractility. Amlodipine and the other second-generation dihy­ dropyridine calcium antagonists (nicardipine, isradipine, longacting nifedipine, and felodipine) are potent vasodilators and are useful in the simultaneous treatment of angina and hypertension. Short-acting dihydropyridines should be avoided because of the risk of precipitating infarction, particularly in the absence of con­ comitant beta blocker therapy.

Choice Between Beta Blockers and Calcium Channel Blockers for Initial Therapy  Since beta blockers have been shown to improve life expectancy after acute myocardial infarction (Chaps. 285 and 286) and calcium channel blockers have not, the former may also be preferable in patients with angina and a damaged left ventricle. However, calcium channel blockers are indicated in patients with the following: (1) inadequate responsiveness to the combination of beta blockers and nitrates; many of these patients do well with a combination of a beta blocker and a dihydropyridine calcium chan­ nel blocker; (2) adverse reactions to beta blockers such as depression, sexual disturbances, and fatigue; (3) angina and a history of asthma or chronic obstructive pulmonary disease; (4) sick-sinus syndrome or significant atrioventricular conduction disturbances; (5) vaso­ spastic angina; or (6) symptomatic peripheral arterial disease.

PART 6 Disorders of the Cardiovascular System Ranolazine, a piperazine derivative, may be useful for patients with chronic angina despite standard medical therapy (Table 284-7). Its antianginal action is believed to occur via inhibition of the late inward sodium current (INa). The benefits of INa inhibition include limitation of the Na overload of ischemic myocytes and prevention of Ca2+ overload via the Na+–Ca2+ exchanger. A dose of 500–1000 mg orally twice daily is usually well tolerated. Ranolazine is contra­ indicated in patients with hepatic impairment or with conditions or drugs associated with QTc prolongation, and when drugs that inhibit the CYP3A metabolic system (e.g., ketoconazole, diltiazem, verapamil, macrolide antibiotics, HIV protease inhibitors, and large quantities of grapefruit juice) are being used. A comparison of the common side effects, contraindications, and potential drug interactions of many of the frequently presented antianginal agents is shown in Table 284-7. Antiplatelet Drugs  Aspirin is an irreversible inhibitor of platelet cyclooxygenase and thereby interferes with platelet activation. Chronic administration of 75–325 mg orally per day has been shown to reduce coronary events in asymptomatic adult men over age 50, patients with chronic stable angina, and patients who have or have survived unstable angina and myocardial infarction. There is a dose-dependent increase in bleeding when aspirin is used chronically. It is preferable to use an enteric-coated formulation in the range of 75–162 mg/d. Administration of this drug should be considered in all patients with IHD in the absence of gastroin­ testinal bleeding, allergy, or dyspepsia. Clopidogrel (300–600 mg TABLE 284-7  Antianginal Agents AGENT COMMON SIDE EFFECTS CONTRAINDICATIONS POTENTIAL DRUG INTERACTIONS Agents That Have a Physiologic Effect Short-acting and long-acting nitrates Headache, flushing, hypotension, syncope and postural hypotension, reflex tachycardia, methemoglobinemia Hypertrophic obstructive cardiomyopathy Phosphodiesterase type 5 inhibitors (sildenafil and similar agents), betaadrenergic blockers, calcium channel blockers Beta blockers Fatigue, depression, bradycardia, heart block, bronchospasm, peripheral vasoconstriction, postural hypotension, impotence, masked signs of hypoglycemia Low heart rate or heart conduction disorder, cardiogenic shock, asthma, severe peripheral vascular disease, decompensated heart failure, vasospastic angina; use with caution in patients with COPD (cardioselective beta blockers may be used if patient receives adequate treatment with long-acting beta agonists) Calcium-channel blockers       Heart rate–lowering agents Bradycardia, heart conduction defect, low ejection fraction, constipation, gingival hyperplasia Cardiogenic shock, severe aortic stenosis, obstructive cardiomyopathy Dihydropyridine Headache, ankle swelling fatigue, flushing, reflex tachycardia Low heart rate or heart rhythm disorder, sick-sinus syndrome, congestive heart failure, low blood pressure Agents That Affect Myocardial Metabolism Ranolazine Dizziness, constipation, nausea, QT interval prolongation Liver cirrhosis CYP3A4 substrates (digoxin, simvastatin, cyclosporine), drugs that prolong the corrected QT interval Abbreviations: AV, atrioventricular; COPD, chronic obstructive pulmonary disease; CYP3A4, cytochrome P450 3A4. Source: Data from SE Husted: Lancet 386:691, 2015, and EM Ohman: N Engl J Med 374:1167, 2016.

loading and 75 mg/d) is an oral agent that blocks P2Y12 ADP recep­ tor–mediated platelet aggregation. It provides benefits similar to those of aspirin in patients with stable chronic IHD and may be substituted for aspirin if aspirin causes the side effects listed above. Clopidogrel combined with aspirin reduces death and coronary ischemic events in patients with an acute coronary syndrome (Chap. 285) and also reduces the risk of thrombus formation in patients undergoing implantation of a stent in a coronary artery (Chap. 287). Alternative antiplatelet agents that block the P2Y12 platelet receptor such as prasugrel and ticagrelor have been shown to be more effective than clopidogrel for prevention of ischemic events after placement of a stent for an acute coronary syndrome but are associated with an increased risk of bleeding. Although combined treatment with clopidogrel and aspirin for at least a year is recommended in patients with an acute coronary syndrome treated with implantation of a drug-eluting stent, studies have not shown any benefit from the routine addition of clopidogrel to aspi­ rin in patients with chronic stable IHD. OTHER THERAPIES ACE inhibitors and ARBs are widely used in the treatment of survi­ vors of myocardial infarction, patients with hypertension or chronic IHD including angina pectoris, and those at high risk of vascular diseases such as diabetes. The benefits of ACE inhibitors and ARBs are most evident in IHD patients at increased risk, especially if dia­ betes mellitus or LV dysfunction is present, and those who have not achieved adequate control of blood pressure and LDL cholesterol on beta blockers and statins. However, the routine administration of ACE inhibitors or ARBs to IHD patients who have normal LV function and have achieved blood pressure and LDL goals on other therapies does not reduce the incidence of events and therefore is not cost-effective. Despite treatment with nitrates, beta blockers, calcium chan­ nel blockers, and ranolazine, some patients with IHD continue to experience angina, and additional medical therapy is now available to alleviate their symptoms. Originally introduced for the management of diabetes mellitus, the SGLT-2 inhibitor drugs have emerged as important agents with cardiovascular and renal protective effects. They promote weight loss, lower blood pressure, and reduce plasma volume—all of which are desirable in patients with IHD. In addition, they decrease Heart rate–lowering calcium channel blockers, sinus node or AV conduction depressors CYP3A4 substrates (digoxin, simvastatin, cyclosporine) Agents with cardiodepressant effects (beta blockers, flecainide), CYP3A4 substrates

intraglomerular hypertension and hyperfiltration. Evidence exists that they are helpful in patients with and without diabetes who have a reduced LV ejection fraction. Colchicine exhibits a number of broad cellular effects (interferes with chemotaxis and phagocytosis of inflammatory cells, reduces the expression of adhesion molecules, modifies cytokine produc­ tion) that result in an anti-inflammatory effect and may favorably affect the progression of atherosclerosis. In placebo-controlled randomized trials after myocardial infarction, low-dose colchicine (0.5 mg daily) prevented future cardiovascular events; however because it has a narrow therapeutic window, has a long half-life dependent upon renal clearance, is metabolized by CYP3A4, and is a substrate for P-glycoprotein (both of which that may result in drug-drug interactions), additional monitoring is required. In contrast, nonsteroidal anti-inflammatory drug (NSAID) use in patients with IHD may be associated with a small but finite increased risk of myocardial infarction and mortality. For this rea­ son, they generally should be avoided in IHD patients. If they are required for symptom relief, it is advisable to coadminister aspirin and strive to use an NSAID associated with the lowest risk of car­ diovascular events, in the lowest dose required, and for the shortest period of time. Nicorandil opens ATP-sensitive potassium channels in myo­ cytes, leading to a reduction of free intracellular calcium ions. It is typically administered orally in a dose of 20 mg twice daily for prevention of angina. Nicorandil is not available for use in the United States but is used in several other countries and is recommended as second-line treatment in the European chronic coronary disease (CCD) guidelines. Similarly, trimetazidine, which improves mitochondrial metabolism through inhibition of myocardial fatty acid uptake and oxidation and consequent stimulation of glucose oxidation, is recommended as a secondline antianginal in CCD and is available in many countries out­ side the United States. Ivabradine (2.5–7.5 mg orally twice daily) is a specific sinus node inhibiting agent that may be helpful for preventing cardiovascular events in patients with IHD who have a resting heart rate ≥70 beats/ min (alone or in combination with a beta blocker) and LV systolic dysfunction. However, the data are mixed regarding its clinical benefit, with the most recent U.S. CCD guideline recommend­ ing against its use in patients with normal LV function due to an increased risk of death or myocardial infarction). Angina and Heart Failure  Transient LV failure with angina can be controlled by the use of nitrates. For patients with established congestive heart failure, the increased LV wall tension raises myo­ cardial oxygen demand. See Chap. 265 for the “pillars” of treatment for heart failure. Treatment of congestive heart failure (Chap. 264) reduces heart size, wall tension, and myocardial oxygen demand, which helps control angina and ischemia. If the symptoms and signs of heart failure are controlled, an effort should be made to use beta blockers not only for angina but because trials in heart failure have shown significant improvement in survival. A trial of the intra­ venous ultra-short-acting beta blocker esmolol may be useful to establish the safety of beta blockade in selected patients. Nocturnal angina often can be relieved by the treatment of heart failure. The combination of congestive heart failure and angina in patients with IHD usually indicates a poor prognosis and war­ rants serious consideration of cardiac catheterization and coronary revascularization. CORONARY REVASCULARIZATION Clinical trials have confirmed that with the initial diagnosis of stable IHD, it is first appropriate to initiate a medical regimen as described above. Revascularization should be considered in the presence of unstable phases of the disease, intractable symptoms, high-risk coro­ nary anatomy, diabetes, and impaired LV function. Revascularization should be employed in conjunction with but not replace the continuing

Initiate medical therapy:

  1. Decrease demand ischemia
  2. Minimize IHD risk factors
  3. ASA (clopidogrel if ASA intolerant) CHAPTER 284 Any high-risk features? Low exercise capacity or ischemia at low workload, EF <40%, ACS presentation Ischemic Heart Disease No Yes Are exertional symptoms controlled? Refer for coronary arteriography Anatomy suitable for revascularization? Yes No Yes No Consider unconventional treatments Single-vessel disease LM +/or multivessel disease PCI Assess: PCI vs CABG Continue medical therapy periodic stress assessment (see Fig. 284-3) FIGURE 284-4  Algorithm for management of a patient with ischemic heart disease. All patients should receive the core elements of medical therapy as shown at the top of the algorithm. If high-risk features are present, as established by the clinical history, exercise test data, and imaging studies, the patient should be referred for coronary arteriography. Based on the number and location of the diseased vessels and their suitability for revascularization, the patient is treated with a percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery or should be considered for unconventional treatments. See text for further discussion. ACS, acute coronary syndrome; ASA, aspirin; EF, ejection fraction; IHD, ischemic heart disease; LM, left main. need to modify risk factors and assess medical therapy. An algorithm for integrating medical therapy and revascularization options in patients with IHD is shown in Fig. 284-4. ■ ■PERCUTANEOUS CORONARY INTERVENTION (See also Chap. 287) PCI involving balloon dilatation usually accom­ panied by coronary stenting is widely used to achieve revascularization of the myocardium in patients with symptomatic IHD and suitable stenoses of epicardial coronary arteries. Whereas patients with steno­ sis of the left main coronary artery and those with three-vessel IHD (especially with diabetes and/or impaired LV function) who require revascularization are best treated with CABG, PCI is widely employed in patients with symptoms and evidence of ischemia due to stenoses of one or two vessels and even in selected patients with three-vessel disease (and, perhaps, in some patients with left main disease) and may offer many advantages over surgery. Indications and Patient Selection  The most common clinical indication for PCI is symptom-limiting angina pectoris, despite medi­ cal therapy, accompanied by evidence of ischemia during a stress test. PCI is more effective than medical therapy for the relief of angina. PCI improves outcomes in patients with unstable angina or when used early in the course of myocardial infarction with and without cardiogenic shock. However, in patients with stable exertional angina, clinical trials

have confirmed that PCI does not reduce the occurrence of death or myocardial infarction compared to optimum medical therapy. PCI can be used to treat stenoses in native coronary arteries as well as in bypass grafts in patients who have recurrent angina after CABG.

Risks  When coronary stenoses are discrete and symmetric, two and even three vessels can be treated in sequence. However, case selection is essential to avoid a prohibitive risk of complications, which are usu­ ally due to dissection or thrombosis with vessel occlusion, uncontrolled ischemia, and ventricular failure (Chap. 287). Oral aspirin, a P2Y12 antagonist, and an antithrombin agent are given to reduce coronary thrombus formation. Left main coronary artery stenosis generally is regarded as a lesion that should be treated with CABG. In selected cases such as patients with prohibitive surgical risks, PCI of an unpro­ tected left main can be considered, but such a procedure should be performed only by a highly skilled operator; importantly, there are regional differences in the use of this approach internationally. PART 6 Disorders of the Cardiovascular System Efficacy  Primary success, with relief of angina, is achieved in >95% of cases. In diseased vein grafts, procedural success has been improved by the use of an embolic protection device, when feasible, to prevent isch­ emia and infarction. The use of current-generation drug-eluting stents that locally deliver antiproliferative drugs have a lower rate of restenosis (<5%) than the initial bare metal stents and are now the standard of care in PCI. Of note, however, the delayed endothelial healing in the region of a drug-eluting stent also extends the period during which the patient is at risk for subacute stent thrombosis. Aspirin should be administered indefinitely and a P2Y12 antagonist daily (dual antiplatelet therapy [DAPT]) ideally for 1 year after implantation of a drug-eluting stent. Evi­ dence exists of a benefit of continuing DAPT for up to 30 months, albeit at the cost of a higher risk of bleeding. Shorter courses of DAPT may be used in patients who are at high bleeding risk (see Chap. 69) or who have a long-term indication for oral anticoagulation (see Chap. 121). Efforts are underway to develop new antithrombotic regimens to reduce the risk of bleeding. These include (1) shortening the duration of DAPT by eliminating aspirin after 1 or 3 months and continuing a P2Y12 antagonist alone, (2) de-escalating from a potent P2Y12 inhibitor (i.e., prasugrel, ticagrelor) after 1 month to clopidogrel or reduced-dose prasugrel 5 mg daily, and (3) switching from DAPT to dual pathway inhibition with an antiplatelet agent and a low-dose direct oral anti­ coagulant. While each of these has been compared to standard DAPT regimens, such studies tend to be unpowered for ischemic events, and these alternative strategies have not been compared to one another. When a situation arises in which temporary discontinuation of antiplatelet therapy is necessary, the clinical circumstances should be reviewed with the operator who performed the PCI and a coordinated plan should be established for minimizing the risk of late stent throm­ bus; central to this plan is the discontinuation of antiplatelet therapy for the shortest acceptable period. The risk of stent thrombosis is dependent on stent size and length, complexity of the lesions, age, dia­ betes, and technique. However, compliance with DAPT and individual responsiveness to platelet inhibition are very important factors as well. Successful PCI produces effective relief of angina in >95% of cases. The majority of patients with symptomatic IHD who require revascu­ larization can be treated initially by PCI. Successful PCI is less invasive and expensive than CABG and permits savings in the initial cost of care. Successful PCI avoids the risk of stroke associated with CABG surgery and allows earlier return to work and resumption of an active life. However, the early health-related and economic benefits of PCI are reduced over time because of the greater need for follow-up and the increased need for repeat procedures. When directly compared in patients with diabetes or three-vessel or left main CAD, CABG was superior to PCI in preventing major adverse cardiac or cerebrovascular events over a 12-month follow-up. ■ ■CORONARY ARTERY BYPASS GRAFTING Anastomosis of one or both of the internal mammary arteries or a radial artery to the coronary artery distal to the obstructive lesion is the preferred procedure. For additional obstructions that cannot be bypassed by an artery, a section of a vein (usually the saphenous) is

used to form a venous bypass conduit between the aorta and the coro­ nary artery distal to the obstructive lesion. Although some indications for CABG are controversial, certain areas of agreement exist:

  1. The operation is relatively safe, with mortality rates <1% in patients without serious comorbid disease and normal LV function and when the procedure is performed by an experienced surgical team.
  2. Intraoperative and postoperative mortality rates increase with the severity of ventricular dysfunction, comorbidities, age ≥80 years, and lack of surgical experience. The effectiveness and risk of CABG vary widely depending on case selection and the skill and experience of the surgical team.
  3. Occlusion of venous grafts is observed in 10–20% of patients during the first postoperative year and in ~2% per year during 5- to 7-year follow-up and 4% per year thereafter. Long-term patency rates are considerably higher for internal mammary and radial artery implantations than for saphenous vein grafts. In patients with left anterior descending coronary artery obstruction, survival is better when coronary bypass involves the internal mammary artery rather than a saphenous vein. Graft patency and outcomes are improved by meticulous treatment of risk factors, particularly dyslipidemia.
  4. Angina is abolished or greatly reduced in ~90% of patients after complete revascularization. Although this usually is associated with graft patency and restoration of blood flow, the pain may also have been alleviated as a result of infarction of the ischemic segment, denervation due to median sternotomy, or a placebo effect.
  5. Survival may be improved by operation in patients with stenosis of the left main coronary artery as well as in patients with three- or two-vessel disease with significant obstruction of the proximal left anterior descending coronary artery. The survival benefit is greater in patients with abnormal LV function (ejection fraction <35). Sur­ vival may also be improved in the following patients: (a) patients with obstructive CAD who have survived sudden cardiac death or sustained ventricular tachycardia; (b) patients who have undergone previous CABG and have multiple saphenous vein graft stenoses, especially of a graft supplying the left anterior descending coronary artery; and (c) patients with recurrent stenosis after PCI and highrisk criteria on noninvasive testing.
  6. Minimally invasive CABG through a small thoracotomy and/or offpump surgery can reduce morbidity and shorten convalescence in suitable patients but does not appear to reduce significantly the risk of neurocognitive dysfunction postoperatively.
  7. Among patients with type 2 diabetes mellitus and multivessel coronary disease, CABG surgery plus optimal medical therapy is superior to optimal medical therapy alone in preventing major cardiovascular events, a benefit mediated largely by a significant reduction in nonfatal myocardial infarction. The benefits of CABG are especially evident in patients with diabetes mellitus treated with an insulin-sensitizing strategy as opposed to an insulin-providing strategy. CABG has also been shown to be superior to PCI (includ­ ing the use of drug-eluting stents) in preventing death, myocardial infarction, and repeat revascularization in patients with diabetes mellitus and multivessel IHD. Indications for CABG usually are based on the severity of symp­ toms, coronary anatomy, and ventricular function. The ideal candidate has no other complicating disease and has troublesome or disabling angina that is not adequately controlled by medical therapy or does not tolerate medical therapy. Great symptomatic benefit can be anticipated if a patient wishes to lead a more active life and has severe stenoses of two or three epicardial coronary arteries with objective evidence of myocardial ischemia as a cause of the chest discomfort. Congestive heart failure and/or LV dysfunction, advanced age (≥80 years), reop­ eration, urgent need for surgery, and the presence of diabetes mellitus are all associated with a higher perioperative mortality rate. LV dysfunction can be due to noncontractile or hypocontractile segments that are viable but are chronically ischemic (hibernating myocardium). As a consequence of chronic reduction in myocardial blood flow, these segments downregulate their contractile function.

They can be detected by using radionuclide scans of myo­ cardial perfusion and metabolism, PET, cardiac MRI, or delayed scanning with thallium-201 or by improvement of regional functional impairment provoked by low-dose dobutamine. In such patients, revascularization improves myocardial blood flow, can return function, and can improve survival. The Choice Between PCI and CABG  All the clinical characteristics of each individual patient must be used to decide on the method of revascularization (e.g., LV function, diabetes, lesion complexity). A number of randomized clinical trials have compared PCI and CABG in patients with multivessel CAD who were suitable technically for both procedures. The redevelopment of angina requiring repeat coronary angiography and repeat revascularization is higher with PCI. This is a result of restenosis in the stented segment (a problem largely solved with drug-eluting stents) and the development of new ste­ noses in unstented portions of the coronary vasculature. It has been argued that PCI with stenting focuses on culprit lesions, whereas a bypass graft to the target vessel also pro­ vides a conduit around future culprit lesions proximal to the anastomosis of the graft to the native vessel (Fig. 284-5). By contrast, stroke rates are lower with PCI. Based on available evidence, it is now recommended that patients with lifestyle-limiting angina despite guide­ line-directed medical management and therapy be con­ sidered for coronary revascularization. Patients with single- or two-vessel disease with normal LV function and anatomically suitable lesions ordinarily are advised to undergo PCI (Chap. 287). For patients who are poor candidates for surgery, it is reasonable to choose PCI over CABG to improve symptoms and reduce major adverse cardiac events. FIGURE 284-5  Difference in the approach to the lesion with percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). PCI is targeted at the “culprit” lesion or lesions, whereas CABG is directed at the epicardial vessel, including the culprit lesion or lesions and future culprits, proximal to the insertion of the vein graft, a difference that may account for the superiority of CABG, at least in the intermediate term, in patients with multivessel disease. (From The New England Journal of Medicine, Quantitative Determinants of the Outcome of Asymptomatic Mitral Regurgitation, M Enriquez-Sarano et al. 352, 2235. Copyright © 2005. Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.) In patients with left main disease associated with high-complexity CAD, CABG remains preferred to PCI to improve survival. Similarly, in patients with diabetes and multivessel disease involving the left anterior descending artery, CABG (with a left internal mammary conduit) is preferred over PCI, although in patients with low- or intermediate-complexity CAD, PCI may be considered. Patients with three-vessel disease (or two-vessel disease that includes the proximal left descending coronary artery) and impaired global LV function (LV ejection fraction <50%) or diabetes mel­ litus and those with left main CAD or other lesions unsuitable for catheter-based procedures should be considered for CABG as the initial method of revascularization. In light of the complexity of the decision-making, it is desirable to have a multidisciplinary team, including a cardiologist and a cardiac surgeon in conjunction with the patient’s primary care physician, provide input along with ascer­ taining the patient’s preferences before committing to a particular revascularization option. ■ ■UNCONVENTIONAL TREATMENTS FOR IHD On occasion, clinicians will encounter a patient who has persistent, disabling angina despite maximally tolerated medical therapy and for whom revascularization is not an option (e.g., small diffusely diseased vessels not amenable to stent implantation or acceptable targets for bypass grafting). In such situations, unconventional treatments should be considered. Enhanced external counterpulsation utilizes pneumatic cuffs on the lower extremities to provide diastolic augmentation and systolic unloading of blood pressure to decrease cardiac work and oxygen consumption while enhancing coronary blood flow. Clinical trials have shown that regular application improves angina, exercise capacity, and regional myocardial perfusion. Neuromodulation (e.g., spinal cord simulation, transcutaneous or subcutaneous electrical neural stimulation, sympathectomy) and

PCI CHAPTER 284 Lesion Stent Ischemic Heart Disease CABG Coronary artery Future culprit lesion A Lesion Bypass graft Future culprit lesion B coronary sinus constriction (using a reducer device) have shown promise in small studies. Experimental approaches, such as stem cell therapies and cardiac repair with small noncoding RNA molecules (miRNA), are also under active study. ASYMPTOMATIC (SILENT) ISCHEMIA Obstructive CAD, acute myocardial infarction, and transient myocar­ dial ischemia can occur in the absence of symptoms. During continuous ambulatory ECG monitoring, the majority of ambulatory patients with typical chronic stable angina are found to have objective evidence of myocardial ischemia (ST-segment depression) during episodes of chest discomfort while they are active outside the hospital. In addition, many of these patients also have more frequent episodes of asymptomatic ischemia. Frequent episodes of ischemia (symptomatic and asymptom­ atic) during daily life appear to be associated with an increased likeli­ hood of adverse coronary events (death and myocardial infarction). In addition, patients with asymptomatic ischemia after a myocardial infarction are at greater risk for a second coronary event. The wide­ spread use of exercise ECG during routine examinations has also identi­ fied some of these previously unrecognized patients with asymptomatic CAD. Longitudinal studies have demonstrated an increased incidence of coronary events in asymptomatic patients with positive exercise tests. TREATMENT Asymptomatic Ischemia The management of patients with asymptomatic ischemia must be individualized. When coronary disease has been confirmed, the aggressive treatment of hypertension and dyslipidemia is essential and will decrease the risk of infarction and death. In addition, the physician should consider the following: (1) the degree of positivity

49 - 286 ST-Segment Elevation Myocardial Infarction

286 ST-Segment Elevation Myocardial Infarction

Simultaneous with these important advances in the high-income countries, the low- and middle-income countries have moved in the opposite direction. Improvements in agriculture, nutrition, sanitation, prevention and treatment of infections, and management of maternal/ early childhood disorders, urbanization, and a reduction of physical labor have, in combination, led to marked increases in coronary risk factors—hypertension, cigarette smoking, obesity, diabetes mellitus, and elevations of circulating LDL-C. These changes have been most prominent in Central and South Asia, as well as in the more developed regions of sub-Saharan Africa and the Middle East. The current challenge is to apply what was learned in high-income countries to the large populations in the low- and middle-income countries that are now at high risk. This will require large educational efforts directed at both the populations and their caregivers. An addi­ tional challenge will be to provide the trained specialized personnel, facilities, drugs, and devices to deal with these threats. The successful implementation of these measures is now principally a socio-politicoeconomic issue. One mitigating factor is that many of the important drugs to prevent and treat these disorders, such as statins, ezetimibe, ACE inhibitors, diuretics, beta blockers, and calcium antagonists, are off patent and are now inexpensive. ■ ■FURTHER READING Byrne RA et al: 2023 ESC guidelines for the management of acute coronary syndromes. Eur Heart J 23:44, 2023. Capodanno D et al: Defining strategies of modulation of antiplatelet therapy in patients with coronary artery disease. Circulation 147: 1933, 2023. Hokimoto S et al: JCS/CVIT/JCC 2023 guideline focused update on diagnosis and treatment of vasospastic angina (coronary spastic angina) and coronary microvascular dysfunction. Circ J 87:879, 2023. Kontos MC et al: 2022 ACC Expert Consensus Decision Pathway on the evaluation and disposition of acute chest pain in the emergency department. J Am Coll Cardiol 80:1925, 2022. Lawton JS et al: 2021 ACC/AHA/SCAI guideline for coronary artery revascularization. J Am Coll Cardiol 79:e21, 2021. Mach F et al: ESC/EAS guidelines for the management of dyslipidae­ mias: Lipid modification to reduce cardiovascular risk. Eur Heart J 41:111, 2020. Martin SS et al: 2024 Heart disease and stroke statistics: A report of US and global data from the American Heart Association. Circulation 149:e347, 2024. Thygesen K et al: Fourth universal definition of myocardial infarction. J Am Coll Cardiol 72:2231, 2018. David A. Morrow, Elliott M. Antman,

Joseph Loscalzo

ST-Segment Elevation Myocardial Infarction Acute myocardial infarction (AMI) is a common diagnosis in hospital­ ized patients in industrialized countries. In the United States, ~605,000 patients experience a new AMI and 200,000 experience a recurrent AMI each year. About half of AMI-related deaths occur before the stricken individual reaches the hospital. The in-hospital mortality rate after admission for AMI has declined from 10 to ~5%. The 1-year mortality rate after AMI is ~15%. Mortality is approximately fourfold higher in patients aged >75 years as compared with younger patients. When patients with prolonged ischemic discomfort at rest are first seen, the working clinical diagnosis is that they are suffering from an acute coronary syndrome (Fig. 286-1). The 12-lead electrocardiogram (ECG) is a pivotal diagnostic and triage tool because it is at the center of the decision pathway for management, permitting distinction of

those patients presenting with ST-segment elevation from those pre­ senting without ST-segment elevation. Circulating cardiac biomarkers of myocardial injury are measured to distinguish unstable angina (UA) from non-ST-segment elevation myocardial infarction (NSTEMI) and to estimate preliminarily the magnitude of myocardial necrosis in an ST-segment elevation myocardial infarction (STEMI). Epidemiologic studies indicate there has been a shift in the pattern of AMI over the past several decades with more patients with NSTEMI than STEMI. This chapter focuses on the evaluation and management of patients with STEMI, while Chap. 286 discusses UA/NSTEMI. PATHOPHYSIOLOGY: ROLE OF ACUTE PLAQUE RUPTURE/EROSION STEMI usually occurs when coronary blood flow decreases abruptly after a thrombotic occlusion of a coronary artery previously affected by atherosclerosis. Slowly developing, high-grade coronary artery stenoses do not typically precipitate STEMI because of the develop­ ment of a rich collateral network over time. Instead, STEMI occurs when a coronary artery thrombus develops rapidly at a site of vascular injury. This injury is produced or facilitated by factors such as ciga­ rette smoking, hypertension, lipid accumulation, and inflammation. In most cases, STEMI occurs when the surface of an atherosclerotic plaque becomes disrupted either through erosion or rupture (expos­ ing its contents to the blood) and conditions (local or systemic) favor thrombogenesis. Histologic studies indicate that the coronary plaques prone to disruption are those with a rich lipid core and a thin fibrous cap. However, current clinical data have demonstrated that less than 5% of such thin-capped fibroatheromas are a nidus for AMI during long-term follow-up. Other morphologic characteristics associated with rupture-prone plaque include expansive remodeling, neovascular­ ization (angiogenesis), plaque hemorrhage, adventitial inflammation, and a “spotty” pattern of calcification.

CHAPTER 286 ST-Segment Elevation Myocardial Infarction A mural thrombus forms at the site of plaque disruption, and the involved coronary artery becomes occluded. After an initial platelet monolayer forms at the site of the disrupted plaque, various agonists (collagen, ADP, epinephrine, serotonin) promote platelet activation. After agonist stimulation of platelets, thromboxane A2 (a potent local vasoconstrictor) is released, further platelet activation occurs, and potential resistance to fibrinolysis develops. In addition to the generation of thromboxane A2, activation of plate­ lets by agonists promotes a conformational change in the glycoprotein IIb/IIIa receptor (Chap. 120). Once converted to its functional state, this receptor develops a high affinity for soluble adhesive proteins (i.e., integrins) such as fibrinogen. Since fibrinogen is a multivalent mol­ ecule, it can bind to two different platelets simultaneously, resulting in platelet cross-linking and aggregation. The coagulation cascade is activated on exposure of tissue factor in damaged endothelial cells at the site of the disrupted plaque. Fac­ tors VII and X are activated, ultimately leading to the conversion of prothrombin to thrombin, which then converts fibrinogen to fibrin (Chap. 121). Fluid-phase and clot-bound thrombin participate in an autoamplification reaction, leading to further activation of the coagulation cascade. The culprit coronary artery eventually becomes occluded by a thrombus containing platelet aggregates and fibrin strands (Fig. 286-2). In rare cases, STEMI may be due to coronary artery occlusion caused by coronary emboli, congenital coronary abnormalities, coro­ nary spasm, or spontaneous coronary artery dissection. The amount of myocardial damage caused by coronary occlusion depends on (1) the territory supplied by the affected vessel, (2) whether or not the vessel becomes totally occluded, (3) the duration of coronary occlusion, (4) the quantity of blood supplied by collateral vessels to the affected tis­ sue, (5) the demand for oxygen of the myocardium whose blood supply has been suddenly limited, (6) endogenous factors that can produce early spontaneous lysis of the occlusive thrombus, and (7) the adequacy of myocardial perfusion in the infarct zone when flow is restored in the occluded epicardial coronary artery. Patients at increased risk for developing STEMI include those with multiple coronary risk factors and those with UA (Chap. 285). Less

PART 6 Disorders of the Cardiovascular System Ischemic Discomfort Presentation Working diagnosis Supply-demand imbalance (nonthrombotic Acute coronary syndrome (atherothrombotic) ECG No ST elevation ST elevation – + + + – Biomarkers Final diagnosis Unstable angina (demand related) Non-ST elevation MI (type 2) Non-ST elevation MI (type 1) ST elevation MI (type 1) Unstable angina (thrombotic mediated) Final ECG manifestation FIGURE 286-1  Acute coronary syndromes. Following disruption of a vulnerable plaque, patients experience ischemic discomfort resulting from a reduction of flow through the affected epicardial coronary artery. The flow reduction may be caused by a completely occlusive thrombus (right) or subtotally occlusive thrombus (middle). Patients with ischemic discomfort may present with or without ST-segment elevation. Of patients with ST-segment elevation, the majority ultimately develop a Q wave on the electrocardiogram (ECG; Q-wave myocardial infarction [MI]), while a minority do not develop Q waves and, in the past, were said to have sustained a non-Q-wave MI (NQMI). Patients who present without ST-segment elevation are suffering from either unstable angina or a non-ST-segment elevation MI (NSTEMI), a distinction that is ultimately made based on the presence or absence of a biomarker of myocardial injury such as cardiac troponin detected in the blood. (Reproduced with permission from Hamm Scirica BM, Libby P, Morrow DA: ST-elevation myocardial infarction: Pathophysiology and clinical evolution, in Braunwald’s Heart Disease, 12th ed, Libby P et al (eds). New York, Elsevier, 2022, Figure 37-1, pp 636-661.) common underlying medical conditions predisposing patients to STEMI include hypercoagulability, collagen vascular disease, systemic inflammatory diseases, cocaine abuse, and intracardiac thrombi or masses that produce coronary emboli. There have been major advances in the management of STEMI with recognition that the “chain of survival” involves a highly integrated system starting with prehospital care and extending to early hospital management so as to provide expeditious implementation of a reperfu­ sion strategy. CLINICAL PRESENTATION In up to one-half of cases, a precipitating factor appears to be present before STEMI, such as vigorous physical exercise, emotional stress, or a medical or surgical illness. Although STEMI may commence at any time of the day or night, circadian variations have been reported such that clusters are seen in the morning within a few hours of awakening.

Plaque rupture with thrombus Vasospasm or endothelial dysfunction Causes of myocardial oxygen supply-demand imbalance Fixed atherosclerosis and supply-demand imbalance Supply-demand imbalance alone Q-wave MI Non-Q-wave MI Pain is the most common presenting complaint in patients with STEMI. The pain is deep and visceral; adjectives commonly used to describe it are heavy, squeezing, and crushing; although, occasionally, it is described as stabbing or burning (Chap. 15). It is similar in char­ acter to the discomfort of angina pectoris (Chap. 284) but commonly occurs at rest, is usually more severe, and lasts longer. Typically, the pain involves the central portion of the chest and/or the epigastrium, and, on occasion, it radiates to the arms. Less common sites of radiation include the abdomen, back, lower jaw, and neck. The frequent location of the pain beneath the xiphoid and epigastrium and the patients’ denial that they may be suffering a heart attack are chiefly responsible for the common mistaken impression of indigestion. The pain of STEMI may radiate as high as the occipital area but not below the umbilicus. It is often accompanied by sweating, nausea, vomiting, anxiety, and a sense of impending doom. The pain may commence when the patient is at rest, but when it begins during a period of exertion, it does not usually subside with cessation of activity, in contrast to angina pectoris.

Thrombogenic blood • inflammation • comorbidities • environmental factors • genetic background Vulnerable plaque • inflammation • extension • severity • location plaque ion Vulnerable myocardium • inflammation • ischemia duration/extent • individual susceptibility Cardiomyocyte swelling Interstitial edema Thrombus debris Endothelial dysfunction Leukocyte and platelet activation/interaction FIGURE 286-2  Critical determinants of myocardial infarction injury. The overlapping of vulnerable plaque and thrombogenic blood are critical determinants for myocardial infarction occurrence and extension. In addition, myocardial vulnerability, which is largely due to coronary microvascular dysfunction, contributes to extension and severity of ischemic injury. In the most severe form (known as no-reflow), structural and functional impairments sustain vascular obstruction. Endothelial dysfunction triggers leukocyte and platelet activation/interaction, whereas thrombotic debris may worsen the obstruction. Furthermore, cardiomyocyte swelling, interstitial edema, and tissue inflammation promote extravascular compression. (Modified from F Montecucco, F Carbone, TH Schindler. Pathophysiology of ST-segment elevation myocardial infarction: Novel mechanisms and treatments. Eur Heart J 37:1268, 2016.) The pain of STEMI can simulate pain from acute pericarditis (Chap. 281), pulmonary embolism (Chap. 290), acute aortic dis­ section (Chap. 291), costochondritis, and gastrointestinal disorders. These conditions should therefore be considered in the differential diagnosis. Radiation of discomfort to the trapezius is not seen in patients with STEMI and may be a useful distinguishing feature that suggests pericarditis is the correct diagnosis. However, pain is not uniformly present in patients with STEMI. The proportion of painless STEMIs is greater in patients with diabetes mellitus, and it increases with age. STEMI may present as sudden-onset breathlessness. Other less common presentations, with or without pain, include sudden loss of consciousness, a confusional state, a sensation of profound weakness, the appearance of an arrhythmia, evidence of peripheral embolism, or merely an unexplained drop in arterial pressure. ■ ■PHYSICAL FINDINGS Most patients are anxious and restless, attempting unsuccessfully to relieve the pain by moving about in bed, altering their position, and stretching. Pallor associated with perspiration and coolness of the extremities occurs commonly. The combination of substernal chest pain persisting for >30 min and diaphoresis strongly suggests STEMI. Although many patients have a normal pulse rate and blood pressure within the first hour of STEMI, patients with anterior infarction may

have manifestations of sympathetic nervous system hyperactivity (tachycardia and/or hypertension), and those with inferior infarction may show evidence of parasympathetic hyperactivity (bradycardia and/or hypotension).

The precordium is usually quiet, and the apical impulse may be difficult to palpate. Other physical signs of ventricular dysfunction include fourth and third heart sounds, decreased intensity of the first heart sound, and paradoxical splitting of the second heart sound (Chap. 246). A transient midsystolic or late systolic apical systolic murmur due to dysfunction of the mitral valve apparatus may be pres­ ent. A pericardial friction rub may be heard in patients with transmural STEMI at some time in the course of the illness. The carotid pulse is often decreased in volume, reflecting reduced stroke volume. Tem­ perature elevations up to 38°C may be observed during the first week after STEMI. LABORATORY FINDINGS STEMI progresses through the following temporal stages: (1) acute (first few hours–7 days), (2) healing (7–28 days), and (3) healed (≥29 days). The myocardium undergoes a series of cellular responses in the infarct zone, beginning with recruitment of polymorphonuclear leukocytes (for removal of dead cells and clearance of extracellular macromol­ ecules) followed by monocytes. Experimental work has now detailed this sequence of accumulation of subpopulations of mononuclear phagocytes with an initial wave of monocytes characterized by high proteolytic and phagocytic capacity and elaboration of proinflamma­ tory cytokines followed by the repair monocytes that release a media­ tors that stimulate angiogenesis and extracellular matrix production (Fig. 286-3). New microvessels and fibrosis are key constituents of forming granulation tissue, and these processes establish a foundation for myocardial scar formation, ventricular remodeling, and infarct healing. In addition, emerging evidence reveals a role for an “emer­ gency hematopoiesis” that mobilizes leukocyte progenitor cells that ultimately participate in myocardial healing. CHAPTER 286 ST-Segment Elevation Myocardial Infarction When evaluating the results of diagnostic tests for STEMI, the tem­ poral phase of the infarction must be considered. The tests of value in confirming the diagnosis may be divided into four groups: (1) ECG, (2) blood-based cardiac biomarkers, (3) cardiac imaging, and (4) nonspe­ cific indices of tissue necrosis and inflammation. ■ ■ELECTROCARDIOGRAM The electrocardiographic manifestations of STEMI are described in Chap. 247. During the initial stage, total occlusion of an epicardial coronary artery produces ST-segment elevation. Most patients initially presenting with ST-segment elevation ultimately evolve Q waves on the ECG. However, Q waves in the leads overlying the infarct zone may vary in magnitude and appear only transiently, depending on the reperfusion status of the ischemic myocardium and restoration of transmembrane potentials over time. A small proportion of patients initially presenting with ST-segment elevation will not develop Q waves when the obstructing thrombus is not totally occlusive, obstruction is transient, or a rich collateral network is present. Among patients pre­ senting with ischemic discomfort but without ST-segment elevation, if a cardiac biomarker of necrosis (see below) is detected, the diagnosis of NSTEMI is ultimately made (Fig. 286-1). A minority of patients who present initially without ST-segment elevation may develop a Q-wave myocardial infarction (MI). Previously, it was believed that transmural MI is present if the ECG demonstrates Q waves or loss of R waves, and nontransmural MI may be present if the ECG shows only transient ST-segment and T-wave changes. However, electrocardiographicpathologic correlations are far from perfect, and terms such as Q-wave MI, non-Q-wave MI, transmural MI, and nontransmural MI have been replaced by STEMI and NSTEMI (Fig. 286-1). Contemporary studies using magnetic resonance imaging (MRI) suggest that the development of a Q wave on the ECG is more dependent on the volume of infarcted tissue rather than the transmurality of infarction. ■ ■CARDIAC BIOMARKERS OF MYOCARDIAL INJURY Certain proteins, referred to as cardiac biomarkers, are released from necrotic heart muscle after STEMI. The rate of liberation of specific

Polymorphonuclear leukocyte Pro-inflammatory monocyte PART 6 Disorders of the Cardiovascular System • Phagocytosis • Proteolysis-matrix degradation • Pro-inflammatory • Reactive O2 species Early damage clearance phase: • Recruitment of leukocytes • Removal of dead cells • Dissolution and clearance of damaged extracellular matrix macromolecules • Preparing the injured myocardium for repair Monocyte-derived fibroblasts Regulation of the responses to myocardial ischemic injury FIGURE 286-3  Phases of myocardial injury and healing. Immediate recruitment of polymorphonuclear leukocytes precedes the accumulation of proinflammatory monocytes (typically bearing the chemokine receptor 2 [CCR2]). These phagocytic cells release the mediators of the early phase response to ischemic injury by clearing dead cells and debris and prompting additional inflammatory cells to enter the injured area. Reparative monocytes stimulate the production of extracellular matrix macromolecules that reinforce the cardiac skeleton during healing as well as microvessel formation characteristic of granulation tissue. Monocyte-derived fibroblasts are capable of interstitial collagen synthesis that reinforces repair of the myocardial skeleton, potentially mitigating expansive remodeling of the infarct and promoting healing with less risk for chronic heart failure. (Reproduced with permission from P Libby et al: The myocardium: More than just myocytes. J Am Coll Cardiol 74:3137, 2019.) proteins differs depending on their intracellular location, their molecu­ lar weight, and the local blood and lymphatic flow. Cardiac biomarkers become detectable in the peripheral blood once the capacity of the car­ diac lymphatics to clear the interstitium of the infarct zone is exceeded and spillover into the venous circulation occurs. The criteria for AMI require a rise and/or fall in cardiac biomarker values with at least one value above the 99th percentile of the upper reference limit for normal individuals. Cardiac-specific troponin T (cTnT) and cardiac-specific troponin I (cTnI) have amino-acid sequences that differ from those of the skeletal muscle forms of these proteins. These differences permitted the devel­ opment of quantitative assays for cTnT and cTnI using highly specific monoclonal antibodies. cTnT and cTnI may increase after STEMI to levels many times higher than the upper reference limit (set at the 99th percentile of values in a reference population). The measurement of cTnT or cTnI is of considerable diagnostic usefulness, and they are now the preferred biochemical markers for MI when measured with highsensitivity assays (Fig. 286-4 and Chap. 15). In practical terms, the high-sensitivity troponin assays are of less immediate value in patients with STEMI. Contemporary urgent reperfusion strategies necessitate making a decision (based largely on a combination of clinical and ECG findings) before the results of blood tests have returned from the labo­ ratory. Levels of cTnI and cTnT typically remain elevated for at least 7–10 days after STEMI. Historically, creatine phosphokinase (CK) and its MB isoenzyme (CK-MB) were used for the diagnosis of AMI. A ratio (relative index) of CK-MB mass to CK activity ≥2.5 suggests but is not diagnostic of a myocardial rather than a skeletal muscle source for the CK-MB eleva­ tion. It is not cost-effective to measure both a cardiac-specific troponin and CK-MB. Because of its more rapid decline after the onset of AMI, CK-MB may be useful for the discrimination of early reinfarction

Reparative monocyte CCR2 F4/80 • Transforming growth factor β • Vascular endothelial growth factor Later repair/healing phase: • Resolution of inflammation • Angiogenesis • Stimulation of extracellular matrix • Interstitial collagen production during the period that cardiac troponin remains elevated following the index event (Fig. 286-3). While it has long been recognized that the total quantity of protein released correlates with the size of the infarct, the peak protein con­ centration correlates only weakly with infarct size. Recanalization of a coronary artery occlusion (either spontaneously or by mechanical or pharmacologic means) in the early hours of STEMI causes earlier peaking of biomarker measurements (Fig. 286-4) because of a rapid washout from the interstitium of the infarct zone, quickly overwhelm­ ing lymphatic clearance of the proteins. The nonspecific reaction to myocardial injury is associated with polymorphonuclear leukocytosis, which appears within a few hours after the onset of pain and persists for 3–7 days; the white blood cell count often reaches levels of 12,000–15,000/μL. The erythrocyte sedimentation rate rises more slowly than the white blood cell count, peaking during the first week and sometimes remaining elevated for 1 or 2 weeks. ■ ■CARDIAC IMAGING Abnormalities of wall motion on two-dimensional echocardiography (Chap. 248) are almost universally present in patients with STEMI. Although acute STEMI cannot be distinguished from an old myo­ cardial scar or from acute severe ischemia by echocardiography, the ease and safety of the procedure make its use appealing as a screening tool in the emergency department. When the ECG is not diagnostic of STEMI, early detection of the presence or absence of wall motion abnormalities by echocardiography can aid in management decisions, such as whether the patient should receive reperfusion therapy (e.g., percutaneous coronary intervention [PCI] or fibrinolysis). Echocar­ diographic estimation of left ventricular (LV) function is useful prog­ nostically; detection of reduced function serves as an indication for

Zone of necrosing myocardium Troponin free in cytoplasm Cardiomyocyte Myosin Actin Troponin complex bound to actin filament Lymphatic system Venous system Myoglobin and CK isoforms

Multiples of the AMI cutoff limit

Troponin (large MI)

CKMB

Troponin (small MI)

99th percentile

Days after onset of AMI FIGURE 286-4  The zone of necrosing myocardium is shown at the top of the figure, followed in the middle portion of the figure by a diagram of a cardiomyocyte that is in the process of releasing biomarkers. The biomarkers that are released into the interstitium are first cleared by lymphatics followed subsequently by spillover into the venous system. After disruption of the sarcolemmal membrane of the cardiomyocyte, the cytoplasmic pool of biomarkers is released first (left-most arrow in bottom portion of figure). Markers such as myoglobin and CK isoforms are rapidly released, and blood levels rise quickly above the cutoff limit; this is then followed by a more protracted release of biomarkers from the disintegrating myofilaments that may continue for several days. Cardiac troponin levels rise to about 20–50 times the upper reference limit (the 99th percentile of values in a reference control group) in patients who have a “classic” acute myocardial infarction (MI) and sustain sufficient myocardial necrosis to result in abnormally elevated levels of the MB fraction of creatine kinase (CK-MB). Clinicians can now diagnose episodes of microinfarction by sensitive assays that detect cardiac troponin elevations above the upper reference limit, even though CK-MB levels may still be in the normal reference range (not shown). CV, coefficient of variation. (Modified from EM Antman: Decision making with cardiac troponin tests. N Engl J Med 346:2079, 2002, and; bottom image: Reproduced with permission from AS Jaffe: Biomarkers in acute cardiac disease: The present and the future. J Am Coll Cardiol 48:1, 2006.)

therapy with an inhibitor of the renin-angiotensin-aldosterone system. Echocardiography may also identify the presence of right ventricular (RV) infarction, ventricular aneurysm, pericardial effusion, and LV thrombus. In addition, Doppler echocardiography is useful in the detection and quantitation of a ventricular septal defect and mitral regurgitation, two serious complications of STEMI.

CHAPTER 286 Radionuclide imaging techniques (Chap. 248) are available but rarely used for evaluating patients with suspected STEMI. Myocardial perfu­ sion imaging with [99mTc]-sestamibi, which is distributed in proportion to myocardial blood flow and concentrated by viable myocardium (Chap. 285), reveals a defect (“cold spot”) in most patients during the first few hours after development of a transmural infarct. However, the technique cannot distinguish acute infarcts from chronic scars and, thus, is not specific for the diagnosis of acute MI. ST-Segment Elevation Myocardial Infarction An Expert Consensus Task Force for the Universal Definition of Myocardial Infarction has provided a comprehensive set of criteria for the definition of MI that integrates the clinical and laboratory findings discussed earlier as well as a classification of MI into five types that reflect the clinical circumstances in which it may occur (Table 286-1). INITIAL MANAGEMENT ■ ■PREHOSPITAL CARE The prognosis in STEMI in the era of primary PCI is largely related to the occurrence of two general classes of complications: (1) electri­ cal complications (arrhythmias) and (2) mechanical complications (“pump failure”). Most out-of-hospital deaths from STEMI result from the sudden development of ventricular fibrillation. The vast majority of deaths due to ventricular fibrillation occur within the first 24 h of the onset of symptoms, and of these, over half occur in the first hour. Therefore, the major elements of prehospital care of patients with sus­ pected STEMI include (1) recognition of symptoms by the patient and prompt seeking of medical attention; (2) rapid deployment of an emer­ gency medical team capable of performing resuscitative maneuvers, including defibrillation; (3) expeditious transportation of the patient to a hospital facility that is continuously staffed by physicians and nurses skilled in managing arrhythmias and providing advanced cardiac life support; and (4) expeditious implementation of reperfusion therapy. The greatest delay usually occurs not during transportation to the hos­ pital but, rather, between the onset of pain and the patient’s decision to call for help. This delay can best be reduced by health care professionals educating the public concerning the significance of chest discomfort and the importance of seeking early medical attention. Regular office visits with patients having a history of, or who are at risk for, ischemic heart disease are important “teachable moments” for clinicians to review the symptoms of AMI and the appropriate action plan. Increasingly, monitoring and treatment are carried out by trained personnel in the ambulance, further shortening the time between the onset of the infarction and appropriate treatment. In areas remote from PCI centers, fibrinolytic therapy may be administered prehospi­ tal. General guidelines for initiation of fibrinolysis in the prehospital setting include the ability to transmit 12-lead ECGs to confirm the diagnosis, the presence in the ambulance of personnel trained in the interpretation of ECGs and management of STEMI, and online medi­ cal command and control that can authorize the initiation of treatment in the field. MANAGEMENT IN THE EMERGENCY DEPARTMENT In the emergency department, the goals for the management of patients with suspected STEMI include control of cardiac discomfort, rapid identification of patients who are candidates for urgent reperfu­ sion therapy, triage of lower-risk patients to the appropriate location in the hospital, and avoidance of inappropriate discharge of patients with STEMI. Many aspects of the treatment of STEMI are initiated in the emergency department and then continued during the in-hospital phase of management. The overarching goal is to minimize the time from first medical contact to initiation of reperfusion therapy (Fig. 286-5). This may involve transfer from a non-PCI hospital to one

TABLE 286-1  Definitions of Myocardial Injury and Infarction Criteria for Myocardial Injury The term myocardial injury should be used when there is evidence of elevated cardiac troponin (cTn) levels with at least one value above the 99th percentile upper reference limit (URL). The myocardial injury is considered acute if there is a rise and/or fall of cTn values. PART 6 Disorders of the Cardiovascular System Criteria for Acute Myocardial Infarction (types 1, 2, and 3 MI) The term acute myocardial infarction (MI) should be used when there is acute myocardial injury with clinical evidence of acute myocardial ischemia and with detection of a rise and/or fall of cTn values with at least one value above the 99th percentile URL and at least one of the following: • Symptoms of myocardial ischemia • New ischemic electrocardiographic (ECG) changes • Development of pathologic Q waves • Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischemic etiology • Identification of a coronary thrombus by angiography or autopsy (not for types 2 or 3 MIs) Postmortem demonstration of acute atherothrombosis in the artery supplying the infarcted myocardium meets criteria for type 1 MI. Evidence of an imbalance between myocardial oxygen supply and demand unrelated to acute atherothrombosis meets criteria for type 2 MI. Cardiac death in patients with symptoms suggestive of myocardial ischemia and presumed new ischemic ECG changes before cTn values became available or abnormal meets criteria for type 3 MI. Criteria for Coronary Procedure–Related MI (types 4 and 5 MI) Percutaneous coronary intervention (PCI)–related MI is termed type 4a MI. Coronary artery bypass grafting (CABG)–related MI is termed type 5 MI. Coronary procedure–related MI <48 h after the index procedure is arbitrarily defined by an elevation of cTn values >5 times for type 4a MI and >10 times for type 5 MI of the 99th percentile URL in patients with normal baseline values. Patients with elevated preprocedural cTn values, in whom the preprocedural cTn levels are stable (<20% variation) or falling, must meet the criteria for a

5- or >10-fold increase and manifest a change from the baseline value of 20%. In addition, they must have at least one of the following: • New ischemic ECG changes (this criterion is related to type 4a MI only) • Development of new pathologic Q waves • Imaging evidence of loss of viable myocardium that is presumed to be new and in a pattern consistent with an ischemic etiology • Angiographic findings consistent with a procedural flow-limiting complication such as coronary dissection, occlusion of a major epicardial artery or graft, side-branch occlusion-thrombus, disruption of collateral flow, or distal embolization Isolated development of new pathologic Q waves meets the type 4a MI or type 5 MI criteria with either revascularization procedure if cTn levels are elevated and rising, but less than the prespecified thresholds for PCI and CABG. Other types of type 4 MI include type 4B MI stent thrombosis and type 4C MI restenosis that both meet type 1 MI criteria. Postmortem demonstration of a procedure-related thrombus meets the type 4a MI and type 5 MI criteria if associated with a stent. Criteria for Prior or Silent/Unrecognized MI Any one of the following criteria meets the diagnosis for prior or silent/ unrecognized MI: • Abnormal Q waves with or without symptoms in the absence of nonischemic causes • Imaging evidence of loss of viable myocardium in a pattern consistent with ischemic etiology • Pathoanatomical findings of a prior MI Source: Reproduced with permission from K Thygesen et al: Fourth universal definition of myocardial infarction (2018). Circulation 138:e618, 2018. that is PCI capable, with a goal of initiating PCI within 120 min of first medical contact (Fig. 286-5). Aspirin is essential in the management of patients with suspected STEMI and is effective across the entire spectrum of acute coronary syndromes. Rapid inhibition of cyclooxygenase-1 in platelets followed by a reduction of thromboxane A2 levels is achieved by buccal absorp­ tion of a chewed 160–325-mg tablet in the emergency department. This measure should be followed by daily oral administration of aspirin in a dose of 75–162 mg.

In patients whose arterial oxygen (O2) saturation is normal, supple­ mental O2 is not recommended. However, when hypoxemia is present (O2 saturation <90%), O2 should be administered to correct the hypox­ emia; the patient should then be reassessed to determine if there is a continued need for such treatment. CONTROL OF DISCOMFORT Sublingual nitroglycerin can be given safely to most patients with STEMI. Up to three doses of 0.4 mg should be administered at about 5-min intervals in patients with persistent ischemic symptoms. In addi­ tion to diminishing or abolishing chest discomfort, nitroglycerin may be capable of both decreasing myocardial O2 demand (by lowering pre­ load) and increasing myocardial O2 supply (by dilating infarct-related coronary vessels or collateral vessels and by improving subendocardial perfusion). In patients whose initially favorable response to sublingual nitroglycerin is followed by the return of chest discomfort, particularly if accompanied by other evidence of ongoing ischemia such as further ST-segment or T-wave shifts, the use of intravenous nitroglycerin may be considered. Therapy with nitrates should be avoided in patients who present with low systolic arterial pressure (<90 mmHg) or in whom there is clinical suspicion of RV infarction (inferior infarction on ECG, elevated jugular venous pressure, clear lungs, and hypotension). Nitrates should not be administered to patients who have taken a phos­ phodiesterase-5 inhibitor for erectile dysfunction within the preceding 24 h because it may potentiate the hypotensive effects of nitrates. An idiosyncratic reaction to nitrates, consisting of sudden marked hypo­ tension, sometimes occurs but can usually be reversed promptly by the rapid administration of intravenous atropine. Morphine is a very effective analgesic for the pain associated with STEMI. However, it may reduce sympathetically mediated arteriolar and venous constriction, and the resulting venous pooling may reduce cardiac output and arterial pressure. These hemodynamic distur­ bances usually respond promptly to elevation of the legs, but in some patients, volume expansion with intravenous saline is required. The patient may experience diaphoresis and nausea, but these events usually pass and are replaced by a feeling of well-being associated with the relief of pain. Morphine also has a vagotonic effect and may cause bradycardia or advanced degrees of heart block, particularly in patients with inferior infarction. These side effects usually respond to atropine (0.5 mg intravenously). Morphine may also slow the gastrointestinal absorption of oral medicines, which may delay the onset of action of orally administered antiplatelet therapy; however, currently available clinical data have not demonstrated an increase in the risk of adverse clinical outcomes as a result of any interaction between morphine and antiplatelet agents. Therefore, it is reasonable to use morphine in patients with STEMI to relieve pain. Morphine is administered by repetitive (every 5 min) intravenous injection of small doses (2–4 mg). Intravenous beta blockers are also useful in mitigating the ischemic pain of STEMI. These drugs control pain effectively in some patients, presumably by diminishing myocardial O2 demand and hence isch­ emia. More important, there is evidence that intravenous beta blockers reduce the risks of reinfarction and ventricular fibrillation (see “BetaAdrenoceptor Blockers” below). A commonly employed regimen is metoprolol, 5 mg every 2–5 min for a total of three doses, provided the patient has a heart rate >60 beats/min, systolic pressure >100 mmHg, a PR interval <0.24 s, and no signs of acute heart failure. Patient selection is important when considering beta blockers for STEMI. Oral beta blocker therapy should be initiated in the first 24 h for patients who do not have any of the following: (1) signs of acute heart failure, (2) evidence of a low-output state, (3) increased risk for cardiogenic shock, or (4) other relative contraindications to beta blockade (bradycardia, PR interval >0.24 s, second- or third-degree heart block, active asthma, or reactive airway disease). In eligible patients, 15 min after the last intravenous dose, an oral regimen is initiated with 50 mg every 6 h for 48 h, followed by 100 mg every 12 h. Unlike beta blockers, calcium antagonists are of little value in the acute setting, and there is evidence that short-acting dihydropyridines may be associated with an increased mortality risk.

STEMI patient who is a candidate for reperfusion Initially seen at a PCI-capable hospital Send to cath lab for primary PCI FMC-device time ≤90 min (Class I, LOE: A) Diagnostic angiogram Medical therapy only PCI CABG *Patients with cardiogenic shock or severe heart failure initially seen at a non–PCI-capable hospital should be transferred for cardiac catheterization and revascularization as soon as possible, irrespective of time delay from myocardial infarction (MI) onset (Class I, LOE: B). †Angiography and revascularization should not be performed within the first 2–3 h after administration of fibrinolytic therapy. FIGURE 286-5  Reperfusion therapy for patients with ST-segment elevation myocardial infarction (STEMI). Performance of percutaneous coronary intervention (PCI) is dictated by an anatomically appropriate culprit stenosis. CABG, coronary artery bypass graft; DIDO, door-in–door-out; FMC, first medical contact; LOE, level of evidence. (Reproduced with permission from PT O’Gara: 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction. Circulation 127:e362, 2013.) MANAGEMENT STRATEGIES The primary tool for screening patients and making triage decisions is the initial 12-lead ECG. When ST-segment elevation meeting the Universal Definition of MI criteria (Table 286-2) is present, a patient should be considered a candidate for reperfusion therapy (Figs. 286-1 and 286-5). The process of selecting patients for fibrinolysis versus primary PCI (Chap. 287) is discussed below. In the absence of STsegment elevation, fibrinolysis is not helpful, and evidence exists sug­ gesting that it may be harmful. LIMITATION OF INFARCT SIZE The quantity of myocardium that becomes necrotic as a consequence of a coronary artery occlusion is determined by factors other than just the location of occlusion. While the central zone of the infarct contains necrotic tissue that is irretrievably lost, the fate of the surrounding isch­ emic myocardium (ischemic penumbra) may be improved by timely restoration of coronary perfusion, reduction of myocardial O2 demands, prevention of the accumulation of noxious metabolites, and blunting of the impact of mediators of reperfusion injury (e.g., calcium overload and oxygen-derived free radicals). Up to one-third of patients with STEMI may achieve spontaneous reperfusion of the infarct-related coronary artery within 24 h and experience improved healing of infarcted tissue. TABLE 286-2  Electrocardiographic Criteria for ST-Elevation Myocardial Infarction New ST-elevation at the J-point in 2 contiguous leads with the cut-point: • In all leads other than leads V2–V3: ≥0.1 mV (1 mm on standard scale) • In leads V2–V3: • ≥0.2 mV (2 mm) in men ≥40 years old • ≥0.25 mV (2.5 mm) in men <40 years • ≥0.15 mV (1.5 mm) in women regardless of age Source: Reproduced from K Thygesen et al: Fourth universal definition of myocardial infarction (2018). Circulation 138:e618, 2018.

Initially seen at a non–PCI-capable hospital* CHAPTER 286 DIDO time ≤30 min ST-Segment Elevation Myocardial Infarction Transfer for primary PCI Administer fibrinolytic agent within 30 min of arrival when anticipated FMCdevice >120 min (Class I, LOE: B) FMC-device time as soon as possible and ≤120 min (Class I, LOE: B) Transfer for angiography and revascularization within 3–24 h for other patients as part of an invasive strategy† Urgent transfer for PCI for patients with evidence of failed reperfusion or reocclusion (Class IIa, LOE: B) (Class IIa, LOE: B) Reperfusion, either pharmacologically (by fibrinolysis) or by primary PCI, accelerates the opening of infarct-related arteries in those patients in whom spontaneous fibrinolysis ultimately would have occurred and also greatly increases the number of patients in whom restoration of flow in the infarct-related artery is accomplished. Timely restoration of flow in the epicardial infarct–related artery combined with improved perfusion of the downstream zone of infarcted myocardium results in a limitation of infarct size. Protection of the ischemic myocardium by the maintenance of an optimal balance between myocardial O2 supply and demand through pain control, treatment of heart failure (HF), and minimization of tachycardia and hypertension extends the “window” of time for the salvage of myocardium by reperfusion strategies. Glucocorticoids and nonsteroidal anti-inflammatory agents, with the exception of aspirin, should be avoided in patients with STEMI. They can impair infarct healing and increase the risk of myocardial rupture, and their use may result in a larger infarct scar. In addition, they can increase coronary vascular resistance, thereby potentially reducing flow to ischemic myocardium. ■ ■PRIMARY PERCUTANEOUS CORONARY INTERVENTION (See also Chap. 287) PCI, usually stenting without preceding fibrino­ lysis, referred to as primary PCI, is effective in restoring perfusion in STEMI when carried out on an emergency basis in the first few hours of MI. It has the advantage of being applicable to patients who have contraindications to fibrinolytic therapy (see below) but otherwise are considered appropriate candidates for reperfusion. Primary PCI is more effective than fibrinolysis in opening occluded coronary arteries and, when performed by experienced teams in dedicated medical centers, is associated with better short-term and long-term clinical outcomes. Compared with fibrinolysis, primary PCI is preferred unless the time to delivery of the first coronary device is anticipated to be longer than 120 min. Primary PCI is also preferred when the diagnosis is in doubt, cardiogenic shock is present, bleeding risk is high, or symptoms have

been present for longer than 2–3 h, at which time the clot is less easily lysed by fibrinolytic drugs. Contemporary studies (PRAMI, CvLPRIT, COMPLETE) provide evidence that, in patients with STEMI without shock, performing PCI on nonculprit coronary vessels, either during the index procedure or within 45 days, results in a lower rate of car­ diovascular events and a lower need for subsequent ischemia-driven revascularization. In contrast, among patients with cardiogenic shock, routine PCI of nonculprit arteries during the initial primary PCI is contraindicated due to an increase in the rate of death or severe renal failure compared with culprit-only PCI.

PART 6 Disorders of the Cardiovascular System ■ ■FIBRINOLYSIS If timely primary PCI is not available and no contraindications are present (see below), fibrinolytic therapy should ideally be initiated within 30 min of presentation (i.e., door-to-needle time ≤30 min). The principal goal of fibrinolysis is prompt restoration of full coronary arterial patency. The fibrinolytic agents tissue plasminogen activator (tPA), streptokinase, tenecteplase (TNK), and reteplase (rPA) have been approved by the U.S. Food and Drug Administration for intra­ venous use in patients with STEMI. These drugs all act by promoting the conversion of plasminogen to plasmin, which subsequently lyses fibrin thrombi. Although considerable emphasis was first placed on a distinction between more fibrin-specific agents, such as tPA, and non-fibrin-specific agents, such as streptokinase, it is now recognized that these differences are only relative, as some degree of systemic fibrinolysis occurs with the former agents. TNK and rPA are referred to as bolus fibrinolytics since their administration does not require a prolonged intravenous infusion. When assessed angiographically, flow in the culprit coronary artery is described by a simple qualitative scale called the Thrombolysis in Myocardial Infarction (TIMI) grading system: grade 0 indicates com­ plete occlusion of the infarct-related artery; grade 1 indicates some penetration of the contrast material beyond the point of obstruction, but without perfusion of the distal coronary bed; grade 2 indicates per­ fusion of the entire infarct vessel into the distal bed, but with flow that is delayed compared with that of a normal artery; and grade 3 indicates full perfusion of the infarct vessel with normal flow. The latter is the goal of reperfusion therapy, because full perfusion of the infarct-related coronary artery yields far better results in terms of limiting infarct size, maintenance of LV function, and reduction of both short- and longterm mortality rates. tPA and the other relatively fibrin-specific plasminogen activators, rPA and TNK, are more effective than streptokinase at restoring full perfusion—i.e., TIMI grade 3 coronary flow—and have a small edge in improving survival as well. The recommended regimen of tPA consists of a 15-mg bolus followed by 50 mg intravenously over the first 30 min, followed by 35 mg over the next 60 min. Streptokinase is administered as 1.5 million units (MU) intravenously over 1 h. rPA is administered in a double-bolus regimen consisting of a 10-MU bolus given over 2–3 min, followed by a second 10-MU bolus 30 min later. TNK is given as a single weight-based intravenous bolus of 0.53 mg/kg over 10 s. In addition to the fibrinolytic agents discussed earlier, pharmacologic reperfusion typically involves adjunctive antiplatelet and antithrom­ botic drugs, as discussed subsequently. Clear contraindications to the use of fibrinolytic agents include a history of cerebrovascular hemorrhage at any time, a nonhemor­ rhagic stroke or other cerebrovascular event within the past year, marked hypertension (a reliably determined systolic arterial pressure

180 mmHg and/or a diastolic pressure >110 mmHg) at any time during the acute presentation, suspicion of aortic dissection, and active internal bleeding (excluding menses). While advanced age is associated with an increase in hemorrhagic complications, the benefit of fibrinolytic therapy in the elderly appears to justify its use if no other contraindications are present, the amount of myocardium in jeopardy appears to be substantial, and timely access to primary PCI is not available. Relative contraindications to fibrinolytic therapy, which require assessment of the risk-to-benefit ratio, include current use of anti­ coagulants (international normalized ratio ≥2), a recent (<2 weeks)

invasive or surgical procedure or prolonged (>10 min) cardiopulmo­ nary resuscitation, known bleeding diathesis, pregnancy, a hemor­ rhagic ophthalmic condition (e.g., hemorrhagic diabetic retinopathy), active peptic ulcer disease, and a history of severe hypertension that is currently adequately controlled. Because of the risk of an allergic reac­ tion, patients should not receive streptokinase if that agent had been received within the preceding 5 days to 2 years. Allergic reactions to streptokinase occur in ~2% of patients who receive it. While a minor degree of hypotension occurs in 4–10% of patients given this agent, marked hypotension occurs, although rarely, in association with severe allergic reactions. Hemorrhage is the most frequent and potentially the most serious complication. Because bleeding episodes that require transfusion are more common when patients require invasive procedures, unneces­ sary venous or arterial interventions should be avoided in patients receiving fibrinolytic agents. Hemorrhagic stroke is the most serious complication and occurs in ~0.5–0.9% of patients being treated with these agents. This rate increases with advancing age, with patients

70 years experiencing roughly twice the rate of intracranial hemor­ rhage as those <65 years. Large-scale trials have suggested that the rate of intracranial hemorrhage with tPA or rPA is slightly higher than with streptokinase. ■ ■INTEGRATED REPERFUSION STRATEGY Timely performance of PCI is the preferred reperfusion strategy in the management of STEMI. Prior approaches that segregated the pharma­ cologic and catheter-based approaches to reperfusion have now been replaced with an integrated approach to triage and transfer STEMI patients to receive PCI (Fig. 286-5). To achieve the degree of integra­ tion required to care for a patient with STEMI, all communities should create and maintain a regional system of STEMI care that includes assessment and continuous quality improvement of emergency medi­ cal services and hospital-based activities. In patients who have been treated with a fibrinolytic, urgent coro­ nary angiography should be performed if there is evidence of either (1) failure of reperfusion (persistent chest pain and ST-segment eleva­ tion >90 min), in which case a rescue PCI should be considered; or (2) coronary artery reocclusion (re-elevation of ST segments and/or recurrent chest pain) or the development of recurrent ischemia. More­ over, transfer to a PCI-capable center is recommended in all patients immediately after fibrinolysis with intent for angiography and PCI of the infarct-related artery, if indicated, between 3 and 24 h after suc­ cessful fibrinolysis. Coronary artery bypass surgery should be reserved for patients whose coronary anatomy is unsuited to PCI but in whom revascularization appears to be advisable because of extensive jeopar­ dized myocardium or recurrent ischemia. HOSPITAL PHASE MANAGEMENT ■ ■CARDIAC INTENSIVE CARE UNITS These units, previously described as coronary care units, are routinely equipped with continuous monitoring of the cardiac rhythm of each patient and hemodynamic monitoring in selected patients. Equally important is the organization of a highly trained team of nurses who can recognize arrhythmias and perform cardiac resuscitation, includ­ ing electroshock, when necessary. The availability of electrocardio­ graphic monitoring and trained personnel outside the coronary care unit has made it possible to admit lower-risk patients (e.g., those not hemodynamically compromised and without active arrhythmias) to “intermediate care units.” However, it remains reasonable to admit patients with STEMI to a cardiac intensive care unit when high-risk features are present (e.g., hemodynamic or electrical instability) or when suitably equipped and staffed intermediate care units are not available. The duration of stay in the coronary care unit is dictated by the ongoing need for intensive care. In general, patients with STEMI who remain at low risk (no persistent chest discomfort, HF, hypotension, or cardiac arrhythmias) may be safely transferred out of the coronary care unit within 24–48 h.

Activity  Factors that increase the work of the heart during the ini­ tial hours of infarction may increase the size of the infarct. Therefore, patients with STEMI should generally be kept at bed rest for the first 6–12 h. However, in the absence of complications, patients should be encouraged, under supervision, to resume an upright posture by dangling their feet over the side of the bed and sitting in a chair within the first 24 h. This practice is psychologically beneficial and usually results in a reduction in the pulmonary capillary wedge pressure. In the absence of hypotension and other complications, patients typically are ambulating with increasing duration, anticipating that they may be discharged after 3–5 days. Diet  Because of the risk of emesis and aspiration soon after STEMI, patients should receive either nothing or only clear liquids by mouth for the first 4–12 h. The typical diet after AMI should provide ≤30% of total calories as fat and have a cholesterol content of ≤300 mg/d. Complex carbohydrates should make up 50–55% of total calories. Por­ tions should not be unusually large, and the menu should be enriched with foods that are high in potassium, magnesium, and fiber, but low in sodium. Diabetes mellitus and hypertriglyceridemia are managed by restriction of concentrated sweets in the diet. PHARMACOTHERAPY ■ ■ANTITHROMBOTIC AGENTS The use of antiplatelet and anticoagulant therapy during the initial phase of STEMI is based on extensive laboratory and clinical evidence that thrombosis plays an important role in the pathogenesis of this condition. The primary goal of treatment with antiplatelet and antico­ agulant agents is to maintain patency of the infarct-related artery, in conjunction with reperfusion strategies. A secondary goal is to reduce the patient’s tendency to thrombosis and, thus, the likelihood of mural thrombus formation or deep-venous thrombosis. The degree to which antiplatelet and anticoagulant therapy achieves these goals partly determines how effectively it reduces the risk of mortality from STEMI. As noted previously (see “Management in the Emergency Depart­ ment” earlier), aspirin is the standard antiplatelet agent for patients with STEMI. The most compelling evidence for the benefits of anti­ platelet therapy (mainly with aspirin) in STEMI is found in the com­ prehensive overview by the Antiplatelet Trialists’ Collaboration. Data from nearly 20,000 patients with MI enrolled in 15 randomized trials were pooled and revealed a relative reduction of 27% in the mortal­ ity rate, from 14.2% in control patients to 10.4% in patients receiving antiplatelet agents. Inhibitors of the P2Y12 ADP receptor prevent activation and aggre­ gation of platelets. The addition of the P2Y12 inhibitor clopidogrel to background treatment with aspirin to STEMI patients reduces the risk of clinical events (death, reinfarction, stroke) and, in patients receiving fibrinolytic therapy, has been shown to prevent reocclusion of a suc­ cessfully reperfused infarct artery. Third-generation oral P2Y12 ADP receptor antagonists, such as prasugrel and ticagrelor, are more effec­ tive than clopidogrel in preventing ischemic complications in STEMI patients undergoing PCI but are associated with an increased risk of bleeding. Glycoprotein IIb/IIIa receptor inhibitors may be used when thrombotic complications occur during PCI. The anticoagulant agent most commonly used in clinical practice is unfractionated heparin (UFH). Use of UFH is recommended in patients with STEMI undergoing primary PCI. In addition, the avail­ able data suggest that when UFH is added to a regimen of aspirin and a non-fibrin-specific thrombolytic agent such as streptokinase, addi­ tional mortality benefit occurs (about 5 lives saved per 1000 patients treated). The immediate administration of intravenous UFH, in addi­ tion to a regimen of aspirin and relatively fibrin-specific fibrinolytic agents (tPA, rPA, or TNK), helps to maintain patency of the infarctrelated artery. This effect is achieved at the cost of a small increased risk of bleeding. The recommended dose of UFH is an initial bolus of 60 U/kg (maximum 4000 U) followed by an initial infusion of 12 U/kg per h (maximum 1000 U/h). The activated partial thromboplastin time during maintenance therapy should be 1.5–2 times the control value.

Alternatives to UFH for anticoagulation of patients with STEMI are the low-molecular-weight heparin (LMWH) preparations, a synthetic version of the critical pentasaccharide sequence (fondaparinux), and the direct antithrombin bivalirudin. Advantages of LMWHs include high bioavailability permitting administration subcutaneously, reliable anticoagulation without monitoring, and greater anti-Xa:IIa activity. Enoxaparin has been shown to reduce significantly the composite endpoints of death/nonfatal reinfarction and death/nonfatal reinfarc­ tion/urgent revascularization compared with UFH in STEMI patients who receive fibrinolysis. Treatment with enoxaparin is associated with higher rates of serious bleeding, but net clinical benefit—a composite endpoint that combines efficacy and safety—still favors enoxaparin over UFH. Interpretation of the data on fondaparinux is difficult because of the complex nature of the pivotal clinical trial evaluating it in STEMI (OASIS-6). Fondaparinux appears superior to placebo in STEMI patients not receiving reperfusion therapy, but its relative efficacy and safety compared with UFH are less certain. Owing to the risk of catheter thrombosis, fondaparinux should not be used alone at the time of coronary angiography and PCI but should be combined with another anticoagulant with antithrombin activity such as UFH or bivalirudin. Trials of bivalirudin used an open-label design to evaluate its efficacy and safety compared with UFH plus a glycoprotein IIb/ IIIa inhibitor. Bivalirudin was associated with a lower rate of bleeding, largely driven by reductions in vascular access site hematomas ≥5 cm or the administration of blood transfusions. Bivalirudin is an alterna­ tive to UFH in patients undergoing primary PCI.

CHAPTER 286 ST-Segment Elevation Myocardial Infarction Patients with an anterior location of the infarction, severe LV dys­ function, HF, a history of embolism, or two-dimensional echocardio­ graphic evidence of mural thrombus are at increased risk of systemic or pulmonary thromboembolism. Patients with suspected mural throm­ bus should receive full therapeutic levels of anticoagulant therapy (LMWH or UFH) while hospitalized, followed by at least 3 months of oral anticoagulant therapy. It is reasonable to consider extended oral anticoagulant therapy (i.e., up to 3 months after presentation with STEMI) in patients with a high risk of developing systemic thrombo­ embolism because of a large area of akinetic myocardium. ■ ■BETA-ADRENOCEPTOR BLOCKERS The benefits of beta blockers in patients with STEMI can be divided into those that occur immediately when the drug is given acutely and those that accrue over the long term when the drug is given for second­ ary prevention after an infarction. Acute intravenous beta blockade, although no longer routinely recommended because of the risk of precipitating heart failure, improves the myocardial O2 supply-demand relationship, decreases pain, reduces infarct size, and decreases the incidence of serious ventricular arrhythmias. In patients who undergo fibrinolysis soon after the onset of chest pain, no incremental reduction in mortality rate is seen with beta blockers, but recurrent ischemia and reinfarction are reduced. Oral beta-blocker therapy after STEMI is useful for most patients (including those treated with an angiotensin-converting enzyme [ACE] inhibitor) except those in whom it is specifically contraindicated (patients with HF or severely compromised LV function, heart block, orthostatic hypotension, or a history of asthma) and perhaps those whose excellent long-term prognosis (defined as an expected mortality rate of <1% per year, patients <55 years, no previous MI, with normal ventricular function, no complex ventricular ectopy, and no angina) markedly diminishes any potential benefit. ■ ■INHIBITION OF THE RENIN-ANGIOTENSINALDOSTERONE SYSTEM ACE inhibitors reduce the mortality rate after STEMI, and the mortality benefits are additive to those achieved with aspirin and beta blockers. The maximum benefit is seen in high-risk patients (those who have an anterior infarction, a prior infarction, and/or globally depressed LV function), but evidence suggests that a short-term benefit occurs when ACE inhibitors are prescribed unselectively to all hemodynamically stable patients with STEMI (i.e., those with a systolic pressure >100 mmHg). The mecha­ nism involves a reduction in ventricular remodeling after infarction (see

“Ventricular Dysfunction” later) with a subsequent reduction in the risk of HF. The rate of recurrent infarction may also be lower in patients treated chronically with ACE inhibitors after infarction.

ACE inhibitors should be continued indefinitely in patients who have clinically evident HF, in patients in whom an imaging study shows a reduction in global LV function or a large regional wall motion abnormality, or in those who are hypertensive. PART 6 Disorders of the Cardiovascular System Angiotensin receptor blockers (ARBs) should be administered to STEMI patients who are intolerant of ACE inhibitors and who have either clinical or radiologic signs of HF. Long-term mineralocorticoid receptor inhibition (spironolactone, eplerenone) should be prescribed for STEMI patients who are already receiving therapeutic doses of an ACE inhibitor, have an LV ejection fraction ≤40%, and have either symptomatic HF or diabetes mellitus and do not have significant renal dysfunction (creatinine ≥2.5 mg/dL in men and ≥2.0 mg/dL in women) or hyperkalemia (potassium ≥5.0 mEq/L). Although angiotensin receptor–neprilysin inhibition with sacubi­ tril/valsartan is more effective than ACE inhibitor therapy in patients with symptomatic HF with a reduced ejection fraction, sacubitril/val­ sartan was not more effective than an ACE inhibitor in preventing the development of incident HF in patients early post-MI. ■ ■OTHER AGENTS Favorable effects on the ischemic process and ventricular remodeling (see below) previously led many physicians to routinely use intravenous nitroglycerin (5–10 μg/min initial dose and up to 200 μg/min as long as hemodynamic stability is maintained) for the first 24–48 h after the onset of infarction. However, a subsequent large, randomized trial demonstrated no benefit of intravenous nitroglycerin with respect to major outcomes in patients with STEMI. Use of intravenous nitroglyc­ erin may be considered in patients with STEMI who have persistent hypertension, HF, or ongoing ischemia. Results of multiple trials of different calcium antagonists have failed to establish a role for these agents in the treatment of most patients with STEMI. Therefore, the routine use of calcium antagonists can­ not be recommended. Targeted control of blood glucose in diabetic patients with STEMI has been shown to reduce the mortality rate. Serum magnesium should be measured in all patients on admission, and any demonstrated deficits should be corrected to minimize the risk of arrhythmias. COMPLICATIONS AND THEIR MANAGEMENT Recognition and management of the complications of STEMI are essential elements of the care of this patient population (Table 286-3). TABLE 286-3  Mechanical Complications of ST-Elevation Myocardial Infarction CHARACTERISTIC VENTRICULAR SEPTAL RUPTURE RUPTURE OF THE VENTRICULAR FREE WALL PAPILLARY MUSCLE RUPTURE Incidence 0.2–3% without reperfusion therapy, 0.2–0.34% with fibrinolytic therapy, 3.9% in patients with cardiogenic shock Approximately 0.3–1%; fibrinolytic therapy does not reduce risk; primary PCI seems to reduce risk Time course Bimodal peak; within 24 h and 3–5 days; range, 1–14 days Bimodal peak; within 24 h and 3–5 days; range, 1–14 days Clinical manifestations Chest pain, shortness of breath, hypotension Anginal, pleuritic, or pericardial chest pain; syncope; hypotension; restlessness; sudden death Physical findings Harsh holosystolic murmur, thrill, S3, accentuated S2, pulmonary edema, RV and LV failure, cardiogenic shock Jugular venous distention (29% of patients), pulsus paradoxus (47%), electromechanical dissociation, cardiogenic shock Echocardiographic findings Ventricular septal rupture, left-to-right shunt on color flow Doppler echocardiography through the ventricular septum, pattern of RV overload

5 mm pericardial effusion not visualized in all cases; layered, high-acoustic echoes within the pericardium (blood clot); direct visualization of tear; signs of tamponade Right-heart catheterization Increase in oxygen saturation from the RA to RV, large v waves Ventriculography insensitive, classic signs of tamponade not always present (equalization of diastolic pressures in the cardiac chambers) Abbreviations: LV, left ventricle; PCI, percutaneous coronary intervention; PCWP, pulmonary capillary wedge pressure; RA, right atrium; RV, right ventricle. Source: Reproduced with permission from Bohula EA, Morrow DA: ST-elevation myocardial infarction: Management, in Braunwald’s Heart Disease, 12th ed, Libby P et al (eds). New York, Elsevier, 2022, pp 662-713.

■ ■VENTRICULAR DYSFUNCTION After STEMI, the left ventricle undergoes a series of changes in shape, size, and thickness in both the infarcted and noninfarcted segments. This process is referred to as ventricular remodeling and generally precedes the development of clinically evident HF in the months to years after infarction. Soon after STEMI, the left ventricle begins to dilate. Acutely, this results from expansion of the infarct, i.e., slip­ page of muscle bundles, disruption of normal myocardial cells, and tissue loss within the necrotic zone, resulting in disproportionate thinning and elongation of the infarct zone. Later, lengthening of the noninfarcted segments occurs as well. The overall chamber enlarge­ ment that occurs is related to the size and location of the infarct, with greater dilation following infarction of the anterior wall and apex of the left ventricle and causing more marked hemodynamic impair­ ment, more frequent HF, and a poorer prognosis. Progressive dilation and its clinical consequences may be ameliorated by therapy with ACE inhibitors. In patients with an ejection fraction <40%, regard­ less of whether or not HF is present, ACE inhibitors or ARBs, and eventually a beta blocker, should be prescribed (see “Inhibition of the Renin-Angiotensin-Aldosterone System” earlier). ■ ■HEMODYNAMIC ASSESSMENT Pump failure is now the primary cause of in-hospital death from STEMI. The extent of infarction correlates well with the degree of pump failure and with mortality, both early (within 10 days of infarction) and later. The most common clinical signs are pulmo­ nary rales and an S3 gallop sound. Pulmonary congestion is also frequently seen on the chest roentgenogram. Elevated LV filling pressure and elevated pulmonary artery pressure are the charac­ teristic hemodynamic findings, but these findings may result from a reduction of ventricular compliance (diastolic failure) and/or a reduction of stroke volume with secondary cardiac dilation (systolic failure) (Chap. 264). A classification originally proposed by Killip divides patients into four groups: class I, no signs of pulmonary or venous congestion; class II, moderate HF as evidenced by rales at the lung bases, S3 gallop, tachypnea, or signs of failure of the right side of the heart, including venous and hepatic congestion; class III, severe HF and pulmonary edema; and class IV, shock with systolic pressure <90 mmHg and evidence of peripheral vasoconstriction, peripheral cyanosis, mental confusion, and oliguria. When this classification was estab­ lished in 1967, the expected hospital mortality rate of patients in these classes was as follows: class I, 0–5%; class II, 10–20%; class III, 35–45%; and class IV, 85–95%. With advances in management, the mortality rate in each class has fallen, perhaps by as much as Approximately 0.1–1% (posteromedial more frequent than anterolateral papillary muscle rupture) Bimodal peak; within 24 h and 3–5 days; range, 1–14 days Abrupt onset of shortness of breath and pulmonary edema; hypotension A soft murmur in some cases, no thrill, variable signs of RV overload, severe pulmonary edema, cardiogenic shock Hypercontractile LV, torn papillary muscle or chordae tendineae, flail leaflet, severe mitral regurgitation on color flow Doppler echocardiography No increase in oxygen saturation from the RA to RV, large v waves, very high PCWP

one-third to one-half. However, the mortality rate for patients with cardiogenic shock (class IV) has plateaued without additional improvement for the past 25 years. Hemodynamic evidence of abnormal global LV function appears when contraction is seriously impaired in 20–25% of the left ventricle. Infarction of ≥40% of the left ventricle usually results in cardiogenic shock (Chap. 316). Positioning of a balloon flotation (Swan-Ganz) catheter in the pulmonary artery permits monitoring of LV filling pressure as well as estimation of the cardiac output; this technique may be useful in patients who exhibit hypotension and/or clinical evidence of HF. With the addition of intraarterial pressure monitoring, systemic vascular resistance can be calculated as a guide to adjusting vasopres­ sor and vasodilator therapy. Some patients with STEMI have markedly elevated LV filling pressures (>22 mmHg) and normal cardiac indices (2.6–3.6 L/[min/m2]), while others have relatively low LV filling pres­ sures (<15 mmHg) and reduced cardiac indices. The former patients usually benefit from diuresis, while the latter may respond to volume expansion. ■ ■HYPOVOLEMIA This is an easily corrected condition that may contribute to the hypo­ tension and vascular collapse associated with STEMI in some patients. It may be secondary to previous diuretic use, to reduced fluid intake during the early stages of the illness, and/or to vomiting associated with pain or medications. Consequently, hypovolemia should be identified and corrected in patients with STEMI and hypotension by cautious fluid administration during continuous monitoring of oxygenation before more vigorous forms of therapy are begun. Eventually, the cardiac output plateaus, and further increases in LV filling pressure only increase congestive symptoms and decrease systemic oxygenation without raising arterial pressure. TREATMENT Heart Failure The management of HF in association with STEMI is similar to that of acute HF secondary to other forms of heart disease (avoidance of hypoxemia, diuresis, afterload reduction, inotro­ pic support) (Chap. 264), except that the benefits of digitalis administration to patients with STEMI are unimpressive. By contrast, diuretic agents are extremely effective, as they diminish pulmonary congestion in the presence of systolic and/or diastolic HF. LV filling pressure falls, and orthopnea and dyspnea improve after the intravenous administration of furosemide or other loop diuretics. Nitrates in various forms may be used to decrease pre­ load and congestive symptoms. Oral isosorbide dinitrate, topical nitroglycerin ointment, and intravenous nitroglycerin all have the advantage over a diuretic of lowering preload through veno­ dilation without decreasing the total plasma volume. In addition, nitrates may improve ventricular compliance if ischemia is pres­ ent, as ischemia causes an elevation of LV filling pressure. Vasodi­ lators must be used with caution to prevent serious hypotension. As noted earlier, ACE inhibitors are an ideal class of drugs for management of ventricular dysfunction after STEMI, especially for the long term. (See “Inhibition of the Renin-AngiotensinAldosterone System” earlier.) ■ ■CARDIOGENIC SHOCK Prompt reperfusion, efforts to reduce infarct size, and treatment of ongoing ischemia and other complications of MI appear to have reduced the incidence of cardiogenic shock from 20 to ~7%. Among those who exhibit cardiogenic shock, only 10% of patients with this condition present with it on admission, while 90% develop it during hospitalization. Typically, patients who develop cardiogenic shock have severe multivessel coronary artery disease with evidence of “piece­ meal” necrosis extending outward from the original infarct zone. The evaluation and management of cardiogenic shock after STEMI are discussed in detail in Chap. 316.

■ ■RIGHT VENTRICULAR INFARCTION Approximately one-third of patients with inferior infarction demon­ strate at least a minor degree of RV necrosis. An occasional patient with inferoposterior LV infarction also has extensive RV infarction, and rare patients present with infarction limited primarily to the RV. Clinically significant RV infarction causes signs of severe RV failure (jugular venous distention, Kussmaul’s sign, hepatomegaly [Chap. 246]) with or without hypotension. ST-segment elevations of right-sided precordial ECG leads, particularly lead V4R, are fre­ quently present in the first 24 h in patients with RV infarction. Twodimensional echocardiography is helpful in determining the degree of RV dysfunction. Catheterization of the right side of the heart often reveals a distinctive hemodynamic pattern resembling constrictive pericarditis (steep right atrial “y” descent and an early diastolic dip and plateau in RV waveforms) (Chap. 281). Therapy consists of volume expansion to maintain adequate RV preload and efforts to improve LV performance with attendant reduction in pulmonary capillary wedge and pulmonary arterial pressures.

CHAPTER 286 ST-Segment Elevation Myocardial Infarction ■ ■ARRHYTHMIAS (See also Chaps. 251 and 253) The incidence of arrhythmias after STEMI is higher in patients seen early after the onset of symptoms. The mechanisms responsible for infarction-related arrhythmias include autonomic nervous system imbalance, electrolyte disturbances, isch­ emia, and slowed conduction in zones of ischemic myocardium. An arrhythmia can usually be managed successfully if trained personnel and appropriate equipment are available when it develops. Since most deaths from arrhythmia occur during the first few hours after infarc­ tion, the effectiveness of treatment relates directly to the speed with which patients come under medical observation. The prompt manage­ ment of arrhythmias constitutes a significant advance in the treatment of STEMI. Ventricular Premature Beats  Infrequent, sporadic ventricular premature depolarizations occur in almost all patients with STEMI and do not require therapy. Whereas in the distant past, frequent, multifocal, or early diastolic ventricular extrasystoles (so-called warn­ ing arrhythmias) were routinely treated with antiarrhythmic drugs to reduce the risk of development of ventricular tachycardia and ventricular fibrillation, pharmacologic therapy is now reserved for patients with sustained ventricular arrhythmias. Prophylactic antiar­ rhythmic therapy (either intravenous lidocaine early or oral agents later) is contraindicated for ventricular premature beats in the absence of clinically important ventricular tachyarrhythmias because such therapy may increase the mortality rate. Beta-adrenoceptor block­ ing agents are effective in abolishing ventricular ectopic activity in patients with STEMI and in the prevention of ventricular fibrillation. As described earlier (see “Beta-Adrenoceptor Blockers”), they should be used routinely in patients without contraindications. In addition, hypokalemia and hypomagnesemia are risk factors for ventricular fibrillation in patients with STEMI; to reduce the risk, the serum potassium concentration should be adjusted to ~4.5 mmol/L and magnesium to ~2.0 mmol/L. Ventricular Tachycardia and Fibrillation  Sustained ventricular tachycardia that is well tolerated hemodynamically should be treated with an intravenous regimen of amiodarone (bolus of 150 mg over 10 min, followed by infusion of 1.0 mg/min for 6 h and then 0.5 mg/ min). A less desirable but alternative regimen is procainamide (bolus of 15 mg/kg over 20–30 min; infusion of 1–4 mg/min). If ventricular tachycardia does not stop promptly, electrical cardioversion should be used (Chap. 253). An unsynchronized discharge of 200 J (biphasic waveform) is used immediately in patients with ventricular fibrillation or when ventricular tachycardia causes hemodynamic deterioration. Ventricular tachycardia or fibrillation that is refractory to electroshock may be more responsive after the patient is treated with amiodarone (150-mg bolus). Ventricular arrhythmias, including the unusual form of ventricular tachycardia known as torsades des pointes (Chaps. 259 and 261), may occur in patients with STEMI as a consequence of ongoing ischemia or

other concurrent problems (e.g., hypoxia, hypokalemia, or other elec­ trolyte disturbances) or of the toxic effects of a QT-prolonging agent being administered to the patient. A search for such secondary causes should always be undertaken.

Although the in-hospital mortality rate is increased, the long-term survival is excellent in patients who survive to hospital discharge after primary ventricular fibrillation; i.e., ventricular fibrillation that is a primary response to acute ischemia that occurs during the first 48 h and is not associated with predisposing factors such as HF, shock, bundle branch block, or ventricular aneurysm. This natural history is in sharp contrast to the poor prognosis for patients who develop ventricular fibrillation secondary to severe pump failure. For patients who develop ventricular tachycardia or ventricular fibrillation late in their hospital course (i.e., after the first 48 h), the mortality rate is increased both in-hospital and during long-term follow-up. Such patients should be considered for implantation of a cardioverter-defibrillator (ICD) (Chap. 259). A more challenging issue is the prevention of sudden cardiac death from ventricular fibrillation late after STEMI in patients who have not exhibited sustained ventricular tachyarrhythmias during their index hospitalization. An algorithm for selection of patients who warrant prophylactic implantation of an ICD is shown in Fig. 286-6. PART 6 Disorders of the Cardiovascular System Accelerated Idioventricular Rhythm  Accelerated idioventricu­ lar rhythm (AIVR, “slow ventricular tachycardia”), a ventricular rhythm with a rate of 60–100 beats/min, often occurs transiently during fibrinolytic therapy at the time of reperfusion. For the most part, AIVR, whether it occurs in association with fibrinolytic therapy or spontaneously, is benign, and does not presage the development of classic ventricular tachycardia. Most episodes of AIVR do not require treatment if the patient is monitored carefully, as degeneration into a Yes Primary prevention in pts with IHD, LVEF ≤40% EP study (especially in the presence of NSVT) MI <40 d and/or revascularization <90 d Yes* No NYHA class II or III LVEF ≤35% LVEF ≤40%, NSVT, inducible sustained VT on EP study NYHA class I LVEF ≤30% Yes Yes No No ICD (Class I)* ICD (Class I) ICD (Class IIa) GDMT ICD should not be implanted (Class III: No benefit) FIGURE 286-6  Primary prevention of SCD in patients with ischemic heart disease, including recent MI. *Scenarios exist for early ICD placement in select circumstances such as patients with a pacing indication or syncope. †Advanced HF therapy includes CRT, cardiac transplant, and left ventricular assist device. CRT, cardiac resynchronization therapy; EP, electrophysiologic; GDMT, guideline-directed management and therapy; HF, heart failure; ICD, implantable cardioverter-defibrillator; IHD, ischemic heart disease, LVEF, left ventricular ejection fraction; MI, myocardial infarction; NSVT, nonsustained ventricular tachycardia; NYHA, New York Heart Association; pts, patients; SCD, sudden cardiac death; VT, ventricular tachycardia; WCD, wearable cardioverter-defibrillator. The available evidence does not suggest there is a survival advantage to the use of an ICD early after MI, and the WCD is a potential option while waiting until the ejection fraction is reassessed (see figure). While the WCD appears to be effective in patients who wear the device, it is associated with frequent alarms, skin irritation, and emotional distress, which results in reduced wear time in a large number of patients. (Reproduced with permission from SM Al-Khatib et al: 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Circulation 138:e272, 2018.)

more serious arrhythmia is rare; overly aggressive treatment can lead to complete heart block. Supraventricular Arrhythmias  Sinus tachycardia is the most common supraventricular arrhythmia. If it occurs secondary to another cause (such as anemia, fever, HF, or a metabolic derangement), the primary problem should be treated first. However, if it appears to be due to sympathetic overstimulation (e.g., as part of a hyperdynamic state), then treatment with a beta blocker is indicated. Other common arrhythmias in this group are atrial flutter and atrial fibrillation, which are often secondary to LV failure. Digoxin may be considered for supraventricular arrhythmias if HF with reduced ejection fraction is present. If left ventricular systolic dysfunction is absent, beta blockers, verapamil, and diltiazem are suitable alternatives for controlling the ventricular rate, as they may also help to control ischemia. If the abnor­ mal rhythm persists for a prolonged period with a high ventricular rate (e.g., >120 beats/min) or if tachycardia induces HF, shock, or ischemia (as manifested by recurrent pain or ECG changes), a synchronized electroshock should be used. Accelerated junctional rhythms have diverse causes but may occur in patients with inferoposterior infarction. Digitalis excess must be ruled out. In some patients with severely compromised LV function, the loss of appropriately timed atrial systole results in a marked reduc­ tion of cardiac output. Right atrial or coronary sinus pacing is indicated in such instances. Sinus Bradycardia  Treatment of sinus bradycardia is indicated if hemodynamic compromise results from the slow heart rate. Atro­ pine is the most useful drug for increasing heart rate and should be given intravenously in doses of 1.0 mg initially. If the rate remains Inducible sustained VT ICD (Class I) No GDMT (Class I) Reassess LVEF >40 d after MI and/or >90 d after revascularization WCD (Class IIb) NYHA class IV candidate for advanced HF therapy† Yes

<50–60 beats/min, additional doses, up to a total of 3.0 mg, may be given. Persistent bradycardia (<40 beats/min) despite atropine may be treated with electrical pacing. Atrioventricular and Intraventricular Conduction Disturbances 

(See also Chap. 251) Both the in-hospital mortality rate and the post­ discharge mortality rate of patients who have complete atrioventricular (AV) block in association with anterior infarction are markedly higher than those of patients who develop AV block with inferior infarction. This difference is related to the fact that heart block in inferior infarc­ tion is commonly a result of increased vagal tone and/or the release of adenosine and, therefore, is transient. In anterior wall infarction, however, heart block is usually related to ischemic malfunction of the conduction system, which is commonly associated with extensive myocardial necrosis. Temporary electrical pacing provides an effective means of increas­ ing the heart rate of patients with bradycardia due to AV block. How­ ever, acceleration of the heart rate may have only a limited impact on prognosis in patients with anterior wall infarction and complete heart block in whom the large size of the infarct is the major factor determin­ ing outcome. It should be carried out if it improves hemodynamics. Pacing does appear to be beneficial in patients with inferoposterior infarction who have complete heart block associated with HF, hypo­ tension, marked bradycardia, or significant ventricular ectopic activity. A subgroup of these patients, those with RV infarction, often respond poorly to ventricular pacing because of the loss of the atrial contribu­ tion to ventricular filling. In such patients, dual-chamber AV sequen­ tial pacing may be required. External noninvasive pacing electrodes should be positioned in a “demand” mode for patients with sinus bradycardia (rate <50 beats/ min) that is unresponsive to drug therapy, Mobitz II second-degree AV block, third-degree heart block, or bilateral bundle branch block (e.g., right bundle branch block plus left anterior fascicular block). Retrospective studies suggest that permanent pacing may reduce the long-term risk of sudden death due to bradyarrhythmias in the rare patient who develops combined persistent bifascicular and transient third-degree heart block during the acute phase of MI. ■ ■OTHER COMPLICATIONS Recurrent Chest Discomfort  Because recurrent or persistent ischemia often heralds extension of the original infarct or reinfarc­ tion in a new myocardial zone and is associated with a near tripling of mortality after STEMI, patients with these symptoms should be referred for prompt coronary arteriography and mechanical revascu­ larization. Administration of a fibrinolytic agent is an alternative to early mechanical revascularization in patients with recurrent ischemic ST-segment elevation. Pericarditis  (See also Chap. 281) Pericardial friction rubs and/or pericardial pain are frequently encountered in patients with STEMI involving the epicardium. This complication can usually be managed with aspirin (650 mg four times daily). It is important to diagnose the chest pain of pericarditis accurately because failure to recognize it may lead to the erroneous diagnosis of recurrent ischemic pain and/or infarct extension, with resulting inappropriate use of anticoagulants, nitrates, beta blockers, or coronary arteriography. When it occurs, complaints of pain radiating to either trapezius muscle is helpful because such a pattern of discomfort is typical of pericarditis but rarely occurs with ischemic discomfort. Anticoagulants potentially could cause tamponade in the presence of acute pericarditis (as manifested by either pain or persistent rub) and therefore should not be used unless there is a compelling indication. Thromboembolism  Clinically apparent thromboembolism com­ plicates STEMI in ~10% of cases, but embolic lesions are found in 20% of patients in necropsy series, suggesting that thromboembolism is often clinically silent. Thromboembolism is considered to be an important contributing cause of death in 25% of patients with STEMI who die after admission to the hospital. Arterial emboli originate from LV mural thrombi, while most pulmonary emboli arise in the leg veins.

Thromboembolism typically occurs in association with large infarcts (especially anterior), HF, and an LV thrombus detected by echocardiog­ raphy. The incidence of arterial embolism from a clot originating in the ventricle at the site of an infarction is small but real. Two-dimensional echocardiography reveals LV thrombi in about one-third of patients with anterior wall infarction but in few patients with inferior or poste­ rior infarction. Arterial embolism often presents as a major complica­ tion, such as hemiparesis when the cerebral circulation is involved. When a thrombus has been clearly demonstrated by echocardiographic or other techniques, systemic anticoagulation should be undertaken (in the absence of contraindications), as the incidence of embolic complica­ tions appears to be markedly lowered by such therapy. The appropriate duration of therapy is unknown, but 3–6 months is reasonable.

CHAPTER 286 ST-Segment Elevation Myocardial Infarction Left Ventricular Aneurysm  The term ventricular aneurysm is usually used to describe dyskinesis or local expansile paradoxical wall motion. Normally functioning myocardial fibers must shorten more if stroke volume and cardiac output are to be maintained in patients with ventricular aneurysm; if they cannot, overall ventricular function is impaired. True aneurysms are composed of scar tissue and neither predispose to nor are associated with cardiac rupture. The complications of LV aneurysm do not usually occur for weeks to months after STEMI; they include HF, arterial embolism, and ven­ tricular arrhythmias. Apical aneurysms are the most common and the most easily detected by clinical examination. The physical finding of greatest value is a double, diffuse, or displaced apical impulse. Ven­ tricular aneurysms are readily detected by two-dimensional echocar­ diography, which may also reveal a mural thrombus in an aneurysm. Rarely, myocardial rupture may be contained by a local area of peri­ cardium, along with organizing thrombus and hematoma. Over time, this pseudoaneurysm enlarges, maintaining communication with the LV cavity through a narrow neck. Because a pseudoaneurysm often ruptures spontaneously, it should be surgically repaired if recognized. POSTINFARCTION RISK STRATIFICATION AND MANAGEMENT Many clinical and laboratory factors have been identified that are associated with an increase in cardiovascular risk after initial recovery from STEMI. Some of the most important factors include persistent ischemia (spontaneous or provoked), depressed LV ejection fraction (<40%), rales above the lung bases on physical examination or con­ gestion on chest imaging, and symptomatic ventricular arrhythmias. Other features associated with increased risk include a history of previous MI, age >75, diabetes mellitus, prolonged sinus tachycardia, hypotension, ST-segment changes at rest without angina (“silent isch­ emia”), an abnormal signal-averaged ECG, nonpatency of the infarctrelated coronary artery (if angiography is undertaken), and persistent advanced heart block or a new intraventricular conduction abnormal­ ity on the ECG. Therapy must be individualized on the basis of the relative importance of the risk(s) present. The goal of preventing reinfarction, pump failure, and death after recovery from STEMI has led to strategies to evaluate risk after infarction. The risk of early recurrent ischemic events has diminished substantially in the era of primary PCI, with further reduction in the setting of current practice recommendations for routine revascular­ ization of suitable severely stenosed nonculprit coronary arteries. In contrast, in stable patients after fibrinolysis who have not undergone revascularization, submaximal exercise stress testing may be carried out before hospital discharge to detect residual ischemia and ven­ tricular ectopy and to provide the patient with a guideline for exercise in the early recovery period. Alternatively, or in addition, a maximal (symptom-limited) exercise stress test may be carried out 4–6 weeks after infarction. Patients in whom angina is induced at relatively low workloads, those who have a large reversible defect on perfusion imag­ ing, those with demonstrable ischemia, and those in whom exercise provokes symptomatic ventricular arrhythmias should be considered at high risk for recurrent MI or death from arrhythmia. Cardiac catheter­ ization with coronary angiography and/or invasive electrophysiologic evaluation is advised.

51 - 288 Hypertension

288 Hypertension

■ ■FURTHER READING Bhatt DL: Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease. Philadelphia, Elsevier, 2024. Kumar V et al: Transcatheter aortic valve replacement programs: Clin­ ical outcomes and developments. J Am Heart Assoc 9:120.015921, 2020. Lawton JS et al: 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: A report of the American College of Cardiology/ American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 145:e18, 2022. Paul K. Whelton

Hypertension High blood pressure (BP) is a leading risk factor for cardiovascular disease (CVD), including ischemic and hemorrhagic stroke, coro­ nary heart disease (CHD), heart failure (HF), peripheral arterial dis­ ease (PAD), chronic kidney disease (CKD)/end-stage kidney disease (ESKD), dementia, and all-cause mortality. Hypertension, a subset of high BP, is very common no matter how it is defined and results in a huge burden due to death, morbidity, disability, social and workplace disruption, and cost to the individual and society. According to data from the National Ambulatory Medical Care Survey (NAMCS), hyper­ tension is a component for more than one-third of all visits to officebased physicians by U.S. adults. Likewise, global estimates have ranked hypertension as the most common reason for primary care visits worldwide. Hypertension is often associated with other CVD risk fac­ tors, resulting in a higher risk of complications and related burden of illness. The optimal approach to high BP is to prevent its development, but diagnosis, treatment, and control of hypertension also provide an effective means to reduce the risk of BP-related CVD. Unfortunately, both strategies are poorly implemented worldwide, resulting in a high burden of preventable disease. BLOOD PRESSURE PHYSIOLOGY AND PATHOPHYSIOLOGY Complex and incompletely understood mechanisms control blood flow in individual organs and the arteriolar system. At the most basic level, arterial BP is controlled by cardiac output and peripheral resis­ tance (Fig. 288-1). However, arterial pressure is largely thought to be controlled by a renal-volume-endocrine pressure control system, in which the blood volume and total peripheral resistance are manipu­ lated slowly to adjust arterial BP. Cardiac output is influenced by stroke volume and heart rate, with stroke volume being related to myocardial contraction and the size of the intravascular compartment. Changes in cardiac output play an important role in acute BP responses to stressors. Peripheral vascular resistance is determined by functional and anatomic changes in small arteries and arterioles. The vascular endothelium is composed of a single layer of endothelial cells that constitute the inner cellular lining of arterioles. It serves as a direct contact with circulating blood and regulates exchanges between the bloodstream and surrounding tissues. Endothelial cells control vascular tone and, thereby, blood flow by syn­ thesizing and releasing relaxing and contracting factors such as nitric oxide; metabolites of arachidonic, lipoxygenase, and cytochrome path­ ways; peptides, including endothelin; adenosine; purines; and reactive oxygen species; and by generating endothelial enzymes that produce vasoactive hormones such as angiotensin II. Endothelial dysfunction may play an important role in the initiation or progression of hyper­ tension and atherosclerosis. A wide variety of systems interplay to keep cardiac output and peripheral resistance in balance, including sodium

Stroke volume Cardiac output Heart rate Arterial blood pressure CHAPTER 288 Vascular structure Peripheral resistance Vascular function FIGURE 288-1  Schematic depiction of factors that influence the control of blood pressure. Hypertension handling, primarily by the kidney, and many neural and hormonal systems that influence peripheral resistance by stimulating vascular constriction (e.g., the sympathetic system and the renin-angiotensinaldosterone system [RAAS]) or inducing vasodilation (e.g., bradykinin system), and by modulating hormones that result in excretion or reten­ tion of sodium (natriuretic peptides and aldosterone, respectively). Most vascular beds have the capacity to autoregulate blood flow. When peripheral arterial resistance is increased, the autoregulatory systems tend to increase vascular resistance within the vascular bed to maintain constant blood flow. During the 1960s, Arthur Guyton hypothesized that the capacity of the kidney to excrete sodium ulti­ mately dictates long-term changes in levels of BP. Although the Guyton model has been challenged and alternatives proposed, it has had a profound influence on the understanding of BP regulation. A com­ monly accepted theory is that initial elevation of BP is due to increased cardiac output and expanded intravascular volume; peripheral resis­ tance increases and cardiac output reverts toward normal over time. Whether or not this is the typical sequence of events in the pathogen­ esis of hypertension, salt can activate a number of neural, endocrine, paracrine, and vascular mechanisms that have the potential to increase arterial pressure. As arterial pressure increases in response to a high intake of sodium chloride, urinary sodium excretion increases, and sodium balance is maintained at the expense of an increase in arterial pressure. The mechanism for this “pressure-natriuresis” phenomenon may involve a subtle increase in glomerular filtration rate (GFR), decreased sodium absorption capacity in the renal tubules, and hor­ monal factors such as atrial natriuretic factor. In individuals with an impaired capacity to excrete sodium, greater increases in arterial pres­ sure are required to achieve natriuresis and sodium balance. Many of the drugs used to manage high BP work though influ­ ences on the various BP control mechanisms. For example, direct vasodilators and calcium channel blockers (CCBs) work by induc­ ing arteriolar vasodilation. Agents that block the RAAS, such as angiotensin-converting enzyme inhibitors (ACEIs), angiotensin recep­ tor blockers (ARBs), and renin inhibitors, act by blocking the vaso­ constricting effects of angiotensin II and sodium-retaining effects of aldosterone. ACEIs also inhibit inactivation of the vasodilator bradyki­ nin, resulting in angioedema in some patients treated with this agent. Beta blockers tend to affect BP by impairing the action of sympathetic system neurotransmitters that stimulate vasoconstriction and heart rate. For example, beta blockers can antagonize the neurotransmitter acetylcholine as well as epinephrine and norepinephrine. In addition to being the most important site for the effect of agents that block the RAAS activity, many drugs affect electrolyte and fluid exchange in the kidneys. Carbonic anhydrase inhibitors have a diuretic effect in the proximal tubules, but due to side effects and diminishing efficacy over time, they are rarely used for BP control. Thiazide and thiazidelike diuretics work to enhance sodium excretion in the distal convo­ luted tubule and are a mainstay of drug therapy for BP control. They work by reducing intravascular volume, but over the long term, their effect on BP is through reducing peripheral arteriolar resistance. Loop diuretics are more potent diuretics that produce sodium excretion in the loop of Henle. They tend to be relatively short-acting agents that are better suited for sodium excretion than BP reduction. Mineralo­ corticoid receptor antagonists (MRAs) or aldosterone antagonists are diuretic drugs that work in the distal tubule of the kidney, including the distal convoluted tubule, connecting the tubule and cortical collect­ ing duct, to antagonize the action of aldosterone at mineralocorticoid

receptor sites. These are examples of presumed principal mechanisms of action, but many drugs have other effects on the control of vascular tone and cardiac output that play a role in their effects on BP.

BLOOD PRESSURE MEASUREMENT Commonly, BP measurements are used to estimate an individual’s average level of BP; estimate their risk of CVD, in combination with other indicators; and determine the need for hypertension prevention or treatment. Office and clinic BP measurements are among the most common procedures in clinical practice and arguably provide the best assessment of BP because they have been used in almost all of the landmark BP-CVD risk prediction cohort studies and hypertension prevention and treatment trials. The need for standardization of the BP measurement procedure was recognized by early advocates of BP assessment. Subsequently, the effects of factors that can systematically (predictably) result in falsely high or low BP estimates were quanti­ fied, which formed the basis for BP measurement recommendations by professional societies and clinical practice guideline committees. BP also varies randomly (nonpredictably) within and between visits, resulting in corresponding recommendations to rely on an average of repeated readings obtained at more than one visit for classification of an individual’s average level of BP. For many years, U.S. clinical prac­ tice guidelines have recommended using an average of two or more BP measurements obtained at two or more visits to estimate the usual level of BP. The most important elements for obtaining accurate office BP measurements are visually depicted in Fig. 288-2 and outlined below. PART 6 Disorders of the Cardiovascular System • Instruct the patient to avoid a full bladder and abstain from caffeine, smoking, alcohol, or exercise for 30 min prior to the measurements. • Use a quiet room with a comfortable ambient temperature. • Explain the procedure to the patient, including the number of readings. • Instruct the patient to rest for 3–5 min prior to the first measure­ ment and avoid talking or distractions such as cell phone use during the rest period and subsequent BP measurements. • Seat the patient in a chair with upright back support. The patient’s feet should be flat on the ground and the measurement arm com­ fortably supported such that the cuff is at heart level. • Use a clinically validated, preferably automated BP measurement device. Choose a cuff that is the correct size for the patient’s arm, and measure their BP at the mid-brachial level. • The BP measurements should be obtained by a trained, preferably certified, member of the health care team using the arm with the highest pressure at the first visit. No talking during rest period and between measurements Apply the cuff to bare upper arm, approximately 2–3 cm above the elbow crease Arm bare and resting. Mid-arm at heart level Back supported Feet flat on floor FIGURE 288-2  Schematic depiction of the important elements for accurate measurement of office blood pressure. (Reproduced with permission from AK Cheung et al: International consensus on standardized clinic blood pressure measurement: A call to action. Am J Med 136:438, 2023.)

TABLE 288-1  American College of Cardiology/American Heart Association Blood Pressure Classification System in Adults SYSTOLIC BP, mmHg DIASTOLIC BP, mmHg BP CATEGORY Normal BP <120 and <80 Elevated BP 120–129 and <80 Stage 1 hypertension 130–139 or 80–89 Stage 2 hypertension ≥140 or ≥90 Abbreviation: BP, blood pressure. • Use an average of two or more readings at two or more visits to estimate the patient’s usual level of BP. • Provide the patient with the results and an interpretation of their clinical implications. Most clinical practice guidelines recommend use of a clinically vali­ dated oscillometric BP measurement device, a method that eliminates several sources of measurement error and does not require periodic recalibration. Several websites provide a listing of BP measurement devices that have been clinically validated to international standards. These include the Validate BP website in the United States (https:// www.validatebp.org/) and the STRIDE BP website in Europe (https:// stridebp.org/bp-monitors). Similarly, many free office and home BP measurement training and certification courses are available, includ­ ing an easy-to-access course sponsored by the Pan American Health Organization, World Hypertension League, and others (https://campus. paho.org/en/node/29166). DEFINITION OF HYPERTENSION BP classifications systems differ by country and have changed substan­ tially over time. The current classification proposed by the American College of Cardiology (ACC) and American Heart Association (AHA) for office/clinic BP measurements in U.S. adults is displayed in Table 288-1. Correct classification presumes accurate BP measurement and aver­ aging of two or more readings obtained at two or more occasions. When the systolic BP (SBP) and diastolic BP (DBP) readings are in different categories of BP, the higher classification should be chosen. In children and adolescents <13 years of age, hypertension is generally based on a comparison with age-, sex-, and height-specific normative data. Hypertension is defined as an average of three SBP or DBP readings at or above the 95th percentile or an SBP or DBP ≥130 or 80 mmHg, respectively. This chapter is focused on BP in adults ≥18 years. Despite the importance and relative simplicity of accurate BP readings, errors in BP measurement are common in routine clinical practice. Generally, SBP is overestimated by an average of ~7 mmHg, which results in a 15–20% overestimation of hypertension prevalence. However, underestimation of BP and failure to diagnose hypertension are also common. Clinical practice errors vary by level of BP and practice settings and are inconsistent over time, making it impos­ sible to use formulae to correct the errors. For those who aspire to practice evidence-based medicine, the only solu­ tion is to follow the recommendations for accurate and precise BP measurements that are advocated by the AHA, ACC, and many other organizations. Having a trained non­ physician staff member obtain routine BP measurements provides an efficient and cost-effective means of obtaining high-quality observations. This is the common practice in research studies and in many large U.S. systems of care. OUT-OF-OFFICE BLOOD PRESSURE MEASUREMENT Office BP measurements provide a limited and potentially biased depiction of an individual’s usual level of BP. Guide­ lines commonly recommend complementing office BP readings with out-of-office BP measurements to confirm high office readings and to probe for higher or lower BPs

Hypertension

CHAPTER 288 outside the office. White coat hypertension, in which office BPs meet the criteria for hypertension but out-of-office BPs are nonhypertensive, and masked hypertension, in which office BPs are nonhypertensive but out-of-office BPs meet the criteria for hypertension, are common, with prevalence estimates of 15–25% for both conditions. Adults with white coat hypertension have a CVD risk profile that is more like those with­ out than those with sustained high BPs in and out of the office and they may be best treated with nonpharmacologic interventions, with careful monitoring to recognize a transition to sustained hypertension. In con­ trast, adults with masked hypertension have a CVD risk profile that is like those with sustained hypertension and may be better treated with a combination of antihypertensive drugs in addition to nonpharma­ cologic therapy. Masked hypertension should be suspected especially in adults with an elevated but nonhypertensive office BP and evidence of end-organ damage such as left ventricular hypertrophy or protein­ uria. Home BP measurements provide the most practical approach to obtaining out-of-office BP readings and provide the additional benefit of engaging patients in their own care. When home BP measurements are desired, patients should be instructed to use a clinically validated BP measurement device and trained to measure their BPs accurately and precisely using the same approaches outlined for measurement of office BPs. Most guidelines recommend using an average of two to three measurements obtained in the morning (before taking antihyper­ tensive medications) and evening. In the United States, obtaining home BP measurements for about 3 days prior to an office visit represents a reasonable and practical option for estimating a patient’s usual level of home BP. The BP for recognition of hypertension is the same for office and home BP measurements (SBP ≥130 and DBP ≥80 mmHg). Likewise, the BP control is defined as an SBP/DBP <130/80 mmHg in both settings. Many home BP measurement devices allow for storage of the readings on a memory chip and for transfer to the physician’s office by use of telemetry. This approach thwarts the potential for the bias of more favorable readings that can occur with written patient self-reports. Ambulatory BP measurements are best obtained by prac­ titioners with special expertise in this technique and interpretation of the results. The equivalent SBP/DBP readings for an office average of 130/80 mmHg are 130/80, 110/65, and 125/75 mmHg for daytime, nighttime, and 24-h ambulatory readings, respectively. Ambulatory BP measurements provide the potential for scrutiny of nighttime readings, which may provide the best BP prediction of CVD risk. Specifically, those whose BPs fail to follow the usual pattern of a pronounced decre­ ment during the nighttime (nondippers) tend to have a higher risk of CVD. BP nondipping is more common in non-Hispanic blacks than the other major racial/ethnic groups in the United States. Ambula­ tory BP measurement is relatively expensive and intrusive. Patients in the United States are usually reluctant to undergo repeat ambulatory BP measurements, making this measurement method most useful in confirming the diagnosis of hypertension, especially where uncertainty is a special concern. Wearable devices, including watches, hold great promise for the provision of convenient ways to obtain a more com­ prehensive assessment of daytime and nighttime BPs, but none of the currently available options are clinically valid. PREVALENCE OF HYPERTENSION Prevalence estimates vary depending on the criteria for definition of hypertension, the methods for BP measurement, and the population being studied; hypertension is very common, especially at older age. Age-related increases in BP are noted in almost all countries. Gener­ ally, SBP increases progressively until about the eighth decade of life. DBP also increases with age, but less steeply than SBP, until about the fifth decade of life and remains stable or declines thereafter. Iso­ lated systolic hypertension is common late in life due to a widening of the pulse pressure (difference between SBP and DBP). Generally, those who have the highest or lowest BPs early in life tend to “track” in the same extremes of BP over life, with high pressures early in life providing a crude opportunity to identify those at higher risk for hypertension in adulthood. Little or no age-related change in BP has been observed in many isolated populations and in subsets of popula­ tions in countries where age-related increases in BP are common. This observation indicates that there is no biological necessity for the com­ monly observed age-related increase in BP and underscores the value of interventions aimed at prevention of hypertension. Migrant studies that have tracked isolated populations from their native environment to nonnative settings have uniformly reported progression to the more common pattern of age-related increases in BP. These BP changes have been associated with increases in dietary sodium and decreases in potassium intake, consumption of a less healthy diet, decreased physi­ cal activity, increases in body weight, and increased intake of alcohol. Based on the ACC/AHA criteria for diagnosis, >103 million adults in the United States have hypertension, making it one of the most com­ mon health conditions reported. Hypertension is present in ~20–30% of U.S. adults aged 20–44 years, but the prevalence increases to 80–85% in those aged 75 years or older. The overall prevalence of hyperten­ sion in U.S. adults has remained fairly stable in recent decades (~46% overall). Men have slightly higher BPs compared to women during the first half of life, but the opposite is true in later life. In the United States, non-Hispanic black adults have a prevalence of hypertension (59%) that is substantially higher compared to whites (45%), Hispanics (47%), or Asians (46%). Adjusted estimates of hypertension in adult non-Hispanic black men and women are reported to be 59 and 56%, respectively, whereas the corresponding estimates for non-Hispanic white men and women are 47 and 41%, respectively. In addition, hypertension in non-Hispanic black adults tends to begin at a younger age and result in more CVD and kidney complications compared to the other major racial/ethnic groups in the United States. The prevalence of hypertension and CVD complications (especially stroke) is higher in the southeastern United States compared to other regions of the coun­ try, especially the northwest. No matter how defined, hypertension is very common in all parts of the world, with a progressively increasing prevalence in low- and middle-income countries and a slight decline in high-income countries. Using the hypertension definition of SBP ≥140 mmHg, DBP ≥90 mmHg, or taking antihypertensive medication, the prevalence in adults was estimated to be 31.5% (1.04 billion) in low- and middle-income countries and 28.5% (349 million) in high-income countries in 2010. As in the United States, hypertension prevalence is very age-dependent and varies by region, race/ethnicity, and other fac­ tors, including importantly socioeconomic factors, in most countries. LABORATORY AND OTHER INVESTIGATIONS In patients with newly diagnosed hypertension, basic laboratory test­ ing is indicated to (1) recognize the presence and extent of target organ damage; (2) facilitate the identification of secondary causes of hypertension, including kidney disease and primary aldosteronism; (3) recognize comorbid conditions, including diabetes mellitus and hyperlipidemia; (4) estimate atherosclerotic CVD (ASCVD) risk in patients without a history of a CVD; and (5) assist in the optimal choice of antihypertensive drug therapy. At a minimum, a complete blood count, serum electrolytes (sodium, potassium, calcium), serum creati­ nine and estimated GFR (eGFR), lipid profile, glycemic status (hemo­ globin A1c or fasting blood glucose), thyroid-stimulating hormone level, urinalysis and urine albumin-to-creatinine ratio, and 12-lead electrocardiogram (ECG) should be obtained. These basic tests can be complemented by other evaluations as clinically indicated. In some countries, it is not possible to obtain the minimally recommended laboratory results. Guidelines written for clinicians in such countries, including the 2021 World Health Organization (WHO) guideline for the treatment of hypertension in adults, recommend that this should not be an impediment to BP reduction. ESTIMATION OF CARDIOVASCULAR DISEASE RISK Abundant studies have shown that BP is associated with CVD risk in a continuous, progressive, log-linear fashion from low to high levels of SBP and DBP. For SBP, the risk relationship has been documented from as low as 90 mmHg to more than 180 mmHg, suggesting rela­ tively low levels of BP, if physiological, may be optimal to prevent the genesis of BP-related atherosclerotic complications. It also suggests that

one might reasonably expect a “lower BP is better” finding in antihy­ pertensive randomized controlled treatment (RCT) trials. In addition to CVD, the level of BP is strongly associated with other diseases, including CKD, ESKD, and dementia. The BP-CVD risk association in observational studies is equally true for men and women. The BPrelated slope for relative risk of CVD is steeper at younger age when BP elevation is often an isolated risk predictor. In older adults, the corresponding slope for CVD risk is less steep, but the absolute risk of CVD is far higher because other CVD risk factors are common in those with an elevated BP. At any level of BP, the risk of a CVD complication varies dramatically with more than a 30-fold difference in 10-year predicted risk of CVD for those with an isolated elevation of BP compared to their counterparts with multiple CVD risk factors in addition to an elevated BP. This observation has special relevance for clinical decision-making in patients with a usual SBP between 130 and 139 mmHg. In individuals with stage 1 hypertension as an isolated CVD risk factor, the 5- or 10-year risk of a CVD event may be quite small and limit enthusiasm for introducing antihypertensive drug therapy. However, when stage 1 hypertension is accompanied by other CVD risk factors, the corresponding risk of ASCVD may be quite high and make prescription of antihypertensive drug therapy much more appealing. In antihypertensive clinical trials, the relative risk reductions for CVD events are similar in groups with different levels of underlying CVD risk, but the absolute benefit is much greater in the groups at higher risk for ASCVD. For both these reasons, CVD risk assessment should be part of the initial evaluation.

PART 6 Disorders of the Cardiovascular System Patients with a history of a prior CVD complication are known to be at high risk for recurrent CVD events. In those without a history of prior CVD, ASCVD risk should be estimated using a risk calculator. For U.S. adults 40–75 years of age, use of the ACC/AHA pooled cohort equations estimator is recommended because it has been validated in non-Hispanic white and black adults. Those with a 10-year risk of ASCVD ≥10% should be considered at high risk. PREVENT is an updated risk predicting model that is based on a larger and more cur­ rent dataset than that used for the pooled cohort equations model. It incorporates an assessment of kidney (glomerular) function and allows for inclusion of urinary albumin/creatinine ratio, zip code for assess­ ment of the social determinants of health, and hemoglobin A1c where indicated and has been introduced by the AHA as a replacement for the pooled cohort equations. It can be used in U.S. adults aged 30–70 years to predict 10- and 30-year CVD risk. It includes the prediction of heart failure risk, an important feature in the care of patients with hyperten­ sion. Over time, the PREVENT instrument is expected to replace the current pooled cohort equations risk prediction model. CAUSES OF HYPERTENSION ■ ■PRIMARY HYPERTENSION Most adults have “primary” hypertension, with no obvious underlying anatomic cause of their high BP. Adoption, twin, clinical, and family studies provide evidence for a heritable component of high BP and hypertension. However, much of this may be due to a shared environ­ ment because, with rare exceptions, genetic investigations have only identified modest polygenic associations between multiple genes and BP. While genetic research remains an important area for investigation, the clinical implications of genetic studies for diagnosis and manage­ ment of high BP are currently very limited. Strong associations with level of BP have been reported for several general environmental exposures, including heavy metals such as lead, mercury, cadmium, and arsenic. Several indicators of air pollu­ tion, commonly including levels of particulate matter with a diam­ eter of 2.5 microns (PM2.5) or less, have been associated with higher levels of SBP and DBP. In most studies, the increase in SBP has been ~3–5 mmHg, but the magnitude can vary depending on quantity and duration of the exposure. Air pollution is a challenge worldwide, but the level of exposure to pollutants varies widely by geography, climate, season, and extent of economic development. In addition to air pollution, clinically important changes in BP are recognized in geographic regions that experience large seasonal variations in ambient

temperature, with lower and higher BPs during the warmest and cold­ est seasons, respectively. BP also tends to be higher in those who are acutely exposed to high altitudes, possibly due to a combination of hypoxia and cold temperatures. Personal environmental exposures related to components of diet, physical activity, and alcohol consumption seem to be responsible for much of the age-related increases in BP that are common in most countries. A large body of ecological, migrant, and longitudinal cohort studies have documented higher BPs in those who consume unhealthy diets, have an excessive intake of sodium or an inadequate intake of potassium, are physically inactive, are overweight or obese, or consume alcohol. Many of these exposures have also been linked to CVD com­ plications. For example, insufficient dietary intake of potassium has been identified as a risk factor for stroke in many studies. Stress and other psychosocial indicators have also been associated with higher BPs and CVD events. The six personal exposures identified in Table 288-2 (diet quality, body weight, excessive dietary sodium intake, insufficient dietary potassium intake, physical inactivity, and alcohol consumption) are all highly prevalent and strongly associated with higher BP and age-related increases in BP. About half of U.S. adults report attempts to eat a heart healthy diet, but this is likely to represent an overestimate. Almost all adults worldwide exceed the intake of dietary sodium and fail to meet the level of dietary potassium recommended by the WHO and national organizations. Likewise, excess body weight is very com­ mon in many countries. For example, approximately three-quarters of U.S. adults are either overweight (body mass index [BMI] 25–29 kg/m2) or obese (BMI ≥30 kg/m2). More than a quarter of U.S. adults report no physical activity outside their workplace, and about half report less than the recommended level of physical activity (≥150 min of aero­ bic exercise/week). About 85% of U.S. adults report consumption of alcohol at some point during their life, with >60% reporting alcohol consumption during the previous year and 25% reporting binge drink­ ing during the previous month. Thus, these six exposures are not only closely related to level of BP and targets for interventions aimed at BP lowering but also extremely common exposures. ■ ■SECONDARY HYPERTENSION A minority of patients have “secondary” hypertension, with an overt underlying anatomic or biochemical cause for their high BP. Second­ ary hypertension should be considered during the evaluation of all patients with new-onset hypertension and in selected patients with prevalent hypertension who have indicators that suggest the possibil­ ity of a complicating secondary cause of hypertension, including (1) treatment-resistant hypertension; (2) abrupt worsening of hyperten­ sion; (3) disproportionate target organ damage for level of BP; and (4) laboratory or diagnostic findings such as unprovoked hypokalemia, proteinuria, or left ventricular hypertrophy. The approximate preva­ lence, pathophysiology, possible clinical and physical examination findings, common screening and confirmatory tests, and potential treatments for the six most common causes of secondary hypertension are summarized in Table 288-3. Obstructive Sleep Apnea  Obstructive sleep apnea (OSA) is probably the most common cause of secondary hypertension. It is closely associated with overweight, obesity, and other comorbidities. The reported prevalence of OSA varies substantially depending on the criteria used for definition and methods of ascertainment. However, it is very common and may be present in as many as 15–30% of adult men and 10–15% of adult women in the United States. More than half of U.S. adults with OSA have hypertension and >30% of U.S. adults with hypertension have OSA. OSA and hypertension share many common pathophysiologic features, including being overweight, obe­ sity, unhealthy lifestyles, and abnormalities of the renin-angiotensin system and fluid distribution. Sympathetic system activation due to intermittent hypoxia is also an important component of the underly­ ing pathophysiology in OSA. Almost three-quarters of patients with OSA are overweight or obese. In general, there is a direct association between the severity of OSA and an individual’s level of BP as well as their resistance to antihypertensive therapy. Resistant hypertension,

TABLE 288-2  Summary Information for the Six Best Proven Nonpharmacologic Interventions That Lower Blood Pressure CHARACTERISTIC BP ASSOCIATION INTERVENTION REGIMEN EXPECTED CHANGE IN BP Diet BPs are lower in those who consume heart-healthy diets. Consumption of a hearthealthy diet, especially the Dietary Approaches to Stop Hypertension (DASH) diet. Body weight Increased body weight is directly associated with SBP/ DBP. Almost 75% of U.S. adults are overweight (BMI 25–<30 kg/ m2; 31%) or obese (BMI ≥30 kg/ m2; 42%). In most patients, weight loss should be achieved by behavioral counseling. In a minority, drug therapy should be considered. Bariatric surgery should be confined to adults with a BMI ≥40 kg/m2 or ≥35 kg/m2 and hypertension or another obesityrelated comorbidity. Sodium intake Dietary sodium is directly associated with SBP, and excessive intake may be important in age-related increases in BP. Behavioral counseling, use of salt substitutes, public health messaging, and policy to reduce the amount of sodium added during food processing and commercial preparation. Potassium intake Potassium intake is inversely associated with BP and a lower risk of CVD, especially stroke. Dietary or pill supplementation, but the former is preferred. An additional intake of 2000 mg/d (~50 mmol/d). Physical activity Observational studies identify a strong inverse association between physical activity and BP, hypertension, and CVD. Aerobic, dynamic resistance, and isometric resistance exercises. Alcohol consumption Alcohol intake is associated with BP and hypertension in a direct and roughly linear fashion, with no threshold for the association. Most commonly, substitution of lower alcoholic or nonalcoholic beverages, but behavioral counseling and abstinence, without access to alcohol, have been used in some trials. Abbreviations: BMI, body mass index; BP, blood pressure; CVD, cardiovascular disease; DASH, Dietary Approaches to Stop Hypertension; DBP, diastolic BP; RCT, randomized controlled trials; SBP, systolic BP. snoring, poor quality sleep, breathing pauses during sleep, and day­ time sleepiness are common clinical indicators of OSA. Several simple questionnaire-based tests are available to screen for those who should be evaluated more carefully with a sleep study (polysomnography). Lifestyle improvements, especially those resulting in weight loss, are an important component of treatment for both OSA and any associated hypertension. OSA-specific treatment includes continuous positive airway pressure (CPAP), but meta-analyses demonstrate limited BP lowering due to CPAP treatment. As a result, hypertension in patients with OSA should be treated with antihypertensive drug therapy in addition to nonpharmacologic therapy. Medication and Other Substances  Prescription and over-thecounter medications, herbal and food additives, and illegal substances are often identified as secondary causes of new-onset hypertension or diminished BP control in patients being treated for hypertension. Typically, the increase in BP results from a direct pressor effect of the agents, but these exposures can also have an indirect effect on

DASH diet meal plans are readily available. With good adherence to the DASH diet plan, an average SBP reduction of about 5 mmHg can be expected in patients with and 2–3 mmHg in those without hypertension. CHAPTER 288 Behavioral interventions are aimed at a combination of calorie reduction and increased physical activity. Generally, SBP is reduced by ~1 mmHg for every kilogram reduction in body weight. In high-quality RCTs, an average reduction of about 10 lb (4.5 kg) has been common at 6–12 months. Hypertension The sodium-BP dose response is almost linear, so any reduction in sodium intake is beneficial. Optimal target recommendations vary from <1500 to 2300 mg sodium intake per day. In high-quality behavior change trials, average sodium intake is reduced by ~25% and SBP by ~5 mmHg and 2–3 mmHg for adults with and without hypertension, respectively. Use of salt substitutes has resulted in prevention of stroke (14%), CVD (13%), and allcause mortality (12%) in addition to BP lowering. The recommended intake of potassium in adults is ~3500 mg/d. A dose-response meta-analysis suggests supplementing usual intake by ~1200 mg/d may be optimal. Potassium supplementation is contraindicated in patients with hyperkalemia or advanced kidney disease or who are taking medicines that increase the risk of hyperkalemia. Clinical trial meta-analyses have repeatedly shown that potassium supplementation by diet or pill use lowers BP. The average reduction in SBP has been ~5 and 3 mmHg in adults with and without hypertension, respectively. Greater reductions are observed in adult black patients and those consuming large amounts of dietary sodium. Most trials have evaluated aerobic exercise interventions, and this type of exercise is commonly prescribed. Most guidelines recommend ≥150 min of aerobic exercise per week. However, any increase in physical activity and any type of exercise are likely to be be beneficial. In adults with hypertension, aerobic exercise is likely to reduce SBP by ~5 mmHg and, when combined with dynamic resistance exercise, by ~7 mmHg. The extent of BP lowering depends on the starting level of BP and success of the intervention. Most interventions have targeted a reduction in alcohol consumption, often to ≤2 and ≤1 standard drinks per day in men and women, respectively. However, any reduction in alcohol consumption is helpful. The extent of BP lowering depends on the starting level of alcohol consumption and the magnitude of the reduction in alcohol intake. Commonly, alcohol reduction trials have resulted in an SBP reduction of >5 mmHg in adults with hypertension. BP as a result of drug-drug or drug-nondrug exposure interactions. Some of the most common prescription drugs that can increase BP include amphetamines, angiogenesis inhibitors, antidepressants and antipsychotic agents, decongestants, oral contraceptives, nonsteroidal anti-inflammatory drugs (NSAIDs), and systemic corticosteroids. Examples of illicit drugs that can result in a higher BP include cocaine, marijuana, amphetamines, and methylenedioxymethamphetamine. Herbal treatments that have been reported to raise BP include arnica, ephedra (Ma-Huang), ginseng, guarana, consumption of large quanti­ ties of licorice, and St. John’s wort. Finally, caffeine and several anes­ thetic agents can result in short-term elevation of BP. A careful history will identify most of these agents and will allow for use of alternatives or a reduced dosage in most patients. The exact prevalence of expo­ sure to any of these agents is uncertain but high. For example, in the nationally representative 1999–2004 National Health and Nutrition Examination Survey (NHANES), >26% of U.S. adults reported regular NSAID use, and the percentage was much higher in older adults and in non-Hispanic whites.

Continuous positive airway pressure alternative therapy, or maintenance Management of the specific kidney (CPAP) treatment for OSA has little aimed at weight loss, is indicated (sleep study) Lifestyle improvement, especially Treatment of ASCVD risk factors, Adrenalectomy (laparoscopic or of exposure but management of History taking History taking Discontinuation, substitution of Antihypertensive drug therapy. for both OSA and associated including hypertension. PART 6 Disorders of the Cardiovascular System disease, if feasible. hypertension. TESTS TREATMENT effect on BP. high BP. sonography, CT, or MRI Saline suppression Polysomnography CAUSE PREVALENCE PATHOPHYSIOLOGY CLINICAL INDICATORS PHYSICAL EXAMINATION SCREENING TESTS CONFIRMATORY Renal biopsy Imaging by albuminuria, glucose (several have been edema, report of hematuria Proteinuria, renal mass Serum creatinine, airway narrowing OSA screening questionnaires clinical examination High plasma abnormality validated) Obesity and signs of upper physical exam findings, No specific findings on by medical history report Occasionally, specific e.g., signs suggesting cocaine use Resistant hypertension, snoring, Severe or resistant hypertension Resistant hypertension, fatigue, Varies depending on exposure. Usually exposure best detected pauses during sleep, daytime poor quality sleep, breathing sleepiness, overweight and TABLE 288-3  Summary Description of the Most Common Secondary Causes of Hypertension obesity Various kidney diseases, including polycystic renal disease, chronic many common pathophysiologic glomerulonephritis, diabetic and features, including overweight hypertensive kidney disease, OSA and hypertension share recurrent stones, and kidney the sympathetic system due important component of the to intermittent hypoxia is an Idiopathic bilateral adrenal and obesity. Activation of pathophysiology for OSA. infections. One of the most common hypertension, and ~30% adults reporting regular (10–30% of U.S. adults). with hypertension have More than 50% of U.S. exposures. For NSAID adults with OSA have causes of secondary OSA is very common Numerous potential hypertension (>5%). alone, >26% of U.S. High prevalence. aldosteronism One of the more OSA. use. parenchymal sleep apnea Obstructive Medication substances and other Primary disease. Renal (OSA)

Abbreviations: ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; ASCVD, atherosclerotic cardiovascular disease; BP, blood pressure; CCB, calcium channel blocker; CT, computed tomography; MRI, magnetic preferred in patients with ASCVD and those with very diffuse fibromuscular with inclusion of a mineralocorticoid and ARBs should not be used. Initial safety record and known efficacy in with discrete fibromuscular disease antihypertensive medication. ACEIs hyperplasia best treated medically, surgical) for many patients with an or the CCB nifedipine is commonly use of the β-blocker labetalol and/ changes to reduce sodium intake receptor antagonist, and lifestyle improve hypertension in patients recommended because of their angiography PTA may cure or substantially lesions. Medical treatment is Hypertension due to adrenal Lifestyle counseling and adrenal adenoma. and body weight. pregnancy. disease. measured BP readings recognition of high BP, generally accepted as the gold standard test. taken on ≥2 occasions based on an average aldosterone levels is helpful, but adrenal Digital subtraction challenge test are vein sampling for of ≥2 accurately test or captopril screening tests Diagnosis by ratio, when measured magnetic resonance, under standardized CT of the abdomen aldosterone/renin or CT angiography options, including ultrasonography, Various imaging proteinuria No specific conditions Doppler High BP, with or without abdominal renal artery Bruits, especially bruit Early, abrupt-onset hypertension (consider fibromuscular disease) accompanied by proteinuria or other evidence of target organ Rapidly worsening or resistant Family history of early-onset Incidental finding of adrenal Nonspecific fatigue, muscle hypertension in older adults Preeclampsia if high BP is Obstructive sleep apnea resonance imaging; NSAID, nonsteroidal anti-inflammatory drug; PTA, percutaneous transluminal angioplasty. hypertension or stroke cramps, or weakness (consider ASCVD) Hypokalemia adenoma damage High BP from reduced placental perfusion approximate 5%. Usually unilateral disease due to usually disappears after delivery. ASCVD (90%) with >70% arterial About 10% due to fibromuscular disease, typically occurring in Varies depending on whether hypertension seems to result onset or chronic. New-onset peripheral resistance, which and subsequent elevation in middle-aged white women. Rarely due to other causes Benign adrenal adenoma the hypertension is new hyperplasia (60–70%) Occasionally, familial lumen narrowing. (30–40%) secondary hypertension, approximate prevalence BP in ~5% of adults with responsible for the high preeclampsia 3%, and disease Generally reported to of hypertension 10%, eclampsia 0.1–0.3%. common causes of During pregnancy, hypertension. Renovascular Hypertensive disorders of pregnancy

Hypertension

CHAPTER 288 Renal Parenchymal Disease  This is also relatively common and probably accounts for >5% of all non-OSA and medication-related secondary causes of hypertension. It can result from almost any type of underlying kidney disease but is somewhat more common with glomerular than interstitial disorders. Most patients with CKD dis­ ease have hypertension. Importantly, it is often difficult to determine the extent to which a patient’s high BP is the cause or a consequence of their kidney disease. Activation of the RAAS is often a part of the underlying pathophysiology that leads to hypertension. Clinical indicators of hypertension due to renal parenchymal disease include treatment resistance, fatigue, palpation of a renal mass, hematuria, pro­ teinuria, elevated creatinine, or hyperglycemia. Imaging with sonog­ raphy, computed tomography (CT), or magnetic resonance imaging (MRI) can be helpful for the diagnosis of some forms of underlying kidney disease. Renal biopsy is most helpful when glomerulonephritis is suspected. Most patients with CKD have a variety of both conven­ tional and novel risk factors for ASCVD placing them at high risk for CVD complications. Improvement of CVD risk factors, including hypertension, is an essential element of treating patients with CKD. Often, control of hypertension may require use of three or more anti­ hypertensive agents in addition to lifestyle management. Diuretics and RAAS inhibitors such as ACEIs and ARBs are obvious components of the antihypertensive drug treatment regimen. Traditionally, thiazide and thiazide-like diuretics were thought to be relatively ineffective for the management of patients with a serum creatinine >3 mg/dL, but a recent well-conducted trial documented substantial BP and albu­ minuria reduction in patients with advanced CKD who were treated with the long-acting diuretic chlorthalidone. Finerenone, a newer MRA, has also been shown to enhance BP reduction in patients with advanced CKD. Gliflozins or sodium-glucose cotransporter 2 (SGLT2 inhibitors), which are often very useful in the management of patients with CKD, are diuretics and may provide a small reduction in BP. If possible, the underlying kidney disease should be treated with specific therapy. Primary Aldosteronism  A relatively common cause of secondary hypertension, primary aldosteronism may be the underlying cause of high BP in ~5% of adults with non-OSA and medication-related sec­ ondary hypertension. However, the reported prevalence varies widely depending on the criteria for diagnosis and the population studied. Most patients with primary aldosteronism (60–70%) have idiopathic bilateral adrenal hyperplasia but ~30–40% have a benign adenoma, usually unilateral. Often, the clinical presentation is subtle with no more than resistant hypertension or nonspecific symptoms. However, in some patients with more pronounced aldosteronism, unprovoked hypokalemia or hypokalemia-related cardiac arrhythmias, such as atrial fibrillation, may be present. Common screening tests for pri­ mary aldosteronism include abdominal imaging by CT to detect an adenoma and measurement, under standardized conditions, of a high aldosterone/renin ratio in conjunction with high plasma aldosterone levels. Several noninvasive investigations, including the saline suppres­ sion and captopril challenge tests, can provide more definitive evidence of primary aldosteronism, but adrenal vein aldosterone sampling is generally accepted as the gold standard test for diagnosis. The most important goal is to recognize the minority of patients with a benign unilateral adenoma whose hypertension can be cured or substantially improved by adrenalectomy. The latter can be accomplished by mini­ mally invasive laparoscopy or by use of traditional surgical techniques. Medical management of hypertension in patients with aldosteronism should include the use of MRA agents. In most patients, spirono­ lactone is well tolerated but occasionally adverse effects, including hyperkalemia, breast tenderness, or gynecomastia in men, require the substitution of newer, more expensive, alternative MRAs. The screen­ ing tests and especially the more definitive diagnostic tests for primary aldosteronism require careful attention to detail and are generally best conducted by those who have specialized experience in the evaluation of patients who may have primary aldosteronism. Likewise, most adre­ nal adenomas are very small, and removal by laparoscopy or surgery is most successful when performed by an experienced treatment team. Rarely, primary aldosteronism can be caused by an adrenal carcinoma, ectopic malignancy, or rare genetic disorders. Renovascular Hypertension  Renovascular obstructions that result in substantial and hemodynamically important occlusion of the renal artery can result in hypertension and impaired renal function. Renovascular disease is found in as many as 25% of patients at autopsy, but renovascular hypertension only accounts for ~1% of the high BP in all patients with hypertension. In ~90% of patients with renovascular hypertension, renal artery obstruction is caused by atherosclerosis. Commonly, atherosclerotic renovascular disease is unilateral and the principal obstruction tends to present as a discrete lesion found close to the origin of the renal artery. Patients with atherosclerotic renovascular disease tend to be older and have other indications of ASCVD, including an abnormal risk factor profile and atherothrom­ botic lesions in other vascular beds. At times, a bruit can be heard over the renal artery or over the carotid or femoral arteries. A minority of patients with renovascular disease have fibromuscular disease. They tend to be younger, mostly white, women. Their renal artery lesions are more diffuse, with an irregular sawtooth appearance, and they are frequently located in more distal parts of the renal artery compared with atherosclerotic lesions. In addition, bilateral real artery disease is more common in patients with fibromuscular disease than is the case for renovascular disease due to ASCVD. Fibromuscular disease should be suspected in any patient with abrupt-onset hypertension, especially in young white women, and in those with resistant hypertension, or recent worsening of hypertension. Underlying atherosclerosis should be suspected in older patients with other indications of ASCVD and in those with otherwise unexplained worsening of kidney function. The threshold for additional diagnostic investigations should be lower when fibromuscular disease is suspected. A variety of screening tests, including renal ultrasound studies, CT and magnetic resonance angiography imaging studies, renograms, and standardized measurement of plasma renin activity, can be used to exclude other causes of hypertension and to screen for evidence of renovascular disease. Renal angiography provides more definitive evidence of the extent and type of renovascular disease and is cur­ rently considered to be the gold standard diagnostic test. Skilled inter­ ventional radiologists can employ digital subtraction angiography to generate high-quality studies with less contrast exposure compared to standard angiography. Hypertension due to renovascular disease is more likely in patients with lesions that occlude >70% of the ves­ sel lumen. For many years, renal venous renin sampling was a gold standard diagnostic test but is now rarely performed due to a high frequency of false-positive and false-negative results. In many patients with hypertension due to fibromuscular disease, percutaneous transluminal angioplasty results in a cure for their hyper­ tension or substantially improves the control of their high BP. For this reason, the most important goal in evaluating patients with suspected renovascular hypertension is to recognize individuals with underlying fibromuscular disease. As is the case for some other forms of second­ ary hypertension, screening, diagnosis, and treatment results tend to be better when conducted by teams with experience in caring for patients with renovascular disease. Several well-conducted random­ ized controlled trials, with relatively large sample sizes, have failed to demonstrate any special benefit for BP control or renal preservation following percutaneous transluminal angioplasty or renovascular sur­ gery compared to medical care in patients with atherosclerotic reno­ vascular hypertension. Most patients with suspected atherosclerotic renovascular hypertension should be managed using a combination of nonpharmacologic and antihypertensive drug therapy, including the use of agents that block the RAAS. In rare instances, arteritis and other inflammatory disease can be the underlying cause of renovascular hypertension. The underlying cause should be treated in addition to medical management of hypertension. Hypertensive Disorders of Pregnancy  Hypertension occurs in >10% of pregnancies in the United States and about 3–5% are complicated by preeclampsia, in which hypertension is accompanied by proteinuria or other evidence of target organ damage. The HELLP

syndrome, in which hypertension is accompanied by hemolysis, elevated liver enzymes, and low platelets, represents a more severe form of preeclampsia. Progression to eclampsia, with seizures as the cardinal feature, occurs in <1% of women with mild and about 3% of those with severe preeclampsia. Hypertension during pregnancy is associated with a higher rate of fetal complications and of hyperten­ sion and CVD complications for the mother later in life. Hypertensive disorders of pregnancy include the following: (1) chronic hypertension, in which the high BP proceeds pregnancy; (2) gestational hyperten­ sion, in which new-onset hypertension is recognized after 20 weeks of gestation; (3) preeclampsia potentially culminating in eclampsia; and (4) chronic hypertension with superimposed preeclampsia. Manage­ ment of hypertension in pregnancy often includes bed rest, nonphar­ macological interventions, and pharmacotherapy. Clinical trials and meta-analyses provide strong evidence that antihypertensive therapy during pregnancy reduces the risk of progression to more severe hypertension, compared to placebo, but less convincing evidence for prevention of preeclampsia and other fetal complications. ACEI and ARB therapy should be avoided due to the potential for teratogenic side effects. Few high-quality studies have compared the benefits and risks of treatment with other commonly used antihypertensive drugs during pregnancy. Usually, treatment with the beta blocker labetalol, the CCB nifedipine, or the centrally acting α2-adrenergic agonist methyldopa is recommended as providing safe first-line antihypertensive drug therapy, with one trial suggesting that labetalol and nifedipine may be superior to methyldopa for prevention of preeclampsia. A review of prescribing habits in the United States identified labetalol, nifedipine, and the direct vasodilator hydralazine as the three most commonly used antihypertensive agents during pregnancy. Clinical trials have failed to demonstrate a benefit for more intensive therapy to a SBP/ DBP <130/80 mmHg compared to <140/90 mmHg.

PART 6 Disorders of the Cardiovascular System Less Common Causes of Secondary Hypertension  There are many other secondary causes of hypertension, but they tend to be infrequent and are generally best considered when patients are referred to consultants with expertise in recognizing rare causes of second­ ary hypertension. These include Cushing’s syndrome in which large amounts of cortisol are produced in response to excessive levels of adrenocorticotropic hormone (ACTH) produced by a pituitary gland adenoma or ectopic ACTH-producing tumor, an adrenal adenoma, or treatment with glucocorticoids. Clinical signs of note include weight gain in the face (moon face) and trunk, a fatty lump between the shoulders (buffalo hump), thin arms and legs, pink or purple stretch marks on the stomach, hips, thighs, breasts, and underarms, easy bruising, slow healing, and acne. Screening and diagnosis are usually based on an assessment of 24-h urinary corticosteroid levels, imag­ ing tests, and an overnight dexamethasone-suppression test. More than 75% of patients with Cushing’s syndrome have hypertension. Treatment depends on the underlying cause of the syndrome. Pheo­ chromocytoma is another rare form of secondary hypertension and is caused by excessive production of catecholamines, usually due to a benign neuroendocrine tumor composed of chromaffin cells located in the adrenal medulla (80–85%) or in extra-adrenal paraganglion tis­ sue (paraganglioma). Most patients with pheochromocytoma present with hypertension at a relatively young age (often 30–50 years). Many have nonspecific signs and symptoms, but some have paroxysmal attacks characterized by high BP, sweating, headaches, and cardiac arrhythmias. Screening and diagnosis are usually based on blood and 24-h urinary catecholamine values and abdominal CT, MRI, or positron emission tomography imaging studies. Typically, pheochro­ mocytomas are treated by complete or partial adrenalectomy using minimally invasive surgical techniques. A small minority of patients with pheochromocytoma have an inherited genetic predisposition such as multiple endocrine neoplasia type 2 (MEN 2), von Hippel-Landau disease, neurofibromatosis, and hereditary paraganglioma syndromes. Coarctation of the aorta is the most common congenital cause of hypertension and results from a birth defect in which a portion of the aorta is narrower than usual. When the defect is severe, the coarctation is likely to be detected early in life and may be associated with other

congenital abnormalities. When the defect is mild, the disorder may not be recognized until early adulthood. The classical physical exami­ nation findings are delayed and diminished femoral and distal pulses. A systolic mummer may be heard in the posterior intrascapular area, and signs of left ventricular hypertrophy may be detected. Screening and diagnostic tests include imaging studies such as echocardiography, CT, and angiography. Treatment options include balloon angioplasty, surgery, and medical management. Other rare causes of hypertension include hyper- and hypothyroidism, acromegaly, and hypercalcemia. PREVENTION AND TREATMENT OF PRIMARY HYPERTENSION Both nonpharmacologic interventions, mostly lifestyle improvements, and antihypertensive medication play a role in the management of high BP. The overall approach to prevention and treatment of hypertension, which is depicted in Fig. 288-3, is to encourage a healthy lifestyle in adults with a normal BP (SBP/DBP <120/80 mmHg) and actively advise nonpharmacologic therapy in adults with an elevated BP (SBP 120–129 mmHg and DBP <80 mmHg). Adults with stage 2 hyperten­ sion (SBP ≥140 mmHg or DBP ≥90 mmHg) should be treated with a combination of nonpharmacologic and antihypertensive drug therapy. Most adults with stage 1 hypertension (SBP 130–139 mmHg or DBP 80–89 mmHg) should be managed by active application of nonphar­ macologic interventions, but in the minority (~30% in the United States) who have a history of CVD or are at high risk for ASCVD, anti­ hypertensive medication should be added to the nondrug approaches to lower BP. In RCTs, low-dose pharmacotherapy has been effective for BP lowering, prevention of hypertension, regression of left ventricular mass, and prevention of left ventricular hypertrophy in nonhyper­ tensive patients. However, drug therapy is not recommended for this purpose in any major clinical practice guideline. The next two sections provide a more detailed guide to the selection and application of non­ pharmacologic and antihypertensive drug treatments. ■ ■NONPHARMACOLOGICAL INTERVENTIONS TO PREVENT AND TREAT HYPERTENSION Many nondrug interventions have been reported to lower BP. Most of them are based on changing personal exposures associated with higher BP. The best proven approaches to nonpharmacologic lowering of BP are displayed in Table 288-2. Generally, the nonpharmacologic interventions used in clinical practice settings require a change in behavior. However, pill supple­ mentation to enhance potassium intake, renal denervation therapy in selected patients with resistant hypertension, and baroreceptor activa­ tion therapy are examples of nonpharmacologic treatments that are not primarily based on achieving behavior change. For the nonphar­ macologic interventions based on behavior modification, the difficulty of achieving the desired changes varies by intervention and patient, but generally, behavior change can be hard to achieve and maintain over long periods of time. Behavior change interventions are most suc­ cessful when patients accept the need for change, pledge to embrace the behavioral changes that are necessary, and can be counseled by a member of the health care team who is knowledgeable in the tech­ niques for behavior change. For weight loss, abstinence from alcohol, physical activity, and high-quality counseling programs that are avail­ able in convenient locations close to a patient’s home or workplace may provide an alternative option to office/clinic-based counseling. Behavior change can be successful in any patient but is especially likely in those with or at high risk for CVD and in patients who have the time, resources, and desire to concentrate on improving their health behav­ iors. Not surprisingly, older adults and those with higher socioeco­ nomic status (SES) tend to be more successful than their younger and lower SES counterparts. The following are brief summaries of specific aspects of the six interventions identified in Table 288-2. Diet Quality  Heart healthy diets tend to lower BP and improve other diet-related CVD risk factors, such as low-density lipoprotein cholesterol and blood glucose. For example, a reduction in BP has

Recommendations for management by category of blood pressure SBP/DBP <120/80 mmHg (Normal BP) SBP 120–129/DBP <80 mmHg (Elevated BP) SBP 130–139 or DBP 80–89 mmHg (Stage 1 Hypertension) Not at high risk No prior CVD, or No CVD and not at high risk

CHAPTER 288 SBP ≥140 or DBP ≥90 mmHg (Stage 2 Hypertension) Assess patient’s overall risk of ASCVD Hypertension At high risk for ASCVD Prior CVD, or No CVD but high risk of CVD

the corresponding decreases in BP. This finding was quite robust, being noted for every subgroup studied. An SBP/DBP difference of ~15/10 mmHg was noted between those with the highest (~7000 mg/d) and lowest (<1000 mg/d) intakes of sodium. An average reduction of ~5.5 mmHg was noted for every 2300-mg (100-mmol) decrement in dietary sodium intake. As expected, the effect was greater in adults with compared to those without hypertension and in SBP compared with DBP. The results were consistent with a “lower is better than higher” conclusion for intake of dietary sodium. In healthy U.S. adults, consumption of a diet with 1500 mg sodium provides adequate opportunity to meet the other recommended dietary requirements. Recommendations for daily sodium intake in adults vary considerably. The U.S. federal Dietary Guidelines for Americans recommends a daily sodium intake <2300 mg, whereas the World Health Organization recommends <2000 mg and others recommend much lower intakes. More than 95% of U.S. adults exceed the 2000 mg/d threshold, and almost 100% exceed the 1500 mg/d threshold. However, any reduction in dietary sodium intake is likely to be beneficial.

PART 6 Disorders of the Cardiovascular System The traditional approach to reducing dietary sodium intake in clini­ cal settings is by means of behavior change interventions. In addition to helping patients estimate and track their sodium intake, trying to avoid high-sodium foods and maximizing home preparations using fresh, natural foods are desirable. In countries like the United States, where most of the population consume commercial food products, >80% of an individual’s sodium intake is generally due to sodium added during food processing or commercial preparation of foods and only ~10% is due to naturally occurring sources of sodium. Careful scrutiny of food labels for packaged foods while shopping, reducing meal portion size, choosing condiments and seasonings with low sodium content, salt substitution using herbs and spices, and use of salt substitutes that replace ~25% of the sodium content with potassium are other well-proven strategies to reduce dietary sodium intake. Salt substitutes provide a relatively easy and well-accepted way to achieve a mod­ est reduction in sodium intake and an increase in potassium intake, especially in those who primarily eat foods prepared in the home and/ or add a lot of salt at the table. A large cluster-designed clinical trial conducted in Chinese adults with stroke or at high risk for stroke dem­ onstrated an impressive and statistically significant 14% reduction in stroke (the primary outcome), other major CVD events, and all-cause mortality in adults randomized to use a salt with 25% substitution of potassium for sodium compared to those who used regular salt. There was no evidence of a difference in hyperkalemic events in the two treat­ ment groups. Public health messaging based on simple educational and action recommendations is also useful. Policy aimed at reducing the amount of sodium added to foods has great potential but has been difficult to implement in the United States. Long-term follow-up for 10–15 years in participants who had been randomized to a behavioral change sodium reduction intervention or usual care has also suggested a significant reduction of 30% in new-onset CVD events. Potassium Supplementation  A higher intake of potassium is associated with a lower BP and a reduced risk of CVD, especially stroke. U.S. Dietary Reference Intake committees have not made a dietary allowance intake recommendation due to insufficient evidence but have identified 2600 and 3400 mg/d in women and men, respec­ tively, as adequate intake levels. Individual RCTs and meta-analyses provide strong evidence that potassium supplementation reduces BP. This has been achieved with pill therapy and dietary supplementation, with the latter being the preferred approach in clinical practice because this usually results in consumption of a more heart-healthy diet and a lower intake of dietary sodium. In most RCTs, routine potassium intake has been supplemented by about 2300 mg (60 mmol) per day, and the average reduction in SBP has been ~5 mmHg in trials with a successful intervention (net change in urinary potassium ≥20 mmol [870 mg] per day). As expected, the SBP reduction is greater in adults with (~5 mmHg) than without hypertension (~2 mmHg) trials. The SBP lowering is almost three times greater in black compared with white adults. Finally, there is a strong linear association between BP reduction with potassium supplementation and consumption of

dietary sodium, possibly reflecting the well-known natriuretic effects of potassium. A dose-response meta-analysis has suggested a U-shaped BP response to potassium intake, with an optimal supplemental intake of ~1200 mg/d. However, the unexpected BP response findings at the upper and lower end of the U-shaped curve were based on indirect estimates and a relatively small number of trials. Many foods contain potassium, but fruits, vegetables, legumes, and leafy greens are especially high in potassium content. By design, the DASH diet targets provision of 4700 mg of potassium per day, exceed­ ing the recommended intake of 3500 mg/d in U.S. adults. Potassium supplementation is contraindicated in patients with hyperkalemia or advanced kidney disease and in those taking pills that can block the urinary excretion of potassium, including potassium-sparing diuretics, inhibitors of the RAAS, and MRA agents, such as aldosterone, eplere­ none, and finerenone. Physical Activity  Observational studies identify a strong inverse association between physical activity (leisure time or total) and BP as well as CVD. In like manner, high-quality RCTs have demonstrated that increased physical activity lowers BP in adults with and without hypertension. Most of the trials have been based on aerobic exercise interventions such as brisk walking, swimming, or dancing. Metaanalyses of aerobic exercise RCTs have been consistent in document­ ing substantial BP-lowering efficacy, but the quantitative estimates for average reduction in BP have varied considerably, with reports of 5–10 mmHg for SBP in studies restricted to adults with hypertension and 3–5 mmHg for studies in those without hypertension. Dynamic resistance exercises such as climbing stairs, push-ups, weightlifting, and squats have also been shown to lower BP and are often employed concurrently with aerobic exercise. Isometric resistance exercises, during which muscles or muscle groups are tightened without any visible movement of the surrounding joints, include yoga poses, wall sit, plank, and bench press exercises. Fewer high-quality RCTs have assessed the efficacy of isometric resistance exercise, but individual trials and meta-analyses indicate this approach is effective for BP lowering. In the largest meta-analysis (~400 trials) of physical activity, aerobic exercise reduced SBP by ~5 mmHg in adults with hypertension and when combined with dynamic resistance exercise by ~6.5 mmHg. In trials that allowed for a direct comparison with antihypertensive drug therapy, physical activity yielded an almost identical level of BP lowering. Most guidelines recommend moderate-intensity aerobic exercise as the principal approach to lowering BP but acknowledge that dynamic and isometric resistance exercises are a useful comple­ ment. Based on clinical trial evidence, an aerobic exercise duration of 40–60 min three or more times per week for a total ≥150 min per week may be optimal. Although more intensive physical activity may be ideal for overall cardiac fitness, less intensive physical activity is sufficient for BP reduction. Less frequent but more intensive physical activity (e.g., “weekend warrior” exercise) has been shown to lower BP. Alcohol Consumption  Alcohol has long been known to be a pres­ sor. Observational dose-response meta-analyses demonstrate a roughly linear association between alcohol consumption and both BP and hypertension, with no threshold for the association. For each 14-mg increased intake of alcohol (amount in a U.S. standard alcoholic drink), SBP is ~1.5 mmHg higher. RCTs have studied the efficacy of reducing alcohol intake on BP by substitution of lower-alcohol or no-alcohol drinks, use of behavior change interventions, or abstinence without access to alcohol. The overall effect of alcohol reduction on SBP in the largest meta-analysis was a reduction of ~5.5 mmHg. However, the magnitude of the effect is greatly influenced by baseline level of BP and alcohol intake and by the success of the intervention. Most current U.S. guidelines recommend an alcohol intake goal of ≤2 and ≤1 standard drinks per day for men and women, respectively. In part, this reflects the possibility that a modest intake of alcohol may favorably influence other CVD risk factors, such as high-density lipoprotein cholesterol. The WHO recommends abstinence from alcohol. Summary for Nonpharmacologic Interventions to Lower BP  In summary, a strong body of evidence supports the value of

interventions based on the six exposures highlighted in Table 288-2. In general, the interventions exhibit a linear-type dose-response for BP reduction. Consequently, more successful interventions result in greater BP reduction, and even smaller than desired changes in the exposure are likely to be beneficial. In addition, greater BP lowering can be expected in adults with compared to adults without hyperten­ sion, in those who start with more abnormality in the exposure, and when two or more interventions are combined. For example, a greater reduction in BP can be expected when the intervention combines the DASH diet with weight loss or sodium reduction. However, the behav­ ioral changes needed for combination interventions are typically more challenging and require a greater commitment by the therapist and patient. Finally, nonpharmacologic interventions often enhance the effect of antihypertensive medications. This has been especially well demonstrated for reductions in sodium intake. A practical approach is to focus initially on the behavior that is most abnormal and most amenable to change, with a longer-term goal of more comprehensive improvements. With the exception of salt substitution, change in BP has been the primary outcome in most of the nonpharmacologic treat­ ment trials, but some have demonstrated improvements in intermedi­ ate CVD outcomes, especially left ventricular mass and left ventricular hypertrophy. In addition, randomized comparisons following long periods of posttrial follow-up have suggested CVD benefits for both sodium reduction and weight loss. ■ ■PHARMACOLOGIC THERAPY TO PREVENT CARDIOVASCULAR DISEASE Efficacy of Pharmacologic Therapy in Uncomplicated Primary Hypertension  In most adults, primary hypertension is uncomplicated and relatively easy to manage. The introduction of diuretics in the late 1950s and early 1960s revolutionized pharmaco­ therapy of high BP, and these drugs were the principal agents in the early antihypertensive drug treatment trials. The first antihypertensive drug RCT reported a substantial benefit of active therapy compared to placebo in 1966, but it was quickly superseded by two larger placebocontrolled multicenter Veterans Administration Cooperative Group RCT analyses. The first analysis was for adults with an average DBP between 115 and 129 mmHg, and this component was stopped early due to benefit and published in 1967. The second analysis, for adults with an average DBP between 90 and 114 mmHg, was published in 1970. Both analyses demonstrated that antihypertensive drug therapy resulted in a dramatic CVD benefit compared to placebo. Subsequent trials confirmed these findings and documented benefits when SBP reductions were targeted, either in combination with an elevated DBP or as an isolated elevation of SBP in older adults. In a group metaanalysis of 123 trials, active treatment resulted in a reduction of major CVD (20%), CHD (17%), stroke (27%), HF (28%), and all-cause mor­ tality (13%). In this and other meta-analyses, the relative reduction in risk has been almost identical for those with or without prior CVD, albeit only adults at high risk for CVD could participate in the included trials, and benefit has accrued to those with a baseline SBP from 130 to 139 mmHg and above. Choice of Antihypertensive Drug Classes  Characteristics of the 11 most commonly used classes of antihypertensive medication, including examples, usual daily dosage, frequency of administration, proposed mechanism of action, approximate BP lowering compared to placebo, most common side effects, frequency of adverse events, and special aspects of the drug class are shown in Table 288-4. Initial therapy with agents from five classes of drug therapy (diuretics, beta blockers, CCB, ACEI, and ARB) has been shown to prevent CVD compared to placebo. However, in head-to-head RCTs, beta blockers have been inferior to agents from the other four antihypertensive drug classes, especially for prevention of stroke. CCBs are good for preven­ tion of stroke but inferior for prevention of HF, especially compared to diuretics. Generally, meta-analyses have identified diuretics as being the “best in class” for first-step prevention of CVD. Recognizing these differences in antihypertensive drug classes, RCTs and meta-analyses also provide evidence that BP lowering, however achieved, is more

important than the drugs used to achieve it. Most clinical practice guidelines, including the U.S. ACC/AHA BP guideline, recommend an approach similar to that outlined in Fig. 288-4 in which diuretics, CCBs, and ACEIs or ARBs, alone or in combination, are used for initial drug therapy in patients without a compelling indication for use of a beta blocker.

CHAPTER 288 One or more nonpharmacologic therapies should be used to man­ age adults with stage 1 hypertension who are not at high risk for CVD (no CVD and a calculated 10-year risk of ASCVD <10% based on use of the ACC/AHA pooled cohort equations calculator). If BP cannot be controlled to an SBP/DBP <130/80 mmHg after 6 months of nonphar­ macologic therapy, it may be reasonable to add an antihypertensive medication, especially in younger adults with a high lifetime risk of ASCVD. The latter can be estimated using a calculator that is readily available on the ACC website and elsewhere. Antihypertensive drug therapy should be used in addition to nonpharmacologic therapy in adults with stage 1 hypertension who are at high risk for ASCVD and for all individuals with stage 2 hypertension. A minority of such persons with an average SBP/DBP close to 130/80 mmHg can be man­ aged successfully with single antihypertensive agent combined with nonpharmacologic therapy. However, most patients with hypertension require treatment with more than one antihypertensive agent. This is especially the case for adults with stage 2 hypertension with an SBP ≥140 mmHg and all non-Hispanic black adults with hypertension. Hypertension In clinical practice settings, it is common for patients with hyperten­ sion to have other comorbid conditions, including diabetes mellitus, CHD, and CKD, requiring use of agents from other drug classes that concurrently lower BP. Longer-acting versions of the recommended four first-step drug classes should be used to ensure the adequacy of once-daily treatment. For example, longer-acting diuretics such as chlorthalidone or indapamide are preferred over shorter acting agents such as hydrochlorothiazide because the long half-life of these agents is better suited for the provision of nighttime as well as daytime control of BP and because chlorthalidone has been used in almost all of the land­ mark U.S. trials of antihypertensive drug treatment. The most common side effects with thiazide and thiazide-like diuretics are biochemical changes, such as hypokalemia and slight increases in blood glucose. Potassium-sparing agents, such as amiloride or triamterene, can be combined with diuretics to counter these effects. The biochemical changes with diuretics are generally mild and do not counteract their well-proven CVD benefits. Although there are differences between individual ACEI agents, their clinical effects are more similar than dif­ ferent. Use of longer-acting agents such as lisinopril is preferred. The most common problematic side effect with ACEIs is a dry cough. This side effect is usually resolved quickly by switching to a corresponding dosage of an ARB. Side effects with ARBs are rare. ACEIs and ARBs should not be used in combination because this unnecessarily increases the risk of hyperkalemia, especially in vulnerable patients and provides little if any additional benefit over using either drug class on its own. Neither an ACEI nor an ARB should be used in pregnancy or planned pregnancy due to the risk of teratogenic side effects in the fetus. In contrast to the other antihypertensive drug classes, there are substantial clinical differences between dihydropyridine and nondihydropyridine CCB agents, with the former being primarily vasoactive and the latter having greater effect on the heart. Typically, dihydropyridine CCBs should be used in the treatment of hypertension. Peripheral edema occurs in ~10% of patients taking dihydropyridine CCBs but is often mild and can be minimized by dose reduction or eliminated by switch­ ing to an agent from another class. Nondihydropyridine CCBs should rarely be employed to treat hypertension unless there is another compelling indication for their use. Particular caution is necessary in patients at risk for bradycardia, heart block, or HF. The earliest beta blocker drugs were relatively nonselective block­ ers of β-adrenergic receptors, including the heart (β1 receptors) and lungs (β2 receptors). They are rarely prescribed for hypertension due to the potential for bronchospasm. The second class of beta blocker agents, including metoprolol, contain more cardioselective and longeracting drugs. Although cardioselective, atenolol is not recommended because several meta-analyses have reported that it has been less

TABLE 288-4  Summary Information for the Major Antihypertensive Drug Classes Used to Manage High Blood Pressure DOSE RANGE, mg DOSE FREQUENCY/D METHOD OF ACTION CLASS EXAMPLES PART 6 Disorders of the Cardiovascular System First-Step Drugs Diuretics (thiazide and thiazide-like). Chlorthalidone Hydrochlorothiazide Indapamide 12.5–25 12.5–50 1.25–2.5

Block sodium reabsorption in distal convoluted tubule ACE inhibitors Enalapril Lisinopril Benazepril Ramipril Trandolapril 5–40 10–40 10–40 2.5–20 1–4 1 or 2

1 or 2

Inhibit ACE activity and Ang II production ARB Losartan Valsartan Azilsartan Candesartan Olmesartan 50–100 80–320 40–80 8–32 20–40 1 or 2

Block Ang II binding to Ang receptors CCB (DHP) Amlodipine Felodipine Nifedipine LA 2.5–10 2.5–10 30–90

Blocks calcium from entering cells, primarily inhibiting vasoconstriction CCB (non-DHP) Diltiazem ER Verapamil ER 120–360 100–300

(evening administration recommended) Blocks calcium from entering cells, reducing heart rate and vasoconstriction Other Drugs β-Blocker Metoprolol Carvedilol Nebivolol 50–200 20–80 5–40

Block β-adrenergic receptors MRA Spironolactone Eplerenone Finerenone 25–100 50–100 10–20

Block distal tubule mineralocorticoid receptor activity K+-sparing diuretics Amiloride Triamterene 5–10 50–100 1 or 2 1 or 2 Block distal tubule sodium reabsorption

SBP REDUCTION VERSUS PLACEBO, mmHg (APPROXIMATE) MOST COMMON ADVERSE EFFECTS FREQUENCY OF ADVERSE EVENTS COMMENTS

Hyponatremia Hypokalemia Hypercalcemia Hyperuricemia Hyperglycemia Dyslipidemia Similar to placebo Chlorthalidone preferred due to long half-life and use in most U.S. trials 12.0 Cough Hyperkalemia in CKD AKF in severe bilateral RAS Hypotension Angioedema Similar to placebo Do not use in combination with ARB; contraindicated in pregnancy

Hyperkalemia in CKD Reduced GFR AKF in severe bilateral RAS Hypotension Similar to placebo Do not use in combination with ACE inhibitor; contraindicated in pregnancy

Peripheral edema (dose-dependent) Gingival hyperplasia Similar to placebo Amlodipine may be preferred CCB if tolerated Not recommended in HFrEF 9.0 Bradycardia Nausea Constipation. Similar to placebo Do not use in combination with β-blockers Do not use in HFrEF or in highgrade AV or SA block

Asthma Bradycardia Fatigue Exercise intolerance Impaired concentration Similar to placebo First-step drugs when clinically indicated, e.g., in IHD and HF Contraindicated in high-grade heart block

Hyperkalemia, especially in CKD and with potassiumsparing agents Spironolactone may cause tender breasts, gynecomastia, and erectile dysfunction in men 9–20% Especially useful in resistant hypertension and low-renin states NA Hyperkalemia, especially in CKD or with other agents that favor potassium retention Similar to placebo Minimal effect on BP Used to counteract hypokalemic effect of diuretics (Continued)

TABLE 288-4  Summary Information for the Major Antihypertensive Drug Classes Used to Manage High Blood Pressure DOSE RANGE, mg DOSE FREQUENCY/D METHOD OF ACTION CLASS EXAMPLES Loop diuretics Furosemide Torsemide 20–80 5–10

Inhibits reabsorption of sodium in loop of Henle Doxazosin 1–16

Inhibit α1-adrenergic receptors α1-Receptor blockers Direct vasodilator Hydralazine Minoxidil 100–200 5–100 2 or 3 1–3 Dilate peripheral arterioles Central α2-agonist and other centrally acting drugs Clonidine (oral) Clonidine patch Guanfacine Methyldopa 0.1–0.8 0.1–0.3 0.5–2.0 250–1000

1/wk

2–3 Stimulate central nervous system α2adrenergic receptors Note: Adverse event estimates based on U.S. Food and Drug Administration labeling at http://dailymed.nlm.nih.gov/dailymed/index.cfm. Estimates of BP lowering versus placebo are “artificially” higher with older agents than with newer agents because the former were compared to placebo alone, whereas the latter were evaluated in patients who were already being treated with other antihypertensive medications. Abbreviations: ACE, angiotensin-converting enzyme; AKF, acute kidney failure; Ang II, angiotensin II; ARB, angiotensin receptor blocker; AV, atrioventricular; BP, blood pressure; CCB, calcium channel blocker; CKD, chronic kidney disease; DHP, dihydropyridine; ER, extended release; GFR, glomerular filtration; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; IHD, ischemic heart disease; LA, long acting; MRA, mineralocorticoid receptor antagonist; NA, not applicable; RAS, renal artery stenosis; SA, sinoatrial. cardioprotective than other drug classes, including diuretics, when used for treatment of hypertension. The third-generation beta blocker drugs are cardioselective and have additional vasodilatory properties (nebivolol), used alone or in combination with α-receptor blockade (carvedilol). No RCT has documented improved CVD event protection with use of the newer agents. The remaining agents in Table 288-4 are covered in other sections of this chapter. It has become increasingly clear that starting with lower doses of a two-drug combination provides superior BP control and results in fewer side effects compared to use of a single drug at a high dose. Initial therapy is especially important because surveys of clinical practice have repeatedly demonstrated that the initial drug choice is often materially unaltered due to therapeutic inertia despite unsatisfactory BP control. RCTs using stepped-care drug therapy, in which antihypertensive medications are added sequentially if BP control has not been achieved at full doses of the proceeding drugs, demonstrate that this approach can be successful if well applied. However, initial combination drug therapy has proven to be more effective for rapid achievement of target BP and medication adherence compared to the stepped-care approach.

(Continued) SBP REDUCTION VERSUS PLACEBO, mmHg (APPROXIMATE) MOST COMMON ADVERSE EFFECTS FREQUENCY OF ADVERSE EVENTS COMMENTS CHAPTER 288 NA Hypokalemia Volume depletion Hyperuricemia Infrequent Preferred in CKD with GFR <30, in symptomatic HF, and when using potent direct vasodilator minoxidil Hypertension

Orthostatic hypotension, especially in older adults 9% Less cardioprotective than diuretics Mostly used in men with prostrate hypertrophy NA Reflex tachycardia Fluid retention Hydralazineinduced lupus syndrome (rare) Minoxidil-induced hirsutism in women Up to 80% Potent antihypertensive agents Usually reserved for fourth- or fifthstep treatment in resistant hypertension Usually combined with diuretic (loop agents for minoxidil) and β-blocker to minimize side effects NA Sedation Dry mouth Bradycardia Fatigue Constipation Orthostatic hypotension. 6–20% Infrequently used due to side effects and potential for hypertensive crisis following abrupt withdrawal Methyldopa has a good safety record in pregnancy Antihypertensive drug combinations should be based on use of drugs with complementary physiologic actions. For example, a diuretic or CCB combined with an ACEI or ARB is suitable for dual therapy and a diuretic combined with a CCB and an ACEI or ARB for tripletherapy combinations. Use of single-pill combinations results in better adherence compared to treatment with multiple drugs. In RCTs, the average number of drugs to achieve an SBP/DBP <140/90 mmHg has been two and to achieve an SBP/DBP <130/80 mmHg has been three. Antihypertensive Treatment Blood Pressure Target  Many clinical trials have reported better prevention of CVD in groups ran­ domized to lower compared with higher achieved treatment BPs. Metaanalyses of RCTs to compare different achieved BPs have typically pooled the experience in trials that compared active versus placebo treatments, more versus less intensive treatments, and groups random­ ized to different BP targets. Most of these meta-analyses have reported greater benefit for a lower versus higher achieved BP, with the ben­ efit being greatest for those who start at a higher BP and achieve a greater reduction in BP that their counterparts who achieve the

Nonpharmacologic therapy (only)

Initial combination drug therapy in most patients, especially in black adults and those with an average SBP >20 mmHg above treatment goal

Confirm resistant hypertension diagnosis

CHAPTER 288 Exclude Hypertension Management useful in patients with kidney disease because they are usually taking a large number of medications. Electrolyte levels should be monitored carefully, especially serum potassium levels, in kidney disease patients who are treated with potassium-sparing agents, including ACEI, ARB, and MRA drugs. Dual therapy with an ACEI, ARB, or ACEI-ARB com­ bination is dangerous because of the risk of hyperkalemia and decline in kidney function. PATIENTS WITH DIABETES MELLITUS  The combination of hyperten­ sion and diabetes is common, resulting in a substantial risk for CVD and kidney disease. In patients with longstanding severe diabetes mel­ litus, autonomic neuropathy or volume depletion can cause orthostatic hypotension (10 mmHg difference in SBP between sitting and upright pressures), making management of hypertension difficult and requir­ ing careful monitoring. Symptomatic hypotension (syncope) is a more important finding and may require a stepdown in antihypertensive therapy. Numerous RCTs in adults with diabetes have demonstrated that antihypertensive drug therapy reduces the risk of ASCVD, HF, and microvascular complications. The recommended antihypertensive treatment target is an SBP/DBP <130/90 mmHg. Almost all patients with hypertension and diabetes mellitus require antihypertensive com­ bination therapy, with many requiring three or four agents to achieve satisfactory BP control. Inclusion of an ACEI or ARB in the combina­ tion is recommended, especially in those with heavy proteinuria or kidney insufficiency. In addition, most patients require a diuretic. CCBs are commonly part of the antihypertensive drug regimen as well. In patients with diabetes mellitus and resistant hypertension, the addi­ tion of an MRA has been effective; however, serum potassium should be monitored carefully. Many drugs used to treat diabetes mellitus affect BP. Perhaps the best documented are SGLT2 inhibitors, which in meta-analyses result in an SBP/DBP reduction of ~5/2 mmHg, a mod­ est reduction that does not meet the FDA requirement for classification as an antihypertensive agent. Given that patients with diabetes mellitus are often taking many medications, use of single-pill dual- or triplecombination therapy is especially useful. OLDER ADULTS  Vascular stiffening increases with aging, and as a result, isolated elevation of SBP and a wide pulse pressure are common

in older adults. Comorbidity is common, resulting in the potential for a compelling nonhypertensive indications for use of BP-lowering agents. Drug-drug interactions and delayed drug excretion due to kidney or liver disease are also possible. Despite these challenges, most older adults with hypertension can be treated in a manner similar to younger patients. Indeed, the RCT evidence for antihypertensive drug therapy generally comes from studies in which the average age was close to 70 years at baseline. Older adults tend to be at high risk for CVD and all-cause mortality and have a disproportionately large treatmentrelated reduction in the absolute CVD and all-cause mortality ben­ efit. A natural concern in treating hypertension in older adults is the potential for excessive BP reduction resulting in syncope and resultant falls, or organ hypoperfusion with resultant infarction, especially in the distribution of the coronary arteries. Thus far, RCTs of antihyper­ tensive drug treatment in older adults have been reassuring, resulting in substantial prevention of CVD and all-cause mortality with limited evidence of adverse events. An increased incidence of hypotension has been noted in some but not all trials of antihypertensive treatment in older adults. However, there has been no evidence of a resultant increase in syncope, falls, or infarctions in the RCTs. Nonrandomized analyses of data sets have identified a J-shaped association between BP and CVD risk. However, J-curves are common in observational epidemiology, and randomized comparisons, which are more helpful in guiding treatment decisions, have revealed prevention of CVD and all-cause mortality in those randomized to more versus less intensive antihypertensive therapy at any point in the J-curve. A reasonable approach is to initiate or enhance existing treatment using lower doses of medications than in younger patients. Because congestive heart failure becomes increasingly common at older age, use of a diuretic rather than a CCB for dual-therapy combinations with an ACEI or ARB is sensible. Many older patients require triple therapy or have comorbidities that necessitate treatment with a CCB. As is the case generally, BP lowering is more important than the treatment combina­ tion used to achieve the desired SBP goal of <130 mmHg. Recent trials have provided compelling evidence that more intensive antihyperten­ sive treatment in older adults reduces the risk of cognitive impairment compared to less intensive treatment, and increasing evidence suggests that it reduces the risk of dementia.

PART 6 Disorders of the Cardiovascular System RACE/ETHNICITY  Non-Hispanic blacks have disproportionately high BP levels and higher prevalence of hypertension compared to whites and other major race/ethnicity groups in the United States. In addi­ tion, hypertension tends to occur earlier in life and is associated with a higher risk of CVD and kidney disease in blacks compared to whites and the other major race/ethnicity groups. Non-Hispanic blacks have the highest awareness of hypertension of any race/ethnicity group

in the United States and have an antihypertensive drug treatment rate that is at least as high as that of whites. However, their rate of control to <140/90 mmHg in the 2017–2020 NHANES survey was 15% lower than in whites (37 vs 52%) and 6% lower for the 130/80 mmHg cut point (20 vs 26%). Genetic differences seem to explain a small fraction of the high prevalence of hypertension in black Americans, but most of the disparity is likely due to differences in the social determinants of health, including access to and quality of education and health care, neighborhood of residence and the related built environment factors, economic instability, and the social and community context. The BP, CVD, and kidney disease health discrepancies between black and nonblack U.S. adults are not only sizable but have also been persistent, with little improvement in recent decades. RCT experience dem­ onstrates that the gap can be eliminated with high-quality care, but following termination of RCT care, there has been a relatively rapid reversion to previous patterns of inadequate BP control. Resolution of the situation is unlikely without structural change in the approach to provision of care and a multilevel effort that involves patient engage­ ment, a team-based approach to care that frees up clinicians to address social determinants of health, health system policies that enhance the provision of high-quality care, and payors with a focus on quality and use of contemporary BP goals for BP control. Diuretics and CCBs are especially effective for lowering BP in U.S. blacks, but many patients

require triple antihypertensive therapy, and use of BP-lowering agents for management of comorbid conditions is common. SEX  Although there are well-described differences in the underlying pathophysiology of hypertension in women and men, RCT experience indicates a similar benefit in prevention of CVD in both sexes in the landmark antihypertensive drug treatment trials. In the United States, women are more likely to be aware of hypertension, to be treated with antihypertensive medication, and to achieve the desired level of BP control compared with men, especially at younger ages. ACEIs and ARBs should not be used in pregnancy or women of child-bearing age who are contemplating pregnancy. Antihypertensive agents with a good safety record in pregnancy are highlighted in the section on hypertension in pregnancy. Observational studies and RCTs, includ­ ing meta-analyses, have reported a reduced risk of fractures in women being treated with thiazide diuretics. This is postulated to result from decreased urinary calcium excretion and increased osteoblast cell for­ mation. In contrast to thiazide diuretics, loop diuretics increase urinary calcium excretion. However, analyses of large observational studies have failed to associate loop diuretic use in postmenopausal women with fractures or a decrease in bone marrow density. Women report more cough with ACEIs and more pedal edema with CCB treatment compared with men. Hypertensive Urgencies and Emergencies  Adults present­ ing with a very high level of BP, usually designated as an SBP/DBP ≥180/100 mmHg, should be classified as having a hypertensive urgency if they are asymptomatic or a hypertensive emergency if there is evidence of active ongoing hypertensive end-organ damage such as hypertensive encephalopathy, often manifesting with headaches, vision defects, nausea, vomiting, seizures, acute left ventricular failure, or acute kidney failure. Hypertensive urgency is far more common than hyper­ tensive emergency and should be treated with institution, reinstitution, or intensification of oral antihypertensive agents in an outpatient set­ ting. In contrast, a hypertensive emergency requires immediate, care­ fully supervised management with intravenous antihypertensive agents in an emergency room or inpatient setting. A hypertensive emergency associated with acute aortic dissection, eclampsia or severe preeclamp­ sia, or a pheochromocytoma in crisis signals the need for particularly rapid care. Several drug classes can be used intravenously to achieve a rapid reduction in BP. Intravenous sodium nitroprusside is a potent vasodilator with a long history of success in managing hypertensive emergencies but must be monitored carefully to avoid overshooting the goal BP and causing hypotension. The dihydropyridine CCB nicardip­ ine, given intravenously, is perhaps the most commonly utilized agent for acute BP reduction in patients with a hypertensive emergency in the contemporary practice of medicine. No dose adjustment is required for its use in older adults, but it is contraindicated in patients with severe aortic stenosis. Intravenous administration of the beta blocker labet­ alol is also effective but is contraindicated in patients with obstructive airways diseases, chronic obstructive pulmonary disease, bradycardia, or second- or third-degree heart block. Whichever drug is employed, a reduction rather than immediate normalization of BP is sufficient, with subsequent management of the patient’s hypertension with oral agents. Secondary causes of hypertension, especially renovascular disease, are relatively common in patients with a hypertensive emergency and should be considered after the immediate reduction in BP. PREVALENCE, AWARENESS, TREATMENT, AND CONTROL OF HYPERTENSION NHANES provides a way to monitor prevalence, awareness, treat­ ment, and control of hypertension in the U.S. general population. The NHANES definition of hypertension is based on BPs measured at a single visit, which results in an overestimation of hypertension, and the HHANES definition of treatment and control do not take into account nondrug therapy of hypertension. However, the methods used in NHANES have been consistent and careful over time, providing very helpful estimates for the temporal trends in hypertension prevalence and BP control. NHANES hypertension prevalence estimates have been fairly stable at ~46 and 32% for definitions based on use of the

SBP/DBP cut points of 130/80 and 140/90 mmHg, respectively, with higher prevalence rates in older versus younger adults, nonHispanic blacks versus all other major race/ ethnicity groups, and men compared with women. Treatment (with antihypertensive agents) and hypertension control rates increased progressively until about 2009– 2012, with close to 53% of U.S. adults being controlled to an SBP/DBP <140/90 mmHg (the recommended goal at the time) and ~26% for an SBP/DBP <130/90 mmHg. After that, there was a progressive decline in control rates, with ~48 and 24% having an SBP/DBP <140/90 and <130/80 mmHg, respectively, by 2017–2020. The percentage controlled was higher when the analysis was confined to adults being treated for hypertension, but the temporal trends pat­ tern was similar. The decrement in hyper­ tension control was especially prominent in adults ≥75 years old. There has been a persistent gap in hypertension control rates between non-Hispanic black adults and all other race/ethnicity groups in the United States, with the percentage of non-Hispanic blacks and whites controlled to an SBP/ DBP <140/90 mmHg in 2017–2020 being ~37 and 52%, respectively (20 and 26% for an SBP/DBP <130/80 mmHg). Worldwide, the situation is worse, with a recent global estimate reporting control to an SBP/DBP <140/90 mmHg in <14% of adults and in <8% of adults in low- and middle-income countries, where most of the world’s population resides. Community-based patient-centered team care Commitment by provider, system of care, or country to specific goals Health promotion for BP-lowering and antihypertensive medication augementation Manage uncomplicated hypertension with patient-centered, team-based care Ensure access to effective and affordable meds, preferably at the point of care Use simple evidence-based protocols and algorithms for team management Engage patients in their own care with HBPM and other options Track progress and employ case management for immediate corrective actions FIGURE 288-6  Best practices for control of hypertension. BP, blood pressure; HBPM, home blood pressure monitoring. ■ ■IMPROVING THE CONTROL OF HYPERTENSION Clearly, the current hypertension control rates are unacceptable, and the traditional model of one-on-one physician-patient care for hyper­ tension is not yielding a satisfactory outcome. Primary care physicians, who care for most patients with hypertension, are overburdened with responsibilities and have very limited time for direct provision of care in those with “routine” uncomplicated hypertension. A number of approaches have been shown to improve hypertension control rates in RCTs and clinical practice settings. Among these, team-based care has resulted in the biggest improvement in RCTs and meta-analyses. In the typical model of team-based care for hypertension management, a physician coordinates care provided by a team that may include nurses, pharmacists, community health care workers, social workers, lifestyle counselors, medical technicians, or others who have been specially trained in the provision of hypertension care. The specifics of the team composition depend on what is feasible in a practice setting and can be extended to engage front-office staff, spouses/partners, and close friends. In RCTs, team-based care has resulted in an average SBP reduction of ~7 mmHg, but in a recent high-quality, well-executed RCT, the SBP reduction exceeded 23 mmHg. It has been especially effective when trained nonphysician professionals have had the author­ ity, usually with physician oversight, to prescribe antihypertensive medications in patients with uncomplicated hypertension. This frees up physician time to address patients with more complex care require­ ments. Most team-based care interventions have been multifaceted, incorporating health counseling, home BP monitoring (HBPM) and electronic support systems, and use of simple algorithms for health counseling and management of antihypertensive drug therapy. HBPM provides an excellent way to engage patients in their own care and to complement office BP management (OBPM) for monitoring long-term control of hypertension. Use of HBPM mandates advising patients on the purchase of clinically valid BP measurement devices and training in accurate measurement of BP (see BP measurement section). In U.S.

CHAPTER 288 Information systems to track progress and case management Reliable access to effective and affordable medication Hypertension Health Promotion Simple evidence-based tools for lifestyle counseling and drug treatment Lifestyle improvements Antihypertensive drug treatment adults, getting three morning (prior to taking BP medications) and three evening HBPM measurements for 3 days prior to a clinic visit is a reasonable strategy for assessing average home BP. Team-based care approaches have not only been successful in RCTs but also yielded excellent results in clinical practice settings, with Kaiser-Permanente, Northern California reporting an improvement in SBP/DBP control to <140/90 mmHg from 44% in 2001 to 90% in 2015 based on institution of a multifaceted systemwide program of health care quality improve­ ment that incorporated many of the previously mentioned approaches. Likewise, many of these approaches have been used to good effect in the U.S. Department of Veterans Affairs Health System. An overall best practices approach is outlined in Fig. 288-6. While it may not be possible for an individual practitioner to imple­ ment all of the suggestions in the figure, they should advocate for those that are beyond their direct control. There is great need to improve the management and control of hypertension in the United States and world­ wide. Hypertension is among the most important, prevalent, modifiable, and cost-effective risk factors for CVD, kidney disease, and all-cause mortality. Its detection, treatment, and control should be a high priority for individual clinicians, systems of care, and countries worldwide. ■ ■FURTHER READING Blood Pressure Lowering Treatment Trialists, Collabora­ tion: Pharmacological blood pressure lowering for primary and secondary prevention of cardiovascular disease across different levels of blood pressure: An individual participant-level data meta-analysis. Lancet 397:1625, 2021. Bundy JD et al: Systolic blood pressure reduction and risk of cardio­ vascular disease and mortality: A systematic review and network meta-analysis. JAMA Cardiol 2:775, 2017. Carey RM et al: Treatment of hypertension. A review. JAMA 328:1848, 2022. Fuchs FD, Whelton PK: High blood pressure and cardiovascular disease. Hypertension 75:285, 2020. Panagiotis G, Agarwal R: Hypertension in chronic kidney disease: Treatment standard 2023. Nephrol Dial Transplant 3:2694, 2023.

52 - 289 Renovascular Disease

289 Renovascular Disease

Whelton P et al: 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/

ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: A report of the American College of Cardiology/American Heart Asso­ ciation Task Force on Clinical Practice Guidelines. Hypertension 71:e13, 2018. Wright JT Jr. et al: SPRINT revisited: Updated results and implications. PART 6 Disorders of the Cardiovascular System Hypertension 78:1701, 2021. Stephen C. Textor*

Renovascular Disease The renal vasculature is unusually complex with high arteriolar flow to the cortex in excess of metabolic requirements, consistent with its primary function as a filtering organ. After delivering blood to cortical glomeruli, the postglomerular circulation supplies deeper medullary segments that support energy-dependent solute transport at multiple levels of the renal tubule. These postglomerular vessels deliver less blood and, coupled with high oxygen consumption, leave the deeper medullary regions at the margin of hypoxemia. Vascular disorders that commonly threaten the blood supply of the kidney include largevessel atherosclerosis, fibromuscular diseases, and embolic disorders. Microvascular injury, including inflammatory and primary hema­ tologic disorders, is described in Chap. 329. MECHANISMS OF VASCULAR INJURY

AND HYPERTENSION The glomerular capillary endothelium shares susceptibility to oxidative stress, pressure injury, and inflammation with other vascular territo­ ries. Endothelial injury can be manifest by urinary albumin excretion (UAE), which is predictive of systemic atherosclerotic disease events. Increased UAE may develop years before cardiovascular events. UAE and the risk of cardiovascular events are both reduced with pharmaco­ logic therapy such as antihypertensive drugs and statins. Experimen­ tal studies demonstrate functional changes and rarefaction of renal microvessels under conditions of accelerated atherosclerosis and/or compromise of proximal perfusion pressures with large-vessel disease (Fig. 289-1). Large-vessel renal artery occlusive disease can result from multiple conditions, including extrinsic compression of the vessel, intimal dis­ section, aortic stent graft placement, fibromuscular dysplasia (FMD), or, most commonly, atherosclerotic disease. Any disorder that reduces perfusion pressure to the kidney can activate mechanisms that tend to restore renal pressures at the expense of developing systemic hyper­ tension. Because restoration of perfusion pressures can reverse these pathways, renovascular disease is considered a specifically treatable “secondary” cause of hypertension. Renal artery stenosis is common, usually gradually progressive, and often has only minor hemodynamic effects. FMD is reported in 3–5% of normal subjects presenting as potential kidney donors without hypertension. It may present clinically with hypertension in younger individuals (between age 15 and 50), most often women. FMD does not often threaten kidney function, but sometimes produces total occlu­ sion and can be associated with renal artery aneurysms. Atheroscle­ rotic renal artery stenosis (ARAS) is common in the general population (6.8% of a community-based sample above age 65). The prevalence increases with age and for patients with other vascular conditions such as coronary artery disease (18–23%) and/or peripheral aortic or lower *Deceased

extremity disease (>30%). If untreated, ARAS progresses in nearly 50% of cases over a 5-year period, sometimes to total occlusion. Intensive treatment of arterial blood pressure and statin therapy can slow these rates and improve clinical outcomes. Critical levels of stenosis (usually >70–80% luminal obstruction) lead to a reduction in perfusion pressure that activates the reninangiotensin system, reduces sodium excretion, and activates sympa­ thetic adrenergic pathways. These events lead to systemic hypertension characterized by angiotensin dependence in the early stages, widely varying pressures, loss of circadian blood pressure (BP) rhythms, and accelerated target organ injury, including left ventricular hypertrophy and renal fibrosis. Renovascular hypertension can be treated with agents that block the renin-angiotensin system and other drugs that modify these pressor pathways. It can also be treated with restoration of renal blood flow by either endovascular or surgical revasculariza­ tion. Most patients require continued antihypertensive drug therapy due to preexisting hypertension and because revascularization alone rarely lowers BP to normal. ARAS and systemic hypertension tend to affect both the postste­ notic and contralateral kidneys, reducing overall glomerular filtration rate (GFR) in ARAS. When kidney function is threatened by largevessel disease primarily, it has been labeled ischemic nephropathy. Moderately reduced blood flow that develops gradually is associated with reduced GFR and limited oxygen consumption with preserved tissue oxygenation. Hence, kidney function often remains reduced but stable during medical therapy, sometimes for years. With more advanced disease, reductions in cortical perfusion and overt tissue hypoxia develop. Unlike FMD, ARAS develops in patients with other risk factors for atherosclerosis and is commonly superimposed upon preexisting small-vessel disease in the kidney resulting from hyperten­ sion, aging, and diabetes. Nearly 85% of patients considered for renal revascularization have stage 3–5 chronic kidney disease (CKD) with estimated GFR <60 mL/min per 1.73 m2. The presence of ARAS is a strong predictor of morbidity- and mortality-related cardiovascular events, independent of whether renal revascularization is undertaken. DIAGNOSIS OF RENOVASCULAR DISEASE Diagnostic approaches to renovascular disease necessarily include evaluation of the kidney vasculature and depend on the specific clini­ cal questions to be addressed. Noninvasive characterization of the renal vasculature may be achieved by several techniques, summarized in Table 289-1. Although activation of the renin-angiotensin system is a key step in developing renovascular hypertension, it is transient. Levels of renin activity are therefore subject to timing, the effects of drugs, and sodium intake, and do not reliably predict the response to vascular therapy. Peak systolic renal artery velocities by Doppler ultrasound

200 cm/s generally predict lesions with more than >60% vessel lumen occlusion, although some treatment trials have required velocity >300 cm/s to avoid false positives. The renal resistive index has predictive value regarding the viability of the kidney. It remains operator- and institution-dependent, however. Contrast-enhanced computed tomog­ raphy (CT) with vascular reconstruction provides excellent vascular images and functional assessment but carries a small risk of contrast toxicity. It provides a more reliable evaluation of accessory vessels and the distal vasculature than duplex or magnetic resonance imaging (MRI). Magnetic resonance angiography (MRA) is less often used than previously, as gadolinium contrast has been associated with neph­ rogenic systemic fibrosis particularly in patients with reduced GFR. Captopril-enhanced renography has a strong negative predictive value when entirely normal. TREATMENT Renal Artery Stenosis While restoring renal blood flow and perfusion seems intuitively beneficial for high-grade occlusive lesions, revascularization proce­ dures also pose hazards and expense. Patients with FMD are com­ monly younger females with otherwise normal vessels and a long

Cortex Medulla Normal MV proliferation (early atherosclerosis) MV rarefaction (chronic renal ischemia) FIGURE 289-1  Examples of micro-CT images from vessels defined by radiopaque casts injected into the renal vasculature. These illustrate the complex, dense cortical capillary network supplying the kidney cortex that can either proliferate or succumb to rarefaction under the influence of atherosclerosis and/or occlusive disease. Changes in blood supply are followed by tubulointerstitial fibrosis and loss of kidney function. MV, microvascular. (Reproduced with permission from LO Lerman, AR Chade. Angiogenesis in the kidney: A new therapeutic target? Curr Opin Nephrol Hypertens 18:160, 2009.) life expectancy. These patients often respond well to percutaneous renal artery angioplasty. If BP can be controlled to goal levels and kidney function remains stable in patients with ARAS, it may be argued that medical therapy with follow-up for disease progression is equally effective over periods of 3–5 years. Multiple prospective randomized controlled trials for individuals with moderate stenosis have failed to identify compelling additional benefits for interven­ tional revascularization procedures regarding short-term results of BP and renal function. Studies of cardiovascular outcomes, includ­ ing stroke, congestive heart failure, myocardial infarction, and end-stage renal failure, suggest a small mortality benefit for stented patients without proteinuria. Medical therapy should include block­ ade of the renin-angiotensin system, attainment of goal BPs, cessa­ tion of tobacco, statins, and aspirin. Follow-up requires surveillance for progressive occlusion manifest by worsening renal function TABLE 289-1  Summary of Imaging Modalities for Evaluating the Kidney Vasculature Perfusion Studies to Assess Differential Renal Blood Flow Captopril renography with technetium-99m mertiatide (99mTc MAG3) Captopril-mediated fall in filtration pressure amplifies differences in renal perfusion Normal study excludes renovascular hypertension Vascular Studies to Evaluate the Renal Arteries Duplex ultrasonography Shows the renal arteries and measures flow velocity as a means of assessing the severity of stenosis Inexpensive; widely available, suitable for follow-up studies Computed tomographic angiography Shows the renal arteries and perirenal aorta Provides excellent images; stents do not cause artifacts Magnetic resonance angiography Shows the renal arteries and perirenal aorta Not nephrotoxic, but concerns for gadolinium toxicity exclude use in GFR <30 mL/min/1.73 m2; provides excellent images Intraarterial angiography Shows location and severity of vascular lesion Considered “gold standard” for diagnosis of large-vessel disease, usually performed simultaneous with planned intervention Abbreviation: GFR, glomerular filtration rate.

CHAPTER 289 Renovascular Disease and/or loss of BP control. Renal revascularization should be consid­ ered for patients with rapidly progressive clinical syndromes, failing medical therapy, and/or developing additional complications. Techniques of renal revascularization are improving. With expe­ rienced operators, major complications occur in <5% of cases, including renal artery dissection, capsular perforation, hemorrhage, and occasional atheroembolic disease. Although not common, atheroembolic disease can be catastrophic and accelerate both hypertension and kidney failure, precisely the events that revascu­ larization is intended to prevent. Although renal blood flow usually can be restored by endovascular stenting, recovery of renal function is limited to ~25% of cases, with no change in 50% and some dete­ rioration evident in others. Patients with rapid loss of kidney func­ tion, sometimes associated with antihypertensive drug therapy, or with vascular disease affecting the entire functioning kidney mass Multiple limitations in patients with advanced atherosclerosis or creatinine >2.0 mg/dL (177 μmol/L) Heavily dependent on operator’s experience; less useful than invasive angiography for the diagnosis of fibromuscular dysplasia and abnormalities in accessory renal arteries Expensive, moderate volume of contrast required Expensive; gadolinium excluded in renal failure, unable to visualize stented vessels Expensive, associated hazard of atheroemboli, contrast toxicity, procedure-related complications, e.g., dissection

TABLE 289-2  Clinical Factors That Determine the Role of Revascularization in Addition to Medical Therapy for Renal Artery Stenosis Factors Favoring Medical Therapy with Revascularization for Renal Artery Stenosis PART 6 Disorders of the Cardiovascular System • Progressive decline in GFR during treatment of systemic hypertension • Failure to achieve adequate blood pressure control with optimal medical therapy (medical failure) • Rapid or recurrent decline in the GFR in association with a reduction in systemic pressure • Decline in the GFR during therapy with ACE inhibitors or ARBs • Recurrent congestive heart failure in a patient in whom left ventricular dysfunction does not fully explain the cause Factors Favoring Medical Therapy and Surveillance of Renal Artery Disease • Controlled blood pressure with stable renal function (e.g., stable renal insufficiency) • Stable renal artery stenosis without progression on surveillance studies (e.g., serial duplex ultrasound) • Advanced age and/or limited life expectancy • Extensive comorbidity that make revascularization too risky • High risk for or previous experience with atheroembolic disease • Other concomitant renal parenchymal diseases that cause progressive renal dysfunction (e.g., interstitial nephritis, diabetic nephropathy), particularly with proteinuria Abbreviations: ACE, angiotensin-converting enzyme; ARBs, angiotensin receptor blockers; GFR, glomerular filtration rate. are more likely to recover function after restoring blood flow. When hypertension is refractory to effective therapy, revascularization offers real benefits. Table 289-2 summarizes currently accepted guidelines for considering renal revascularization in addition to optimal medical therapy. ATHEROEMBOLIC RENAL DISEASE Emboli to the kidneys arise most frequently as a result of cholesterol crystals breaking free of atherosclerotic vascular plaque and lodging in downstream microvessels. Most clinical atheroembolic events follow angiographic procedures, often of the coronary vessels. It has been argued that nearly all arterial interventional procedures lead to plaque fracture and release of microemboli, but clinical manifestations develop only in a fraction of these. The incidence of clinical atheroemboli has been increasing with more vascular procedures and longer life spans. Atheroembolic renal disease is suspected in >3% of elderly subjects with end-stage renal disease (ESRD) and is likely underdiagnosed. It is more frequent in males with a history of diabetes, hypertension, and ischemic cardiac disease. Atheroemboli in the kidney are strongly associated with aortic aneurysmal disease and renal artery stenosis. Most clinically evident cases can be linked to precipitating events, such as angiography, vascular surgery, anticoagulation with heparin, thrombolytic therapy, or trauma. Clinical manifestations of this syndrome commonly develop between 1 and 14 days after an inciting event and may continue to develop for weeks thereafter. Systemic embolic disease manifestations, such as fever, abdominal pain, and weight loss, are present in less than half of patients, although cutaneous manifestations including livedo reticularis and localized toe gangrene may be more common. Wors­ ening hypertension and deteriorating kidney function are common, sometimes reaching a malignant phase. Progressive renal failure can occur and require dialytic support. These cases often develop after a stuttering onset over many weeks and have an ominous prognosis. Mor­ tality rate after 1 year exceeds 38%, and although some may eventually recover sufficiently to no longer require dialysis, many do not. Beyond the clinical manifestations above, laboratory findings include rising creatinine, transient eosinophilia (60–80%), elevated sedimentation rate, and hypocomplementemia (15%). Establishing this diagnosis can be difficult and is often by exclusion. Definitive diagnosis depends on kidney biopsy demonstrating microvessel occlusion with

cholesterol crystals that leave a “cleft” in the vessel. Biopsies obtained from patients undergoing surgical revascularization of the kidney indicate that silent cholesterol emboli are frequently present before any further manipulation is performed. No effective therapy is available for atheroembolic disease once it has developed. Withdrawal of anticoagulation is recommended. Late recovery of kidney function after supportive measures sometimes occurs, and statin therapy may improve outcome. The role of embolic protection devices in the renal circulation during angiography is unclear, but a few prospective trials have failed to demonstrate major benefits. The effect of such devices is limited to distal protection during the endovascular procedure, and they offer no protection from embolic debris developing after removal. THROMBOEMBOLIC RENAL DISEASE Thrombotic occlusion of renal vessels or branch arteries can lead to declining renal function and hypertension. It is difficult to diagnose and is often overlooked, especially in elderly patients. Thrombosis can develop as a result of local vessel abnormalities, such as local dissec­ tion, trauma, inflammatory vasculitis, or systemic infections, such as COVID-19. Local microdissections sometimes lead to patchy, transient areas of infarctions labeled “segmental arteriolar mediolysis.” Although hypercoagulability conditions sometimes present as renal artery throm­ bosis, this is rare. It can also derive from distant embolic events, e.g., the left atrium in patients with atrial fibrillation or from fat emboli originat­ ing from traumatized tissue, most commonly large bone fractures. Car­ diac sources include vegetations from subacute bacterial endocarditis. Systemic emboli to the kidneys may also arise from the venous circula­ tion if right-to-left shunting occurs, e.g., through a patent foramen ovale. Clinical manifestations vary depending on the rapidity of onset and extent of occlusion. Acute arterial thrombosis may produce flank pain, fever, leukocytosis, nausea, and vomiting. If kidney infarction results, enzymes such as lactate dehydrogenase (LDH) rise transiently to extreme levels. If both kidneys are affected, renal function will decline precipitously with a drop in urine output. If a single kidney is involved, renal functional changes may be minor. Hypertension related to sud­ den release of renin from ischemic tissue can develop rapidly, as long as some viable tissue in the “peri-infarct” border zone remains. If the infarct zone demarcates precisely, the rise in BP and renin activity may resolve. Diagnosis of renal infarction may be established by vascular imaging with CT angiography, MRI, or arteriography (Fig. 289-2). ■ ■MANAGEMENT OF ARTERIAL THROMBOSIS OF THE KIDNEY Options for interventions of newly detected arterial occlusion include surgical reconstruction, anticoagulation, thrombolytic therapy, endo­ vascular procedures, and supportive care, particularly antihypertensive drug therapy. Application of these methods depends on the patient’s overall condition, the precipitating factors (e.g., local trauma or sys­ temic illness), the magnitude of renal tissue and function at risk, and the likelihood of recurrent events in the future. For unilateral disease, for example, arterial dissection with thrombosis and supportive care with anticoagulation may suffice. Acute, bilateral occlusion is potentially catastrophic, producing anuric renal failure. Depending on the precipi­ tating event, surgical or thrombolytic therapies can sometimes restore kidney viability if undertaken early in the course of the acute event. MICROVASCULAR INJURY ASSOCIATED WITH HYPERTENSION ■ ■ARTERIOLONEPHROSCLEROSIS “Malignant” Hypertension  Although BP rises with age, it has long been recognized that some individuals develop rapidly progressive BP elevations with target organ injury including retinal hemorrhages, encephalopathy, and declining kidney function. Pla­ cebo arms during the early controlled trials of hypertension therapy identified progression to severe levels in 20% of subjects over 5 years. If untreated, patients with target organ injury including papilledema

A B   FIGURE 289-2  A. CT angiogram illustrating loss of circulation to the upper pole of the right kidney in a patient with fibromuscular disease and a renal artery aneurysm. Activation of the renin-angiotensin system produced rapidly developing hypertension. B. Angiogram illustrating high-grade renal artery stenosis affecting the left kidney. This lesion is often part of widespread atherosclerosis and sometimes is an extension of aortic plaque. This lesion develops in older individuals with preexisting atherosclerotic risk factors. and declining kidney function suffered mortality rates in excess of 50% over 6–12 months, hence the designation “malignant.” Postmor­ tem studies of such patients identified vascular lesions, designated “fibrinoid necrosis,” with breakdown of the vessel wall, deposition of eosinophilic material including fibrin, and a perivascular cellular infiltrate. A separate lesion was identified in the larger interlobu­ lar arteries in many patients with hyperplastic proliferation of the vascular wall cellular elements, deposition of collagen, and separa­ tion of layers, designated the “onionskin” lesion. For many of these

CHAPTER 289 Renovascular Disease patients, fibrinoid necrosis led to obliteration of glomeruli and loss of tubular structures. Progressive kidney failure ensued and, without dialysis support, led to early mortality in untreated malignant-phase hypertension. These vascular changes could develop with pressurerelated injury from a variety of hypertensive pathways, including but not limited to activation of the renin-angiotensin system and severe vasospasm associated with catecholamine release. Occasionally, endothelial injury is sufficient to induce microangiopathic hemolysis, as discussed below.

53 - 290 Deep-Venous Thrombosis and Pulmonary Thromboembolism

290 Deep-Venous Thrombosis and Pulmonary Thromboembolism

Antihypertensive therapy is the mainstay of therapy for malignant hypertension. With effective BP reduction, manifestations of vascular injury, including microangiopathic hemolysis and renal dysfunction, can improve over time. Whereas prior reports before the era of drug therapy suggested that 1-year mortality rates exceeded 90%, current survival over 5 years exceeds 50%.

PART 6 Disorders of the Cardiovascular System Malignant hypertension is less common in Western countries, although it persists in parts of the world where medical care and antihy­ pertensive drug therapy are less available. It most commonly develops in patients with treated hypertension who neglect to take medications or who may use vasospastic drugs, such as cocaine. Renal abnormalities typically include rising serum creatinine and occasionally hematuria and proteinuria. Biochemical findings may include evidence of hemo­ lysis (anemia, schistocytes, and reticulocytosis) and changes associated with kidney failure. African-American males are more likely to develop rapidly progressive hypertension and kidney failure than are whites in the United States. Genetic polymorphisms for APOL1 that are common in the African-American population predispose to focal sclerosing glo­ merular disease, with severe hypertension developing at younger ages secondary to renal disease in this instance. “Hypertensive Nephrosclerosis”  Based on experience with malignant hypertension and epidemiologic evidence linking BP with long-term risks of kidney failure, it has long been believed that lesser degrees of hypertension induce less severe, but prevalent, changes in kidney vessels and loss of kidney function. As a result, a large portion of patients reaching ESRD without a specific etiologic diagnosis are assigned the designation “hypertensive nephrosclerosis.” Pathologic examination commonly identifies afferent arteriolar thickening with deposition of homogeneous eosinophilic material (hyaline arteriolo­ sclerosis) associated with narrowing of vascular lumina. Clinical mani­ festations include retinal vessel changes associated with hypertension (arteriolar narrowing, arteriovenous crossing changes), left ventricular hypertrophy, and elevated BP. The role of these vascular changes in kidney function is unclear. Multiple studies of nephrectomy and biopsy samples from normotensive kidney donors demonstrate changes of nephrosclerosis associated with aging, dyslipidemia, and glucose intol­ erance, with only modest association with BP. Antihypertensive drug therapy does not alter the course of kidney dysfunction identified spe­ cifically as hypertensive nephrosclerosis, although BP reduction does slow progression of proteinuric kidney diseases and is warranted to reduce the excessive cardiovascular risks associated with CKD. ■ ■FURTHER READING Bhalla V et al: Revascularization for renovascular disease: A scientific statement from the American Heart Association. Hypertension 79:e128, 2022. De Mast Q, Beutler JJ: The prevalence of atherosclerotic renal artery stenosis in risk groups: A systemic literature review. J Hypertens 27:1333, 2009. Freedman BI, Cohen AH: Hypertension-attributed nephropathy: What’s in a name? Nat Rev Nephrol 12:27, 2016. Gornik HL et al: First International Consensus on the diagnosis and management of fibromuscular dysplasia. Vasc Med 24:164. 2019. Herrmann SM et al: Management of atherosclerotic renovascular dis­ ease after Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL). Nephrol Dial Transplant 30:366, 2015. Modi KS, Rao VK: Atheroembolic renal disease. J Am Soc Nephrol 12:1781 2001. Parikh SA et al: SCAI expert consensus statement for renal artery stent­ ing appropriate use. Catheter Cardiovasc Interv 84:1163, 2014. Persu A et al: European consensus on the diagnosis and manage­ ment of fibromuscular dysplasia. J Hypertens 32:1367, 2014. Textor SC, Lerman LO: The role of hypoxia in ischemic chronic kidney disease. Semin Nephrol 39:589, 2019.

Samuel Z. Goldhaber

Deep-Venous Thrombosis

and Pulmonary Thromboembolism ■ ■EPIDEMIOLOGY Venous thromboembolism (VTE) encompasses deep-venous throm­ bosis (DVT) and pulmonary embolism (PE) and causes cardiovascular death, chronic disability, and emotional distress. Hospitalizations in the United States have decreased for acute myocardial infarction (MI), heart failure, and stroke among Medicare beneficiaries, but PE hospi­ talizations increased. Pulmonary Embolism Mortality  PE-related mortality in the United States decreased from 6 per 100,000 in 2000 and plateaued at approximately 4.5 per 100,000 in 2017. In contrast, Europe’s age-standardized annual PE-related mortality rate has continued to decrease linearly since 2000. In the United States, PE-related mortal­ ity is increasing among young and middle-aged adults. Consequently, the median age at death from PE decreased from 73 years in 2000 to 68 years in 2018. During this period, the annual PE mortality was up to 50% higher in African Americans compared with Caucasians. Socioeconomic Status  To evaluate the relationship between socioeconomic status and PE, as well as other cardiovascular diseases, 10,942,483 Medicare beneficiaries were studied to determine whether they were hospitalized for PE, MI, heart failure, or stroke between 2003 and 2019. Hospitalizations for MI, heart failure, and stroke declined in socioeconomically disadvantaged and nondisadvantaged communi­ ties. In contrast, PE hospitalizations increased in both disadvantaged and nondisadvantaged communities. The heat map (Fig. 290-1) shows marked regional differences in the rates of PE hospitalization and degrees of social and community disadvantage throughout the United States. By 2019, 30-day mortality was similar between hospitalized beneficiaries from socioeconomically disadvantaged and nondisadvan­ taged communities for MI, heart failure, and ischemic stroke. In con­ trast, mortality among patients hospitalized with PE was consistently higher in disadvantaged areas (Fig. 290-2). This finding may be due, in part, to poor outpatient follow-up and impeded access to anticoagulant medications. Pulmonary Embolism Readmissions   From 2010 to 2018, 721,710 fee-for-service Medicare beneficiaries were hospitalized with PE. The 30-day all-cause readmission rate was 11%, and the 90-day all-cause readmission rate was 15% (Fig. 290-3). The most common reason for readmission was recurrent PE, accounting for about 11% of readmissions within 30 days. COVID-19  In 2020, COVID-19 erupted and caused a global pan­ demic. The most notable clinical feature was a life-threatening acute respiratory syndrome requiring prolonged mechanical ventilation and resulting in a high case–fatality rate. This viral illness was associated with a high incidence of DVT and PE. At autopsy, about one-fourth of PE patients with COVID had both macrovascular and microvascular PE. Contributing etiologies included excessive inflammation with cytokine storm, platelet activation, endothelial dysfunction, and stasis (Fig. 290-4). Long-Term Sequelae of Pulmonary Embolism  With respect to quality of life, about half of PE patients report persistent dyspnea, fatigue, and reduced exercise capacity, and about one-quarter have per­ sistent right ventricular dysfunction on echocardiogram. This constel­ lation of findings is being recognized more frequently and is called the “post-PE syndrome” (Fig. 290-5). A less frequent complication of PE is the development of chronic thromboembolic pulmonary hypertension (CTEPH), which usually causes breathlessness, especially with exertion.

Non-disadvantaged: >227.5 Non-disadvantaged: 119.2–173.1 Non-disadvantaged: 0–119.2 Disadvantaged: 0–119.2 Disadvantaged: 119.2–173.1 Disadvantaged: 173.1–227.5 Disadvantaged: >227.5 FIGURE 290-1  Observed hospitalizations for PE are shown per 100,000 Medicare beneficiaries aged 65 year or older residing in socioeconomically disadvantaged (orange) and nondisadvantaged (blue) counties of the United States in 2019. Lower hospitalization rates are represented with lighter shades of each color, and higher hospitalization rates are represented with darker shades. The range of hospitalizations per 100,000 represented by each shade of orange and each shade of blue are shown in the legend. (Reproduced with permission from RK Wadhera et al: Circ Cardiovasc Qual Outcomes 17:e010090, 2024.)

Observed 30-day mortality risk

2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 Non-disadvantaged community Disadvantaged community FIGURE 290-2  Trends in 30-day mortality among Medicare beneficiaries hospitalized with pulmonary embolism by community socioeconomic disadvantage from 2003 to 2019. The red lines represent beneficiaries from disadvantaged communities, and the blue line, beneficiaries from nondisadvantaged communities. The bands represent 95% confidence intervals for estimates. Trends in observed 30-day mortality among Medicare beneficiaries hospitalized with cardiovascular conditions by community socioeconomic disadvantage from 2003 to 2019. (Reproduced with permission from RK Wadhera et al: Circ Cardiovasc Qual Outcomes 17:e010090, 2024.)

Non-disadvantaged: 173.1–227.5 CHAPTER 290 Deep-Venous Thrombosis and Pulmonary Thromboembolism With 95% Confidence limits Year

All cause readmission trends

18.8

20.2

17.7 16.2

(%) PART 6 Disorders of the Cardiovascular System

9.7

11.2 10.2

30-day readmissions 90-day readmissions FIGURE 290-3  Graph showing all-cause readmission rates for pulmonary embolism (PE) patients within 30 days and within 90 days from 2010 to 2018. (Reproduced from M Murthi: Am J Cardiol 184:133, 2022.) Postthrombotic Syndrome  Postthrombotic syndrome (also known as chronic venous insufficiency) damages the venous valves of the leg and worsens quality of life by causing ankle or calf swelling and leg aching, especially after prolonged standing. In its most severe form, postthrombotic syndrome causes deep skin ulceration (Fig. 290-6). ■ ■PATHOPHYSIOLOGY Inflammation  Inflammation takes center stage as a trigger of acute PE and DVT. Inflammation-related risk factors and medical illnesses are now linked as precipitants of VTE (Table 290-1). Prothrombotic States  The two most common autosomal domi­ nant genetic mutations are (1) factor V Leiden, which causes resistance to the endogenous anticoagulant, protein C, and (2) the prothrombin gene mutation, which increases the plasma prothrombin concentration (Chaps. 69 and 122). Antithrombin, protein C, and protein S are natu­ rally occurring coagulation inhibitors. Deficiencies of these inhibitors A B C Risk factors Acute illness Bed-ridden, stasis Genetics Fever Diarrhea Sepsis Liver injury CKD COPD HF Malignancy Sars-COV-2 Inflammatory response
Endothelial dysfunction Superinfected Tissue factor TFPI Lymphopenia Inflammatory cytokines IL-6, CRP FIGURE 290-4  Postulated mechanisms of coagulopathy and pathogenesis of thrombosis in COVID-19. A. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection activates an inflammatory response, leading to release of inflammatory mediators. Endothelial and hemostatic activation ensues, with decreased levels of TFPI and increased tissue factor. The inflammatory response to severe infection is marked by lymphopenia and thrombocytopenia. Liver injury may lead to decreased coagulation and antithrombin formation. B. COVID-19 may be associated with hemostatic derangement and elevated troponin. C. Increased thromboembolic state results in venous thromboembolism, myocardial infarction, or, in case of further hemostatic derangement, disseminated intravascular coagulation. CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; FDP, fibrin degradation product; HF, heart failure; IL, interleukin; LDH, lactate dehydrogenase; PT, prothrombin time; TFPI, tissue factor pathway inhibitor. (Reproduced with permission from B Bikdeli et al: COVID-19 and thrombotic or thromboembolic disease: Implications for prevention, antithrombotic therapy, and follow-up. J Am Coll Cardiol 75:2950, 2020.)

are associated with VTE but are rare. Antiphospholipid syndrome (APS) is an acquired (not genetic) thrombophilic disorder that predis­ poses to both venous and arterial thrombosis. Patients with APS often warrant lifetime anticoagulation, even if the initial VTE was provoked by trauma or surgery. 19.4 Clinical Risk Factors  Common comorbid VTE risk factors include cancer, obesity, cigarette smoking, systemic arterial hyperten­ sion, chronic obstructive pulmonary disease, chronic kidney disease, long-haul air travel, air pollution, estrogen-containing contraceptives, pregnancy, the first 6–12 weeks postpartum, postmenopausal hormone replacement, surgery, and trauma. A sedentary lifestyle is an increas­ ingly prevalent risk factor. A Japanese study found that each 2 hours per day increment of television watching is associated with a 40% increased likelihood of fatal PE. 11.8 Polygenic Risk Scores  Ghouse and colleagues reported a genomewide association study of VTE that incorporated 81,190 cases and 1,419,671 controls from six cohorts. They identified 93 risk loci, 62 of which were previously unreported. Many risk loci affected the coagu­ lation cascade or platelet function. A VTE polygenic risk score (PRS) enabled identification of both high- and low-risk individuals. Individu­ als within the top 0.1% of PRS distribution had a VTE risk similar to homozygous or compound heterozygous carriers of factor V Leiden or the prothrombin gene mutation. In contrast, in the bottom 10% of the PRS distribution, factor V Leiden and prothrombin gene mutation carriers had a VTE risk similar to that of the general population. PRS improved individual risk prediction beyond that of genetic and clini­ cal risk factors. Some risk factors for arterial thrombosis, such as body mass index and smoking, were concordant with VTE risk, whereas others, such as blood pressure and triglyceride levels, were discordant. Activated Platelets  Virchow’s triad of venous stasis, hypercoagu­ lability, and endothelial injury, usually coupled with an inflammatory trigger, leads to recruitment of activated platelets, which release mic­ roparticles. These microparticles contain proinflammatory mediators Hemostatic abnormalities Clinical outomes Pulmonary microthrombi Intravascular coagulopathy Myocardial injury Cardiac biomarkers Venous thromboembolism D-dimer, FDPs, PT Platelets Myocardial infarction Disseminated intravascular coagulation

Description Flowchart for patient self-report of the Post-VTE Functional Status scale PVFS scale grade All usual duties/activities at home or at work can be carried out at the same level of intensity. Symptoms, pain and anxiety are absent.

No functional limitations Can you live alone without any assistance from another person? (e.g., independently being able to eat, walk, use the toilet and manage routine daily hygiene) All usual duties/activities at home or at work can be carried out at the same level of intensity, despite some symptoms, pain, or anxiety.

Negligible functional limitations Some usual duties/activities at home or at work are carried out at a lower level of intensity or are occasionally avoided due to symptoms, pain, or anxiety. Slight functional limitations

Usual duties/activities at home or at work have been structurally modified (reduced) due to symptoms, pain, or anxiety. Moderate functional limitations

Assistance needed in activities of daily living due to symptoms, pain, or anxiety: nursing care and attention are required. Severe functional limitations

Grade 0 Death Death occurred before the scheduled assessment. D FIGURE 290-5  Flow chart for patient self-report of the Post-Venous Thromboembolism (VTE) Functional Status scale. (Reproduced with permission from GJAM Boon et al: Thromb Res 190:45, 2020, Figure 2.) that bind neutrophils, stimulating them to release their nuclear material and form web-like extracellular networks called neutrophil extracellular traps. These prothrombotic networks contain histones that stimu­ late platelet aggregation and promote platelet-dependent thrombin FIGURE 290-6  Skin ulceration in the medial malleolus from postthrombotic syndrome of the leg.

CHAPTER 290 Yes No Are there duties/activities at home or at work which you are no longer able to perform yourself? Deep-Venous Thrombosis and Pulmonary Thromboembolism No Yes Do you suffer from symptoms, pain, or anxiety? Yes No Do you need to avoid or reduce duties/ activities or spread these over time? No Yes Grade 1 Grade 2 Grade 3 Grade 4 generation. Venous thrombi form and flourish in this environment of stasis, low oxygen tension, and upregulation of proinflammatory genes. Interaction Between Venous Thromboembolism and

Atherothrombosis  VTE (red clot) and arterial thrombotic (white clot) events were previously considered separate entities. However, the presence of carotid artery plaque is associated with double the risk of incident VTE. This observation led to the discovery of a broad interac­ tion of VTE with acute coronary syndrome and with acute ischemic stroke (Fig. 290-7). These three vascular conditions share similar risk factors and similar pathophysiology: inflammation, hypercoagulability, and endothelial injury. Patients who suffer VTE are more than twice TABLE 290-1  Inflammation-Linked Conditions That Can Trigger PE or DVT Ulcerative colitis Crohn’s disease Rheumatoid arthritis Psoriasis Diabetes mellitus, type 2 Obesity/metabolic syndrome Hypercholesterolemia, especially elevated LDL cholesterol Lipoprotein(a) Pneumonia Acute coronary syndrome Acute stroke Cigarette smoking Sepsis/septic shock Erythropoiesis-stimulating agents Blood transfusion Cancer Abbreviations: DVT, deep-venous thrombosis; LDL, low-density lipoprotein; PE, pulmonary embolism.

PE PE PART 6 Disorders of the Cardiovascular System MI MI Stroke Stroke Inflammation: A common underlying process FIGURE 290-7  Broad interaction between venous thromboembolism and atherothrombosis. MI, myocardial infarction; PE, pulmonary embolism. as likely to have a future MI or stroke. Conversely, patients with MI or stroke are more than twice as likely to suffer a future VTE. Embolization  When DVTs (Fig. 290-8) detach from their site of formation, they embolize to the vena cava, right atrium, and right ven­ tricle and lodge in the pulmonary arterial circulation, thereby causing acute PE. Many patients with PE have no evidence of DVT because the leg thrombus has already embolized to the lungs. Paradoxically, these thrombi occasionally embolize to the arterial circulation through a pat­ ent foramen ovale or atrial septal defect. Physiology  The most common gas exchange abnormalities are arterial hypoxemia and an increased alveolar-arterial O2 tension gra­ dient, which represent the inefficiency of oxygen transfer across the lungs. Anatomic dead space increases because breathed gas does not enter gas exchange units of the lung. Physiologic dead space increases because ventilation to gas exchange units exceeds venous blood flow through the pulmonary capillaries (Fig. 290-9). Other pathophysiologic abnormalities include:

  1. Increased pulmonary vascular resistance due to vascular obstruction or platelet secretion of vasoconstricting neurohumoral agents such as serotonin. Release of vasoactive mediators can produce venti­ lation-perfusion mismatching at sites remote from the embolus, thereby accounting for discordance between a small PE and a large alveolar-arterial O2 gradient.
  2. Impaired gas exchange due to increased alveolar dead space from vascular obstruction, hypoxemia from alveolar hypoventilation rela­ tive to perfusion in the nonobstructed lung, right-to-left shunting, or impaired carbon monoxide transfer due to loss of gas exchange surface.
  3. Alveolar hyperventilation due to reflex stimulation of irritant receptors. FIGURE 290-8  Deep-venous thrombosis at autopsy.

RV pressure overload RV wall tension RV dysfunction RV ischemia or infarction LV preload Coronary perfusion LV Cardiac output Systemic pressure FIGURE 290-9  Pathophysiology of pulmonary embolism (PE). LV, left ventricular; RV, right ventricular. 4. Increased airway resistance due to constriction of airways distal to the bronchi. 5. Decreased pulmonary compliance due to lung edema, lung hemor­ rhage, or loss of surfactant. Pulmonary Hypertension, Right Ventricular (RV) Dysfunction, and RV Microinfarction  Pulmonary artery obstruction and neu­ rohumoral mediators cause a rise in both pulmonary artery pressure and pulmonary vascular resistance. When RV wall tension rises, RV dilation, stretch, and dysfunction ensue, with release of the cardiac biomarker brain natriuretic peptide. The interventricular septum bulges into and compresses an intrinsically normal left ventricle (LV). Dia­ stolic LV dysfunction reduces LV distensibility and impairs LV filling. Increased RV wall tension also compresses the right coronary artery, limits myocardial oxygen supply, and precipitates right coronary artery ischemia and RV microinfarction, with release of cardiac biomarkers such as troponin. Underfilling of the LV may lead to a fall in LV cardiac output and systemic arterial pressure, with consequent circulatory col­ lapse and death (Fig. 290-9). ■ ■CLASSIFICATION OF PULMONARY EMBOLISM AND DEEP-VENOUS THROMBOSIS Pulmonary Embolism  Massive (high-risk) PE accounts for 5–10% of cases and is usually characterized by systemic arterial hypotension and extensive thrombosis affecting at least half of the pulmonary vas­ culature. Dyspnea, syncope, hypotension, and cyanosis are hallmarks of massive PE. Patients with massive PE may present in cardiogenic shock and can die from multisystem organ failure. Submassive (intermediaterisk) PE accounts for 20–25% of patients and is characterized by RV dysfunction despite normal systemic arterial pressure. The combina­ tion of right heart failure and release of cardiac biomarkers such as troponin indicates a high risk of clinical deterioration. Low-risk PE constitutes about 65–75% of cases. These patients have an excellent prognosis. Deep-Venous Thrombosis  Lower extremity DVT usually begins in the calf and can propagate proximally to the popliteal, femoral, and iliac veins. Leg DVT is ~10 times more common than upper extremity DVT, which is often precipitated by placement of pacemakers, internal cardiac defibrillators, or indwelling central venous catheters. The likeli­ hood of upper extremity DVT increases as the catheter diameter and number of lumens increase. Superficial venous thrombosis usually presents with erythema, ten­ derness, and a “palpable cord”; it is most common in the lower extremi­ ties because of varicose veins and in the upper extremities because of indwelling intravenous catheters. Superficial veins may be visible in the chest wall (Urschel’s sign). Patients are at risk for extension of the superficial vein thrombosis to the deep-venous system.

■ ■DIAGNOSIS Clinical Evaluation  PE is known as “the great masquerader.” Diagnosis is difficult because symptoms and signs are nonspecific. The most common symptom of PE is unexplained breathlessness. When occult PE occurs concomitantly with overt congestive heart failure or pneumonia, clinical improvement often fails to ensue despite standard medical treatment of the concomitant illness. This scenario provides a clinical clue to the possible coexistence of PE. With DVT, the most common symptom is a cramp or “charley horse” in the lower calf that persists and intensifies over several days. Wells Point Score criteria, validated in ambulatory patients but not in hospitalized patients, help estimate the clinical likelihood of DVT and PE (Table 290-2). Patients with a low likelihood of DVT or a low-tomoderate likelihood of PE should undergo initial diagnostic evaluation with d-dimer testing alone (see “Blood Tests”), without obligatory imaging tests if the d-dimer test result is normal (Fig. 290-10). How­ ever, patients with a high clinical likelihood of VTE should skip d-dimer testing and undergo imaging as the next step in the diagnostic algorithm. Clinical Pearls  Not all leg pain is due to DVT, and not all dyspnea is due to PE (Table 290-3). Sudden, severe calf discomfort suggests a ruptured Baker’s cyst. Fever and chills often herald cellulitis rather than DVT. Physical findings, if present, may consist only of mild palpation discomfort in the lower calf. However, massive DVT often presents with marked thigh swelling, tenderness, and erythema. If a leg is dif­ fusely edematous, DVT is unlikely, except for the most serious form of DVT, phlegmasia cerulea dolens. Recurrent left thigh edema, especially in young women, raises the possibility of May-Thurner syndrome, with right proximal iliac artery compression of the left proximal iliac vein. This syndrome may be associated with a DVT. Upper extremity venous thrombosis may present with asymmetry in the supraclavicular fossa or in the circumference of the upper arms. Pulmonary infarction usually indicates a small PE. This condition is exquisitely painful because the thrombus lodges peripherally, near the innervation of pleural nerves. Nonthrombotic PE etiologies include fat embolism after pelvic or long bone fracture, tumor embolism, bone marrow, and air embolism. Cement embolism and bony fragment embolism can occur after total hip or knee replacement. Intravenous drug users may inject themselves with a wide array of substances that TABLE 290-2  Clinical Decision Rules Low Clinical Likelihood of DVT if Point Score Is Zero or Less; Moderate Likelihood if Score Is 1 to 2; High Likelihood if Score Is 3 or Greater CLINICAL VARIABLE DVT SCORE Active cancer

Paralysis, paresis, or recent cast

Bedridden for >3 days; major surgery <12 weeks

Tenderness along distribution of deep veins

Entire leg swelling

Unilateral calf swelling >3 cm

Pitting edema

Collateral superficial nonvaricose veins

Alternative diagnosis at least as likely as DVT –2 High Clinical Likelihood of PE if Point Score Exceeds 4 CLINICAL VARIABLE PE SCORE Signs and symptoms of DVT 3.0 Alternative diagnosis less likely than PE 3.0 Heart rate >100/min 1.5 Immobilization >3 days; surgery within 4 weeks 1.5 Prior PE or DVT 1.5 Hemoptysis 1.0 Cancer 1.0 Abbreviations: DVT, deep-venous thrombosis; PE, pulmonary embolism.

Suspect DVT or PE Assess clinical likelihood CHAPTER 290 DVT PE Deep-Venous Thrombosis and Pulmonary Thromboembolism Not low Not high High Low D-dimer D-dimer Normal High Normal High No DVT Imaging test needed No PE Imaging test needed FIGURE 290-10  How to decide whether diagnostic imaging is needed. For assessment of clinical likelihood, see Table 290-2. DVT, deep-venous thrombosis; PE, pulmonary embolism. can embolize, such as hair, talc, and cotton. Amniotic fluid embolism occurs when fetal membranes leak or tear at the placental margin. Nonimaging Diagnostic Modalities  •  BLOOD TESTS  The quantitative plasma d-dimer enzyme-linked immunosorbent assay (ELISA) rises in the presence of DVT or PE because of the breakdown of fibrin by plasmin. Elevation of d-dimer indicates endogenous, although often clinically ineffective, thrombolysis. The sensitivity of an abnormally elevated d-dimer is >95% for PE. A normal d-dimer is a useful “rule out” test for PE in patients with low pretest probability. However, the d-dimer assay is not specific. Levels increase in patients with MI, pneumonia, sepsis, cancer, and the postoperative state, and those in the second or third trimester of pregnancy. Therefore, d-dimer testing rarely has a useful role among hospitalized patients because levels are frequently elevated due to systemic illness. The upper limit of normal for d-dimer was considered to be 500 ng/mL; however, guidelines now recommend use of an ageadjusted d-dimer when ruling out acute PE. The age-adjusted d-dimer applies to patients older than 50 years of age with low or intermedi­ ate clinical probability of PE. To calculate the upper limit of normal d-dimer in these patients, multiply the age by 10. For example, a 70-year-old patient suspected of PE would have 700 ng/mL as the upper limit of normal for d-dimer. Implementing routine use of the TABLE 290-3  Differential Diagnosis of DVT and PE DVT Ruptured Baker’s cyst Muscle strain/injury Cellulitis Acute postthrombotic syndrome/venous insufficiency PE Pneumonia, asthma, chronic obstructive pulmonary disease Congestive heart failure Pericarditis Pleurisy: “viral syndrome,” costochondritis, musculoskeletal discomfort Rib fracture, pneumothorax Acute coronary syndrome Anxiety Vasovagal syncope Abbreviations: DVT, deep-venous thrombosis; PE, pulmonary embolism.

I aVR PART 6 Disorders of the Cardiovascular System aVL II aVF III II FIGURE 290-11  Electrocardiogram with both the S1Q3T3 sign and T-wave inversions in leads V1-V4—typical of an anatomically large pulmonary embolism. This patient’s CT pulmonary angiogram is shown as Fig. 290-13A and B. age-adjusted d-dimer reduces the number of computed tomogra­ phy (CT) pulmonary angiograms that are ordered. However, the age-adjusted d-dimer does not apply to patients suspected of acute DVT. ELEVATED CARDIAC BIOMARKERS  Serum troponin increases because of RV microinfarction. Myocardial stretch causes release of brain natri­ uretic peptide or NT-pro-brain natriuretic peptide. ELECTROCARDIOGRAM  The most frequently cited abnormality, in addition to sinus tachycardia, is the S1Q3T3 sign: an S wave in lead I, a Q wave in lead III, and an inverted T wave in lead III (Chap. 247). This finding is relatively specific but insensitive. RV strain and ischemia cause the most common abnormality, T-wave inversion in leads V1 to V4 (Fig. 290-11). Noninvasive Imaging Modalities  •  VENOUS ULTRASONOGRAPHY

Ultrasonography of the deep-venous system relies on loss of vein compressibility as the primary diagnostic criterion for DVT. When a normal vein is imaged in cross-section, it readily collapses with gentle manual pressure on the ultrasound transducer. This creates the illusion No Compression CFA CFV FIGURE 290-12  Venous ultrasound, with and without compression of the leg veins. CFA, common femoral artery; CFV, common femoral vein; GSV, great saphenous vein; LT, left.

V1 V4 V2 V5 V3 V6 of a “wink.” With acute DVT, the vein loses its compressibility because of passive distention by acute thrombus. The diagnosis of acute DVT is even more secure when thrombus is directly visualized; it appears homogeneous, is located in the center of the vein, and has low echo­ genicity (Fig. 290-12). The vein itself often appears mildly dilated, and collateral channels may be absent. Venous flow dynamics can be examined with Doppler imaging. Normally, manual calf compression causes augmentation of the Dop­ pler flow pattern. Loss of normal respiratory variation is caused by an obstructing DVT or by any obstructive process within the pelvis. For patients with a technically poor or nondiagnostic venous ultrasound, consider alternative imaging modalities such as CT and magnetic resonance imaging. CHEST ROENTGENOGRAPHY  A normal or nearly normal chest x-ray often occurs in PE. Well-established abnormalities include focal olige­ mia (Westermark’s sign), a peripheral triangular-shaped density usually located at the pleural base (Hampton’s hump—which is usually due to pulmonary infarction), and an enlarged right descending pulmonary artery (Palla’s sign). Compression CFA CFV

A RV LV B FIGURE 290-13  A. Massive bilateral proximal pulmonary embolism on an axial chest CT image in a 53-year-old man (whose electrocardiogram is shown in Fig. 290-11) with filling defects in the right and left main pulmonary arteries (white arrows). B. Four-chamber view in the same patient showing the right ventricle (RV) larger than the left ventricle (LV). CHEST CT  CT pulmonary angiography with intravenous contrast is the principal imaging test for the diagnosis of PE (Fig. 290-13A). Thin-cut chest CT images can provide exquisite detail, with ≤1 mm of resolution during a short breath hold. Sixth-order branches can be visualized with resolution superior to that of conventional invasive contrast pulmonary angiography. The CT scan also provides an excel­ lent four-chamber view of the heart (Fig. 290-13B). RV enlargement on chest CT indicates an increased likelihood of death within the next 30 days compared with PE patients who have normal RV size (commonly defined as a right to left ventricular diameter ratio >1). In patients without PE, the lung parenchymal images may establish alter­ native diagnoses not apparent on chest x-ray that explain the present­ ing symptoms and signs, such as pneumonia, emphysema, pulmonary fibrosis, pulmonary mass, and aortic pathology. LUNG SCANNING  Ventilation/perfusion lung scanning has become a second-line diagnostic test for PE, used mostly for patients who cannot tolerate intravenous contrast. Small particulate aggregates of albumin labeled with a gamma-emitting radionuclide are injected intravenously and trapped in the pulmonary capillary bed. The perfusion scan defect indicates absent or decreased blood flow, possibly due to PE. Ventila­ tion scans, obtained with a radiolabeled inhaled gas such as xenon or krypton, improve the specificity of the perfusion scan. Abnormal ven­ tilation scans indicate abnormal nonventilated lung, thereby providing possible explanations for perfusion defects other than acute PE, such as asthma or chronic obstructive pulmonary disease. A high-probability

scan for PE is defined as two or more segmental perfusion defects in the presence of normal ventilation. The diagnosis of PE is very unlikely in patients with normal and nearly normal scans and, in contrast, is ~90% certain in patients with high-probability scans.

CHAPTER 290 MAGNETIC RESONANCE (MR) (CONTRAST-ENHANCED) IMAGING  When pelvic or leg ultrasound is equivocal, MR venography with gadolinium contrast is an excellent imaging modality to diagnose DVT. MR pulmo­ nary angiography may detect large proximal PE but is not reliable for smaller segmental and subsegmental PE. ECHOCARDIOGRAPHY  Echocardiography is not a reliable diagnostic imaging tool for acute PE because most patients with PE have nor­ mal echocardiograms. However, echocardiography is very useful for detecting conditions that may mimic PE, such as acute MI, pericar­ dial tamponade, and aortic dissection. Transthoracic echocardiogra­ phy rarely images thrombus directly in the main pulmonary artery or the right or left main branches. The best-known indirect sign of PE on transthoracic echocardiography is McConnell’s sign: hypokinesis of the RV free wall with normal or hyperkinetic motion of the RV apex. Deep-Venous Thrombosis and Pulmonary Thromboembolism Invasive Diagnostic Modalities  •  PULMONARY ANGIOGRAPHY 

Chest CT pulmonary angiography with contrast (see above) has vir­ tually replaced invasive pulmonary angiography as a diagnostic test. Invasive catheter-based diagnostic testing is reserved for patients with technically unsatisfactory chest CTs and for those in whom an interventional procedure such as catheter-directed thrombolysis or embolectomy is planned. A definitive diagnosis of PE requires visual­ ization of an intraluminal filling defect in more than one projection. Secondary signs of PE include abrupt occlusion (“cut-off”) of vessels, segmental oligemia, avascularity, and a prolonged arterial phase with slow filling and tortuous, tapering peripheral vessels. CONTRAST PHLEBOGRAPHY  Venous ultrasonography has virtually replaced contrast phlebography as the principal diagnostic test for suspected DVT. However, contrast phlebography is used when an interventional procedure is planned. Integrated Diagnostic Approach  An integrated diagnostic approach streamlines the workup of suspected DVT and PE (Fig. 290-14). TREATMENT Deep-Venous Thrombosis UPPER EXTREMITY DVT As peripherally inserted central catheter (PICC) use has increased, so has the rate of upper extremity DVT. This rate can be decreased by more judicious selection of patients who require a PICC, use of single-lumen rather than double- or triple-lumen PICCs, and use of the smallest possible lumen size, ideally 4 French rather than 5 or 6 French. ISOLATED CALF DVT The GARFIELD-VTE Registry recruited 2145 patients with isolated calf DVT and 3846 patients with proximal DVT with or without calf DVT. Isolated calf DVT patients were more likely to have either undergone surgery or have experienced leg trauma, and they were less likely to have active cancer or a prior history of VTE. Almost all isolated calf DVT patients received anticoagulation, and nearly half were anticoagulated for at least 1 year. FIBRINOLYSIS If advanced therapy beyond anticoagulation is warranted, one can utilize clot dissolution or clot extraction therapy with catheterdirected therapy. The open vein hypothesis postulates that patients who receive primary therapy will sustain less long-term damage to venous valves, with consequent lower rates of postthrombotic syndrome. However, the ATTRACT trial randomized 692 patients with femoral or iliofemoral DVT to catheter-directed therapy plus

DVT imaging test Venous ultrasound PART 6 Disorders of the Cardiovascular System Diagnostic Nondiagnostic Stop MR CT Phlebography PE imaging test Chest CT Diagnostic Nondiagnostic, unavailable, or unsafe Stop Lung scan Diagnostic Nondiagnostic Stop Venous ultrasound Positive Negative Treat for PE Transesophageal ECHO or MR or invasive pulmonary angiography FIGURE 290-14  Integrated diagnostic approach. CT, computed tomography; DVT, deep-venous thrombosis; ECHO, echocardiography; MR, magnetic resonance; PE, pulmonary embolism. anticoagulation versus usual care with anticoagulation alone. After 2 years of follow-up, there was no overall reduction in postthrom­ botic syndrome in the thrombolysis group. However, there was a trend toward less postthrombotic syndrome among patients with iliofemoral DVT (compared with only femoral DVT) who received catheter-directed thrombolysis compared with anticoagulation alone. COMPRESSION STOCKINGS For patients with swelling of the legs when acute DVT is diag­ nosed, below-knee graduated compression stockings may be pre­ scribed, usually 30–40 mmHg or 20–30 mmHg, to lessen patient discomfort. They should be replaced every 3–6 months because they lose their elasticity. However, prescription of vascular com­ pression stockings in asymptomatic newly diagnosed acute DVT patients does not prevent the development of postthrombotic syndrome. TREATMENT Pulmonary Embolism RISK STRATIFICATION Hemodynamic instability, RV dysfunction on echocardiography, RV enlargement on chest CT, and elevation of the troponin level due to RV microinfarction portend a high risk of adverse clinical outcomes despite anticoagulation. However, in most cases, RV

Risk stratify Normotension plus normal RV Normotension plus RV hypokinesis Hypotension Secondary prevention Individualize therapy Primary therapy Anticoagulation plus thrombolysis IVC filter Embolectomy: catheter/surgical Anticoagulation alone FIGURE 290-15  Acute management of pulmonary thromboembolism. IVC, inferior vena cava; PE, pulmonary embolism; RV, right ventricular. function and hemodynamic function remain normal, which por­ tend an excellent prognosis and clinical outcome (Fig. 290-15). ANTICOAGULATION There are three major strategies for anticoagulation: (1) the well-established—but waning—strategy of parenteral anticoagu­ lation with unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or fondaparinux either as monotherapy or more often “bridged” to warfarin; (2) parenteral anticoagulation, switched after 5 days to dabigatran (a direct thrombin inhibi­ tor) or edoxaban (an anti-Xa agent); or (3) oral anticoagulation monotherapy with rivaroxaban or apixaban (both anti-Xa agents) with a 3-week or 1-week loading dose, respectively. For patients with VTE in the setting of suspected or proven heparin-induced thrombocytopenia, one can choose between two intravenous direct thrombin inhibitors: argatroban (metabolized by the liver) or bivalirudin (metabolized by the kidney), or subcutaneously administered fondaparinux (Table 290-4). Unfractionated Heparin  UFH binds to and accelerates the activity of antithrombin, thus preventing additional thrombus formation. Intravenous UFH is typically dosed to achieve a target activated partial thromboplastin time (aPTT) of 60–80 s, which usually corresponds to a chromogenic anti-Xa level of 0.3–0.7 U/mL. When switching from a direct oral anticoagulant (DOAC) to intravenous UFH, monitor the aPTT, not the chromogenic antiXa assay. However, the anti-Xa assay is more accurate than the aPTT in critically ill patients, APS, pregnancy, and suspected heparin resistance. In patients with normal liver function, use an initial bolus of 80 U/kg as a loading dose of UFH, followed by an initial infusion rate of 18 U/kg per h in patients with normal liver function. The short half-life of UFH is especially useful in patients in whom hourto-hour control of anticoagulation intensity is desired. Heparin also has pleiotropic effects that may decrease systemic and local inflammation. Low-Molecular-Weight Heparins  These fragments of UFH exhibit less binding to plasma proteins and endothelial cells and consequently have greater bioavailability, a more predictable dose response, and a longer half-life than UFH. No monitoring or dose adjustment is needed unless the patient is markedly obese or has chronic kidney disease. Fondaparinux  Fondaparinux, an anti-Xa pentasaccharide, is essentially an ultra-low-molecular-weight heparin. It is adminis­ tered as a weight-based, once-daily subcutaneous injection in a pre­ filled syringe. No laboratory monitoring is required. Fondaparinux is synthesized in a laboratory and, unlike LMWH or UFH, is not derived from animal products. It does not cause heparininduced thrombocytopenia. For patients with renal dysfunction, the fondaparinux dose must be adjusted downward.

TABLE 290-4  Anticoagulation of VTE Non-Warfarin Anticoagulation Unfractionated heparin, bolus and continuous infusion, to achieve aPTT 2–3 times the upper limit of the laboratory normal, or Enoxaparin 1 mg/kg twice daily with normal renal function, or Dalteparin 200 U/kg once daily or 100 U/kg twice daily, with normal renal function, or Tinzaparin 175 U/kg once daily with normal renal function, or Fondaparinux weight-based once daily; adjust for impaired renal function Direct thrombin inhibitors: argatroban or bivalirudin (with suspected or proven heparin-induced thrombocytopenia) Rivaroxaban 15 mg twice daily for 3 weeks, followed by 20 mg once daily with the dinner meal thereafter. For CrCl 15–50 mL/min: 10 mg twice daily. Apixaban 10 mg twice daily for 1 week, followed by 5 mg twice daily thereafter. In patients with at least 2 of the following characteristics: age >80 years, body weight <60 kg, or serum creatinine >1.5 mg/dL, the recommended dose is 2.5 mg orally twice daily. Dabigatran: 5 days of unfractionated heparin, LMWH, or fondaparinux followed by dabigatran 150 mg twice daily with CrCl >30 mL/min. For CrCl 15–30 mL/min: 75 mg twice daily. Edoxaban: 5 days of unfractionated heparin, LMWH, or fondaparinux followed by edoxaban 60 mg once daily with normal renal function, weight

60 kg, in the absence of potent P-glycoprotein inhibitors. For CrCl 15–50 mL/ min: 30 mg once daily. Warfarin Anticoagulation Requires 5–10 days of administration to achieve effectiveness as monotherapy Use full-dose unfractionated heparin, LMWH, or fondaparinux as “bridging agents” when initiating warfarin. Continue parenteral anticoagulation for a minimum of 5 days and until two sequential INR values, at least 1 day apart, achieve the target INR range. Usual start dose is 5 mg Titrate to INR, target 2.0–3.0 Abbreviations: aPTT, activated partial thromboplastin time; CrCl, creatinine clearance; INR, international normalized ratio; LMWH, low-molecular-weight heparin; VTE, venous thromboembolism. Warfarin  This vitamin K antagonist prevents carboxylationdependent activation of coagulation factors II, VII, IX, and X (Chap. 69). The full effect of warfarin is attained after daily therapy for 5–7 days. Overlapping UFH, LMWH, fondaparinux, or parenteral direct thrombin inhibitors during initiation of war­ farin provides therapeutic levels of anticoagulation. Parenteral anticoagulation is discontinued when warfarin has achieved a target international normalized ratio (INR) of 2.5. Warfarin can cause major hemorrhage, including intracranial hemorrhage, even when the INR remains within the desired therapeutic range. Warfarin can also cause “off-target” side effects such as alopecia or arterial vascular calcification. Centralized anticoagulation clinics have improved the efficacy and safety of warfarin dosing. Some patients can self-monitor their INR with a home point-of-care fingerstick machine, and a few can be taught to self-dose their warfarin. Direct Oral Anticoagulants  DOACs are administered in a fixed dose, establish effective anticoagulation within hours of ingestion, do not require laboratory coagulation monitoring or limitation of green leafy vegetables, and have few drug-drug interactions. DOACs should not be prescribed during pregnancy or breastfeed­ ing. Warfarin, not DOACs, is the standard treatment for APS. The efficacy and safety of DOACs remain uncertain in patients with end-stage kidney disease or cirrhosis. Management of Bleeding from Anticoagulants  For life-threatening or intracranial hemorrhage due to heparin or LMWH, administer protamine sulfate. The dabigatran antibody, idarucizumab, is an effective, rapidly acting antidote for dabigatran. Andexanet alfa or protein complex concentrate reverses major bleeding caused by anti-Xa DOACs, but beware of rebound thrombosis. With minor

TABLE 290-5  Take-Home Points from the European Society of Cardiology 2019 Pulmonary Embolism Guidelines

  1. Terminology such as “provoked” versus “unprovoked” PE/DVT is no longer supported by the guidelines, as it is potentially misleading and not helpful for decision-making regarding the duration of anticoagulation.
  2. Extended oral anticoagulation without an end date should be considered for CHAPTER 290 patients with a first episode of PE and:

a. No identifiable risk factor

b. A persistent risk factor

c. A minor transient or reversible risk factor Deep-Venous Thrombosis and Pulmonary Thromboembolism Abbreviations: DVT, deep-venous thrombosis; PE, pulmonary embolism. bleeding, fresh-frozen plasma, vitamin K, or observation without pharmacologic intervention can be considered. Cancer and Venous Thromboembolism  For patients with can­ cer and VTE, prescribe LMWH as monotherapy or a DOAC in the absence of a gastrointestinal cancer, and continue extendedduration anticoagulation until the patient is declared cancer-free. The National Comprehensive Cancer Network guidelines endorse treatment of VTE with apixaban or edoxaban. Duration of Anticoagulation  Data-driven guidelines from the European Society of Cardiology are changing our conceptual approach to determining the optimal duration of anticoagulation (Tables 290-5 and 290-6). We should no longer classify VTE as “provoked” or “unprovoked,” given that many types of provoked VTE have a similar recurrence rate to unprovoked VTE once anti­ coagulation is discontinued. Enduring risk factors such as heart failure, chronic lung disease, and inflammatory bowel diseases can heighten the risk of recurrence. INFERIOR VENA CAVA FILTERS The two principal indications for insertion of an inferior vena cava filter are (1) active bleeding that precludes anticoagulation and (2) recurrent venous thrombosis despite intensive anticoagulation. Prevention of PE in patients who are not candidates for anticoagu­ lation is a much “softer” indication for filter placement. The filter itself may fail by permitting the passage of small- to medium-size clots via collateral veins that develop. Paradoxically, by providing a nidus for clot formation, filters may increase the DVT rate even though they usually prevent PE. In most situations, place a retriev­ able rather than a permanent filter. MANAGEMENT OF MASSIVE PE For patients with massive PE and hypotension, replete volume with 500 mL of normal saline. Excessive fluid administration exacerbates RV wall stress, causes more profound RV ischemia, and worsens LV compliance and filling by causing further interventricular septal shift toward the LV. Norepinephrine and dobutamine are first-line vasopressor and inotropic agents, respectively, for treatment of PErelated shock. Norepinephrine increases systemic arterial pressure. Dobutamine increases RV inotropy and lowers filling pressures. If TABLE 290-6  Risk of Recurrent Venous Thromboembolism After Discontinuing Anticoagulation (European Society of Cardiology 2019 Pulmonary Embolism Guidelines) RISK OF RECURRENCE EXAMPLES Low risk (<3% per year) Major surgery or trauma Intermediate risk (3–8% per year) Minor surgery Hospitalized with acute medical illness Pregnancy/estrogens Long-haul flight Inflammatory bowel disease Autoimmune disease No identifiable risk factor (formerly called “unprovoked”) High risk (>8% per year) Active cancer Antiphospholipid syndrome

additional hemodynamic circulatory support is required, available, and within the scope of the patient’s goals of care, consider venoarterial extracorporeal membrane oxygenation (ECMO).

FIBRINOLYSIS Successful fibrinolytic therapy rapidly reverses right heart failure and may result in a lower rate of death and recurrent PE by (1) dis­ solving much of the anatomically obstructing pulmonary arterial thrombus, (2) preventing the continued release of serotonin and other neurohumoral factors that exacerbate pulmonary hyperten­ sion, and (3) lysing much of the source of the thrombus in the pelvic or deep leg veins, thereby potentially decreasing the likelihood of recurrent PE. PART 6 Disorders of the Cardiovascular System For massive PE, the U.S. Food and Drug Administration has approved systemically administered 100 mg of recombinant tissue plasminogen activator (tPA) (alteplase) prescribed as a continuous intravenous infusion over 2 h. The sooner thrombolysis is admin­ istered, the more effective it is. However, systemic fibrinolysis can be utilized effectively for at least 14 days after the PE has occurred. A popular but controversial off-label dosing regimen is 50 mg of tPA administered over 2 h. This lower dose appears less effective than full-dose tPA but may be associated with fewer bleeding complications. Contraindications to fibrinolysis include intracranial disease, recent surgery, and trauma. The overall major bleeding rate is ~10%, including a 2–3% risk of intracranial hemorrhage. Careful screening of patients for contraindications to fibrinolytic therapy (Chap. 286) is the best way to minimize bleeding risk. For patients with submassive PE who have preserved systolic blood pressure but moderate or severe RV dysfunction, use of fibrinolysis remains controversial. A 2019 American Heart Associa­ tion Scientific Statement suggests consideration of thrombolysis or embolectomy in patients with a lack of clinical improvement, clini­ cal deterioration, clot in transit, severe or persistent RV strain, or signs of low cardiac output. CATHETER-DIRECTED THERAPY There are three types of catheter-directed therapy to treat VTE: (1) pharmacologic only, (2) mechanical only, or (3) pharmacomechani­ cal. Pharmacologic therapy usually utilizes a low-dose continuous infusion of tPA. Mechanical therapy serves as a percutaneous thrombectomy. The procedure usually employs suction, snaring, and extraction of thrombus without using thrombolytic therapy. One mechanical device is a catheter with expandable nitinol disks that traps the thrombus, which is then removed. Pharmacomechani­ cal therapy is epitomized by low-energy ultrasound-facilitated lowdose thrombolysis. The low-dose thrombolysis strategy most likely explains the lower major bleeding complication rate compared with systemically administered fibrinolysis. SURGICAL PULMONARY EMBOLECTOMY The substantial risk of major hemorrhage with systemically admin­ istered fibrinolysis reawakened interest in alternative treatment with surgical embolectomy, an operation that had almost become extinct. More rapid referral for surgery before the onset of irrevers­ ible multisystem organ failure, improved surgical technique, and utilization of ECMO have increased the survival rate of surgical pulmonary embolectomy and have markedly improved right ven­ tricular function. PULMONARY THROMBOENDARTERECTOMY CTEPH develops in about 2% of acute PE patients. Therefore, PE patients who have initial pulmonary hypertension (often detected initially during echocardiography) should be followed up at about 6 weeks and, if necessary, at 6 months, with repeat echo­ cardiograms to determine whether pulmonary arterial pressure has worsened, plateaued, or abated. Patients impaired by dyspnea due to CTEPH should be considered for pulmonary thromboen­ darterectomy, which can markedly reduce, and sometimes even cure, pulmonary hypertension (Chap. 294). The operation requires

TABLE 290-7  Prevention of Venous Thromboembolism Among Hospitalized Patients CONDITION PROPHYLAXIS STRATEGY High-risk nonorthopedic surgery Unfractionated heparin 5000 units SC bid or tid Enoxaparin 40 mg daily Dalteparin 2500 or 5000 units daily Medical oncology (ambulatory) Apixaban or rivaroxaban for up to 6 months in high-risk patients with cancer starting a new chemotherapy regimen Cancer surgery, including gynecologic cancer surgery Enoxaparin 40 mg daily, consider 1 month of prophylaxis Major orthopedic surgery Aspirin 81 mg twice daily Rivaroxaban 10 mg daily, beginning 6–10 h postoperatively Dabigatran 110 mg first day, then 220 mg daily Apixaban 2.5 mg bid, beginning 12–24 h postoperatively Warfarin (target INR 2.0) Enoxaparin 40 mg daily Dalteparin 2500 or 5000 units daily Fondaparinux 2.5 mg daily Medically ill patients, especially if immobilized, with a history of prior VTE, with an indwelling central venous catheter, or with cancer (but without active gastroduodenal ulcer, major bleeding within 3 months, or platelet count <50,000) Unfractionated heparin 5000 units bid or tid Enoxaparin 40 mg daily Dalteparin 2500 or 5000 units daily Fondaparinux 2.5 mg daily Medically ill patients about to be discharged from hospital Rivaroxaban 10 mg daily for about 5 weeks (rarely prescribed for this indication) Anticoagulation contraindicated Intermittent pneumatic compression devices and/ or graduated vascular below-knee compression stockings Abbreviations: INR, international normalized ratio; VTE, venous thromboembolism. median sternotomy, cardiopulmonary bypass, deep hypothermia, and periods of hypothermic circulatory arrest. The mortality rate at experienced centers is 1–5%. Inoperable patients should be man­ aged with pulmonary vasodilator therapy and balloon angioplasty of pulmonary arterial webs. ■ ■PREVENTION OF VTE Prevention of DVT and PE (Table 290-7) is of paramount importance because VTE is difficult to detect and poses a profound medical and economic burden. Low-dose UFH or LMWH is the most common form of in-hospital prophylaxis. Computerized reminder systems in ambulatory and in-hospital practices can increase the use of preventive measures and, at Brigham and Women’s Hospital, have reduced the symptomatic VTE rate. ■ ■EMOTIONAL SUPPORT Patients with VTE may feel overwhelmed when they learn that they are suffering from PE or DVT. Some have never previously encoun­ tered serious cardiovascular illness. They often assume they will have a reduced life expectancy. They worry about the health of their families and the genetic implications of their illness. At Brigham and Women’s Hospital, a physician-nurse–facilitated PE support group was initiated to address these concerns and has met monthly for >30 years. The non­ profit North American Thrombosis Forum (www.thrombosis.org) runs monthly online support groups that garner worldwide participation. ■ ■FURTHER READING Barco S et al: Age-sex specific pulmonary embolism-related mortality in the USA and Canada, 2000–18: An analysis of the WHO Mortality Database and of the CDC Multiple Cause of Death database. Lancet Respir Med 9:33, 2021.

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291 Diseases of the Aorta

Bejjani A et al: When direct oral anticoagulants should not be stan­ dard treatment. JACC State-of-the-Art Review. J Am Coll Cardiol 83:444, 2024. Bikdeli B et al: COVID-19 and thrombotic or thromboembolic disease: Implications for prevention, antithrombotic therapy, and follow-up. J Am Coll Cardiol 75:2590, 2020. Ghouse J et al: Genome-wide meta-analysis identifies 93 risk loci and enables risk prediction equivalent to monogenic forms of venous thromboembolism. Nat Genet 55:399, 2023. Goldberg JB et al: Survival and right ventricular function after surgi­ cal management of acute pulmonary embolism. J Am Coll Cardiol 76:903, 2020. Kobayashi T et al: Contemporary management of outcomes of patients with high-risk pulmonary embolism. J Am Coll Cardiol 83:35, 2024. Konstantinides SV et al: 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in col­ laboration with the European Respiratory Society (ERS). Eur Heart J 41:543, 2020. Luijten D et al: Post-pulmonary embolism syndrome and functional outcomes after acute pulmonary embolism. Semin Thromb Hemost 49:848, 2023. Murthi M et al: Pulmonary embolism readmission trend over the years (from a National Readmission Database). Am J Cardiol 184:133, 2022. Wadhera RK et al: Community socioeconomic status, acute cardio­ vascular hospitalizations and mortality among Medicare beneficia­ ries, 2003 to 2019. Circ Cardovasc Qual Outcomes 17:e010090. 2024. Mark A. Creager, Joseph Loscalzo

Diseases of the Aorta The aorta is the conduit through which blood ejected from the left ventricle is delivered to the systemic arterial bed. In adults, its diameter is ~3.5 cm at the origin and in the ascending portion, ~2.5 cm in the descending portion in the thorax, and 1.8–2.0 cm in the abdomen. The aortic wall consists of a thin intima composed of endothelium, subendothelial connective tissue, and an internal elastic lamina; a thick tunica media composed of smooth muscle cells, elastic fibers, collagen, and extracellular matrix; and an adventitia composed primarily of con­ nective tissue enclosing the vasa vasorum and nervi vascularis. In addi­ tion to the conduit function of the aorta, its viscoelastic and compliant properties serve a buffering function. The aorta is distended during systole to allow a portion of the stroke volume and elastic energy to be stored, and it recoils during diastole so that blood continues to flow to the periphery. Owing to its continuous exposure to high pulsatile pres­ sure and shear stress, the aorta is particularly prone to injury and dis­ ease resulting from mechanical trauma. The aorta is also more prone to rupture than is any other vessel, especially with the development of aneurysmal dilation, since its wall tension, as governed by Laplace’s law (i.e., proportional to the product of pressure and radius), will be increased. CONGENITAL ANOMALIES OF THE AORTA Congenital anomalies of the aorta usually involve the aortic arch and its branches. Symptoms such as dysphagia, stridor, and cough may occur if an anomaly causes a ring around or otherwise compresses the esophagus or trachea. Anomalies associated with symptoms include double aortic arch, origin of the right subclavian artery distal to the left subclavian artery, and right-sided aortic arch with an aberrant left subclavian artery. A Kommerell diverticulum

is an anatomic remnant of a right aortic arch. Most congenital anomalies of the aorta do not cause symptoms and are detected during catheter-based procedures. The diagnosis of suspected con­ genital anomalies of the aorta typically is confirmed by computed tomographic (CT) or magnetic resonance (MR) angiography. Sur­ gery is used to treat symptomatic anomalies.

CHAPTER 291 Coarctation of the aorta (Chap. 280) typically occurs near the insertion of the ligamentum arteriosum, adjacent to the left subclavian artery. It may be associated with a bicuspid aortic valve, aortic arch hypoplasia, other congenital heart defects, and intracranial aneu­ rysms. A pulse delay or pressure differential between the upper and lower extremities should raise suspicion of aortic coarctation. Imaging modalities, including echocardiography, CT, and MR angiography are used to confirm the diagnosis. If untreated, hypertension develops in the arteries proximal to the coarctation. Treatment of hemodynami­ cally significant aortic coarctation includes endovascular stent implan­ tation if feasible or surgical repair. Diseases of the Aorta AORTIC ANEURYSM An aneurysm is defined as a pathologic dilation of a segment of a blood vessel. A true aneurysm involves all three layers of the vessel wall and is distinguished from a pseudoaneurysm, in which the intimal and medial layers are disrupted and the dilated segment of the aorta is lined by adventitia only and, at times, by perivascular clot. Aneurysms also may be classified according to their gross appearance. A fusiform aneurysm affects the entire circumference of a segment of the vessel, resulting in a diffusely dilated artery. In contrast, a saccular aneurysm involves only a portion of the circumference, resulting in an outpouching of the vessel wall. Aortic aneurysms also are classified according to location, i.e., abdominal versus thoracic. Aneurysms of the descending thoracic aorta are usually contiguous with infradiaphragmatic aneurysms and are referred to as thoracoabdominal aortic aneurysms. ■ ■ETIOLOGY Aortic aneurysms result from conditions that cause degradation or abnor­ mal production of the structural components of the aortic wall: elastin and collagen. The causes of aortic aneurysms may be broadly categorized as degenerative or sporadic, heritable, congenital, aortitis, infective, and trauma (Table 291-1). Inflammation, oxidative stress, proteolysis, and biomechanical wall stress contribute to the degenerative processes that characterize most aneurysms of the abdominal and descending thoracic aorta. These are mediated by B-cell and T-cell lymphocytes, macro­ phages, inflammatory cytokines, and matrix metalloproteinases that degrade elastin and collagen and alter the tensile strength and ability of the aorta to accommodate pulsatile stretch. The associated histopathol­ ogy demonstrates destruction of elastin and collagen, decreased vascular smooth muscle, in-growth of new blood vessels, and inflammation. Factors associated with degenerative aortic aneurysms include aging, cigarette smoking, hypercholesterolemia, hypertension, and male sex. The most common pathologic condition associated with degen­ erative aortic aneurysms is atherosclerosis. Many patients with aortic aneurysms have coexisting risk factors for atherosclerosis, as well as atherosclerosis in other blood vessels. The pathologic condition of aortic aneurysms associated with genetic or developmental diseases is medial degeneration, a histopath­ ologic term used to describe the degeneration of collagen and elastic fibers in the tunica media of the aorta as well as the loss of medial cells that are replaced by multiple clefts of mucoid material, such as pro­ teoglycans. Medial degeneration characteristically affects the proximal aorta, results in circumferential weakness and dilation, and leads to the development of fusiform aneurysms involving the ascending aorta and the sinuses of Valsalva. It is found in patients with Marfan syndrome, Loeys-Dietz syndrome, vascular Ehlers-Danlos syndrome (Chap. 425), hypertension, bicuspid aortic valves, Turner syndrome, and familial thoracic aortic aneurysm syndromes. It sometimes appears as an isolated condition in patients without any other apparent disease. Thoracic and abdominal aortic aneurysms also occur in patients with fibromuscular dysplasia, although the nature of the aortic pathology is not established.

TABLE 291-1  Diseases of the Aorta: Etiology and Associated Factors Aortic aneurysm      Degenerative/sporadic           Aging           Cigarette smoking PART 6 Disorders of the Cardiovascular System           Hypercholesterolemia           Hypertension           Atherosclerosis      Heritable           Marfan syndrome           Loeys-Dietz syndrome           Ehlers-Danlos syndrome type IV           Aneurysm-osteoarthritis syndrome           Smooth muscle dysfunction syndrome           Familial (nonsyndromic)      Congenital           Bicuspid aortic valve           Turner syndrome           Aortic coarctation      Fibromuscular dysplasia      Chronic aortic dissection      Aortitis (see below)      Infective (see below)      Trauma Acute aortic syndromes (aortic dissection, acute intramural hematoma, penetrating atherosclerotic ulcer)      Degenerative disorders (see above)      Heritable/disorders (see above)      Congenital disorders (see above)      Hypertension      Aortitis (see below)      Pregnancy      Trauma Aortic occlusion      Atherosclerosis      Thromboembolism Aortitis      Vasculitis           Takayasu’s arteritis           Giant cell arteritis           IgG4-related aortitis           Isolated aortitis      Rheumatic           Rheumatoid aortitis           HLA-B27–associated spondyloarthropathies           Behçet syndrome           Cogan syndrome      Infective           Syphilis           Tuberculosis           Mycotic (Salmonella, staphylococcal, streptococcal, fungal) Familial clusterings of aortic aneurysms occur in 20% of patients, suggesting a hereditary basis for the disease. Mutations of the gene that encodes fibrillin-1 are present in patients with Marfan syndrome. Fibrillin-1 is an important component of extracellular microfibrils, which support the architecture of elastic fibers and other connective tissue. Deficiency of fibrillin-1 in the extracellular matrix leads to excessive signaling by transforming growth factor β (TGF-β). LoeysDietz syndrome is caused by mutations in the genes that encode

TGF-β isoforms (TGFB2 and TGFB3), TGF-β receptors 1 (TGFBR1) and 2 (TGFBR2), and SMAD3, which encodes a downstream signaling protein involved with TGF binding to its receptors. Increased signal­ ing by TGF-β and mutations of TGFBR1, TGFBR2, as well as TGFB2 and TGFB3, may cause thoracic aortic aneurysms. Thoracic aortic aneurysm is associated with autosomal dominant polycystic kidney disease, which is caused by mutations in PKD1. Mutations of the genes encoding the smooth muscle–specific alpha-actin (ACTA2), smooth muscle cell–specific myosin heavy chain 11 (MYH11), myosin light chain kinase (MYLK), and type I cGMP-dependent protein kinase (PRKG1), as well as mutations of TGFBR2 and SMAD3 and several other pathogenic variants, have been reported in some patients with nonsyndromic familial thoracic aortic aneurysms. Mutations in type III procollagen (COL3A1) have been implicated in vascular EhlersDanlos syndrome. The infectious causes of aortic aneurysms include syphilis, tubercu­ losis, and other bacterial infections. Syphilis (Chap. 187) is a relatively uncommon cause of aortic aneurysm. Syphilitic periaortitis and meso­ aortitis damage elastic fibers, resulting in thickening and weakening of the aortic wall. Approximately 90% of syphilitic aneurysms are located in the ascending aorta or aortic arch. Tuberculous aneurysms (Chap. 183) typically affect the thoracic aorta and result from direct extension of infection from hilar lymph nodes or contiguous abscesses as well as from bacterial seeding. Loss of aortic wall elasticity results from granu­ lomatous destruction of the medial layer. A mycotic aneurysm is a rare condition that develops as a result of staphylococcal, streptococcal, Sal­ monella, or other bacterial or fungal infections of the aorta, usually at an atherosclerotic plaque. These aneurysms are usually saccular. Blood cultures are often positive and reveal the nature of the infective agent. Vasculitides associated with aortic aneurysm include Takayasu arte­ ritis and giant cell arteritis, which may cause aneurysms of the aortic arch and descending thoracic aorta. Thoracic and abdominal aortic aneurysms also occur in patients with IgG4-related systemic disease or those with isolated aortitis. Spondyloarthropathies such as anky­ losing spondylitis, rheumatoid arthritis, psoriatic arthritis, relapsing polychondritis, and reactive arthritis are associated with dilation of the ascending aorta. Aortic aneurysms also occur in patients with Behçet syndrome (Chap. 376) and Cogan syndrome. Traumatic aneurysms may occur after penetrating or nonpenetrating chest trauma and most commonly affect the descending thoracic aorta just beyond the site of insertion of the ligamentum arteriosum. Chronic aortic dissections are associated with weakening of the aortic wall that may lead to the development of aneurysmal dilatation. ■ ■THORACIC AORTIC ANEURYSMS A contemporary definition of an aneurysm affecting the aortic root and ascending aorta is that of the diameter ≥4.5 cm, whereas a diam­ eter of 4.0 cm to 4.4 cm is defined as aortic dilation. An aneurysm of the descending thoracic aorta and abdominal aorta is designated when their diameters are dilated 50% more than the adjacent normal diam­ eter. The clinical manifestations and natural history of thoracic aortic aneurysms depend on their cause and location. Medial degeneration is the most common pathology associated with ascending aortic aneu­ rysms, whereas atherosclerosis is the condition most frequently associ­ ated with aneurysms of the descending thoracic aorta. The average growth rate of thoracic aortic aneurysms is 0.1–0.2 cm per year. The risk of rupture is related to the size of the aneurysm and the presence of symptoms, ranging approximately from 2–3% per year for thoracic aortic aneurysms <4.0 cm in diameter to 7% per year for those >6 cm in diameter. Thoracic aortic aneurysms associated with Marfan syn­ drome may expand at a greater rate. Some patients with Loeys-Dietz syndrome, such as those with the TGFBR1 and TGFBR2 pathogenic variants and some with nonsyndromic familial thoracic aortic disease, are at greater risk of rupture at smaller aortic root sizes than those with Marfan syndrome. Most thoracic aortic aneurysms are asymptomatic; however, compression or erosion of adjacent tissue by aneurysms may cause symptoms such as chest pain, shortness of breath, cough, hoarse­ ness, and dysphagia. Aneurysmal dilation of the ascending aorta may cause congestive heart failure as a consequence of aortic regurgitation,

FIGURE 291-1  A chest x-ray of a patient with a thoracic aortic aneurysm.   and compression of the superior vena cava may produce congestion of the head, neck, and upper extremities. A chest x-ray may be the first test that suggests the diagnosis of a thoracic aortic aneurysm (Fig. 291-1). Findings include widening of the mediastinal shadow and displacement or compression of the trachea or left main stem bronchus. Echocardiography, particularly transesophageal echocardiography, can be used to assess the proximal ascending aorta and descending thoracic aorta. Contrast-enhanced CT, magnetic resonance imaging (MRI), and conventional invasive aor­ tography are sensitive and specific tests for assessment of aneurysms of the thoracic aorta and involvement of branch vessels (Fig. 291-2). In asymptomatic patients whose aneurysms are too small to justify surgery, noninvasive testing with either contrast-enhanced CT or MRI should be performed initially at least every 6–12 months to monitor expansion. Subsequent surveillance imaging should be performed every 6–24 months depending on the size, stability of prior measure­ ments, and the underlying cause. FIGURE 291-2  A magnetic resonance angiogram demonstrating a fusiform aneurysm of the ascending thoracic aorta. (Courtesy of Dr. Michael Steigner, Brigham and Women’s Hospital, Boston, MA, with permission.)

Genetic testing is recommended in patients with ascending thoracic aortic disease who have features of Marfan syndrome, Loeys-Dietz syndrome, or vascular Ehlers-Danlos syndrome, or who present when they are <60 years of age.

CHAPTER 291 TREATMENT Thoracic Aortic Aneurysms Many of the treatment recommendations herein are derived from the recent American Heart Association (AHA)/American College of Cardiology (ACC) Aortic Disease Clinical Practice Guidelines. Treatment with either a β-adrenergic blocker or angiotensin recep­ tor antagonist currently is recommended for patients with thoracic aortic aneurysms associated with Marfan syndrome and LoeysDietz syndrome who have evidence of aortic root dilatation to reduce the rate of further expansion. Clinical outcome trials have found that the rate of aortic root enlargement in patients with Marfan syndrome was similar with a β-adrenergic blocker, such as atenolol, and an angiotensin receptor antagonist, such as losartan. These classes of drugs likely confer beneficial effects by different mechanisms. β-adrenergic blockers may decrease the rate of aortic dilation in these patients by reducing stiffness, and angiotensin receptor antagonists may reduce the rate of aortic dilation by block­ ing TGF-β signaling. Combination therapy with both a β-adrenergic blocker and angiotensin receptor antagonist may be considered. In patients with Ehlers-Danlos syndrome, celiprolol, a β-adrenergic blocker with vasodilator properties, has shown efficacy, but is not available in the United States. For these and other patients with tho­ racic aortic aneurysms, additional medical therapy should be given as necessary to control hypertension. Risk factor modification with lipid-lowering therapy, smoking cessation interventions, as well as low-dose aspirin, is advised for patients with degenerative thoracic aortic aneurysms associated with atherosclerosis. Operative repair with placement of a prosthetic graft is indicated in patients with symptomatic ascending thoracic aortic aneurysms, and for most asymptomatic aneurysms, including those associated with bicuspid aortic valves, when the aortic root or ascending aortic diameter is ≥5.0 to ≥5.5 cm. The lower threshold applies to patients with high-risk features, such as a family history of aortic dissection or an aortic growth rate ≥0.3 cm per year for 2 years or when the growth rate is >0.5 cm per year, and when performed under the direction of an experienced multidisciplinary aortic team. Replacement of the ascending aorta ≥4.5 cm is reasonable in patients with bicuspid aortic valves undergoing aortic valve replacement because of severe aortic stenosis or aortic regurgitation. In patients with Marfan syn­ drome, aortic root and ascending thoracic aortic aneurysms of ≥4.5 to ≥5.0 cm should be considered for surgery, with the threshold also depending on the presence of high-risk features. Due to the higher risk of dissection at smaller aortic sizes in patients with LoeysDietz syndrome and those with nonsyndromic familial thoracic aortic aneurysms, the aortic diameter threshold for operative repair ranges from ≥4.0 to ≥5.0 cm, depending on the genetic variant and presence of high-risk features. Repair is indicated for patients with isolated aortic arch aneurysms and descending thoracic aortic aneurysms when the diameter is ≥5.5 cm. The threshold for repair of a descending thoracic aortic aneurysm of ≥5.0 cm may be con­ sidered in patients with syndromic and nonsyndromic heritable aortopathies or when the diameter of a descending thoracic aortic aneurysm has increased >0.5 cm per year. Diseases of the Aorta ■ ■ABDOMINAL AORTIC ANEURYSMS Abdominal aortic aneurysms occur more frequently in males than in females, and the incidence increases with age. Cigarette smoking is a potent modifiable risk factor. Abdominal aortic aneurysms ≥4.0 cm may affect 1–2% of men aged >50 years. At least 90% of all abdomi­ nal aortic aneurysms >4.0 cm are related to atherosclerotic disease, and most of these aneurysms are below the level of the renal arteries.

PART 6 Disorders of the Cardiovascular System A   FIGURE 291-3  A computed tomographic angiogram depicting a fusiform abdominal aortic aneurysm before (A) and after (B) treatment with a bifurcated stent graft. (Courtesy of Drs. Elizabeth George and Frank Rybicki, Brigham and Women’s Hospital, Boston, MA, with permission.) Prognosis is related to both the size of the aneurysm and the severity of coexisting coronary artery and cerebrovascular disease. The risk of rupture increases with the size of the aneurysm: the 5-year risk for aneurysms <5 cm is 1–2%, whereas it is 20–40% for aneurysms >5 cm in diameter. The formation of mural thrombi within aneurysms may predispose to peripheral embolization. An abdominal aortic aneurysm commonly produces no symptoms. It usually is detected on routine examination as a palpable, pulsatile, expansile, and nontender mass, or it is an incidental finding observed on an abdominal imaging study performed for other reasons. As abdominal aortic aneurysms expand, however, they may become painful. Some patients complain of strong pulsations in the abdomen; others experience pain in the chest, lower back, or scrotum. Aneurys­ mal pain is usually a harbinger of rupture and represents a medical emergency. More often, acute rupture occurs without any prior warn­ ing, and this complication is always life-threatening. Rarely, there is leakage of the aneurysm with severe pain and tenderness. Acute pain and hypotension occur with rupture of the aneurysm, which requires an emergency operation or endovascular repair. Abdominal radiography may demonstrate the calcified outline of the aneurysm; however, ~25% of aneurysms are not calcified and cannot be visualized by x-ray imaging. An abdominal ultrasound can delineate the transverse and longitudinal dimensions of an abdominal aortic aneurysm and may detect mural thrombus. Abdominal ultra­ sound is useful for serial documentation of aneurysm size and can be used to screen patients at risk for developing an aortic aneurysm. In a large study, ultrasound screening of men aged 65–74 years was associated with a risk reduction in aneurysm-related death of 42%. In a meta-analysis of population-based randomized clinical trials, ultrasound screening of men aged 65 years or older was associated with a 35% risk reduction in aneurysm-related death over 12–15 years. According to the AHA/ACC Guidelines on Aortic Disease, screening by ultrasonography is recommended for men aged ≥65 years who have ever smoked. Although the prevalence of abdominal aortic aneurysms is less in women than in men, the risk of abdominal aortic aneurysms is still substantially increased in women who have smoked. Accordingly, it is reasonable to consider abdominal aortic aneurysm screening in women aged ≥65 years who have ever smoked. In addition, screen­ ing for abdominal aortic aneurysms is recommended for males and

B females ≥65 years who have siblings or offspring with abdominal aortic aneurysms. Individuals with thoracic aortic or peripheral arterial aneu­ rysms should also undergo screening for abdominal aortic aneurysms. CT with contrast and MRI are accurate noninvasive tests to determine the location and size of abdominal aortic aneurysms and to plan endovascular or open surgical repair (Fig. 291-3A). Contrast aortog­ raphy may be used for the evaluation of patients with aneurysms, but the procedure carries a small risk of complications such as bleeding, allergic reactions, and atheroembolism. Since the presence of mural thrombi may reduce the luminal size, aortography may underestimate the diameter of an aneurysm. TREATMENT Abdominal Aortic Aneurysms Many of the treatment recommendations for abdominal aortic aneurysms are derived from the AHA/ACC Aortic Disease Practice Guidelines. Statins are indicated to reduce the risk of cardiovas­ cular events related to atherosclerosis. Medical therapies, such as β-adrenergic blockers and renin-angiotensin inhibitors, have not proven effective in reducing the rate of aneurysm growth. None­ theless, antihypertensive therapy to lower the blood pressure to <130/<80 mmHg is recommended to reduce the risk of adverse cardiovascular events. Similarly, antiplatelet agents, such as aspirin, are recommended in patients with abdominal aortic aneurysms to reduce the risk of adverse cardiovascular outcomes, but their effects on abdominal aortic aneurysm–specific outcomes are not established. Operative repair of the aneurysm with insertion of a prosthetic graft or endovascular placement of an aortic stent graft (Fig. 291-3B) is indicated for abdominal aortic aneurysms of any size that are expanding rapidly or are associated with symptoms. For asymptomatic aneurysms, abdominal aortic aneurysm repair is indicated if the diameter is ≥5.5 cm in men and ≥5.0 cm in women. In randomized trials of patients with abdominal aortic aneurysms <5.5 cm, there was no difference in the long-term (>8-year) mor­ tality rate between those followed with ultrasound surveillance and those undergoing elective endovascular or surgical repair. The risk of rupture, however, was higher in woman than in men at smaller diameters. Thus, serial noninvasive follow-up of smaller aneurysms

(<5.5 cm in men and <5.0 cm in women) is an alternative to imme­ diate repair. The decision to perform an open surgical operation or endovascular repair is based in part on the vascular anatomy and comorbid conditions. Endovascular repair of abdominal aortic aneurysms has a lower short-term morbidity rate but a compa­ rable long-term mortality rate with open surgical reconstruction. Long-term surveillance with CT or MR aortography is indicated after endovascular repair to detect leaks and possible aneurysm expansion. In surgical candidates, careful preoperative cardiac and general medical evaluations (followed by appropriate therapy for complicat­ ing conditions) are essential. Preexisting coronary artery disease, congestive heart failure, pulmonary disease, diabetes mellitus, and advanced age add to the risk of surgery. With careful preoperative cardiac evaluation and postoperative care, the operative mortality rate approximates 1–2%. After acute rupture, the mortality rate of emergent operation is 45–50%. Endovascular repair with stent placement is an alternative approach to treat ruptured aneurysms and may be associated with a lower mortality rate. ACUTE AORTIC SYNDROMES The four major acute aortic syndromes are aortic rupture (discussed earlier), aortic dissection, intramural hematoma, and penetrating ath­ erosclerotic ulcer. Aortic dissection is caused by a tear of the intima. It often occurs along the right lateral wall of the ascending aorta where the hydraulic shear stress is high. Another common site is the descend­ ing thoracic aorta just below the ligamentum arteriosum. The initiating event is either a primary intimal tear with secondary dissection into the media or a medial hemorrhage that dissects into and disrupts the intima. The pulsatile aortic flow then dissects along the elastic lamel­ lar plates of the aorta and creates a false lumen. The dissection usu­ ally propagates distally down the descending aorta and into its major branches, but it may propagate proximally. Distal propagation may be limited by atherosclerotic plaque. In some cases, a secondary distal intimal disruption occurs, resulting in the reentry of blood from the false to the true lumen. There are at least two important pathologic and radiologic variants of aortic dissection: intramural hematoma without an intimal flap and penetrating atherosclerotic ulcer. Acute intramural hematoma is thought to result from rupture of the vasa vasorum with hemor­ rhage into the wall of the aorta. Most of these hematomas occur in the descending thoracic aorta. Acute intramural hematomas may progress to dissection and rupture. Penetrating atherosclerotic ulcers are caused by erosion of a plaque into the aortic media, are usually localized, but may evolve into an intramural hematoma and also progress to dissection and rupture. They are found primarily in the middle and distal portions of the descending thoracic aorta and are associated with extensive atherosclerotic disease. The ulcer can erode beyond the internal elastic lamina, leading to medial hematoma, and may progress to false aneurysm formation or rupture. Several classification schemes have been developed for thoracic aortic dissections. DeBakey and colleagues initially classified aortic dissections as type I, in which an intimal tear occurs in the ascending aorta but the dissection may propagate to the aortic arch, the descend­ ing thoracic aorta, and even the abdominal aorta; type II, in which the dissection is limited to the ascending aorta; and type III, in which the intimal tear is located in the descending aorta with distal propagation of the dissection (Fig. 291-4). Another classification (Stanford) is that of type A, in which the dissection involves the ascending aorta (proxi­ mal dissection), and type B, in which it is limited to the arch and/or descending aorta (distal dissection). From a management standpoint, classification of aortic dissections and intramural hematomas into type A or B is more practical and useful, since DeBakey types I and II are managed in a similar manner. The factors that predispose to aortic dissection include those asso­ ciated with medial degeneration and others that increase aortic wall stress (Table 291-1). Systemic hypertension is a coexisting condition in 70% of patients. Aortic dissection is the major cause of morbidity and

Type A CHAPTER 291 Diseases of the Aorta Type B FIGURE 291-4  Classification of aortic dissections. Stanford classification: Type A dissections (top) involve the ascending aorta independent of site of tear and distal extension; type B dissections (bottom) involve transverse and/or descending aorta without involvement of the ascending aorta. DeBakey classification: Type I dissection involves ascending to descending aorta (top left); type II dissection is limited to ascending or transverse aorta, without descending aorta (top center + top right); type III dissection involves descending aorta only (bottom left). (Reproduced with permission from DC Miller, in RM Doroghazi, EE Slater [eds]: Aortic Dissection. New York, McGraw-Hill, 1983.) mortality in patients with Marfan syndrome (Chap. 425) or LoeysDietz syndrome, and similarly may affect patients with Ehlers-Danlos syndrome. The incidence also is increased in patients with inflamma­ tory aortitis (i.e., Takayasu’s arteritis, giant cell arteritis), congenital aortic valve anomalies (e.g., bicuspid valve), coarctation of the aorta, and a history of aortic trauma. In addition, the risk of dissection is increased in otherwise normal women during the third trimester of pregnancy. Aortic dissection also may occur as a consequence of weightlifting, cocaine use, or deceleration injury. ■ ■CLINICAL MANIFESTATIONS The peak incidence of aortic dissection is in the sixth and seventh decades. Men are more affected than women by a ratio of 2:1. The presentations of aortic dissection and its variants are the consequences of intimal tear, dissecting hematoma, occlusion of involved arteries, and compression of adjacent tissues. Acute aortic dissection presents with the sudden onset of pain (Chap. 15), which often is described as very severe and tearing and is associated with diaphoresis. The pain may be localized to the front or back of the chest, often the interscapu­ lar region, and typically migrates with propagation of the dissection. Other symptoms include syncope, dyspnea, and weakness. Physical findings may include hypertension or hypotension, loss of pulses, aor­ tic regurgitation, pulmonary edema, and neurologic findings due to carotid artery obstruction (hemiplegia, hemianesthesia) or spinal cord ischemia (paraplegia). Bowel ischemia, hematuria, and myocardial ischemia all may occur. These clinical manifestations reflect complica­ tions resulting from the dissection occluding the major arteries. Fur­ thermore, clinical manifestations may result from the compression of adjacent structures (e.g., superior cervical ganglia, superior vena cava, bronchus, esophagus) by the expanding dissection causing aneurysmal dilation and include Horner’s syndrome, superior vena cava syndrome, hoarseness, dysphagia, and airway compromise. Hemopericardium and cardiac tamponade may complicate a type A lesion with retrograde dissection. Acute aortic regurgitation is an important and common (>50%) complication of proximal dissection. It is the outcome of either

a circumferential tear that widens the aortic root or a disruption of the annulus by a dissecting hematoma that tears a leaflet(s) or displaces it inferior to the line of closure. Signs of aortic regurgitation include bounding pulses, a wide pulse pressure, a diastolic murmur often radiating along the right sternal border, and evidence of congestive heart failure. The clinical manifestations depend on the severity of the regurgitation.

PART 6 Disorders of the Cardiovascular System In dissections involving the ascending aorta, the chest x-ray often reveals a widened superior mediastinum. A pleural effusion (usually left-sided) also may be present. This effusion is typically serosanguine­ ous and not indicative of rupture unless accompanied by hypotension and falling hematocrit. In dissections of the descending thoracic aorta, a widened mediastinum may be observed on chest x-ray. In addition, the descending aorta may appear to be wider than the ascending por­ tion. An electrocardiogram that shows no evidence of myocardial ischemia is helpful in distinguishing aortic dissection from myocardial infarction among patients who present with chest pain. Rarely, the dis­ section involves the right or, less commonly, left coronary ostium and causes acute myocardial infarction. The diagnosis of aortic dissection can be established by noninvasive techniques such as echocardiography, CT, and MRI. Aortography is used less commonly because of the accuracy of these noninvasive tech­ niques. Transthoracic echocardiography can be performed simply and rapidly and has an overall sensitivity of 60–85% for aortic dissection. For diagnosing proximal ascending aortic dissections, its sensitivity exceeds 80%; it is less useful for detecting dissection of the arch and descending thoracic aorta. Transesophageal echocardiography requires greater skill and patient cooperation but is very accurate in identifying dissections of the ascending and descending thoracic aorta but not the arch, achieving 98% sensitivity and ~90% specificity. Echocardiogra­ phy also provides important information regarding the presence and severity of aortic regurgitation and pericardial effusion. CT and MRI are both highly accurate in identifying the intimal flap and the extent of the dissection and involvement of major arteries; each has a sensi­ tivity and specificity >90%. They are useful in recognizing intramural hemorrhage and penetrating ulcers. The relative utility of CT, MRI, and transesophageal echocardiography depends on the availability and expertise in individual institutions, although among these, CT is the imaging method most often used due to the presence of CT scanners near emergency rooms and the rapidity of performance. TREATMENT Aortic Dissection Medical therapy should be initiated as soon as the diagnosis is considered. The patient should be admitted to an intensive care unit for hemodynamic monitoring. Unless hypotension is present, therapy should be aimed at reducing cardiac contractility and sys­ temic arterial pressure, and thus shear stress. For acute dissection, unless contraindicated, β-adrenergic blockers should be adminis­ tered parenterally, using intravenous propranolol, metoprolol, or the short-acting esmolol to achieve a heart rate of 60–80 beats/ min. This should be accompanied by intravenous dilators, such as sodium nitroprusside, if needed to lower systolic blood pressure to ≤120 mmHg. Labetalol (Chap. 288), a drug with both β- and α-adrenergic blocking properties, also may be used as a parenteral agent in acute therapy for dissection. The calcium channel antagonists verapamil and diltiazem may be used intravenously if nitroprusside or β-adrenergic blockers can­ not be employed. The addition of a parenteral angiotensin-converting enzyme (ACE) inhibitor such as enalaprilat to a β-adrenergic blocker also may be considered. Isolated use of a direct vasodilator such as hydralazine is contraindicated because these agents can increase hydraulic shear and heart rate and may propagate the dissection. Emergent or urgent surgical correction is the preferred treatment for acute ascending aortic dissections and intramural hematomas (type A). Surgery involves excision of the intimal flap, obliteration of the false lumen, and placement of an interposition graft. Aortic

valve repair or aortic root replacement with a composite valvegraft conduit is used if the aortic valve is disrupted. The overall in-hospital mortality rate after surgical treatment of patients with aortic dissection is reported to be 15–25%. The major causes of perioperative mortality and morbidity include myocardial infarc­ tion, paraplegia, renal failure, tamponade, hemorrhage, and sepsis. Thoracic endovascular aortic repair with an endoluminal stent graft is indicated for complicated type B dissections, including those characterized by propagation, compromise of major aortic branches, impending rupture, or continued pain. Other transcath­ eter techniques, such as fenestration of the intimal flaps and stent­ ing of narrowed branch vessels to increase flow to compromised organs, are used in selected patients. Surgical correction is indicated for complicated type B dissections, particularly if endovascular repair is not feasible. Hybrid procedures consisting of both surgery and endovascular repair may be used when the dissection involves both the aortic arch and the descending thoracic aorta. For uncom­ plicated and stable distal dissections and intramural hematomas (type B), medical therapy is the preferred treatment. The in-hospital mortality rate of medically treated patients with type B dissection is ~12%. Long-term therapy for patients with aortic dissection and intramural hematomas (with or without surgery) consists of control of hypertension and reduction of cardiac contractility with the use of β-adrenergic blockers plus other antihypertensive agents, such as ACE inhibitors or calcium antagonists. Patients with chronic type B dissection and intramural hematomas should be followed on an outpatient basis initially at 1 month, 6 months, and 12 months, and then, if stable, every 12 months with contrast-enhanced CT or MRI to detect propagation or expansion. Patients with Marfan syndrome are at high risk for postdissection complications. The long-term prognosis following hospital discharge for patients with treated dissections is generally good with careful follow-up; the 10-year survival rate is ~60%. ■ ■CHRONIC ATHEROSCLEROTIC OCCLUSIVE DISEASE Atherosclerosis may affect the thoracic and abdominal aorta. Occlusive aortic disease caused by atherosclerosis usually is confined to the distal abdominal aorta below the renal arteries. Frequently the disease extends to the iliac arteries (Chap. 292). Claudication characteristically involves the buttocks, thighs, and calves and may be associated with impotence in males (Leriche syndrome). The severity of the symptoms depends on the adequacy of collaterals. With sufficient collateral blood flow, a com­ plete occlusion of the abdominal aorta may occur without the develop­ ment of ischemic symptoms. The physical findings include the absence of femoral and other distal pulses bilaterally and the detection of an audible bruit over the abdomen (usually at or below the umbilicus) and the common femoral arteries. Atrophic skin, loss of hair, and coolness of the lower extremities usually are observed. In advanced ischemia, rubor on dependency and pallor on elevation can be seen. The diagnosis usually is established by physical examination and noninvasive testing, including leg pressure measurements, Doppler velocity analysis, pulse volume recordings, and duplex ultrasonog­ raphy. The anatomy may be defined by MRI, CT, or conventional contrast angiography, typically performed when one is considering revascularization. Catheter-based endovascular or operative treatment is indicated in patients with lifestyle-limiting or debilitating symptoms of claudication and patients with chronic limb-threatening ischemia. ■ ■ACUTE AORTIC OCCLUSION Acute occlusion in the distal abdominal aorta constitutes a medical emergency because it threatens the viability of the lower extremities; it usually results from an occlusive (saddle) embolus that almost always originates from the heart. Rarely, acute occlusion may occur as the result of in situ thrombosis in a preexisting severely narrowed segment of the aorta. The clinical picture is one of acute ischemia of the lower extremi­ ties. Severe rest pain, coolness, and pallor of the lower extremities and the absence of distal pulses bilaterally are the usual manifestations.

Diagnosis should be established rapidly by MRI, CT, or aortography. Emergency thrombectomy or revascularization is indicated. AORTITIS Aortitis, a term referring to inflammatory disease of the aorta, may be caused by large vessel vasculitides such as Takayasu arteritis, giant cell arteritis, IgG4-related systemic disease, isolated aortitis, rheumatic and HLA-B27–associated spondyloarthropathies, Behçet syndrome, antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides, Cogan syndrome, Erdheim-Chester disease, and infections such as syphilis, tuberculosis, and Salmonella, or it may be associated with retroperitoneal fibrosis. Aortitis may result in aneurysmal dilation and aortic regurgitation, occlusion of the aorta and its branch vessels, or acute aortic syndromes. ■ ■TAKAYASU ARTERITIS (See also Chap. 375) This inflammatory disease often affects the ascending aorta and aortic arch, causing obstruction of the aorta and its major arteries. Takayasu arteritis is also termed pulseless disease because of the frequent occlusion of the large arteries originating from the aorta. It also may involve the descending thoracic and abdominal aorta and occlude large branches such as the renal arteries. Aortic aneurysms also may occur. The pathology is a panarteritis character­ ized by mononuclear cells and occasionally giant cells, with marked intimal hyperplasia, medial and adventitial thickening, and, in the chronic form, fibrotic occlusion. The disease is most prevalent in young females of Asian descent but does occur in women of other geographic and ethnic origins and also in young men. During the acute stage, fever, malaise, weight loss, and other systemic symptoms may be evident. Elevations of the erythrocyte sedimentation rate and C-reactive protein are common. The chronic stages of the disease, which is intermittently active, present with symptoms related to large artery occlusion, such as upper extremity claudication, cerebral ischemia, and syncope. The pro­ cess is progressive, and there is no definitive therapy. Glucocorticoids are effective in most patients during the acute phase. Other immuno­ suppressive agents, such as methotrexate, azathioprine, leflunomide, or mycophenolate, are prescribed to some patients to lower glucocorticoid requirements and treat relapses. Biologically targeted agents, such as the tumor necrosis factor (TNF) inhibitors etanercept and infliximab, are also used, but efficacy has not been established in randomized clini­ cal trials. Surgical bypass or endovascular intervention of a critically stenotic artery may be necessary. ■ ■GIANT CELL ARTERITIS (See also Chap. 375) This vasculitis occurs in older individuals and affects women more often than men. Primarily large and mediumsize arteries are affected. The pathology is that of focal granulomatous lesions involving the entire arterial wall; it frequently is associated with polymyalgia rheumatica. Obstruction of medium-size arteries (e.g., temporal and ophthalmic arteries) and major branches of the aorta and the development of aortitis and aortic regurgitation are important complications of the disease. High-dose glucocorticoid therapy should be administered early and then gradually tapered. Immunosuppressive therapy with methotrexate may allow reduction in steroid dosage and reduce the risk of relapse. Tocilizumab, an interleukin-6 antagonist, demonstrated efficacy in several randomized trials. Other biologically targeted therapies are under investigation. ■ ■IGG4-RELATED AORTITIS Aortitis may occur in patients with IgG4-related disease (Chap. 380) and is associated with retroperitoneal fibrosis and hydronephrosis. It can affect the thoracic and abdominal aorta, as well as the iliac arteries. Serum IgG4 levels may be elevated but are not diagnostic. Histopatho­ logic characteristics include a lymphoplasmacytic infiltrate that com­ prises IgG4-positive plasma cells, fibrosis, and obliterative adventitial phlebitis; it affects men more than women and typically occurs in middle age. Glucocorticoids are used for initial treatment. Case series have reported efficacy with rituximab, an anti-CD20 monoclonal antibody. Immunosuppressive agents such as azathioprine are steroid sparing and may be effective.

■ ■ISOLATED AORTITIS Isolated abdominal aortitis is characterized by adventitial and periaor­ tic inflammation with thickening of the aortic wall; it is associated with abdominal aortic aneurysms and idiopathic retroperitoneal fibrosis. Affected individuals may present with vague constitutional symptoms, fever, and abdominal pain. Retroperitoneal fibrosis can cause ureteral obstruction and hydronephrosis. Glucocorticoids and immunosup­ pressive agents may reduce the inflammation.

CHAPTER 291 ■ ■RHEUMATIC AORTITIS Rheumatoid arthritis (Chap. 370), ankylosing spondylitis (Chap. 374), psoriatic arthritis (Chap. 374), reactive arthritis (formerly known as Reiter’s syndrome) (Chap. 374), relapsing polychondritis, and inflam­ matory bowel disorders may all be associated with aortitis involving the ascending aorta. The inflammatory lesions usually involve the ascending aorta and may extend to the sinuses of Valsalva, the mitral valve leaflets, and adjacent myocardium. The clinical manifestations are aneurysm, aortic regurgitation, and involvement of the cardiac conduction system. Diseases of the Aorta ■ ■INFECTIVE AORTITIS Infective aortitis may result from direct invasion of the aortic wall by bacterial pathogens such as Staphylococcus, Streptococcus, and Salmo­ nella or by fungi. These bacteria cause aortitis by infecting the aorta at sites of atherosclerotic plaque. Bacterial proteases lead to degradation of collagen, and the ensuing destruction of the aortic wall leads to the formation of a saccular aneurysm referred to as a mycotic aneurysm. Mycotic aneurysms have a predilection for the suprarenal abdominal aorta. The pathologic characteristics of the aortic wall include acute and chronic inflammation, abscesses, hemorrhage, and necrosis. Mycotic aneurysms typically affect the elderly and occur in men three times more frequently than in women. Patients may present with fever, sepsis, and chest, back, or abdominal pain; there may have been a pre­ ceding diarrheal illness. Blood cultures are positive in the majority of patients. Both CT and MRI are useful to diagnose mycotic aneurysms. Treatment includes antibiotic therapy and surgical removal of the affected part of the aorta and revascularization of the lower extremities with grafts placed in uninfected tissue. Syphilitic aortitis is a late manifestation of luetic infection (Chap. 187) that usually affects the proximal ascending aorta, particularly the aortic root, resulting in aortic dilation and aneurysm formation. Syphilitic aortitis occasionally may involve the aortic arch or the descending aorta. The aneurysms may be saccular or fusiform and are usually asymptomatic, but compression of and erosion into adjacent structures may result in symptoms; rupture also may occur. The initial lesion is an obliterative endarteritis of the vasa vasorum, especially in the adventitia. This is an inflammatory response to the invasion of the adventitia by the spirochetes. Destruction of the aortic media occurs as the spirochetes spread into this layer, usually via the lymphatics accompanying the vasa vasorum. Destruction of collagen and elastic tissues leads to dilation of the aorta, scar formation, and calcification. These changes account for the characteristic radiographic appearance of linear calcification of the ascending aorta. The disease typically presents as an incidental chest radiographic finding 15–30 years after initial infection. Symptoms may result from aortic regurgitation, narrowing of coronary ostia due to syphilitic aortitis, compression of adjacent structures (e.g., esophagus), or rup­ ture. Diagnosis is established by a positive serologic test, such as rapid plasmin regain (RPR), Venereal Disease Research Laboratory (VDRL), or fluorescent treponemal antibody absorption (FTA-ABS). Treatment includes penicillin and surgical excision and repair. ■ ■FURTHER READING Chou E et al: Genetics and mechanisms of thoracic aortic disease. Nat Rev Cardiol 20:168, 2023. Fletcher AJ et al: Inherited thoracic aortic disease: New insights and translational targets. Circulation 141:1570, 2020. Guirguis-Blake JM et al: Primary care screening for abdominal aortic aneurysm: Updated evidence report and systematic review for the US Preventive Services Task Force. JAMA 322:2211, 2019.

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Hensley SE, Upchurch GR Jr: Repair of abdominal aortic aneu­

rysms: JACC focus seminar, part 1. J Am Coll Cardiol 80:831, 2022. Isselbacher EM et al: 2022 ACC/AHA guideline for the diagnosis and management of aortic disease: A report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation 146:e334, 2022. Kadian-Dodov D et al: Inflammatory diseases of the aorta: JACC PART 6 Disorders of the Cardiovascular System focus seminar, part 2. J Am Coll Cardiol 80:832, 2022. Pitcher A et al: Angiotensin receptor blockers and β blockers in Marfan syndrome: An individual patient data meta-analysis of ran­ domised trials. Lancet 400:822, 2022. Vilacosta I et al: Acute aortic syndrome revisited: JACC state-of-theart review. J Am Coll Cardiol 78:2106, 2021. Mark A. Creager, Joseph Loscalzo

Arterial Diseases of the Extremities ■ ■PERIPHERAL ARTERY DISEASE Peripheral artery disease (PAD) is defined as a clinical disorder in which there is a stenosis or occlusion in the aorta or the arteries of the limbs. Atherosclerosis is the leading cause of PAD in patients >40 years old. Other causes include thrombosis, embolism, vasculitis, fibromus­ cular dysplasia, entrapment, cystic adventitial disease, and trauma. The highest prevalence of atherosclerotic PAD occurs in the sixth and sev­ enth decades of life. Prevalence of PAD is similar in men and women, is greater in persons identified as black than non-Hispanic white, and is associated with lower socioeconomic status. As in patients with atherosclerosis of the coronary and cerebral vasculature, there is an increased risk of developing PAD in cigarette smokers and in persons with diabetes mellitus, hypercholesterolemia, elevated lipoprotein(a), hypertension, or renal insufficiency. Pathology  Segmental lesions that cause stenosis or occlusion are usually localized to large and medium-size vessels. The pathology of the lesions includes atherosclerotic plaques with calcium deposition, thinning of the media, patchy destruction of muscle and elastic fibers, fragmentation of the internal elastic lamina, and thrombi composed of platelets and fibrin. The primary sites of involvement are the abdomi­ nal aorta and iliac arteries (30% of symptomatic patients), the femoral and popliteal arteries (80–90% of patients), and the more distal ves­ sels, including the tibial and peroneal arteries (40–50% of patients). Atherosclerotic lesions occur preferentially at arterial branch points, which are sites of increased turbulence, altered shear stress, and intimal injury. Involvement of the distal vasculature is most common in elderly individuals and patients with diabetes mellitus. Clinical Evaluation  Fewer than 50% of patients with PAD are symp­ tomatic, although many have a slow or impaired gait. The most typical symptom is intermittent claudication, which is defined as a pain, ache, cramp, numbness, or a sense of fatigue in the muscles; it occurs during exercise and is relieved by rest. The site of claudication is distal to the location of the occlusive lesion. For example, buttock, hip, thigh, and calf discomfort occurs in patients with aortoiliac disease, whereas calf claudica­ tion develops in patients with femoral-popliteal disease. Symptoms are far more common in the lower than in the upper extremities because of the higher incidence of obstructive lesions in the former region. In patients with severe arterial occlusive disease in whom resting blood flow cannot accommodate basal nutritional needs of the tissues, chronic limb-threat­ ening ischemia may develop. Patients complain of rest pain or a feeling of

cold or numbness in the foot and toes. Frequently, these symptoms occur at night when the legs are horizontal and improve when the legs are in a dependent position. With severe ischemia, rest pain may be persistent. A comprehensive vascular examination includes palpation of the peripheral pulses, including the femoral, popliteal, dorsalis pedis, and posterior tibial arteries; auscultation of the abdomen and groin for bruits; and inspection of the legs and feet. Important physical findings of PAD include decreased or absent pulses distal to the obstruction, the presence of bruits over the narrowed artery, and muscle atrophy. With more severe disease, hair loss, thickened nails, smooth and shiny skin, reduced skin temperature, and pallor or cyanosis are common physical signs. In patients with chronic limb-threatening ischemia, ulcers or gangrene may occur. Elevation of the legs and repeated flex­ ing of the calf muscles produce pallor of the soles of the feet, whereas rubor, secondary to reactive hyperemia, may develop when the legs are dependent. The time required for rubor to develop or for the veins in the foot to fill when the patient’s legs are transferred from an elevated to a dependent position is related to the severity of the ischemia and the presence of collateral vessels. Patients with severe ischemia may develop peripheral edema because they keep their legs in a dependent position much of the time. Ischemic neuropathy can result in numb­ ness and hyporeflexia. Noninvasive Testing  The history and physical examination are often sufficient to establish the diagnosis of PAD. An objective assess­ ment of the presence and severity of disease is obtained by noninvasive techniques. Arterial pressure can be recorded noninvasively in the legs by placement of sphygmomanometric cuffs at the ankles and the use of a Doppler device to auscultate or record blood flow from the dorsalis pedis and posterior tibial arteries. Normally, systolic blood pressure in the legs and arms is similar. Indeed, ankle pressure may be slightly higher than arm pressure due to pulse-wave amplification. In the presence of hemodynamically significant stenoses, the systolic blood pressure in the leg is decreased. Thus, the ratio of the ankle and brachial artery systolic pressures (termed the ankle-brachial index, or ABI) is 1.00–1.40 in normal individuals. ABI values of 0.91–0.99 are considered “borderline,” and those ≤0.90 are abnormal and diagnostic of PAD. ABIs >1.40 indicate noncompressible arteries secondary to vascular calcification, as may occur in patients with diabetes mellitus or chronic kidney disease. When an ABI cannot be accurately assessed due to vascular calcification, the presence of PAD can be detected by measuring the systolic pressure of the great toe and calculating a toebrachial index (TBI). A TBI of ≤0.70 is considered abnormal. Other noninvasive tests include segmental pressure measurements, segmental pulse volume recordings, duplex ultrasonography (which combines B-mode imaging and Doppler flow velocity waveform analysis), transcutaneous oximetry, and stress testing (usually using a treadmill). Placement of pneumatic cuffs enables assessment of systolic pressure along the legs. The presence of pressure gradients between sequential cuffs provides evidence of the presence and location of hemodynamically significant stenoses. In addition, the amplitude of the pulse volume contour becomes blunted in the presence of signifi­ cant PAD. Duplex ultrasonography is used to image and detect stenotic lesions in native arteries and bypass grafts. Treadmill testing allows the physician to assess functional limi­ tations objectively. Decline of the ABI immediately after exercise provides further support for the diagnosis of PAD in patients with equivocal symptoms and findings on examination. Magnetic resonance angiography (MRA), computed tomographic angiography (CTA), and conventional catheter-based angiography should not be used for routine diagnostic testing, but are performed before potential revascularization (Fig. 292-1). Each test is useful in defining the anatomy to assist planning for endovascular and surgical revascularization procedures. Prognosis  The natural history of patients with PAD is influenced primarily by the extent of coexisting coronary artery and cerebrovascu­ lar disease. Approximately one-third to one-half of patients with symp­ tomatic PAD have evidence of coronary artery disease (CAD) based on clinical presentation and electrocardiogram, and over one-half have

B A FIGURE 292-1  Magnetic resonance angiography of a patient with intermittent claudication, showing stenoses of the distal abdominal aorta and right common iliac artery (A) and stenoses of the right and left superficial femoral arteries (B). (Courtesy of Dr. Edwin Gravereaux, with permission.) significant CAD by coronary angiography. Patients with PAD have a 15–25% 5-year mortality rate and a two- to fourfold increased risk of death from cardiovascular disease. Measurement of ABI is useful for detecting PAD and identifying persons at risk for adverse cardiovascu­ lar and limb events. Mortality rates are highest in those with the most severe PAD. The ABI worsens in almost 40% of patients, and symptoms progress in ~20–25% when assessed over a period of 5 years. Approxi­ mately 11% of patients with symptomatic PAD ultimately develop chronic limb-threatening ischemia, and without revascularization, approximately 25% of patients with chronic limb-threatening ischemia undergo amputation within 1 year. The prognosis is worse in patients who continue to smoke cigarettes or have diabetes mellitus. TREATMENT Peripheral Artery Disease Patients with PAD should receive therapies to reduce the risk of associated cardiovascular events, such as myocardial infarction and death, and to improve limb symptoms, prevent progression to chronic limb-threatening ischemia, and preserve limb viability. Risk factor modification and antithrombotic therapy should be initiated to improve cardiovascular outcomes. The importance of discontin­ uing cigarette smoking cannot be overemphasized. The physician must assume a major role in this lifestyle modification. Counseling and adjunctive drug therapy with the nicotine patch, bupropion, or varenicline increase smoking cessation rates and reduce recidivism. It is important to control blood pressure in hypertensive patients. Angiotensin-converting enzyme inhibitors and angiotensin recep­ tor blockers may reduce the risk of cardiovascular events in patients with symptomatic PAD. β-Adrenergic blockers do not worsen claudication and may be used to treat hypertension, especially in patients with coexistent CAD. Treatment of hypercholesterolemia with statins and, if needed, adjunctive lipid-lowering agents such as ezetimibe or a PCSK9 inhibitor, are advocated to reduce the risk of myocardial infarction, stroke, and death. Statins and PCSK9 inhibitors also are associated with a decreased risk of adverse limb events, including amputation, in patients with PAD. The 2018 American Heart Association (AHA)/American College of Cardiol­ ogy (ACC) Guideline on the Management of Blood Cholesterol recommends high-intensity statin treatment in patients with ath­ erosclerotic disorders, including PAD, with the aim of achieving a 50% or greater reduction in low-density lipoprotein cholesterol.

CHAPTER 292 Arterial Diseases of the Extremities Intensive glucose lowering reduces the risk of amputations in patients with diabetes mellitus. Among patients with diabetes and established cardiovascular disease, including PAD, the glucagonlike protein (GLP)-1 agonists and the sodium-glucose cotrans­ porter 2 (SGLT2) inhibitors have beneficial cardiovascular effects. GLP-1 agonists also may reduce the risk of amputation. Platelet inhibitors, including aspirin and the adenosine diphosphate (ADP) antagonist clopidogrel, reduce the risk of adverse cardiovascular events in patients with atherosclerosis and are recommended for patients with symptomatic PAD, including those with intermittent claudication or chronic limb-threatening ischemia or prior lower extremity revascularization. Outcomes with ticagrelor are similar to those with clopidogrel. The benefit of dual antiplatelet therapy with both aspirin and clopidogrel compared with aspirin alone in reducing cardiovascular morbidity and mortality rates in patients with PAD is uncertain. When added to other antiplatelet therapy, vorapaxar, a protease-activated receptor-1 antagonist that inhibits thrombin-mediated platelet activation, decreases the risk of adverse cardiovascular events in patients with atherosclerosis, including PAD. It also reduces the risk of acute limb ischemia and peripheral revascularization; however, it is associated with an increased rate of moderate bleeding. The anticoagulant warfarin is as effective as antiplatelet therapy in preventing adverse cardiovascular events but causes more major bleeding; therefore, it is not indicated to improve outcomes in patients with chronic PAD. The combination of a low dose of the oral factor Xa inhibitor rivaroxaban and aspirin improves cardiovascular and limb outcomes in patients with ath­ erosclerosis, including those with established PAD, as well as those who have undergone peripheral revascularization, but is associated with increased risk of bleeding. Therapies for intermittent claudication and chronic limbthreatening ischemia include supportive measures, medications, exer­ cise training, endovascular interventions, and surgery. Supportive measures include meticulous care of the feet, which should be kept clean and protected against excessive drying with moisturizing creams. Well-fitting and protective shoes are advised to reduce trauma. Elastic support hose should be avoided, as it reduces blood flow to the skin. In patients with chronic limb-threatening ischemia, shock blocks under the head of the bed together with a canopy over the feet may improve perfusion pressure and ameliorate some of the rest pain. Patients with claudication should be encouraged to exercise regu­ larly and at progressively more strenuous levels. Supervised exercise

training programs for 30- to 45-min sessions, at least three times per week for 12 weeks, prolong walking distance. The beneficial effect of supervised exercise training on walking performance in patients with claudication often is similar to or greater than that realized after a revascularization procedure. Structured home and community-based exercise programs are also effective. Pharmaco­ logic treatment of PAD has not been as successful as the medical treatment of CAD (Chap. 284). In particular, vasodilators as a class have not proved to be beneficial. During exercise, peripheral vasodilation occurs distal to sites of significant arterial stenoses. As a result, perfusion pressure falls, often to levels lower than those generated in the interstitial tissue by the exercising muscle. Drugs such as α-adrenergic blocking agents, calcium channel antagonists, and other vasodilators have not been shown to be effective in patients with PAD.

PART 6 Disorders of the Cardiovascular System Cilostazol, a phosphodiesterase-3 inhibitor with vasodilator and antiplatelet properties, increases claudication distance by 40–60% and improves measures of quality of life. The mechanism of action accounting for its beneficial effects is not known. Pentoxifylline, a substituted xanthine derivative, increases blood flow to the micro­ circulation and enhances tissue oxygenation. Although several placebo-controlled studies have found that pentoxifylline modestly increases the duration of exercise, its efficacy has not been con­ firmed in other clinical trials. Statins appeared effective for treat­ ment of intermittent claudication in initial clinical trials, but more studies are needed to confirm the efficacy of this class of drugs. There is no definitive medical therapy for chronic limbthreatening ischemia. Vasodilators, including prostaglandins, are not effective in relieving symptoms or preventing limb loss. Enthu­ siasm for therapy with angiogenic growth factors abated when clinical trials of intramuscular gene transfer of DNA encoding vas­ cular endothelial growth factor, fibroblast growth factor, hepatocyte growth factor, or hypoxia-inducible factor 1α failed to demonstrate improvement in symptoms or outcomes in patients with intermit­ tent claudication or critical limb ischemia. Most clinical trials of bone marrow–derived vascular progenitor cells to promote angio­ genesis and preserve limb viability in patients with critical limb isch­ emia have failed to demonstrate benefit, although a meta-analysis of these trials suggested a modest reduction in the risk of amputation. REVASCULARIZATION Revascularization procedures, including catheter-based, open sur­ gical, and hybrid interventions, are indicated for patients with chronic limb-threatening ischemia to relieve pain and prevent limb loss. These procedures are also indicated for patients with disabling, progressive, or severe symptoms of intermittent claudica­ tion despite medical therapy in order to improve walking distance and functional capacity. When revascularization is performed in conjunction with a supervised exercise program, walking distance improves more than with exercise training alone. MRA, CTA, or conventional angiography should be performed to assess vascular anatomy in patients who are being considered for revascularization. Endovascular interventions include percutaneous transluminal balloon angioplasty (PTA) (including drug-coated balloons), stent placement (including drug-eluting stents), stent grafts, and ather­ ectomy (Chap. 287). Several operative procedures are available for treating patients with PAD. The preferred operative procedure depends on the location and extent of the obstruction(s) and the general medical condition of the patient. Operative procedures for aortoiliac disease include aortobifemoral bypass, axillofemo­ ral bypass, femoro-femoral bypass, and aortoiliac endarterectomy. Operative therapy for femoral-popliteal and tibioperoneal artery disease includes in situ and reverse autogenous saphenous vein bypass grafts, placement of polytetrafluoroethylene (PTFE) or other synthetic grafts, and thromboendarterectomy. The decision to use an endovascular, open surgical, or a hybrid revascularization strategy depends on the vascular anatomy, including the location and extent of the arterial occlusions, the availability of suitable saphenous vein segments, comorbidities, and the skill and experience of the operator.

Preoperative cardiac risk assessment may identify individuals who are especially likely to experience an adverse cardiac event during the perioperative period. Patients with angina, prior myo­ cardial infarction, heart failure, diabetes, or renal insufficiency are among those at increased risk. Stress testing with treadmill exercise (if feasible), radionuclide myocardial perfusion imaging, or echocardiography permits further stratification of risk in these patients, particularly those with poor or unknown functional capacity (Chap. 287). Patients with abnormal test results require close supervision and adjunctive management with anti-ischemic medications. Coronary angiography and coronary artery revas­ cularization compared with optimal medical therapy do not improve outcomes in most patients undergoing peripheral vas­ cular surgery, but cardiac catheterization should be considered in patients with unstable angina and angina refractory to medical therapy as well as those suspected of having left main or threevessel CAD. ■ ■FIBROMUSCULAR DYSPLASIA Fibromuscular dysplasia (FMD) is a hyperplastic disorder that typi­ cally affects medium-size and small arteries, but it can also affect larger arteries. The most common histologic characteristics include medial deposition of collagen causing fibromuscular ridges alternating with areas of thinned media. FMD occurs predominantly in females and usually involves the renal and carotid/vertebral arteries but can involve coronary and mesenteric arteries, as well as extremity vessels such as the iliac and subclavian arteries. FMD may cause stenosis, dissection, aneurysm, or thrombosis in affected arteries. When limb vessels are involved, clinical manifestations are similar to those for atherosclerosis, including claudication and rest pain. A contemporary classification based on the angiographic appear­ ance divides FMD into two types: multifocal, identified by a “string of beads” appearance caused by the thickened fibromuscular ridges contiguous with thin, less-involved portions of the arterial wall; and focal, identified as either unifocal (<1 cm) or tubular (≥1 cm) stenoses. Aspirin is recommended to reduce the risk of thrombosis in affected vessels. PTA and surgical reconstruction are beneficial in patients with debilitating symptoms or threatened limbs. ■ ■THROMBOANGIITIS OBLITERANS Thromboangiitis obliterans (Buerger’s disease) is an inflammatory occlusive vascular disorder involving small and medium-size arteries and veins in the distal upper and lower extremities. Cerebral, visceral, and coronary vessels may be affected rarely. This disorder develops most frequently in men <40 years of age. The prevalence is higher in Asians and individuals of Eastern European descent. Although the cause of thromboangiitis obliterans is not known, there is a definite relationship to cigarette smoking in patients with this disorder. In the initial stages of thromboangiitis obliterans, polymorpho­ nuclear leukocytes infiltrate the walls of the small and medium-size arteries and veins. The internal elastic lamina is preserved, and a cellular, inflammatory thrombus develops in the vascular lumen. As the disease progresses, mononuclear cells, fibroblasts, and giant cells replace the neutrophils. Later stages are characterized by perivascular fibrosis, organized thrombus, and recanalization. The clinical features of thromboangiitis obliterans often include a triad of claudication of the affected extremity, Raynaud phenom­ enon, and migratory superficial vein thrombophlebitis. Claudica­ tion usually is confined to the calves and feet or the forearms and hands because this disorder primarily affects distal vessels. In the presence of severe digital ischemia, trophic nail changes, painful ulcerations, and gangrene may develop at the tips of the fingers or toes. The physical examination shows normal brachial and popliteal pulses but reduced or absent radial, ulnar, and/or tibial pulses. MRA, CTA, and conventional arteriography are helpful in making the diag­ nosis. Smooth, tapering segmental lesions in the distal vessels are characteristic, as are collateral vessels at sites of vascular occlusion. Proximal atherosclerotic disease is usually absent. The diagnosis can

be confirmed by excisional biopsy and pathologic examination of an involved vessel. There is no specific treatment except abstention from tobacco. The prognosis is worse in individuals who continue to smoke, but results are discouraging even in those who stop smoking. Arterial bypass of the larger vessels may be used in selected instances, as well as local debridement, depending on the symptoms and severity of ischemia. Antibiotics may be useful; anticoagulants and glucocorticoids are not helpful. If these measures fail, amputation may be required. ■ ■OTHER VASCULITIDES Other vasculitides may affect the arteries that supply the upper and lower extremities. Takayasu arteritis and giant cell (temporal) arteri­ tis are discussed in Chap. 375. ■ ■ACUTE LIMB ISCHEMIA Acute limb ischemia occurs when arterial occlusion results in the sud­ den cessation of blood flow to an extremity. The severity of ischemia and the viability of the extremity depend on the location and extent of the occlusion and the presence and subsequent development of collat­ eral blood vessels. Principal causes of acute arterial occlusion include embolism, thrombus in situ, arterial dissection, and trauma. The most common sources of arterial emboli are the heart, aorta, and large arteries. Cardiac disorders that cause thromboembolism include atrial fibrillation; acute myocardial infarction; ventricular aneurysm; cardiomyopathy; infectious and marantic endocarditis; thrombi associated with prosthetic heart valves; and atrial myxoma. Emboli to the distal vessels may also originate from proximal sites of atherosclerosis and aneurysms of the aorta and large vessels. Less frequently, an arterial occlusion results paradoxically from a venous thrombus that has entered the systemic circulation via a patent fora­ men ovale or another septal defect. Arterial emboli tend to lodge at vessel bifurcations because the vessel caliber decreases at those sites; in the lower extremities, emboli lodge most frequently in the femoral artery, followed by the iliac artery, aorta, and popliteal and tibiopero­ neal arteries. Acute arterial thrombosis in situ occurs most frequently in athero­ sclerotic vessels at the site of an atherosclerotic plaque or aneurysm and in arterial bypass grafts. Trauma to an artery may disrupt continuity of blood flow and cause acute limb ischemia via formation of an acute arterial thrombus or by disruption of an artery’s integrity and extrava­ sation of blood. Arterial occlusion may complicate arterial punctures and placement of catheters; it also may result from arterial dissection if the intimal flap obstructs the artery. Less common causes include thoracic outlet compression syndrome, which causes subclavian artery occlusion, and entrapment of the popliteal artery by abnormal place­ ment of the medial head of the gastrocnemius muscle. Polycythemia and hypercoagulable disorders (Chaps. 108 and 121) are also associ­ ated with acute arterial thrombosis. ■ ■CLINICAL FEATURES The symptoms of an acute arterial occlusion depend on the location, duration, and severity of the obstruction. Often severe pain, paresthe­ sia, numbness, and coldness develop in the involved extremity within 1 h. Paralysis may occur with severe and persistent ischemia. Physi­ cal findings include loss of pulses distal to the occlusion, cyanosis or pallor, mottling, decreased skin temperature, muscle stiffening, loss of sensation, weakness, and/or absent deep tendon reflexes. If acute arterial occlusion occurs in the presence of an adequate collateral circulation, as is often the case in acute graft occlusion, the symp­ toms and findings may be less severe. In this situation, the patient complains about an abrupt decrease in the distance walked before claudication occurs or of modest pain and paresthesia. Pallor and coolness are evident, but sensory and motor functions generally are preserved. The clinical evaluation includes Doppler assessment of peripheral blood flow. The diagnosis of acute limb ischemia is usu­ ally apparent from the clinical presentation. In most circumstances, duplex ultrasound, MRA, CTA, or catheter-based arteriography is used to confirm the diagnosis and demonstrate the location and extent of arterial occlusion.

TREATMENT Acute Limb Ischemia Once the diagnosis is made, the patient should be anticoagu­ lated with intravenous heparin to prevent propagation of the clot and recurrent embolism. In cases of severe ischemia of recent onset, particularly when limb viability is jeopardized, immediate intervention to ensure reperfusion is indicated. Catheter-directed thrombolysis/thrombectomy, surgical thromboembolectomy, and arterial bypass procedures are used to restore blood flow to the ischemic extremity promptly, particularly when a large proximal vessel is occluded. CHAPTER 292 Arterial Diseases of the Extremities Intraarterial thrombolytic therapy with recombinant tissue plas­ minogen activator, reteplase, or tenecteplase is most effective when acute arterial occlusion is recent and caused by a thrombus in an atherosclerotic vessel, arterial bypass graft, or occluded stent. Thrombolytic therapy is also indicated when the patient’s overall condition contraindicates surgical intervention or when smaller distal vessels are occluded, thus preventing surgical access. Meticu­ lous observation for hemorrhagic complications is required during intraarterial thrombolytic therapy. Ultrasound-emitting catheters may accelerate reperfusion by improving thrombus permeability to thrombolytic agents. Another endovascular approach to thrombus removal is percutaneous mechanical thrombectomy using devices that employ hydrodynamic forces or rotating baskets to fragment and remove the clot. These treatments may be used alone but usu­ ally are used in conjunction with pharmacologic thrombolysis. Surgical revascularization is preferred when restoration of blood flow must occur within 24 h to prevent limb loss. Amputation is performed when the limb is not viable, as characterized by loss of sensation, paralysis, and the absence of Doppler-detected blood flow in both arteries and veins. Long-term anticoagulation is indicated when acute limb ischemia is caused by cardiac thromboembolism. Emboli resulting from infec­ tive endocarditis, the presence of prosthetic heart valves, or atrial myxoma often require surgical intervention to remove the cause. ■ ■ATHEROEMBOLISM Atheroembolism is another cause of limb ischemia. In this condi­ tion, multiple small deposits of fibrin, platelets, and cholesterol debris embolize from proximal atherosclerotic lesions or aneurysmal sites. Large protruding aortic atheromas are a source of emboli that may lead to limb ischemia, as well as stroke and renal insufficiency. Atheroem­ bolism may occur after intraarterial procedures. Since atheroemboli to limbs tend to lodge in the small vessels of the muscle and skin and may not occlude the large vessels, distal pulses usually remain palpable. Patients complain of acute pain and tenderness at the site of emboliza­ tion. Digital vascular occlusion may result in ischemia and the “blue toe” syndrome; digital necrosis and gangrene may develop (Fig. 292-2). Localized areas of tenderness, pallor, and livedo reticularis (see below) occur at sites of emboli. Skin or muscle biopsy may demonstrate cho­ lesterol crystals. Ischemia resulting from atheroemboli is notoriously difficult to treat. Local foot care and occasionally amputation may be needed to treat necrotic areas. Analgesics are indicated for pain relief. Usually neither surgical revascularization procedures nor thrombolytic therapy is helpful because of the multiplicity, composition, and distal location of the emboli. Therapy with antiplatelet drugs and statins improves cardiovascular outcome in patients with atherosclerosis, but it is not established whether either class of drugs prevents recurrent athero­ embolism. Similarly, it is not known whether anticoagulant therapy is effective. Endovascular or surgical intervention to exclude or bypass the atherosclerotic vessel or aneurysm that causes the recurrent ath­ eroemboli may be necessary. ■ ■THORACIC OUTLET COMPRESSION SYNDROME This is a symptom complex resulting from compression of the neu­ rovascular bundle (artery, vein, or nerves) at the thoracic outlet as it

PART 6 Disorders of the Cardiovascular System FIGURE 292-2  Atheroembolism causing cyanotic discoloration and impending necrosis of the toes (“blue toe” syndrome). courses through the neck and shoulder. Cervical ribs, abnormalities of the scalenus anticus muscle, proximity of the clavicle to the first rib, or abnormal insertion of the pectoralis minor muscle may compress the subclavian artery, subclavian vein, and brachial plexus as these struc­ tures pass from the thorax to the arm. Depending on the structures affected, thoracic outlet compression syndrome is divided into arte­ rial, venous, and neurogenic forms. Patients with neurogenic thoracic outlet compression may develop shoulder and arm pain, weakness, and paresthesias. Patients with arterial compression may experience claudication, Raynaud phenomenon, and even ischemic tissue loss and gangrene. Venous compression may cause thrombosis of the subclavian and axillary veins; this is often associated with effort and is referred to as Paget-Schroetter syndrome. APPROACH TO THE PATIENT Arterial Thoracic Outlet Compression Syndrome Examination of a patient with arterial thoracic outlet compres­ sion syndrome is often normal unless provocative maneuvers are performed. Occasionally, distal pulses are decreased or absent and digital cyanosis and ischemia may be evident. Several maneuvers that support the diagnosis of arterial thoracic outlet compression syndrome may be used to precipitate symp­ toms, cause a subclavian artery bruit, and diminish arm pulses. These maneuvers include the abduction and external rotation test, in which the affected arm is abducted by 90° and the shoulder is externally rotated; the scalene maneuver (extension of the neck and rotation of the head to the side of the symptoms); the cos­ toclavicular maneuver (posterior rotation of shoulders); and the hyperabduction maneuver (raising the arm 180°). A chest x-ray will indicate the presence of cervical ribs. Duplex ultrasonography, CTA, MRA, and contrast angiography can be performed during provocative maneuvers to demonstrate thoracic outlet compression of the subclavian artery. Neurophysiologic tests such as the electro­ myogram, nerve conduction studies, and somatosensory evoked potentials may be abnormal if the brachial plexus is involved, but the diagnosis of neurogenic thoracic outlet syndrome is not necessarily excluded if these tests are normal owing to their low sensitivity. Most patients can be managed conservatively. They should be advised to avoid the positions that cause symptoms. Many patients benefit from shoulder girdle exercises. Surgical procedures such as removal of the first rib and resection of the scalenus anticus muscle are necessary occasionally for relief of symptoms or treatment of ischemia.

■ ■POPLITEAL ARTERY ENTRAPMENT Popliteal artery entrapment typically affects young athletic men and women when the gastrocnemius or popliteus muscle compresses the popliteal artery and causes intermittent claudication. Thrombo­ sis, embolism, or popliteal artery aneurysm may occur. The pulse examination may be normal unless provocative maneuvers such as ankle dorsiflexion and plantar flexion are performed. The diagnosis is confirmed by duplex ultrasound, CTA, MRA, or conventional angi­ ography. Treatment involves surgical release of the popliteal artery or vascular reconstruction. ■ ■POPLITEAL ARTERY ANEURYSM Popliteal artery aneurysms are the most common peripheral artery aneurysms. Approximately 50% are bilateral. Patients with popliteal artery aneurysms often have aneurysms of other arteries, especially the aorta. The most common clinical presentation is limb ischemia secondary to thrombosis or embolism. Rupture occurs less frequently. Other complications include compression of the adjacent popliteal vein or peroneal nerve. Popliteal artery aneurysm can be detected by palpa­ tion and confirmed by duplex ultrasonography. Repair is indicated for symptomatic aneurysms or when the diameter exceeds 2–3 cm, owing to the risk of thrombosis, embolism, or rupture. ■ ■ARTERIOVENOUS FISTULA Abnormal communications between an artery and a vein, bypassing the capillary bed, may be congenital or acquired. Congenital arterio­ venous fistulas are a result of persistent embryonic vessels that fail to differentiate into arteries and veins; they may be associated with birthmarks, can be located in almost any organ of the body, and frequently occur in the extremities. Acquired arteriovenous fistulas either are created to provide vascular access for hemodialysis or occur as a result of a penetrating injury such as a gunshot or knife wound or as complications of arterial catheterization or surgical dissection. An uncommon cause of arteriovenous fistula is rupture of an arterial aneurysm into a vein. The clinical features depend on the location and size of the fistula. Frequently, a pulsatile mass is palpable, and a thrill and a bruit last­ ing throughout systole and diastole are present over the fistula. With long-standing fistulas, clinical manifestations of chronic venous insufficiency, including peripheral edema; large, tortuous varicose veins; and stasis pigmentation become apparent because of the high venous pressure. Evidence of ischemia may occur in the distal por­ tion of the extremity. Skin temperature is higher over the arteriove­ nous fistula. Large arteriovenous fistulas may result in an increased cardiac output with consequent cardiomegaly and high-output heart failure (Chap. 264). The diagnosis is often evident from the physical examination. Com­ pression of a large arteriovenous fistula may cause reflex slowing of the heart rate (Nicoladoni-Branham sign). Duplex ultrasonography may detect an arteriovenous fistula, especially one that affects the femoral artery and vein at the site of catheter access. CTA and conventional angiography can confirm the diagnosis and are useful in demonstrat­ ing the site and size of the arteriovenous fistula. Management of arteriovenous fistulas may involve surgery, radio­ therapy, or embolization. Congenital arteriovenous fistulas are often difficult to treat because the communications may be numerous and extensive, and new communications frequently develop after ligation of the most obvious ones. Many of these lesions are best treated conserva­ tively using elastic support hose to reduce the consequences of venous hypertension. Occasionally, embolization with autologous material, such as fat or muscle, or with hemostatic agents, such as gelatin sponges or silicon spheres, is used to obliterate the fistula. Acquired arteriove­ nous fistulas are usually amenable to surgical treatment that involves division or excision of the fistula. Occasionally, autogenous or synthetic grafting is necessary to reestablish continuity of the artery and vein. ■ ■RAYNAUD PHENOMENON Raynaud phenomenon is characterized by episodic digital isch­ emia, manifested clinically by the sequential development of digital

B C A E F D FIGURE 292-3  Vascular diseases associated with temperature: A. Raynaud phenomenon; B. acrocyanosis; C. livedo reticularis; D. pernio; E. erythromelalgia; and F. frostbite. blanching, cyanosis, and rubor of the fingers or toes after cold expo­ sure and subsequent rewarming. Emotional stress may also precipitate Raynaud phenomenon. The color changes are usually well demarcated and are confined to the fingers or toes. Typically, one or more digits will appear white when the patient is exposed to a cold environment or touches a cold object (Fig. 292-3A). The blanching, or pallor, rep­ resents the ischemic phase of the phenomenon and results from vaso­ spasm of digital arteries. During the ischemic phase, capillaries and venules dilate, and cyanosis results from the deoxygenated blood that is present in these vessels. A sensation of cold or numbness or paresthesia of the digits often accompanies the phases of pallor and cyanosis. With rewarming, the digital vasospasm resolves, and blood flow into the dilated arterioles and capillaries increases dramatically. This “reactive hyperemia” imparts a bright red color to the digits. In addi­ tion to rubor and warmth, patients often experience a throbbing, painful sensation during the hyperemic phase. Although the triphasic color response is typical of Raynaud phenomenon, some patients may develop only pallor and cyanosis; others may experience only cyanosis. Raynaud phenomenon is broadly separated into two categories: idiopathic, termed primary Raynaud phenomenon, and secondary Raynaud phenomenon, which is associated with other disease states or known causes of vasospasm (Table 292-1). Primary Raynaud Phenomenon  This appellation is applied when the secondary causes of Raynaud phenomenon have been excluded. Over 50% of patients with Raynaud phenomenon have the primary form. Women are affected about five times more often than men, and the age of presentation is usually between 20 and 40 years. The fingers are involved more frequently than the toes. Initial episodes may involve only one or two fingertips, but subsequent attacks may involve the entire finger and may include all the fingers. The toes are affected in 40% of patients. Although vasospasm of the toes usually occurs in patients with symptoms in the fingers, it may happen alone.

CHAPTER 292 Arterial Diseases of the Extremities Rarely, the earlobes, the tip of the nose, tongue, nipple, or penis are involved. Raynaud phenomenon occurs frequently in patients who also have migraine headaches or variant angina from coronary vasospasm. These associations suggest that there may be a common predisposing cause for the vasospasm. Results of physical examination are often entirely normal; the radial, ulnar, and pedal pulses are normal. The fingers and toes may be cool between attacks and may perspire excessively. Nailfold capillaroscopy reveals normal superficial capillaries, which appear as regularly spaced hairpin loops. Thickening and tightening of the digital subcutaneous tissue (sclerodactyly) develop in 10% of patients. Angiography of the digits for diagnostic purposes is not indicated. TABLE 292-1  Classification of Raynaud Phenomenon Primary or idiopathic Raynaud phenomenon Secondary Raynaud phenomenon      Collagen vascular diseases: scleroderma, systemic lupus erythematosus, rheumatoid arthritis, dermatomyositis, polymyositis, mixed connective tissue disease, Sjögren syndrome      Arterial occlusive diseases: atherosclerosis of the extremities, thromboangiitis obliterans, acute arterial occlusion, thoracic outlet syndrome      Pulmonary hypertension      Neurologic disorders: intervertebral disk disease, syringomyelia, spinal cord tumors, stroke, poliomyelitis, carpal tunnel syndrome, complex regional pain syndrome      Blood dyscrasias: cold agglutinins, cryoglobulinemia, cryofibrinogenemia, myeloproliferative disorders, lymphoplasmacytic lymphoma      Trauma: vibration injury, hammer hand syndrome, electric shock, cold injury, typing, piano playing      Drugs and toxins: ergot derivatives, methysergide, b-adrenergic receptor blockers, bleomycin, vinblastine, cisplatin, gemcitabine, vinyl chloride

In general, patients with primary Raynaud disease have milder clinical manifestations. Fewer than 1% of these patients lose a part of a digit. After the diagnosis is made, the disease improves spontaneously in ~15% of patients and progresses in ~30%.

Secondary Causes of Raynaud Phenomenon  Raynaud phe­ nomenon occurs in 80–90% of patients with systemic sclerosis (sclero­ derma) and is the presenting symptom in 30% (Chap. 372). It may be the only symptom of scleroderma for many years. Abnormalities of the digital vessels may contribute to the development of Raynaud phenomenon in this disorder. Ischemic fingertip ulcers may develop and progress to gangrene and autoamputation. About 20% of patients with systemic lupus erythematosus (SLE) have Raynaud phenomenon (Chap. 368). Occasionally, persistent digital ischemia develops and may result in ulcers or gangrene. In most severe cases, the small ves­ sels are occluded by a proliferative endarteritis. Raynaud phenomenon occurs in ~30% of patients with dermatomyositis or polymyositis (Chap. 377). It frequently develops in patients with rheumatoid arthri­ tis and may be related to the intimal proliferation that occurs in the digital arteries. PART 6 Disorders of the Cardiovascular System Atherosclerosis of the extremities is a common cause of Raynaud phenomenon in men aged >50 years. Thromboangiitis obliterans is an uncommon cause of Raynaud phenomenon but should be consid­ ered in young men, particularly those who are cigarette smokers. The development of cold-induced pallor in these disorders may be confined to one or two digits of the involved extremity. Occasionally, Raynaud phenomenon may follow acute occlusion of large and medium-sized arteries by a thrombus or embolus. Embolization of atheroembolic debris may cause digital ischemia. The latter situation often involves one or two digits and should not be confused with Raynaud phenom­ enon. In patients with thoracic outlet compression syndrome, Raynaud phenomenon may result from diminished intravascular pressure, stimulation of sympathetic fibers in the brachial plexus, or a combina­ tion of both. Raynaud phenomenon occurs in patients with primary pulmonary hypertension (Chap. 294); this is more than coincidental and may reflect a neurohumoral abnormality that affects both the pul­ monary and digital circulations. A variety of blood dyscrasias may be associated with Raynaud phe­ nomenon. Cold-induced precipitation of plasma proteins, hyperviscos­ ity, and aggregation of red cells and platelets may occur in patients with cold agglutinins, cryoglobulinemia, or cryofibrinogenemia. Hypervis­ cosity syndromes that accompany myeloproliferative disorders and lym­ phoplasmacytic lymphoma (Waldenström macroglobulinemia) should also be considered in the initial evaluation of patients with Raynaud phenomenon. Raynaud phenomenon occurs often in patients whose vocations require the use of vibrating hand tools, such as chain saws or jackham­ mers. The frequency of Raynaud phenomenon also seems to be increased in pianists and keyboard operators. Electric shock injury to the hands or frostbite may lead to the later development of Raynaud phenomenon. Several drugs have been causally implicated in Raynaud phenom­ enon. They include ergot preparations, methysergide, β-adrenergic receptor antagonists, and the chemotherapeutic agents bleomycin, vinblastine, cisplatin, and gemcitabine. TREATMENT Raynaud Phenomenon Most patients with Raynaud phenomenon experience only mild and infrequent episodes. These patients need reassurance and should be instructed to dress warmly and avoid unnecessary cold exposure. In addition to gloves and mittens, patients should protect the trunk, head, and feet with warm clothing to prevent cold-induced reflex vasoconstriction. Tobacco use is contraindicated. Drug treatment should be reserved for severe cases. Dihy­ dropyridine calcium channel antagonists such as nifedipine and amlodipine decrease the frequency and severity of Raynaud phe­ nomenon. Diltiazem may be considered but is less effective. The postsynaptic α1-adrenergic antagonist prazosin has been used with

favorable responses; doxazosin and terazosin may also be effective. Phosphodiesterase type 5 inhibitors such as sildenafil, tadalafil, and vardenafil may improve symptoms in patients with secondary Raynaud phenomenon, as occurs with systemic sclerosis. There is also evidence that topical nitroglycerin preparations are effective. Digital sympathectomy is helpful in some patients who are unre­ sponsive to medical therapy. Injection of botulinum toxin into the perivascular tissue of the wrist or palm improved ischemic mani­ festations of severe Raynaud phenomenon in case series, although controlled clinical trials have yielded inconsistent results. ■ ■ACROCYANOSIS In this condition, there is arterial vasoconstriction and secondary dila­ tion of the capillaries and venules with resulting persistent cyanosis of the hands and, less frequently, the feet. Cyanosis may be intensified by exposure to a cold environment. Acrocyanosis may be categorized as primary or secondary to an underlying condition. In primary acrocya­ nosis, women are affected much more frequently than men, and the age of onset is usually <30 years. Generally, patients are asymptomatic but seek medical attention because of the discoloration. The prognosis is favorable, and pain, ulcers, and gangrene do not occur. Examina­ tion reveals normal pulses, peripheral cyanosis, and moist palms (Fig. 292-3B). Trophic skin changes and ulcerations do not occur. The disorder can be distinguished from Raynaud phenomenon because it is persistent and not episodic, the discoloration extends proximally from the digits, and blanching does not occur. Ischemia secondary to arterial occlusive disease can usually be excluded by the presence of normal pulses. Central cyanosis and decreased arterial oxygen saturation are not present. Patients should be reassured and advised to dress warmly and avoid cold exposure. Pharmacologic intervention is not indicated. Secondary acrocyanosis may result from hypoxemia, vasopressor medications, connective tissue diseases, atheroembolism, antiphospho­ lipid antibodies, cold agglutinins, or cryoglobulins and is associated with anorexia nervosa and postural orthostatic tachycardia syndrome. Treatment should be directed at the underlying disorder. ■ ■LIVEDO RETICULARIS In this condition, localized areas of the extremities develop a mottled or rete (netlike) appearance of reddish to blue discoloration (Fig. 293-3C). There are primary and secondary forms of livedo reticularis. The pri­ mary, or idiopathic, form of this disorder may be benign or associated with ulcerations. The benign form occurs more frequently in women than in men, and the most common age of onset is the third decade. The mottling typically is symmetric and uniform and may be more prominent after cold exposure and improve with warming. Patients with the benign form are usually asymptomatic and seek attention for cosmetic reasons. These patients should be reassured and advised to avoid cold environments. No drug treatment is indicated. Primary livedo reticularis with ulceration is also called atrophie blanche en plaque. The ulcers are painful and may take months to heal. Secondary livedo reticularis can occur with atheroembolism (see above), SLE and other vasculitides, antiphospholipid antibodies, hyperviscosity, cryo­ globulinemia, and Sneddon’s syndrome (ischemic stroke and livedo reticularis). Livedo racemosa is the term used to characterize second­ ary livedo reticularis, when the mottling is irregular and disrupted, and does not improve with warming. Rarely, skin ulcerations develop. ■ ■PERNIO (CHILBLAINS) Pernio is a vasculitic disorder associated with exposure to cold; acute forms have been described. Raised erythematous lesions develop most commonly on the toes or fingers in cold weather (Fig. 292-3D). They are associated with pruritus and a burning sensation, and they may blister and ulcerate. Pathologic examination demonstrates angiitis characterized by intimal proliferation and perivascular infiltration of mononuclear and polymorphonuclear leukocytes. Giant cells may be present in the subcutaneous tissue. Patients should avoid exposure to cold, and ulcers should be kept clean and protected with sterile dressings. Sympatholytic drugs and dihydropyridine calcium channel antagonists may be effective in some patients.

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293 Chronic Venous Disease and Lymphedema

■ ■ERYTHROMELALGIA This disorder is characterized by burning pain and erythema of the extremities (Fig. 292-3E). The feet are involved more frequently than the hands, and males are affected more frequently than females. Eryth­ romelalgia may occur at any age but is most common in middle age. It may be primary (also termed erythermalgia) or secondary. Mutations in the SCN9A gene, which encodes the Nav1.7 voltage-gated sodium chan­ nel expressed in sensory and sympathetic nerves, have been described in inherited forms of erythromelalgia. The most common causes of sec­ ondary erythromelalgia are myeloproliferative disorders such as polycy­ themia vera and essential thrombocytosis. Less common causes include drugs, such as calcium channel blockers, bromocriptine, and pergolide; neuropathies; connective tissue diseases such as SLE; and paraneoplas­ tic syndromes. Patients complain of burning in the extremities that is precipitated by exposure to a warm environment and aggravated by a dependent position. The symptoms are relieved by exposing the affected area to cool air or water or by elevation. Erythromelalgia can be distinguished from ischemia secondary to peripheral arterial disorders because the peripheral pulses are present. There is no specific treatment; aspirin may produce relief in patients with erythromelalgia secondary to myeloproliferative disease. Topical anesthetics, such as lidocaine, or a combination of amitriptyline and ketamine may be considered to relieve pain. Topical midodrine may also be considered. Treatment of associ­ ated disorders in secondary erythromelalgia may be helpful. ■ ■FROSTBITE In this condition, tissue damage results from severe environmental cold exposure or from direct contact with a very cold object. Tissue injury results from both freezing and vasoconstriction. Frostbite usu­ ally affects the distal aspects of the extremities or exposed parts of the face, such as the ears, nose, chin, and cheeks. Superficial frostbite involves the skin and subcutaneous tissue. Patients experience pain or paresthesia, and the skin appears white and waxy. After rewarming, there is cyanosis and erythema, wheal-and-flare formation, edema, and superficial blisters. Deep frostbite involves muscle, nerves, and deeper blood vessels. It may result in edema of the hand or foot, vesicles and bullae, tissue necrosis, and gangrene (Fig. 292-3F). Initial treatment is rewarming, performed in an environment where reexposure to freezing conditions will not occur. Rewarming is accom­ plished by immersion of the affected part in a water bath at tempera­ tures of 40°–44°C (104°–111°F). Massage, application of ice water, and extreme heat are contraindicated. The injured area should be cleansed with soap or antiseptic, and sterile dressings should be applied. Analge­ sics are often required during rewarming. Antibiotics are used if there is evidence of infection. The efficacy of sympathetic blocking drugs is not established. After recovery, the affected extremity may exhibit increased sensitivity to cold. ■ ■FURTHER READING Aboyans V et al: Antithrombotic therapies in aortic and peripheral arterial diseases in 2021: A consensus document from the ESC work­ ing group on aorta and peripheral vascular diseases, the ESC working group on thrombosis, and the ESC working group on cardiovascular pharmacotherapy. Eur Heart J 42:4013, 2021. Aday AW, Matsushita K: Epidemiology of peripheral artery disease and polyvascular disease. Circ Res 128:1818, 2021. Bonaca M et al: Contemporary medical management of peripheral artery disease. Circ Res 128:1868, 2021. Choi E, Henkin S: Raynaud’s phenomenon and related vasospastic disorders. Vasc Med 26:56, 2021. Creager MA et al: Reducing nontraumatic lower-extremity amputa­ tions by 20% by 2030: Time to get to our feet: A policy statement from the American Heart Association. Circulation 143:e875, 2021. GBD 2019 Peripheral Artery Disease Collaborators: Global burden of peripheral artery disease and its risk factors, 1990–2019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet Glob Health 11:e1553, 2023. Gornik HL et al: First International Consensus on the diagnosis and management of fibromuscular dysplasia. Vasc Med 24:164, 2019.

Gornik HL et al: 2024 AHA/ACC guideline on the management of

patients with lower extremity peripheral artery disease: A report of the American College of Cardiology/American Heart Associa­ tion Task Force on Clinical Practice Guidelines. Circulation. JACC 83:2497, 2024. Polonsky TS, McDermott MM: Lower extremity peripheral artery CHAPTER 293 disease without chronic limb-threatening ischemia. A review. JAMA 325:2188, 2021. Chronic Venous Disease and Lymphedema Mark A. Creager, Robert T. Eberhardt,

Joseph Loscalzo

Chronic Venous Disease

and Lymphedema ■ ■CHRONIC VENOUS DISEASE Chronic venous diseases range from telangiectasias and reticular veins, to varicose veins, to chronic venous insufficiency with edema, skin changes, and ulceration. This section of the chapter will focus on identification and treatment of varicose veins and chronic venous insufficiency, since these problems are encountered frequently by the internist. The estimated prevalence of varicose veins in the United States is ~15% in men and 30% in women. Chronic venous insufficiency with edema affects ~7.5% of men and 5% of women, and the prevalence increases with age ranging from 2% among those <50 years of age to 10% of those 70 years of age. Approximately 20% of patients with chronic venous insufficiency develop venous ulcers. ■ ■VENOUS ANATOMY Veins in the extremities can be broadly classified as either superficial or deep. The superficial veins are located between the skin and deep fascia. In the legs, these include the great and small saphenous veins and their tributaries. The great saphenous vein is the longest vein in the body. It originates on the medial side of the foot and ascends anterior to the medial malleolus and then along the medial side of the calf and thigh and drains into the common femoral vein. The small saphenous vein originates on the dorsolateral aspect of the foot, ascends posterior to the lateral malleolus and along the posterolateral aspect of the calf, and drains into the popliteal vein. The deep veins of the leg accom­ pany the major arteries. There are usually paired peroneal, anterior tibial, and posterior tibial veins in the calf, which converge to form the popliteal vein. Soleal tributary veins drain into the posterior tibial or peroneal veins, and gastrocnemius tributary veins drain into the pop­ liteal vein. The popliteal vein ascends in the thigh as the femoral vein. The confluence of the femoral vein and deep femoral vein form the common femoral vein, which ascends in the pelvis as the external iliac and then common iliac vein, which converges with the contralateral common iliac vein at the inferior vena cava. Perforating veins con­ nect the superficial and deep systems in the legs at multiple locations, normally allowing blood to flow from the superficial to deep veins. In the arms, the superficial veins include the basilic, cephalic, and median cubital veins and their tributaries. The basilic and cephalic veins course along the medial and lateral aspects of the arm, respectively, and these are connected via the median cubital vein in the antecubital fossa. The deep veins of the arms accompany the major arteries and include the radial, ulnar, brachial, axillary, and subclavian veins. The subcla­ vian vein converges with the internal jugular vein to form the brachio­ cephalic vein, which joins the contralateral brachiocephalic vein to form the superior vena cava. Bicuspid valves are present throughout the venous system to direct the flow of venous blood centrally.

Pathophysiology of Chronic Venous Disease  Varicose veins are dilated, bulging, tortuous superficial veins, measuring at least 3 mm in diameter. The smaller and less tortuous reticular veins are dilated intradermal veins, which appear blue-green, measure 1–3 mm in diameter, and do not protrude from the skin surface. Telangiectasias, or spider veins, are small, dilated veins, <1 mm in diameter, located near the skin surface, and form blue, purple, or red linear, branching, or spider-web patterns.

PART 6 Disorders of the Cardiovascular System Varicose veins can be categorized as primary or secondary. Primary varicose veins originate in the superficial system and result from defective structure and function of the valves of the saphenous veins, intrinsic weakness of the vein wall, and high intraluminal pressure. Approximately one-half of these patients have a family history of varicose veins. Other factors associated with primary varicose veins include aging, pregnancy, hormonal therapy, obesity, and prolonged standing. Secondary varicose veins result from venous hypertension, associated with deep-venous insufficiency or deep-venous obstruc­ tion, and incompetent perforating veins that cause enlargement of superficial veins. Arteriovenous fistulas also cause varicose veins in the affected limb. Chronic venous insufficiency is a consequence of incompetent veins in which there is venous hypertension and extravasation of fluid and blood elements into the tissue of the limb. It may occur in patients with varicose veins and superficial venous disease, but more advanced manifestations are usually caused by disease in the deep veins. It also is categorized as primary or secondary. Primary venous insufficiency is a consequence of an intrinsic structural or functional abnormality in the vein wall or venous valves leading to valvular reflux. Secondary deep-venous insufficiency is caused by obstruction and/or valvular incompetence from previous deep-vein thrombosis (Chap. 290). Deep-venous insufficiency occurs following deep-vein thrombosis, as the delicate valve leaflets become thickened and contracted and can no longer prevent retrograde flow of blood and the vein itself becomes rigid and thick walled. Although most veins recanalize after an epi­ sode of thrombosis, the large proximal veins may remain occluded. Secondary incompetence develops in valves distal to the obstruction because high pressures distend the vein and separate the leaflets. Other causes of secondary deep-venous insufficiency include May-Thurner syndrome, where the left iliac vein is occluded or stenosed by extrinsic compression from the overlapping right common iliac artery; extrinsic compression from tumor or retroperitoneal fibrosis; arteriovenous fistulas resulting in increased venous pressure; congenital deep-vein agenesis or hypoplasia; and venous malformations as may occur in Klippel-Trénaunay and Parkes-Weber syndromes. Clinical Presentation  Patients with venous varicosities are often asymptomatic but still concerned about the cosmetic appearance of their legs. Superficial venous thrombosis may be a recurring problem, and rarely, a varicosity ruptures and bleeds. Symptoms in patients with varicose veins or venous insufficiency, when they occur, include a dull ache, throbbing or heaviness, or pressure sensation in the legs typically after prolonged standing; these symptoms usually are relieved with leg elevation. Additional symptoms may include cramping, burning, pruritus, leg swelling, and skin ulceration. The legs are examined in both the supine and standing positions. Visual inspection and palpation of the legs in the standing position confirm the presence of varicose veins. The location and extent of the varicose veins should be noted. Chronic venous insufficiency is characterized by the development of edema or other skin manifesta­ tions. Edema, stasis dermatitis, and skin ulceration near the ankle may be present if there is superficial venous insufficiency and venous hypertension. Findings of deep-venous insufficiency include increased leg circumference, venous varicosities, edema, and skin changes. The edema, which is usually pitting, may be confined to the ankles, extend above the ankles to the knees, or involve the thighs in severe cases. Over time, the edema may become less pitting and more indurated, particularly with the secondary development of lymphatic dysfunction. Dermatologic findings associated with venous stasis include hyperpig­ mentation, erythema, eczema, lipodermatosclerosis, atrophie blanche,

FIGURE 293-1  Venous insufficiency with active venous ulcer near the medial malleolus. (Courtesy of Dr. Steven Dean, with permission.) and a phlebectasia corona. Lipodermatosclerosis is the combination of induration, hemosiderin deposition, and inflammation, and typi­ cally occurs in the lower part of the leg just above the ankle. Atrophie blanche is a white patch of scar tissue, often with focal telangiectasias and a hyperpigmented border; it usually develops near the medial mal­ leolus. A phlebectasia corona is a fan-shaped pattern of intradermal veins near the ankle or on the foot. Skin ulceration may occur near the medial and lateral malleoli. A venous ulcer is often shallow and characterized by an irregular border, a base of granulation tissue, and the presence of exudate (Fig. 293-1). Bedside maneuvers can be used to distinguish primary varicose veins from secondary varicose veins caused by deep-venous insuffi­ ciency. With the contemporary use of venous ultrasound (see below), however, these maneuvers are employed infrequently. The BrodieTrendelenburg test is used to determine whether varicose veins are secondary to deep-venous insufficiency. As the patient is lying supine, the leg is elevated and the veins allowed to empty. Then, a tourniquet is placed on the proximal part of the thigh and the patient is asked to stand. Filling of the varicose veins within 30 s indicates that the varicose veins are caused by deep-venous insufficiency and incompe­ tent perforating veins. Primary varicose veins with superficial venous insufficiency are the likely diagnosis if venous refilling occurs promptly after tourniquet removal. The Perthes test assesses the possibility of deep-venous obstruction. A tourniquet is placed on the midthigh after the patient has stood, and the varicose veins are filled. The patient is then instructed to walk for 5 min. A patent deep-venous system and competent perforating veins enable the superficial veins below the tourniquet to collapse. Deep-venous obstruction is likely to be present if the superficial veins distend further with walking. Differential Diagnosis  The duration of leg edema helps to distin­ guish chronic venous insufficiency from acute deep-vein thrombosis. Lymphedema, as discussed later in this chapter, is often confused with chronic venous insufficiency, and both may occur together when venous insufficiency impairs lymphatic function leading to phlebo­ lymphedema. Other disorders that cause leg swelling should be con­ sidered and excluded when evaluating a patient with presumed venous insufficiency. Bilateral leg swelling occurs in patients with congestive heart failure, hypoalbuminemia secondary to nephrotic syndrome or severe hepatic disease, or myxedema caused by hypothyroidism or pre­ tibial myxedema associated with Graves’ disease, and with drugs such as dihydropyridine calcium channel blockers and thiazolidinediones. Unilateral causes of leg swelling also include ruptured leg muscles,

hematomas secondary to trauma, and popliteal cysts. Cellulitis may cause erythema and swelling of the affected limb. Leg ulcers may be caused by severe peripheral artery disease and chronic limb threaten­ ing ischemia; neuropathies, particularly those associated with diabetes; and less commonly, skin cancer, vasculitis, or rarely as a complication of hydroxyurea. The location and characteristics of venous ulcers help to differentiate these from other causes. Classification of Chronic Venous Disease  The CEAP (clinical, etiologic, anatomic, pathophysiologic) classification schema incor­ porates the range of symptoms and signs of chronic venous disease to characterize its severity. It also broadly categorizes the etiology as primary, secondary, or congenital; identifies the affected veins as superficial, deep, or perforating; and characterizes the pathophysiology as reflux, obstruction, both, or neither (Table 293-1). Diagnostic Testing  The principal diagnostic test to evaluate patients with chronic venous disease is venous duplex ultrasonogra­ phy. A venous duplex ultrasound examination uses a combination of B-mode imaging and spectral Doppler to detect the presence of venous obstruction and venous reflux in superficial and deep veins. Colorassisted Doppler ultrasound is useful to visualize venous flow patterns. Obstruction may be diagnosed by the absence of flow, the presence of an echogenic thrombus within the vein, or failure of the vein to col­ lapse when a compression maneuver is applied by the sonographer, the last implicating the presence of an intraluminal thrombus. Venous reflux is detected by prolonged reversal of venous flow direction dur­ ing a Valsalva maneuver, particularly for the common femoral vein or TABLE 293-1  CEAP (Clinical, Etiologic, Anatomic, Pathophysiologic) Classification Clinical Classification C0 No visible or palpable signs of venous disease C1 Telangiectasias or reticular veins C2 Varicose veins   C2r Recurrent varicose veins C3 Edema C4 Changes in skin and subcutaneous secondary to CVD   C4a Pigmentation or eczema   C4b Lipodermatosclerosis or atrophie blanche   C4c Corona phlebectatica C5 Healed venous ulcer C6 Active venous ulcer   C6r Recurrent active venous ulcer Etiologic Classification Ep Primary Es Secondary   Esi Secondary – intravenous   Ese Secondary – extravenous Ec Congenital En No cause identified Anatomic Classification As Superficial Ap Perforator Ad Deep An No venous anatomic location identified Pathophysiologic Classification Pr Reflux Po Obstruction Pr,o Reflux and obstruction Pn No pathophysiology identified Abbreviation: CVD, chronic venous disease. Source: Data from F Lurie et al: J Vasc Surg 8:342, 2020.

saphenofemoral junction, or after compression and release of a cuff placed on the limb distal to the area being interrogated.

Some vascular laboratories use air or strange gauge plethysmogra­ phy to assess the severity of venous reflux and complement findings from the venous ultrasound examination. Venous volume and venous refilling time are measured when the legs are placed in a dependent position and after calf exercise to quantify the severity of venous reflux and the efficiency of the calf muscle pump to affect venous return. CHAPTER 293 Magnetic resonance, computed tomographic, and conventional venography are rarely required to determine the cause and plan treatment for chronic venous insufficiency unless there is suspicion for pathology that might warrant intervention. These modalities are used to identify obstruction or stenosis of the inferior vena cava and iliofemoral veins, as may occur in patients with previous proximal deep-vein thrombosis; occlusion of inferior vena cava filters; extrinsic compression from tumors; and May-Thurner syndrome. Chronic Venous Disease and Lymphedema TREATMENT Chronic Venous Disease SUPPORTIVE MEASURES Varicose veins usually are treated with conservative measures. Symptoms often decrease when the legs are elevated periodically, prolonged standing is avoided, and elastic support hose are worn. External compression with elastic stockings, multilayer elastic wraps, stretch bandages, or inelastic garments provides a counter­ balance to the hydrostatic pressure in the veins. Although compres­ sion garments may improve symptoms and are recommended in patients with healed or active venous ulceration, they are not cura­ tive and do not prevent progression of varicose veins. Graduated compression stockings with pressures of 20–30 mmHg are suitable for most patients with simple varicose veins, although higher pres­ sures may be required for patients with varicose veins and manifes­ tations of venous insufficiency such as edema and ulcers. Patients with chronic venous insufficiency also should be advised to avoid prolonged standing or sitting; frequent leg elevation is help­ ful. Graded compression therapy consisting of stockings or multi­ layered compression bandages is the standard of care for advanced chronic venous insufficiency characterized by edema, skin changes, or venous ulcers defined as CEAP clinical class C3–C6. Graduated compression stockings of 30–40 mmHg are more effective than lesser grades for healing venous ulcers. The length of stocking depends on the distribution of edema. Calf-length stockings are tolerated better by most patients, particularly elderly patients; for patients with varicose veins or edema extending to the thigh, thighlength stockings or panty hose should be considered. Exercise train­ ing, including leg muscle strengthening, may improve calf muscle pump function and antegrade venous flow, and reduce the severity of chronic venous insufficiency. Overweight and obese patients should be advised to lose weight via caloric restriction and exercise or consult an obesity specialist for more advanced therapies. In addition to a compression bandage or stocking, patients with venous ulcers also may be treated with low-adherent absorbent dressings that take up exudates while maintaining a moist environ­ ment. Other types of dressings include hydrocolloid (an adhesive dressing composed of polymers such as carboxymethylcellulose that absorbs exudates by forming a gel), hydrogel (a nonabsor­ bent dressing comprising >80% water or glycerin that moisturizes wounds), foam (an absorbent dressing made with polymers such as polyurethane), and alginate (an absorbent, biodegradable dress­ ing that is derived from seaweed), but there is little evidence that these are more effective than low-adherent absorbent dressings. The choice of specific dressing depends on the amount of drain­ age, presence of infection, and integrity of the skin surrounding the ulcer. Ulcers should be debrided of necrotic tissue. Antibiotics are not indicated unless the ulcer is infected. The multilayered com­ pression bandage or graduated compression garment is then put over the dressing.

MEDICAL THERAPIES There are no drugs approved by the U.S. Food and Drug Adminis­ tration for the treatment of chronic venous insufficiency. Diuretics may reduce edema, but at the risk of volume depletion and com­ promise in renal function. Topical steroids may be used for a short period of time to treat inflammation associated with stasis dermati­ tis. Several herbal supplements, such as horse chestnut seed extract (aescin); ruscus extract; flavonoids, including diosmin, hesperidin, or the two combined as micronized purified flavonoid fraction; and French maritime pine bark extract, are touted to have venoconstric­ tive and anti-inflammatory properties. Several meta-analyses have suggested that ruscus extract and micronized purified flavonoid fraction reduce pain, leg heaviness, and/or sensation of swell­ ing, and that micronized purified flavonoid fraction, and perhaps pentoxifylline, in conjunction with compression therapy facilitates venous ulcer healing; however, there remains insufficient evidence to recommend the general use of these substances in patients with chronic venous insufficiency.

PART 6 Disorders of the Cardiovascular System INTERVENTIONAL AND SURGICAL THERAPIES Ablative procedures, including endovenous thermal and nonther­ mal ablation, sclerotherapy, and surgery, are used to treat varicose veins in selected patients who have persistent symptoms, great saphenous vein incompetency, and complications of venous insuf­ ficiency including dermatitis, edema, and ulcers in order to treat symptoms, accelerate healing, and prevent recurrence. Ablative therapy may also be indicated for cosmetic reasons. Endovenous thermal ablation procedures of the saphenous veins include endovenous laser and radiofrequency ablation. To ablate the great saphenous vein, a catheter is placed percutaneously and advanced from the level of the knee to just below the sapheno­ femoral junction via ultrasound guidance. Thermal energy is then delivered as the catheter is pulled back. The heat injures the endo­ thelium and media and promotes thrombosis and fibrosis, resulting in venous occlusion. Average 1- and 5-year occlusion rates exceed 90% following endovenous laser therapy and are slightly less after radiofrequency ablation. Deep-vein thrombosis of the common femoral vein adjacent to the saphenofemoral junction is an uncom­ mon but potential complication of endovenous thermal ablation. Other adverse effects of thermal ablation procedures include pain, paresthesias, bruising, hematoma, and hyperpigmentation. Nonthermal ablation procedures of the saphenous veins include endovenous delivery of a cyanoacrylate tissue adhesive, which causes fibrosis, and mechanochemical ablation, which involves insertion of a rotating wire to injure the endothelium and infusion of a liquid sclerosant. One-year occlusion rates approximate or exceed 90%, respectively. Adverse effects of nonthermal ablation procedures include superficial thrombophlebitis, deep vein throm­ bosis, ecchymoses, hematomas, and hyperpigmentation. Sclerotherapy involves the injection of a chemical into a vein to cause fibrosis and obstruction. Sclerosing agents approved by the U.S. Food and Drug Administration include sodium tetradecyl sulfate, polidocanol, sodium morrhuate, and glycerin. The scleros­ ing agent is administered as a liquid or mixed with air or CO2/O2 to create a foam. It may be used to treat the great saphenous vein, but most commonly sclerotherapy is used to treat the affected tributaries of the great saphenous vein or incompetent perforating veins either as a standalone procedure or concomitant or staged with ablative procedures of the truncal superficial veins. Follow­ ing completion of the procedure, elastic bandages are applied, or 30–40 mmHg compression stockings are worn for 1–2 weeks. Average 1- and 5-year occlusion rates are 81 and 74%, respectively, following sclerotherapy. Complications are uncommon and include deep-vein thrombosis, hematomas, damage to adjacent saphenous or sural nerves, and infection. Anaphylaxis is a very rare but severe complication. Surgical therapy usually involves ligation and stripping of the great and small saphenous veins. The procedure is performed under general anesthesia. Incisions are made at the groin and the upper

calf. The great saphenous vein is ligated below the saphenofemoral junction, and a wire is inserted into the great saphenous vein and advanced distally. The proximal part of the great saphenous vein is secured to the wire and retrieved, i.e., stripped, via the calf incision. Stripping of the great saphenous vein below the knee and stripping of the small saphenous vein usually are not performed because of the respective risks of saphenous and sural nerve injury. Complica­ tions of great saphenous vein ligation and stripping include deepvein thrombosis, bleeding, hematoma, infection, and nerve injury. Recurrent varicose veins occur in up to 50% patients by 5 years, due to technical failures, deep-venous insufficiency, and incompetent perforating veins. Endovenous ablation techniques are generally favored over ligation and stripping. Stab phlebectomy is another surgical treatment for varicose veins. A small incision is made alongside the varicose vein, and it is avulsed by means of a forceps or hook. This procedure may be per­ formed in conjunction with saphenous vein ligation and stripping or thermal or nonthermal ablation. Subfascial endoscopic perfora­ tor surgery (SEPS) uses endoscopy to identify and occlude incom­ petent perforating veins. It has largely been replaced, however, by ablative techniques applied directly to the perforating veins and performed in a staged manner for persistent or recurrent symptoms after treatment for the truncal veins. Endovascular interventions, surgical bypass, and reconstruction of the valves of the deep veins are performed when feasible to treat patients with advanced chronic venous insufficiency who have not responded to other therapies. Catheter-based interventions, usu­ ally involving placement of endovenous stents, may be considered to treat some patients with chronic occlusion or stenosis of the iliac veins. Technical success rates exceed 85% in most series, and long-term patency is achieved in ~75% of these patients. Iliocaval bypass, femoroiliac venous bypass, and femorofemoral crossover venous bypass are procedures used occasionally to treat iliofemoral vein occlusion; saphenopopliteal vein bypass can be used to treat chronic femoropopliteal vein obstruction. Long-term patency rates for venous bypass procedures generally exceed 60% and are associ­ ated with improvement in symptoms. Surgical reconstruction of the valves of the deep veins and valve transfer procedures rarely are used to treat valvular incompetence. Valvuloplasty involves tightening the valve by commissural apposition. With valve trans­ fer procedures, a segment of vein with a competent valve, such as a brachial or axillary vein, or adjacent saphenous or deep femoral vein, is inserted as an interposition graft in the incompetent vein. Both valvuloplasty and vein transfer operations may result in ulcer healing in the majority of patients, although they are uncom­ monly performed and the success rates are somewhat better with valvuloplasty. Lymphedema  Lymphedema is a chronic condition caused by impaired transport of lymph and characterized by swelling of one or more limbs and occasionally the trunk and genitalia. Fluid accumu­ lates in interstitial tissues when there is an imbalance between lymph production and lymph absorption, a process governed in large part by Starling forces. Deficiency, reflux, or obstruction of lymph vessels per­ turbs the ability of the lymphatic system to reabsorb proteins that had been filtered by blood vessels, and the tissue osmotic load promotes interstitial accumulation of water. Persistent lymphedema leads to inflammatory and immune responses characterized by infiltration of mononuclear cells, fibroblasts, and adipocytes, leading to adipose and collagen deposition in the skin and subcutaneous tissues. Lymphatic Anatomy  Lymphatic capillaries are blind-ended tubes formed by a single layer of endothelial cells. The absent or widely fenestrated basement membrane of lymphatic capillaries allows access to interstitial proteins and particles. Lymphatic capillaries merge to form microlymphatic precollector vessels, which contain few smooth muscle cells. The precollector vessels drain into collecting lymphatic vessels, which comprise endothelial cells, a basement membrane, smooth muscle, and bileaflet valves. The collecting lymphatic vessels

in turn merge to form larger lymphatic conduits. Analogous to venous anatomy, there are superficial and deep lymphatic vessels in the legs, which communicate at the popliteal and inguinal lymph nodes. Pelvic lymphatic vessels drain into the thoracic duct, which ascends from the abdomen to the thorax and connects with the left brachiocephalic vein. Superficial and deep lymphatic vessels of the arm communicate with axillary lymph nodes, and the efferent lymphatic vessels join lymphatic vessels from the head to form the right and left subclavian lymphatic trunks, which ultimately enter the right brachiocephalic vein and thoracic duct, respectively. Lymph is propelled centrally by the phasic contractile activity of lymphatic smooth muscle and facilitated by the contractions of contiguous skeletal muscle. The presence of lymphatic valves ensures unidirectional flow. Etiology  Lymphedema may be categorized as primary or second­ ary (Table 293-2). The prevalence of primary lymphedema is ~1.15 TABLE 293-2  Causes of Lymphedema Primary Sporadic (no identified cause) Genetic disorders   Milroy’s disease (VEGFR3, VEGF-C)   Meige’s disease (gene mutation not established)   Lymphedema-distichiasis syndrome (FOXC2)   Cholestasis-lymphedema (LSC1)   Hennekam’s lymphangiectasia-lymphedema syndrome (LCCBE1)   Emberger’s syndrome-lymphedema and predisposition to AML (GATA2)   Microcephaly-lymphedema syndrome (KIF11)   Hypotrichosis-lymphedema-telangiectasia (SOX18) Chromosomal aneuploidies   Turner’s syndrome   Klinefelter’s syndrome   Trisomy 13, 18, or 21 Other disorders associated with primary lymphedema   Noonan’s syndrome   Klippel-Trénaunay syndrome   Parkes-Weber syndrome   Yellow nail syndrome   Intestinal lymphangiectasia syndrome   Lymphangiomyomatosis   Neurofibromatosis type 1 Secondary Infection   Bacterial lymphangitis (Streptococcus pyogenes, Staphylococcus aureus)   Lymphogranuloma venereum (Chlamydia trachomatis)   Filariasis (Wucheria bancrofti, Brugia malayi, B. timori)   Tuberculosis Neoplastic infiltration of lymph nodes   Lymphoma   Prostate   Others Surgery or irradiation of axillary or inguinal lymph nodes for treatment of cancer Iatrogenic   Lymphatic division (during peripheral bypass surgery, varicose vein surgery, or harvesting of saphenous veins) Miscellaneous Chronic venous insufficiency   Contact dermatitis   Podoconiosis   Rheumatoid arthritis   Pregnancy   Factitious

per 100,000 persons <20 years of age. Females are affected more fre­ quently than males. Primary lymphedema may be caused by agenesis, hypoplasia, hyperplasia, or obstruction of the lymphatic vessels. There are three clinical subtypes: congenital lymphedema, which appears shortly after birth; lymphedema praecox, which has its onset at the time of puberty; and lymphedema tarda, which usually begins after age 35. Familial forms of congenital lymphedema (Milroy’s disease) and lymphedema praecox (Meige’s disease) may be inherited in an autosomal dominant manner with variable penetrance; autosomal or sex-linked recessive forms are less common. At least 19 genes are associated with inherited forms of lymphedema. Mutations in the FLT4 gene expressing vascular endothelial growth factor receptor 3 (VEGFR3), which is a determinant of lymphangiogenesis, cause Mil­ roy’s disease; and a mutation of the gene encoding VEGF-C, a ligand for VEGFR3, may cause a Milroy’s disease-like phenotype. A muta­ tion of the LSC1 gene is associated with the cholestasis-lymphedema syndrome. Mutations in the FOXC2 gene, which encodes a transcrip­ tion factor that interacts with a signaling pathway involved in the development of lymphatic vessels, cause the lymphedema-distichiasis syndrome, in which lymphedema praecox occurs in patients who also have a double row of eyelashes. A mutation of SOX18, a transcription factor upstream of lymphatic endothelial cell differentiation, has been described in patients with lymphedema, alopecia, and telangiectasias (hypotrichosis, lymphedema, telangiectasia syndrome). Mutations of the CCBE1 gene, which enhances the lymphangiogenic effects of VEGF-C, cause Hennekam’s lymphangiectasia-lymphedema syn­ drome, and KIF11 gene mutations are associated with microcephalylymphedema syndrome. Mutations of the GATA2 gene, which is involved in the development of lymphatic valves, cause lymphedema and a predisposition to acute myeloid leukemia. Patients with a chro­ mosomal aneuploidy, such as Turner’s syndrome, Klinefelter’s syn­ drome, or trisomy 18, 13, or 21, may develop lymphedema. Syndromic vascular anomalies associated with lymphedema also include KlippelTrénaunay syndrome and Parkes-Weber syndrome. Other disorders associated with lymphedema include Noonan’s syndrome, yellow nail syndrome, intestinal lymphangiectasia syndrome, lymphangiomyo­ matosis, and neurofibromatosis type 1.

CHAPTER 293 Chronic Venous Disease and Lymphedema Secondary lymphedema is an acquired condition that results from damage to or obstruction of previously normal lymphatic channels. Recurrent episodes of bacterial lymphangitis, usually caused by streptococci, are a very common cause of lymphedema. The most common etiology of secondary lymphedema worldwide is lymphatic filariasis, affecting >120 million children and adults and causing lymphedema and elephantiasis in 14 million of these affected individ­ uals (Chap. 240). Recurrent bacterial lymphangitis by Streptococcus may result in chronic lymphedema. Other infectious causes include lymphogranuloma venereum and tuberculosis. A common acquired cause of lymphedema in tropical countries is podoconiosis, which results from barefoot exposure and absorption of silicate particles in soil derived from volcanic rock. In developed countries, the most common secondary cause of lymphedema is surgical excision or irra­ diation of axillary and inguinal lymph nodes for treatment of cancers, such as breast, cervical, endometrial, and prostate cancer, sarcomas, and malignant melanoma. Lymphedema of the arm occurs in 13% of breast cancer patients after axillary node dissection and in 22% after both surgery and radiotherapy. Lymphedema of the leg affects ~15% of patients with cancer after inguinal lymph node dissection. Tumors, such as prostate cancer and lymphoma, also can infiltrate and obstruct lymphatic vessels. Chronic venous insufficiency is gaining recognition as a cause of lymphedema termed phlebolymphedema. Less common causes include contact dermatitis, rheumatoid arthritis, pregnancy, and self-induced or factitious lymphedema after applica­ tion of tourniquets. Clinical Presentation  Lymphedema is generally a painless condi­ tion, but patients may experience a chronic dull, heavy sensation in the leg, and most often, they are concerned about the appearance of the leg. Lymphedema of the lower extremity initially involves the foot and gradually progresses up the leg so that the entire limb becomes

PART 6 Disorders of the Cardiovascular System B A FIGURE 293-2  A. Lymphedema characterized by swelling of the leg, nonpitting edema, and squaring of the toes. (Courtesy of Dr. Marie Gerhard-Herman, with permission.) B. Advanced chronic stage of lymphedema illustrating the woody appearance of the leg with acanthosis and verrucous overgrowths. (Courtesy of Dr. Jeffrey Olin, with permission.) edematous (Fig. 293-2). In the early stages, the edema is soft and pits easily with pressure. Over time, subcutaneous adipose tissue accumulates, the limb enlarges further and loses its normal contour, and the toes appear square. Thickening of the skin is detected by Stemmer’s sign, which is the inability to tent the skin at the base of the toes. Peau d’orange is a term used to describe dimpling of the skin, resembling that of an orange peel, caused by lymphedema. In the chronic stages, the edema no longer pits and the limb acquires a woody texture as the tissues become indurated and fibrotic. The International Society of Lymphology describes four clinical stages of lymphedema (Table 293-3). Differential Diagnosis  Lymphedema should be distinguished from other disorders that cause unilateral leg swelling, such as deep-vein thrombosis and chronic venous insufficiency. In the lat­ ter condition, the edema is softer, and there is often evidence of a stasis dermatitis, hyperpigmentation, and superficial venous vari­ cosities, as described earlier. Other causes of leg swelling that resemble TABLE 293-3  Stages of Lymphedema Stage 0 (or Ia) A latent or subclinical condition where swelling is not evident despite impaired lymph transport. It may exist for months or years before overt edema occurs. Stage I Early accumulation of fluid relatively high in protein content that subsides with limb elevation. Pitting may occur. An increase in proliferating cells may also be seen. Stage II Limb elevation alone rarely reduces tissue swelling, and pitting is manifest. Late in stage II, the limb may or may not pit as excess fat and fibrosis supervene. Stage III Lymphostatic elephantiasis where pitting can be absent and trophic skin changes such as acanthosis, further deposition of fat and fibrosis, and warty overgrowths have developed. Source: Adapted from The 2013 Consensus Document of the International Society of Lymphology: Lymphology 46:1, 2013.

lymphedema are myxedema and lipedema. Lipedema usually occurs in women and is caused by accumulation of adipose tissue in the leg from the thigh to the ankle with sparing of the feet. Diagnostic Testing  Physical examination is usually sufficient to establish a diagnosis of lymphedema. The evaluation of patients with lymphedema should include diagnostic studies to clarify the cause. Abdominal and pelvic ultrasound and computed tomography (CT) can be used to detect obstructing lesions such as neoplasms. Magnetic resonance imaging (MRI) of the affected limb may reveal a honeycomb pattern characteristic of lymphedema in the epifascial compartment and identify enlarged lymphatic channels and lymph nodes. MRI also is useful to distinguish lymphedema from lipedema. Lymphoscintigraphy and lymphangiography are rarely indicated, but either can be used to confirm the diagnosis or differentiate pri­ mary from secondary lymphedema. Lymphoscintigraphy involves the injection of radioactively labeled technetium-containing colloid into the distal subcutaneous tissue of the affected extremity, which is imaged with a scintigraphic camera to visualize lymphatic vessels and lymph nodes. Findings indicative of primary lymphedema include absent or delayed filling of the lymphatic vessels or dermal back flow caused by lymphatic reflux. Findings of secondary lymphedema include dilated lymphatic vessels distal to an area of obstruction. In lymphangiography, iodinated radiocontrast material is injected into a distal lymphatic vessel that has been isolated and cannulated. In primary lymphedema, lymphatic channels are absent, hypoplastic, or ectatic. In secondary lymphedema, lymphatic channels often appear dilated beneath the level of obstruction. The complexities of lym­ phatic cannulation and the risk of lymphangitis associated with the contrast agent limit the utility of lymphangiography. Optical imaging with a near-infrared fluorescence dye enables quantitative imaging of peripheral superficial lymph flow and is useful in the operative setting. TREATMENT Lymphedema Patients with lymphedema of the lower extremities must be instructed to take meticulous care of their feet and legs to prevent cellulitis and lymphangitis. Skin hygiene is important, and emol­ lients can be used to prevent drying. Prophylactic antibiotics are often helpful, and fungal infection should be treated aggressively. Patients should be encouraged to participate in physical activity, as exercise may minimize symptoms and maintain functionality; fre­ quent leg elevation can reduce the amount of edema. Psychosocial support is indicated to assist patients cope with anxiety or depres­ sion related to body image, self-esteem, functional disability, and fear of limb loss. Physical therapy, including massage to facilitate lymphatic drain­ age, may be helpful. The type of massage, termed manual lymphatic drainage, is part of comprehensive decongestive physiotherapy for lymphedema and involves mild compression of the skin of the affected extremity to dilate the lymphatic channels and enhance lymphatic motility. Multilayered, compressive bandages are applied after each massage session to reduce recurrent edema. After optimal reduction in limb volume by decongestive physiotherapy, patients can be fitted with graduated compression hose or other adjustable compression garments. Sequential intermittent pneumatic com­ pression devices can also be applied at home to facilitate reduc­ tion of the edema, improve quality of life, and reduce recurrent cellulitis. Diuretics are contraindicated and may cause depletion of intravascular volume and metabolic abnormalities. Failure to control limb edema may lead to recurrent infections, progressive trophic skin changes, and rarely a highly lethal complication of lymphangiosarcoma. Liposuction in conjunction with decongestive physiotherapy may be considered to treat lymphedema, particularly postmastectomy

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294 Pulmonary Hypertension

lymphedema. Other surgical interventions, including lymph node transfer, are rarely used and often not successful in ameliorat­ ing lymphedema. Microsurgical lymphaticovenous anastomotic procedures have been performed to rechannel lymph flow from obstructed lymphatic vessels into the venous system and may improve lymphatic transport and quality of life in secondary lymphedema. Limb reduction procedures to resect subcutaneous tissue and excessive skin are performed occasionally in severe cases of lymphedema to improve mobility. Modification of surgi­ cal techniques to minimize impact upon the lymphatic system or enhance drainage with prophylactic lymphatic-venous shunts are being employed during operations that require lymph node dis­ section to reduce the risk of lymphedema. Therapeutic lymphangiogenesis has intriguing potential as it has been studied in animal models of lymphedema. Overexpres­ sion of VEGF-C generates new lymphatic vessels and improves lymphedema in a murine model of primary lymphedema. The administration of recombinant VEGF-C or VEGF-D stimulated lymphatic growth in preclinical models of postsurgical lymph­ edema. There may be additional benefits when administered in conjunction with lymph node transfer. However, clinical trials in patients with lymphedema are still required to determine efficacy of gene transfer and cell-based therapies for lymphedema. ■ ■FURTHER READING Aspelund A et al: Lymphatic system in cardiovascular medicine. Circ Res 118:515, 2016. Brouillard P et al: Genetics of lymphatic anomalies. J Clin Invest 124:898, 2014. Executive Committee: The diagnosis and treatment of peripheral lymphedema: 2020 consensus document of the International Society of Lymphology. Lymphology 53:3, 2020. Gloviczki P et al: The 2022 Society for Vascular Surgery, American Venous Forum, and American Vein and Lymphatic Society clini­ cal practice guidelines for the management of varicose veins of the lower extremities. Part I. Duplex Scanning and Treatment of Super­ ficial Truncal Reflux. J Vasc Surg Venous Lymphat Disord 11:231. e6, 2023. Jayaraj A, Gloviczki P: Chronic venous insufficiency, in Vascular Medicine, MA Creager, JA Beckman, J Loscalzo (eds). Philadelphia, Elsevier, 2020, pp 709-727. Kahn SR et al: The postthrombotic syndrome: Evidence-based preven­ tion, diagnosis, and treatment strategies: A scientific statement from the American Heart Association. Circulation 130:1636, 2014. Lurie F et al: The American Venous Forum, American Vein and Lym­ phatic Society and the Society for Vascular Medicine expert opinion consensus on lymphedema diagnosis and treatment. Phlebology 37:252, 2022. Masuda E et al: The 2020 appropriate use criteria for chronic lower extremity venous disease of the American Venous Forum, the Society for Vascular Surgery, the American Vein and Lymphatic Society, and the Society of Interventional Radiology. J Vasc Surg Venous Lymphat Disord 8:505.e4, 2020. Rabinovich A, Kahn SR: The postthrombotic syndrome: Current evidence and future challenges. J Thromb Haemost 15:230, 2017. Rockson SG: Diseases of the lymphatic circulation, in Vascular Medicine, MA Creager, JA Beckman, J Loscalzo (eds). Philadelphia, Elsevier, 2020, pp 771-784. Schleimer K et al: Update on diagnosis and treatment strategies in patients with post-thrombotic syndrome due to chronic venous obstruction and role of endovenous recanalization. J Vasc Surg Venous Lymphat Disord 7:592, 2019. Sharma A, Wasan S: Varicose veins, in Vascular Medicine, MA Creager, JA Beckman, J Loscalzo (eds). Philadelphia, Elsevier, 2020, pp 693-708.

Bradley A. Maron, Joseph Loscalzo

Pulmonary Hypertension CHAPTER 294 Pulmonary hypertension (PH) is a heterogeneous disease involving pathogenic remodeling of the pulmonary vasculature, which increases pulmonary artery pressure and pulmonary vascular resistance (PVR). The most common causes of PH are left heart or primary lung disease. Additionally, PH is observed in some patients as a later complication of luminal pulmonary embolism and may be observed variably in patients with various hematologic, myeloproliferative, and other systemic dis­ eases. Pulmonary arterial hypertension (PAH) is an uncommon, but distinct, PH subtype characterized by the interplay between molecular and genetic events that cause an obliterative arteriopathy and symp­ toms of dyspnea, chest pain, and syncope. If left untreated, PH carries a high mortality rate, largely owing to decompensated right heart failure. Pulmonary Hypertension There have been significant advances in diagnosis, classification, and treatment of PH patients. For example, the mean pulmonary artery pressure (mPAP) used to diagnose PH has been lowered from ≥25 mmHg to >20 mmHg, and the PVR level used to identify patients with PAH and other forms of precapillary PH has been lowered from ≥3 to

2 Wood units (WU). These adjustments emphasize earlier disease detection, as a substantial delay in diagnosis of up to 2 years is common in PAH and has important implications for both quality of life and life span. Clinicians should be able to recognize the signs and symptoms of PH and complete a systematic evaluation in at-risk patients. In this way, prompt diagnosis, appropriate treatment, and optimized patient outcome are achievable. ■ ■PATHOBIOLOGY Apoptosis resistance, cell proliferation, dysregulated metabolism, and increased oxidant stress involving pulmonary vascular cells, pericytes, and adventitial fibroblasts underlie the pathogenesis of PAH. These events lead to hypertrophic, fibrotic, and plexogenic remodeling of distal (small) pulmonary arterioles, which decreases vascular compli­ ance and promotes in situ thrombosis (Fig. 294-1). The remodeling pattern also includes extracellular matrix expansion, which is rich in integrins, nonfibrillar collagens, fibronectin, and other tensile proteins that stiffen affected blood vessels further. A minority of patients appear to have a vasoconstriction-dominant phenotype, which, if present, requires a unique treatment strategy discussed in greater detail below. There is now greater understanding that in PAH, right ventricular dys­ function occurs due not only to increased right ventricular afterload but also as a consequence of depressed right ventricular sarcomere function from chronic inflammation or autoimmune mechanisms. Genetic Drivers  Several germline variants in genes that regulate fundamental cellular processes such as growth, proliferation, or pheno­ type switching are associated with incident PAH and follow a familial pattern. A variant in the gene encoding bone morphogenetic protein receptor-2 (BMPR2) is the most common cause of hereditary PAH, although penetrance is variable and may be as low as 20% in some populations. Sporadic mutations involving BMPR2 are also reported in PAH patients. BMPR2 is within the (super)family of transforming growth factor- β (TGF-β) receptors that transduce a wide range of cellular events via stimulation by activins, inhibins, and bone morpho­ genetic proteins (Fig. 294-2). Indeed, imbalance between proliferative and antiproliferative TGF-β receptor signaling in PAH has emerged as a bona fide therapeutic target based on clinical trials testing the effect of activin signal inhibitor therapy on outcome in PAH (see section on sotatercept). The advance of genome-wide association studies has expanded the range of genetic drivers linked to pathogenic mechanisms underly­ ing PAH, to include TBX4 and SOX17, which regulate activation of fibroblast growth factor-10 and hepatocyte growth factor, respectively. Genetic predisposition to PH in the setting of left heart disease is unresolved, although single-gene polymorphisms that target actin

PART 6 Disorders of the Cardiovascular System Br A B C D E F FIGURE 294-1  Panels on the left show examples of plexogenic pulmonary arteriopathy. Representative images of a normal lung (A) and examples of pulmonary vascular remodeling in pulmonary arterial hypertension (B–F), including idiopathic pulmonary arterial hypertension (B–E) and pulmonary venoocclusive disease (F), are shown. A. Normal pulmonary artery (arrow) adjacent to a terminal bronchiole (Br). B. Marked media and intima thickening of small vessels (arrow), partly surrounded by lymphoid cells, form a cluster reminiscent of a primary follicle (arrowhead). C. Idiopathic pulmonary hypertension lung with a markedly muscularized medium-sized pulmonary artery (arrow), which distally branches into a plexiform lesion (lower arrowhead) and an adjacent plexiform lesion (upper arrowhead). D. Complex vascular lesion (circle) with a combination of telangiectatic-like dilations of the pulmonary artery (arrowheads) and a plexiform lesion (arrow). E. Medium-sized pulmonary artery with complete lumen obliteration with a loose collagen, poorly cellular matrix (arrows). F. Interlobular septal, medium-sized vein (arrowhead) obliterated by loose connective tissue (arrows), likely the result of an organized thrombus, characteristic of venoocclusive disease. (These representative images were provided courtesy of Dr. Rubin Tuder. The samples were obtained through the evaluation of lungs collected by the Pulmonary Hypertension Breakthrough Initiative, with similar pulmonary vascular pathology spectrum as reported in reference E Stacher et al: Modern age pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med 186:261, 2012. Adapted with permission of the American Thoracic Society. Copyright © 2021 American Thoracic Society. All rights reserved. Reproduced with permission from BA Maron et al: Pulmonary Arterial Hypertension: Diagnosis, Treatment, and Novel Advances. Am J Respir Crit Care Med 203:1472, 2021.) binding, basement membrane, and major histocompatibility complex II proteins have been reported in lung tissue of affected patients. A variant in EIF2AK4 is an established genetic risk factor for pulmonary venoocclusive disease with a recessive mode of transmission, although clinical expression among carriers is evident initially across a wide age range (10–60 years). Epigenetics in PH  The baseline DNA damage profile is increased in pulmonary artery endothelial cells and circulating blood mononuclear Pulmonary arterial hypertension Antiproliferative BMPs BMPR-II ALK 1/2/3/6 pSmad1/5/8 Smad4 pSmad2/3 Extracellular Gremlin-1 and noggin FIGURE 294-2  Pulmonary arterial hypertension is associated with dysregulation of the bone morphogenetic protein (BMP) receptor type II (BMPR-II)–Smad1/5/8 pathway in pulmonary vascular smooth muscle and endothelial cells, causing an imbalance between proproliferative and antiproliferative signaling pathways. BMPR-II–Smad1/5/8 pathway downregulation leads to increased production of activin ligands, such as activin A, growth differentiation factor 8 (GDF8), and GDF11, which contributes to activin receptor type IIA (ActRIIA)–Smad2/3 pathway upregulation. Increased phosphorylated Smad (pSmad) 2/3 activity promotes expression of the endogenous BMP antagonists gremlin-1 and noggin. Gremlin-1 and noggin further reduce BMP–Smad1/5/8 signaling. The overall result is that antiproliferative signaling is reduced, shifting the balance toward proproliferative activin–Smad2/3 signaling, which leads to pulmonary vascular remodeling. (Adapted from M Humbert et al: N Engl J Med 384:1204, 2021.)

cells from PAH patients. This finding implicates DNA itself as a target of injury and is accompanied by epigenetic disease mechanisms involv­ ing methylation and demethylation that include translocation methyl­ cytosine dioxygenase 2 (TET2) and methyltransferase 3B (DNMT3B). The extent to which these events are transmissible across generations remains limited to experimental disease models. Nevertheless, bromo­ domain-containing 4 and histone deacetylation inhibition, particularly for HDAC-1 and HDAC-5, are promising future PAH therapeutics. Long noncoding RNAs, which regulate epigenetic (among other) Activins and GDFs Proproliferative ALK 4/5/7 ActRIIA/B

processes that underpin hypertrophic vascular remodeling in PAH, include the tyrosine kinase receptor–inducing long noncoding RNA through its effects on p53/platelet-derived growth factor receptor β in lung pericytes. At present, hypoxia is the most well-studied epigenetic driver linked to PH, but a practical framework to predict disease onset through this mechanism in individual patients is unresolved. Endothelial-Mesenchymal Transition  Plexigenic and fibrotic pulmonary arterial remodeling in PAH is linked to cellular phenotype switching, particularly endothelial-mesenchymal transition (End-MT) for which specific markers are identified in ~6% of cells in explanted lungs from patients or at autopsy. Inflammation as well as hypoxia plus vascular endothelial growth factor receptor inhibition have been shown to increase End-MT, which in affected cells is characterized by migration, gain of smooth muscle actin fibers, and loss of cell-cell con­ tacts. Interestingly, End-MT is related to a loss of BMPR2 expression, tying together a monogenic risk to a key endophenotype that drives PAH pathology. Hypoxia, Metabolism, and Matrix Remodeling  Abnormali­ ties in multiple molecular pathways, genes, and cell types are associated with potentially modifying therapeutics, particularly those that focus on extracellular matrix remodeling (Fig. 294-3). The tyrosine kinase Janus kinase 2 (JAK2) is overactivated in PAH, which is inhibited by ruxolitinib to attenuate cellular proliferation and experimental PH. Hypoxia-inducible factor (HIF) signaling is a potentially modifiable disease-causing pathway, as treatment with the novel HIF-2α inhibitor PT2567 improves hemodynamics and vascular remodeling in PAH. Classical treatment Sotatercept

BMPR2mediated ET-1 Activin L-Arginine NOS AA ActRIIA/B ET-1 L-citrulline GFs/ cytokines pSmad2/3 pSmad1/5/8 Prostacyclin derivatives NO PGI2 ETA/ETB2 sGC stimulator

Epigenetic/TF: -DNMT3B -HIF-1/HIF-2 -SOX9 -SOX17 -TBX4 -TET2 -TWIST-1 -TYKRIL ETA/ETB2 antagonists PDE5 inhibitor Vasoconstriction äProliferation Vasodilation åProliferation Fibroblast Immune cell PAEC PASMC Pericyte FIGURE 294-3  Modifiable pathobiological targets in pulmonary arterial hypertension. Current treatment approaches focus on endothelin, nitric oxide, and prostacyclin signaling. Novel treatment targets address (1) epigenetic mechanisms/transcriptional factors; (2) oxidative stress; (3) hypoxia and metabolic signaling; (4) BMPR2mediated signaling; (5) tyrosine kinase and growth factor signaling; (6) fibrosis and extracellular matrix remodeling; and (7) inflammation and immune cell infiltration. 4PBA, 4-phenylbutyric acid; AA, arachidonic acid; ActRII, activin receptor type II; BMP, bone morphogenetic protein; BMPR2, bone morphogenetic protein receptor type 2; cDC, conventional dendritic cell; DNMT3B, DNA methyltransferase 3 b; ET, endothelin; GDFs, growth and differentiation factors; HIF = hypoxia-inducible factor; JAGGED-1, jagged canonical Notch ligand 1; JAK, Janus kinase; MAO-A, monoaminoxidase A; MMP, matrix metalloproteinase; NUDT1, nudix hydrolase 1; NEDD9, neural precursor cell–expressed developmentally downregulated protein 9; NFU1, NFU1 iron-sulfur cluster scaffold; NO, nitric oxide; NOS, nitric oxide synthase; PAEC, pulmonary artery endothelial cell; PASMC, pulmonary arterial smooth muscle cell; PDE5, phosphodiesterase 5; PGI2, prostacyclin; PINK1, phosphatase and tensin homolog–induced kinase 1; SDF1, stromal cell–derived factor 1; sGC, soluble guanylate cyclase; SOX9, SRY-box transcription factor 9; SOX17, SRY-box transcription factor 17; SPARC, secreted protein acidic and rich in cysteine; TBX4, T-box transcription factor 4; TET2, Tet methylcytosine dioxygenase 2; TWIST1, Twist family BHLH transcription factor 1; TYKRIL, tyrosine kinase receptor–inducing long noncoding RNA. (Reproduced with permission from SJ Johnson et al: Am J Respir Crit Care Med 208:528, 2023.)

Pulmonary artery smooth muscle cells isolated from PAH patients preferentially synthesize lactic acid in the presence of abundant molecular oxygen (Warburg effect). This metabolic change results in a proliferative cellular phenotype and has stimulated intense interest on metabolic modulating therapies. Dichloroacetate, which inhibits pyruvate dehydrogenase kinase to normalize voltage-gated K+ chan­ nels and promote pulmonary artery smooth muscle cell apoptosis, has been tested clinically with overall mixed results but a signal toward predicting treatment response by SIRT3 and UCP2 genotype. Nonetheless, numerous alternative metabolic targets show therapeutic promise, including SOD2, PPARγ, and NFAT. Finally, there is greater interest in reverse remodeling pathways in PAH. For example, matrix metalloproteinase (MMP)-8 is protective against PAH by stabiliz­ ing mechanosensitive focal adhesion kinase–yes-associated protein/ transcriptional coactivator with PDZ-binding motif (FAK-YAP/TAZ). This stabilization, in turn, suppresses extracellular matrix expansion and vascular fibrosis.

CHAPTER 294 Pulmonary Hypertension ■ ■PATHOPHYSIOLOGY In PAH, plexogenic and fibrotic remodeling of pulmonary arterioles impairs pulmonary arterial compliance and results in a progressive increase in total PVR. The resting PVR increases through the temporal progression of PAH, corresponding to a rise in mPAP. To preserve cardiac output (CO) in the face of elevated right ventricular afterload, right ventricular work must increase. A sustained (or progressive) increase in right ventricular work causes a shift in the efficiency of right ventricular systolic function by which maintaining pulmonary New treatment

Inflammation/ Immune cells: -cDCs -T-cells -JAGGED-1 4PBA BMP9/10

Tyrosine kinase/ Growth factors Degradation

Fibrosis and ECM remodeling: -MMP-8 -NEDD9 -SPARC BMPRII -Capmatinib -Crizotinib -Imatinib -Seralutinib JAK2 Ruxolitinib

Hypoxia/metabolism: -Glutaminolysis -Glucose/Prolin -HIF-2` -NFU1 -PINK1 -Sirtuin 3 Clorgyline Oxidative stress -MAO-A Oxidative stress PT2567 NDUT1 (S)-Crizotinib SDF1

RISK STRATIFICATION EARLY AND AGGRESSIVE INTERVENTION Dual Pharmacotherapy Prescription Exercise Treat Systemic Targets Intervention Focus PART 6 Disorders of the Cardiovascular System Genetic Screen Exercise Testing Developmental Screen Clinical “Stage” A CO Hemodynamic PAP PVR RAP Histologic SMC Elastin Pericyte EC Structural Adv. Fibroblast Proliferation of fibroblasts and SMCs, swelling of ECs, and fragmented elastin Endothelial channel formation Smooth muscle–like cells encroach on lumen inflammation Time FIGURE 294-4  An integrated overview of pulmonary arterial hypertension (PAH). In PAH, initial changes in the histopathophenotype of distal pulmonary arterioles precede significant changes in hemodynamics or the development of symptoms in most patients (clinical stage A). As vascular remodeling progresses, there is an increase in pulmonary vascular resistance (PVR), pulmonary artery pressure (PAP), and right atrial pressure (RAP). In clinical stage B, symptoms are evident and, when diagnosed, prompt early, aggressive treatment. Effacement of pulmonary arterioles results in severely increased PVR that promotes right heart failure, defined by a decrease in cardiac output (CO) and PAP. Patients in clinical stage C have severe symptoms and require full therapeutic intervention. Identifying clinical stage A patients remains challenging, although genetic risk factors or symptoms with exercise may be informative. EC, endothelial cell; SMC, smooth muscle cell. (Reproduced with permission from Maron BA, Abman SH: Focusing on Developmental Origins and Disease Inception for the Prevention of Pulmonary Hypertension. Am J Respir Crit Care Med 195:292, 2017.) circulatory pressure depletes myocardial energy. These changes occur at the expense of energy normally reserved to maintain optimal blood perfusion through the alveolar-capillary interface for blood oxygenation, a process termed right ventricular–pulmonary arterial uncoupling. In end-stage PAH, the CO declines, leading to a decrease in mPAP (Fig. 294-4), with extrapulmonary vascular manifestations. These include overactivation of neurohumoral signaling, renal failure, abnormal episcleral vessels (seen in patients with hereditary PAH due to BMPR2 mutation), and hyper- or hypothyroidism. Volitional muscle atrophy in PAH is associated with reduced muscle strength, type I fiber switching to fatigable type II fibers, and decreased capillary density. This myopathy affects respiratory function, as well, including impair­ ment of maximal inspiratory and expiratory pressure. Overall, sarcope­ nia in PAH with right ventricular heart failure is likely multifactorial, driven by deconditioning and alternative pathophysiological mecha­ nisms linked to impaired cardiac output (i.e., neurohumoral signaling) and possibly through the ectopic effects of molecular intermediaries such as miR-136 downregulation (Fig. 294-5). ■ ■DIAGNOSIS The diagnosis of PH can be missed without a reasonable index of sus­ picion. Indeed, findings from clinical registries suggest that PH is often overlooked, even among patients with numerous risk factors. This shortcoming may be because PH symptoms are nonspecific, insidi­ ous, and overlap considerably with many common conditions, such as asthma, heart failure with preserved ejection fraction, and decon­ ditioning. Additionally, there is a misconception that in patients with comorbid cardiopulmonary conditions (e.g., interstitial lung disease, mitral valve disease), PH is merely an extension of the underlying dis­ ease rather than a specific clinical entity.

FULL INTERVENTION Maximal Medical Therapy Surgical Referral B C Inflamatory Cell Most patients will present with dyspnea and/or fatigue, whereas edema, chest pain, presyncope, and syncope are less common and associated with more advanced disease. In early phases of PAH, the physical examination is often unrevealing. As the disease progresses, there may be evidence of right ventricular failure with elevated jugular venous pressure, lower extremity edema, and ascites. Additionally, the cardiovascular examination may reveal an accentuated P2 component of the second heart sound, a right-sided S3 or S4, and a holosystolic tricuspid regurgitant murmur. It is also important to seek signs of the diseases that are commonly concurrent with PH: clubbing may be seen in some chronic lung diseases, sclerodactyly and telangiectasia may signify scleroderma (or the limited cutaneous form, CREST [calci­ nosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia]), and crackles on examination of the lungs and systemic hypertension may be clues to left-sided systolic or diastolic heart failure. Overview of the Diagnostic Clinical Evaluation  Once clini­ cal suspicion is raised, a systematic approach to diagnosis and assessment is essential. In advanced disease, electrocardiography may show right ventricular hypertrophy or strain, and enlargement of pulmonary arteries and obliteration of the retrosternal space are often observed on chest roentgenography (Fig. 294-6). In turn, echocardiography with agitated saline (bubble) study is the most important initial screening test. Elevated estimated pulmonary artery systolic pressure (>35 mmHg), notched waveform on continuous wave Doppler interrogation of the right ventricular outflow tract, or a hypertrophied or dilated right ventricle supports the diagnosis of PH. Important additional information can be gleaned about specific etiologies of PH, such as valvular disease, left ventricular systolic

Eyes: • Open-angle glaucoma • Retinal detachment • Venous stasis retinopathy • Central retinal vein occlusion Thyroid: • Hypothyroidism • Hyperthyroidism • Grave’s disease Liver: • Congestive hepatopathy • Hepatic fibrosis • Cardiac cirrhosis • Ischemic hepatitis Iron homeostasis: • Iron deficiency • Impaired absorption • Anemia Endocrine system: • Metabolic syndrome • Diabetes • Estrogen/testosterone Immune system: • Systemic inflammation • Innate/adaptive immunity • Autoimmunity Skin: • Subacute prurigo simplex FIGURE 294-5  Systemic manifestations of right heart failure. (Reproduced with permission from S Rosenkranz et al: Systemic consequences of pulmonary hypertension and right-sided heart failure. Circulation 141:67, 2020.) dysfunction, left atrial enlargement, and intracardiac shunt. In addi­ tion, hypertrophic cardiomyopathy (HCM), amyloid cardiomyopathy, and sarcoid cardiomyopathy, which are specific forms of left heart dis­ ease that predispose to PH, are linked to disease-specific approaches to treatment. A high-quality echocardiogram that is absolutely normal may obvi­ ate the need for further PH evaluation. However, this is distinct from an echocardiogram in which tricuspid regurgitation is not detected. In this scenario, the information required to estimate pulmonary artery pressure is lacking, and PH is observed in one-third of such patients. Patients with evidence of PH on echocardiography or in whom unex­ plained dyspnea or hypoxemia is evident despite an unremarkable echocardiogram often require further assessment. Additional tests focusing on functional capacity are useful for quan­ tifying disease burden, such as a 6-minute walk distance (6-MWD) assessment, which also aids in assessing prognosis. Cardiopulmonary exercise testing (CPET) may differentiate between cardiac and pul­ monary limitations to exercise thereby providing pathophysiologic insights on the cause of dyspnea. Peak volume of oxygen consumption (pVO2), which is an integrated parameter of cardiopulmonary fitness, is prognostic in PH patients when <15 mL/kg/min. However, low pVO2 is an important clinical finding across the spectrum of heart-lung disease and, thus, is not diagnostic of PH per se. In patients with a normal CPET, further invasive testing is often unnecessary. One exception to this approach is in patients with reassuring CPET results but in whom a significant decrease in exercise tolerance from baseline is nonetheless reported, often observed in elite athletes or highly conditioned indi­ viduals with early-stage PH or subacute pulmonary embolism.

Brain: • Cognitive function • Depression • Anxiety • Sleep CHAPTER 294 Autonomic system: • Sympathetic hyperactivity • Increased susceptibility for syncope and arrhythmias • Endothelial dysfuntion Pulmonary Hypertension Left heart: • Mechanical compression • Underfilling/deconditioning • Functional (systolic/diastolic) • Cardiomyocyte atrophy Kidneys: • Low perfusion renal injury • Congestive nephropathy • Renal fibrosis/sclerosis • “Acute-on-chronic” renal injury Gut/Bowel: • “Leaky bowel syndrome” • Malabsorption • Appetite loss/cachexia • Gut microbiota Skeletal muscle: • Deconditioning • Impaired function of skeletal and respiratory muscles • Reduced aerobic capacity Invasive hemodynamic monitoring with right heart catheterization (RHC) is the gold standard for PH diagnosis and severity assessment. Interpretation of RHC data, however, is often optimized by informa­ tion from diagnostic tests that support and frame the clinical context of pulmonary vascular disease. Stepwise Approach to Diagnosing PH  One common PH diagnostic strategy is outlined in Figure 294-7; however, the approach should be individualized in practice according to a particular patient’s clinical and risk factor profile. For example, patients with a strong his­ tory of inhaled tobacco use may benefit from prioritizing diagnostic tests assessing pulmonary function and the lung parenchyma, whereas a myocardial ischemia evaluation should be considered early in the evaluation of patients with left-sided cardiomyopathy. PULMONARY FUNCTION AND LUNG IMAGING  Pulmonary function testing results may suggest restrictive or obstructive lung diseases as the cause of dyspnea or PH. In PAH, an isolated reduction in diffusing capacity of the lungs for carbon monoxide (DLCO) is a classic finding. High-resolution computed tomography (CT) provides useful informa­ tion, particularly enlargement of the main pulmonary artery, right ventricle, and atria, as well as peripheral pruning of small vessels; how­ ever, high-resolution CT may also reveal signs of venous congestion, including centrilobular ground glass infiltrate and thickened septa. In the absence of left heart disease, these findings suggest pulmonary venous disease, a rare cause of PAH that can be quite challenging to diagnose. CT is also critical for distinguishing comorbid interstitial lung disease, emphysema, or overlap syndromes that include fibrosis and obstructive pulmonary disease.

PART 6 Disorders of the Cardiovascular System A B C E FIGURE 294-6  Electrocardiography, chest roentgenography, and two-dimensional echocardiography in advanced pulmonary arterial hypertension. A. Standard 12-lead electrocardiogram shows peaked R waves in lead V1 and ST-segment depression in leads V2–V3, suggestive of right ventricular hypertrophy with strain (arrows). B, C. Anterior-posterior and lateral chest roentgenogram demonstrating enlargement of central pulmonary arteries and obliteration of the retrosternal space, indicative of right ventricular hypertrophy. D, E. Apical four-chamber and two-chamber short axis views acquired by transthoracic echocardiography demonstrate right ventricular (RV) and right atrial (RA) enlargement, as well as interventricular septal flattening in diastole consistent with pressure overload. LV, left ventricle. SLEEP STUDIES  Nocturnal desaturation is a common finding in PH, even in the absence of sleep-disordered breathing. Thus, all patients should undergo nocturnal oximetry screening, regardless of whether classic symptoms of obstructive sleep apnea or obesity-hypoventilation syndrome are present. ASSESSMENT OF PULMONARY ARTERIAL THROMBOSIS  Patients with prior luminal pulmonary embolism are at increased risk for chronic Right Heart Catheterization mPAP >20 mmHg Identify Hemodynamic Classification Pre-Capillary PH PVR >2.0 WU; PAWP ≤15 mmHg Isolated Post-Capillary PH PVR ≤2.0 WU; PAWP >15 mmHg Combined Pre-/Post-Capillary PH PVR >2.0 WU; PAWP >15 mmHg Clinical Group Clinical Group 1: PAH, PVOD, CHD, others 2: Chronic lung disease and hypoxia 4: CTEPH 5: Multi-factorial PH 3: LHD FIGURE 294-7  Integrating the cardiopulmonary hemodynamic and clinical profile of patients with pulmonary hypertension (PH). Diagnosing PH is achieved by right heart catheterization and requires a mean pulmonary artery pressure (mPAP) >20 mmHg. Patients are then classified by hemodynamic category, which together with the clinical profile and other supporting data (e.g., chest imaging, serology, genetic testing) is used to determine the PH clinical group. Certain clinical groups are incompatible with hemodynamic classifications; for example, pulmonary arterial hypertension (PAH) cannot be diagnosed in patients with isolated postcapillary or combined pre-/ postcapillary PH hemodynamics. CHD, congenital heart disease; CTEPH, chronic thromboembolic PH; LHD, left heart disease; PAWP, pulmonary artery wedge pressure; PVOD, pulmonary venoocclusive disease; PVR, pulmonary vascular resistance. (Reproduced with permission from BA Maron et al: Cardiopulmonary hemodynamics in pulmonary hypertension and heart failure: JACC Review Topic of the Week. J Am Coll Cardiol 76:2671, 2020.)

RV RA D RV LV thromboembolic pulmonary hypertension (CTEPH), which is a spe­ cific PH subtype characterized by vascular fibrosis and arterial micro­ thrombus. Although CTEPH is curable in many patients by surgical endarterectomy, it is also widely underdiagnosed. Ventilation-perfusion (V./Q.) scanning is still the primary test used to screen and diagnose CTEPH, which should be considered in any patient with PH of unclear etiology. Nonetheless, CT angiography is increasingly used in clinical Clinical Group 3: Chronic LHD 4: CTEPH (rare) 5: Multi-factorial PH

practice to manage CTEPH especially for staging anatomic throm­ boembolic burden, which may be ultimately necessary to determine operative candidacy. The definitive diagnostic procedure is digital subtraction pulmonary angiography since contrast enhancement in this study provides detailed information on webbing, stricture, and vascular tapering patterns pathognomonic for CTEPH. SEROLOGY  Laboratory data that are important for screening include a human immunodeficiency virus (HIV) test when clinically indicated. In addition, all patients should have antinuclear antibodies, rheuma­ toid factor, and anti-Scl-70 antibodies assessed to screen for the most common rheumatologic diseases associated with PH. Liver function and hepatitis serology tests are important to screen for underlying liver disease. Methamphetamine use is recognized increasingly as a cause of PAH, and screening should be considered in patients from endemic regions or in whom the cause of PAH is not otherwise established. Finally, brain natriuretic peptide (BNP) and the N-terminus of its propeptide (NT-proBNP) correlate with right ventricular dysfunction, hemodynamic severity, and functional status in PAH. Medical therapy also lowers NT-proBNP levels in PAH, and therefore, this test may be used as a biomarker for assessing treatment response in clinical prac­ tice once a baseline level is established. INVASIVE CARDIOPULMONARY HEMODYNAMICS  The RHC remains the gold standard test to both establish the diagnosis of PH and guide selection of appropriate medical therapy. The hemodynamic criteria for diagnosing PH requires, first, an mPAP >20 mmHg. Precapillary and postcapillary PH are then distinguished by virtue of a pulmo­ nary artery wedge pressure (PAWP) (or left ventricular end-diastolic pressure [LVEDP]) ≤15 mmHg or >15 mmHg, respectively. Isolated precapillary PH also requires a PVR >2.0 WU, whereas isolated post­ capillary PH is defined by PVR ≤2.0 WU. Increasingly, combined pre- and postcapillary PH is recognized, defined by elevated mPAP

20 mmHg, PVR >2.0 WU, and PAWP >15 mmHg (Fig. 294-7). These hemodynamic profiles inform PH clinical categorization. For example, isolated precapillary PH is most often due to primary lung disease, PAH, or CTEPH. Isolated postcapillary PH occurs in patients with mitral valvular disease, left ventricular systolic dysfunction, heart failure with preserved ejection faction, HCM, and amyloid cardiomy­ opathy. The same etiologies for isolated postcapillary PH also underlie combined pre- and postcapillary PH. When present, this indicates that chronic vascular congestion due to left atrial hypertension has resulted in substantial pulmonary vascular remodeling, although the precise mechanisms that transition patients from isolated postcapillary PH to combined pre-/postcapillary PH are not known. Patients with left heart disease risk factors who are diuresed aggressively prior to RHC may appear to have an isolated precapillary PH profile, tempting a diagnosis of PAH. However, these patients require specific consideration given the potential effects of diuresis on masking the true underlying PH hemodynamic classification. Vasoreactivity testing should be reserved for patients with idiopathic or hereditary PAH. Vasodilators with a short duration of action, such as inhaled nitric oxide (NO•) or inhaled epoprostenol, are preferred for testing. A decrease in mPAP by ≥10 mmHg to an absolute level ≤40 mmHg without a decrease in CO is defined as a positive pulmo­ nary vasodilator response, and such responders are considered for long-term treatment with calcium channel blockers. Less than 5% of patients are deemed vasoreactive, although prognosis among these patients is particularly favorable. ■ ■PULMONARY HYPERTENSION CLASSIFICATION The current classification system, last revised in 2018 during the Sixth World Symposium on Pulmonary Hypertension (WSPH), recognizes five PH categories listed here sequentially as groups 1–5: PAH; PH due to left heart disease; PH due to chronic lung disease or sleep-disordered breathing; CTEPH; and a group of miscellaneous diseases that rarely (or inconsistently) cause PH (Table 294-1). Pulmonary Arterial Hypertension  WSPH group 1 PH, or PAH, involves marked pulmonary arterial precapillary remodeling,

TABLE 294-1  World Symposium on Pulmonary Hypertension Clinical Classification GROUP 1 Pulmonary arterial hypertension (PAH)   1.1  Idiopathic CHAPTER 294     1.1.1  Non-responders at vasoreactivity testing     1.1.2  Acute responders at vasoreactivity testing   1.2  Heritablea   1.3  Associated with drugs and toxinsa   1.4  Associated with: Pulmonary Hypertension     1.4.1  Connective tissue disease     1.4.2  HIV infection     1.4.3  Portal hypertension     1.4.4  Congenital heart disease     1.4.5  Schistosomiasis   1.5  PAH with features of venous/capillary (PVOD/PCH) involvement   1.6  Persistent PH of the newborn GROUP 2 PH associated with left heart disease   2.1  Heart failure:     2.1.1  with preserved ejection fraction     2.1.2  with reduced or mildly reduced ejection fractionb   2.2  Valvular heart disease   2.3  Congenital/acquired cardiovascular conditions leading to post-capillary PH GROUP 3 PH associated with lung diseases and/or hypoxia   3.1  Obstructive lung disease or emphysema   3.2  Restrictive lung disease   3.3  Lung disease with mixed restrictive/obstructive pattern   3.4  Hypoventilation syndromes   3.5  Hypoxia without lung disease (e.g. high altitude)   3.6  Developmental lung disorders GROUP 4 PH associated with pulmonary artery obstructions   4.1  Chronic thrombo-embolic PH   4.2  Other pulmonary artery obstructionsc GROUP 5 PH with unclear and/or multifactorial mechanisms   5.1  Hematological disordersd   5.2  Systemic disorderse   5.3  Metabolic disordersf   5.4  Chronic renal failure with or without hemodialysis   5.5  Pulmonary tumor thrombotic microangiopathy   5.6  Fibrosing mediastinitis Note: Patients with heritable PAH or PAH associated with drugs and toxins might be acute responders. Left ventricular ejection fraction for HF with reduced ejection fraction: ≤40%; for HF with mildly reduced ejection fraction: 41–49%. Other causes of pulmonary artery obstructions include: sarcomas (high or intermediate grade or angiosarcoma), other malignant tumors (e.g., renal carcinoma, uterine carcinoma, germ-cell tumors of the testis), non-malignant tumors (e.g., inherited and acquired chronic hemolytic anemia and chronic myeloproliferative disorders, sarcoidosis, pulmonary Langerhans’s cell histiocytosis, and neurofibromatosis type 1, glycogen storage diseases and Gaucher disease.) Abbreviations: HF, heart failure; HIV, human immunodeficiency virus; PAH, pulmonary arterial hypertension; PCH, pulmonary capillary hemangiomatosis; PH, pulmonary hypertension; PVOD, pulmonary veno-occlusive disease. Source: Reproduced with permission of the © ERS 2024: Eur Resp J 61:2200879, 2023; DOI:10.1183/13993003.00879-2022. including intimal fibrosis, increased medial thickness, pulmonary arteriolar occlusion, and classic plexiform lesions (described in detail above in the Pathobiology section). The hemodynamic criteria for PAH are sustained elevation in resting mPAP >20 mmHg, PVR >2.0 WU, and PAWP or LVEDP of ≤15 mmHg based on RHC. Idiopathic PAH (IPAH) is a progressive disease that leads to right heart failure and early mortality. From the original National Institutes of Health registry on IPAH in 1987, the average age at diagnosis was 36 years, with only 9% of patients with IPAH over the age of 60. However, contemporary data now inclusive of numerous international registries suggest a dif­ ferent clinical profile. The mean age of PAH patients is reported to be 54–68 years old across studies. This reflects, in part, rising awareness

of this disease in the elderly. The prevalence of IPAH favors women to men by ~3.1-fold; however, the hemodynamics at diagnosis are more severe, and the prognosis is less favorable in men compared to women. Patients with hereditary PAH from a BMPR2 mutation tend to be younger at diagnosis with more severe cardiopulmonary hemodynam­ ics and are associated with comparatively greater clinical risk compared to IPAH. The rate of conversion to PAH among carriers without clini­ cal evidence of disease is ~2.3% per year.

PART 6 Disorders of the Cardiovascular System Diseases Associated with PAH  Other forms of PAH that deserve specific consideration are those associated with congenital heart dis­ ease with intracardiac shunt, connective tissue disease, portal hyper­ tension, and HIV. CONGENITAL HEART DISEASE  PAH in the setting of congenital heart disease is important to recognize since surgical correction may be indi­ cated and when successful is associated with favorable prognosis. This is particularly salient today, as more congenital heart disease patients live to adulthood and populate general medical practices. Still, refer­ ral to adult congenital heart disease centers should be considered for patients with suspected PAH, which in this population is subclassified into four groups: Eisenmenger’s syndrome, systemic-to-pulmonary shunts, coincidental or small defects causing shunts, and postoperative/ closed defects causing shunts. Surgical repair of congenital anatomic lesions may be indicated prior to elevation in PVR >3.0 WU to avoid the development of Eisenmenger’s syndrome, a pathophysiologic consequence of progressive pulmonary vascular remodeling due to a large-volume left-to-right shunt that is associated with cyanosis, hyperviscosity, weakness, and shortened life span. Indeed, the effect of changing the PVR threshold to define precapillary PH from 3.0 to 2.0 WU on the timing of shunt repair is an evolving concept. CONNECTIVE TISSUE DISEASE  Patients with connective tissue disease– associated PAH are encountered relatively commonly in clinical prac­ tice. Although case series link rheumatoid arthritis and systemic lupus erythematosus with pulmonary vascular disease, the predominant clinical phenotype is systemic sclerosis-associated PAH. It is important to distinguish patients with limited cutaneous scleroderma from those with diffuse scleroderma because PH in the former is likely PAH and PH in the latter often occurs in the setting of interstitial lung disease. Although the average age of scleroderma onset is between 30 and 50 years old, patients who eventually develop scleroderma-associated PAH tend to be older at the time of scleroderma diagnosis. The development of PAH in scleroderma is particularly worrisome prog­ nostically, although implementation of modern therapies improves outcome. Overlap between pulmonary circulatory and interstitial lung disease is encountered commonly in clinical practice. It is tempting to focus on the hemodynamic derangement of these patients as a focal point of clinical care, although the efficacy of implementing PAHspecific treatment to these overlap syndrome patients is unproven. PORTOPULMONARY HYPERTENSION  Among patients with estab­ lished portal hypertension, 2–10% develop portopulmonary hyper­ tension independent of the cause of liver disease. Furthermore, portopulmonary hypertension is observed in patients with nonhepatic etiologies of portal hypertension. A hyperdynamic circulatory state is common, as in most patients with advanced liver disease; however, the same pulmonary vascular remodeling observed in other forms of PAH is seen in the pulmonary vascular bed in portopulmonary hyperten­ sion. It is important to distinguish this process from hepatopulmonary syndrome, which can also manifest with dyspnea and hypoxemia but is pathophysiologically distinct from portopulmonary hypertension in that abnormal vasodilation of the pulmonary vasculature leads to intrapulmonary shunting. Portopulmonary hypertension is an estab­ lished marker of adverse outcome in the post–liver transplant period with 100% mortality reported in one study among patients with mPAP ≥50 mmHg. The optimal preoperative PVR threshold used to predict elevated postoperative risk must also consider morbidity linked to pro­ longed transplant wait time. At present, PVR >3.0 WU is considered a strong predicter of unfavorable outcome after transplant, although PVR >2.0 WU also appears to capture potential risk.

HIV-PAH  The true prevalence of HIV-PAH is not known; however, this PAH subtype is an important cause of mortality in the HIVinfected population, and prognosis in these patients is among the least favorable for all PH subgroups. There is no correlation between the stage of HIV infection and the development of PAH. By contrast, popu­ lation data from the U.S. Veterans Administration database suggest a positive and inverse correlation, respectively, between CD4+ count and viral load with estimated pulmonary artery systolic pressure (ePASP) on echocardiography. An ePASP >40 mmHg in HIV-infected patients is associated with a 40% increase in all-cause mortality compared to uninfected counterparts. Although delineating patients with PAH from within this cohort and other unselected populations is not possible, there is a pressing need to understand further the role of HIV-PH in prognosis patients, particularly in endemic areas of the world. Pulmonary Hypertension Associated with Left Heart Disease  Patients with PH due to left ventricular systolic dysfunc­ tion, aortic and mitral valve disease, and heart failure with preserved ejection fraction (HFpEF) are classified in WSPH group 2. The hall­ mark of this PH phenotype is elevated left atrial pressure with resulting pulmonary venous hypertension. In left-sided systolic heart failure or HFpEF, even mildly elevated mPAP is associated with adverse clinical outcome. It should be noted that PH in the setting of mitral stenosis or regurgitation is an indication for surgical (or percutaneous) valve intervention. Recent data suggest that PH is common in obstructive HCM and associated with fibroproliferative remodeling of distal pul­ monary arterials even when mPAP is only mildly elevated (Fig. 294-8). In amyloid cardiomyopathy, ~75% of patients have elevated mPAP, and combined pre-/postcapillary PH is the most common hemodynamic subgroup. Regardless of the cause of elevated left atrial pressure, left atrial hypertension causes pulmonary venule sclerosis and thickening that leads to PH and, ultimately, pathogenic changes to pulmonary arterioles. Pulmonary Hypertension Associated with Lung Disease 

Intrinsic lung disease is the second most common cause of PH and has been observed in both chronic obstructive pulmonary disease (COPD) and interstitial lung disease. Additionally, PH is also diagnosed in dis­ eases of mixed obstructive/restrictive pathophysiology: bronchiectasis, cystic fibrosis, mixed obstructive-restrictive disease marked by fibrosis in the lower lung zones, and emphysema predominantly in the upper lung zones. When associated with chronic lung disease, PH is usually modest. For example, 90% of COPD patients have mPAP >20 mmHg, but an mPAP >35 mmHg is observed in only 5% of patients. Nonethe­ less, the subgroup of patients with primary lung disease and severe PH is challenging clinically, as extensive pulmonary arterial involvement, very low DLCO on pulmonary function testing, and inhibition of nor­ mal vasoreactivity are observed and are associated with poor outcome. Sleep-disordered syndromes generally result in mild PH. Pulmonary Hypertension Associated with Chronic Throm­ boembolic Disease  The development of PH after chronic throm­ boembolic obstruction of the pulmonary arteries, termed CTEPH, is well described. The incidence of CTEPH following a single pulmo­ nary embolic event is difficult to determine accurately, but probably is between 3 and 7% of patients. Importantly, 25% of patients with CTEPH have no history of clinical venous thromboembolism, sug­ gesting that CTEPH may develop following a subclinical pulmonary embolism or through a diverse range of mechanisms. Obstruction of the proximal pulmonary vasculature due to webbing, stricture, or focal fibrotic occlusion signifies proximal vessel involvement. Distal pulmonary arterioles remodel by luminal narrowing or obliteration. Approximately 10–15% of patients will develop a disease very similar clinically and pathologically to PAH after resection of the proximal thrombus (Fig. 294-9). Chronic thromboembolic disease refers to patients with thrombotic pulmonary arterial remodeling and dimin­ ished exercise capacity with correlative symptoms in the absence of PH. This subtype is less common than CTEPH but requires consider­ ation in patients with prior PE and dyspnea even if echocardiography is reassuring.

Elastin Trichrome Hematoxylin and Eosin Control HCM HCM FIGURE 294-8  Pulmonary vascular remodeling in patients with obstructive hypertrophic cardiomyopathy (HCM) and mild pulmonary hypertension. Photomicrographs showing pulmonary arterial histopathophenotype of HCM. Paraffin-embedded tissue sections from control donors without lung disease and example autopsy specimens from patients with symptomatic obstructive HCM were analyzed after hematoxylin and eosin, Masson trichrome, and Verhoeff-Van Gieson staining. (Adapted with permission from BA Maron et al: Chest 163:678, 2023.) ■ ■OTHER DISORDERS AFFECTING THE PULMONARY VASCULATURE Sarcoidosis  Patients with sarcoidosis can develop PH as a result of lung involvement, and those who present with progressive dyspnea and PH require a thorough evaluation. In sarcoidosis, PH develops mainly due to granulomatous inflammation of the pulmonary vessels, although mechanical compression of pulmonary arteries by enlarged lymph nodes is also reported. Sickle Cell Disease  Cardiovascular system abnormalities are prominent in the clinical spectrum of sickle cell disease (and other hemoglobinopathies), including PH, which occurs in 6–10% of patients. The etiology is multifactorial, including hemolysis, hypoxemia, throm­ boembolism, chronically high CO, and chronic liver disease. Schistosomiasis  Schistosomiasis affects >230 million people worldwide, of whom 5% develop PAH. Thus, this infection is among the most common causes of PAH worldwide. The development of PAH occurs in the setting of hepatosplenic disease and portal hypertension. Indeed, even in the absence of schistosomiasis, splenectomy is a risk factor for PAH, presumably through impaired platelet sequestration and associated microthrombosis of pulmonary arterioles. Studies suggest that inflammation from a schistosomiasis infection induces pulmonary vascular injury through a combination of the following A B C FIGURE 294-9  Chronic thromboembolic pulmonary hypertension (CTEPH) imaging findings and surgical endarterectomy specimen. A. Contrast-enhanced computed tomography of the chest shows an obstructive vascular pattern involving segmental pulmonary arteries (yellow arrows) in a 63-year-old man with exertional dyspnea and remote history of pulmonary embolism. B. Still image of a pulmonary angiography of the right lung (submaximal injection shown) shows pulmonary artery stricture, webbing, and severe dearborization that is classic for CTEPH. C. Fibrotic, chronic clot specimens resected during surgical pulmonary endarterectomy, which is curative in most CTEPH patients. (Panel C is reproduced with permission from IM Lang, M Madani: Update on chronic thromboembolic pulmonary hypertension. Circulation 130:508, 2014.)

CHAPTER 294 Pulmonary Hypertension mechanisms: luminal obstruction by worm eggs, pulmonary artery endothelial cell inflammation, or portal hypertension that promotes a portopulmonary hypertension-PH phenotype The diagnosis is con­ firmed by finding the parasite ova in the urine or stool of patients with symptoms, which can be difficult. The efficacy of therapies directed toward PAH in these patients is unknown. ■ ■PHARMACOLOGIC TREATMENT OF PAH There are 14 U.S. Food and Drug Administration (FDA)–approved medical therapies for PAH, and standardized treatment strategies have been developed that emphasize early, aggressive pharmaco­ therapy initiated at a specialty clinical center. Among optimally treated patients, the 1-, 3-, and 5-year survival estimates are 82, 67, and 58%, respectively, but this may overestimate risk since outcome data in the era of routine dual (and in some cases triple) therapy are lacking. All approved medical therapies target the prostacyclin, NO•, or endothelin receptor signaling pathways. Drug delivery methods now include oral, inhaled, subcutaneous (including via surgically implanted devices), and intravenous routes. Prostanoids  In PAH, endothelial dysfunction and platelet activation cause an imbalance of arachidonic acid metabolites with reduced prostacyclin levels and increased thromboxane A2 produc­ tion. Prostacyclin (PGI2) activates cyclic adenosine monophosphate 1cm

(cAMP)–dependent pathways that mediate vasodilation. PGI2 also has antiproliferative effects on vascular smooth muscle and inhibits platelet aggregation. Protein levels of prostacyclin synthase are decreased in pulmonary arteries of patients with PAH. This imbalance of media­ tors is offset therapeutically by the administration of either exogenous prostacyclin (and analogues, termed prostanoids) or a prostacyclin receptor agonist.

PART 6 Disorders of the Cardiovascular System Epoprostenol was the first prostanoid available for the management of PAH. Epoprostenol delivered as a continuous intravenous infusion improves functional capacity and survival in PAH. The efficacy of epo­ prostenol in World Health Organization (WHO) Functional Class (FC) III and IV PAH patients was demonstrated in a clinical trial that showed improved quality of life, mPAP, PVR, 6-MWD, and mortality. Trepro­ stinil has a longer half-life than epoprostenol (~4 h vs ~6 min), which allows for subcutaneous administration. Treprostinil has been shown to improve pulmonary hemodynamics, symptoms, exercise capacity, and survival in PAH. Inhaled prostacyclin provides the beneficial effects of infused prostacyclin therapy without the inconvenience and side effects of infusion catheters (e.g., risk of infection and infusion site reactions). Both inhaled iloprost and treprostinil have been approved for patients with PAH and severe heart failure symptoms. Oral prostacyclin is also efficacious in clinical trials, but the maximal dose is modest and, there­ fore, generally reserved as a second-line therapy. Selexipag is an oral nonprostanoid diphenylpyrazine derivative that binds the prostaglandin I2 (IP) receptor with high affinity. The active metabolite of selexipag has a prolonged half-life in comparison with prostanoid analogues and permits twice-daily dosing. The efficacy of selexipag was evaluated in patients with PAH in New York Heart Association (NYHA) FC II to III on background therapy with either an endothelin-1 (ET-1) receptor antagonist or sildenafil, or both. This trial represents the largest randomized placebo-controlled trial among patients with PAH ever completed, enrolling 1156 patients treated for a median of 1.4 years. Selexipag reduced the risk of hospitalization and the risk of disease progression by 43% (p < .0001) compared to those who received placebo. There were no significant differences in mortal­ ity between the two study groups, and the side effect profile was similar to that of prostacyclins. Endothelin Receptor Antagonists  Endothelin receptor antago­ nists (ERAs) inhibit the detrimental effects of ET-1, a potent endog­ enous vasoconstrictor and vascular smooth muscle mitogen. In PAH, ET-1 associates positively with PVR and mPAP and inversely with CO and 6-MWD. The ET-1 signaling axis is complex and cell type–specific: ET type A (ETA) and type B (ETB) receptors expressed in pulmonary artery smooth muscle cells mediate vasoconstriction, whereas human pulmonary artery endothelial cells express ETB receptors that promote ET-1 clearance and vasodilation through endothelial nitric oxide synthase activation and prostacyclin release. The three ERAs approved for use in the United States are the non­ selective ETA/B receptor antagonists bosentan and macitentan and the selective ETA antagonist ambrisentan. Studies have shown that bosen­ tan improves hemodynamics and exercise capacity and delays clinical worsening. The randomized, placebo-controlled, phase 3 Bosentan Randomized Trial of Endothelin Antagonist Therapy (BREATHE)-1 trial comparing bosentan to placebo demonstrated improved symp­ toms, 6-MWD, and WHO FC in patients treated with bosentan. The Endothelin Antagonist Trial in Mildly Symptomatic Pulmonary Arterial Hypertension Patients (EARLY) study comparing bosentan to placebo demonstrated improved PVR and 6-MWD in patients with WHO FC II. Several studies, including the phase 3, placebo-controlled Ambris­ entan in Pulmonary Arterial Hypertension, (ARIES)-1 trial, have demonstrated that ambrisentan improves exercise tolerance, WHO FC, hemodynamics, and quality of life in patients with PAH. More recently, the Study with an Endothelin Receptor Antagonist in Pulmonary Arte­ rial Hypertension to Improve Clinical Outcome (SERAPHIN) trial randomized 742 PAH patients to receive placebo or macitentan, which is an ETA/B antagonist with optimized receptor binding affinity. The majority of patients were on some form of background PAH therapy. Over an average treatment duration of 85 weeks, the hazard ratio for

achieving the composite primary endpoint of PAH-related clinical worsening, which included death or disease progression, was decreased by 45% in the 10-mg dose arm. Nitric Oxide Pathway Effectors  The gaseous, lipophilic mol­ ecule NO• is generated by endothelial nitric oxide synthase in endo­ thelial cells and activates soluble guanylyl cyclase (sGC) to generate cyclic guanosine monophosphate (cGMP) in vascular smooth muscle cells and platelets. The cyclic nucleotide cGMP is a second messenger that induces vasodilation through relaxation of arterial smooth muscle cells and inhibits platelet activation. Phosphodiesterase type 5 (PDE5) enzymes are highly expressed in lung vascular tissue (and the corpus carvernosum of the penis). The PDE5 inhibitors prevent hydrolysis (inactivation) of cGMP to maximize NO•-dependent vasodilation, serving as the basis for use of this drug class in the treatment of PH (and erectile dysfunction). The two PDE5 inhibitors used for the treat­ ment of PAH are sildenafil and tadalafil. Both agents have been shown to improve hemodynamics and 6-MWD. Riociguat increases bioactive cGMP by (1) stabilizing the molecular interaction between NO• and sGC, and (2) directly stimulating sGC independent of NO• bioavailability. Riociguat significantly improved exercise capacity, pulmonary hemodynamics, WHO FC, and time to clinical worsening in patients with PAH and is the sole approved pharmacotherapy for CTEPH patients for whom surgical pulmonary endarterectomy is ineffective or contraindicated. Activin Signal Inhibitor Therapy  Motivated by basic and trans­ lational data suggesting that treatment with a TGF-β ligand trap inhib­ its the proproliferative activity of activin ligands in pulmonary vascular cells, sotatercept was developed as a novel fusion protein of the Fc domain of human IgG and the extracellular domain of activin receptor type II. Sotatercept blocks activin receptor II–ALK 4/5/7 signal trans­ duction to upregulate BMPR2 bioactivity. The putative effect of this drug’s reaction in PAH is rebalancing of the TGF-β–BMPR2 pathway to restore normal cellular survival and growth patterns. The PULSAR trial was a large, phase 2, placebo-controlled trial demonstrating a dose-dependent decrease in PVR by sotatercept (0.3 and 0.7 mg/kg administered as an injection) at study week 24 compared to baseline of –1.8 WU and 3.0 WU, respectively. The STELLAR trial was a phase 3 placebo-controlled trial that studied the effect of sotatercept 0.3 mg/kg with target dose of 0.7 mg/kg on 6-MWD. The patients in the study had moderate or severe symptom burden despite ongoing pulmonary vasodilator treatment. In fact, ~60% of patients were on triple therapy, including 40% who were on treatment with intravenous prostacyclin treatment, typically reserved for high-risk or very-highrisk patients (see below). Despite this prior treatment, sotatercept therapy resulted in an average of +40 m improvement in 6-MWD compared to –1.4 m for placebo and was associated with significant improvement in nearly all secondary endpoints including WHO FC improvement, reduction in NT-proBNP level, and shorter time to death or PAH worsening. Telangiectasia development was observed in 10.4% of patients in the sotatercept group, which tracks with the angio­ proliferative bioactivity reported for TGF-β, although the clinical rel­ evance of these vascular anomalies is not known. Finally, the long-term open-label study that tracked clinical progress up to 1 year in patients from PULSAR demonstrated a sustained (but not progressive) benefit in PVR reduction by sotatercept without an unexpected change in the proportion of side effects given the duration of the follow-up period. ■ ■APPROACH TO PAH TREATMENT Treatment aims to achieve a low clinical risk profile, defined as a 1-year mortality risk of <5%. Generally, this describes a patient with mini­ mal symptoms, WHO FC I or II, 6-WMD >440 m, and cardiac index ≥2.5 L/min per m2. To accomplish this goal, early referral to an expert center is advised since most patients will ultimately require two or more PAH pharmacotherapies in addition to risk factor modification (such as a low-sodium diet), diuretic use to include mineralocorticoid receptor antagonists if tolerated, supplemental oxygen, and prescrip­ tion (or supervised) exercise (Fig. 294-10). It is clear that targeting the diverse pathobiologic and pathophysiologic events involved in vascular

Unexplained Dyspnea or Suspected PH Fast Track Referral: -PAH -CTEPH -Warning Signs General Practitioner -Medical History -Physical Examination -ECG -BNP/NT-pro-BNP O2 Saturation Suspected Cause Lung Disease PH or Cardiac Disease Lung Assessment -PFT -ABG -Chest XR -Chest CT -CPET Rapid CrossReferral as Needed Low Causes other than PH Identified? No Mange Accordingly Further Work up Suspect PAH or CTEPH Refer to PH Center FIGURE 294-10  Strategy for diagnosing pulmonary hypertension (PH) in clinical practice. Diagnostic algorithm of patients with unexplained dyspnea and/or suspected pulmonary hypertension. ABG, arterial blood gas analysis; BNP, brain natriuretic peptide; CPET, cardiopulmonary exercise testing; CT, computed tomography; CTEPH, chronic thromboembolic pulmonary hypertension; ECG, electrocardiogram; NT-proBNP, N-terminal pro-brain natriuretic peptide; PAH, pulmonary arterial hypertension; PFT, pulmonary function tests; PH, pulmonary hypertension. Warning signs include rapid progression of symptoms, severely reduced exercise capacity, presyncope or syncope on mild exertion, and signs of right heart failure. Lung and heart assessment by specialist as per local practice. CT pulmonary angiography recommended if PH suspected. Includes connective tissue disease (especially systemic sclerosis), portal hypertension, HIV infection, and family history of PAH. (Reproduced with permission of the © ERS 2024: Eur Resp J 61:2200879, 2023; DOI:10.1183/13993003.00879-2022.) remodeling is needed to optimize treatment. The concept of combina­ tion therapy in PAH is modeled after other complex diseases in which a similar approach has been effective, including HIV, cancer, and left heart failure. The approach to therapy in a patient with incident PAH is outlined in Fig. 294-11. The role of early, aggressive therapy with combination oral treatments was addressed in the landmark Initial Use of Ambrisen­ tan plus Tadalafil in Pulmonary Arterial Hypertension (AMBITION) trial. Treatment-naïve, incident PAH patients (n = 500) were ran­ domized to a combination of ambrisentan and tadalafil, ambrisentan monotherapy, or tadalafil monotherapy. Up-front combination therapy with ambrisentan and tadalafil was associated with a 50% lower risk of clinical worsening (composite of death, lung transplantation, hospital­ ization for PAH worsening, and worsening PAH) when compared with the monotherapy groups. This difference was driven primarily by the delay in time to first hospitalization. Importantly, initial combination therapy was not associated with an increase in adverse events. Registry data suggest that patients on dual therapy with a PDE5 inhibitor plus ERA combinations alternative to the drugs studied in AMBITION also have better outcomes compared to patients treated with monotherapy, suggesting that the attendant benefit from combination therapy may not be drug specific. The paradigm shift toward early, aggressive pharmacotherapy in PAH is expanding to up-front triple combination therapy. Clinical

CHAPTER 294 Pulmonary Hypertension Heart Assessment -Echocardiography -CPET Intermediate or High PH probability studies on up-front triple therapy remain mixed, which is likely driven by challenges surrounding patient selection given the precarious bal­ ance between cumulative off-target effects occurring when multiple vasoactive drugs are initiated at the same time, frailty and limited hemodynamic reserve associated with advanced PAH, and need for aggressive treatment to mitigate severely abnormal hemodynamics or right ventricular heart failure. Generally, treatment deescalation, esca­ lation, or class switching for patients with established PAH should be decided in partnership with a PAH clinical center of excellence. Treatment of HFpEF  Disease-specific treatments for HFpEF-PH are lacking. The focus of care should be to optimize contemporary treatment of HFpEF, including minimizing excessive salt and fluid intake while advancing SGLT-2 therapy, mineralocorticoid therapy, and diuretics, and encouraging regular exercise to promote weight loss and conditioning. Invasive PA pressure monitoring may be helpful for tracking elevation in LVEDP, detected as PH, to avert hospitalization. Treatment of PH due to Lung Disease  Inhaled iloprost improved 6-MWD on average +33 m in a placebo-controlled random­ ized clinical trial studying patients with interstitial lung disease and PH and moderate-to-severe exercise limitation. Although a promising future strategy for the routine management of patients, additional data are needed to confirm efficacy and clarify the criteria defining optimal patients for treatment since dosing is frequent and a substantial rate

Incident PAH Patient Non-Vasoreactive With chest pain, syncope, WHO FC IV or other high risk findings1 Vasoreactive Without chest pain, syncope, WHO FC IV or other high risk findings1 PART 6 Disorders of the Cardiovascular System Initial Therapy Initial Therapy Oral Calcium Channel Antagonist Therapy i.v. or s.c. Prostacyclin + Ambrisentan + Tadalafil Ambrisentan + Tadalafil or Macitentan + Tadalafil 1pVO2 <11 mL/kg/min; NT-pro-BNP >1100 ng/mL; at least moderate pericardial effusion; cardiac index <2.0 L/min/m2, PVR ≥12 WU. FIGURE 294-11  Treatment strategy overview for patients with newly diagnosed pulmonary arterial hypertension (PAH). Newly diagnosed patients with idiopathic, hereditary, or drug-induced PAH should be considered for vasoreactivity testing in the cardiac catheterization laboratory at an expert pulmonary hypertension center. In the absence of a high-risk clinical profile, patients who demonstrate a positive vasoreactivity response, defined by decrease in mean pulmonary artery pressure ≥10 mmHg from baseline to ≤40 mmHg without a decrease in cardiac output, should be initiated on calcium channel antagonist therapy dose titrated to optimal clinical benefit/ adverse effect balance. For patients with PAH without evidence of vasoreactivity but with high-risk findings, consideration of up-front therapy with the prostacyclin analogue treprostinil administered by intravenous (IV) or subcutaneous (SC) route plus the phosphodiesterase type 5 inhibitor tadalafil and endothelin receptor antagonist ambrisentan is indicated. For patients with PAH without vasoreactivity or high-risk findings, initial combination therapy with tadalafil and ambrisentan or the alternate endothelin receptor antagonist macitentan should be considered. NT-proBNP, N-terminal pro-B-type natriuretic peptide; pVO2, peak volume of oxygen consumption; PVR, pulmonary vascular resistance; WHO-FC, World Health Organization Functional Class; WU, Wood units. (Reproduced with permission from BA Maron: Revised definition of pulmonary hypertension and approach to management: A clinical primer. J Am Heart Assoc 12:e029024, 2023.) of treatment attrition is notable. It is also unclear if inhaled iloprost is generalizable to other lung-PH phenotypes, as at least one study focus­ ing on COPD-PH was terminated early, presumably owing to a lack of benefit or adverse effects. Treatment of CTEPH  Pulmonary endarterectomy performed at a high-volume surgical referral center is the preferred therapy in patients with favorable anatomy and profile. Distal fibrothrombotic remodel­ ing, PVR >12 WU, right heart failure, and NYHA FC IV are viewed Assessment by Multi-disciplinary CTEPH Expert Team PH Clinician Chest Radiologist Thoracic Surgery Interventional Cardiology Proximal vs. distal clot Comorbidities PVR >12 WU Right heart failure NYHA FC IV Pulmonary Endarterectomy: Operable Pulmonary Endarterectomy FIGURE 294-12  Algorithm for the management of chronic thromboembolic pulmonary hypertension (CTEPH). BPA, balloon pulmonary angioplasty; NYHA FC, New York Heart Association functional class; PH, pulmonary hypertension; PVR, pulmonary vascular resistance. (Adapted from NH Kim et al: Eur Respir J 53:1801915, 2019.)

Non-Vasoreactive Without chest pain, syncope, WHO FC IV or other high risk findings1 Initial Therapy as high-risk findings and may be prohibitive in terms of postoperative risk. Patients who are ineligible for pulmonary endarterectomy or do not experience a complete clinical result in the postoperative phase should be considered for treatment with riociguat (sGC stimulator) therapy, balloon pulmonary angioplasty (BPA), or a combination of both. Compared to riociguat, BPA modulates a decrease in mPAP of –9.3 mmHg but requires on average five procedural attempts and is associated with some important potential complications, including hemoptysis and reperfusion pulmonary edema (Fig. 294-12). CTEPH Diagnosis Lifelong Anticoagulation (warfarin preferred) Pulmonary Endarterectomy: Non-Operable Riociguat (sildenafil, treprostinil) ± BPA Refractory Symptoms + PH

TABLE 294-2  FDA-Approved Therapies for the Treatment of Pulmonary Arterial Hypertension (PAH) ROUTE OF ADMINISTRATION DRUG CLASS INDICATION GENERIC NAME Epoprostenol IV Prostacyclin derivative Treatment of PAH to improve exercise capacity Iloprost Inhaled Prostacyclin derivative Treatment of PAH to improve a composite endpoint consisting of exercise tolerance, symptoms (NYHA class), and lack of deterioration Treprostinil IV or SC Prostacyclin derivative Treatment of PAH to diminish symptoms associated with exercise Treprostinil Inhaled Prostacyclin derivative Treatment of PAH to improve exercise ability Treprostinil Oral Prostacyclin derivative Treatment of PAH to improve exercise ability Selexipag Oral Selective IP receptor agonist Treatment of PAH to improve a composite endpoint lack of clinical deterioration Bosentan Oral Endothelin receptor antagonist Treatment of PAH to improve exercise capacity and to decrease clinical worsening Ambrisentan Oral Endothelin receptor antagonist Treatment of PAH to improve exercise capacity and delay clinical worsening Macitentan Oral Endothelin receptor antagonist Treatment of PAH to improve a composite endpoint of delay of clinical worsening Sildenafil Oral or IV PDE5 inhibitor Treatment of PAH to improve exercise capacity and delay clinical worsening Tadalafil Oral PDE5 inhibitor Treatment of PAH to improve exercise ability Riociguat Oral Soluble guanylyl cyclase stimulator Treatment of PAH to improve exercise ability Abbreviations: FDA, U.S. Food and Drug Administration; IV, intravenous; NYHA, New York Heart Association; PAH, pulmonary arterial hypertension; PDE5, phosphodiesterase-5; SC, subcutaneous. ■ ■UNMET AND FUTURE RESEARCH NEEDS IN PULMONARY HYPERTENSION Delayed diagnosis is a major barrier to improving outcome in PAH. Improved awareness among clinicians and patients could lead to more timely diagnosis that will affect the response to therapy and survival. At-risk patients should be referred early to a specialty center that focuses on treatment of patients with pulmonary vascular disease, which will ensure their access to state-of-the-art (multidisciplinary) care. In addition, the role of currently available drugs in early-stage disease is not known and requires further investigation (Table 294-2). The anticipated approval of sotatercept is exciting and paves a path toward the availability of the first novel drug class in PAH in nearly two decades. However, clinical trial data continue to lack information from diverse patient subgroups, suggesting that health inequity in PH remains a critical opportunity for progress. ■ ■FURTHER READING Alba GA et al: NEDD9 is a novel and modifiable mediator of plateletendothelial adhesion in the pulmonary circulation. Am J Respir Crit Care Med 203:1533, 2021. Bernardo RJ et al: Health care disparities in pulmonary arterial hypertension. Clin Chest Med 44:543, 2023.

CHAPTER 294 Pulmonary Hypertension Hemnes AR et al: Clinical characteristics and transplant-free survival across the spectrum of pulmonary vascular disease. J Am Coll Car­ diol 80:697, 2022. Ho JE et al: Exercise pulmonary hypertension predicts clinical out­ comes in patients with dyspnea on effort. J Am Coll Cardiol 75:17, 2020. Hoeper MM et al: Phase 3 trial of sotatercept for treatment of pulmo­ nary arterial hypertension. N Engl J Med 388:1478, 2023. Johnson S et al: Pulmonary hypertension: A contemporary review. Am J Respir Crit Care Med 208:528, 2023. Sommer N et al: Current and future treatments of pulmonary arterial hypertension. Br J Pharmacol 178:6, 2021. Walters R et al: SOX17 enhancer variants disrupt transcription factor binding and enhancer inactivity drives pulmonary hypertension. Circulation 147:1606, 2023. Yung LM et al: ACTRIIA-Fc rebalances activin/GDF versus BMP signaling in pulmonary hypertension. Sci Transl Med 12:eaaz5660, 2020. Zeder K et al: Elevated pulmonary vascular resistance predicts mortal­ ity in COPD patients. Eur Respir J 58:2100944, 2021.

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