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C H A P T E R 45 Systemic Hypertension: Mechanisms and DiagnosisRonald G. Victor

DEFINITION, PREVALENCE, VARIABILITY, AND DETERMINANTS OF HYPERTENSION, 935De!nition, 935Prevalence, 935Blood Pressure Variability and Its Determinants, 936

MECHANISMS OF PRIMARY (ESSENTIAL) HYPERTENSION, 937Hemodynamic Subtypes, 937Neural Mechanisms, 938Renal Mechanisms, 939Vascular Mechanisms, 939Hormonal Mechanisms: Renin-Angiotensin-Aldosterone

System, 940

PATHOGENESIS OF HYPERTENSIVE HEART DISEASE, 941Pressure Overload Hypertrophy, 941Heart Failure, 943

DIAGNOSIS AND INITIAL EVALUATION OF HYPERTENSION, 943Initial Evaluation of the Hypertensive Patient, 943

ADRENAL AND OTHER CAUSES OF HYPERTENSION, 948Primary Aldosteronism and Other Forms of

Mineralocorticoid-Induced Hypertension, 948Cushing Syndrome, 949Pheochromocytoma and Paraganglioma, 950Other Causes of Hypertension, 950

SPECIAL CONSIDERATIONS FOR HYPERTENSIVE DISEASES IN WOMEN, 950Oral Contraceptive Use, 950Postmenopausal Sex Hormone Therapy, 951Hypertension During Pregnancy, 951

HYPERTENSIVE CRISIS, 952De!nitions, 952Incidence, 952Pathophysiology, 952Manifestations and Course, 953Di"erential Diagnosis, 953

FUTURE PERSPECTIVES, 953

REFERENCES, 953

Definition, Prevalence, Variability, and Determinants of HypertensionAffecting 70 million Americans and 1 billion people worldwide, hyper-tension remains the most common, readily identifiable, and reversible risk factor for myocardial infarction, stroke, heart failure, atrial fibril-lation, aortic dissection, and peripheral arterial disease. Because of escalating obesity and population aging, the global burden of hyper-tension is rising and projected to affect 1.5 billion persons—one third of the world’s population—by the year 2025. Currently, high blood pressure (BP) causes about 54% of stroke and 47% of ischemic heart disease worldwide.1 Half of this disease burden is in people with hypertension; the other half is in people with lesser degrees of high BP (prehypertension). Thus, high BP remains the leading cause of death worldwide and one of the world’s great public health problems (see Chap. 1).

The asymptomatic nature of the condition delays diagnosis. Effec-tive treatment requires continuity of care by a knowledgeable physi-cian and frequent medical checkups, which are less common in men and low-income minorities.2 In most patients diagnosed with hyperten-sion, a single disease-causing mechanism cannot be identified and treatment remains empiric, often requiring three or more pharmaco-logic agents with complementary mechanisms of action along with lipid-lowering drugs, antiplatelet drugs, and drugs for concomitant medical conditions such as diabetes. Pill burden, prescription drug costs, medication side effects, and insufficient time for education of the patient contribute to nonadherence. Physicians often hesitate to initiate and to intensify antihypertensive medication. For all these reasons, BP is controlled to a value below 140/90 mm Hg in less than one third of affected individuals, even in higher-income countries with the most advanced systems of health care.

Even among patients whose hypertension control meets current standards, fewer than one in three is protected from subsequent stroke, myocardial infarction, or heart failure. This chapter and the subsequent chapter review the scientific basis for current recommen-dations for the diagnosis, evaluation, and treatment of hypertension

and present emerging concepts from clinical and basic research that have begun to affect clinical decision making.

DefinitionHypertension currently is defined as a usual BP of 140/90 mm Hg or higher, for which the benefits of drug treatment have been definitively established in randomized placebo-controlled trials.3 This conserva-tive definition has been called into question by epidemiologic data showing continuous positive relationships between the risk of coro-nary artery disease (CAD) and stroke deaths with systolic or diastolic BP down to values as low as 115/75 mm Hg (Fig. 45-1).4 This artificial dichotomy between “hypertension” and “normotension” can delay medical treatment until vascular health has been irreversibly compro-mised by elevated BP values previously considered to be normal. Thus, for certain high-risk patients, especially those with CAD, the recommended medical treatment threshold recently has been lowered to 130/80 mm Hg (see Chap. 46).5

PrevalenceIn the United States and other developed countries, the prevalence of hypertension increases with age, rising exponentially after the age of 30 years (see Chap. 1). Before the age of 50 years, the prevalence of hypertension is somewhat lower in women than in men. After meno-pause, the prevalence of hypertension increases rapidly in women and exceeds that in men. Eventually, by the age of 75 years, below the average life span of U.S. men and women, almost 90% will have hypertension.

Among U.S. adults, more than 40% of blacks have hypertension, compared with 25% of whites and Hispanics. In U.S. blacks, hyperten-sion not only is more prevalent than in other racial and ethnic groups but also starts at a younger age, is more severe, and causes greater target organ damage, leading to greater premature disability and death. In contrast, hypertension prevalence does not vary between blacks and nonblacks in Cuba and other less developed countries. Further-more, hypertension is more prevalent in several predominantly white European countries than in black Americans and is uncommon among blacks living in Africa (Fig. 45-2).6 Although many genetic factors may explain the disproportionate burden of hypertension in black Americans, these international data underscore the importance of environment. In 90% to 95% of hypertensive patients, a single

Portions of the previous edition of this chapter were written by Dr. Norman M. Kaplan (Adrenal and Other Causes of Hypertension, Hypertensive Diseases of Women) and have been revised.

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FIGURE 45!1 Absolute risks of coronary artery disease mortality (left) and stroke mortality (right) for each decade of life (plotted on a logarithmic scale) by usual systolic BP level (plotted on a linear scale). CI = con!dence interval. (From Lewington S, Clarke R, Qizilbash N, et al: Age-speci!c 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, 2002.)

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FIGURE 45!2 Geographic variation in hypertension prevalence in populations of African descent (pink bars) and European descent (blue bars). (Modi!ed from Cooper RS, Wolf-Maier K, Luke A, et al: An international comparative study of blood pressure in populations of European vs. African descent. BMC Med 3:2, 2005.)

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reversible cause of the elevated BP cannot be identified, hence the term primary hypertension. In the remaining 5% to 10%—cases denoted secondary or identifiable hypertension—a more discrete mechanism can be identified.

Blood Pressure Variability and Its DeterminantsBEHAVIORAL DETERMINANTS. In most patients with primary hypertension, readily identifiable behaviors contribute to the elevated

BP. The nicotine in cigarette smoke transiently raises BP by 10 to 20 mm Hg, thereby elevating the average daytime BP in habitual smokers. The risk for development of hypertension is generally lower in moderate alcohol drinkers (one or two drinks per day) than in teetotalers but increases in heavy drinkers (three or more drinks per day). Hypertension is rare in Asian men who abstain from alcohol to avoid the nausea and flushing reaction associated with their loss-of-function mutation in the alcohol dehydrogenase gene (ALDH2).7 Caf-feine consumption typically causes only a small transient rise in BP, which in some individuals habituates after the first cup of coffee. The risk for development of hypertension does not vary with coffee consumption but increases steeply when caffeine is consumed in diet sodas; thus, coffee may contain protective antioxidant polyphenols not present in sodas. Physical inactivity also increases the risk for development of hypertension.

Lifetime dietary habits clearly influence the risk for devel-opment of hypertension (see Chap. 48). Diets low in fresh fruit may increase the risk for development of hypertension, perhaps from lower citrate intake. The two most important behavioral determinants of hypertension, however, are excessive consumption of calories and sodium. Across various populations, hypertension prevalence increases lin-early with average body mass index. Currently, more than 50% of all cases of hypertension may result from obesity. The risk for development of hypertension increases with dietary sodium intake and decreases with dietary potassium intake.8 Individual variability in BP responses to dietary sodium

loading and sodium restriction indicates an important genetic underpinning.

GENETIC DETERMINANTS (see Chap. 8). Concordance of BPs is higher in families than in unrelated individuals, higher between mono-zygotic than dizygotic twins, and higher between biologic than adop-tive siblings living in the same household. As much as 70% of the familial aggregation of BP is attributed to shared genes rather than to shared environment.

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SYSTOLIC HYPERTENSION IN YOUNG ADULTS. At one end of the age spectrum is isolated systolic hypertension (ISH) in young adults (typically 17 to 25 years of age). The key hemodynamic abnor-malities are increased cardiac output and a stiff aorta, both presum-ably reflecting an overactive sympathetic nervous system.11 The prevalence is estimated to be as high as 25% in young men but only 2% in young women. These figures may be too high because brachial artery BP overestimates central aortic pressure by approximately 20 mm Hg in young adults from peripheral pulse wave amplification. However, in the largest study to date, central aortic pressures were 20 mm Hg higher than normal in young adults with ISH.11 A hyperdy-namic circulation in youth may precede diastolic hypertension in middle age.

DIASTOLIC HYPERTENSION IN MIDDLE AGE. When hyperten-sion is diagnosed in middle age (typically, 30 to 50 years of age), the most common BP pattern is elevated diastolic pressure, with systolic pressure being normal (isolated diastolic hypertension) or elevated (combined systolic-diastolic hypertension). This pattern constitutes classic “essential hypertension.” Isolated diastolic hypertension is more common in men and is often associated with middle-age weight gain.12 Without treatment, isolated diastolic hypertension often pro-gresses to combined systolic-diastolic hypertension. The fundamental hemodynamic fault is an elevated systemic vascular resistance coupled with an inappropriately normal cardiac output. Vasoconstric-tion at the level of the resistance arterioles results from increased neurohormonal drive and an autoregulatory reaction of vascular smooth muscle to an expanded plasma volume, the latter because of impairment in the kidneys’ ability to excrete sodium.

ISOLATED SYSTOLIC HYPERTENSION IN OLDER ADULTS. After the age of 55 years, ISH (systolic BP >140 mm Hg and diastolic BP <90 mm Hg) is the most common form.13 In developed countries, systolic pressure rises steadily with age; in contrast, diastolic pressure rises until about 55 years of age, then falls progressively thereafter (Fig. 45-4). The resultant widening of pulse pressure indicates stiffen-ing of the central aorta and a more rapid return of reflected pulse waves from the periphery, causing an augmentation of systolic aortic pressure (see Fig. 45-4; also see Figs. 45-e1, 45-e2, and 45-e3 on website).14 Accumulation of collagen (which is poorly distensible) adversely affects its ratio to elastin in the aortic wall.

ISH may represent an exaggeration of this age-dependent stiffening process, although systolic BP and pulse pressure do not rise with age in the absence of urbanization (e.g., cloistered nuns). ISH is more

FIGURE 45!3 Reduced prevalence of hypertension among mutation carriers. Prevalence of hypertension at the last examination within ages 25-40, 41-50, and 51-60 years, for mutation carriers and noncarriers of genes causing Bartter and Gitelman syndromes. The genotype relative risk (GRR) for mutation carriers is shown. (From Ji W, Foo JN, O’Roak BJ, et al: Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet 40:592, 2008.)

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FIGURE 45!4 A, Age-dependent changes in systolic and diastolic blood pressure in the United States. B, Schematic representation of the relationship between aortic compliance and pulse pressure. (A from Burt V, Whelton P, Rocella EJ, et al: Prevalence of hypertension in the U.S. adult population. Results from the Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension 25:305, 1995. B from Dr. Stanley Franklin, University of California at Irvine, with permission.)

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The complex regulation of BP has thwarted the genetic dissection of primary human hypertension.9 Whereas mutations in 20 salt-handling genes cause ultrarare monogenic forms of severe early-onset hypoten-sion (salt-wasting syndromes) and hypertension (all inherited as men-delian traits), the applicability to common primary hypertension has been difficult to show. The first genome-wide associations for hyper-tension were recently reported, with small affect sizes for each loci.10,10a New data from the Framingham Heart Study indicate that gene muta-tions underlying the pediatric salt-wasting syndromes (Bartter and Gitelman) are carried by 1% to 2% of the general adult population and confer resistance against primary hypertension (Fig. 45-3).10b

Mechanisms of Primary (Essential) HypertensionHemodynamic SubtypesPrimary hypertension can be divided into three distinctly different hemodynamic subtypes that vary sharply by age.

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938renal sympathetic nerves17—has rekin-dled excitement about neural mecha-nisms, even before the procedures have approval by the Food and Drug Administration.

BARORECEPTORS AND HYPERTENSION. In hypertension, the baroreceptors reset to defend a higher level of BP. Barore!ex control of sinus node func-tion is abnormal even in mild hyperten-sion, but barore!ex control of systemic vascular resistance and BP is well pre-served until diastolic function is impaired.18 The surgically implanted carotid baroreceptor pacemaker pro-duces sustained BP reductions in dog models of hypertension and is being evaluated in patients with medically refractory hypertension.16 Complete barore!ex failure (see Chap. 94) rarely causes labile hypertension, most often seen in throat cancer survivors as a late complication of radiation therapy, which causes a gradual destruction of the baroreceptor nerves. In contrast, partial baroreceptor dysfunction is common in elderly hypertensives and typically is manifested with a triad of orthostatic hypotension, supine hyper-tension, and symptomatic postprandial hypotension, the last initiated by splanchnic pooling after carbohydrate-rich meals.

OBESITY-RELATED HYPERTENSION. Neural mechanisms of obesity-related hypertension deserve special mention. With weight gain, re!ex sympathetic activation may be an important com-pensation to burn fat but at the expense of sympathetic overactivity in target tissues (i.e., vascular smooth muscle and kidney) that produces hyperten-sion.19 Hypertensive patients with the metabolic syndrome with or without new-onset type 2 diabetes have near-maximal rates of sympathetic

"ring. Although the sympathetic activation associates with insulin resis-tance, the precise stimulus to sympathetic out!ow is unknown; candi-dates include leptin, other adipokines, and A II. Why weight loss causes much less improvement in hypertension than in diabetes remains unknown.20

OBSTRUCTIVE SLEEP APNEA AS A CAUSE OF NEUROGENIC HYPERTENSION (See Chap. 79.). Patients with obstructive sleep apnea can have mark-edly elevated plasma and urine catecholamine levels, mimicking those seen in patients with pheochromocytoma (see Chap. 86). With repeated arterial desaturation during apneas, activation of carotid body chemore-ceptors causes dramatic pressor episodes throughout the night and resets the chemoreceptor re!ex; daytime normoxia is misinterpreted as hypoxia, producing sustained re!ex sympathetic activation and hyper-tension even during waking hours.21 Obstructive sleep apnea also accel-erates the risk of several hypertensive complications (e.g., stroke, atrial "brillation, and cardiovascular death) beyond that explained by BP eleva-tion alone.

LONG-TERM SYMPATHETIC REGULATION OF BLOOD PRESSURE. The sympa-thetic nervous system is well known to regulate short-term changes in BP, such as transient surges in BP during physical and emotional stress. In addition, sustained sympathetic activation contributes to long-term BP regulation because the renal sympathetic nerves potently stimulate renin release by stimulation of beta1-adrenergic receptors in the juxta-glomerular apparatus and renal sodium reabsorption by stimulation of alpha1-adrenergic receptors regulating Na+,K+-ATPase in the collecting duct. Catheter-based radiofrequency ablation of the renal sympathetic nerves seems to markedly lower BP in patients with medically refractory hypertension.17 In addition, norepinephrine’s action on alpha1-adrenergic receptors stimulates cardiac and vascular smooth muscle hypertrophy. In patients with hypertension and left ventricular hypertrophy (LVH), cardiac norepinephrine spillover increases and may predispose to sudden cardiac death.

common in women and is a major risk factor for diastolic heart failure, which also is more common in women (see Chaps. 30, 80, and 81). Most cases of ISH arise de novo after the age of 55 years and are not “burned-out” middle-age diastolic hypertension.12 Compared with young or middle-aged adults with optimal BP, those with BP in the high-normal range (prehypertension) are more likely to develop ISH after 55 years of age.12

A multitude of neurohormonal, renal, and vascular mechanisms interact to varying degrees in contributing to these different hemody-namic forms of hypertension.

Neural MechanismsIn young adults, primary hypertension consistently is associated with increased heart rate and cardiac output, plasma and urinary norepineph-rine levels, regional norepinephrine spillover, peripheral postganglionic sympathetic nerve "ring (determined by microelectrode recordings), and alpha-adrenergic receptor–mediated vasoconstrictor tone in the peripheral circulation.15 Sympathetic overactivity has been demon-strated in early primary hypertension and in several other forms of estab-lished human hypertension, including hypertension associated with obesity, sleep apnea, early type 2 diabetes mellitus and prediabetes, chronic kidney disease (CKD), heart failure, and immunosuppressive therapy with calcineurin inhibitors such as cyclosporine. In these condi-tions, central sympathetic out!ow can be driven by deactivation of inhibitory neural inputs (e.g., baroreceptors), activation of excitatory neural inputs (e.g., carotid body chemoreceptors, renal a#erents), or cir-culating angiotensin II (A II), which activates pools of excitatory brain-stem neurons without a blood-brain barrier (Fig. 45-5). The emergence of new invasive procedures for lowering of sympathetic activity and BP in patients with refractory hypertension—an implantable carotid baro-receptor pacemaker16 and catheter-based radiofrequency ablation of the

FIGURE 45!5 Sympathetic nervous system. Dotted arrows represent inhibitory neural in"uences and solid arrows represent excitatory neural in"uences on sympathetic out"ow to the heart, peripheral vasculature, and kidneys. A II = angiotensin II; Ach = acetylcholine; EPI = epinephrine; NE = norepinephrine; NTS = nucleus tractus solitarius.

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GENETIC CONTRIBUTIONS. Animal and human studies have implicated an important genetic contribution to salt-sensitive hypertension. Rats with inbred defects in the kidneys’ ability to excrete sodium remain rela-tively normotensive on a sodium-restricted diet but become severely hypertensive when fed a high-sodium diet, a model of salt-sensitive hypertension that can be cured by interstrain renal transplantation. A similar gene-environment interaction has been postulated to explain why persons of sub-Saharan African ancestry remain normotensive on a sodium-restricted diet but are predisposed to hypertension when they are exposed to a high-sodium Western diet. Ancestral gene analysis has not de"ned the molecular basis for salt-dependent human hypertension but has identi"ed a common genetic predisposition of African-origin populations to all nondiabetic forms of CKD, including focal glomerulo-sclerosis, AIDS, and hypertensive nephropathy. Sequence variations in the MYH9 gene encoding nonmuscle myosin found in podocytes associ-ate strongly with African ancestry and confer a twofold to fourfold increased risk of end-stage renal disease, independent of BP.25 As the kidneys fail, BP becomes increasingly salt dependent.

Vascular MechanismsAlterations in the structure and function of small and large arteries play a pivotal role in the pathogenesis and progression of hypertension.

ENDOTHELIAL CELL DYSFUNCTION. The endothelial lining of blood vessels is critical to vascular health and constitutes a major defense against hypertension. Dysfunctional endothelium is charac-terized by impaired release of endothelium-derived relaxing factors (e.g., nitric oxide, endothelium-derived hyperpolarizing factor) and enhanced release of endothelium-derived constricting, proinflamma-tory, prothrombotic, and growth factors (Fig. 45-6).26

The endothelium of all blood vessels expresses the enzyme nitric oxide synthase, which can be activated by bradykinin, acetylcholine, or cyclic laminar shear stress. Nitric oxide synthase generates nitric oxide, a volatile gas that diffuses to the adjacent vascular smooth muscle and activates a series of G kinases that culminate in vasodila-tion (see Fig. 45-6).

Renal MechanismsIn many forms of experimental and human hypertension, the fundamen-tal abnormality is an acquired or inherited defect in the kidneys’ ability to excrete the excessive sodium load imposed by a modern diet high in salt.22 As humans evolved in a low-sodium/high-potassium environment, the human kidney is ill-equipped to handle the current exposure to high sodium and low potassium.8 Renal sodium retention expands the plasma volume, increasing cardiac output and triggering autoregulatory responses that increase systemic vascular resistance. Salt retention also augments the smooth muscle contraction produced by endogenous vasoconstrictors. Beyond raising BP, a high-salt diet also accelerates hypertensive target organ damage. A successful 30-year campaign in Finland to lower salt intake by one third was associated with a population-level fall in systolic and diastolic BP of 10 mm Hg and a 75% reduction in the incidence of CAD and stroke deaths.

RESETTING OF PRESSURE-NATRIURESIS. In normotensive individuals, BP elevation invokes an immediate increase in renal sodium excretion to shrink plasma volume and to return BP to normal. In almost all forms of hypertension, the pressure-natriuresis curve is shifted to the right, and in salt-sensitive hypertension, the slope is reduced. Resetting of the pressure-natriuresis curve prevents the return of BP to normal so that !uid balance is maintained but at the expense of high BP. It also leads to nocturia, one of the most common and bothersome symptoms in patients with uncontrolled hypertension. Hypertensive individuals excrete the same amount of a given dietary sodium load as normoten-sive individuals do, but at a higher BP, and require many more hours to excrete the sodium load and to achieve sodium balance. Renal in!am-mation is both the cause and consequence of renal medullary ischemia, the hallmark of both the initiation and progression of salt-dependent hypertension in rodent models.23

LOW BIRTH WEIGHT. Because of fetal undernutrition, low birth weight with reduced nephrogenesis increases the risk for development of adult salt-dependent hypertension. This association is independent of shared genes, shared postnatal environment, and adult risk factors for hyperten-sion.24 Adult hypertensives have fewer glomeruli per kidney but very few obsolescent glomeruli, suggesting that nephron dropout with decreased total "ltration surface area is the cause and not the consequence of the hypertension. When they are exposed to a fast-food diet, low-birth-weight children are susceptible to rapid postnatal weight gain, leading to adolescent obesity and hypertension.

FIGURE 45!6 Endothelium-derived relaxing and constricting factors. Various blood- and platelet-derived substances can activate speci!c receptors (orange circles) on the endothelial membrane to release relaxing factors such as nitric oxide (NO), prostacyclin (PGI2), and an endothelium-derived hyperpolarizing factor (EDHF). Contracting factors also are released, such as endothelin (ET-1), angiotensin (A II), and thromboxane A2 (TXA2), as well as prostaglandin H2 (PGH2). ACE = angiotensin-converting enzyme; 5-HT = serotonin; Bk = bradykinin; ECE = endothelin-converting enzyme; L-Arg = L-arginine; NOS = nitric oxide synthase; O2

# = superoxide; TGF!1 = transforming growth factor !1; Thr = thrombin. (From Ruschitzka F, Corti R, Noll G, et al: A rationale for treatment of endothelial dysfunction in hypertension. J Hypertens 17[Suppl 1]:25, 1999.)

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940involves an increase in the size of vascular smooth muscle cells and an accumulation of extracellular matrix proteins, such as collagen, because of activation of transforming growth factor-! (TGF-!). The resultant large artery stiffness is the hemodynamic hallmark of ISH.

Antihypertensive therapy may not provide optimal cardio-vascular protection unless it prevents or reverses vascular remodeling by normalizing hemodynamic load, restoring normal endothelial cell function, and eliminating the under-lying neurohormonal activation.30

Hormonal Mechanisms: Renin-Angiotensin-Aldosterone System (See Fig.

25-3.)

Activation of the renin-angiotensin-aldosterone system (RAAS) is one of the most important mechanisms contribut-ing to endothelial cell dysfunction, vascular remodeling, and hypertension (Fig. 45-8). Renin, a protease produced solely by the renal juxtaglomerular cells, cleaves angiotensinogen (renin substrate produced by the liver) to A I, which is con-

verted by angiotensin-converting enzyme (ACE) to A II (see Chap. 93). ACE is most abundant in the lungs but is also present in the heart and systemic vasculature (tissue ACE). Chymase, a serine protease in the heart and systemic arteries, provides an alternative pathway for conver-sion of A I to A II. The interaction of A II with G protein–coupled AT1 receptors activates numerous cellular processes that contribute to hypertension and accelerate hypertensive end-organ damage (see Fig. 45-8), including vasoconstriction, generation of reactive oxygen species, vascular inflammation, vascular and cardiac remodeling, and produc-tion of aldosterone, the principal mineralocorticoid. There is increas-ing evidence that aldosterone, A II, and even renin and prorenin activate multiple signaling pathways that can damage vascular health and cause hypertension.

ALDOSTERONE AND EPITHELIAL SODIUM CHANNEL REGULATION. RAAS activation is a major homeostatic mechanism to counter hypovolemic hypotension (as with hemorrhage or salt and water deprivation). Interac-tion of aldosterone with cytosolic mineralocorticoid receptors in the renal collecting duct cells recruits sodium channels from the cytosol to the surface of the renal epithelium. The recruited epithelial sodium chan-nels (ENaCs) increase sodium reabsorption, thereby reexpanding plasma volume. Conversely, modern high-salt diets should engender continual feedback inhibition of the RAAS. Suppression of serum aldosterone should trigger sequestration of ENaCs by endocytosis and increased renal sodium excretion, thereby shrinking plasma volume to protect against salt-sensitive hypertension.

Thus, in the setting of high dietary sodium and elevated BP, the RAAS should be completely suppressed, and any degree of RAAS activity is inappropriate. In normotensive individuals, the risk for development of hypertension increases with increasing levels of serum aldosterone that are well within the normal range. By stimulating mineralocorticoid recep-tors in the heart and kidney, circulating aldosterone may contribute to the development of cardiac and renal "brosis in hypertension.31 By stim-ulating mineralocorticoid receptors in the brainstem, aldosterone also may contribute to sympathetic overactivity.

RECEPTOR-MEDIATED ACTIONS OF ANGIOTENSIN II. Two main angioten-sin receptor types (AT) are known. AT1 receptors are widely expressed in the vasculature, kidneys, adrenals, heart, liver, and brain. A I receptor activation explains most of the hypertensive actions of A II (see Fig. 45-8). Furthermore, enhanced AT1-mediated signaling provides a central mech-anistic explanation for the frequent coexistence of elevated BP with insulin resistance and atherosclerosis and constitutes a major therapeu-tic target for interruption of every step in cardiovascular disease progres-sion, from vascular remodeling and formation of atherosclerotic plaque to stroke, myocardial infarction, and death (Fig. 45-9).

In contrast, AT2 receptors distribute widely in the fetus, but in adults they localize only in the adrenal medulla, uterus, ovaries, vascular endo-thelium, and distinct brain regions. In rodents, AT2 receptor activation opposes some of the deleterious e#ects of AT1 receptors by promoting endothelium-dependent vasodilation by bradykinin and nitric oxide pathways. Animal studies have suggested that AT2 receptors can be pro-"brotic, but their role in human hypertension remains speculative. The

In humans, endothelium-dependent vasodilation can be assessed by measuring increases in the large artery (forearm or coronary) diam-eter after intra-arterial infusion of acetylcholine or release of ischemia (e.g., arrested forearm circulation) or a sudden elevation in BP (cold pressor test; see Chaps. 52 and 61).

Mounting evidence indicates that smoldering vascular inflamma-tion plays a central role in the genesis and complications of high BP. C-reactive protein (CRP; see Chap. 44), an easily measured serum biomarker, reports on inflammation.27 Cross-sectional studies show strong correlations between elevated CRP and arterial stiffness and elevated pulse pressure. Longitudinal studies implicate elevated CRP levels as a risk marker (or risk factor) for new onset of hypertension and accelerated progression of hypertensive target organ disease, pos-sibly beyond that explained by BP elevation alone.

Oxidative stress also contributes to endothelial cell vasodilator dys-function in hypertension. Superoxide anion and other reactive oxygen species quench nitric oxide, thereby reducing its bioavailability.28 Several pathways produce superoxide in arteries: nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, which are expressed in all vascular cell types and activated by circulating A II; nitric oxide synthase, which produces superoxide only when an important cofactor (tetrahydrobiopterin) is deficient, a process known as nitric oxide synthase uncoupling; xanthine oxidase, which pro-duces uric acid; and mitochondria. Generation of reactive oxygen species by xanthine oxidase accounts for the association of hyperuri-cemia with endothelial dysfunction and hypertension. The xanthine oxidase inhibitor allopurinol can normalize BP in two thirds of ado-lescents with hyperuricemia and recently diagnosed hypertension,29 but allopurinol cannot be recommended as a routine antioxidant because of its serious side effect profile. Vitamins C and E are weak antioxidants that have little effect on BP.

VASCULAR REMODELING. Over time, endothelial cell dysfunc-tion, neurohormonal activation, and elevated BP cause remodeling of blood vessels, which further perpetuates hypertension (Fig. 45-7).30 An increase in the medial thickness relative to lumen diameter (increased media-to-lumen ratio) is the hallmark of hypertensive remodeling in small and large arteries. Vasoconstriction initiates small artery remodeling, which normalizes wall stress. Normal smooth muscle cells rearrange themselves around a smaller lumen diameter, a process termed inward eutrophic remodeling. The media-to-lumen ratio increases, but the medial cross-sectional area remains unchanged. By decreasing lumen diameter in the peripheral circulation, inward eutrophic remodeling increases systemic vascular resistance, the hemodynamic hallmark of diastolic hypertension.

In contrast, large artery remodeling is characterized by the expres-sion of hypertrophic genes, triggering increases in medial thickness and in the media-to-lumen ratio. Such hypertrophic remodeling

FIGURE 45!7 Vascular remodeling of small and large arteries in hypertension. Diagrams represent arteries in cross section showing the tunica adventitia, tunica media, and tunica intima. (Modi!ed from Duprez DA: Role of renin-angiotensin-aldosterone system in vascular remodeling and in"ammation: A clinical review. J Hypertens 24:983, 2006.)

Small arteriesEutrophic remodeling

Media-to-lumen ratio

Medial x-sectional area

Large arteriesHypertrophic remodeling

Media-to-lumen ratio

Medial x-sectional area

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vasoconstriction and vascular remodeling. Homing of activated T cells to perinephric fat promotes renal dysfunction and sodium retention (Fig. 45-10) (see also Fig. 93-2).

Pathogenesis of Hypertensive Heart DiseaseHypertension is a major risk factor not only for CAD but also for LVH and heart failure.

Pressure Overload HypertrophyIn hypertensive patients, LVH powerfully and independently predicts morbidity and mortality, predisposing to heart failure, ventricular tachyarrhythmia, ischemic stroke, atrial fibrillation, and embolic stroke. Major advances have increased our understanding of the molecular signal transduction pathways underlying pressure overload cardiomyocyte hypertrophy.35 Moreover, the structural abnormalities in the hypertensive heart extend beyond myocyte hypertrophy; they also include medial hypertrophy of the intramyocardial coronary arteries and collagen deposition leading to cardiac fibrosis.36 These changes result from pressure overload and the neurohormonal activa-tion that contributes to hypertension. In animal models, A II, aldoste-rone, norepinephrine, and prorenin accelerate pressure overload cardiomyocyte hypertrophy and promote cardiac fibrosis, the hall-marks of pathologic LVH (in contrast to the physiologic hypertrophy of exercise training, which does not involve fibrosis).

"nding of several angiotensin metabolites also has added to the com-plexity of the RAAS (see Fig. 45-e4 on website).

RECEPTOR-MEDIATED ACTIONS OF RENIN AND PRORENIN. Traditionally, prorenin was considered the inactive precursor of renin, an enzyme that functions solely to generate A I by enzymatic cleavage of angiotensino-gen. These concepts are rapidly evolving as newer studies implicate pro-renin and renin as direct cardiac and renal toxins. Prorenin is inactive because a 43–amino acid hinge is closed and prevents it from binding to angiotensinogen. The kidneys convert inactive prorenin to active renin by enzymatic cleavage of this inhibitory hinge region. When circulating prorenin binds to a newly discovered (pro)renin receptor in the heart and kidneys, the hinge is opened (but not cleaved), and this nonenzymatic process fully activates prorenin (see Fig. 45-e5 on website).32 Activation of the (pro)renin receptor increases TGF-! production, leading to colla-gen deposition and "brosis. This receptor-mediated process does not depend on A II generation, ACE inhibitors (ACEIs), or angiotensin receptor blockers (ARBs). Although these are excellent antihypertensives (see Chap. 46), they trigger large reactive increases in prorenin and renin production that may counter some of the cardiovascular protection a#orded by reduced AT1 receptor activation. The reactive increases are even greater with the new direct renin inhibitor aliskiren, which reduces renin’s ability to cleave angiotensinogen and to generate A I but never-theless does not inhibit pro"brotic signaling by the (pro)renin receptor.33 As prorenin blood levels normally exceed those of renin by 100-fold, (pro)renin receptor activation may turn out to be an important factor in human hypertension.

T CELLS AND ANGIOTENSIN II–INDUCED HYPERTENSION. T cells, which express AT1 receptors and NADPH oxidase, may play an important role in the genesis of A II–dependent hypertension, particularly obesity-related hypertension, as the activated T cells are selectively sequestered in adipose tissue.34 Homing of activated T cells to perivascular fat promotes

FIGURE 45!8 The renin-angiotensin-aldosterone system. A I = angiotensin I; A II = angiotensin II; ACE = angiotensin-converting enzyme; AT1R = angiotensin I receptor.

Angiotensinogen

Alternativepathway

(Chymase)

A I

Renin

ACE

Inactive prorenin

Activeprorenin

Proreninreceptor

Fibrosis

Kidney

Kidney Sodiumretention

Aldosterone

A II

CNS

Sympatheticactivation

Endothelialdysfunction

Inflammation

Vascularendothelium

Smoothmuscle

Cardiac(myocardial) cells

Individual cellgrowth

AT1R

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FIGURE 45!9 Schematic representation of the central role of angiotensin 1 receptor (AT1R)–mediated signaling in cardiovas-cular disease progression. A II = angiotensin II; MI = myocardial infarction; NE = norepinephrine.

A II

Remodeling of heart and vessels Plaque progression

Reactive O2 speciesVascular inflammationCell growth, fibrosis

Endothelial dysfunctionAldosterone, NE release

AT1R

Elevated BP

MIstroke

Death

Glucose intolerance Atherosclerosis

FIGURE 45!10 Proposed mecha-nism for the role of adaptive immu-nity in hypertension. Hypertensive stimuli such as angiotensin II (A II) can participate in T-cell activation by directly acting on T cells and via central nervous system activation. Central nervous system activation leads to increased sympathetic out"ow, which also promotes T-cell activation and enhances chemokine production in perivascular fat and perinephric adipose tissue, promot-ing T-cell accumulation at these sites. Diverse in"ammatory stimuli also promote hypertension by acti-vating T cells. Activated T cells enter the perivascular fat, activating the vascular production of reactive oxygen species (ROS) and reducing nitric oxide (NO) production, thus causing vasoconstriction. T cells also a$ect renal sodium and volume handling. These actions on the kidney and vasculature lead to hypertension. (From Harrison DG, Guzik TJ, Goronzy J, Weyand C: Is hypertension an immunologic disease? Curr Cardiol Rep 10:464, 2008.)

Central stimuliaffecting sympathetic outflow

Sodium/volumeretention

Hypertension

ActivatedT cells

T cells

Diverseinflammatory

stimuli

Spleen/lymph nodes

A IIhigh salt

!Vessel ROS

!Sympathetic outflowcatecholamines

"Vessel NO

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at heart level. A large adult-sized cuff should be used to measure BP in overweight adults because the standard-sized cuff can spuriously elevate readings. Tobacco and caffeine should be avoided for at least 30 minutes. BP should be measured in both arms and after 5 minutes of standing, the latter to exclude a significant postural fall in BP, particularly in older persons and in those with diabetes or other conditions (e.g., Parkinson’s disease) that predispose to autonomic insufficiency.

Home and Ambulatory MonitoringAn individual’s BP varies widely throughout a 24-hour period and is therefore impossible to characterize accurately, except by repeated measurements under various conditions (see Fig. 45-e6 on website). Out-of-office readings provide a clear picture of usual BP for accurate diagnosis and management. These readings predict cardiovascular events better than office readings do, and they overcome many of the pitfalls of office measurement, including physician errors and alerting (i.e., “white coat”) reactions. Home BP monitoring also improves medication adherence by actively involving patients in their own medical care.

For these reasons, new position papers on home BP monitoring from both the United States and Europe make the following recom-mendations: that home BP monitoring should become a routine part of the clinical management of patients with known or suspected hypertension the same way that home blood glucose monitoring is essential to the management of diabetes; that two (or three) readings should be taken in the morning and at night for 1 week, with a total of at least 12 readings being averaged to make clinical decisions; and that the target treatment goal is an average home BP <135/85 mm Hg for most patients and <130/80 mm Hg for high-risk patients, such as those with CAD, heart failure, diabetes, or CKD.37,38

A validated electronic oscillometric monitor with an arm cuff should be chosen from the Dabl educational website (dableduca-tional.com). Each patient’s monitor needs to be checked in the office for accuracy and cuff size because many manufacturers provide only a standard adult cuff. Patients need to be taught correct measurement technique and how to avoid reporting bias. Wrist monitors are inac-curate and thus not recommended. The oscillometric method may not work well in patients with atrial fibrillation or frequent extrasysto-les. Some patients become obsessed about taking their BP and need to limit measurement.

Ambulatory monitoring provides automated measurements of BP during a 24-hour period while patients are engaged in their usual activities, including sleep. Prospective outcome studies in both treated and untreated patients have shown that ambulatory BP measurement predicts fatal and nonfatal myocardial infarction and stroke better than standard office measurement does (Fig. 45-11).39 Recommended normal values include an average daytime BP <135/85 mm Hg, night-time BP <120/70 mm Hg, and 24-hour BP <130/80 mm Hg. Some experts have recommended a lower cutoff value of 130/80 mm Hg as a more stringent definition of normal daytime BP.

WHITE COAT HYPERTENSION. About 20% of patients with ele-vated office BPs have normal home or ambulatory BPs. If the daytime BP is <135/85 mm Hg (or preferably <130/80 mm Hg) and there is no target organ damage despite consistently elevated office readings, the patient has “office-only” or white coat hypertension, caused by a tran-sient adrenergic response to the measurement of BP only in the physi-cian’s office. The prognostic importance of white coat hypertension remains unresolved. The cardiovascular risk seems intermediate between that in persons with consistently normal BP and that in persons with consistently high BP.

Many patients do not have pure white coat hypertension but rather “white coat aggravation,” a white coat reaction superimposed on a milder level of out-of-office hypertension that nevertheless needs treat-ment (see Fig. 45-e6 on website). Currently, Medicare reimburses ambulatory BP monitoring for suspected white coat hypertension if the following criteria are met: office BP >140/90 mm Hg on at least three separate office visits with two measurements made at each visit; at least two out-of-office BPs <140/90 mm Hg; and no evidence of target organ damage. The indications for ambulatory monitoring

IMPAIRED CORONARY VASODILATOR RESERVE. The hyper-trophied hypertensive heart has normal resting coronary blood flow, but vasodilator reserve becomes impaired when myocyte mass out-strips the blood supply. Even in the absence of atherosclerosis, the hypertensive heart has blunted or absent coronary vasodilator reserve, leading to subendocardial ischemia under conditions of increased myocardial oxygen demand. The combination of subendocardial ischemia and cardiac fibrosis impairs diastolic relaxation, leading to exertional dyspnea and diastolic heart failure.

Heart Failure (see Chaps. 26 and 30)

Before the advent of effective drug therapy for hypertension in the late 1950s, heart failure caused most deaths from hypertension. Better management has substantially reduced hypertension-related deaths from heart failure and significantly delayed its onset, but hypertension remains the most common cause of heart failure with preserved sys-tolic function. In addition, hypertension indirectly leads to systolic heart failure as a major risk factor for myocardial infarction. It is unclear whether mild or moderate hypertension alone, without myo-cardial infarction, leads to systolic heart failure.36

Diagnosis and Initial Evaluation of HypertensionHypertension has been termed the silent killer, an asymptomatic chronic disorder that, undetected and untreated, silently damages the blood vessels, heart, brain, and kidneys. However, it may not be entirely asymptomatic; in double-blind placebo-controlled trials, patients’ quality of life ratings were often found to improve with suc-cessful drug treatment of hypertension. Control of hypertension can improve exertional dyspnea caused by diastolic dysfunction, nocturia caused by resetting of pressure-natriuresis, and possibly even erectile dysfunction caused by endothelial dysfunction.

Initial Evaluation of the Hypertensive PatientThe initial evaluation for hypertension should accomplish three goals: the accurate measurement of BP; the assessment of the patient’s overall cardiovascular risk; and the detection of secondary (i.e., iden-tifiable and potentially curable) forms of hypertension.

MEASUREMENT OF BLOOD PRESSURE Staging of Office Blood PressureAccording to the 2003 guidelines of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treat-ment of High Blood Pressure (JNC 7),3 which are still in effect until the publication of JNC 8, BP is staged as normal, prehypertension, or hypertension by the average of two or more readings taken at two or more office visits (Table 45-1; see Table 49-5).

MEASUREMENT TECHNIQUE (see Chap. 12). In the office, BP should be measured at least twice after 5 minutes of rest, with the patient seated in a chair, the back supported, and the arm bare and

TABLE 45-1 Staging of O"ce Blood Pressure*

BP STAGESYSTOLIC

BP #MM HG$DIASTOLIC

BP #MM HG$

Normal <120 <80

Prehypertension 120-139 80-89

Stage 1 hypertension 140-159 90-99

Stage 2 hypertension "160 "100*Calculation of seated BP is based on the mean of two or more readings on two separate

o%ce visits.From Chobanian AV, Bakris GL, Black HR, et al: The Seventh Report of the Joint National

Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 report. JAMA 289:2560, 2003.

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OTHER USES OF AMBULATORY MONITORING. Ambulatory monitoring is the only way to detect hypertension during sleep (see Fig. 45-12). BP normally dips during sleep and increases sharply when a person awakens and becomes active (see Fig. 45-e6 on website). Nocturnal hypertension increases the aggregate hemodynamic load on the cardiovascular system and predicts cardiovascular outcomes better than either daytime ambulatory BP or standard office measure-ments (see Fig. 45-11).39 Nocturnal hypertension is particularly common in patients with CKD, presumably because of increased cardiac output (centralization of an expanded plasma volume while supine) and increased systemic vascular resistance (failure of sympa-thetic vasoconstrictor drive to suppress normally during sleep because of persistent activation of an excitatory reflex in the diseased kidneys). In addition, ambulatory BP monitoring is particularly useful in diag-nosis of baroreflex impairment.

CARDIOVASCULAR RISK STRATIFICATION (see Chap. 44). In hypertensive individuals, cardiovascular risk increases sharply with BP stage (see Table 45-1; see Table 49-5), but this is not the only factor to consider. The gradient between increasing levels of BP and cardio-vascular risk becomes progressively steeper as additional risk factors are added. Cardiovascular risk also increases dramatically with hyper-tensive target organ damage and with additional cardiovascular risk factors often present in patients with hypertension or prehypertension (Table 45-2).40 In particular, more than 75% of hypertensive patients meet current criteria for initiation of lipid-lowering medication (low-density lipoprotein cholesterol level >130 mg/dL), and 25% have dia-betes.41 Thus, the minimal laboratory testing required for the initial evaluation of hypertension includes determination of blood electro-lyte values, fasting glucose concentration, and serum creatinine level with calculated glomerular filtration rate (GFR); fasting lipid panel; hematocrit; spot urinalysis, including urine albumin-to-creatinine ratio; and resting 12-lead electrocardiogram.

Definition of High RiskWhereas hypertension is present in 25% of adults in the general popu-lation, it is present in 75% of adults with diabetes and in more than

should be expanded. In up to 30% of treated patients with persistently elevated office BP, for example, ambulatory monitoring documents adequate or excessive control of hypertension, eliminating overtreatment.

MASKED HYPERTENSION. Another example of the importance of ambulatory monitoring is in patients in whom office readings under-estimate out-of-office BP, presumably because of sympathetic overac-tivity in daily life caused by job or home stress, tobacco abuse, or other adrenergic stimulation that dissipates when they come to the office (Fig. 45-12). Such documentation prevents undertreatment of this masked hypertension, which can affect more than 10% of patients and clearly increases cardiovascular risk, despite normal office BP readings.

FIGURE 45!12 A 24-hour ambulatory BP recording in a patient with appar-ently normal o%ce BP but with masked hypertension and nocturnal hyperten-sion. (From Dr. R. G. Victor, Cedars-Sinai Medical Center, Los Angeles, California.)

Maskedhypertension

Nocturnalhypertension

Office BP

0

50

100

150

200

250

BP

mm

Hg

11:0011:00 24:00

HR:MIN

FIGURE 45!11 Superiority of ambulatory over o%ce BP measurement as a measure of cardiovascular risk. Shown is the adjusted 5-year risk of cardiovas-cular death (number of deaths per 100 subjects) in the study cohort of 5292 patients for o%ce BP and ambulatory BP. (From Dolan E, Santon A, Thijs L, et al: Superiority of ambulatory over clinic BP measurement in predicting mortality: The Dublin outcome study. Hypertension 46:156, 2005.)

3.5

0.5

1.0

1.5

2.0

2.5

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90 110 130 150 170 190 210 230

Clinic

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%)

SYSTOLIC BP (mm Hg)

Daytime

24-hour

Nighttime TABLE 45-2 Risks In%uencing Prognosis in Patients with Hypertension

Risk Factors for Cardiovascular DiseaseSystolic and diastolic BP levelsLevels of pulse pressure (in the elderly)Age: men >55 years; women >65 yearsSmokingDyslipidemia (LDL-C >115 mg/dL)Impaired fasting glucose (102-125 mg/dL) or abnormal glucose tolerance

test resultFamily history of premature cardiovascular diseaseAbdominal obesityDiabetes mellitus

Subclinical Target Organ DamageLeft ventricular hypertrophyCarotid wall thickening or plaqueLow estimated glomerular !ltration rate #60 mL/min/1.73 m2

MicroalbuminuriaAnkle-brachial BP index <0.9

Established Target Organ DamageCerebrovascular disease: ischemic stroke, cerebral hemorrhage, transient

ischemic attackHeart disease: myocardial infarction, angina, coronary revascularization,

heart failureRenal disease: diabetic nephropathy, renal impairmentPeripheral arterial diseaseAdvanced retinopathy: hemorrhages or exudates, papilledema

Modi!ed from Mancia G, De Backer G, Dominiczak A, et al: 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 28:1462, 2007.

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On the electrocardiogram, LVH with strain is a serious harbinger of new-onset heart failure and heart failure death.44 Echocardiography detects LVH more sensitively than electrocardiography does. Whereas electrocardiographic LVH is present in 5% to 10% of hypertensives, echocardiographic LVH is present in nearly 30% of unselected hyper-tensive adults and in up to 90% of patients with severe uncontrolled hypertension. Cardiac magnetic resonance imaging (MRI) is even more sensitive, detecting LVH in 28% of white hypertensives but in 62% of black hypertensives.45

LARGE-VESSEL DISEASE (see Chaps. 60 and 61). Hypertension also constitutes a major risk factor for and is present in the overwhelm-ing majority of patients with aortic dissection (distal more than proxi-mal dissection), abdominal aortic aneurysm, and peripheral arterial disease. One-time abdominal ultrasound screening for abdominal aortic aneurysm is recommended after the age of 65 years in smokers and in those with severe systolic hypertension, and it should be per-formed if aortic pulsations are detected below the umbilicus because most abdominal aortic aneurysms occur below the origin of the renal arteries. Hypertension is present in 50% of patients with Takayasu arte-ritis, a large-cell arteritis common in Asia and India.

CEREBROVASCULAR DISEASE (see Chap. 62). Hypertension is a major risk factor for stroke and dementia, often the two most dreaded complications of aging. Hypertension accounts for 50% of strokes. In hypertensives, 80% of strokes are ischemic (thrombotic or embolic) and 20% are hemorrhagic. The onset of ischemic stroke markedly increases on wakening, corresponding to the morning surge in BP. Hypertensive patients with asymptomatic carotid bruits should undergo Doppler ultrasonography. The risk of stroke is greatest in older patients with ISH. In middle-aged and elderly hypertensives, asymptomatic cerebral white matter lesions on MRI are remarkably common and likely accelerate the brain atrophy and vascular demen-tia that occur with aging.

CHRONIC KIDNEY DISEASE (see Chap. 93). Hypertension follows only diabetes as a risk factor for CKD. Traditionally, the typical patho-logic change of small scarred kidneys (termed hypertensive nephro-sclerosis) was assumed to result from chronic exposure of the renal parenchyma to excessive pressure and flow and to be the most common cause of end-stage renal disease among blacks. However, recent work on the MYH9 gene locus suggests that many cases of presumed hypertensive nephrosclerosis in blacks may result primarily from an abnormal gene product: nonmuscle myosin, a protein that regulates podocyte function.46

Quantitative estimates of urinary albumin excretion and GFR (the latter from www.kdoqi.org) should be obtained from a spot urine collection. Microalbuminuria (defined as a urine albumin–to–urine creatinine ratio of 30 to 300 mg/mg) is a sensitive early marker of kidney damage and a powerful independent predictor of cardiovas-cular complications from hypertension, presumably because it reflects systemic vascular disease (see Chaps. 44 and 93). In patients with hypertension, the presence of renal damage dramatically increases the risk of a cardiovascular event. Most patients with hypertension-associated CKD die of heart attack or stroke before renal function deteriorates sufficiently to require chronic hemodialysis.

IDENTIFIABLE (SECONDARY) FORMS OF HYPERTENSION. The third goal of the initial evaluation is to detect identifiable causes of hypertension, thereby offering the possibility of cure to some patients, particularly those with severe or refractory hypertension (Table 45-3).

Renal Parenchymal Disease (see Chap. 93)

Renal parenchymal disease is the most common cause of secondary hypertension, responsible for 2% to 5% of cases. As chronic glomeru-lonephritis has become less common, diabetes and hypertension are the most common risk factors for CKD. The prevalence of chronic renal disease, defined by a reduction in the GFR to less than 60 mL/min/1.73 m2 or persistent albuminuria of more than 300 mg/day, affects some 11% (19.2 million) of the adult U.S. population.47

As previously noted, microalbuminuria of 30 to 300 mg/day relates closely to target organ damage and should be determined in every

90% of those with CKD. Either of these two comorbidities dramatically increases the cardiovascular risk associated with hypertension, and the presence of hypertension greatly accelerates the progression to end-stage renal disease. Therefore, the 2003 JNC 7 guidelines recommend a usual BP of 140/90 mm Hg as the threshold for initiation of antihy-pertensive medication in most patients, with a lower threshold of 130/80 mm Hg for high-risk patients with diabetes or CKD.3 On the basis of more recent data, the operational definition of high-risk patients now includes most cardiology patients—those with estab-lished CAD, CAD risk equivalents, carotid artery disease (carotid bruit or abnormal carotid ultrasound study), peripheral artery disease, abdominal aortic aneurysm, heart failure, or high risk for CAD (10-year Framingham risk score of >10%) (see Chaps. 44 and 49).5 In particular, in patients with established CAD, a continuous relationship exists between systolic BP and the rate of progression of coronary atherosclerosis (determined by intravascular ultrasound) over a wide range of systolic pressures, beginning as low as 100 mm Hg (Fig. 45-13).42

Evaluation of Target Organ DiseaseTraditionally, the complications of hypertension are viewed as hyper-tensive, caused by the increased level of BP per se, or atherosclerotic, caused by concomitant atherosclerosis, with BP elevation playing a variable role. This view is oversimplified, however, because both types of complications frequently coexist, as exemplified by hypertensive retinopathy (see Fig. 45-e7 on website)43 or hypertensive heart disease.

HYPERTENSIVE HEART DISEASE. Hypertension may contribute to CAD more than is commonly realized because hypertensives have more silent ischemia and unrecognized myocardial infarctions, and patients with acute myocardial infarction often have preexisting hypertension that evaded detection or treatment. Assessment of BP is inaccurate during an acute coronary syndrome because of pain-induced BP rise or dysautonomia or pump failure decreasing BP. Preexisting hypertension increases the case-fatality rate associated with an acute myocardial infarction and substantially increases the risk of hemorrhagic stroke during thrombolytic therapy, especially when systolic BP exceeds 175 mm Hg.

FIGURE 45!13 Relationship between systolic blood pressure and the rate of progression of coronary atheroma in 274 patients who completed the intravas-cular ultrasound substudy of the CAMELOT (Comparison of Amlodipine Versus Enalapril to Limit Occurrences of Thrombosis) trial. A systolic blood pressure in the range of 120 to 140 mm Hg corresponded to no net progression or regres-sion of coronary disease. Values above this range were associated with progres-sion and those below were associated with regression of disease. (From Sipahi I, Tuzcu EM, Schoenhagen P, et al: E#ects of normal, pre-hypertensive, and hyperten-sive blood pressure levels on progression of coronary atherosclerosis. J Am Coll Cardiol 48:833, 2006.)

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ated with a higher prevalence of hypertension, and hypertension accelerates the progression of renal damage, regardless of the underly-ing cause of the renal disease. In patients with chronic kidney disease, the control of hypertension slows the progression to end-stage renal disease.49 However, uncertainty remains about the BP goal of antihy-pertensive therapy in patients with CKD. Perhaps the mislabeling of MYH9 nephropathy as hypertensive nephrosclerosis explains why renal function continued to decline 5 years after completion of the African American Study of Kidney Disease (AASK) trial, despite achievement of a BP of 133/78 mm Hg on an ACEI-based regimen.46

With whatever drugs are chosen to treat hypertension with CKD, and particularly with ACEIs and ARBs, caution is needed in lowering BP too rapidly and in the presence of previously unrecognized bilat-eral renovascular disease, found in as many as 20% of patients with progressive renal damage. However, a modest increase in the serum creatinine level, averaging 30% above baseline, predicts a better pres-ervation of renal function, presumably reflecting a successful reduc-tion in intraglomerular pressure. Patients with CKD commonly have nocturnal hypertension detectable by 24-hour ambulatory BP monitor-ing (see Figs. 45-11 and 45-12).50

Patients with diabetic nephropathy (see Chaps. 64 and 93) show particular protection against progressive renal damage by reduction of elevated BP with an ARB- or ACEI-based regimen. The role of the direct renin inhibitors has yet to be established; CKD patients should be monitored often for hyperkalemia. Most CKD patients require the addition of at least two more drugs in addition to ACEI or ARB, typi-cally a loop diuretic and a calcium channel blocker, to control their hypertension.

Hemodialysis Patients

In patients on dialysis, hypertension is a risk factor for mortality. Beyond the primary influence of excess fluid volume, hypertension can be accentuated by the accumulation of endogenous inhibitors of nitric oxide synthase and sympathetic overactivity. With neither the vasoconstrictor effects of renal renin nor the vasodepressor actions of various renal hormones, BP may be particularly labile and sensitive to changes in fluid volume. In patients receiving maintenance hemo-dialysis every 48 hours, elevated BPs tend to fall progressively after dialysis is completed, remain depressed during the first 24 hours, and rise again during the second day as a result of excessive fluid reten-tion. Only gradually achieving and maintaining dry weight, as with 8-hour nocturnal hemodialysis, can control BP.

Renal Transplantation

Although successful renal transplantation may cure primary hyperten-sion, various problems can result, with about 50% of recipients becom-ing hypertensive within 1 year. These problems include stenosis of the renal artery at the site of anastomosis, rejection reactions, high doses of glucocorticoids and cyclosporine or tacrolimus, and excess renin derived from the retained diseased kidneys. ACEI or ARB therapy may obviate the need to remove the native diseased kidneys to relieve hypertension caused by their persistent secretion of renin. The source of the donor kidney may also play a role in the subsequent develop-ment of hypertension in the recipient. Hypertension occurs more fre-quently when donors have had a family history of hypertension or when the donors have died of subarachnoid hemorrhage and had probably had high BP.

Renovascular HypertensionThe prevalence of proven renovascular hypertension in the overall hypertensive population is unknown, but significant renal artery ste-nosis has been found in 14% of hypertensive patients undergoing coronary angiography followed by renal angiography. Such “drive-by” renal angiography is discouraged. Renal artery stenosis is rather easy to find but difficult to prove as the cause of reversible hypertension. Moreover, the risks of revascularization often outweigh the benefits (see Chap. 63).51

Screening should focus on those hypertensive patients who have multiple features known to be associated with renovascular

new hypertensive patient by testing of a single voided urine specimen. Measurement of the serum creatinine level by itself is an inadequate screening test for significant renal damage, particularly in elderly patients. Therefore, creatinine clearance should be calculated with the Cockcroft-Gault equation or the Modification of Diet in Renal Disease (MDRD) equation, taking age, sex, and body weight into account.47 However, the MDRD equation does not account for other factors that affect creatinine generation by muscle, such as diet and physical conditioning. Serum cystatin C, an endogenous 13-kDa protein filtered by the glomeruli and reabsorbed and metabolized by the proximal tubular epithelium, with very little being excreted in the urine, is being evaluated as a potential replacement for serum creati-nine because it is less affected by muscle mass.48 Once renal disease begins, it usually progresses, following the concept that a loss of filtra-tion surface leads to both glomerular and systemic hypertension, which engenders more glomerular sclerosis, setting up a cycle of progressive disease. Therefore, it is critical to identify renal damage early, because removal of causal or aggravating factors can prevent the otherwise inexorable progress of renal damage. These factors include obstruction of the urinary tract, depletion of effective circulat-ing volume, nephrotoxic agents, and most important, uncontrolled hypertension.

ACUTE RENAL DISEASES. Hypertension may appear with any sudden, severe insult to the kidneys that markedly impairs excretion of salt and water, which leads to volume expansion, or reduces renal blood flow (e.g., sudden bilateral renal ischemia because of choles-terol emboli), which activates the RAAS (e.g., bilateral ureteral obstruction). Reversal of hypertension has been particularly striking in men with high-pressure chronic retention of urine, who may mani-fest renal failure and severe hypertension, both of which may be ameliorated by relief of the obstruction. Some vasculitides also produce rapidly progressive renal damage.

Two commonly used classes of drugs, nonsteroidal anti-inflammatory drugs (NSAIDs) and inhibitors of the renin-angiotensin system, may suddenly worsen renal function in patients with preexisting renal dis-eases. NSAIDs block the synthesis of prostaglandins, which act as vasodilators within the kidney. Renin-angiotensin inhibitors, both ACEIs and ARBs, may precipitate acute renal failure in patients with bilateral renovascular disease whose renal perfusion depends on high levels of A II.

TABLE 45-3 Overall Guide to Workup for Identi&able Causes of Hypertension

DIAGNOSIS

DIAGNOSTIC PROCEDURE

INITIAL ADDITIONAL

Chronic renal disease

Urinalysis, serum creatinine, renal sonography

Isotopic renography, renal biopsy

Renovascular disease

Renal sonography (atrophic kidney)

Magnetic resonance or computed tomography (CT) angiography, Duplex Doppler sonography, digital subtraction renal angiography

Coarctation Blood pressure in legs

Echocardiography, magnetic resonance imaging, aortography

Primary aldosteronism

Plasma renin, serum aldosterone

Salt loading, adrenal vein sampling

Cushing syndrome 1-mg dexamethasone suppression test

Urinary cortisol after variable doses of dexamethasone, adrenal CT, scintiscans

Pheochromocytoma Plasma-free metanephrines

24-hr urinary metanephrines and catecholamines, adrenal CT

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decide whether revascularization is indicated (Fig. 45-14) (see Fig. 63-11).51

All screening tests have limitations. Considerable asymmetry of renal blood flow, 25% or more, was found in 148 hypertensive patients whose renal arteries were patent on prior angiography. Such normal asymmetry is likely to account for the low sensitivity and specificity of captopril-enhanced renal scans. Similarly, the sensitivity of renal duplex sonography for the detection of hemodynamically significant renovascular disease is only about 50%. The accuracy of ultrasonog-raphy is operator dependent, but the outcome of revascularization associates with the use of a resistance index to assess flow in renal arteries. Patients with high resistance index values (above 80), reflect-ing marked intrarenal vascular disease, had generally poor outcomes. Those with lower values had generally good outcomes.

During the past decade, contrast-enhanced computed tomography (CT) and magnetic resonance angiography have become the pre-ferred screening tests for renal artery stenosis because initial studies suggested better sensitivity and specificity (see Fig. 45-e8 on website). However, more recent data indicate that even in experienced centers, these imaging modalities cannot reliably exclude renal artery stenosis. Gadolinium-enhanced MRI is contraindicated in patients with advanced CKD to avoid causing nephrogenic systemic fibrosis, a potentially fatal complication seen mainly in patients with low GFR.52

MANAGEMENT. Balloon angioplasty (without stenting) is the treatment of choice for fibromuscular dysplasia of the renal arteries (see also Chap. 63). Pending better outcomes data, however, a con-servative approach based on medical management of cardiovascular risk factors—with antihypertensive medication, statins, and antiplatelet therapy—is the cornerstone for the treatment of patients with

hypertension. The greater the number of clues, the more extensive the search should be (Table 45-4).

CLASSIFICATION. In adults, the two major types of renovascular disease tend to appear at different times and to affect men and women differently. Atherosclerotic disease affecting mainly the proximal third of the main renal artery is seen mostly in older men. Fibroplastic disease involving mainly the distal two thirds and branches of the renal arteries appears most commonly in younger women. As the population grows older, 90% of cases are caused by atherosclerotic disease and only 10% by fibroplastic disease. Although the nonatherosclerotic ste-noses may involve all layers of the renal artery, the most common is fibromuscular dysplasia.

A number of other intrinsic and extrinsic causes of renovascular hypertension are known, including cholesterol emboli in the renal artery or compression of this vessel by nearby tumors. Most renovas-cular hypertension develops from partial obstruction of one main renal artery, but only a branch need be involved; segmental disease has been found in about 10% of cases. On the other hand, if apparent complete occlusion of the renal artery is slow to develop, enough collateral flow will become available to preserve the viability of the kidney. Such seemingly nonfunctioning kidneys may secrete renin and cause hypertension. If recognized, such totally occluded vessels can sometimes be repaired, resulting in return of renal function and relief of hypertension. Renovascular stenosis is often bilateral, although usually one side is predominant. Bilateral disease should be suspected in those with renal insufficiency, particularly if rapidly pro-gressive oliguric renal failure develops without evidence of obstruc-tive uropathy, and even more so if it develops after the start of ACEI or ARB therapy.

MECHANISMS. The sequence of changes in patients with renovas-cular hypertension starts with the release of increased amounts of renin when sufficient ischemia is induced to diminish pulse pressure against the juxtaglomerular cells in the renal afferent arterioles. A reduction in renal perfusion pressure by 50% leads to an immediate and persistent increase in renin secretion from the ischemic kidney, along with suppression of secretion from the contralateral one. With time, an expanded body fluid volume causes renin levels to fall but not to the low level expected from the elevated BP.

DIAGNOSIS. The presence of the clinical features listed in Table 45-4, found in perhaps 5% to 10% of all hypertensive persons, indicates the need for a screening test for renovascular hypertension. A positive screening test result or very strong clinical features call for more defini-tive confirmatory tests. The initial diagnostic study in most patients should be noninvasive and, if abnormal, followed by a study of renal perfusion to ensure that any renovascular lesion is pathogenic and to

TABLE 45-4 Clinical Clues for Renovascular HypertensionHistoryOnset of hypertension before 30 years or after 50 years of ageAbrupt onset of hypertensionSevere or resistant hypertensionSymptoms of atherosclerotic disease elsewhereNegative family history of hypertensionSmokerWorsening renal function after renin-angiotensin inhibitionRecurrent “"ash” pulmonary edema

ExaminationAbdominal bruitsOther bruitsAdvanced fundal changes

Laboratory FindingsSecondary aldosteronismHigher plasma renin levelLow serum potassium levelLow serum sodium levelProteinuria, usually moderateElevated serum creatinine levelUnilateral small (atrophic) kidney size by ultrasound examination

FIGURE 45!14 Algorithm for evaluation of patients in whom renal artery stenosis is suspected. Clinical follow-up includes periodic reassessment with duplex ultrasonography, magnetic resonance angiography, and nuclear imaging to estimate fractional blood "ow to each kidney. The treatment of risk factors includes smoking cessation and the use of aspirin, lipid-lowering agents, and antihypertensive therapy. (Modi!ed from Sa!an RD, Textor SC: Renal-artery steno-sis. N Engl J Med 344:431, 2001.)

Present

Renal arterystenosis absent

Absent

Clinical findings associated with renal artery stenosis

Follow clinicallyTreat risk factors

Follow clinicallyTreat risk factors

Follow clinicallyTreat risk factors

Unilateral renal artery stenosis and asymmetric

perfusion present

Unilateral renal artery stenosis and symmetric

perfusion present

Bilateral renal artery stenosis

present

Noninvasive evaluation (duplex ultrasonography

of renal arteries, magnetic resonance angiography, or computed tomography

angiography)

Consider revascularization

Renal arterystenosis present

Nuclear imaging to estimate fractional flow to each kidney

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Pathophysiology of Mineralocorticoid ExcessUntil recently, the most frequently found source of hyperaldosteronism was a solitary aldosterone-producing adenoma. Recently, measurements of plasma renin and aldosterone have identi"ed milder forms of hyper-aldosteronism, usually associated with bilateral adrenal hyperplasia (BAH).

Aldosterone excess from any source causes hypertension and renal potassium wastage, which should induce hypokalemia (Fig. 45-15), but most patients with aldosteronism caused by BAH are normokalemic. The lack of overt hypokalemia could exist because potassium wastage has lowered the serum potassium level, but not yet to hypokalemic levels; because with milder degrees of aldosteronism, as are typical with BAH, the excess of aldosterone induces hypertension without causing potas-sium wastage, a scenario that has never been experimentally or clinically recognized; or because the BAH is related to the typical progressive increase in adrenal nodular hyperplasia with age that has no relationship to hypertension. The third explanation would "t with the long-held belief that BAH is simply a form of low-renin hypertension, that is, primary hypertension with plasma renin levels that fall progressively with age while plasma aldosterone levels remain stable.

This explanation could account for the common "ndings of an increased aldosterone-to-renin ratio, caused not by increased aldoste-rone but by decreased renin, and by the presence of BAH in most nor-mokalemic hypertensive patients.

DIAGNOSIS. The three steps to the recommended evaluation of primary aldosteronism are screening, salt loading for biochemical con"r-mation, and adrenal vein sampling for localization.56 Screening involves

atherosclerotic renal artery stenosis. The availability of ACEIs and ARBs can be considered a double-edged sword; one edge provides better control of renovascular hypertension than may be possible with other antihypertensive medications, whereas the other edge exposes the already ischemic kidney to further loss of blood flow by inhibiting the high level of A II that was supporting its circulation. Other antihyper-tensive drugs may be almost as effective as ACEIs and perhaps safer, but there are no comparative data. Medically refractory hypertension and progressive decline in renal function (ischemic nephropathy) currently are the only two firm indications for balloon angioplasty. Renal artery stenting should be avoided because it is no more effective than medical management and can cause complications.53

Renin-Secreting TumorsComposed of juxtaglomerular cells or hemangiopericytomas, renin-secreting tumors occur mostly in young patients with severe hyperten-sion, with very high renin levels in both peripheral blood and the kidney harboring the tumor, and with secondary aldosteronism mani-fested by hypokalemia. The tumor can generally be recognized by selective renal angiography, usually performed for suspected renovas-cular hypertension, although a few are extrarenal. More commonly, children with Wilms tumors (nephroblastoma) may have hyperten-sion and high plasma renin and prorenin levels that revert to normal after nephrectomy.

Adrenal and Other Causes of Hypertension (see Chap. 86)

Adrenal causes of hypertension include primary excesses of aldoste-rone, cortisol, and catecholamines; more rarely, excess deoxycortico-sterone is present with congenital adrenal hyperplasia. Together, these conditions cause less than 1% of all hypertension in general practice, although primary aldosteronism accounts for 10% to 20% of patients referred to specialists for the evaluation of refractory hypertension. Each of these adrenal disorders can be recognized with relative ease, but they are easily overlooked because they are rare.

More problematic than the diagnosis of these adrenal disorders is the need to exclude their presence because of the increasing identi-fication of an incidental solitary adrenal mass on abdominal imaging with CT or MRI.54 An adrenal “incidentaloma” is found on about 5% of abdominal CT scans obtained for nonadrenal indications. Some advocate that these findings require screening for hormonal excess (see Table 45-3). Most of these incidentalomas appear to be nonfunc-tional on the basis of normal basal adrenal hormone levels. When more detailed studies are done, however, a significant number show incomplete suppression of cortisol by dexamethasone, that is, sub-clinical Cushing disease that does not appear to progress to overt hypercortisolism but may be associated with insulin resistance and osteopenia.

The probability of adrenal cancer varies by the imaging phenotype. The risk of cancer is low if a non–contrast-enhanced CT scan shows a tumor density of less than 10 HU, consistent with low-density lipid; if an MRI scan confirms a high lipid content by loss of signal on out-of-phase images; and if the tumor is smaller than 4 cm. Tumors 4 cm or larger should be resected because many are malignant.

Primary Aldosteronism and Other Forms of Mineralocorticoid-Induced HypertensionA number of syndromes with mineralocorticoid excess have been recognized (Table 45-5); primary aldosteronism is the most common. Debate continues about the prevalence of primary aldosteronism in an unselected hypertensive population, but most experts agree that the condition is common in patients with resistant hypertension.55 Moreover, in keeping with the profibrotic effects of aldosterone, many more cardiovascular events are seen in patients with primary aldoste-ronism than in patients with primary hypertension matched for age, gender, and BP levels.

TABLE 45-5 Syndromes of Mineralocorticoid ExcessAdrenal origin

Aldosterone excess (primary)Aldosterone-producing adenomaBilateral hyperplasiaPrimary unilateral adrenal hyperplasiaGlucocorticoid-remediable aldosteronism (familial hyperaldosteronism,

type I)Adrenal carcinomaExtra-adrenal tumors

Deoxycorticosterone excessDeoxycorticosterone-secreting tumorsCongenital adrenal hyperplasia11!-Hydroxylase de!ciency17$-Hydroxylase de!ciency

Cortisol excessCushing syndrome from ACTH-producing tumorGlucocorticoid receptor resistance

Renal originActivating mutation of mineralocorticoid receptorPseudohypoaldosteronism, type II (Gordon)11!-Hydroxysteroid dehydrogenase de!ciency

Congenital: apparent mineralocorticoid excessAcquired: licorice, carbenoxolone

FIGURE 45!15 Pathophysiology of primary hyperaldosteronism.

Hypertension

Suppressedrenin-angiotensin

Sodium reabsorption

Hyperaldosteronism

Potassium excretionPlasma volume

Hypokalemia

Hypernatremia

WeaknessParalysis

Metabolicalkalosis

Polyuria

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medication requirements in patients who may have coexisting primary hypertension or renal damage from prolonged exposure to elevated BP and undiagnosed hyperaldosteronism.

Cushing Syndrome (see Chap. 86)

Hypertension occurs in about 80% of patients with Cushing syndrome. If left untreated, it can cause marked LVH and congestive heart failure. As with hypertension of other endocrine causes, the longer it is present, the less likely it is to disappear when the underlying cause is relieved.

MECHANISM OF HYPERTENSION. BP can increase for a number of reasons. The secretion of mineralocorticoids can increase along with cor-tisol, which itself is a potent activator of the mineralocorticoid receptor. The excess cortisol can overwhelm the ability of renal 11!-OHSD2 to convert it to cortisone, which is not a mineralocorticoid receptor ligand; the excess cortisol overstimulates renal mineralocorticoid receptors to retain sodium and expand plasma volume. Cortisol stimulates the syn-thesis of renin substrate and the expression of A I receptors, which may be responsible for enhanced pressor e#ects.

DIAGNOSIS. The syndrome should be suspected in patients with truncal obesity, wide purple striae, thin skin, muscle weakness, and osteoporosis. If clinical features are suggestive, the diagnosis often can be either ruled out or virtually ensured by the measurement of free cortisol in a 24-hour urine sample, the simple overnight dexamethasone suppression test, or the determination of late-night salivary cortisol. Some cases of metabolic syndrome may be caused by subclinical Cushing syndrome.

THERAPY. In about two thirds of patients with Cushing syndrome, the process begins with overproduction of ACTH by the pituitary, which leads to BAH. Although pituitary hyperfunction may re!ect a

measurement of plasma renin and serum aldosterone. Despite the rec-ommendation by a few experts that virtually all hypertensive patients be screened by an aldosterone-to-renin ratio measurement, only 1% will have a surgically correctable adenoma.55 Moreover, if screening is done, rather than using a ratio that could be high only because of a low renin level, a positive result should be based on both an elevated plasma aldosterone level (above 15 ng/dL) and a suppressed low renin level.

Screening is recommended only for hypertensive subjects who have a higher likelihood of aldosterone-producing adenoma, including those with unprovoked hypokalemia or excessive hypokalemia on diuretic therapy, a family history of aldosteronism, resistant hypertension, or an adrenal incidentaloma. Hyperaldosteronism has been found in as many as 20% of patients with resistant hypertension, with half of these being unilateral and thus surgical candidates.55

If the screening plasma aldosterone and renin levels are suggestive, the next step is an oral salt-loading suppression to document the auton-omy of hyperaldosteronism. If the suppression test result is abnormal, adrenal vein sampling by an experienced tertiary center is strongly rec-ommended to di#erentiate unilateral adenoma from bilateral hyperpla-sia and to con"rm exactly which gland should be removed by laparoscopic surgery (see Fig. 45-e9 on website). Because detection of microscopic adenomas may be below the resolution of CT scanning and because minor adrenal nodularity and nonfunctioning adrenal incidentalomas are common, CT "ndings alone may lead to the wrong conclusion almost half of the time.57

DIFFERENTIAL DIAGNOSIS: MENDELIAN FORMS OF HYPERTENSION. In patients presenting with severe hypertension and hypokalemia, primary aldosteronism needs to be distinguished from rare forms of mineralocorticoid-induced hypertension that are inherited as mendelian traits. Clinical clues of syndromic hypertension are the premature onset (often before the age of 30 years), the severity of the hypertension (which is frequently dramatic), and a compelling family history indicative of mendelian inheritance. All these familial syndromes involve excessive activation of ENaC as a "nal common mechanism, caused either by gain-of-function mutations of ENaC or of the mineralocorticoid receptor, or by increased production or decreased clearance of the mineralocorticoid receptor ligands—aldosterone, as well as deoxycorticosterone and cor-tisol (Fig. 45-16).

One type, familial glucocorticoid-remediable aldosteronism, is caused by recombination of genes encoding the aldosterone synthase enzyme (CYP11B2), normally found only in the outer zona glomerulosa, and the 11!-hydroxylase enzyme (CYP11B1) in the zona fasciculata. The chimeric gene induces an enzyme that catalyzes the synthesis of 18-hydroxylated cortisol in the zona fasciculata. Because this zone is under the control of adrenocorticotropic hormone (ACTH), the glucocor-ticoid suppressibility of the syndrome is explained. The diagnosis should be made by genetic testing for the chimeric gene, and treatment should be provided with glucocorticoid suppression.

Another rare form is apparent mineralocorticoid excess caused by de"ciency of the enzyme 11!-hydroxysteroid dehydrogenase type 2 (11!-OHSD2) in the renal tubule, where it normally converts cortisol, which has the ability to act on the mineralocorticoid receptor, to corti-sone, which does not. Persistence of high levels of cortisol induces all the features of mineralocorticoid excess. The 11!-OHSD2 enzyme may be congenitally absent (the syndrome of apparent mineralocorticoid excess) or inhibited by the glycyrrhizic acid contained in licorice. Another unusual syndrome with hypertension and hypokalemia but suppressed mineralocorticoid secretion is Liddle syndrome, in which the kidney reabsorbs excess sodium and wastes potassium because of a mutation in the beta or gamma subunits of the epithelial sodium channel.

In most of these cases, volume expansion and severe hypertension cause feedback suppression of plasma renin, and mineralocorticoid receptor activation leads to renal potassium wasting and hypokalemia. One exception is pseudohypoaldosteronism type II, in which the disease-causing mutation produces both low-renin and salt-sensitive hyperten-sion caused by overactivity of the thiazide-sensitive Na-Cl cotransporter in the distal collecting duct and hyperkalemia caused by underactivity of the renal outer medullary potassium channel.

THERAPY. Once the diagnosis of primary aldosteronism is made and the type of adrenal disorder has been established, the choice of therapy is relatively simple. Patients with a solitary adenoma should have the tumor resected by laparoscopic surgery, and those with bilateral hyperplasia should be treated with an aldosterone antag-onist (spironolactone or eplerenone) and other antihypertensive drugs as needed. Laparoscopic adrenalectomy eliminates the need for antihypertensive medication in up to 50% of patients and reduces

FIGURE 45!16 Mendelian forms of hypertension that cause mineralocorticoid-induced hypertension. AME = apparent mineralocorticoid excess; A I = angio-tensin I; A II = angiotensin II; BP = blood pressure; GRA = glucocorticoid-remediable aldosteronism; 11!-OHSD2 = 11!-hydroxysteroid dehydrogenase type 2; DOC = deoxycorticosterone; ENaC = epithelial sodium channel; MR = mineralocorti-coid receptor; PHA2 = pseudohypoaldosteronism type II; ROMK = rectifying outer medullary potassium channel; WNK = with no lysine kinases; HEP = hyper-tension exacerbated by pregnancy; 11!HD = 11!-hydroxylase; 17$HD = 17$-hydroxylase. The e$ect of PHA2 on the activity of the thiazide-sensitive Na-Cl cotransporter in the distal collecting duct is not shown. See text for explanation. (Modi!ed from Lifton RP, Gharavi AG, Geller DS: Molecular mechanisms of human hypertension. Cell 104:545, 2001.)

AngiotensinogenRenin High BP

A I

A II

DOCAldosteroneGRA17!HD,11"HDdeficiencies

Na+

K+

Progesterone

HEP

Liddlesyndrome

AME

MR

Cortisol

ROMK

Cortical collecting duct

K+

Urine Blood

WNK1+4 PHA2

Cortisone

ENaCNa+

11"-OHSD2

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(e.g., cyclosporine, tacrolimus, erythropoietin), purchased over the counter (e.g., ephedra), and illicit (e.g., cocaine, methamphetamine). As previously noted, obstructive sleep apnea commonly causes sub-stantial, and often reversible, hypertension.

COARCTATION OF THE AORTA (see Chap. 65). Congenital narrow-ing of the aorta can occur at any level of the thoracic or abdominal aorta, but is typically found just beyond the origin of the left subclavian artery or distal to the insertion of the ligamentum arteriosum. With less severe postductal lesions, symptoms may not appear until the teenage years or later, particularly during pregnancy. Hypertension in the arms, weak or absent femoral pulses, and a loud murmur heard over the back are the classic features of coarctation. The pathogenesis of the hypertension can involve more than simple mechanical obstruc-tion and probably involves a generalized vasoconstrictor mechanism. The lesion can be detected by echocardiography, and MRI or contrast aortography proves the diagnosis. Once it is repaired, patients may continue to have hypertension that requires careful monitoring and treatment.

HORMONAL DISTURBANCES (see Chap. 86). Hypertension is seen in as many as half of patients with various hormonal disturbances, including acromegaly, hypothyroidism, and hyperparathyroidism. Diag-nosis of the last two conditions has been made easier by readily avail-able blood tests, and affected hypertensive patients can be relieved of their high BP by correction of the hormonal disturbance. Such relief occurs more frequently in patients with hypothyroidism than in those with hyperparathyroidism.

PERIOPERATIVE HYPERTENSION (see Chap. 85). Preexisting hypertension should be well controlled before elective surgery, with particular attention to correction of diuretic-induced hypokalemia. Antihypertensive agents should not be discontinued perioperatively, in particular to avoid rebound from beta blockers or clonidine. Fortu-nately, intravenous formulations of most classes are available if oral intake is not possible. Hypertension may appear or worsen in the perioperative period, perhaps more commonly with cardiac than with noncardiac surgery (Table 45-7). Hypertension is of particular concern after heart transplantation, appearing for a number of reasons, including immunosuppression with calcineurin inhibitors (cyclospo-rine and tacrolimus) and possibly cardiac denervation; treatment includes dihydropyridine calcium channel blockers, diuretics, and central sympatholytics.

Special Considerations for Hypertensive Diseases in Women (see Chap. 81)

Oral Contraceptive UseThe use of estrogen-containing oral contraceptive (OC) pills can cause secondary hypertension in young women. Most women who

TABLE 45-6 Features Suggestive of PheochromocytomaHypertension, Persistent or ParoxysmalMarkedly variable blood pressures (± orthostatic hypotension)Sudden paroxysms (± subsequent hypertension) in relation to

Stress: anesthesia, angiography, parturitionPharmacologic provocation: histamine, nicotine, ca$eine, beta blockers,

glucocorticoids, tricyclic antidepressantsManipulation of tumors: abdominal palpation, urination

Rare patients persistently normotensiveUnusual settings

Childhood, pregnancy, familialMultiple endocrine adenomas: medullary carcinoma of the thyroid

(MEN-2), mucosal neuromas (MEN-2B)Von Hippel–Lindau syndromeNeurocutaneous lesions: neuro!bromatosis

Associated SymptomsSudden spells with headache, sweating, palpitations, nervousness, nausea,

vomitingPain in chest or abdomen

Associated SignsSweating, tachycardia, arrhythmia, pallor, weight loss

TABLE 45-7 Hypertension Associated with Cardiac Surgery

PreoperativeAnxiety, angina, other manifestationsDiscontinuation of antihypertensive therapyRebound from beta blockers in patients with coronary artery disease

IntraoperativeInduction of anesthesia: tracheal intubationNasopharyngeal, urethral, or rectal manipulationBefore, during, or after cardiopulmonary bypass

PostoperativeObvious cause: hypoxia, hypercarbia, ventilatory di%culties, hypothermia,

shivering, arousal from anesthesiaWith no obvious cause: after myocardial revascularization; less frequently

after valve replacement; after resection of aortic coarctation

hypothalamic disorder, most patients have discrete pituitary adenomas that can usually be resected by selective transsphenoidal microsurgery.

If an adrenal tumor is present, it should be removed surgically. With earlier diagnosis and more selective surgical therapy, it is hoped that more patients with Cushing syndrome will be cured without a need for lifelong glucocorticoid replacement therapy and with permanent relief of their hypertension. Therapy may require one of a number of drugs temporarily, but rarely permanently.

CONGENITAL ADRENAL HYPERPLASIA. Enzymatic defects may induce hypertension by interfering with cortisol biosynthesis. Low levels of cor-tisol lead to increased ACTH levels; this increases the accumulation of precursors proximal to the enzymatic block, speci"cally deoxycorticoste-rone, which induces mineralocorticoid hypertension. The more common of these is 11-hydroxylase de"ciency, which has been attributed to various mutations in the gene and leads to virilization (from excessive androgens) and hypertension with hypokalemia (from excessive deoxy-corticosterone). The other is 17-hydroxylase de"ciency, which also causes hypertension from excess deoxycorticosterone, in addition to failure of secondary sexual development because sex hormones are also de"cient. A#ected children are hypertensive, but the defect in sex hormone syn-thesis may not become obvious until pubertal failure is recognized in adolescence.

Pheochromocytoma and Paraganglioma (see Chaps.

86 and 94)

Pheochromocytomas are rare catecholamine-secreting tumors of the adrenal chromaffin cells. Paragangliomas are even rarer extra-adrenal tumors of the sympathetic or vagal ganglion cells. For clinical pur-poses, the term pheo generally refers to any catecholamine-secreting tumor, whether a true adrenal pheochromocytoma or a functional extra-adrenal paraganglioma. The wild fluctuations in BP and dra-matic symptoms of pheo usually alert both the patient and physician to the possibility of this diagnosis (Table 45-6). However, such fluctuations may be missed or, as occurs in 50% of patients, the hyper-tension may be persistent. On one hand, the spells typical of a pheochromocytoma (with headache, sweating, palpitations, and pallor) may be incorrectly attributed to migraine, menopause, or panic attacks. On the other hand, most patients with severe paroxys-mal hypertension do not have a pheochromocytoma but rather marked anxiety. When they are correctly diagnosed and treated, most pheos are curable. When they are undiagnosed or improperly treated, they can be fatal.58 See Chap. 86 for details regarding the pathophysiol-ogy, diagnosis, and treatment of pheochromocytoma.

Other Causes of HypertensionA host of other causes of hypertension are known. One that is probably becoming more common is the ingestion of various drugs—prescribed

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trimester, so that hypertension present before pregnancy may not be recognized.

MECHANISMS. The hemodynamic features of gestational hyperten-sion are a further rise in cardiac output than is usually seen in normal pregnancy, accompanied by profound vasoconstriction that reduces intravascular capacity even more than blood volume, which may reflect increased central and peripheral sympathetic activity. Increas-ingly strong evidence has indicated that preeclampsia starts from immune maladaptation leading to inadequate placentation; this results in reduced angiogenic growth factors and increased placental debris entering the maternal circulation, where it provokes a maternal inflammatory response with hypertension.60 The mother may be par-ticularly vulnerable to encephalopathy because of her previously normal BP. As described in more detail later (see Hypertensive Crisis), cerebral blood flow is normally maintained constant over a fairly narrow range of mean arterial pressure, roughly between 60 and 100 mm Hg in normotensive individuals. In a previously normotensive young woman, an acute rise in BP to 150/100 mm Hg can exceed the upper limit of autoregulation and result in a breakthrough of cerebral blood flow (acute dilation) that leads to cerebral edema and convulsions.

PREVENTION AND TREATMENT. Beyond delay of pregnancy until after the teenage years and better prenatal care, the only other effective strategy to prevent preeclampsia is the use of low doses of aspirin. The only cure for preeclampsia is delivery, which removes the diseased placenta. To achieve this apparently simple end, the clini-cian must detect the often-symptomless prodromal condition by screening all pregnant women, admitting those with advanced pre-eclampsia to the hospital so as to keep track of an unpredictable situ-ation, and timing preemptive delivery to maximize the safety of mother and baby. Caution is advised in the use of drugs for gestational hypertension; it is traditionally limited to methyldopa in the United States, but other drugs are used elsewhere. Drug treatment of maternal BP does not improve perinatal outcome and may be associated with fetal growth retardation. Most authorities recommend antihyperten-sive drugs only if diastolic pressures remain above 100 mm Hg. The only drugs contraindicated are ACEIs and ARBs because of their pro-pensity to induce neonatal renal failure.

CHRONIC HYPERTENSION. If pregnancy begins while a woman is receiving antihypertensive drug therapy, medications including diuretics but excluding ACEIs and ARBs are usually continued, in the belief that the mother should be protected and that the fetus will not suffer from any sudden hemodynamic shifts that occur when therapy is first begun. However, despite currently available treatment, the

take them experience a slight rise in BP. Moreover, newer progestins such as drospirenone contain a spironolactone-like moiety with mild mineralocorticoid antagonist action; as a result, drospirenone-estrogen combinations generally cause a small decrease in BP.59

CLINICAL FEATURES. In most women, the hypertension is mild, but in some it may accelerate rapidly and cause severe renal damage. When use of the OC is discontinued, BP falls to normal within 3 to 6 months in about 50% of patients. Whether the OC causes permanent hypertension in the other half or just uncovers primary hypertension at an earlier time is not clear.

MECHANISMS. OC use probably causes hypertension by volume expansion because estrogens and some synthetic progestogens used in OC pills cause sodium retention. Although plasma renin levels rise in response to increased levels of angiotensinogen, ACEIs do not alter BP any more in women with OC-induced hypertension than in women with primary hypertension. Drospirenone-containing OC pills may cause a reactive rise in serum aldosterone.

MANAGEMENT. The use of estrogen-containing OCs should be restricted in women older than 35 years, particularly if they also smoke or are hypertensive or obese. Drospirenone-containing OC pills are a better alternative. Women given OCs should be monitored as follows: the initial supply should be limited; they should be asked to return for a BP check before an additional supply is provided; and if BP has risen, an alternative contraceptive method should be offered. If OC remains the only acceptable contraceptive method, the elevated BP can be reduced with appropriate therapy. In women who stop taking OCs, evaluation for secondary hypertensive diseases should be post-poned for at least 3 months to allow changes in the RAAS to remit. If the hypertension does not recede, additional workup and therapy may be needed.

Postmenopausal Sex Hormone TherapyEstrogen therapy does not appear to induce hypertension, although it does induce the various changes in the RAAS seen with oral contra-ceptive use. In fact, most controlled trials have found a decrease in daytime ambulatory BP and a greater dipping of nocturnal BP in users of estrogen replacement therapy. Such lower BPs may reflect a number of effects, including improved endothelium-dependent vaso-dilation and reduced muscle sympathetic nerve activity.

Hypertension During Pregnancy (see Chap. 82)

In about 12% of first pregnancies in previously normotensive women, hypertension appears after 20 weeks (gestational hypertension). In about half of cases, this hypertension will progress to preeclampsia when it is complicated by proteinuria, edema, or hematologic or hepatic abnormalities, which in turn increase the risk of progress to eclampsia, defined by the occurrence of convulsions.60 Women with hypertension predating pregnancy have an even higher incidence of preeclampsia and a greater likelihood of early delivery of small-for-gestational-age babies. Additional predisposing factors include young or older age, multiple gestations, concomitant heart or renal disease, and chronic hypertension.60 The diagnosis is usually based on a rise in pressure of 30/15 mm Hg or more to a level above 140/90 mm Hg. As with other forms of hypertension, ambulatory BP monitoring makes the diagnosis most precisely.

CLINICAL FEATURES. The features shown in Table 45-8 should help distinguish gestational hypertension and preeclampsia from chronic primary hypertension; the distinction should be made because management and prognosis are different. Gestational hyper-tension is self-limited and less commonly recurs in subsequent preg-nancies, whereas chronic hypertension progresses and usually complicates subsequent pregnancies. Differentiation may be difficult because of a lack of knowledge of the pre-pregnancy BP and because of the usual tendency for BP to fall considerably during the middle

TABLE 45-8 Di'erences Between Preeclampsia and Chronic Hypertension

FEATURE PREECLAMPSIACHRONIC

HYPERTENSION

Age Young (<20 years) Older (>30 years)

Parity Primigravida Multigravida

Onset After 20 weeks of pregnancy

Before 20 weeks of pregnancy

Weight gain and edema Sudden Gradual

Systolic blood pressure <160 mm Hg >160 mm Hg

Funduscopic !ndings Spasm, edema Arteriovenous nicking, exudates

Left ventricular hypertrophy Rare More common

Proteinuria Present Absent

Plasma uric acid level Increased Normal

Blood pressure after delivery Normal Elevated

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IncidenceLess than 1% of patients with primary hypertension progress to an accelerated-malignant phase. The incidence probably has receded because of more widespread treatment of hypertension. Any hyper-tensive disease can be manifested as a crisis. Some, including pheo-chromocytoma and renovascular hypertension, do so at a higher rate than that seen with primary hypertension. However, because hyper-tension is of unknown cause in more than 90% of all patients, most hypertensive crises appear in the setting of preexisting primary hypertension.

PathophysiologyWhenever BP rises and remains above a critical level, various pro-cesses set off a series of local and systemic effects that cause further rises in pressure and vascular damage, eventually resulting in accelerated-malignant hypertension. Classic studies in animals and humans elucidated the mechanism of hypertensive encephalopathy. The caliber of pial arterioles over the cerebral cortex was measured in normotensive cats whose BP was varied over a wide range of infu-sion by vasodilators or A II. As the pressure fell, the arterioles became dilated; as the pressure rose, they became constricted. Thus, constant cerebral blood flow was maintained by means of autoregulation, which depends on the cerebral sympathetic nerves. However, when mean arterial pressure rose above 180 mm Hg (i.e., 220/110), the tightly constricted vessels could no longer withstand the pressure and suddenly dilated. The dilation began in an irregular manner, first in areas with less muscle tone and then diffusely, with production of generalized vasodilation. This breakthrough of cerebral blood flow hyperperfuses the brain under high pressure and causes leakage of fluid into the perivascular tissue, resulting in cerebral edema and the syndrome of hypertensive encephalopathy.

In humans, cerebral blood flow has been measured repetitively by an isotopic technique while BP was lowered or raised with vasodila-tors or vasoconstrictors in a manner similar to that used in animal studies. Curves depicting cerebral blood flow as a function of arterial pressure demonstrated autoregulation, with a constancy of flow over mean pressures in normotensive persons from about 60 to 120 mm Hg and in hypertensive patients from about 110 to 180 mm Hg (Fig. 45-17). This shift to the right in hypertensive patients results from structural thickening of the arterioles as an adaptation to the chroni-cally elevated pressure. When pressure was raised beyond the upper limit of autoregulation, the same breakthrough with hyperperfusion occurred as was seen in the animal studies. In previously normoten-sive persons whose vessels have not been altered by prior exposure to high pressure, breakthrough occurred at a mean arterial pressure

incidence of perinatal mortality and fetal growth restriction remains higher in patients with chronic hypertension.

MANAGEMENT OF ECLAMPSIA. With appropriate care of gesta-tional hypertension, eclampsia hardly ever supervenes; when it does, however, maternal and fetal mortality increase markedly. Excellent results have been reported with the use of magnesium sulfate to prevent and to treat convulsions.60 Caution is needed to avoid volume overload because pulmonary edema is the most common cause of maternal mortality. Compared with women who were normotensive, the overall prognosis for women who had hypertension during preg-nancy is not as good, probably because of causes other than pre-eclampsia, including unrecognized chronic primary hypertension. After delivery, transient or persistent hypertension can develop in the mother. In many cases, early primary hypertension may have been masked by the hemodynamic changes of pregnancy.

Hypertensive CrisisDefinitionsA number of clinical circumstances require prompt reduction of BP (Table 45-9). These circumstances can be separated into emergen-cies, which require immediate (but controlled) reduction of BP (within 1 hour), and urgencies, which can be treated more slowly. A persistent diastolic pressure exceeding 130 mm Hg is often associated with acute vascular damage; some patients may suffer vascular damage from lower levels of pressure, whereas others are able to withstand even higher levels without apparent harm. The rapidity of the rise may be more important than the absolute level in producing acute vascular damage, as explained later. Therefore, in practice, all patients with diastolic BP above 130 mm Hg should be treated, some more rapidly with parenteral drugs and others more slowly with oral agents. When the rise in pressure causes retinal hemorrhages, exu-dates, or papilledema, the term accelerated-malignant hypertension is used. Hypertensive encephalopathy is characterized by headache, irritability, alterations in consciousness, and other manifestations of central nervous dysfunction with sudden and marked elevations in BP.

TABLE 45-9 Circumstances Requiring Rapid Treatment of Hypertension

Accelerated-malignant hypertension with papilledemaCerebrovascular

Hypertensive encephalopathyAtherothrombotic brain infarction with severe hypertensionIntracerebral hemorrhageSubarachnoid hemorrhage

CardiacAcute aortic dissectionAcute left ventricular failureAcute or impending myocardial infarctionAfter coronary bypass surgery

RenalAcute glomerulonephritisRenal crises from collagen-vascular diseasesSevere hypertension after kidney transplantation

Excessive circulating catecholaminesPheochromocytoma crisisFood or drug interactions with monoamine oxidase inhibitorsSympathomimetic drug use (cocaine)Rebound hypertension after sudden cessation of antihypertensive drugs

EclampsiaSurgical

Severe hypertension in patients requiring immediate surgeryPostoperative hypertensionPostoperative bleeding from vascular suture lines

Severe body burnsSevere epistaxisThrombotic thrombocytopenic purpura

FIGURE 45!17 Idealized curves of cerebral blood "ow at varying levels of systemic blood pressure in normotensive and hypertensive subjects. A right-ward shift in autoregulation is shown with chronic hypertension. (Modi!ed from Strandgaard S, Olesen J, Skinhtoi E, Lassen NA: Autoregulation of brain circulation in severe arterial hypertension. Br Med J 1:507, 1973.)

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7. Chen L, Davey SG, Harbord RM, Lewis SJ: Alcohol intake and blood pressure: A systematic review implementing a Mendelian randomization approach. PLoS Med 5:e52, 2008.

8. Adrogue HJ, Madias NE: Sodium and potassium in the pathogenesis of hypertension. N Engl J Med 356:1966, 2007.

9. Ehret GB, Morrison AC, O’Connor AA, et al: Replication of the Wellcome Trust genome-wide association study of essential hypertension: The Family Blood Pressure Program. Eur J Hum Genet 16:1507, 2008.

10. Levy D, Ehret GB, Rice K, et al: Genome-wide association study of blood pressure and hypertension. Nat Genet 41:677, 2009.

10a. Newton-Cheh C, Johnson T, Gateva V, et al: Genome-wide association study identi"es eight loci associated with blood pressure. Nat Genet 41:666, 2009.

10b. Ji W, Foo JN, O’Roak BJ, et al: Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet 40:592, 2008.

11. McEniery CM, Yasmin, Wallace S, et al: Increased stroke volume and aortic sti#ness contribute to isolated systolic hypertension in young adults. Hypertension 46:221, 2005.

12. Franklin SS, Pio JR, Wong ND, et al: Predictors of new-onset diastolic and systolic hypertension: The Framingham Heart Study. Circulation 111:1121, 2005.

13. Franklin SS: Hypertension in older people: Part 1: J Clin Hypertens (Greenwich) 8:444, 2006.14. Agabiti-Rosei E, Mancia G, O’Rourke MF, et al: Central blood pressure measurements and

antihypertensive therapy: A consensus document. Hypertension 50:154, 2007.

Pathophysiology of Hypertension15. Victor RG, Sha"q MM: Sympathetic neural mechanisms in human hypertension. Curr Hypertens

Rep 10:241, 2008.16. Mohaupt MG, Schmidli J, Luft FC: Management of uncontrollable hypertension with a carotid

sinus stimulation device. Hypertension 50:825, 2007.17. Krum H, Schlaich M, Whitbourn R, et al: Catheter-based renal sympathetic denervation for

resistant hypertension: A multicentre safety and proof-of-principle cohort study. Lancet 373:1275, 2009.

18. Grassi G, Seravalle G, Quarti-Trevano F, et al: Sympathetic and barore!ex cardiovascular control in hypertension-related left ventricular dysfunction. Hypertension 53:205, 2009.

19. Landsberg L: A teleological view of obesity, diabetes and hypertension. Clin Exp Pharmacol Physiol 33:863, 2006.

20. Mark AL; Dietary therapy for obesity: An emperor with no clothes. Hypertension 51:1426, 2008.

21. Butt M, Dwivedi G, Khair O, Lip GY: Obstructive sleep apnea and cardiovascular disease. Int J Cardiol 139:7, 2010. Epub 2009 Jun 7.

22. He FJ, MacGregor GA: Salt, blood pressure and cardiovascular disease. Curr Opin Cardiol 22:298, 2007.

23. Rodriguez-Iturbe B, Romero F, Johnson RJ: Pathophysiological mechanisms of salt-dependent hypertension. Am J Kidney Dis 50:655, 2007.

24. Bergvall N, Iliadou A, Johansson S, et al: Genetic and shared environmental factors do not confound the association between birth weight and hypertension: A study among Swedish twins. Circulation 115:2931, 2007.

25. Kao WH, Klag MJ, Meoni LA, et al: MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat Genet 40:1185, 2008.

26. Munzel T, Sinning C, Post F, et al: Pathophysiology, diagnosis and prognostic implications of endothelial dysfunction. Ann Med 40:180, 2008.

27. Ridker PM, Silvertown JD: In!ammation, C-reactive protein, and atherothrombosis. J Periodontol 79(Suppl):1544, 2008.

28. Harrison DG, Gongora MC: Oxidative stress and hypertension. Med Clin North Am 93:621, 2009.

29. Feig DI, Soletsky B, Johnson RJ: E#ect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: A randomized trial. JAMA 300:924, 2008.

30. Duprez DA: Role of the renin-angiotensin-aldosterone system in vascular remodeling and in!ammation: A clinical review. J Hypertens 24:983, 2006.

31. Schi#rin EL: E#ects of aldosterone on the vasculature: Hypertension 47:312, 2006.32. Danser AH: Prorenin: Back into the arena. Hypertension 47:824, 2006.33. Feldt S, Batenburg WW, Mazak I, et al: Prorenin and renin-induced extracellular signal-regulated

kinase 1/2 activation in monocytes is not blocked by aliskiren or the handle-region peptide. Hypertension 51:682, 2008.

34. Harrison DG, Guzik TJ, Goronzy J, Weyand C: Is hypertension an immunologic disease? Curr Cardiol Rep 10:464, 2008.

35. Hill JA, Olson EN: Cardiac plasticity. N Engl J Med 358:1370, 2008.36. Gradman AH, Alfayoumi F: From left ventricular hypertrophy to congestive heart failure:

Management of hypertensive heart disease. Prog Cardiovasc Dis 48:326, 2006.37. Parati G, Stergiou GS, Asmar R, et al: European Society of Hypertension guidelines for blood

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38. Pickering TG, Miller NH, Ogedegbe G, et al: Call to action on use and reimbursement for home blood pressure monitoring: A joint scienti"c statement from the American Heart Association, American Society of Hypertension, and Preventive Cardiovascular Nurses Association. J Cardiovasc Nurs 23:299, 2008.

39. Dolan E, Stanton A, Thijs L, et al: Superiority of ambulatory over clinic blood pressure measurement in predicting mortality: The Dublin outcome study. Hypertension 46:156, 2005.

40. Messerli FH, Williams B, Ritz E: Essential hypertension. Lancet 370:591, 2007.41. Mancia G, De Backer G, Dominiczak A, et al: 2007 Guidelines for the Management of Arterial

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of about 120 mm Hg (i.e., 140/80 mm Hg); in hypertensive patients, the breakthrough occurred at about 180 mm Hg (i.e., 220/110 mm Hg).

These studies have confirmed clinical observations. In previously normotensive persons, severe encephalopathy occurs with relatively little hypertension. In children with acute glomerulonephritis and in women with eclampsia, convulsions can occur as a result of hyper-tensive encephalopathy, with BP readings as low as 150/100 mm Hg. Obviously, chronically hypertensive patients withstand such pressures without difficulty, but when pressure increases significantly, encepha-lopathy can develop even in these patients.

Manifestations and CourseThe symptoms and signs of hypertensive crises are usually dramatic (Table 45-10), probably reflecting acute damage to endothelium and platelet activation. However, some patients may be relatively asymp-tomatic, despite markedly elevated pressure and extensive organ damage. Young black men are particularly prone to hypertensive crisis, with severe renal insufficiency. Even in elderly persons, however, hypertension can initially present in an accelerated-malignant phase. If left untreated, patients die quickly of brain damage or more gradually of renal damage. Before effective therapy was avail-able, less than 25% of patients with malignant hypertension survived 1 year and only 1% survived 5 years. With therapy, including renal dialysis, more than 90% survive 1 year and about 80% survive 5 years.

Differential DiagnosisThe presence of hypertensive encephalopathy or accelerated-malignant hypertension demands immediate aggressive therapy to lower BP effectively, often before the specific cause is known. However, certain serious diseases and psychological problems can mimic a hypertensive crisis, and management of these conditions usually requires different diagnostic and therapeutic approaches. In particular, BP should not be lowered too abruptly, if at all, in a patient with a stroke.61 See Chap. 46 for specific therapy for hyperten-sive crises.

Future PerspectivesThe measurement of BP will become more accurate for diagnosis and cardiovascular risk stratification with the greater use of out-of-office measurements and assessments of vascular health by measures of vascular compliance, central aortic pressure, and inflammatory bio-markers. Future research on underlying mechanisms of primary hyper-tension should aim to make treatment less empiric and more effective than current practice.

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TABLE 45-10 Clinical Characteristics of Hypertensive Crisis

Blood pressure: usually >140 mm Hg diastolicFunduscopic !ndings: hemorrhages, exudates, papilledemaCardiac !ndings: prominent apical impulse, cardiac enlargement,

congestive heart failureRenal !ndings: oliguria, azotemiaGastrointestinal !ndings: nausea, vomitingHematologic !ndings: microangiopathic hemolysis

CH 45

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