16.17 Hypertension 3735 16.17.1 Essential hyperten

16.17 Hypertension 3735 16.17.1 Essential hypertension: Definition, epidemiology, and pathophysiology 3735 Bryan Williams and John D. Firth

16.17 Hypertension CONTENTS 16.17.1 Essential hypertension: Definition, epidemiology,
and pathophysiology  3735 Bryan Williams and John D. Firth 16.17.2 Essential hypertension: Diagnosis, assessment,
and treatment  3753 Bryan Williams and John D. Firth 16.17.3 Secondary hypertension  3778 Morris J. Brown and Fraz A. Mir 16.17.4 Mendelian disorders causing hypertension  3796 Nilesh J. Samani and Maciej Tomaszewski 16.17.5 Hypertensive urgencies and emergencies  3800 Gregory Y.H. Lip and Alena Shantsila 16.17.1  Essential hypertension: Definition, epidemiology, and pathophysiology Bryan Williams and John D. Firth ESSENTIALS ‘Essential hypertension’ is high blood pressure for which there is no clearly defined aetiology. From a practical perspective, it is best defined as that level of blood pressure at which treatment to lower blood pressure results in significant clinical benefit—​a level which will vary from patient to patient depending on their absolute cardiovascular risk. Historically, most guidelines define ‘hypertension’ as an of- fice blood pressure greater than or equal to 140/​90  mm Hg, but some recent recommendations prefer home or ambulatory blood pressure (blood pressure) averages. When using 24 h am- bulatory blood pressure or home blood pressure averages to define hypertension, the diagnostic thresholds are lower than
those used with office measurement, with a value of 135/​85 mm Hg
typically used for both daytime ambulatory blood pressure and home measurements. Isolated diastolic hypertension (systolic blood pressure (SBP) <140 mm Hg, and diastolic blood pressure (DBP) >90 mm Hg) is more common in younger people, and isolated systolic hyperten- sion (SBP >140 mm Hg, DBP <90 mm Hg) is the most common form of hypertension in older people. American guidelines include a category of ‘prehypertension’ (SBP 120–​139 mm Hg and/​or DBP 80–​89 mm Hg), the reason for this being that blood pressure in this range is associated with both adverse cardiovascular outcome and a high rate of progression to hypertension. Epidemiology In 2000, it was estimated 25% of the world’s adult population were hypertensive, and predicted that this would rise to 29% by 2025. By the age of 60, more than one-​half of adults in most regions of the world will be hypertensive. There is a continuous relationship between blood pressure and cardiovascular risk from blood pressure values as low as
115/​75  mm Hg. The relationship is steeper for stroke than it is for coronary heart disease, and is magnified by age. There is a doubling in risk of stroke and ischaemic heart disease mortality for every 20/​10 mm Hg increase in blood pressure. Most people with hypertension are over the age of 50 years,
and in these SBP is by far the most important contributor to the burden of cardiovascular disease attributable to hypertension. Pathogenesis and pathophysiology The pathogenesis of essential hypertension is a complex inter- play between (1) genetic predisposition, (2) lifestyle and environ- mental influences, and (3)  disturbances in vascular structure and neurohumoral control mechanisms. Genetic predisposition—​blood pressure runs in families, with a remarkably consistent level of correlation of around 0.2 between first-​degree relatives found in many studies. This means that if the blood pressure of one member of the family deviates from the norm by +10 mm Hg, the first-​degree relative will deviate by +2 mm Hg on average. Variants in a large number of genes, involving virtually
all of the main physiological systems affecting blood pressure, have shown association with blood pressure in one or more studies, but the effect of any individual variant is likely to be modest.

section 16  Cardiovascular disorders 3736 Lifestyle and environmental influences—​the exploding prevalence of hypertension in economically developing regions reflects lifestyle changes, so-​called ‘Westernization’, more than anything else, with the most important influences on blood pressure being sodium in- take, obesity, and alcohol intake. Pathophysiology—​a characteristic finding in essential hypertension is an inappropriate increase in peripheral vascular resistance relative to the cardiac output. This is due to remodelling of small arteries (ar- terioles), which is characterized by an increase in their media/​lumen ratio, but it is not clear whether these changes are a consequence or a cause of raised blood pressure. The functional integrity of large conduit arteries (i.e. the aorta), which becomes stiffer, also influences the development of hypertension—​especially systolic hypertension. The specific role of the renin–​angiotensin–​aldosterone system in the development of essential hypertension remains unclear, but thera- peutic agents that inhibit this system have proved to be very effective treatments. The sympathetic nervous system is involved in the acute and chronic regulation of blood pressure, but whether disturbances in it play a major role in the initiation and maintenance of chronic essential hypertension remains unknown. The hypertensive phenotype and target organ damage Although blood pressure measurement is used to define hyperten- sion, hypertension is more than just blood pressure. Essential hyper- tension is commonly associated with metabolic disturbances (the ‘insulin resistance phenotype’) and multisystem structural damage that conspire to enhance cardiovascular risk beyond that which can be attributed to blood pressure alone. Left ventricular hypertrophy is a classic feature of untreated or in- adequately treated long-​standing hypertension, and is a very potent predictor of premature cardiovascular disease and death. Inhibition of the renin–​angiotensin–​aldosterone system is particularly effective at regressing left ventricular hypertrophy, which is associated with dramatically improved prognosis for people with hypertension. Hypertension is the single most important risk factor for stroke, and is increasingly recognized as a major factor contributing to the rate of cognitive decline in later life. Patients with renal disease often have hypertension, people with hypertension can develop renal dis- ease, and the age-​related decline in GFR is more rapid in people with essential hypertension, but renal function is usually well pre- served throughout life in patients with mild to moderate essential hypertension. Retinal changes caused by hypertension are discussed in Chapter 16.17.2. Implications of the evolution of hypertensive injury The process of hypertensive injury to target organs evolves silently over many years. Current treatment guidelines have been devel- oped from an evidence base relating to changes in hard clinical end-​points derived from studies in elderly patients at the end of the hypertensive disease process. Future treatment strategies must surely focus on preventing the evolution of the silent disease pro- cess, rather than simply battling with its consequences. Definitions of hypertension The commonest form of hypertension has been termed ‘essential hypertension’, i.e. hypertension for which there is no clearly defined aetiology. Blood pressure is normally distributed within populations and thus the definition of ‘hypertension’ is a moving target. From a practical perspective it is best defined as that level of blood pressure at which treatment to lower blood pressure results in significant clin- ical benefit, which will change as new evidence from clinical trials emerges. This statement also highlights the conundrum in definition of ‘hypertension’ because the risk associated with blood pressure is a continuum and the level of pressure at which treatment results in ‘significant clinical benefit’ for any individual will depend on their absolute cardiovascular risk. There is substantial evidence that treating systolic pressure (SBP) above 160 mm Hg and/​or a diastolic pressure (DBP) above 100 mm Hg is beneficial; there is also evidence that treating pressures above 140/​90  mm Hg is worthwhile, especially in higher-​risk patients. Historically, most guidelines have therefore defined ‘hypertension’ as an office blood pressure of 140/​90 mm Hg or more, with various grades of hypertension also specified (Table 16.17.1.1). The hyper- tension guidelines in the United States of America include a category of ‘prehypertension’ (SBP 120–​139 mm Hg and/​or DBP 80–​89 mm Hg), which is discussed later in this chapter. NICE guidance in the United Kingdom has rather confusingly created additional termin- ology, with stage 1 hypertension being clinic BP more than 140/​ 90 mm Hg with ambulatory blood pressure monitoring (ABPM) or home blood pressure monitoring (HBPM) more than 135/​85 mm Hg, stage 2 hypertension being clinic BP more than 160/​100 mm Hg with ABPM or HBPM more than 150/​95 mm Hg, and severe hyper- tension being clinic SBP more than 180 mm Hg or clinic DBP more than 110 mm Hg. It is important to note that the diagnostic thresholds for hyperten- sion vary according to the method of measurement. The aforemen- tioned blood pressure thresholds for diagnosis have been defined according to seated blood pressure measurements, so-​called ‘office blood pressures’. However, the increasing use of automated blood pressure monitoring, either at home or with ambulatory devices, has shown that there can be marked discrepancies between clinic blood pressure measurements and those obtained at home or when ambulatory. This has led to much discussion as to whether conven- tional clinic blood pressure measurements are still the best way of establishing the diagnosis of hypertension. When using 24 h am- bulatory blood pressure or home blood pressure averages to define Table 16.17.1.1  Classification of hypertension. Grades 1–​3 replace the old terminology of ‘mild’, ‘moderate’, and ‘severe’. The ‘high normal’ blood pressure range corresponds to ‘prehypertension’ in the United States guideline Category Systolic Diastolic Optimal <120 and <80 Normal 120–​129 and/​or 80–​84 High normal 130–​139 and/​or 85–​89 Grade 1 hypertension 140–​159 and/​or 90–​99 Grade 2 hypertension 160–​179 and/​or 100–​109 Grade 3 hypertension

180 and/​or 110 Isolated systolic hypertension 140 and <90 Reproduced from Mancia G, et al. (2007). 2007 ESH-​ESC Practice Guidelines for the Management of Arterial Hypertension: ESH-​ESC Task Force on the Management of Arterial Hypertension. J Hypertens, 25, 1751–​62.

16.17.1  Essential hypertension 3737 hypertension, the diagnostic thresholds are lower than these office blood pressures, typically quoted values being 135/​85 mm Hg for both daytime ambulatory blood pressure monitoring and home blood pressure measurements. Subtypes of hypertension Various categories of blood pressure can be identified in popula- tions, with isolated diastolic hypertension (IDH) (SBP <140 mm Hg, DBP >90 mm Hg) being more common in younger people and isolated systolic hypertension (SBP >140 mm Hg, DBP <90 mm Hg) being the most common form of hypertension in older people, with systolic/​diastolic hypertension (SDH) (SBP>140 mm Hg and DBP

90 mm Hg) bridging the two extremes of age (Fig. 16.17.1.1). Although traditionally DBP was considered to carry the greatest prognostic significance, it is now clear that this is not the case. Most people with hypertension are over the age of 50 years, and in them SBP is by far the most important contributor to the burden of cardiovascular disease attributable to hypertension. The different patterns of blood pressure and the relative import- ance of DBP and SBP with regard to prognosis reflect progression of the underlying pathology. The pathogenesis of hypertension in younger people is characterized by an increased peripheral vas- cular resistance. This results in an increased diastolic pressure, with any associated rise in systolic pressure ‘cushioned’ by a com- pliant aorta, hence the commonly observed IDH. With ageing there is progressive stiffening of the aorta, a consequent reduction in large-​artery compliance, and a reduced capacity to sustain dia- stolic pressure and to cushion systolic pressure. The result is an age-​related widening of pulse pressure as diastolic pressure falls alongside a progressive rise in SBP, hence the emergence of ISH (Fig. 16.17.1.2). Epidemiology Global prevalence The global prevalence of hypertension when defined either as a blood pressure of 140/​90  mm Hg or over, or the use of antihypertensive medication, was estimated to be 972 million in the year 2000, representing about 25% of the world’s adult popula- tion. The global prevalence of hypertension is expected to rise dra- matically by about 60% by 2025, representing 29% of the world’s 17% 100% 80% 60% 40% 20% 0% <40 Age (y) Frequency of hypertension subtypes in all untreated subjects (%) 60–69 16% 80+ 70–79 50–59 40–49 11% 20% 20% 16% Fig. 16.17.1.1  Blood pressure subtypes in the United States of America according to age. The percentage values at the top of each column indicate the prevalence of hypertension in that age band. Blue shaded bar, isolated systolic hypertension; brown shaded bar, systolic/​diastolic hypertension; purple shaded bar, isolated diastolic hypertension. Reproduced from Franklin SS, et al. (2001). Predominance of isolated systolic hypertension among middle-​aged and elderly US hypertensives, Hypertension,
37, 869–​74. 0 70 80 110 mm Hg 130 150 (a) (b) Diastolic blood pressure Systolic blood pressure Men Diastolic blood pressure Systolic blood pressure Women Age, y 0 70 80 110 mm Hg 130 150 30–39 30–39 50–59 50–59 Age, y 60–69 60–69 70–79 70–79 ≥80 ≥80 40–49 40–49 18–29 18–29 Non-Hispanic black Mexican American Non-Hispanic white Fig. 16.17.1.2  Data from the United States of America NHANES III population survey (1988–​91) showing the progressive rise in SBP with age and the rise in DBP up until age c.50 years, after which DBP falls and pulse pressure widens. This pattern is typical of Westernized countries and explains the high prevalence of isolated systolic hypertension in older people in these countries. Reproduced from Burt VL, et al. (1995). Prevalence of hypertension in the US adult population. Hypertension, 23, 305–​13.

section 16  Cardiovascular disorders 3738 adult population and affecting 1.6 billion people (Fig. 16.17.1.3). Most of this increase in the worldwide burden of hypertension is expected to result from an increase in the number of people with hypertension in economically developing regions, hence almost 75% of the world’s hypertensive populations will be in economic- ally developing regions by 2025. The prevalence of hypertension in almost all regions of the world increases with age and more steeply in women. By the age of 60, more than one-​half of adults in most regions of the world will be hypertensive. India and Asia have and will most likely continue to have the lowest rates of hypertension, whereas the highest rates are likely to remain in Latin America, the Caribbean, former Soviet re- publics, and sub-​Saharan Africa. Consequently, hypertension is set to remain the single most important preventable cause of premature death worldwide over the next two decades, with the World Health Organization (WHO) estimating that about 7.1 million deaths per year may be attributable to hypertension, and that suboptimal blood pressure (SBP ≥115 mm Hg by their definition) is responsible for 50 2000 37.4 39.1 20.6 40.7 34.8 22.0 23.7 Men Women 22.6 19.7 17.0 14.5 26.9 28.3 40 30 20 10 0 50 2025 Rate of hypertension (%) 41.6 42.5 Established market economies Middle eastem crescent China Other Asia and islands Sub-Saharan Africa Latin America and the Caribbean India Former socialist economies 39.1 45.9 22.9 23.6 44.5 40.2 24.0 27.0 27.7 18.8 17.1 27.0 28.2 40 30 20 10 0 27.0 20.9 35.3 37.2 Fig. 16.17.1.3  Frequency of hypertension in people aged 20 years and older by world region and gender in 2000 (upper panel) and projected to 2025 (lower panel). Reprinted from The Lancet, Vol. 365, Kearney PM, et al., Global burden of hypertension: analysis of world-​wide data, pp. 217–​23. Copyright (2005), with permission from Elsevier. Women aged 65 years 100 (a) 80 60 40 20 0 Years of follow-up Risk of hypertension, % 1976–1998 1952–1975 100 80 60 40 20 0 0 2 4 6 8 10 12 14 16 18 Years of follow-up 20 0 2 4 6 8 10 12 14 16 18 20 Men aged 65 years (b) Fig. 16.17.1.4  Lifetime risk of hypertension in women and men aged 65 years. Reprinted from Vasan RS, et al. (2002). Residual lifetime risk for developing hypertension in middle-​aged women and men, the Framingham Heart Study. JAMA, 287, 1003–​10. Copyright © 2002, American Medical Association.

16.17.1  Essential hypertension 3739 62% of cerebrovascular disease and 49% of ischaemic heart disease worldwide, with little variation by sex. Lifetime risk The prevalence of hypertension increases with age, affecting over one-​half of those aged 60–​69 years and over three-​quarters of those aged over 70 years in the United States of America and most devel- oped countries. As indicated earlier, almost all of the age-​related rise in the prevalence of hypertension is due to a progressive rise in SBP. The lifetime probability of developing hypertension is about 90% for men and women who were not hypertensive at 55 or 65 years old and survived to age 80 to 85 (Fig. 16.17.1.4). Cardiovascular morbidity and mortality associated with hypertension Elevated blood pressure increases the risk of cardiovascular mor- bidity and mortality. Data from observational studies of over 1 mil- lion people has indicated a continuous relationship between blood pressure and cardiovascular risk from blood pressure values as low as 115/​75 mm Hg (Fig. 16.17.1.5). The relationship is steeper 120 140 160 180 120 140 160 180 1 2 4 8 16 32 64 128 256 Age at risk: 80–89 years 70–79 years 60–69 years 50–59 years 40–49 years Usual systolic blood pressure (mm Hg) Systolic blood pressure (a) (b) (a) (b) IHD mortality (floating absolute risk and 95% CI) 80 70 1 2 4 8 16 32 64 128 256 Age at risk: 80–89 years 70–79 years 60–69 years 50–59 years 40–49 years 90 Usual diastolic blood pressure (mm Hg) Diastolic blood pressure IHD mortality (floating absolute risk and 95% CI) 1 2 4 8 16 32 64 128 256 Age at risk: 80–89 years 70–79 years 60–69 years 50–59 years Usual systolic blood pressure (mm Hg) Systolic blood pressure Stroke mortality (floating absolute risk and 95% CI) 1 2 4 8 16 32 64 128 256 Age at risk: 80–89 years 70–79 years 60–69 years 50–59 years Usual diastolic blood pressure (mm Hg) Diastolic blood pressure Stroke mortality (floating absolute risk and 95% CI) 110 100 80 70 90 110 100 Fig. 16.17.1.5  Relationship between usual blood pressure at the start of a decade and the risk of ischaemic heart disease (IHD, top panel) and stroke (bottom panel) mortality rates in that decade, for each decade for each decade of life. Reprinted from The Lancet, Vol. 360, Lewington S, et al., Age-​specific relevance of usual blood pressure
to vascular mortality: a meta-​analysis of individual data for one million adults in 61 prospective studies, pp. 1903–​13. Copyright (2002), with permission from Elsevier.

section 16  Cardiovascular disorders 3740 for stroke than it is for coronary heart disease and is magnified by age. For every 20/​10 mm Hg increase in blood pressure, there is a doubling in risk of stroke and ischaemic heart disease mortality. Hypertension also increases the risk of congestive cardiac failure, end-​stage renal disease, and dementia. Moreover, data from the Framingham Heart Study also indicates that there is a doubling of risk of cardiovascular complications in patients with blood pressure levels above normal but not yet classified as having overt hyperten- sion (Fig. 16.17.1.6). This was the basis for the American guide- lines introducing the term ‘prehypertension’ (SBP 120–​139 mm Hg and/​or DBP 80–​89 mm Hg) to emphasize that this level of blood pressure (1) is not benign, (2) is associated with an elevated car- diovascular disease risk, and (3)  predicts with a high degree of certainty that blood pressure is on an upward trajectory and that affected people are almost certain to develop more severe hyper- tension, unless there is intervention with effective lifestyle changes and/​or drug therapy. Systolic blood pressure as the main risk factor For many years DBP was considered the main denominator for defining the threshold and treatment targets for hypertension. This is no longer the case. As indicated earlier, there is a pro- gressive rise in DBP up to about the age of 50 years and there- after it usually falls. By contrast, SBP begins to rise relentlessly from the age of around 40 years (Figs. 16.17.1.1 and 16.17.1.2). Thus, at the age of peak prevalence of hypertension (i.e. older than 60 years), SBP is the major contributor to the diagnosis of the condition and its associated risk. Below the age of 50 years, DBP is also important. Fig. 16.17.1.7 illustrates the shift in the major risk burden attributable to hypertension, from DBP to SBP, at about the age of 50 years. However, because most hypertension (>75%) occurs over the age of 50 years, SBP rather than DBP is by far the most important contributor to the huge global cardio- vascular risk burden attributable to hypertension. SBP is also the most difficult to treat, which has led some to argue that for pa- tients over the age of 50 years the attention of doctors should be focused solely on the SBP. What method of blood pressure measurement best predicts cardiovascular outcome? It has been known for many years that ambulatory blood pressure measurement (ABPM) provides better prediction of mortality than clinic measurements (Fig. 16.17.1.8). The US Preventive Services Task Force (2015) conducted a thorough review of the literature looking at studies comparing ABPM vs. office blood pressure measurement (OBPM), and home blood pressure measurement (HBPM) vs. OBPM. Eleven studies reported that daytime, night-​time, and 24-​hour ABPM predicted stroke and other fatal and non​fatal CV events independently of OBPM (Fig. 16.17.1.9). Five studies suggested similar results for HBPM, but there was insufficient data to allow firm conclusions. Only a single study compared HBPM with ABPM, which was insufficient to allow conclusions to be drawn. OBPM added no significant predictive capacity independently of ABPM (Fig. 16.17.1.10). In healthcare sys- tems where they are readily available, ABPM or HBPM should be used as the basis for diagnosing (and therefore treating) hypertension. Time (yr) Optimal Normal High normal Optimal Normal High normal Women (a) No. at risk Optimal 1875 1867 1851 1839 1821 1734 887 1126 1115 1097 1084 1061 974 649 891 874 859 840 812 722 520 Normal High normal Optimal 1005 995 973 962 934 892 454 1059 1039 1012 982 952 892 520 903 879 857 795 795 726 441 Normal High normal 0 0 2 4 6 8 10 Cumulative incidence (%) 2 4 6 8 10 12 Time (yr) Men (b) No. at risk 0 4 2 6 8 10 12 14 Cumulative incidence (%) 14 0 2 4 6 8 10 12 14 Fig. 16.17.1.6  High normal blood pressure and the risk of cardiovascular disease. Cumulative incidence of cardiovascular events in women (a) and men (b) without hypertension, according to blood pressure category at the baseline examination. For this analysis, optimal blood pressure was defined as SBP less than 120 mm Hg and DBP less than 80 mm Hg, normal blood pressure as SBP 120–​129 mm Hg and/​or DBP 80–​84 mm Hg, and high normal blood pressure as SBP 130–​139 mm Hg and/​or DBP 85–​89 mm Hg (95% confidence intervals are shown). Reprinted from Vasan RS, et al. (2001). Impact of high-​normal blood pressure on the risk of cardiovascular disease. N Engl J Med, 345, 1291–​7. Copyright © 2001, Massachusetts Medical Society. P = 0.008 25 −1.5 −1.0 −0.5 0.0 0.5 1.0 35 Age (years) β(SBP) - β(DBP) 65 75 55 45 Fig. 16.17.1.7  The impact of DBP and SBP on the risk of coronary heart disease as a function of age. A β-​coefficient level less than 0.0 indicates a stronger effect of DBP on coronary heart disease (CHD) risk, a β-​coefficient level greater than 0.0 indicates a greater importance of SBP. The ‘switch’ from DBP to SBP occurs at around age 50 years. Reprinted from Franklin SS, et al. (2001). Does the relation of blood pressure to coronary heart disease risk change with aging? Circulation, 103, 1245. (http://​circ. ahajournals.org/​cgi/​content/​abstract/​103/​9/​1245).

16.17.1  Essential hypertension 3741 3.5 2.2 1.9 1.6 1.3 1.0 0.7 Nighttime Nighttime 24-hour 24-hour Daytime Daytime Clinic Clinic 3.0 2.5 2.0 1.5 5-Year risk of cardiovascular death (%) 1.0 0.5 90 110 130 150 Systolic BP (mm Hg) 170 190 210 230 50 60 70 80 Diastolic BP (mm Hg) 90 100 110 120 130 Fig. 16.17.1.8  Adjusted five-​year risk of cardiovascular death in 5292 patients. Curves are for average night-​time, 24-​hour, and daytime ambulatory readings, and for clinic readings. Reprinted from Dolan E, et al. (2005). Superiority of ambulatory over clinic blood pressure measurement in predicting mortality: the Dublin outcome study. Hypertension, 46, 156–​61. Study Cardiac events or mortality Staessen, 1999 Systolic: Cardiac end points, fatal and nonfatal 1.11 (0.91, 1.35) 1.06 (1.01, 1.10) 1.06 (1.02, 1.10) 1.10 (0.94, 1.29) 1.25 (1.10, 1.42) 1.32 (1.03, 1.68) 1.10 (0.98, 1.25) 1.30 (1.19, 1.42) 1.07 (1.00, 1.15) 1.21 (1.04, 1.42) 1.29 (0.98, 1.71) 1.17 (1.05, 1.32) 1.02 (0.99, 1.05) 1.05 (0.96, 1.14) 1.24 (1.03, 1.49) .5 1 2 Systolic: CV mortality Systolic: CV mortality Systolic: CV mortality Systolic: CV mortality Systolic: MI or stroke, fatal and monfatal Systolic: Stroke, fatal Systolic: Stroke, fatal or nonfatal Systolic: Stroke, fatal or nonfatal Systolic: All-cause mortality Systolic: All-cause mortality Systolic: All-cause mortality Systolic: All-cause mortality Systolic: Major CV events (CV death, MI or stroke) Systolic: Cardiac mortality (fatal HF, MI, sudden death) Dolan, 2005 CV events or mortality Dolan, 2005 Gasowski, 2008 Hansen, 2005 Staessen, 1999 Clement, 2003 Hemida, 2011 Stroke Dolan, 2005 Clement, 2003 Staessen, 1999 All cuase mortality Clement, 2003 Dolan, 2005 Hansen, 2005 Staessen, 1999 Note: Weights are from random effects analysis Abbreviations: CI = confidence interval; CV = cardiovascular; HF = heart failure; HR = hazard ratio; MI = myocardial infarction. Outcome HR (95% Cl) Fig. 16.17.1.9  Risk for cardiovascular and mortality outcomes: systolic 24 hr ABPM, adjusted for OBPM. Each 10 mm Hg increase in systolic 24 hr ABPM, adjusted for OBPM, was consistently associated with an increased risk for fatal or non​fatal stroke or cardiovascular events. From Piper MA, et al. (2014). Screening for high blood pressure in adults: A systematic evidence review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 121. AHRQ Publication No. 13-​05194-​EF-​1. Rockville, MD: Agency for Healthcare Research and Quality.

section 16  Cardiovascular disorders 3742 Pathogenesis and pathophysiology of hypertension The pathogenesis of essential hypertension has remained some- thing of an enigma, in part reflecting the fact that the basis for the diagnosis (i.e. an elevated blood pressure), has so many potential causes. From a physiological perspective, the pressure in the circu- lation is the product of the cardiac output (CO) and impedance to flow, that is, peripheral resistance (PR): blood pressure CO PR.

× Both cardiac output and peripheral resistance can be influenced by several control mechanisms, including activity of the renin–​ angiotensin–​aldosterone system, activity of the sympathetic nervous system, and other factors influencing salt and water homeostasis. In addition, vascular structural changes associated with hypertension play a role in accentuating its severity and con- ferring resistance to treatment. These structural changes include small-​artery remodelling that results in a reduced media/​lumen ratio (which increases peripheral resistance) and large-​artery stiffening (which changes pulse wave characteristics and reduces the compliance of the circulation). Recent reports suggest that a reduced diameter of the proximal aorta may also be a factor con- tributing to the development of hypertension. Whether structural changes precede and predispose to the onset of hypertension, or follow it, or both, remains a subject of considerable debate. In some cases (probably <10%) a discrete cause for hyper- tension will be identified (see Chapter  16.17.3). In most other circumstances the pathogenesis of essential hypertension (i.e. hypertension that is not due to a recognized secondary cause), is a complex interplay between (1) genetic predisposition, (2) lifestyle and environmental influences, and (3) disturbances in structure and the aforementioned control mechanisms. These are in turn compounded by the effects of ageing on the cardiovascular and renal systems. Genetic factors (this section written
by Professor Nilesh J. Samani) Historical perspective The history of the genetics of hypertension is marked by a celebrated debate in the 1950s and 1960s between Platt and Pickering, two doyens of British medicine. On the basis of a finding of a bimodal distribution of blood pressures in some families of patients with hypertension, and evidence of hypertension transmitted over three generations in a few pedigrees, Platt argued that hypertension was a distinct genetic disorder with a likely autosomal dominant mode of inheritance. By contrast, Pickering and colleagues showed that in the general population there was no obvious discontinuity of blood pressure distribution and that the familial resemblance of blood pressure spanned the whole range of blood pressures, and was not different for those with hypertension. Thus, Pickering argued that blood pressure, like height and weight, was a quantitative trait; and that although there was a significant genetic contribution, this was polygenic and that hypertension represented one extreme of the trait but was not a distinct disorder, except perhaps for rare monogenetic forms embedded in the blood pressure distribution curve. Today, the overwhelming mass of evidence supports the Pickering concept, although several mendelian disorders that predispose to hyperten- sion have been described (see Chapter 16.17.4). Genetic epidemiology of blood pressure and hypertension The extent of familial aggregation of blood pressure has been studied in diverse ethnic groups living in distinct places, ranging from Polynesians to Middle Americans. A remarkably consistent level of correlation of around 0.2 between first-​degree relatives has been found, meaning that if the blood pressure of one member of the family deviates from the norm by + 10 mm Hg, the first-​degree rela- tive will deviate by + 2 mm Hg on average. Studies in children and infants suggest that the familial resemblance in blood pressure starts very early and is maintained throughout life. Attempts to partition the familial resemblance of blood pressure between shared genes and shared environment have been made through studies of adoptees and twins. In the Montreal Adoption Study, correlations between natural siblings compared with adoptive siblings, and between parents and natural children compared with parents and adopted children, were at least twice as great. Similarly, several studies have documented much higher correlations in blood pressure between monozygotic twins (0.55–​0.85) compared with dizygotic twins (0.25–​0.50), although the results from twin studies have to be viewed with caution as there is substantial evidence of ex- cess sharing of sociocultural environments by twin pairs, especially monozygotic. However, taken altogether the epidemiological data suggest that genetic factors account for about 40 to 45% of the population vari- ability of blood pressure, common household environment for about 10–​15%, and non​familial factors for the remaining 40 to 45%. Although determination of familial correlations of blood pressure provides an overall view of the impact of heredity in determining blood pressure, a more relevant measure of the importance of genetic factors in determining susceptibility to Study Any stroke Ohkubo, 2005 CV mortality Gasowski, 2008 Ohkubo, 2005 Note: Weights are from random effects analysis .5 1 2 Systolic: CV mortality Systolic: CV mortality Systolic: Stroke, fatal or nonfatal 1.04 (0.94, 1.15) 0.96 (0.79, 1.16) 1.04 (0.91, 1.19) Outcome HR (95% Cl) Abbreviations: CI = confidence interval; CV = cardiovascular; HF = heart failure; HR = hazard ratio; MI = myocardial infarction. Fig. 16.17.1.10  Risk for cardiovascular and mortality outcomes: systolic OBPM, adjusted for systolic 24 hr ABPM. Systolic OBPM adds no significant predictive capacity for cardiovascular and mortality outcomes when systolic 24 hr ABPM data is available. From Piper MA, et al. (2014). Screening for high blood pressure in adults: A systematic evidence review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 121. AHRQ Publication No. 13-​05194-​EF-​1. Rockville, MD: Agency for Healthcare Research and Quality.

16.17.1  Essential hypertension 3743 hypertension is relative risk. This is the ratio of the risk of an indi- vidual developing the condition given its presence in a first-​degree relative compared with the overall population risk. For relatively rare monogenetic conditions such as cystic fibrosis, relative risk is as high as 500. For common and complex polygenic disorders, relative risk tends to be much lower. For hypertension, relative risk estimates vary between 2 and 5 depending on the criteria used to define family history. Values are highest when both parents have hypertension before the age of 55 years. Genes involved in ‘essential hypertension’ Given the importance of hypertension as a risk factor for several cardiovascular diseases, a huge effort has been made in the last 20 years to identify genes where variants affect blood pressure and increase risk of hypertension or hypertension-​related end-​organ damage. Most of the studies have involved association analyses of so-​called candidate genes whose products are known or suspected to be involved in regulation of blood pressure. A smaller number have used linkage analyses in collections of affected sib pairs to iden- tify genetic loci in a systematic manner. Variants in a large number of genes, involving virtually all the main physiological systems af- fecting blood pressure, such as the renin–​angiotensin–​aldosterone system (Table 16.17.1.2) and the sympathetic system, have shown association with blood pressure in one or more studies. The findings to date suggest that the effect of any individual variant is likely to be modest. For example, a meta-​analysis of 32 case–​control studies (corresponding to 13 760 patients) of the methionine to threo- nine (M235T) polymorphism in the angiotensinogen gene, one of the most studied variants, found that the TT genotype conferred a 31% increased risk of hypertension compared with the MM geno- type. There is evidence that variants may act in an additive or epi- static fashion. For example, one prospective study of 678 initially normotensive subjects found that combined carriage of the angio- tensin converting enzyme DD genotype (at the insertion (I)/​deletion (D) polymorphism in the gene), the tryptophan (Trp) allele at codon 460 in the α-​adducin gene, and the CC genotype at the –​344C/​T promoter polymorphism in aldosterone synthase CC genotype, in- creased the risk of developing hypertension by 252% over a median follow-​up of 9.1 years compared with other genotypes. The Trp allele of α-​adducin, part of a ubiquitous α/​β heterodimeric cytoskeletal protein which affects sodium absorption in the kidney, has also been associated with greater blood-​pressure-​lowering response to thiazide diuretics. Also, in one study of hypertensive subjects diuretic therapy was associated with a lower risk of com- bined myocardial infarction or stroke than other antihypertensive therapies in carriers of this adducin variant. Such findings raise the prospect of better prediction and individually tailored treatment for hypertension. However, inconsistent findings between studies re- flecting, at least in part, poorly understood gene–​gene and gene–​ environment interactions, have hampered progress and significant clinical application so far. While genetic dissection of essential hypertension has proved challenging, the genetic basis of several monogenic forms of hyper- tension has been elucidated during the same period. The findings have provided novel and illuminating insights into the molecular regulation of blood pressure and particularly the role of the kidney and sodium homeostasis. See Chapter 16.17.4 for further discussion. Environmental and lifestyle influences on the development of hypertension The prevalence of hypertension can be powerfully influenced by local lifestyles and customs. There are several lines of evidence that support this conclusion, including studies of migrant populations, comparisons between different communities, prospective popula- tion studies, and randomized trials of lifestyle interventions. There is little doubt that the exploding prevalence of hypertension in eco- nomically developing regions reflects lifestyle changes, so-​called Westernization, more than anything else. Migrant studies Migration studies have provided powerful evidence to illustrate the importance of the local environment and lifestyle on the level of blood pressure and the prevalence of hypertension. Studies of mi- gration from rural to urban areas of Africa and Australia typically report marked increases in migrant blood pressure, body weight, and sodium intake, coincident with the adoption of more sedentary lifestyles, usually within months of migration. This latter point is important because it helps discriminate between powerful lifestyle factors and genetics—​that is, the changes in blood pressure are more nurture than nature. Population studies Studies of specific populations are often very informative. Populations in specific regions of the world (e.g. primitive rural populations such as the Yanomamo Indians of Brazil), do not show much evidence of an age-​related rise in blood pressure, suggesting that the progressive rise in SBP seen in urban populations is not inevitable. This could reflect genetic differences in vascular structure in discrete popula- tions, but most likely reflects influence of the local environment, and customs. Evidence in support of this conclusion comes from a classic study which compared Italian nuns with a control group of women from the same town. In the control group, blood pres- sure typically rose with age, whereas the nuns, from a similar genetic background, showed no such rise in blood pressure over 20 years of follow-​up. Thus, essential hypertension is undoubtedly a ‘disease of urbanization’, reflecting the impact of lifestyle factors. Specific lifestyle influences on blood pressure The most important lifestyle/​environmental influences on blood pressure are sodium intake, obesity, and alcohol intake. Early Table 16.17.1.2  Some genes with evidence for common variants influencing blood pressure or risk of hypertension Gene Role Angiotensinogen Substrate for renin Angiotensin converting enzyme Converts angiotensin I to angiotensin II Angiotensin receptor (type 1) Main vascular receptor for angiotensin II Aldosterone synthase Promotes synthesis of aldosterone α-​Adducin Cytoskeletal protein involved in sodium homeostasis G-​protein β3 subunit Involved in G-​protein signalling Reprinted from The Lancet, Vol. 349, Cusi D, et al. Polymorphisms of α-​adducin and salt sensitivity in patients with essential hypertension, pp. 1353–​7, Copyright 1997, with permission from Elsevier.

section 16  Cardiovascular disorders 3744 nutritional deficiency may be important, and recent evidence sug- gests that psychosocial factors are likely to play some role in the development of essential hypertension. A  small socioeconomic gradient of blood pressure has also been observed. Interestingly, this gradient is negative for developed countries and positive for developing countries, which probably reflects the higher preva- lence of obesity and higher intakes of alcohol and salt among those of higher socioeconomic status in developing countries, com- pared to the reverse in more economically developed regions of the world. With regard to dietary influences on blood pressure, recent evidence (discussed later) suggests that diets rich in fruit and vegetables with low total and saturated fats may protect against hypertension. Low calcium intake, although associated with hypertension in population studies, is now considered to play no part in pathogenesis. Dietary salt intake There has been vigorous debate about the role of dietary salt in the genesis of hypertension. It is clear that sodium balance is a key factor determining the blood pressure of an individual. Moreover, it is intriguing that the various monogenic forms of hypertension that have been characterized by genetic studies all involve disturbances to renal sodium handling (see Chapter 16.17.4). Review of the evi- dence from population-​based studies and studies of dietary inter- vention support the hypothesis that dietary sodium intake has an important impact on blood pressure, and recent studies have also highlighted the importance of salt intake in the genesis of hyper- tension in children and the effectiveness of sodium restriction at reducing blood pressure. That said, there will clearly be some pa- tients whose blood pressure will be more sensitive to dietary so- dium intake than others. As indicated in Chapter 16.17.2, dietary sodium restriction forms part of the lifestyle interventions recom- mended by all guidelines as part of the treatment strategy for hyper- tension, and to delay the development of hypertension in people with prehypertension. A related but different question is whether dietary sodium restric- tion could influence not only blood pressure, but also cardiovascular disease outcomes. Recent studies suggest that this is likely to be the case. People allocated to a sodium-​restricted diet experienced a 30% lower incidence of cardiovascular events in the next 10–​15 years, irrespective of sex, ethnic origin, age, body mass, and blood pres- sure. As the people randomized into these studies were not hyper- tensive (blood pressure c.125/​85 mm Hg) it is conceivable that the benefits, impressive as they are, might have been even greater in a hypertensive population. These findings support current guideline recommendations and underline the importance of education and national health policies to reduce dietary sodium intake. Obesity and blood pressure Fat people generally have higher blood pressures than lean people. Fat arms can lead to overestimation of blood pressure when small cuffs are used, but the relation between body weight and blood pressure persists after correcting for arm circumference. Although body mass index (BMI) is often used to define obesity, visceral adi- posity seems to be more important in defining the relationship be- tween blood pressure and obesity. Visceral obesity also increases the likelihood of coexisting ‘metabolic syndrome’ (see ‘Hypertension and the metabolic syndrome’ later in the chapter) in people with hypertension. In untreated hypertensive people, fat tends to pref- erentially accumulate intra-​abdominally and intrathoracically, and the magnitude of the visceral adiposity is quantitatively related to the blood pressure. Importantly, the adiposity–​blood pressure link is observable from early childhood and a key predictor of the likeli- hood of developing overt hypertension. Recent analysis of longitudinal data from the Bogalusa Heart Study (Louisiana, USA) tracked the association between obesity in childhood and the risk of developing hypertension. Excess adi- posity was present in one-​fifth of those with normal blood pressure, one-​third of those with prehypertension, and more than one-​half of those with hypertension. Moreover, these associations were evident in children as young as 4 to 11 years, suggesting that the avoidance of obesity could markedly reduce the prevalence of hypertension in middle-​aged adults. In support of the strength of the association be- tween BMI and the risk of developing hypertension, in a study of 36 424 Israel Defense Forces employees (mean age c.35 years), BMI was the strongest predictor of prehypertension, with a 10–​15% increase in risk for every 1 kg/​m2 increase in BMI. The strong cause–​effect relationship between obesity and hypertension has been confirmed by intervention studies showing that weight reduction results in a fall in blood pressure. Alcohol intake and blood pressure Epidemiological data have consistently shown an association be- tween alcohol intake and blood pressure, and intervention trials confirm that blood pressure falls when alcohol is withdrawn from heavy drinkers. Analysis of data from the National Health and Nutrition Examination Survey (NHANES, 1999–​2000) showed that an alcohol intake of up to two drinks per day had no effect on blood pressure, which is consistent with previous reports that moderate drinking (2–​3 units daily) does not appear to exert a pressor effect. Heavier alcohol intakes, patterns of alcohol con- sumption, and the types of alcohol consumed can also influence blood pressure. Binge drinking can exert a pressor effect, but the mechanism accounting for the pressor effects of alcohol remain undefined. However, whatever the mechanism, data from the WHO Global Burden of Disease survey in 2000 attributed 16% of all hypertensive disease to alcohol. There has been controversy about whether moderate alcohol con- sumption might actually reduce cardiovascular disease risk. For example, in a prospective study of almost half a million men and women in the United States of America, the relative risk of death from cardiovascular disease in moderate drinkers compared with non​drinkers was 0.7 for men and 0.6 for women. However, it is im- portant to emphasize that these kinds of analyses run the risk of con- founding by an unmeasured disease effect modifier that tracks with different patterns of alcohol consumption. Sleep and blood pressure Blood pressure characteristically falls during sleep. A recent longitu- dinal analysis of the first NHANES (n = 4810) examined the impact of sleep duration on the risk of developing hypertension. This risk was increased by about twofold in adults in middle age who sleep for less than 5 h each night. Even after adjusting for obesity and dia- betes (the risk of which also increase with sleep deprivation), the risk remained around 1.6-​fold. There are some mechanisms that might account for this relationship: it may simply reflect a longer duration

16.17.1  Essential hypertension 3745 of sympathetic nervous system activation as a consequence of less time asleep and hence a higher 24 h average blood pressure load, giving rise to a higher risk of longer-​term cardiovascular structural damage and hence to sustained hypertension. There is also a clear association between obstructive sleep apnoea and hypertension. An apnoea–​hypopnoea index of 15 or more (i.e. breathing decreases or stops ≥15 times per hour of sleep) is associ- ated with a threefold increase in the risk of developing hyperten- sion. Moreover, in such patients continuous positive airway pressure can be effective in lowering both night-​time and, to a lesser extent, daytime blood pressure. Doctors should therefore consider sleep de- privation and obstructive sleep apnoea in their assessment of people developing hypertension. Psychosocial stress and blood pressure Blood pressure elevation is a well-​recognized acute stress response, and the act of taking the blood pressure can increase the SBP by up to 75 mm Hg in some patients. However, the role of chronic stress in the pathogenesis of hypertension has been difficult to assess, (1) be- cause of individual variability in the response to stress, (2) because it is difficult to objectively measure chronic stress, and (3) because stress can induce behavioural and lifestyle choices that could influ- ence blood pressure independently of stress per se. One measure of stress that appears to be robust in predicting blood pressure is an individual’s perception of control in their em- ployment. Using ABPM it has been shown that in men—​but not in women—​job strain is associated with an elevated blood pressure, both at work and also while at home and during sleep. Job strain in this context was defined as having a highly demanding job, but with the individual having little control over it. By contrast, people em- ployed in equally demanding jobs, but where they have an element of control over their work, have less stress, and less elevation of blood pressure. This effect of job strain on blood pressure is independent of other environmental and lifestyle influences, and is as strong as the impact of obesity. Early origins of hypertension—​impact of fetal and infant growth An association between low birth weight and risk of developing hypertension and premature cardiovascular disease has been recog- nized in many epidemiological studies. A large family-​based study explored the mechanisms underlying the associations of birth weight and gestational age with SBP measured at 17 to 19 years of age. This suggested that the inverse associations of birth weight and gesta- tional age with SBP are not explained by confounding resulting from a family’s socioeconomic status, or other factors that are shared by siblings. Variations in maternal metabolic or vascular health during pregnancy, or placental implantation and function, may explain these associations. Other studies have suggested that this relationship may relate to fetal programming of increased risk for hypertension via a reduction in nephron number, thereby increasing salt sensitivity. Another hypothesis has suggested that increased nutritional support to promote ‘catch-​up growth’ in the immediate postnatal period for babies who are small for gestational age could ameli- orate the risk for developing hypertension. This hypothesis was tested in a cohort of small for gestational age babies who had been fed with either a standard or nutrient-​enriched (28% more protein than standard) formula after birth. The enriched feed promoted faster postnatal weight gain and was associated with higher (not lower) blood pressure in later childhood, which does not sup- port the promotion of faster weight gain in infants born small for gestational age. Prehypertension predicts hypertension The presence of mild elevation in blood pressure for age pre- dicts the likelihood of developing hypertension. In a study of pa- tients with prehypertension (SBP 120–​139 mm Hg and/​or DBP 80–​89 mm Hg) the annual rate of progression to hypertension (≥140/​90  mm Hg) was greater than 15% per year despite life- style advice. In addition to an elevated blood pressure, people with prehypertension often also have the characteristic meta- bolic phenotype associated with hypertension (see later section in this chapter) and evidence of endothelial dysfunction and cardiovascular structural damage. This may explain why an ana- lysis of data from the Women’s Health Study in the United States of America, involving over 60 000 women followed for 7 years, showed that the presence of prehypertension was associated with an almost doubling in risk of any cardiovascular event—​including death, myocardial infarction, stroke, or hospitalization for heart failure—​when compared to those with normal blood pressure. Prehypertension was also more common in people with diabetes, when it was associated with an almost fourfold increase in risk of cardiovascular disease when compared to people without diabetes and normal blood pressure. Kidney, vascular structure, and neurohumoral control systems and the development of hypertension The maintenance of an adequate mean arterial pressure is funda- mental to life, hence there are many homeostatic mechanisms de- signed to achieve this despite fluctuations in posture, volume status, exercise, and other metabolic demands. There is considerable re- dundancy within these control systems, such that inhibition of one system is compensated for by increased activity of another, which is important when considering the design of effective strategies to lower blood pressure. Kidney The kidney is important for blood pressure regulation via two key mechanisms: (1) the regulation of sodium and volume homeostasis, and (2)  the regulation of the activity of the renin–​angiotensin–​ aldosterone system. The transplantation of a kidney from a genet- ically hypertensive rat into a normotensive control rat results in the development of hypertension in the recipient, and the converse is also true. In humans, significant renal impairment is almost invari- ably associated with hypertension, which in large part relates to dis- turbances in sodium handling, and as stated previously almost all of the single-​gene defects resulting in the development of hypertension involve disturbances in the renal tubular handling of sodium (see Chapter 16.17.4). The kidney is also intimately involved with sensing and setting of blood pressure via the activity of the renin–​angiotensin–​aldosterone system. Reduced renal perfusion pressure (e.g. in renal artery sten- osis) results in activation of the renin–​angiotensin–​aldosterone system, which in turn elevates blood pressure to try and restore renal perfusion pressure via several mechanisms (see later in this section of this chapter).

section 16  Cardiovascular disorders 3746 Structure of small arteries A characteristic finding in essential hypertension is an inappropriate increase in peripheral vascular resistance relative to the cardiac output. The main site of this resistance is small arteries (arterioles), which undergo inward eutrophic remodelling that is characterized by an increase in their media/​lumen ratio. These changes result from vascular remodelling (i.e. rearrangement of existing material in the vascular media around a smaller lumen), and there is often also evidence of some hypertrophy and/​or hyperplasia of the resi- dent myocytes. There has been much debate about whether these changes in small-​artery structure antedate and thus contribute to the develop- ment of hypertension, and/​or whether they are the consequence of an elevated blood pressure and the trophic effects of neurohumoral activation (i.e. sympathetic nervous system and the renin–​ angiotensin–​aldosterone system) in people with hypertension. Whatever the mechanism, studies of small arteries isolated from bi- opsies in humans, or retinal vascular structural changes (especially narrowing), suggest that the magnitude of structural changes of the small arteries is strongly predictive of future cardiovascular events. It is also predictive of the likelihood and magnitude of structural changes elsewhere (i.e. left ventricular hypertrophy). Structure of large arteries The functional integrity of large conduit arteries such as the aorta also influences the development of hypertension, especially sys- tolic hypertension. The pulsatile nature of blood flow exerts chronic cyclical stress on the walls of these arteries, and over time this re- sults in deterioration in their elastic properties as a consequence of thinning, splitting, and fragmentation of the elastin fibres within the media. This process is accelerated in people with hypertension, resulting in progressive dilatation in aortic root diameter and ar- terial stiffening. In turn, this reduction in arterial compliance in- creases pulse wave velocity, increases systolic pressure and central aortic pulse pressure, and reduces diastolic pressure. This explains the very high prevalence of systolic hypertension with advancing age (see Fig. 16.17.1.2) and the progressive age-​related disappearance of diastolic hypertension. The process of age-​related stiffening of the aorta is accelerated by post-​translational modification of vascular wall proteins such as col- lagen by the formation of advanced glycation end products (AGEs). AGE formation is accelerated in people with diabetes, thereby ex- plaining the earlier onset of isolated systolic hypertension in patients with this condition. It is conceivable that if aortic function and es- pecially its elasticity were genetically determined, then accelerated degeneration of aortic elastic function could also be a factor in the development of systolic hypertension in younger people. Aside from aortic function, there is current debate about whether the diameter of the aortic root is causally related to the likelihood of developing hypertension. This has been prompted by recent observations that central aortic pulse pressure appears to be inversely related to aortic root diameter, prompting speculation that a smaller effective root diameter might also contribute to the development of hypertension. Endothelium The endothelium plays a key role in the regulation of vascular tone. Endothelial cells form nitric oxide (NO) from L-​arginine via the activity of nitric oxide synthase (eNOS), which is tonically activated by shear stress and relaxes vascular tone. NO also inhibits platelet aggregation and inhibits vascular smooth muscle cell proliferation. Hypertension, even in its earliest stages, has been associated with ‘endothelial dysfunction’, usually by demonstrating a reduction in forearm blood flow in response to agents that promote NO release such as acetyl choline or its mimetics. NO production has also been shown to be decreased in people with hypertension. It is not clear whether endothelial dysfunction and decreased NO production are a cause or consequence of an elevated blood pres- sure, but the latter seems most likely. Whatever the mechanism, a reduction in NO production would be expected to increase vascular tone and may also contribute to vascular proliferation and remod- elling (see earlier). NO donors such as glyceryl trinitrate (GTN) are very effective at lowering blood pressure in the acute setting, and are especially effective at reducing central aortic pressure. However, the use of NO donors to lower blood pressure outside of the acute setting has been bedevilled by their short duration of action and the fact that tolerance to them develops rapidly. The actions of some commonly used antihypertensive drugs, angiotensin converting en- zyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), have in part been attributed to their local potentiation of NO. The endothelium also produces a powerful vasoconstrictor, endothelin. This seems less important in the chronic regulation of blood pressure, even though inhibitors of endothelin have been shown to lower it. The biology and actions of NO and endothelin are discussed in greater detail elsewhere (Chapter 16.1.1). Oxidative stress Numerous studies in experimental animals and humans have in- dicated that hypertension is associated with markers of increased systemic oxidative stress (i.e. the increased production of oxygen free radicals such as superoxide and hydrogen peroxide). These are short-​lived reactive species that have the potential to cause cellular damage via oxidation of proteins, lipids, and DNA. They also react with and inactivate NO, thereby providing a mechanism for reduced NO levels and increased vascular tone. The mechanism for increased oxidative stress in hypertension is not known, but studies have sug- gested that this may in part relate to activation of NADH/​NADPH oxidase within vascular cells. Of interest, this vascular oxidase is ac- tivated by angiotensin II, which provides a link between the renin–​ angiotensin–​aldosterone system and endothelial dysfunction and may contribute to the pressor effect of angiotensin II. Renin–​angiotensin–​aldosterone system The renin–​angiotensin–​aldosterone system, whose main ef- fector molecules are angiotensin II and aldosterone, plays an important role in the regulation of blood pressure. Angiotensin II is produced by an enzymatic cascade (Fig. 16.17.1.11). Renin synthesis—​the rate-​limiting step for the production of angio- tensin II—​may take place in several tissues apart from the kidney, including the adrenal, heart, the blood vessel wall, and brain. In the kidney renin is produced by the juxtaglomerular apparatus in response to falls in renal perfusion pressure, sodium depletion, and increased sympathetic nerve activity. However, the renin–​ angiotensin–​aldosterone system is active both in the circulation and locally within tissues.

16.17.1  Essential hypertension 3747 The two principle angiotensin receptors are AT1 and AT2. The major actions of angiotensin II are via the AT1 receptor, which is the target for the ARB class of blood-​pressure-​lowering agents. The AT2 receptor is less ubiquitously expressed than the AT1 receptor, is markedly up-​regulated during tissue repair, and its activation produces effects that appear to oppose those of AT1 activation, sug- gesting that the two receptors may operate a yin–​yang relationship. Angiotensin II elevates blood pressure by several different mech- anisms: (1) it is a direct pressor agent promoting vasoconstriction, and it also increases superoxide production by the endothelium, which reduces NO availability (see earlier); (2) it increases sodium reabsorption by the kidney via direct tubular effects and via simu- lation of aldosterone release from the adrenal cortex; (3) it can have trophic effects on vascular cell growth and has been implicated in the small-​artery remodelling process that results in increased per- ipheral vascular resistance; (4) it acts centrally on AT1 receptors in the nucleus tractus solitarius (NTS) to desensitize the afferent com- ponent of the baroreceptor reflex. In addition to these pressor actions, angiotensin II has also been implicated in the development of end-​organ damage through (1) trophic effects on the myocardium, resulting in left ventricular hypertrophy; (2) the development of glomerular hypertension, al- buminuria, and interstitial fibrosis, leading to chronic renal disease; (3) pro-​oxidant effects, contributing to the development of athero- sclerosis. Consequently, the renin–​angiotensin–​aldosterone system has become a popular target for drug therapy to lower blood pres- sure and limit its cardiovascular consequences. Aldosterone is the other effector molecule of the renin–​ angiotensin–​aldosterone system. It is produced by the adrenal cortex in response to many stimuli, including sodium and volume depletion, angiotensin II, excess potassium intake, trauma, and stress. It acts on the distal tubule of the kidney to promote sodium absorption in exchange for potassium. An inappropriate increase in production of aldosterone can lead to the development of hyperten- sion (e.g. Conn’s syndrome and adrenal hyperplasia), as discussed in Chapter 16.17.3. The specific role of the renin–​angiotensin–​aldosterone system in the development of essential hypertension remains unclear, al- though therapeutic agents that inhibit this system have proved to be very effective treatments. Plasma renin levels vary widely in es- sential hypertension, from low (30%), to normal (50%), to high (20%): they are inversely related to sodium loading and tend to de- cline with ageing. Thus, patients with low renin levels are gener- ally older and have volume-​dependent hypertension. Hypertensive patients with higher renin levels are generally younger, and their increased renin may reflect increased levels of sympathetic nervous system activity (see next section). Black people at any age have a high prevalence of low-​renin hypertension, suggesting a primary role for sodium retention in the pathogenesis of their hyperten- sion. Although the baseline renin level is rarely measured in rou- tine clinical practice, age has been used as a surrogate in the recent hypertension guidelines in the United Kingdom for predicting the most effective initial therapy in people with essential hypertension. If plasma renin levels are measured, it is important to recognize that they can be affected by concomitant blood-​pressure-​lowering therapy, with almost all commonly used classes of antihypertensive drugs increasing plasma renin, the main exception being β-​blockers which suppress it. Sympathetic nervous system The sympathetic nervous system is involved in the acute and chronic regulation of blood pressure. It is known to be involved in the regu- lation of arteriolar resistance, cardiac output, and volume regulation, renin release by the kidney, and catecholamine and mineralocorticoid release by the adrenal gland. It is by necessity a complex system that in- volves (1) vasomotor control centres within the brain; (2) the periph- eral nervous system providing efferent and afferent signals; and (3) the adrenal medulla. Several nuclei within the central nervous system are involved in the regulation of blood pressure, with control integrated in the rostral ventrolateral nucleus of the medulla oblongata—​the vaso- motor centre—​that is particularly influenced by the nucleus tractus solitarius (NTS) which receives its input from peripheral afferents such as baroreceptor activation in the aortic arch, carotid sinus, and cardiac ventricles and atria. The NTS also receives excitatory and in- hibitory inputs from other regions of the brain (e.g. the brain stem and cortex), and its outputs to the vasomotor centre tend to inhibit sym- pathetic outflow and thus buffer acute rises in blood pressure—​the baroreceptor reflex arc. Another important influence on the rostral ventrolateral nucleus–​NTS complex is the action of angiotensin II. The area postrema in the floor of the fourth ventricle does not have a blood–​brain barrier, which allows circulating angiotensin II to blunt the inhibitory effect of the NTS on the rostral ventrolateral nucleus, thereby increasing central sympathetic outflow. The various inputs and outputs are summarized in Fig. 16.17.1.12. Environmental and behavioural impacts on blood pressure are pri- marily coordinated via the hypothalamus. The posterolateral hypo- thalamus is responsible for the classical ‘fight or flight’ response, and lesions in this area reduce blood pressure. By contrast, lesions in the anterior hypothalamus can substantially increase blood pressure. The peripheral vascular α-​adrenergic system (α1 receptors) is also important in maintaining enhanced vascular resistance in Angiotensinogen Renin ACE Angiotensin II Angiotensin I AT-1 receptor AT-n receptor Chymase Cathepsin-G tonin t-PA Fig. 16.17.1.11  The renin–​angiotensin system. The enzyme renin cleaves its substrate angiotensinogen to generate the decapeptide angiotensin I, which is then cleaved by angiotensin converting enzyme (ACE) to generate angiotensin II, which binds to a family of specific angiotensin receptors. Its main effect on blood pressure regulation is via the AT-​1 receptor, the functions of other angiotensin receptors (AT-​ n) being poorly defined. Angiotensin II can also be generated by other proteolytic enzyme systems such as chymases and tissue plasminogen activators (t-​PA). These pathways may be important for local angiotensin II generation in disease.

section 16  Cardiovascular disorders 3748 hypertension, with some studies suggesting that peripheral α-​adrenergic responsiveness might be especially enhanced in black people with hypertension. The importance of the sympathetic nervous system in the regu- lation of blood pressure is beyond question, but a key unanswered question is whether disturbances to the regulation of the sympa- thetic nervous system play a major role in the initiation and main- tenance of chronic essential hypertension. Most surveys of younger people with prehypertension or grade 1 hypertension indicate the presence of an elevated heart rate, indicative of sympathetic nervous system activation. Other studies have reported elevated circulating catecholamine levels in young patients with prehypertension, and that such elevations predict the risk of developing hypertension. Further studies have used radiolabelled nor-​epinephrine (noradren- aline) to demonstrate enhanced ‘spillover’ indicative of enhanced sympathetic nervous system activity, or microneurography to dem- onstrate increased sympathetic nervous system activity in young hypertensives. It must be emphasized, however, that simple demon- stration of enhanced activity of a particular system at a single snap- shot in time cannot be taken as evidence of a direct causal role: the critical question is whether the level of activity is appropriate or inappropriate in the context of the overall integrated physiological regulation of blood pressure. In this regard, a full understanding of the role of the sympathetic nervous system in the genesis of essential hypertension in humans has been hindered by the complexity of the system and the rather crude instruments used to evaluate the system in vivo. Some remain to be convinced of the importance of the sym- pathetic nervous system in the genesis of essential hypertension, while others argue that given the importance of the sympathetic nervous system in regulating blood pressure, then—​even if essen- tial hypertension has an unrelated aetiology—​abnormal activity of the sympathetic nervous system must be permissive in maintaining blood pressure elevation. Sympathetic nervous system, obesity, and
the metabolic syndrome Obesity is associated with increased muscle sympathetic nerve ac- tivity, and increased sympathetic nervous system activity has been implicated in the pathogenesis of obesity-​related hypertension. Hypertension is often associated with features of a metabolic syn- drome (see ‘Hypertension and the metabolic syndrome’ in the next section) characterized by insulin resistance, dyslipidaemia, and im- paired glucose tolerance. Increased sympathetic nervous system ac- tivity has also been implicated in the development of this syndrome, and drugs therapies that reduce central sympathetic outflow or block α1 adrenergic receptors improve insulin sensitivity and fea- tures of the metabolic syndrome. Natriuretic peptides The natriuretic peptide system—​including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-​type natriuretic pep- tide (CNP)—​is an endocrine system that is involved in the regulation of salt and water homeostasis. ANP is secreted primarily by the right atrium in response to atrial wall stretch. BNP was initially identified in the brain, hence the name, but is predominantly produced in the ventricles in response to stretch. CNP is produced by vascular endo- thelial cells and in the kidney. These natriuretic peptides bind to spe- cific cell membrane receptors on target tissues and induce natriuresis and diuresis; they also decrease renin secretion and aldosterone, and induce vasodilatation and a modest fall in blood pressure. These physiological actions suggested a potential role for reduced natriuretic peptide levels or action in the pathogenesis of hypertension, hence these have been measured in patients with essential hypertension. The results have been conflicting, with no clear pattern emerging. This in part reflects the fact that levels of natriuretic peptides, especially BNP, will be elevated in people with early or established left ventricular dys- function and other hypertension-​related complications, but it does not preclude a future role for drugs that augment the activity of natri- uretic peptides in the clinical management of hypertension. The hypertensive phenotype and target organ damage in hypertension Although blood pressure measurement is used to define hyper- tension, hypertension is more than just blood pressure. Essential hypertension is commonly associated with metabolic disturbances and multisystem structural damage that conspire to enhance car- diovascular risk beyond that which can be attributed to blood pressure alone. Hypertension and the metabolic syndrome Few people with essential hypertension simply have an elevated blood pressure: many also have associated disturbances in metab- olism which are typical of the ‘insulin resistance phenotype’, notably predisposition to impaired glucose tolerance, elevated triglyceride levels, reduced HDL-​cholesterol values, and hyperuricaemia. These metabolic disturbances appear to precede and may even predict the likelihood of developing hypertension: in large prospective popu- lation studies in the United States of America and Europe the de- velopment of hypertension could be predicted by a person’s initial Inhibitory Excitatory Arterial baroreceptors Vagal afferents NTS Vagal efferents Ach NE Vagal/Sympathetic neurons Emotion central command Hypothalamus supraoptic N. paraventricular N. Cardiopulmonary receptors Ergoreceptors Renal afferents Fig. 16.17.1.12  Organization of the nervous system control of blood pressure. Peripheral inhibitory and excitatory inputs are integrated in the nucleus tractus solitarius (NTS), whose central inputs are integrated via the hypothalamus. The NTS regulates sympathetic outflow via the rostral centrolateral nuclei of the medulla oblongata. The balance of sympathetic and vagal outflow influences cardiac output, heart rate, vasoconstrictor tone, renin release, and renal blood flow, also catecholamine and mineralocorticoid release. Adapted from Abboud FM (1982). The sympathetic system in hypertension. State-​of-​ the-​art review. Hypertension, 4(Suppl II), 208–​25.

16.17.1  Essential hypertension 3749 metabolic profile. Even in those with optimal initial blood pressure levels (<120/​80 mm Hg), increasing obesity and the aforementioned abnormal lipid profile were major predictors of the development of hypertension. With regard to obesity, the accumulation of visceral fat (i.e. ab- dominal obesity) is most strongly associated with hypertension and attendant metabolic disturbances. Indeed, the link between visceral fat content and indices of insulin resistance and metabolic syndrome is demonstrable even in lean patients when MRI is used to quantify visceral fat. Moreover, the link between visceral adiposity and blood pressure is present from early childhood and explains the approxi- mately twofold increase in risk of developing type 2 diabetes in pa- tients with essential hypertension. The frequent coexistence of obesity with other features of meta- bolic syndrome in patients with hypertension underscores the need to view hypertension as more than just blood pressure in the context of cardiovascular disease risk management, and it points to the im- portance of early lifestyle interventions as the foundation for pre- vention and treatment. Vascular structural changes and atherosclerosis Aorta and large arteries The arterial system is designed to convert the pulsatile flow gen- erated by cardiac contraction into steady flow in the capillary bed. Thus, the aorta is both a conduit and an elastic reservoir designed to buffer pulsatile blood flow. Over time, recurrent pulsatile stress pro- duces uncoiling, disruption, and calcification of elastic fibres within the aortic wall. At the same time, relatively inelastic collagen is in- creased and made more rigid by post-​translational modification by the accumulation of AGEs. Such age-​related processes cause loss of the normal elastic reservoir function of the aorta and other large ar- teries. These changes are accelerated by the presence of high blood pressure and hence occur at an earlier age in hypertensive patients. In addition to these structural changes, elevation in pressure it- self contributes to a loss of large-​artery compliance and buffering be- cause, as pressure increases, the elastic fibres become fully stretched, thereby transferring load-​bearing function to the relatively inelastic collagen fibres. As a result of these changes, the pressure wave gener- ated by left ventricular contraction is no longer buffered by the aorta and proximal large arteries, but instead is transmitted into the arterial tree with greater amplitude. This is manifested clinically as increased brachial pulse pressure, with higher systolic and lower diastolic pres- sures. More importantly, the resulting increase in pulse wave velocity and changes in arterial haemodynamics contribute to an elevation in central aortic systolic and pulse pressures and an increase in ven- tricular loading conditions—​changes that cannot always be appreci- ated by measurement of the brachial blood pressure alone. Increased large-​artery stiffening and reduced compliance also re- duces the sensitivity of the carotid and aortic baroceptors to stretch, which blunts the normal rapid buffering of changes in blood pres- sure. As a result, blood pressure becomes more labile and the circu- latory adaptation to acute postural changes may become impaired, producing symptoms of postural dizziness in older people. Resistance vessels The characteristic structural change in the smaller arteries and ar- terioles of hypertensive patients is an increase in wall/​lumen ratio, the characteristics and pathogenesis of which have been discussed earlier. These changes have important functional consequences. The vessels can still dilate in response to stimuli such as warmth or drugs, but maximal vasodilatation is reduced. The converse is also true; responsiveness to pressor agents or stimuli becomes enhanced. These structural changes in resistance vessels also contribute to the characteristic increase in vascular resistance in hypertension, and they render vital organs more susceptible to ischaemic damage at the small-​vessel level (e.g. small-​vessel ischaemic brain damage). Atheroma in hypertension Hypertension is associated with an increased risk of generalized ath- erosclerotic disease. This is likely to result from an interplay of many factors, including pressure and haemodynamic stress, metabolic dis- turbances, inflammatory and oxidative stresses, endothelial disturb- ances, and neurohumoral activation. The overwhelming importance of haemodynamic factors and pressure is illustrated by (1) the predilection for atheroma to develop at sites of increased haemodynamic stress within the circulation (e.g. arterial bifurcations); and (2) the fact that atheroma is rarely observed in a low-​pressure circulation (e.g. the pulmonary circu- lation or venous system, unless pulmonary hypertension develops, or veins are grafted into the arterial circulation). Two recent studies have been important in establishing a direct link between pressure and the development and/​or regression of atherosclerosis. Using a mouse genetically prone to develop atheroma, the placement of a suprarenal clip was used to generate aortic constriction (a high renin state) and hypertension. The atheromatous plaque area was greatly increased by the presence of hypertension and was not obviously ameliorated by administration of an ARB. This study therefore sug- gested that pressure and not activation of the renin–​angiotensin–​ aldosterone system was the main cause of accelerated atheroma in this model. Further data from a human study that used intravascular ultrasonography to quantify changes in coronary atheroma sug- gested that the patients’ in-​trial blood pressure determined whether there was progression, stabilization, or regression of atheromatous plaque over a 2-​year period. Thus, a large body of evidence supports the hypothesis that blood pressure plays a key role in the initiation and progression of atheroma in humans. It is also likely that haemo- dynamic stress plays an important role in the process of plaque rup- ture, as well as the plaque burden. The heart in hypertension Left ventricular hypertrophy is a classic feature of untreated, or in- adequately treated, long-​standing hypertension. In this regard it can be considered the hypertensive equivalent of the glycated HbA1c for patients with diabetes: it is an index of the prevailing blood pres- sure load. Left ventricular hypertrophy is demonstrable in about 50% of untreated hypertensive patients using echocardiography, but only 5 to 10% when using conventional ECG criteria (Sokolov–​ Lyon ­criteria or Cornell voltage duration product). Pressure load on the left ventricle is unquestionably the most important patho- genic factor, with ambulatory monitoring blood pressure meas- urements much better correlated with left ventricular hypertrophy than clinic measurements of pressure. Pressure load is compounded by stiffening of the aorta with ageing, but neurohumoral factors, including the activity of the sympathetic nervous system and renin–​ angiotensin–​aldosterone system, also appear to be important.

section 16  Cardiovascular disorders 3750 Left ventricular hypertrophy is a very potent predictor of pre- mature cardiovascular disease and death. Its presence on the ECG, especially when associated with a characteristic ‘strain pattern’ (see Chapter 16.3.1), is associated with a two-​to threefold increase in risk of cardiovascular disease morbidity and mortality, including a marked increased risk of stroke and heart failure. Using echocardi- ography to characterize left ventricular hypertrophy, recent studies suggest that concentric hypertrophy carries a worse prognosis that eccentric hypertrophy (Fig. 16.17.1.13). Pathological features There are two pathological features of the cardiac changes in hyper- tension that culminate in the development of left ventricular hyper- trophy: an increase in size of cardiomyocytes, which increases the muscular mass of the left ventricle, and an increase in extracellular matrix deposition within the ventricle, which contributes to an in- crease in wall stiffness. The increase in left ventricular mass and stiff- ness manifests initially as impaired relaxation during diastole, which is often detectable on echocardiography in hypertensive patients at diagnosis, even before the left ventricular mass is sufficiently in- creased to be classified as indicating hypertrophy. Over time, in un- treated or poorly treated patients, cardiac changes will progress to impaired systolic function and ultimately overt heart failure. Myocardial ischaemia In addition to impaired cardiac diastolic and systolic function, the hypertensive heart is also predisposed to myocardial ischaemia be- cause of (1) increased myocardial oxygen consumption due to in- creased cardiac afterload; (2) impaired endocardial blood flow due to the structural and functional changes in small arteries just de- scribed; (3) an increase in the systolic time interval and reduced diastolic filling time and pressures due to large-​artery stiffening and impaired ventricular–​vascular coupling, and (4) increased risk of coronary atheroma in people with hypertension. Cardiac arrhythmias The aforementioned structural and ischaemic changes also predispose to an increased prevalence of simple and complex ventricular arrhyth- mias in people with hypertensive left ventricular hypertrophy. In add- ition, it has recently been recognized that atrial fibrillation is much commoner in older people with hypertension. Moreover, in hyperten- sive patients with left ventricular hypertrophy the risk of developing atrial fibrillation is at least twofold greater, and increases further as a function of advancing age, increased systolic pressure, increased left ventricular mass, and increased left atrial diameter. The combination of these latter two cardiac features is a particularly potent predictor of the risk of developing atrial fibrillation in hypertensive patients. Regression of left ventricular hypertrophy Recent clinical studies suggest that inhibition of the renin–​angiotensin–​ aldosterone system is particularly effective at regressing left ven- tricular hypertrophy. This is important, because there is now clear evidence that regression of the ECG manifestations of left ventricular hypertrophy is associated with dramatically improved prognosis for people with hypertension (50% reduction in risk of cardiovascular death over 5 years). Moreover, blockade of the renin–​angiotensin–​ aldosterone system may be particularly effective at reducing the risk of developing atrial fibrillation in people with hypertensive left ven- tricular hypertrophy. Consensus in guidelines is that lowering blood pressure is of paramount importance for patients with left ventricular hypertrophy, but that effective renin–​angiotensin–​aldosterone system blockade should also be part of the treatment strategy. The brain in hypertension Hypertension is the single most important risk factor for stroke and is increasingly recognized as a major factor contributing to the rate of cognitive decline in later life. All categories of stroke—​ischaemic (large and small vessel), haemorrhagic, and embolic—​are increased in hypertensive patients. Cerebral (atherothrombotic) infarction Infarction accounts for about 80% of the strokes suffered by patients with hypertension. It is usually attributable to atheroma of one of the larger cerebral arteries (usually the middle cerebral artery), or to small-​vessel (lacunar) infarction. Although poorly characterized, it is likely that embolic stroke is also more common in people with hypertension, especially those with left ventricular hypertrophy, be- cause of the increased likelihood of paroxysmal or sustained atrial fibrillation on a background of increased left atrial size. Intracerebral haemorrhage This accounts for 10–​15% of strokes in patients with hypertension and is usually the result of rupture of a small intracerebral degenera- tive microaneurysm (Charcot–​Bouchard aneurysm). These lesions develop in the small (<200 µm diameter) perforating arteries in the region of the basal ganglia, thalamus, and internal capsule. Hyaline degeneration (lipohyalinosis) occurs in the aneurysmal wall, with a defect in the media at the neck of the aneurysm. The incidence of Charcot–​Bouchard aneurysms is closely correlated with age and blood pressure, the two factors acting additively so that lesions are rarely if ever seen in younger normotensive people. The relation- ship between blood pressure and haemorrhagic stroke appears to be steeper in people of Chinese/​East Asian origin. Mean LVMI (g/m2) 149±32 79±9 75±11 141±21 104±8 104±7 RWT <0.44 CV events (%) 1 tertile (LVMI < 91 g/m2) 2 tertile (LVMI 91–117 g/m2) 3 tertile (LVMI >117 g/m2) 40 30 20 10 0 RWT ≥0.44 Fig. 16.17.1.13  Concentric vs. eccentric left ventricular hypertrophy and cardiovascular risk in hypertensive patients. All patients had echocardiographic evidence of left ventricular hypertrophy (LVH). Concentric LVH was defined as a relative wall thickness (RWT) greater than or equal to 0.44. Cardiovascular events increased progressively per LVH tertile at follow-​up, and were greater in each tertile of LVH in those with concentric LVH (shaded bars). CV, cardiovascular; LVMI, left ventricular mass index. Data from Muiesan ML, et al. (2004). Hypertension, 43, 731–​8.

16.17.1  Essential hypertension 3751 The remaining strokes in hypertensive patients are due to sub- arachnoid haemorrhage. Transient ischaemic attacks due to dis- ease of extracranial vessels are also more frequent in hypertensive subjects. Hypertension and cognitive function Hypertension is increasingly recognized as an important cause of de- mentia, with increased blood pressure in mid-​life associated with an increased risk of dementia in later life. Cognitive decline is related to diffuse small-​vessel cerebrovascular disease in untreated hyperten- sion and in older patients. Functional imaging studies have shown relative reductions in blood flow in parietal and fore-​brain areas in hypertensive patients during memory tasks and areas of cortical and subcortical hypometabolism. More advanced vascular disease gives rise to multiple, punctate, hyperintense white matter lesions on MRI scanning. These are due to focal ischaemia, either as a re- sult of lipohyalinosis or microatheromatous disease, tortuosity, and narrowing of the perforating arteries. All degrees of impairment of cognitive performance may occur as a result of these lesions, ranging from effects only detectable with sensitive psychometric testing, to lacunar strokes and Binswanger’s disease. Hypertensive encephalopathy The brain is protected from wide fluctuations in blood pressure by blood flow autoregulation (i.e. the intrinsic capacity of the cerebral vessels to constrict in the face of increased pressure and dilate in the face of decreased pressure to maintain a constant flow). Resistance vessel remodelling and hypertrophy may enhance protection against higher perfusion pressures, thereby extending the upper limits of the autoregulatory range in long-​standing hypertension. However, such remodelling may also impair the autoregulation of blood flow when faced with decreased pressure because of impaired capacity of hyper- trophied resistance vessels to dilate, thereby predisposing to small-​ vessel ischaemia. In severe hypertension focal areas of vasodilatation can develop if blood pressure rises above the autoregulatory range, resulting in localized perivascular oedema and fibrinoid necrosis. Focal haemorrhages, ischaemia, and infarction may result, giving rise to the clinical picture of encephalopathy (see Chapter 16.17.5). The kidney in hypertension Patients with renal disease often have hypertension, and people with hypertension can develop renal disease. The age-​related decline in GFR is more rapid in people with essential hypertension. However, GFR is usually well preserved throughout life in patients with mild to moderate essential hypertension, hence the development of end-​ stage renal disease in such patients is unusual in the absence of any other renal lesions. The decline in GFR, when it does occur, is due to progressive glomerulosclerosis, most likely driven by raised intraglomerular capillary pressures, which also explain the increased urinary albumin excretion rates in these patients. Increased urinary albumin excretion rate has in turn been linked to increased likeli- hood of more widespread endothelial/​vascular dysfunction and an increased risk of premature cardiovascular disease and death, hence the kidney—​and urinary albumin excretion rate in particular—​has been proposed as the earliest clinical indicator of significant pres- sure mediated vascular injury. Significant hypertension-​induced glomerulosclerosis is much more likely in two settings (1) severe and accelerated hypertension, resulting in so-​called hypertensive nephropathy; and (2) in the pres- ence of intrinsic renal disease (i.e. due to diabetes or glomeruloneph- ritis). Effective control of blood pressure is of substantial importance in retarding the progression of renal impairment in these settings. Another important association between hypertension and renal disease is atheromatous renal vascular disease. In these patients, hypertension is usually moderate to severe, and the condition is characteristically associated with a progressive ischaemic nephrop- athy due either to proximal renal artery (often ostial) disease and/​or smaller branch artery disease. It may be associated with small-​vessel cholesterol embolization, the affected patients usually being older, with evidence of widespread atheromatous disease. The eye in hypertension The findings in the retina of patients with hypertension range from mild generalized retinal–​arteriolar narrowing, through to the devel- opment of more significant changes of flame-​shaped or blot-​shaped haemorrhages, cottonwool spots, hard exudates, microaneurysms, or a combination of all of these factors. Swelling of the optic disc can also be seen. The classification of these changes and their patho- physiology and significance are discussed in Chapter 16.17.2. The evolution of hypertensive injury—​from physiology to philosophy The process of hypertensive injury to target organs evolves silently over many years, the magnitude and rate of progression determined largely by the level of blood pressure, but also by individual sus- ceptibility (Fig. 16.17.1.14). In the prehypertensive phase, patients may already have disturbances in blood pressure regulation (i.e. re- sponses to pressor stimuli, visceral obesity, and subtle features of the metabolic syndrome). The injurious process and metabolic disturb- ances then progress though a silent phase, often lasting many years, during which there is subtle damage to many target organs as just mentioned (i.e. vascular wall, myocardium, brain, kidney, and eye). This subtle early damage is potentially preventable and/​or revers- ible, but progresses if untreated to more sinister markers of more advanced damage—​the so-​called intermediate or surrogate disease markers that can be detected in many cases by simple tests such as the ECG, or urinalysis for albumin or protein. Untreated or poorly treated, this progressive hypertension-​mediated damage culmin- ates in overt cardiovascular, renal, and cerebrovascular disease and clinical events—​the so-​called ‘hard clinical end-​points’ that form the evidence base for treatment guidelines. Alongside, the meta- bolic syndrome is evolving, increasing the risk of developing dia- betes and magnifying the cardiovascular risk burden associated with the blood pressure elevation. Along the way, the conduit arteries are stiffening with damage and age, and the systolic pressure is rising and becoming more difficult to treat. Current treatment guidelines have been developed from an evi- dence base relating to changes in hard clinical end-​points derived from studies in elderly patients at the end of the hypertensive dis- ease process. Somehow, we have to try to translate that evidence into strategies for treating younger patients at the start of the disease process when their risk of clinical events is low. Future treatment strategies must surely focus on preventing the evolution of the silent disease process, rather than simply battling with its consequences.

section 16  Cardiovascular disorders 3752 To meet that challenge, we need more and better studies of younger patients with hypertension to better characterize the impact of treat- ments on the evolution of hypertensive disease, and to determine the robustness of the associated intermediate or surrogate disease markers at predicting treatment benefit. FURTHER READING Epidemiology Asia Pacific Cohort Studies Collaboration (APCSC) (2005). Joint effects of systolic blood pressure and serum cholesterol on car- diovascular disease in the Asia Pacific region. Circulation, 112, 3384–​90. Chobanian AV (2007). Isolated systolic hypertension in the elderly. N Engl J Med, 357, 789–​96. Dolan E, et  al. (2005). Superiority of ambulatory over clinic blood pressure measurement in predicting mortality: the Dublin outcome study. Hypertension, 46, 156–​61. Ezzati M, et al. (2002). Selected major risk factors and global and re- gional burden of disease. Lancet, 360, 1347–​60. Franklin SS, et  al. (1997). Hemodynamic patterns of age-​related changes in blood pressure: the Framingham Heart Study. Circulation, 96, 308–​15. Lawes CMM, et al. (2006). Blood pressure and the global burden of disease 2000. Part I: estimates of blood pressure levels. J Hypertens, 24, 413–​22. Lawes CMM, et al. (2008). Global burden of blood pressure related disease, 2001. Lancet, 371, 1513–​18. Lewington S, et  al. (2002). Age-​specific relevance of usual blood pressure to vascular mortality: a meta-​analysis of individual data for one million adults in 61 prospective studies. Lancet, 360, 1903–​13. MacMahon S, Meal B, Rodgers A (2005). Hypertension—​time to move on. Lancet, 365, 1108–​9. National Clinical Guideline Centre (2011). Hypertension—​the clinical management of primary hypertension in adults. Clinical guideline. http://​www.nice.org.uk/​guidance/​cg127 Piper MA, et al. (2014). Screening for high blood pressure in adults: a systematic evidence review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 121. AHRQ Publication No. 13-​05194-​EF-​1. Agency for Healthcare Research and Quality, Rockville, MD. Vasan RS, et al. (2001). Impact of high-​normal blood pressure on the risk of cardiovascular disease. New Engl J Med, 345, 1291–​7. Wang Y, Wang QJ (2004). The prevalence of prehypertension and hypertension among US adults according to the new joint national committee guidelines:  new challenges of the old problem. Arch Intern Med, 164, 2126–​34. William B, et al. (2008). Systolic pressure is all that matters. Lancet, 371, 2219–​21. Xie W, et al. (2018). Blood pressure-lowering drugs and secondary prevention of cardiovascular disease: systematic review and meta- analysis. J Hypertens, 36, 1256–65. Yusuf S, et al. (2004). Effect of potentially modifiable risk factors associ- ated with myocardial infarction in 52 countries (the INTERHEART study): case-​control study. Lancet, 364, 937–​52. Pathophysiology Aksnesa TA, et al. (2007). Prevention of new-​onset atrial fibrillation and its predictors with angiotensin II-​receptor blockers in the treat- ment of hypertension and heart failure. J Hypertens, 25, 15–​23. Target organ damage: • LVH • Vascular structural damage • Systolic hypertension • LV dysfunction • Small vessel brain disease • Albuminuria/Declining GFR Metabolic syndrome to diabetes Metabolic syndrome to diabetes Treatment guidelines Treatment guidelines Number of Drugs Clinical Trials Clinical Trials CVD risk Evolution of disease; 10–50 yrs Cardiovascular disease: • CHD / CHF • Stroke / TIA • Dementia • Renal disease • Macular degeneration • Death Older Hypertension: • Lipid disorder • Glucose disorder • BP dysregulation • No TOD • No CVD Younger +/– +/– +/– Drug treatment Hypertensive

• Damage Hypertension
• Clinical disease Pre-hypertensive Hard end-points Surrogate end-points Fig. 16.17.1.14  The clinical progression of hypertension. blood pressure, blood pressure; CHD, coronary heart disease; CHF, congestive heart failure; CVD, cardiovascular disease; GFR, glomerular filtration rate; LV, left ventricular; TIA, transient ischaemic attack; TOD, target organ damage.