The definition of hypertension is somewhat arbitrary, because blood pressure (BP) is not distributed bimodally in the population. Instead, the distribution of BP readings in the population is unimodal, and an arbitrary level of BP must be defined as the threshold above which hypertension can be diagnosed. The correlation between the levels of systolic BP (SBP) and diastolic BP (DBP) and cardiovascular risk has long been recognized. It has become clear that in patients older than 50 years, SBP of more than 140 mmHg is a much more important cardiovascular disease risk factor than is DBP. Increasing BP clearly has an adverse effect on mortality over the entire range of recorded pressures, even those generally considered to be in the normal range. The goal of identifying and treating high BP is to reduce the risk of cardiovascular disease and associated morbidity and mortality. The seventh report of the Joint National Committee (JNC) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) has established criteria for the diagnosis and classification of BP in adult patients (Table 15-1). The optimal BP in an individual who is not acutely ill is lower than 120/80 mmHg. Individuals with an SBP of 120 to 139 mmHg or a DBP of 80 to 89 mmHg should be considered as prehypertensive; these patients require health-promoting lifestyle modifications to prevent cardiovascular disease. Patients with prehypertension are at twice the risk of developing hypertension as those with lower values. Although normotensive by definition, these prehypertensive patients should be rechecked annually to exclude the development of hypertension. Hypertension is arbitrarily defined as an SBP of 140 mmHg or greater or a DBP of 90 mmHg or greater, or by virtue of the patient taking antihypertensive medications. The stage of hypertension (stage 1 or 2) is determined by the levels of both SBP and DBP (Table 15-1). This classification should be based on the average of two or more BP readings at each of two or more visits after the initial BP screening. When SBP and DBP fall into different categories, the higher category should be selected to classify the individual’s BP.

Data from the National Health and Nutrition Examination Survey (NHANES) indicate that approximately 28% of the adult population in the United States has hypertension, a number that has remained relatively stable over the last decade. According to the same study, prevalence of hypertension increases sharply with age. The increasing burden of hypertension is not only the result of the increased size of the population but also reflects the increased prevalence of obesity and the overall aging of the population. Data from the Framingham Heart Study indicate that
even individuals who are normotensive at 55 years have a 90% lifetime risk of developing hypertension. Many hypertensive patients have a positive family history of parental hypertension. The mode of inheritance is complex and probably polygenic in most instances. Black men and women have a twofold higher prevalence of hypertension (30%) than white men and women (15%) in a sampling of almost 18,000 American adults aged 48 to 75 years in the NHANES data. Prevalence appears to be equal in men and women in most surveys. Obese individuals have significantly more hypertension than nonobese individuals. In childhood, obesity is a major cause of hypertension. More than one-half of the adult population is overweight [body mass index (BMI) of 25 to 29.9] or obese (BMI ≥ 30). Data from NHANES III show that among men and women, whites, blacks, and Mexican Americans, the prevalence of hypertension and the mean levels of SBP and DBP increase as BMI increases at ages younger than 60 years. Overall, the prevalence of hypertension in obese adults is 41.4% for men and 37.8% for women; compared with 14.9% for men and 15.2% for women with BMI ≤ 25. Further proof of the significant relationship between body weight and BP is found in the observation that BP falls with even modest weight reduction. The intake of dietary salt (sodium chloride) has significant effects on BP, especially in patients with other factors predisposing to the development of hypertension, such as advancing age, obesity, adult-onset diabetes, positive family history of hypertension, black race, or underlying renal disease. Numerous epidemiologic studies have shown that the dietary intake of salt correlates with the average BP in a population. Northern Japanese fishermen who ingest 450 mEq of sodium daily have a 40% prevalence of hypertension. In contrast, indigenous Alaskan populations and the Yanomamo Indians in Brazil and Venezuela, who have dietary intake of 1 mEq of sodium daily, do not develop hypertension at any age. Intersalt, an international epidemiologic
study, examined the relation between dietary sodium intake (based on 24-hour urinary sodium excretion) and BP in more than 10,000 individuals aged 20 to 59 years from 52 countries around the world. The results demonstrate a significant correlation between median SBP and DBP and dietary sodium intake. These observations can be explained based on the role of abnormal renal sodium handling in the pathogenesis of hypertension, which is discussed in Section IV. The therapeutic implications of these observations include dietary sodium restriction as part of nonpharmacologic therapy and the recommendation of thiazide diuretics as first-line drug therapy for the treatment of hypertension in most patients. Despite the known cardiovascular risks of untreated hypertension and the widespread availability of effective pharmacologic treatment, the identification and effective control of hypertension remain a significant public health problem in the United States. According to the most recent NHANES data, there have been gradual improvements in hypertension control in the United States from 1988 to 2008. In 2008, 81% of patients were aware that they had hypertension and 73% of patients were on treatment. However, only 50% of all patients with hypertension had controlled BP. The continued high prevalence of hypertension and hypertension-related complications such as stroke, cardiovascular complications, heart failure, and end-stage renal disease (ESRD) represents a major public health challenge.

The relationship of BP to cardiovascular risk is continuous and independent of other cardiovascular risk factors. Beginning at 115/75 mmHg and across the entire BP range, each increment of 20/10 mmHg doubles the risk of cardiovascular disease. The overall risk of cardiovascular morbidity and mortality in patients with hypertension is determined not only by the stage of hypertension but also by the presence of other risk factors, such as smoking, hyperlipidemia, and diabetes, and by the existence of target organ damage (Table 15-2). The major target organs affected by hypertension are the heart, peripheral vasculature, central nervous system, kidney, and the eye. Most of the consequences of hypertension are the result of progressive vascular injury. Hypertension accelerates atherosclerotic vascular disease and aggravates the deleterious effects of diabetes, smoking, and hyperlipidemia on the aorta and its major branches. Atherosclerotic disease results in significant morbidity from myocardial infarction (MI), atherothrombotic cerebral infarction, peripheral vascular disease with claudication, and renal disease due to ischemia or cholesterol embolization. Hypertensive renal disease may result from hypertension-induced vasculitis in the setting of malignant hypertension or more insidious renal injury from long-standing essential hypertension with benign hypertensive nephrosclerosis. Hypertension is also an important cofactor in the progression of other renal diseases, especially diabetic nephropathy. Hypertension may also cause cerebrovascular disease in the form of lacunar infarction or intracerebral hemorrhage. Left ventricular hypertrophy (LVH) and congestive heart failure (CHF), often due to isolated diastolic dysfunction, are the result of the heightened peripheral vascular resistance (afterload) imposed by systemic hypertension. In clinical trials, antihypertensive therapy has been associated with significant reductions in the incidence of stroke (35% to 40%), MI (20% to 25%), and heart failure (50%). It has been estimated that in patients with stage 1 hypertension (SBP 140 to 159 mmHg and/or DBP 90 to 99 mmHg) and additional cardiovascular risk factors, achieving a

sustained 12 mmHg reduction in SBP for 10 years will prevent one death for every 11 patients treated. In the setting of preexisting cardiovascular disease or target organ damage, treatment of nine patients would prevent one death.

A large body of experimental data has demonstrated the importance of the kidney in the pathogenesis of hypertension. To date, each of the genetic causes of hypertension that have been elucidated has been shown to relate to an abnormality of renal sodium handling. For example, Liddle’s syndrome results from enhanced distal tubular sodium reabsorption due to an abnormality in sodium channels in the distal nephron. Cross-transplant experiments in hypertensive and normotensive rat strains validate the importance of the kidney in the pathogenesis of hypertension, because the presence or absence of hypertension depends on the donor source of the kidney.

Guyton’s hypothesis states that the most important and fundamental mechanism in determining the long-term control of BP is the renal fluid—volume feedback mechanism. In simple terms, through this basic mechanism, the kidneys regulate arterial pressure by altering renal excretion of sodium and water, thereby controlling circulatory volume and cardiac output. Changes in BP, in turn, directly influence the renal excretion of sodium and water, thereby providing a negative feedback mechanism for the control of extracellular fluid (ECF) volume, cardiac output, and BP. For instance, an increase in systemic BP will lead to an increase in sodium excretion, a process known as pressure natriuresis. The hypothesis is that derangements in this renal fluid—volume pressure control mechanism are the fundamental cause of virtually all hypertensive states (Fig. 15-1). In every hypertensive state, an underlying abnormality exists in the intrinsic natriuretic capacity of the kidney, so that the daily salt intake cannot be excreted at a normal BP, and the development of hypertension is necessary to induce a pressure natriuresis that allows the kidney to excrete the daily salt intake. Normal sodium balance and ECF volume are maintained, but at the expense of systemic hypertension. The underlying cause for the abnormality in the natriuretic capacity depends on the etiology of hypertension. In essential hypertension, some underlying abnormality increases renal avidity for sodium. In patients with obesity and insulin resistance (metabolic syndrome), hyperinsulinemia increases proximal tubular sodium reabsorption. Increased angiotensin II levels and sympathetic nervous system activity also enhance sodium reabsorption. Mineralocorticoids enhance distal tubular sodium reabsorption. Renal parenchymal disease causes nephron loss, resulting in a natriuretic defect. Abnormalities in renal endothelin or nitric oxide levels may also impair natriuresis. Guyton’s hypothesis states that this decreased natriuretic capacity of the kidney initially leads to renal salt and water retention, ECF volume expansion, and increased cardiac output with hypertension. This phase of volume expansion and high cardiac output is short lived. In the setting of high cardiac output, autoregulatory vasoconstriction of each vascular bed matches the blood flow to the metabolic requirements of the tissues. This phenomenon of circulatory autoregulation leads to an increase in systemic vascular resistance (SVR). Therefore, hypertension that was initially caused by high cardiac output becomes high-SVR hypertension.

The development of hypertension represents a protective mechanism, because it induces the kidney to undergo a pressure natriuresis and diuresis,
thereby restoring normal salt balance and returning ECF volume to normal. This mechanism explains why an underlying problem with sodium excretion, as in salt-sensitive hypertension, is manifest as high-SVR hypertension without evidence of overt fluid overload. In the absence of pressure natriuresis, patients with a primary disorder in sodium retention would progressively develop overt fluid overload and consequences such as pulmonary edema. Support for this hypothesis is found in animal models of mineralocorticoid-induced hypertension. To substantiate the role of direct pressure-induced natriuresis in the
regulation of sodium balance in mineralocorticoid hypertension, Hall et al. compared the systemic BP and natriuretic effect of aldosterone infusion in a dog model in which the renal perfusion pressure was either allowed to increase or mechanically servocontrolled to maintain renal artery pressure at normal levels. In the intact animal, continuous aldosterone infusion caused a transient period of sodium and water retention with a mild increase in BP. This sodium retention lasted only a few days, however, and was followed by an escape from the sodium-retaining effects of aldosterone and a restoration of normal sodium balance. In contrast, when the renal perfusion pressure was servocontrolled to maintain normal renal perfusion pressure during aldosterone infusion, no aldosterone escape occurred, and a relentless increase in sodium and water retention occurred, accompanied by severe hypertension, edema, ascites, and pulmonary edema. When the servocontrol device was removed and the renal perfusion pressure was allowed to rise to the systemic level, a prompt natriuresis and diuresis ensued, with the restoration of sodium balance and a fall in BP. These observations highlight the pivotal role of BP in the regulation of renal sodium and water excretion. Moreover, the observation that abnormal renal sodium handling is central in the pathogenesis of all forms of hypertension provides a sound pathophysiologic rationale for the JNC 7 recommendation regarding thiazide-type diuretics as first-line antihypertensive therapy in most patients.

Detection of hypertension begins with proper measurement of BP at each health care encounter. Repeated BP measurements are used to determine whether initial elevations persist and require prompt attention or have returned to normal values and require only periodic surveillance. BP measurement should be standardized as follows: After at least 5 minutes of rest, the patient should be seated in a chair with the back supported and one arm bared and supported at heart level. The patient should refrain from smoking or ingesting caffeine for 30 minutes before the examination. For an appropriately sized cuff, the bladder should encircle at least 80% of the arm. Many patients require a large adult cuff. Measurements should ideally be taken with a mercury sphygmomanometer. Alternatively, a recently calibrated aneroid manometer or a validated electronic device can be used. The first appearance of sound (phase 1) is used to define SBP. The disappearance of sound (phase 5) is used to define DBP. The BP should be confirmed in the contralateral arm. Measurement of BP outside of the physician’s office may provide some valuable information with regard to the diagnosis and treatment of hypertension. Self-measurement is useful in distinguishing sustained hypertension from “white coat hypertension,” a condition in which the patient’s pressure is consistently elevated in the clinician’s office but normal at other times. Selfmeasurement may also be used to assess the response to antihypertensive medications and as a tool to improve patient adherence to treatment. Ambulatory monitoring is useful for the evaluation of suspected white coat hypertension, patients with apparent drug resistance, hypotensive symptoms with antihypertensive medications, and episodic hypertension. However, ambulatory BP measurement is not appropriate for the routine evaluation of patients with suspected hypertension. In elderly patients, the possibility of pseudohypertension should always be considered in the diagnostic evaluation of possible hypertension. Pseudohypertension is a condition in which the indirect measurement of arterial pressure using a cuff sphygmomanometer is artificially high in comparison
to direct intra-arterial pressure measurement. Failure to recognize pseudohypertension can result in unwarranted and sometimes frankly dangerous treatment. Pseudohypertension can result from Monckeberg’s medial calcification (a clinically benign form of arterial calcification) or advanced atherosclerosis with widespread calcification of intimal plaques. In these entities, stiffening of the arterial wall may prevent its collapse by externally applied pressure, resulting in artificially high indirect BP readings affecting both systolic and diastolic measurements. The presence of a positive Osler’s maneuver, in which the radial or brachial artery remains palpable despite being made pulseless by proximal inflation of a cuff above systolic pressure, is an important physical examination finding that should suggest the diagnosis. Roentgenograms of the extremities frequently reveal calcified vessels. The diagnosis can only be made definitely by a direct measurement of intra-arterial pressure. Patients with pseudohypertension are often elderly and therefore may have a critical limitation of blood flow to the brain or heart, such that inappropriate BP treatment may precipitate lifethreatening ischemic events.

The initial history and physical examination of patients with documented hypertension should be designed to assess lifestyle, identify other cardiovascular risk factors, and identify the presence of target organ damage that may affect prognosis and impact treatment decisions (Table 15-2). Although the vast majority of hypertensive patients have essential (primary) hypertension without a clearly definable etiology, the initial evaluation is also designed to screen for identifiable causes of secondary hypertension (Table 15-3). A medical history should include information about prior BP measurements, to assess the duration of hypertension, and details about adverse effects from any prior antihypertensive therapy. History or symptoms of coronary heart disease, CHF, cerebrovascular disease, peripheral vascular disease, or renal disease should be carefully evaluated. Symptoms suggesting unusual secondary causes of hypertension should be queried, such as weakness (hyperaldosteronism) or episodic anxiety, headache, diaphoresis, and palpitations (pheochromocytoma). Information regarding other risk factors, such as diabetes, tobacco use, hyperlipidemia, physical activity, and any recent weight gain, should be obtained. Dietary assessment regarding the intake of salt, alcohol, and saturated fat is also important. Detailed information should be sought regarding all prescription and over-the-counter medication use, including herbal remedies and illicit drugs, some of which may raise BP or interfere with the effectiveness of antihypertensive therapy. For example, nonsteroidal anti-inflammatory drugs impair the response to virtually all antihypertensive agents and increase the risk of hyperkalemia or renal insufficiency with angiotensin-converting enzyme (ACE) inhibitor therapy. Stimulants such as cocaine, ephedra, amphetamines, and anabolic steroids can raise BP. A family history of hypertension, diabetes, premature cardiovascular disease, or renal disease should be sought. A psychosocial history is important to identify family situation, working conditions, employment status, educational level, and sexual dysfunction that may influence adherence to antihypertensive treatment.

Physical examination should include the measurement of height and weight and calculation of BMI (weight in kilogram divided by the square of height in meters). Funduscopic examination is important to identify striate hemorrhages, cotton wool spots, and papilledema, the characteristic findings of hypertensive neuroretinopathy (HNR), which are indicative of the presence
of malignant hypertension. Documentation of the presence of arteriosclerotic retinopathy (e.g., arteriolar narrowing, arteriovenous crossing changes, changes in light reflexes) is less important, given its lack of prognostic significance with regard to the potential long-term cardiovascular complications of hypertension. Examination of the neck for carotid bruits, distended neck veins, and thyromegaly is important. Cardiac examination should include investigation for abnormalities of rate or rhythm, murmurs, and third or fourth heart sounds. The lungs should be examined for rales and evidence of bronchospasm. Abdominal examination should include auscultation for bruits (an epigastric bruit present in both systole and diastole suggests renal artery stenosis), abdominal or flank masses (polycystic kidney disease), or increased aortic pulsation (abdominal aortic aneurysm). Peripheral pulses should be examined for quality and bruits. The lower extremities should be examined for edema. A neurologic screening examination is used to identify prior cerebrovascular events. Routine laboratory tests are recommended before the initiation of antihypertensive therapy to identify other risk factors and screen for the presence of target organ damage. These routine tests include blood chemistry (sodium, potassium, creatinine, fasting glucose), lipid profile [total cholesterol, low-density lipoprotein) and high-density lipoprotein (HDL) cholesterol], and a complete blood cell count. Creatinine clearance should be estimated using either the Cockcroft-Gault or the Modification of Diet in Renal Disease (MDRD) formulae. A urinalysis is used to identify proteinuria or hematuria that would suggest the presence of
underlying primary renal disease. A 12-lead electrocardiogram is used to identify left atrial enlargement, LVH, or prior MI. Optional tests, depending on the clinical situation, include 24-hour creatinine clearance, 24-hour urine protein or a spot urine protein to creatinine ratio, serum uric acid, glycosylated hemoglobin, and thyroid function tests. An echocardiogram to identify the presence of LVH may be useful in selected patients to determine the clinical significance of labile hypertension. Most patients with hypertension have primary (essential) hypertension in which no clearly definable underlying etiology is apparent.

In contrast, a wide variety of uncommon conditions can lead to so-called secondary hypertension, some of which are potentially amenable to surgical correction (Table 15-3). Secondary causes of hypertension include underlying chronic kidney disease (CKD), primary hyperaldosteronism (PHA), pheochromocytoma, renovascular hypertension due to fibromuscular dysplasia or atherosclerotic renal artery stenosis, coarctation of the aorta, and Cushing’s syndrome. Secondary causes of hypertension amenable to surgical intervention are so uncommon that extensive diagnostic testing is not warranted. Secondary hypertension should be considered when the patient has onset of hypertension at an early age (younger than 30 years) or late age (older than 55 years); inadequate BP control in a compliant patient on a three-drug regimen which includes a diuretic (resistant hypertension); previously well-controlled hypertension becomes uncontrolled in a compliant patient; hematuria or proteinuria (underlying renal disease) or elevated serum creatinine (renal disease or ischemic nephropathy due to bilateral renal artery stenosis). The initial history, physical examination, and routine laboratory tests are usually all that is required to evaluate for the possibility of secondary hypertension. A normal estimated creatinine clearance and urinalysis are usually sufficient to exclude underlying renal disease as a secondary cause of hypertension. Detection of abdominal or flank masses may indicate polycystic kidney disease, a diagnosis that can be confirmed with ultrasound. Because most patients with PHA have unprovoked hypokalemia while not on diuretic therapy, a measurement of serum potassium is a suitable screening test, and routine measurement of aldosterone levels or plasma aldosterone/renin ratio is not necessary. However, some patients with PHA are normokalemic (when not receiving diuretic therapy). Although routine screening of all patients with hypertension for PHA is not warranted, in a patient with drugresistant hypertension or significant hypokalemia induced by low-dose diuretic therapy, the possibility of PHA should be considered. In this regard, patients with resistant hypertension due to PHA often have a dramatic BP response following the initiation of a mineralocorticoid antagonist (spironolactone or eplerenone). Assessment for any delay or diminution of pulses in the lower extremities, or a discrepancy between arm and leg BP can be used to screen for coarctation of the aorta. A careful assessment of a history of episodic hypertension, associated with headache, palpitations, diaphoresis, and pallor, is all that is usually required to screen for pheochromocytoma. The routine measurement of serum or urine catecholamines is not warranted. Likewise, evaluation for truncal obesity and abdominal purple striae is all that is usually required to screen for Cushing’s syndrome; therefore, routine measurement of serum cortisol or cortisol suppression testing is unnecessary. Several tests are notably absent from the recommended list of routine screening tests for secondary hypertension. Hypertensive intravenous pyelography, renal scanning, captopril renography, and arterial digital subtraction angiography all lack sufficient specificity to be
of any value as routine screening tests for renovascular hypertension. In this regard, the prevalence of renovascular hypertension in the general hypertensive population is so low that the predictive value of a positive test from any of these procedures is abysmal when used as a general screening test.

Obstructive sleep apnea (OSA) is now recognized as an important treatable cause of hypertension. Clues to the presence of OSA include morbid obesity, daytime hypersomnolence, headache, snoring, or fitful sleep. The diagnosis can be confirmed with a sleep study to document apneic episodes. Appropriate treatment with a continuous positive airway pressure device may result in a significant reduction in BP.

A. Goals of Treatment. The goal of treating hypertension is the reduction of cardiovascular and renal morbidity and mortality. Because SBP correlates best with target organ damage and mortality, the primary focus should be on achieving the SBP goal. The goal of treatment is a SBP less than 140 mmHg and a DBP less than 90 mmHg. In hypertensive patients with diabetes or underlying CKD, a BP goal of less than 130/80 mmHg is recommended.

B. Nonpharmacologic Treatment. Lifestyle modification is recommended in the management of all individuals with hypertension, even in those who require antihypertensive drug treatment. All patients should be encouraged to adopt the lifestyle modifications outlined in Table 15-4, especially if they have additional cardiovascular risk factors such as hyperlipidemia or diabetes. Modest weight reduction of as little as 4 kg (10 lb) significantly reduces BP. In addition to the positive effects on overall health, regular aerobic exercise is associated with a significant reduction in BP.