Hypertension is a prevalent disease in the United States. The National Health and Nutrition Examination Survey (NHANES, 2009-2010) estimates that 64 million or 28.6% of adults older than 18 years in the United States have hypertension.¹ In this survey, hypertension was defined as systolic blood pressure (SBP) higher than 140 mm Hg, diastolic blood pressure (DBP) higher than 90 mm Hg, or individuals taking antihypertensive medication. Therefore, the prevalence of hypertension is increasing, with only 24% affected according to the survey conducted in the previous decade (1988-1991; 1999-2000) (Fig. 30-1).^2,3 This increase in prevalence of hypertension in the United States is attributed to increasing age of the population as a whole² and growing rates of obesity.^4,5

The prevalence of hypertension increases with age; 7% of adults between the ages of 18 and 39 years are affected compared with 67% of those 60 years and older.¹ The prevalence of hypertension varies by other demographics as well. Hypertension is slightly more prevalent among women compared with men (29% vs 27%).¹ Among the different ethnic and racial groups in the United States, blacks have the highest prevalence of hypertension.^1,2,5 Similarly, PAD, as manifested by clinical symptoms and ankle-brachial index (ABI), is more common in older blacks compared with whites.⁶ Data from the NHANES found that PAD is also more common in blacks and Mexican Americans compared with whites.⁷

Both elevated SBP and DBP are associated with increased cardiovascular risk. The relative predictive value of SBP versus DBP for cardiovascular risk varies by age group. SBP is more predictive of cardiovascular risk in individuals older than 60 years, whereas DBP is more predictive among those younger than 50 years; in individuals between 50 and 60 years of age, both SBP and DBP have equal predictability.⁸ This phenomenon is due to the high prevalence of isolated systolic hypertension in the elderly. SBP tends to rise more than DBP with aging and arterial stiffness, resulting in a widened pulse pressure.

Hypertension along with tobacco use and diabetes mellitus is a major risk factor for PAD. It is strongly implicated in the pathogenesis of PAD, and accordingly these patients have a high prevalence of hypertension. Quantifying the risk of PAD among hypertensives in part depends on the manner in which investigators define PAD. Data from the Framingham study, in which PAD was defined by intermittent claudication, demonstrated that risk for PAD increases with increasing SBP and DBP in both men and women.⁹ Subsequently, the Framingham study 38-year follow-up data indicated that in both men and women, hypertension is associated with a more than twofold increased risk for PAD as manifested by intermittent claudication.¹⁰ A stronger association exists between PAD and SBP than between PAD and DBP. The NHANES, which also used intermittent claudication to define PAD, found that both untreated hypertension and treated but uncontrolled hypertension are associated with PAD, particularly among the elderly.⁷ Data from studies that use intermittent claudication as the criterion to define PAD must be weighed with caution as it is now known that many patients with PAD as defined by ABI of less than 0.9 do not have classic symptoms associated with intermittent claudication.¹¹

Other studies define PAD according to ABI measurement. Traditionally, an ABI below 0.9 is considered diagnostic of PAD; however, some studies have more conservative criteria, using ABI of less than 0.80 or less than 0.75. Data from NHANES found that among adults older than 40 years, hypertension was strongly associated with prevalent PAD (ABI < 0.9).¹² The Cardiovascular Heart Study demonstrated an inverse relationship between ABI and hypertension.¹³ In this study, hypertension was defined as a blood pressure higher than 160/90 mm Hg or self-reported use of antihypertensives. After adjustment for confounders, a strong inverse relationship persisted for ABI and SBP but not for DBP. With use of ABI as the criterion for PAD in the Rotterdam Study, the prevalence of hypertension (>160/95 mg Hg or use of antihypertensive medications) was 60% for both men and women.¹⁴

Unfortunately, hypertension tends to be undertreated in patients with PAD compared with patients with other forms of cardiovascular disease.¹⁵ Many patients with PAD are often hypertensive at the time of diagnosis. In the Peripheral Arterial Disease Awareness, Risk and Treatment: New Resources for Survival (PARTNERS) trial, 35% to 55% of PAD patients were hypertensive at the time of presentation.¹⁶ The concurrence of hypertension and PAD is associated with an increased risk for cardiovascular disease events.¹⁷ Conversely, hypertension is associated with PAD progression. In a study of patients with PAD observed over time, SBP and smoking were associated with disease progression defined by change in ABI or clinical events during a 4-year period.¹⁸

Renal artery stenosis, a secondary form of hypertension, is prevalent among patients with PAD and hypertension. In a series of patients with PAD undergoing digital subtraction angiography, 33% had renal artery stenosis; in 10%, stenosis was greater than 60%.¹⁹ This is an important consideration in determining the cause of hypertension in PAD and for subsequent blood pressure management.

In summary, hypertension is prevalent in the population as a whole. It is a major risk for atherosclerotic diseases, such as PAD. Therefore, identification of hypertension is important because, if it is untreated, the associated risk of cardiovascular disease events increases.

Definition

Epidemiologic studies and therapeutic trials have often used different criteria to define hypertension in populations. As the eighth report (JNC 8) of the Joint National Committee (JNC) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure is currently still under review and yet to be released, current guidelines for hypertension diagnosis and management are based on the JNC 7 report.²⁰ The JNC 7 defines hypertension as blood pressure higher than 140/90 mm Hg based on the average of two or more properly measured, seated blood pressure readings at each of two or more office visits.

The JNC 7 report also states that individuals with SBP of 120 to 139 mm Hg or DBP of 80 to 89 mm Hg should be considered prehypertensive and require health-promoting lifestyle modifications to prevent cardiovascular disease. In persons older than 50 years, SBP higher than 140 mm Hg is a much more important cardiovascular disease risk factor than DBP. The presence of hypertension is classified by JNC 7 as stage 1 or stage 2 (Table 30-1).

Routine blood pressure measurements should be made with an appropriate-sized cuff to ensure accuracy. At least two measurements should be made. The patient should be seated comfortably, with feet on the floor and back supported, for at least 5 minutes in a quiet room before measurements are taken. The arm should be supported at the level of the heart. Ideally, patients should be free of caffeine and smoking 30 minutes before measurements are taken.

Hypertension, according to ambulatory blood pressure monitoring measurements, is a 24-hour average higher than 130/80 mm Hg or daytime average higher than 140/85 mm Hg.²¹ White coat hypertension is defined as elevated office blood pressures compared with blood pressures obtained in ambulatory settings. Although initially thought to be a benign condition, white coat hypertension is now believed to carry an increased risk for cardiovascular events compared with normotension.²² Although major guidelines do not address this group, practitioners should evaluate these patients for evidence of target organ damage and counsel about lifestyle modification. Finally, masked hypertension occurs when patients are normotensive in the office setting but with elevated outpatient readings. These individuals, often discovered as a result of participation research studies, may have increased risk for cardiovascular events compared with normotensives.²³

Secondary Causes

Patients with resistant hypertension, as defined before, should be evaluated first with a careful history, with particular attention to use of exogenous substances that may lead to elevations in blood pressure (e.g., corticosteroids, weight loss supplements, herbal medication, nonsteroidal anti-inflammatory drugs). Next, the patient’s medications should be reviewed to ensure that adequate doses are being used (regimen should include a diuretic) and that the patient is taking all medications as directed. If these are unrevealing, the patient should be evaluated for secondary causes of hypertension. Patients, such as the elderly, may have pseudohypertension, in which calcified vessels produce falsely elevated blood pressure readings. These individuals may report orthostasis with antihypertensive therapy, have palpable rigid vessels, and lack other evidence of target organ damage.

Once the diagnosis of hypertension has been established, an evaluation for secondary causes that are potentially curable should be done (Table 30-2). The evaluation of secondary causes of hypertension is reviewed elsewhere.²⁴ The physical examination of patients with hypertension should include auscultation for the presence of an abdominal bruit, palpation for an aneurysm, and palpation of the arteries of the limbs for PAD. The initial evaluation of the patient with hypertension should include a complete blood count; chemistry panel, which includes blood urea nitrogen, glucose, calcium, creatinine, and electrolyte determinations; and a fasting lipid profile. A uric acid level is also recommended, especially for patients who may undergo diuretic therapy as this class of medication may result in hyperuricemia. A urinalysis should also be routinely obtained, especially in the diabetic patient who may have microalbuminuria as an early manifestation of nephropathy. Microalbuminuria is also a known risk factor for atherosclerotic disease. Plasma renin activity is not necessary unless the patient is thought to have primary hyperaldosteronism as may be suggested by hypokalemia.

Genetically engineered mouse models have given insight into the complex interaction of blood pressure and atherogenesis. Most mouse models of hypertension exhibited increased atherosclerotic lesion size, although there are some exceptions.²⁵ In addition, there are several reports of reduction in blood pressure resulting in reduced atherosclerosis.²⁵ However, there are studies demonstrating that atherosclerosis can be altered in hypertensive mice without significant lowering of blood pressure.²⁵ Therefore, the stimulus for hypertension, for example, activation of the renin-angiotensin system, may be as important as the severity of hypertension for development of atherosclerosis.

One of the strongest correlations between blood pressure and atherosclerosis is perturbation in the renin-angiotensin system. This hormonal system is responsible for homeostatic control of arterial pressure, tissue perfusion, and extracellular volume. The juxtaglomerular cells located in each nephron produce renin, which converts angiotensinogen (produced mainly in the liver) to angiotensin I. Angiotensin-converting enzyme (ACE) converts angiotensin I into angiotensin II, which is a potent vasoconstrictor and mediator of aldosterone secretion. Studies of hyperlipidemic mice in which angiotensin II was chronically infused showed promotion of atherosclerosis independent of changes in arterial blood pressure.²⁶ Furthermore, several studies showed that pharmacologic inhibition of the renin-angiotensin system reduces the development of atherosclerosis independently of blood pressure reduction.²⁵

A pathologic interaction between hypercholesterolemia and hypertension has recently emerged. One study evident of this maladaptive relationship involved the administration of angiotensin II to men with normocholesterolemia and to men with hypercholesterolemia. The blood pressure response to angiotensin II was exaggerated in the hyper­cholesterolemia group, and this response was blunted by cholesterol reduction.²⁷ Studies in animals indicate that the combination of renin-angiotensin inhibition and statin significantly reduces atherosclerosis compared with renin-angiotensin inhibition alone, probably through ablation of inflammatory signals.²⁸ The results from randomized trials in human subjects confirm the antihypertensive effect seen in animals. A study of 41 patients taking medication for hypertension was conducted whereby patients were randomized to statin versus dietary control. After 3 months, the statin group had a greater reduction in blood pressure compared with the control group.²⁹ Some data suggest that statins may also have a salutary effect on vascular elasticity.²⁸

Endothelial Dysfunction and Hypertension

Endothelial dysfunction occurs early in the atherosclerotic process, and hypertension is associated with endothelial dysfunction in the coronary, renal, and peripheral circulation. Studies in animals and humans using an agonist-induced vasodilator response show that this response is blunted in the setting of hypertension.³⁰ One key molecule, partially responsible for the vasodilator response and involved in maintaining normal endothelial function, is nitric oxide. A reduction in endothelium-derived nitric oxide may result in not only a reduced vasodilator response but also a proinflammatory, prothrombotic, and procoagulant phenotype (Fig. 30-2). The genetic deletion of endothelial nitric oxide synthase, the enzyme necessary for generating nitric oxide, resulted in significantly increased SBP (128 ± 3 vs 108 ± 5 mm Hg; P < .001) and decreased heart rate (531 ± 22 vs 629 ± 18 beats/minute; P < .001) compared with wild-type controls.³¹ Although it seems clear that endothelial dysfunction is a consequence of hypertension, the data regarding endothelial dysfunction as a precursor to hypertension are mixed. One study in the offspring of essential hypertension patients evaluating forearm blood vessel vasodilatation with acetylcholine found a blunted response compared with those without a family history of hypertension.³² Another more recent study evaluating flow-mediated vasodilatation of the brachial artery did not discern a difference between offspring of hypertensive patients and those without family history.³³ More research is needed to identify those subjects predisposed to development of hypertension.

Renal artery stenosis is most commonly due to atherosclerotic disease and may lead to renovascular hypertension. The consequence of the reduction in blood flow to the kidney is activation of the renin-angiotensin-aldosterone system and possibly ischemic nephropathy. One hypothesis proposed that some of the humoral factors activated by the renal artery stenosis may accelerate the atherosclerotic process.³⁴ Experimental studies of pigs with hypertension secondary to renal artery stenosis showed that increased oxidative stress resulted from this condition and was a stimulus for atherosclerosis independent of cholesterol levels.³⁵ Clinical evidence is also supportive of this hypothesis, which may explain the relatively high prevalence of renal artery stenosis in individuals with cardiovascular disease in other arterial territories.

General Principles

Effective therapy for hypertension usually involves a combination of lifestyle modifications and pharmacotherapy.

Pharmacotherapy

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