298: Hypertensive Vascular Disease

Hypertension is one of the leading causes of the global burden of disease. Approximately 7.6 million deaths (13–15% of the total) and 92 million disability-adjusted life years worldwide were attributable to high blood pressure in 2001. Hypertension doubles the risk of cardiovascular diseases, including coronary heart disease (CHD), congestive heart failure (CHF), ischemic and hemorrhagic stroke, renal failure, and peripheral arterial disease. It often is associated with additional cardiovascular disease risk factors, and the risk of cardiovascular disease increases with the total burden of risk factors. Although antihypertensive therapy reduces the risks of cardiovascular and renal disease, large segments of the hypertensive population are either untreated or inadequately treated.

Blood pressure levels, the rate of age-related increases in blood pressure, and the prevalence of hypertension vary among countries and among subpopulations within a country. Hypertension is present in all populations except for a small number of individuals living in developing countries. In industrialized societies, blood pressure increases steadily during the first two decades of life. In children and adolescents, blood pressure is associated with growth and maturation. Blood pressure “tracks” over time in children and between adolescence and young adulthood. In the United States, average systolic blood pressure is higher for men than for women during early adulthood, although among older individuals the age-related rate of rise is steeper for women. Consequently, among individuals age 60 and older, systolic blood pressures of women are higher than those of men. Among adults, diastolic blood pressure also increases progressively with age until ∼55 years, after which it tends to decrease. The consequence is a widening of pulse pressure (the difference between systolic and diastolic blood pressure) beyond age 60.

In the United States, based on results of the National Health and Nutrition Examination Survey (NHANES), approximately 30% (age-adjusted prevalence) of adults, or at least 65 million individuals, have hypertension (defined as any one of the following: systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, taking antihypertensive medications). Hypertension prevalence is 33.5% in non-Hispanic blacks, 28.9% in non-Hispanic whites, and 20.7% in Mexican Americans. The likelihood of hypertension increases with age, and among individuals age ≥60, the prevalence is 65.4%. Recent evidence suggests that the prevalence of hypertension in the United States may be increasing, possibly as a consequence of increasing obesity. The prevalence of hypertension and stroke mortality rates are higher in the southeastern United States than in other regions. In African Americans, hypertension appears earlier, is generally more severe, and results in higher rates of morbidity and mortality from stroke, left ventricular hypertrophy, CHF, and end-stage renal disease (ESRD) than in white Americans.

Both environmental and genetic factors may contribute to regional and racial variations in hypertension prevalence. Studies of societies undergoing “acculturation” and studies of migrants from a less to a more urbanized setting indicate a profound environmental contribution to blood pressure. Obesity and weight gain are strong, independent risk factors for hypertension. It has been estimated that 60% of hypertensives are >20% overweight. Among populations, hypertension prevalence is related to dietary NaCl intake, and the age-related increase in blood pressure may be augmented by a high NaCl intake. Low dietary intakes of calcium and potassium also may contribute to the risk of hypertension. The urine sodium-to-potassium ratio (an index of both sodium and potassium intakes) is a stronger correlate of blood pressure than is either sodium or potassium alone. Alcohol consumption, psychosocial stress, and low levels of physical activity also may contribute to hypertension.

Adoption, twin, and family studies document a significant heritable component to blood pressure levels and hypertension. Family studies controlling for a common environment indicate that blood pressure heritabilities are in the range 15–35%. In twin studies, heritability estimates of blood pressure are ∼60% for males and 30–40% for females. High blood pressure before age 55 occurs 3.8 times more frequently among persons with a positive family history of hypertension. However, to date, only a fraction of high heritability estimates are accounted for by specific genetic determinants.

GENETIC CONSIDERATIONS

Although specific genetic variants have been identified in rare Mendelian forms of hypertension (Table 298–5), these variants are not applicable to the vast majority (>98%) of patients with hypertension. For most individuals, it is likely that hypertension represents a polygenic disorder in which a combination of genes acts in concert with environmental exposures to make only a modest contribution to blood pressure. Further, different subsets of genes may lead to different phenotypes associated with hypertension, e.g., obesity, dyslipidemia, insulin resistance.

Several strategies are being used in the search for specific hypertension-related genes. Animal models (including selectively bred rats and congenic rat strains) provide a powerful approach for evaluating genetic loci and genes associated with hypertension. Comparative mapping strategies allow for the identification of syntenic genomic regions between the rat and human genomes that may be involved in blood pressure regulation. In association studies, different alleles (or combinations of alleles at different loci) of specific candidate genes or chromosomal regions are compared in hypertensive patients and normotensive control subjects. Current evidence suggests that genes that encode components of the renin-angiotensin-aldosterone system, along with angiotensinogen and angiotensin-converting enzyme (ACE) polymorphisms, may be related to hypertension and to blood pressure sensitivity to dietary NaCl. The alpha-adducin gene is thought to be associated with increased renal tubular absorption of sodium, and variants of this gene may be associated with hypertension and salt sensitivity of blood pressure. Other genes possibly related to hypertension include genes encoding the AT₁ receptor, aldosterone synthase, atrial natriuretic peptide, and the β₂ adrenoreceptor. Genomewide association studies involve rapidly scanning markers across the entire genome to identify loci (not specific genes) associated with an observable trait (e.g., blood pressure) or a particular disease. This strategy has been facilitated by the availability of dense genotyping chips and the International HapMap. Results of candidate gene studies often have not been replicated, and in contrast to several other polygenic disorders, genomewide association studies have had limited success in identifying genetic determinants of hypertension.

Preliminary evidence suggests that there may also be genetic determinants of target organ damage attributed to hypertension. Family studies indicate significant heritability of left ventricular mass, and there is considerable individual variation in the responses of the heart to hypertension. Family studies and variations in candidate genes associated with renal damage suggest that genetic factors also may contribute to hypertensive nephropathy. Specific genetic variants have been linked to CHD and stroke.

In the future, it is possible that DNA analysis will predict individual risk for hypertension and target organ damage and will identify responders to specific classes of antihypertensive agents. However, with the exception of the rare, monogenic hypertensive diseases, the genetic variants associated with hypertension remain to be confirmed, and the intermediate steps by which these variants affect blood pressure remain to be determined.

To provide a framework for understanding the pathogenesis of and treatment options for hypertensive disorders, it is useful to understand factors involved in the regulation of both normal and elevated arterial pressure. Cardiac output and peripheral resistance are the two determinants of arterial pressure (Fig. 298-1). Cardiac output is determined by stroke volume and heart rate; stroke volume is related to myocardial contractility and to the size of the vascular compartment. Peripheral resistance is determined by functional and anatomic changes in small arteries (lumen diameter 100–400 μm) and arterioles.

INTRAVASCULAR VOLUME

Sodium is predominantly an extracellular ion and is a primary determinant of the extracellular fluid volume. When NaCl intake exceeds the capacity of the kidney to excrete sodium, vascular volume may initially expand and cardiac output may increase. However, many vascular beds have the capacity to autoregulate blood flow, and if constant blood flow is to be maintained in the face of increased arterial pressure, resistance within that bed must increase, since

The initial elevation of blood pressure in response to vascular volume expansion may be related to an increase of cardiac output; however, over time, peripheral resistance increases and cardiac output reverts toward normal. Whether this hypothesized sequence of events occurs in the pathogenesis of hypertension is not clear. What is clear is that salt can activate a number of neural, endocrine/paracrine, and vascular mechanisms, all of which have the potential to increase arterial pressure. The effect of sodium on blood pressure is related to the provision of sodium with chloride; nonchloride salts of sodium have little or no effect on blood pressure. As arterial pressure increases in response to a high NaCl intake, urinary sodium excretion increases and sodium balance is maintained at the expense of an increase in arterial pressure. The mechanism for this “pressure-natriuresis” phenomenon may involve a subtle increase in the glomerular filtration rate, decreased absorbing capacity of the renal tubules, and possibly hormonal factors such as atrial natriuretic factor. In individuals with an impaired capacity to excrete sodium, greater increases in arterial pressure are required to achieve natriuresis and sodium balance.

NaCl-dependent hypertension may be a consequence of a decreased capacity of the kidney to excrete sodium, due either to intrinsic renal disease or to increased production of a salt-retaining hormone (mineralocorticoid) resulting in increased renal tubular reabsorption of sodium. Renal tubular sodium reabsorption also may be augmented by increased neural activity to the kidney. In each of these situations, a higher arterial pressure may be required to achieve sodium balance. Conversely, salt-wasting disorders are associated with low blood pressure levels. ESRD is an extreme example of volume-dependent hypertension. In ∼80% of these patients, vascular volume and hypertension can be controlled with adequate dialysis; in the other 20%, the mechanism of hypertension is related to increased activity of the renin-angiotensin system and is likely to be responsive to pharmacologic blockade of renin-angiotensin.

AUTONOMIC NERVOUS SYSTEM

Adrenergic reflexes modulate blood pressure over the short term, and adrenergic function, in concert with hormonal and volume-related factors, contributes to the long-term regulation of arterial pressure. Norepinephrine, epinephrine, and dopamine all play important roles in tonic and phasic cardiovascular regulation.

The activities of the adrenergic receptors are mediated by guanosine nucleotide-binding regulatory proteins (G proteins) and by intracellular concentrations of downstream second messengers. In addition to receptor affinity and density, physiologic responsiveness to catecholamines may be altered by the efficiency of receptor-effector coupling at a site “distal” to receptor binding. The receptor sites are relatively specific both for the transmitter substance and for the response that occupancy of the receptor site elicits. Based on their physiology and pharmacology, adrenergic receptors have been divided into two principal types: α and β. These types have been differentiated further into α₁, α₂, β₁, and β₂ receptors. Recent molecular cloning studies have identified several additional subtypes. α Receptors are occupied and activated more avidly by norepinephrine than by epinephrine, and the reverse is true for β receptors. α₁ Receptors are located on postsynaptic cells in smooth muscle and elicit vasoconstriction. α₂ Receptors are localized on presynaptic membranes of postganglionic nerve terminals that synthesize norepinephrine. When activated by catecholamines, α₂ receptors act as negative feedback controllers, inhibiting further norepinephrine release. In the kidney, activation of α₁-adrenergic receptors increases renal tubular reabsorption of sodium. Different classes of antihypertensive agents either inhibit α₁ receptors or act as agonists of α₂ receptors and reduce systemic sympathetic outflow. Activation of myocardial β₁ receptors stimulates the rate and strength of cardiac contraction and consequently increases cardiac output. β₁ Receptor activation also stimulates renin release from the kidney. Another class of antihypertensive agents acts by inhibiting β₁ receptors. Activation of β₂ receptors by epinephrine relaxes vascular smooth muscle and results in vasodilation.

Circulating catecholamine concentrations may affect the number of adrenoreceptors in various tissues. Downregulation of receptors may be a consequence of sustained high levels of catecholamines and provides an explanation for decreasing responsiveness, or tachyphylaxis, to catecholamines. For example, orthostatic hypotension frequently is observed in patients with pheochromocytoma, possibly due to the lack of norepinephrine-induced vasoconstriction with assumption of the upright posture. Conversely, with chronic reduction of neurotransmitter substances, adrenoreceptors may increase in number or be upregulated, resulting in increased responsiveness to the neurotransmitter. Chronic administration of agents that block adrenergic receptors may result in upregulation, and abrupt withdrawal of those agents may produce a condition of temporary hypersensitivity to sympathetic stimuli. For example, clonidine is an antihypertensive agent that is a centrally acting α₂ agonist that inhibits sympathetic outflow. Rebound hypertension may occur with the abrupt cessation of clonidine therapy, probably as a consequence of upregulation of α₁ receptors.

Several reflexes modulate blood pressure on a minute-to-minute basis. One arterial baroreflex is mediated by stretch-sensitive sensory nerve endings in the carotid sinuses and the aortic arch. The rate of firing of these baroreceptors increases with arterial pressure, and the net effect is a decrease in sympathetic outflow, resulting in decreases in arterial pressure and heart rate. This is a primary mechanism for rapid buffering of acute fluctuations of arterial pressure that may occur during postural changes, behavioral or physiologic stress, and changes in blood volume. However, the activity of the baroreflex declines or adapts to sustained increases in arterial pressure such that the baroreceptors are reset to higher pressures. Patients with autonomic neuropathy and impaired baroreflex function may have extremely labile blood pressures with difficult-to-control episodic blood pressure spikes associated with tachycardia.

In both normal-weight and obese individuals, hypertension often is associated with increased sympathetic outflow. Based on recordings of postganglionic muscle nerve activity (detected by a microelectrode inserted in a peroneal nerve in the leg), sympathetic outflow tends to be higher in hypertensive than in normotensive individuals. Sympathetic outflow is increased in obesity-related hypertension and in hypertension associated with obstructive sleep apnea. Baroreceptor activation via electrical stimulation of carotid sinus afferent nerves lowers blood pressure in patients with “resistant” hypertension. Drugs that block the sympathetic nervous system are potent antihypertensive agents, indicating that the sympathetic nervous system plays a permissive, although not necessarily a causative, role in the maintenance of increased arterial pressure.

Pheochromocytoma is the most blatant example of hypertension related to increased catecholamine production, in this instance by a tumor. Blood pressure can be reduced by surgical excision of the tumor or by pharmacologic treatment with an α₁ receptor antagonist or with an inhibitor of tyrosine hydroxylase, the rate-limiting step in catecholamine biosynthesis.

RENIN-ANGIOTENSIN-ALDOSTERONE

The renin-angiotensin-aldosterone system contributes to the regulation of arterial pressure primarily via the vasoconstrictor properties of angiotensin II and the sodium-retaining properties of aldosterone. Renin is an aspartyl protease that is synthesized as an enzymatically inactive precursor, prorenin. Most renin in the circulation is synthesized in the renal afferent renal arteriole. Prorenin may be secreted directly into the circulation or may be activated within secretory cells and released as active renin. Although human plasma contains two to five times more prorenin than renin, there is no evidence that prorenin contributes to the physiologic activity of this system. There are three primary stimuli for renin secretion: (1) decreased NaCl transport in the distal portion of the thick ascending limb of the loop of Henle that abuts the corresponding afferent arteriole (macula densa), (2) decreased pressure or stretch within the renal afferent arteriole (baroreceptor mechanism), and (3) sympathetic nervous system stimulation of renin-secreting cells via β₁ adrenoreceptors. Conversely, renin secretion is inhibited by increased NaCl transport in the thick ascending limb of the loop of Henle, by increased stretch within the renal afferent arteriole, and by β₁ receptor blockade. In addition, angiotensin II directly inhibits renin secretion due to angiotensin II type 1 receptors on juxtaglomerular cells, and renin secretion increases in response to pharmacologic blockade of either ACE or angiotensin II receptors.

Once released into the circulation, active renin cleaves a substrate, angiotensinogen, to form an inactive decapeptide, angiotensin I (Fig. 298-2). A converting enzyme, located primarily but not exclusively in the pulmonary circulation, converts angiotensin I to the active octapeptide, angiotensin II, by releasing the C-terminal histidyl-leucine dipeptide. The same converting enzyme cleaves a number of other peptides, including and thereby inactivating the vasodilator bradykinin. Acting primarily through angiotensin II type 1 (AT₁) receptors on cell membranes, angiotensin II is a potent pressor substance, the primary tropic factor for the secretion of aldosterone by the adrenal zona glomerulosa, and a potent mitogen that stimulates vascular smooth muscle cell and myocyte growth. Independent of its hemodynamic effects, angiotensin II may play a role in the pathogenesis of atherosclerosis through a direct cellular action on the vessel wall. The angiotensin II type 2 (AT₂) receptor has the opposite functional effects of the AT₁ receptor. The AT₂ receptor induces vasodilation, sodium excretion, and inhibition of cell growth and matrix formation. Experimental evidence suggests that the AT₂ receptor improves vascular remodeling by stimulating smooth muscle cell apoptosis and contributes to the regulation of glomerular filtration rate. AT₁ receptor blockade induces an increase in AT₂ receptor activity.

Renin-secreting tumors are clear examples of renin-dependent hypertension. In the kidney, these tumors include benign hemangiopericytomas of the juxtaglomerular apparatus and, infrequently, renal carcinomas, including Wilms’ tumors. Renin-producing carcinomas also have been described in lung, liver, pancreas, colon, and adrenals. In these instances, in addition to excision and/or ablation of the tumor, treatment of hypertension includes pharmacologic therapies targeted to inhibit angiotensin II production or action. Renovascular hypertension is another renin-mediated form of hypertension. Obstruction of the renal artery leads to decreased renal perfusion pressure, thereby stimulating renin secretion. Over time, possibly as a consequence of secondary renal damage, this form of hypertension may become less renin dependent.

Angiotensinogen, renin, and angiotensin II are also synthesized locally in many tissues, including the brain, pituitary, aorta, arteries, heart, adrenal glands, kidneys, adipocytes, leukocytes, ovaries, testes, uterus, spleen, and skin. Angiotensin II in tissues may be formed by the enzymatic activity of renin or by other proteases, e.g., tonin, chymase, and cathepsins. In addition to regulating local blood flow, tissue angiotensin II is a mitogen that stimulates growth and contributes to modeling and repair. Excess tissue angiotensin II may contribute to atherosclerosis, cardiac hypertrophy, and renal failure and consequently may be a target for pharmacologic therapy to prevent target organ damage.

Angiotensin II is the primary tropic factor regulating the synthesis and secretion of aldosterone by the zona glomerulosa of the adrenal cortex. Aldosterone synthesis is also dependent on potassium, and aldosterone secretion may be decreased in potassium-depleted individuals. Although acute elevations of adrenocorticotropic hormone (ACTH) levels also increase aldosterone secretion, ACTH is not an important tropic factor for the chronic regulation of aldosterone.

Aldosterone is a potent mineralocorticoid that increases sodium reabsorption by amiloride-sensitive epithelial sodium channels (ENaC) on the apical surface of the principal cells of the renal cortical collecting duct (Chap. 332e). Electric neutrality is maintained by exchanging sodium for potassium and hydrogen ions. Consequently, increased aldosterone secretion may result in hypokalemia and alkalosis.

Cortisol also binds to the mineralocorticoid receptor but normally functions as a less potent mineralocorticoid than aldosterone because cortisol is converted to cortisone by the enzyme 11 β-hydroxysteroid dehydrogenase type 2. Cortisone has no affinity for the mineralocorticoid receptor. Primary aldosteronism is a compelling example of mineralocorticoid-mediated hypertension. In this disorder, adrenal aldosterone synthesis and release are independent of renin-angiotensin, and renin release is suppressed by the resulting volume expansion.

Mineralocorticoid receptors are expressed in a number of tissues in addition to the kidney, and mineralocorticoid receptor activation induces structural and functional alterations in the heart, kidney, and blood vessels, leading to myocardial fibrosis, nephrosclerosis, and vascular inflammation and remodeling, perhaps as a consequence of oxidative stress. These effects are amplified by a high salt intake. In animal models, high circulating aldosterone levels stimulate cardiac fibrosis and left ventricular hypertrophy, and spironolactone (an aldosterone antagonist) prevents aldosterone-induced myocardial fibrosis. Pathologic patterns of left ventricular geometry also have been associated with elevations of plasma aldosterone concentration in hypertensive patients. In patients with CHF, low-dose spironolactone reduces the risk of progressive heart failure and sudden death from cardiac causes by 30%. Due to a renal hemodynamic effect, in patients with primary aldosteronism, high circulating levels of aldosterone also may cause glomerular hyperfiltration and albuminuria. These renal effects are reversible after removal of the effects of excess aldosterone by adrenalectomy or spironolactone.

Increased activity of the renin-angiotensin-aldosterone axis is not invariably associated with hypertension. In response to a low-NaCl diet or to volume contraction, arterial pressure and volume homeostasis may be maintained by increased activity of the renin-angiotensin-aldosterone axis. Secondary aldosteronism (i.e., increased aldosterone secondary to increased renin-angiotensin), but not hypertension, also is observed in edematous states such as CHF and liver disease.

VASCULAR MECHANISMS

Vascular radius and compliance of resistance arteries are important determinants of arterial pressure. Resistance to flow varies inversely with the fourth power of the radius, and consequently, small decreases in lumen size significantly increase resistance. In hypertensive patients, structural, mechanical, or functional changes may reduce the lumen diameter of small arteries and arterioles. Remodeling refers to geometric alterations in the vessel wall without a change in vessel volume. Hypertrophic (increased cell size, and increased deposition of intercellular matrix) or eutrophic vascular remodeling results in decreased lumen size and, hence, increased peripheral resistance. Apoptosis, low-grade inflammation, and vascular fibrosis also contribute to remodeling. Lumen diameter also is related to elasticity of the vessel. Vessels with a high degree of elasticity can accommodate an increase of volume with relatively little change in pressure, whereas in a semirigid vascular system, a small increment in volume induces a relatively large increment of pressure.

Hypertensive patients may have stiffer arteries due to arteriosclerosis, and high systolic blood pressures and wide pulse pressures are a consequence of decreased vascular compliance. Due to arterial stiffness, central blood pressures (aortic, carotid) may not correspond to brachial artery pressures. Ejection of blood into the aorta elicits a pressure wave that is propagated at a given velocity. The forward travelling wave generates a reflected wave that travels backward toward the ascending aorta. Although mean arterial pressure is determined by cardiac output and peripheral resistance, pulse pressure is related to the functional properties of large arteries and the amplitude and timing of the incident and reflected waves. Increased arterial stiffness results in increased pulse wave velocity of both incident and reflected waves. Due to the timing of these waves, the consequence is augmentation of aortic systolic pressure and a reduction of aortic diastolic pressure, i.e., an increase in pulse pressure. The aortic augmentation index, an index of arterial stiffening, is calculated as the ratio of central arterial pressure-to-pulse pressure. Central blood pressure may be measured directly by placing a sensor in the aorta or noninvasively by radial tonometry using commercially available devices. Central blood pressure and the aortic augmentation index are strong, independent predictors of cardiovascular disease and all-cause mortality.

Ion transport by vascular smooth muscle cells may contribute to hypertension-associated abnormalities of vascular tone and vascular growth, both of which are modulated by intracellular pH (pH_i). Three ion transport mechanisms participate in the regulation of pH_i: (1) Na⁺-H⁺ exchange, (2) Na⁺-dependent HCO₃⁻-Cl⁻ exchange, and (3) cation-independent HCO₃⁻-Cl⁻ exchange. Based on measurements in cell types that are more accessible than vascular smooth muscle (e.g., leukocytes, erythrocytes, platelets, skeletal muscle), activity of the Na⁺-H⁺ exchanger is increased in hypertension, and this may result in increased vascular tone by two mechanisms. First, increased sodium entry may lead to increased vascular tone by activating Na⁺-Ca²⁺ exchange and thereby increasing intracellular calcium. Second, increased pH_i enhances calcium sensitivity of the contractile apparatus, leading to an increase in contractility for a given intracellular calcium concentration. Additionally, increased Na⁺-H⁺ exchange may stimulate growth of vascular smooth muscle cells by enhancing sensitivity to mitogens.

Vascular endothelial function also modulates vascular tone. The vascular endothelium synthesizes and releases several vasoactive substances, including nitric oxide, a potent vasodilator. Endothelium-dependent vasodilation is impaired in hypertensive patients. This impairment often is assessed with high-resolution ultrasonography before and after the hyperemic phase of reperfusion that follows 5 minutes of forearm ischemia. Alternatively, endothelium-dependent vasodilation may be assessed in response to an intra-arterially infused endothelium-dependent vasodilator, e.g., acetylcholine. Endothelin is a vasoconstrictor peptide produced by the endothelium, and orally active endothelin antagonists may lower blood pressure in patients with resistant hypertension.

Currently, it is not known if the hypertension-related vascular abnormalities of ion transport and endothelial function are primary alterations or secondary consequences of elevated arterial pressure. Limited evidence suggests that vascular compliance and endothelium-dependent vasodilation may be improved by aerobic exercise, weight loss, and antihypertensive agents. It remains to be determined whether these interventions affect arterial structure and stiffness via a blood pressure–independent mechanism and whether different classes of antihypertensive agents preferentially affect vascular structure and function.

Hypertension is an independent predisposing factor for heart failure, coronary artery disease, stroke, renal disease, and peripheral arterial disease (PAD).

HEART

Heart disease is the most common cause of death in hypertensive patients. Hypertensive heart disease is the result of structural and functional adaptations leading to left ventricular hypertrophy, CHF, abnormalities of blood flow due to atherosclerotic coronary artery disease and microvascular disease, and cardiac arrhythmias.

Individuals with left ventricular hypertrophy are at increased risk for CHD, stroke, CHF, and sudden death. Aggressive control of hypertension can regress or reverse left ventricular hypertrophy and reduce the risk of cardiovascular disease. It is not clear whether different classes of antihypertensive agents have an added impact on reducing left ventricular mass, independent of their blood pressure–lowering effect.

CHF may be related to systolic dysfunction, diastolic dysfunction, or a combination of the two. Abnormalities of diastolic function that range from asymptomatic heart disease to overt heart failure are common in hypertensive patients. Approximately one-third of patients with CHF have normal systolic function but abnormal diastolic function. Diastolic dysfunction is an early consequence of hypertension-related heart disease and is exacerbated by left ventricular hypertrophy and ischemia. Cardiac catheterization provides the most accurate assessment of diastolic function. Alternatively, diastolic function can be evaluated by several noninvasive methods, including echocardiography and radionuclide angiography.

BRAIN

Stroke is the second most frequent cause of death in the world; it accounts for 5 million deaths each year, with an additional 15 million persons having nonfatal strokes. Elevated blood pressure is the strongest risk factor for stroke. Approximately 85% of strokes are due to infarction, and the remainder are due to either intracerebral or subarachnoid hemorrhage. The incidence of stroke rises progressively with increasing blood pressure levels, particularly systolic blood pressure in individuals >65 years. Treatment of hypertension decreases the incidence of both ischemic and hemorrhagic strokes.

Hypertension also is associated with impaired cognition in an aging population, and longitudinal studies support an association between midlife hypertension and late-life cognitive decline. Hypertension-related cognitive impairment and dementia may be a consequence of a single infarct due to occlusion of a “strategic” larger vessel or multiple lacunar infarcts due to occlusive small vessel disease resulting in subcortical white matter ischemia. Several clinical trials suggest that antihypertensive therapy has a beneficial effect on cognitive function, although this remains an active area of investigation.

Cerebral blood flow remains unchanged over a wide range of arterial pressures (mean arterial pressure of 50–150 mmHg) through a process termed autoregulation of blood flow. In patients with the clinical syndrome of malignant hypertension, encephalopathy is related to failure of autoregulation of cerebral blood flow at the upper pressure limit, resulting in vasodilation and hyperperfusion. Signs and symptoms of hypertensive encephalopathy may include severe headache, nausea and vomiting (often of a projectile nature), focal neurologic signs, and alterations in mental status. Untreated, hypertensive encephalopathy may progress to stupor, coma, seizures, and death within hours. It is important to distinguish hypertensive encephalopathy from other neurologic syndromes that may be associated with hypertension, e.g., cerebral ischemia, hemorrhagic or thrombotic stroke, seizure disorder, mass lesions, pseudotumor cerebri, delirium tremens, meningitis, acute intermittent porphyria, traumatic or chemical injury to the brain, and uremic encephalopathy.

KIDNEY

The kidney is both a target and a cause of hypertension. Primary renal disease is the most common etiology of secondary hypertension. Mechanisms of kidney-related hypertension include a diminished capacity to excrete sodium, excessive renin secretion in relation to volume status, and sympathetic nervous system overactivity. Conversely, hypertension is a risk factor for renal injury and ESRD. The increased risk associated with high blood pressure is graded, continuous, and present throughout the distribution of blood pressure above optimal pressure. Renal risk appears to be more closely related to systolic than to diastolic blood pressure, and black men are at greater risk than white men for developing ESRD at every level of blood pressure.

Atherosclerotic, hypertension-related vascular lesions in the kidney primarily affect preglomerular arterioles, resulting in ischemic changes in the glomeruli and postglomerular structures. Glomerular injury also may be a consequence of direct damage to the glomerular capillaries due to glomerular hyperperfusion. Studies of hypertension-related renal damage, primarily in experimental animals, suggest that loss of autoregulation of renal blood flow at the afferent arteriole results in transmission of elevated pressures to an unprotected glomerulus with ensuing hyperfiltration, hypertrophy, and eventual focal segmental glomerular sclerosis. With progressive renal injury there is a loss of autoregulation of renal blood flow and glomerular filtration rate, resulting in a lower blood pressure threshold for renal damage and a steeper slope between blood pressure and renal damage. The result may be a vicious cycle of renal damage and nephron loss leading to more severe hypertension, glomerular hyperfiltration, and further renal damage. Glomerular pathology progresses to glomerulosclerosis, and eventually the renal tubules may also become ischemic and gradually atrophic. The renal lesion associated with malignant hypertension consists of fibrinoid necrosis of the afferent arterioles, sometimes extending into the glomerulus, and may result in focal necrosis of the glomerular tuft.

Clinically, macroalbuminuria (a random urine albumin/creatinine ratio >300 mg/g) or microalbuminuria (a random urine albumin/creatinine ratio 30–300 mg/g) are early markers of renal injury. These are also risk factors for renal disease progression and cardiovascular disease.

PERIPHERAL ARTERIES

In addition to contributing to the pathogenesis of hypertension, blood vessels are a target organ for atherosclerotic disease secondary to long-standing elevated blood pressure. In hypertensive patients, vascular disease is a major contributor to stroke, heart disease, and renal failure. Further, hypertensive patients with arterial disease of the lower extremities are at increased risk for future cardiovascular disease. Although patients with stenotic lesions of the lower extremities may be asymptomatic, intermittent claudication is the classic symptom of PAD. The ankle-brachial index is a useful approach for evaluating PAD and is defined as the ratio of noninvasively assessed ankle to brachial (arm) systolic blood pressure. An ankle-brachial index <0.90 is considered diagnostic of PAD and is associated with >50% stenosis in at least one major lower limb vessel. An ankle-brachial index <0.80 is associated with elevated blood pressure, particularly systolic blood pressure.

From an epidemiologic perspective, there is no obvious level of blood pressure that defines hypertension. In adults, there is a continuous, incremental risk of cardiovascular disease, stroke, and renal disease across levels of both systolic and diastolic blood pressure. The Multiple Risk Factor Intervention Trial (MRFIT), which included >350,000 male participants, demonstrated a continuous and graded influence of both systolic and diastolic blood pressure on CHD mortality, extending down to systolic blood pressures of 120 mmHg. Similarly, results of a meta-analysis involving almost 1 million participants indicate that ischemic heart disease mortality, stroke mortality, and mortality from other vascular causes are directly related to the height of the blood pressure, beginning at 115/75 mmHg, without evidence of a threshold. Cardiovascular disease risk doubles for every 20-mmHg increase in systolic and 10-mmHg increase in diastolic pressure. Among older individuals, systolic blood pressure and pulse pressure are more powerful predictors of cardiovascular disease than is diastolic blood pressure.

Clinically, hypertension may be defined as that level of blood pressure at which the institution of therapy reduces blood pressure–related morbidity and mortality. Current clinical criteria for defining hypertension generally are based on the average of two or more seated blood pressure readings during each of two or more outpatient visits. A recent classification recommends blood pressure criteria for defining normal blood pressure, prehypertension, hypertension (stages I and II), and isolated systolic hypertension, which is frequent among the elderly (Table 298-1). In children and adolescents, hypertension generally is defined as systolic and/or diastolic blood pressure consistently >95th percentile for age, sex, and height. Blood pressures between the 90th and 95th percentiles are considered prehypertensive and are an indication for lifestyle interventions.

Home blood pressure and average 24-h ambulatory blood pressure measurements are generally lower than clinic blood pressures. Because ambulatory blood pressure recordings yield multiple readings throughout the day and night, they provide a more comprehensive assessment of the vascular burden of hypertension than do a limited number of office readings. Increasing evidence suggests that home blood pressures, including 24-h blood pressure recordings, more reliably predict target organ damage than do office blood pressures. Blood pressure tends to be higher in the early morning hours, soon after waking, than at other times of day. Myocardial infarction and stroke are more common in the early morning hours. Nighttime blood pressures are generally 10–20% lower than daytime blood pressures, and an attenuated nighttime blood pressure “dip” may be associated with increased cardiovascular disease risk. Recommended criteria for a diagnosis of hypertension, based on 24-h blood pressure monitoring, are average awake blood pressure ≥135/85 mmHg and asleep blood pressure ≥120/75 mmHg. These levels approximate a clinic blood pressure of 140/90 mmHg.

Approximately 15–20% of patients with stage 1 hypertension (as defined in Table 298-1) based on office blood pressures have average ambulatory readings <135/85 mmHg. This phenomenon, so-called white coat hypertension, also may be associated with an increased risk of target organ damage, although to a lesser extent than in individuals with elevated office and ambulatory readings. Individuals with white coat hypertension are also at increased risk for developing sustained hypertension.

Depending on methods of patient ascertainment, ~80–95% of hypertensive patients are diagnosed as having primary, or “essential,” hypertension. In the remaining 5–20% of hypertensive patients, a specific underlying disorder causing the elevation of blood pressure can be identified (Tables 298-2 and 298-3). In individuals with “secondary” hypertension, a specific mechanism for the blood pressure elevation is often more apparent.

PRIMARY HYPERTENSION

Primary hypertension tends to be familial and is likely to be the consequence of an interaction between environmental and genetic factors. The prevalence of primary hypertension increases with age, and individuals with relatively high blood pressures at younger ages are at increased risk for the subsequent development of hypertension. It is likely that primary hypertension represents a spectrum of disorders with different underlying pathophysiologies. In the majority of patients with established hypertension, peripheral resistance is increased and cardiac output is normal or decreased; however, in younger patients with mild or labile hypertension, cardiac output may be increased and peripheral resistance may be normal.

When plasma renin activity (PRA) is plotted against 24-h sodium excretion, ~10–15% of hypertensive patients have high PRA and 25% have low PRA. High-renin patients may have a vasoconstrictor form of hypertension, whereas low-renin patients may have volume-dependent hypertension. Inconsistent associations between plasma aldosterone and blood pressure have been described in patients with primary hypertension. The association between aldosterone and blood pressure is more striking in African Americans, and PRA tends to be low in hypertensive African Americans. This raises the possibility that subtle increases in aldosterone may contribute to hypertension in at least some groups of patients who do not have overt primary aldosteronism. Furthermore, spironolactone, an aldosterone antagonist, may be a particularly effective antihypertensive agent for some patients with primary hypertension, including some patients with “drug-resistant” hypertension.

OBESITY AND THE METABOLIC SYNDROME

(See also Chap. 422) There is a well-documented association between obesity (body mass index >30 kg/m²) and hypertension. Further, cross-sectional studies indicate a direct linear correlation between body weight (or body mass index) and blood pressure. Centrally located body fat is a more important determinant of blood pressure elevation than is peripheral body fat. In longitudinal studies, a direct correlation exists between change in weight and change in blood pressure over time. Sixty percent of hypertensive adults are more than 20% overweight. It has been established that 60–70% of hypertension in adults may be directly attributable to adiposity.

Hypertension and dyslipidemia frequently occur together and in association with resistance to insulin-stimulated glucose uptake. This clustering of risk factors is often, but not invariably, associated with obesity, particularly abdominal obesity. Insulin resistance also is associated with an unfavorable imbalance in the endothelial production of mediators that regulate platelet aggregation, coagulation, fibrinolysis, and vessel tone. When these risk factors cluster, the risks for CHD, stroke, diabetes, and cardiovascular disease mortality are increased further.

Depending on the populations studied and the methodologies for defining insulin resistance, ~25–50% of nonobese, nondiabetic hypertensive persons are insulin resistant. The constellation of insulin resistance, abdominal obesity, hypertension, and dyslipidemia has been designated as the metabolic syndrome. As a group, first-degree relatives of patients with primary hypertension are also insulin resistant, and hyperinsulinemia (a surrogate marker of insulin resistance) may predict the eventual development of hypertension and cardiovascular disease. Although the metabolic syndrome may in part be heritable as a polygenic condition, the expression of the syndrome is modified by environmental factors, such as degree of physical activity and diet. Insulin sensitivity increases and blood pressure decreases in response to weight loss. The recognition that cardiovascular disease risk factors tend to cluster within individuals has important implications for the evaluation and treatment of hypertension. Evaluation of both hypertensive patients and individuals at risk for developing hypertension should include assessment of overall cardiovascular disease risk. Similarly, introduction of lifestyle modification strategies and drug therapies should address overall risk and not focus exclusively on hypertension.

RENAL PARENCHYMAL DISEASES

Virtually all disorders of the kidney may cause hypertension (Table 298-3), and renal disease is the most common cause of secondary hypertension. Hypertension is present in >80% of patients with chronic renal failure. In general, hypertension is more severe in glomerular diseases than in interstitial diseases such as chronic pyelonephritis. Conversely, hypertension may cause nephrosclerosis, and in some instances it may be difficult to determine whether hypertension or renal disease was the initial disorder. Proteinuria >1000 mg/d and an active urine sediment are indicative of primary renal disease. In either instance, the goals are to control blood pressure and retard the rate of progression of renal dysfunction.

RENOVASCULAR HYPERTENSION

Hypertension due to an occlusive lesion of a renal artery, renovascular hypertension, is a potentially curable form of hypertension. In the initial stages, the mechanism of hypertension generally is related to activation of the renin-angiotensin system. However, renin activity and other components of the renin-angiotensin system may be elevated only transiently; over time, recruitment of other pressure mechanisms may contribute to elevated arterial pressure. Two groups of patients are at risk for this disorder: older arteriosclerotic patients who have a plaque obstructing the renal artery, frequently at its origin, and patients with fibromuscular dysplasia. Atherosclerosis accounts for the large majority of patients with renovascular hypertension. Although fibromuscular dysplasia may occur at any age, it has a strong predilection for young white women. The prevalence in females is eightfold that in males. There are several histologic variants of fibromuscular dysplasia, including medial fibroplasia, perimedial fibroplasia, medial hyperplasia, and intimal fibroplasia. Medial fibroplasia is the most common variant and accounts for approximately two-thirds of patients. The lesions of fibromuscular dysplasia are frequently bilateral and, in contrast to atherosclerotic renovascular disease, tend to affect more distal portions of the renal artery.

Several clues from the history and physical examination may suggest renovascular hypertension. The diagnosis should be considered in patients with other evidence of atherosclerotic vascular disease. Although response to antihypertensive therapy does not exclude the diagnosis, severe or refractory hypertension, recent loss of hypertension control or recent onset of moderately severe hypertension, and unexplained deterioration of renal function or deterioration of renal function associated with an ACE inhibitor should raise the possibility of renovascular hypertension. Approximately 50% of patients with renovascular hypertension have an abdominal or flank bruit, and the bruit is more likely to be hemodynamically significant if it lateralizes or extends throughout systole into diastole.

If blood pressure is adequately controlled with a simple antihypertensive regimen and renal function remains stable, there may be little impetus to pursue an evaluation for renal artery stenosis, particularly in an older patient with atherosclerotic disease and comorbid conditions. Patients with long-standing hypertension, advanced renal insufficiency, or diabetes mellitus are less likely to benefit from renal vascular repair. The most effective medical therapies include an ACE inhibitor or an angiotensin II receptor blocker; however, these agents decrease glomerular filtration rate in a stenotic kidney owing to efferent renal arteriolar dilation. In the presence of bilateral renal artery stenosis or renal artery stenosis to a solitary kidney, progressive renal insufficiency may result from the use of these agents. Importantly, the renal insufficiency is generally reversible after discontinuation of the offending drug.

If renal artery stenosis is suspected and if the clinical condition warrants an intervention such as percutaneous transluminal renal angioplasty (PTRA), placement of a vascular endoprosthesis (stent), or surgical renal revascularization, imaging studies should be the next step in the evaluation. As a screening test, renal blood flow may be evaluated with a radionuclide [¹³¹I]-orthoiodohippurate (OIH) scan, or glomerular filtration rate may be evaluated with a [⁹⁹mTc]-diethylenetriamine pentaacetic acid (DTPA) scan before and after a single dose of captopril (or another ACE inhibitor). The following are consistent with a positive study: (1) decreased relative uptake by the involved kidney, which contributes <40% of total renal function, (2) delayed uptake on the affected side, and (3) delayed washout on the affected side. In patients with normal, or nearly normal, renal function, a normal captopril renogram essentially excludes functionally significant renal artery stenosis; however, its usefulness is limited in patients with renal insufficiency (creatinine clearance <20 mL/min) or bilateral renal artery stenosis. Additional imaging studies are indicated if the scan is positive. Doppler ultrasound of the renal arteries produces reliable estimates of renal blood flow velocity and offers the opportunity to track a lesion over time. Positive studies usually are confirmed at angiography, whereas false-negative results occur frequently, particularly in obese patients. Gadolinium-contrast magnetic resonance angiography offers clear images of the proximal renal artery but may miss distal lesions. An advantage is the opportunity to image the renal arteries with an agent that is not nephrotoxic. Contrast arteriography remains the “gold standard” for evaluation and identification of renal artery lesions. Potential risks include nephrotoxicity, particularly in patients with diabetes mellitus or preexisting renal insufficiency.

Some degree of renal artery obstruction may be observed in almost 50% of patients with atherosclerotic disease, and there are several approaches for evaluating the functional significance of such a lesion to predict the effect of vascular repair on blood pressure control and renal function. Each approach has varying degrees of sensitivity and specificity, and no single test is sufficiently reliable to determine a causal relationship between a renal artery lesion and hypertension. Functionally significant lesions generally occlude more than 70% of the lumen of the affected renal artery. On angiography, the presence of collateral vessels to the ischemic kidney suggests a functionally significant lesion. A lateralizing renal vein renin ratio (ratio >1.5 of affected side/contralateral side) has a 90% predictive value for a lesion that would respond to vascular repair; however, the false-negative rate for blood pressure control is 50–60%. Measurement of the pressure gradient across a renal artery lesion does not reliably predict the response to vascular repair.

In the final analysis, a decision concerning vascular repair vs. medical therapy and the type of repair procedure should be individualized. Patients with fibromuscular disease have more favorable outcomes than do patients with atherosclerotic lesions, presumably owing to their younger age, shorter duration of hypertension, and less systemic disease. Because of its low risk-versus-benefit ratio and high success rate (improvement or cure of hypertension in 90% of patients and restenosis rate of 10%), PTRA is the initial treatment of choice for these patients. Surgical revascularization may be undertaken if PTRA is unsuccessful or if a branch lesion is present. In atherosclerotic patients, vascular repair should be considered if blood pressure cannot be controlled adequately despite optimal medical therapy or if renal function deteriorates. Surgery may be the preferred initial approach for younger atherosclerotic patients without comorbid conditions; however, for most atherosclerotic patients, depending on the location of the lesion, the initial approach may be PTRA and/or stenting. Surgical revascularization may be indicated if these approaches are unsuccessful, the vascular lesion is not amenable to PTRA or stenting, or concomitant aortic surgery is required, e.g., to repair an aneurysm. A National Institutes of Health–sponsored prospective, randomized clinical trial is in progress comparing medical therapy alone with medical therapy plus renal artery stenting regarding Cardiovascular Outcomes for Renal Atherosclerotic Lesions (CORAL).

PRIMARY ALDOSTERONISM

Excess aldosterone production due to primary aldosteronism is a potentially curable form of hypertension. In patients with primary aldosteronism, increased aldosterone production is independent of the renin-angiotensin system, and the consequences are sodium retention, hypertension, hypokalemia, and low PRA. The reported prevalence of this disorder varies from <2% to ~15% of hypertensive individuals. In part, this variation is related to the intensity of screening and the criteria for establishing the diagnosis.

History and physical examination provide little information about the diagnosis. The age at the time of diagnosis is generally the third through fifth decade. Hypertension is usually mild to moderate but occasionally may be severe; primary aldosteronism should be considered in all patients with refractory hypertension. Hypertension in these patients may be associated with glucose intolerance. Most patients are asymptomatic; however, infrequently, polyuria, polydipsia, paresthesias, or muscle weakness may be present as a consequence of hypokalemic alkalosis. Although aldosterone is a salt-retaining hormone, patients with primary aldosteronism rarely have edema. Renal dysfunction and cardiovascular disease are strikingly increased in patients with primary aldosteronism compared to those with primary hypertension.

In a hypertensive patient with unprovoked hypokalemia (i.e., unrelated to diuretics, vomiting, or diarrhea), the prevalence of primary aldosteronism approaches 40–50%. In patients on diuretics, serum potassium <3.1 mmol/L (<3.1 meq/L) also raises the possibility of primary aldosteronism; however, serum potassium is an insensitive and nonspecific screening test. Serum potassium is normal in ~25% of patients subsequently found to have an aldosterone-producing adenoma, and higher percentages of patients with other etiologies of primary aldosteronism are not hypokalemic. Additionally, hypokalemic hypertension may be a consequence of secondary aldosteronism, other mineralocorticoid- and glucocorticoid-induced hypertensive disorders, and pheochromocytoma.

The ratio of plasma aldosterone to plasma renin activity (PA/PRA) is a useful screening test. These measurements preferably are obtained in ambulatory patients in the morning. A ratio >30:1 in conjunction with a plasma aldosterone concentration >555 pmol/L (>20 ng/dL) reportedly has a sensitivity of 90% and a specificity of 91% for an aldosterone-producing adenoma. In a Mayo Clinic series, an aldosterone-producing adenoma subsequently was confirmed surgically in >90% of hypertensive patients with a PA/PRA ratio ≥20 and a plasma aldosterone concentration ≥415 pmol/L (≥15 ng/dL). There are, however, several caveats to interpreting the ratio. The cutoff for a “high” ratio is laboratory- and assay-dependent. Some anti­hypertensive agents may affect the ratio (e.g., aldosterone antagonists, angiotensin receptor antagonists, and ACE inhibitors may increase renin; aldosterone antagonists may increase aldosterone). Current recommendations are to withdraw aldosterone antagonists for at least 4–6 weeks before obtaining these measurements. Because aldosterone biosynthesis is potassium-dependent, hypokalemia should be corrected with oral potassium supplements prior to screening. With these caveats, the ratio has been reported to be useful as a screening test in measurements obtained with patients taking their usual antihypertensive medications. A high ratio in the absence of an elevated plasma aldosterone level is considerably less specific for primary aldosteronism since many patients with primary hypertension have low renin levels in this setting, particularly African Americans and elderly patients. In patients with renal insufficiency, the ratio may also be elevated because of decreased aldosterone clearance. In patients with an elevated PA/PRA ratio, the diagnosis of primary aldosteronism can be confirmed by demonstrating failure to suppress plasma aldosterone to <277 pmol/L (<10 ng/dL) after IV infusion of 2 L of isotonic saline over 4 h; post-saline infusion plasma aldosterone values between 138 and 277 pmol/L (5–10 ng/dL) are not determinant. Alternative confirmatory tests include failure to suppress aldosterone (based on test specific criteria) in response to an oral NaCl load, fludrocortisone, or captopril.

Several sporadic and familial adrenal abnormalities may culminate in the syndrome of primary aldosteronism, and appropriate therapy depends on the specific etiology. The two most common causes of sporadic primary aldosteronism are an aldosterone-producing adenoma and bilateral adrenal hyperplasia. Together, they account for >90% of all patients with primary aldosteronism. The tumor is almost always unilateral, and most often measures <3 cm in diameter. Most of the remainder of these patients have bilateral adrenocortical hyperplasia (idiopathic hyperaldosteronism). Rarely, primary aldosteronism may be caused by an adrenal carcinoma or an ectopic malignancy, e.g., ovarian arrhenoblastoma. Most aldosterone-producing carcinomas, in contrast to adrenal adenomas and hyperplasia, produce excessive amounts of other adrenal steroids in addition to aldosterone. Functional differences in hormone secretion may assist in the diagnosis of adenoma vs. hyperplasia. Aldosterone biosynthesis is more responsive to ACTH in patients with adenoma and more responsive to angiotensin in patients with hyperplasia. Consequently, patients with adenoma tend to have higher plasma aldosterone in the early morning that decreases during the day, reflecting the diurnal rhythm of ACTH, whereas plasma aldosterone tends to increase with upright posture in patients with hyperplasia, reflecting the normal postural response of the renin-angiotensin-aldosterone axis. However, there is overlap in the ability of these measurements to discriminate between adenoma and hyperplasia. Rare familial forms of primary aldosteronism include glucocorticoid-remediable primary aldosteronism and familial aldosteronism types II and III. Genetic testing may assist in the diagnosis of these familial disorders.

Adrenal computed tomography (CT) should be carried out in all patients diagnosed with primary aldosteronism. High-resolution CT may identify tumors as small as 0.3 cm and is positive for an adrenal tumor 90% of the time. If the CT is not diagnostic, an adenoma may be detected by adrenal scintigraphy with 6 β-[I¹³¹] iodomethyl-19-norcholesterol after dexamethasone suppression (0.5 mg every 6 h for 7 days); however, this technique has decreased sensitivity for adenomas <1.5 cm.

When carried out by an experienced radiologist, bilateral adrenal venous sampling for measurement of plasma aldosterone is the most accurate means of differentiating unilateral from bilateral forms of primary aldosteronism. The sensitivity and specificity of adrenal venous sampling (95% and 100%, respectively) for detecting unilateral aldosterone hypersecretion are superior to those of adrenal CT; success rates are 90–96%, and complication rates are <2.5%. One frequently used protocol involves sampling for aldosterone and cortisol levels in response to ACTH stimulation. An ipsilateral/contralateral aldosterone ratio >4, with symmetric ACTH-stimulated cortisol levels, is indicative of unilateral aldosterone production.

Hypertension generally is responsive to surgery in patients with adenoma but not in patients with bilateral adrenal hyperplasia. Unilateral adrenalectomy, often done via a laparoscopic approach, is curative in 40–70% of patients with an adenoma. Transient hypoaldosteronism may occur up to 3 months postoperatively, resulting in hyperkalemia. Potassium should be monitored during this time, and hyperkalemia should be treated with potassium-wasting diuretics and with fludrocortisone, if needed. Patients with bilateral hyperplasia should be treated medically. The drug regimen for these patients, as well as for patients with an adenoma who are poor surgical candidates, should include an aldosterone antagonist and, if necessary, other potassium-sparing diuretics.

Glucocorticoid-remediable hyperaldosteronism is a rare, monogenic autosomal dominant disorder characterized by moderate to severe hypertension, often occurring at an early age. These patients may have a family history of hemorrhagic stroke at a young age. Hypokalemia is usually mild or absent. Normally, angiotensin II stimulates aldosterone production by the adrenal zona glomerulosa, whereas ACTH stimulates cortisol production in the zona fasciculata. Owing to a chimeric gene on chromosome 8, ACTH also regulates aldosterone secretion by the zona fasciculata in patients with glucocorticoid-remediable hyperaldosteronism. The consequence is overproduction in the zona fasciculata of both aldosterone and hybrid steroids (18-hydroxycortisol and 18-oxocortisol) due to oxidation of cortisol. The diagnosis may be established by urine excretion rates of these hybrid steroids that are 20 to 30 times normal or by direct genetic testing. Therapeutically, suppression of ACTH with low-dose glucocorticoids corrects the hyperaldosteronism, hypertension, and hypokalemia. Aldosterone antagonists are also therapeutic options. Patients with familial aldosteronism types II and III are treated with aldosterone antagonists or adrenalectomy.

CUSHING’S SYNDROME

(See also Chap. 406) Cushing’s syndrome is related to excess cortisol production due either to excess ACTH secretion (from a pituitary tumor or an ectopic tumor) or to ACTH-independent adrenal production of cortisol. Hypertension occurs in 75–80% of patients with Cushing’s syndrome. The mechanism of hypertension may be related to stimulation of mineralocorticoid receptors by cortisol and increased secretion of other adrenal steroids. If clinically suspected based on phenotypic characteristics, in patients not taking exogenous glucocorticoids, laboratory screening may be carried out with measurement of 24-h excretion rates of urine free cortisol or an overnight dexamethasone-suppression test. Late night salivary cortisol is also a sensitive and convenient screening test. Further evaluation is required to confirm the diagnosis and identify the specific etiology of Cushing’s syndrome. Appropriate therapy depends on the etiology.

PHEOCHROMOCYTOMA

(See also Chap. 407) Catecholamine-secreting tumors are located in the adrenal medulla (pheochromocytoma) or in extra-adrenal paraganglion tissue (paraganglioma) and account for hypertension in ~0.05% of patients. If unrecognized, pheochromocytoma may result in lethal cardiovascular consequences. Clinical manifestations, including hypertension, are primarily related to increased circulating catecholamines, although some of these tumors may secrete a number of other vasoactive substances. In a small percentage of patients, epinephrine is the predominant catecholamine secreted by the tumor, and these patients may present with hypotension rather than hypertension. The initial suspicion of the diagnosis is based on symptoms and/or the association of pheochromocytoma with other disorders (Table 298-4). Approximately 20% of pheochromocytomas are familial with autosomal dominant inheritance. Inherited pheochromocytomas may be associated with multiple endocrine neoplasia (MEN) type 2A and type 2B, von Hippel-Lindau disease, and neurofibromatosis (Table 298-4). Each of these syndromes is related to specific, identifiable germ-line mutations. Additionally, mutations of succinate dehydrogenase genes are associated with paraganglioma syndromes, generally characterized by head and neck paragangliomas. Laboratory testing consists of measuring catecholamines in either urine or plasma, e.g., 24-h urine metanephrine excretion or fractionated plasma free metanephrines. The urine measurement is less sensitive but more specific. Genetic screening is available for evaluating patients and relatives suspected of harboring a pheochromocytoma associated with a familial syndrome. Surgical excision is the definitive treatment of pheochromocytoma and results in cure in ~90% of patients.

MISCELLANEOUS CAUSES OF HYPERTENSION

Independent of obesity, hypertension occurs in >50% of individuals with obstructive sleep apnea. The severity of hypertension correlates with the severity of sleep apnea. Approximately 70% of patients with obstructive sleep apnea are obese. Hypertension related to obstructive sleep apnea also should be considered in patients with drug-resistant hypertension and patients with a history of snoring. The diagnosis can be confirmed by polysomnography. In obese patients, weight loss may alleviate or cure sleep apnea and related hypertension. Continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP) administered during sleep is an effective therapy for obstructive sleep apnea. With CPAP or BiPAP, patients with apparently drug-resistant hypertension may be more responsive to antihypertensive agents.

Coarctation of the aorta is the most common congenital cardiovascular cause of hypertension (Chap. 282). The incidence is 1–8 per 1000 live births. It is usually sporadic but occurs in 35% of children with Turner’s syndrome. Even when the anatomic lesion is surgically corrected in infancy, up to 30% of patients develop subsequent hypertension and are at risk of accelerated coronary artery disease and cerebrovascular events. Patients with less severe lesions may not be diagnosed until young adulthood. Physical findings include diminished and delayed femoral pulses and a systolic pressure gradient between the right arm and the legs and, depending on the location of the coarctation, between the right and left arms. A blowing systolic murmur may be heard in the posterior left interscapular areas. The diagnosis may be confirmed by chest x-ray and transesophageal echocardiography. Therapeutic options include surgical repair and balloon angioplasty, with or without placement of an intravascular stent. Subsequently, many patients do not have a normal life expectancy but may have persistent hypertension, with death due to ischemic heart disease, cerebral hemorrhage, or aortic aneurysm.

Several additional endocrine disorders, including thyroid diseases and acromegaly, cause hypertension. Mild diastolic hypertension may be a consequence of hypothyroidism, whereas hyperthyroidism may result in systolic hypertension. Hypercalcemia of any etiology, the most common being primary hyperparathyroidism, may result in hypertension. Hypertension also may be related to a number of prescribed or over-the-counter medications.

In addition to glucocorticoid-remediable primary aldosteronism, a number of rare forms of monogenic hypertension have been identified (Table 298–4). These disorders may be recognized by their characteristic phenotypes, and in many instances the diagnosis may be confirmed by genetic analysis. Several inherited defects in adrenal steroid biosynthesis and metabolism result in mineralocorticoid-induced hypertension and hypokalemia. In patients with a 17α-hydroxylase deficiency, synthesis of sex hormones and cortisol is decreased (Fig. 298-3). Consequently, these individuals do not mature sexually; males may present with pseudohermaphroditism and females with primary amenorrhea and absent secondary sexual characteristics. Because cortisol-induced negative feedback on pituitary ACTH production is diminished, ACTH-stimulated adrenal steroid synthesis proximal to the enzymatic block is increased. Hypertension and hypokalemia are consequences of increased synthesis of mineralocorticoids proximal to the enzymatic block, particularly desoxycorticosterone. Increased steroid production and, hence, hypertension may be treated with low-dose glucocorticoids. An 11β-hydroxylase deficiency results in a salt-retaining adrenogenital syndrome that occurs in 1 in 100,000 live births. This enzymatic defect results in decreased cortisol synthesis, increased synthesis of mineralocorticoids (e.g., desoxycorticosterone), and shunting of steroid biosynthesis into the androgen pathway. In the severe form, the syndrome may present early in life, including the newborn period, with virilization and ambiguous genitalia in females and penile enlargement in males, or in older children as precocious puberty and short stature. Acne, hirsutism, and menstrual irregularities may be the presenting features when the disorder is first recognized in adolescence or early adulthood. Hypertension is less common in the late-onset forms. Patients with an 11β-hydroxysteroid dehydrogenase deficiency have an impaired capacity to metabolize cortisol to its inactive metabolite, cortisone, and hypertension is related to activation of mineralocorticoid receptors by cortisol. This defect may be inherited or acquired, due to licorice-containing glycyrrhizin acid. The same substance is present in the paste of several brands of chewing tobacco. The defect in Liddle’s syndrome (Chaps. 63 and 406) results from constitutive activation of amiloride-sensitive epithelial sodium channels on the distal renal tubule, resulting in excess sodium reabsorption; the syndrome is ameliorated by amiloride. Hypertension exacerbated in pregnancy (Chap. 8) may be due to activation of the mineralocorticoid receptor by progesterone.

TREATMENT