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Arterial Hypertension Health Article

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Initial Evaluation For Hypertension

The initial evaluation for hypertension should focus on three goals: (1) staging of the blood pressure, (2) assessment of the patient's overall cardiovascular risk, and (3) detection of clues indicating potential identifiable causes of hypertension that require further evaluation. The initial clinical data needed to accomplish these goals are obtained through a thorough history and physical examination, routine blood and urine tests, and a resting 12-lead electrocardiogram. In some patients, ambulatory blood pressure monitoring and an echocardiogram provide helpful additional data about the time-integral burden of blood pressure on the cardiovascular system.

GOAL 1: ACCURATE ASSESSMENT OF BLOOD PRESSURE

OFFICE BLOOD PRESSURE.

Because blood pressure normally varies dramatically throughout a 24-hour period, multiple readings on more than one occasion are required to obtain a clear picture of a person's "usual" blood pressure. For this reason, hypertension should never be diagnosed on the basis of a single elevated reading .

To minimize variability in readings, blood pressure should be measured at least twice after 5 minutes of rest with the patient seated, the back supported, and the arm at heart level. The cuff should not be too small for the arm, and tobacco and caffeine should be avoided for at least 30 minutes. Most overweight adults require a large-adult cuff. To avoid underestimation of systolic pressure in older persons who may have an auscultatory gap, radial artery palpation should be performed to estimate systolic pressure; then the cuff should be inflated to a value 20 mm Hg higher than the level that obliterates the radial pulse and deflated at a rate of 3 to 5 mm Hg/sec. Blood pressure should be measured in both arms and after 5 minutes of standing, the latter to exclude a significant postural fall in blood pressure, particularly in older persons and in those with diabetes or other conditions (e.g., Parkinson's disease) that predispose to autonomic insufficiency.

BLOOD PRESSURE STAGE.

Blood pressure is staged as normal, prehypertension, or hypertension based on the average of two or more readings taken at two or more office visits. When a person's systolic and diastolic pressures fall into different stages, the higher stage should apply (Table 63-1).

The designation of prehypertension has been added to reflect the increased risk of progression to hypertension associated with blood pressures in the 130–139/80–89 mm Hg range. The time interval for recommended followup depends on the degree of blood pressure elevation recorded at the initial examination. Patients with prehypertension should be followed at least annually, patients with stage 1 hypertension should be examined in two months, and patients with stage 2 hypertension should be seen in one month or sooner depending on the patient's overall clinical condition.

HOME AND AMBULATORY BLOOD PRESSURE MONITORING.

Due to the anxiety of going to the physician, blood pressures often are higher in the physician's office than when measured at home. Self-monitoring of blood pressure at home actively engages a patient in his or her own health care and provides a better estimate of a person's usual blood pressure for diagnostic and therapeutic purposes. However, the devices need to be checked for accuracy in the office. Patients should be instructed to record their pressures both when relaxed and when stressed; even then, record-keeping may not be accurate.

Ambulatory blood pressure monitoring provides the best measure of the time-integral blood pressure burden on the cardiovascular system. As such, ambulatory blood pressures correlate better than office readings with target organ damage such as left ventricular hypertrophy (LVH). Recommended standards for normal ambulatory blood pressure values currently include daytime blood pressure less than 135/85 mm Hg, nighttime blood pressure less than 120/70 mm Hg, and 24-hour blood pressure less than 130/80 mm Hg.

Up to 30% of patients with elevated office blood pressures have normal home blood pressures. If the daytime ambulatory blood pressure is completely normal despite consistently elevated office readings, the patient has "office only," or "white coat," hypertension, presumably owing to an excessive adrenergic response to the measurement of blood pressure in the physician's office. In such individuals with rigorously defined white coat hypertension, the 5-year mortality rate was found in one study to be indistinguishable from that for those with normal office blood pressures. However, cross-sectional data suggest that white coat hypertension may not be so benign. For example, echocardiographic left ventricular mass is higher in patients with white coat hypertension than in patients with normal office blood pressures but not as high as in patients with persistent hypertension. For now, patients with white coat hypertension should be followed every 6 months for possible progression to persistent hypertension.

In up to 30% of treated patients with persistently elevated office blood pressures, ambulatory monitoring documents adequate or excessive control of their hypertension, eliminating overtreatment. In other patients, office blood pressures underestimate ambulatory blood pressures, presumably because of sympathetic overactivity in daily life owing to job or home stress, tobacco abuse, or other adrenergic stimulants that are discontinued before coming to the office. Such documentation prevents undertreatment of this masked hypertension.

Blood pressure normally dips during sleep at night and increases sharply when a person awakens and becomes active in the morning (Fig. 63-5). Persistent nocturnal hypertension increases the aggregate blood pressure burden on the cardiovascular system and increases the risk of target organ disease. The morning surge in blood pressure is strongly associated with the peak incidence of stroke, myocardial infarction, and sudden cardiac death. Thus, in high-risk individuals, medications ideally should be finely tuned to optimize the 24-hour blood pressure profile (Table 63-2).

GOAL 2: CARDIOVASCULAR RISK STRATIFICATION

It is important to emphasize that blood pressure is only one component of cardiovascular risk, and the approach to the hypertensive patient should be highly individualized based on a thorough assessment of the person's overall cardiovascular risk. The additive effects of multiple risk factors on atherosclerosis have been firmly established both in autopsy studies that directly measured subclinical atherosclerotic burden in young adults and in numerous longitudinal studies that evaluated clinical cardiovascular outcomes. There are three broad components to cardiovascular risk: (1) blood pressure level, (2) comorbidity, and (3) target organ damage (Table 63-3).

The low-risk group (mild risk) includes individuals who are free of clinical cardiovascular disease, target organ damage, or other associated risk factors. Only 2% of hypertensive patients fall into this low-risk category. Low-risk individuals with prehypertension or stage 1 hypertension may be treated with lifestyle modifications alone for up to 12 months. If blood pressure does not fall to the goal, lifestyle modifications should be supplemented, not replaced, by medications. For low-risk patients with stage 2 hypertension, medications should be initiated without delay.

Moderate-risk patients, who represent by far the largest number of hypertensive patients (60%), include those who have one or more of the major cardiovascular risk factors (e.g., hyperlipidemia, smoking) other than diabetes but do not yet have target organ damage or clinical cardiovascular disease. Lifestyle modifications and medications should be started concomitantly.

High-risk patients are individuals with elevated blood pressure (hypertension or prehypertension) in the presence of clinically evident cardiovascular disease or target organ damage. All patients with diabetes or renal insufficiency are also defined as high risk. More than one third of hypertensive individuals fall into this high-risk category. Medications and lifestyle modifications should be initiated immediately in high-risk patients, even individuals with high-normal blood pressures.

To reduce overall cardiovascular risk in moderate- and high-risk patients, low-dose aspirin (81 mg) and lipid-lowering therapy should be considered, when appropriate, along with antihypertensive therapy and lifestyle modifications. In treated hypertensive patients, low-dose aspirin has been shown to reduce the risk of myocardial infarction by 36% without increasing the risk of intracerebral hemorrhage.

GOAL 3: IDENTIFICATION OF SECONDARY (IDENTIFIABLE) CAUSES OF HYPERTENSION

A thorough search for secondary causes is not cost-effective in most patients with hypertension but becomes critically important in two circumstances: (1) when there is a compelling finding on the initial evaluation, or (2) when the hypertensive process is so severe that it either is refractory to intensive multiple drug therapy or requires hospitalization. Table 63-4 summarizes the major causes of secondary hypertension that should be suspected on the basis of a good history, physical, and routine laboratory tests.

RENAL PARENCHYMAL HYPERTENSION.

Chronic renal failure is the most common cause of secondary hypertension. Hypertension is present in more than 80% of patients with chronic renal failure and is a major factor causing their increased cardiovascular morbidity and mortality. The mechanisms causing the hypertension include an expanded plasma volume and peripheral vasoconstriction, with the latter caused by both activation of vasoconstrictor pathways (renin-angiotensin and sympathetic nervous systems) and inhibition of vasodilator pathways (nitric oxide). Renal insufficiency should be considered when there is proteinuria by dipstick or when the serum creatinine level is greater than 1.2 mg/dL in hypertensive women or greater than 1.4 mg/dL in hypertensive men. The diagnosis is confirmed either by a 24-hour urine collection showing a creatinine clearance of <60 mL/min or a total protein excretion of >150 mg or by a spot urine specimen showing microalbuminuria defined as a urine albumin-to-urine creatinine ratio between 30 and 300 mg/g. In patients with mild or moderate renal insufficiency, stringent blood pressure control is imperative to slow the progression to end-stage renal disease and reduce the excessive cardiovascular risk. Specific treatment recommendations are addressed later. In patients with far-advanced renal insufficiency, hypertension often becomes difficult to treat and may require either (1) intensive medical treatment with loop diuretics, potent vasodilators (e.g., minoxidil 2.5 to 100 mg daily), β-adrenergic blockers, and central sympatholytics or (2) initiation of chronic hemodialysis as the only effective way to reduce plasma volume. In chronic hemodialysis patients, the challenge is to control interdialytic hypertension intensively without exacerbating dialysis-induced hypotension. The gross annual mortality rate in the hemodialysis population is 25%, with half of this excessive mortality being caused by cardiovascular events that are related, at least in part, to suboptimal control of hypertension.

RENOVASCULAR HYPERTENSION.

Unilateral or bilateral renal artery stenosis is present in less than 2% of hypertensive patients in a general medical practice but up to 30% in patients referred to a hypertension specialist for refractory hypertension. The main causes of renal artery stenosis are atherosclerosis (90% of cases), typically in older persons with other manifestations of atherosclerosis, and fibromuscular dysplasia (10% of cases), typically in women between the ages of 15 and 50. Unilateral renal artery stenosis leads to underperfusion of the juxtaglomerular cells, thereby producing renin-dependent hypertension even though the contralateral kidney is able to maintain normal blood volume. In contrast, bilateral renal artery stenosis (or unilateral stenosis with a solitary kidney) constitutes a potentially reversible cause of progressive renal failure and volume-dependent hypertension. The following clinical clues increase the suspicion of renovascular hypertension: any hospitalization for urgent or emergent hypertension, recurrent "flash" pulmonary edema, refractory hypertension, severe hypertension in a young adult or after the age of 50, precipitous and progressive worsening of renal function in response to angiotensin-converting enzyme (ACE) inhibition, unilateral small kidney by any radiographic study, extensive peripheral arteriosclerosis, or a flank bruit.

The evaluation and treatment of fibromuscular dysplasia in a young women with recent-onset hypertension are straightforward. The diagnosis usually is readily supported by noninvasive testing with captopril renography, duplex Doppler ultrasonography, or magnetic resonance (MR) or spiral computed tomography (CT) angiography, the latter imaging studies showing the classic "string-of-beads" appearance of a renal artery. Once the diagnosis is confirmed with invasive angiography, balloon angioplasty is the treatment of choice, with complete cure of hypertension in 40% of patients, improved blood pressure control in almost all patients, and restenosis rates of about 10%. Medical therapy with an ACE inhibitor also may be effective, but the risks of teratogenicity must be considered in women of childbearing age.

In contrast, the approach to the older patient with generalized atherosclerosis and renal artery stenosis (Fig. 63-6) is not straightforward and must be highly individualized. Primary and renovascular hypertension frequently coexist in older persons, and renal artery stenosis can be present without being an important cause of the hypertension. For this reason, revascularization leads to clinical improvement in hypertension in less than 30% of patients, and complete cures are rare.

With current surgical procedures, the perioperative mortality rate is 2 to 6%, late graft failure requiring a second procedure occurs in 5 to 15% of patients, and the 5-year survival rate is 65 to 81%. Randomized trials show a small but probably real benefit of balloon angioplasty. Nevertheless, in this group of patients, the first line of therapy should be intensive medical treatment of hypertension and associated cardiovascular risk factors, with concomitant lipid lowering, smoking cessation, and aspirin. Surgical revascularization or stenting should be considered for the following indications: (1) medically refractory or accelerating hypertension, (2) progressive renal failure on medical therapy, and (3) bilateral renal artery stenosis.

MINERALOCORTICOID-INDUCED HYPERTENSION DUE TO PRIMARY ALDOSTERONISM.

The most common causes of primary aldosteronism are (1) a unilateral aldosterone-producing adenoma in two thirds of cases and (2) bilateral adrenal hyperplasia in one third. Because aldosterone is the principal ligand for the mineralocorticoid receptor in the distal nephron, excessive aldosterone production causes excessive renal Na ⁺ -K ⁺ exchange, resulting in hypokalemia. The initial clue to the diagnosis is either unprovoked hypokalemia (serum K ⁺ <3.5 mmol/L in the absence of diuretic therapy) or a tendency to develop excessive hypokalemia during diuretic therapy (serum K ⁺ <3.0 mmol/L) in a patient with hypertension. However, up to one third of patients do not have hypokalemia on initial presentation, and the diagnosis should be considered in any patient with severe refractory hypertension.

Mendelian Forms of Mineralocorticoid-Induced Hypertension.

Almost all of the mendelian forms of hypertension, although rare, are mineralocorticoid induced and involve excessive activation of the epithelial sodium channel (ENaC) , the final common pathway for reabsorption of sodium from the distal nephron (Fig. 63-6). Thus, salt-dependent hypertension can be caused both by gain-of-function mutations of ENaC or the mineralocorticoid receptor and by increased production or decreased clearance of mineralocorticoid receptor ligands, which are aldosterone, deoxycorticosterone, or cortisol.

Glucocorticoid-Remediable Aldosteronism (GRA).

Fewer than 100 cases of GRA have been reported, but many additional cases likely go undetected or misdiagnosed as bilateral adrenal hyperplasia. Inherited as an autosomal dominant mutation, GRA mimics an aldosterone-producing adenoma by causing severe mineralocorticoid-induced hypertension with hypokalemia, elevated plasma aldosterone, and suppressed plasma renin activity (PRA). In the normal adrenal gland, angiotensin II (Ang II) acts on the enzyme aldosterone synthase in the zona glomerulosa to drive production of aldosterone, whereas ACTH causes transcriptional activation of the enzyme 11-β-hydroxylase in the zona fasciculata to drive production of cortisol. GRA is caused by a gene duplication arising by unequal crossing over between the genes encoding aldosterone synthase and 11-β-hydroxylase. The resulting chimeric gene encodes a hybrid protein that has aldosterone synthase activity, is expressed "ectopically" in the zona fasciculata, and is regulated entirely by ACTH rather than by Ang II. Thus, aldosterone production becomes inappropriately linked to cortisol production. In the attempt to maintain the appropriate production of normal cortisol, aldosterone is constantly produced, resulting in volume-dependent hypertension. Although the expanded plasma volume suppresses PRA, the reduced Ang II cannot downregulate aldosterone production. The clinical clue to the diagnosis is that the hypertension is familial and discovered before age 20. In contrast, primary aldosteronism is sporadic and usually discovered between ages 30 and 60. The diagnosis of GRA is confirmed by Southern blot analysis for the chimeric gene, a test available at no cost through the International Registry for GRA (www.bwh.partners.org/gra/clinhx.htm). By suppressing ACTH, and thus aldosterone secretion from the zona fasciculata, low-dose dexamethasone completely reverses the biochemical abnormalities in GRA and is the recommended antihypertensive therapy.

HYPERTENSION CAUSED BY DEOXYCORTICOSTERONE.

The rare but distinctive hypertensive syndromes caused by deoxycorticosterone include those due to congenital deficiency of either 11β-hydroxylase or 17α-hydroxylase. In both cases, decreased production of cortisol decreases feedback inhibition on ACTH, which drives overproduction of deoxycorticosterone (a potent mineralocorticoid). These patients typically present to the pediatrician with hypertension plus abnormal sexual development.

HYPERTENSION CAUSED BY CORTISOL.

Although cortisol is a glucocorticoid, surprisingly it is equipotent to aldosterone in activating the mineralocorticoid receptor. As a result, both excessive production of cortisol and defective cortisol metabolism cause hypertension plus hypokalemia. Cushing's syndrome (excessive cortisol production) is discussed in detail in.

Cortisol at the mineralocorticoid receptor normally is kept at a very low local concentration because the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) converts cortisol to cortisone, which cannot bind the mineralocorticoid receptor. The syndrome of apparent mineralocorticoid excess is an autosomal recessive disease due to a loss in function mutation of 11β-HSD2. Loss of protection of the mineralocorticoid receptor from an excessive local concentration of cortisol results in early-onset hypertension with hypokalemia accompanied by suppressed PRA and undetectable plasma aldosterone. Glycerrhetinic acid, a metabolite found in licorice, numerous herbal supplements, and chewing tobacco, is a potent inhibitor of 11β-HSD2. Thus, habitual ingestion of these substances by normal individuals causes a phenocopy of apparent mineralocorticoid excess. Biochemical confirmation consists of elevations in urinary free cortisol. The congenital syndrome is treated with spironolactone, whereas the phenocopy is treated with diet.

HYPERTENSION CAUSED BY PROGESTERONE.

A gain-in-function mutation in the mineralocorticoid receptor has been identified as a cause of autosomal dominant, early-onset hypertension that is markedly accelerated during pregnancy. Because of missense mutation in the ligand-binding domain of the mineralocorticoid receptor, steroids that bind but do not activate the normal receptor become potent agonists of the mutant receptor, causing mineralocorticoid receptor-induced hypertension with secondary suppression of plasma renin and aldosterone. These steroids include progesterone and spironolactone, which normally is a potent receptor antagonist. Because progesterone levels increase 100-fold during pregnancy, this mutation constitutes a rare but dramatic cause of accelerated hypertension during pregnancy. All the male carriers in one family developed hypertension before age 20. Amiloride is the suggested treatment of choice, and spironolactone is contraindicated.

LIDDLE'S SYNDROME.

Liddle's syndrome is a rare monogenic form of salt-dependent hypertension due to gain-in-function mutations in ENaC , resulting in an excessive number of channels on the epithelial surface of the distal renal tubule. Mutations that truncate large segments of the cytoplasmic C-terminus of the beta or gamma ENaC subunits disrupt the NEDD4 ubiquitin ligase binding site so that the channels cannot be internalized. Inherited as an autosomal dominant trait, these mutations cause severe salt-dependent hypertension beginning in young adulthood. Plasma renin activity and plasma aldosterone levels are suppressed secondarily. The diagnosis is confirmed by genetic testing for the mutant gene. Because the defect is downstream from the mineralocorticoid receptor, the hypertension is unresponsive to spironolactone but is best treated with thiazides plus amiloride or triamterene, which are potassium-sparing diuretics that block ENaC .

FAMILIAL BRACHYDACTYLY AND HYPERTENSION.

Several large kindreds have been reported to have severe autosomal dominant hypertension associated with brachydactyly and short stature. The gene has been mapped to the short arm of chromosome 12, but the mechanism causing the hypertension is unknown. In contrast to the other mendelian forms of hypertension, plasma renin and aldosterone levels are normal, and this syndrome does not appear to represent volume-dependent hypertension.

PHEOCHROMOCYTOMAS.

Pheochromocytomas are rare catecholamine-producing tumors of the adrenal (or sometimes extra-adrenal) chromaffin cells. The diagnosis should be suspected when hypertension is accompanied by frequent or refractory headaches or by paroxysms of headache, palpitations, pallor, or diaphoresis. In some patients, pheochromocytoma may be misdiagnosed as panic disorder. A family history of early onset hypertension may suggest pheochromocytoma as part of the multiple endocrine neoplasia syndromes. If the diagnosis is missed, outpouring of catecholamines from the tumor can cause unsuspected hypertensive crisis and death during unrelated surgical or radiologic procedures.

Other causes of neurogenic hypertension, which can be confused with pheochromocytoma, include sympathomimetic agents (cocaine, amphetamines;), baroreflex failure, and obstructive sleep apnea. Continuous positive airway pressure or corrective surgery can improve blood pressure control in some patients with sleep apnea.

OTHER CAUSES OF SECONDARY HYPERTENSION.

Coarctation of the aorta typically occurs just distal to the origin of the left subclavian artery, so the blood pressure is lower in the legs than in the arms (the opposite of the normal situation). The clue is that the pulses are weaker in the lower than upper extremities, indicating the need to measure blood pressure in the legs as well as in both arms. Intercostal collaterals can produce bruits on examination and rib notching on the chest radiograph. Coarctations can be cured with surgery or angioplasty.

Thyroid disease is another cause of secondary hypertension . Hyperthyroidism tends to cause systolic hypertension with a wide pulse pressure, whereas hypothyroidism tends to cause mainly diastolic hypertension.

Cyclosporine has emerged as an important cause of secondary hypertension. The mechanism by which this immunosuppressive drug causes hypertension remains an enigma, but hypertension is a general property of immunosuppressive agents (e.g., tacrolimus) that inhibit calcineurin, the Ca ²⁺ -dependent phosphatase that is expressed not only in lymphoid tissue but also in neural, vascular, and renal tissue. In the absence of outcomes data, nondihydropyridine calcium channel blockers (CCBs) have become the drugs of first choice even though they increase cyclosporine blood levels.