ACP medicine, 3rd Edition
Gary L. Schwartz MD, FACP1
Associate Professor of Medicine
Sheldon G. Sheps MD, FACP2
Professor of Medicine (Emeritis)
1Mayo Medical School; Head of Section, Hypertension, Division of Nephrology and Hyptertension, Mayo Clinic
2Department of Hypertension, Mayo Medical School
The authors have no commercial relationships with manufacturers of products or providers of services discussed in this chapter.
Hypertension is the most common chronic disorder in the United States, affecting over 31% of the adult population.1 It is the most common reason adults visit the doctor's office. In the year 2000, hypertension accounted for more than 1 million office visits to health care providers. The prevalence increases with age: for a normotensive middle-aged person in the United States, the lifetime risk of developing hypertension approaches 90%.2 With the increasing age of the population in most developed and developing societies, it seems safe to assume that hypertension will become steadily more widespread in the coming years.
Hypertension is a major risk factor for stroke, myocardial infarction, heart failure, chronic kidney disease, progressive atherosclerosis, and dementia.3,4,5 The treatment of hypertension is highly effective in reducing cardiovascular (CV) morbidity and mortality.6,7 However, despite widespread public and professional education regarding the risks of hypertension and the benefits of treatment, and despite the ready availability of effective therapies, only 58% of adults with hypertension are receiving treatment, and in only 31% is hypertension controlled.8,9 A number of factors have been identified that contribute to poor control rates for hypertension.10 Improving these rates depends on setting appropriate, patient-specific, evidence-based therapeutic goals, understanding and using available treatment options in an efficient and cost-effective manner, involving the patient in goal setting and the care process in an empathetic manner, and employing timely follow-up to monitor and adjust therapy as necessary. It is important to recognize that multiple classes of drugs are often needed for control; that patient education, communication, and involvement in the process are vital to long-term compliance; and that systematic approaches to therapy are required to achieve and maintain control over time.
Blood pressure (BP) is a quantitative trait that is continuously distributed in the population. Essential hypertension represents the upper end of the distribution of this trait and is defined by the BP level associated with a threshold value of increased CV risk. Any definition of hypertension is arbitrary because the risk of CV disease related to BP level increases steadily across the spectrum of BP values. On the basis of a meta-analysis of studies relating BP level to vascular mortality, optimum BP is defined as less than 115/75 mm Hg.11 According to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), normal BP (the level associated with minimal risk) for adults 18 years of age or older is a systolic BP of less than 120 mm Hg and a diastolic BP of less than 80 mm Hg [see Table 1].8 Blood pressures ranging from 120 to 139 mm Hg systolic or 80 to 89 mm Hg diastolic are considered prehypertensive. Patients with BP in this range are at increased risk for the development of target organ injury and for progression to definite hypertension over time.11,12 Therefore, these patients should have annual BP checks and be educated in strategies to lower BP and CV risk and to prevent the development of hypertension [see Prevention of Hypertension, below]. For patients with diabetes or renal disease, BP in the prehypertensive range poses a significantly higher risk than for healthy persons, and a lower threshold for intervention is indicated for these patients: above 130 mm Hg systolic or 80 mm Hg diastolic.
Table 1 Classification of Blood Pressure for Adults 18 Years of Age and Older8
For the general population, hypertension is defined as a systolic BP of 140 mm Hg or higher or a diastolic BP of 90 mm Hg or higher. Hypertension is further divided into two stages, defined on the basis of the highest level of either the systolic or diastolic BP. Prospective drug intervention trials have demonstrated the benefit of treatment for patients with a diastolic BP of 90 mm Hg or higher. Isolated systolic hypertension (ISH), which occurs mainly in persons older than 55 years, is defined as a systolic BP of 140 mm Hg or higher and a diastolic BP of less than 90 mm Hg. ISH is the most common hypertension subtype in older adults, who are the most rapidly growing segment of the population.13 Epidemiologic data clearly demonstrate elevated and graded risk associated with systolic BP higher than 115 mm Hg.11However, those drug intervention trials that showed a benefit enrolled only subjects whose systolic BP was 160 mm Hg or higher7; the benefits of drug intervention for patients with ISH whose pretreatment systolic BP is below 160 mm Hg is inferred.
Currently, it is estimated that at least 65 million adults in the United States have hypertension or are taking antihypertensive medications.1In addition to definitive hypertension, an additional 45 million adults in the United States have prehypertension.
In developed societies, BP increases with age. Diastolic BP plateaus in the fifth decade and may decline thereafter, but systolic BP continues to rise through the seventh decade. In persons younger than 50 years, diastolic BP level is the major predictor of CV risk, whereas in persons older than 60 years, systolic BP is the major predictor.14 Individual risk is related to the level and duration of BP, as well as to the presence of other CV risk factors and of injury to so-called target organs—brain, heart, kidneys, peripheral arteries, and retina.3
The relationship between BP and CV morbidity and mortality begins in patients whose BP is higher than optimal levels (115/75 mm Hg) and is strong, continuous, graded, consistent, and independent. The relationship between BP and CV risk has largely been determined in middle-aged and older people, but above-normal BP in young adulthood is also related to increased long-term CV and all-cause mortality.15 In young adulthood and early middle age, hypertension is more common in men than in women, but the opposite is the case in persons 60 years of age and older.9 At all ages, hypertension is more common in African Americans than in whites; in all ethnic and racial groups, it is more common in the economically disadvantaged. At any given level of BP, CV risk is greater in men than women, in blacks than whites or members of other racial or ethnic groups, in older persons than younger ones, and in patients with target organ disease and longer duration of hypertension.3
Etiology and Genetics
Essential hypertension develops as the consequence of a complex interplay over time between susceptibility genes and environmental factors. Numerous family and population studies suggest a significant role for genetic factors. Hypertension in persons younger than 55 years is four times more common in individuals with a family history of hypertension than in those with no family history of it. Estimates of the genetic contribution to BP variation range from 30% to 50%. However, the genetic contribution to essential hypertension is complex. Multiple genes are likely involved, and although the effects of some genes may affect BP independently, most genetic effects involve both gene-gene interaction (epistasis) and gene-environment interaction. Important interactions between the effects of specific genes and environments may occur at a particular time (perinatal life) or over the lifetime of an individual. Thus, sorting out the genetic contribution to essential hypertension is complex and challenging.
Some insight into the genetic contribution to essential hypertension has been gained from the identification of rare monogenic forms of hypertension.16 Interestingly, most of these forms of hypertension arise from gene mutations that result in impairment of renal sodium excretion; impairment occurs either through the disruption of the renal sodium transport systems or through interference with mineralocorticoid receptor activity. Additional insight has come from studies that employ a candidate gene approach, in which genes are chosen on the basis of animal studies or previous knowledge of genes that encode proteins involved in BP regulatory pathways. Polymorphisms of candidate genes have been studied in association and linkage studies to assess their potential role in essential hypertension in humans. Most extensively studied have been genes encoding components of the renin-angiotensin-aldosterone system. Results of this line of investigation have implicated polymorphisms of the angiotensinogen (AGT) gene (AGT) and the angiotensin-converting enzyme (ACE) gene (ACE) in human essential hypertension.17,18 The M235T variant of AGT has been associated with higher circulating levels of AGT and is found more often in hypertensive than in normotensive persons.18 An insertion/deletion polymorphism of ACE has been associated with differences in ACE activity, with higher levels associated with the deletion allele.19 The deletion allele has also been associated with several cardiovascular phenotypes, including higher BP levels and greater risk of target organ complications in hypertensive individuals.17,20 In large samples, the observed associations have frequently been gender specific, suggesting interaction between the effects of the insertion/deletion polymorphism and gender.17,21
Variants of other genes have been implicated in essential hypertension. Adducin is a membrane skeleton protein consisting of α and β subunits that may influence ion transport across membranes. A variant of the α-adducin gene (Gly 460 Trp) has been associated with essential hypertension in case-control studies and may play a role in salt-sensitive hypertension.22 Linkage studies have also found evidence indicating a role for variants of adrenergic and dopamine receptor genes.23 Some evidence supports a possible role for variants in genes encoding the epithelial sodium channel, atrial naturetic peptide, G-proteins, the glucagon receptor, insulinlike growth factor 1, the endothelin system, endothelial nitric oxidase synthase, apolipoproteins and cytokines.24 Experts expect that the number of gene polymorphisms associated with essential hypertension will continue to grow. However, because of the limitations of candidate gene studies and of linkage and association studies, there is a need for new approaches that can assess the effects of multiple genes and environments. These types of studies will be difficult to perform but will be necessary if we are to someday be able to determine the specific genotypes and environments present in the majority of persons destined to develop hypertension.25
Regarding the role of genetics in hypertension, it is important to note that hypertension is virtually nonexistent in primitive peoples who follow a preagricultural hunter-gatherer lifestyle. This lifestyle involves significant daily physical activity and a diet rich in potassium and low in fat and sodium. Obesity is uncommon. Dietary patterns involve periods of feasting interspersed with long periods with minimal food. Given that the human gene pool has changed little over the past 30,000 years, some suggest that hypertension is the consequence of a human genome selected for a hunter-gatherer lifestyle but now interacting with a modern one. In contrast to primitive societies, modern societies are characterized by a low level of physical activity and constant availability of abundant food that is rich in sodium and fat and low in potassium; the result is an increase in body weight with aging and a high incidence of obesity. Genetic adaptation to the hunter-gatherer lifestyle provided survival advantages in that environment but may now be contributing to many modern diseases such as obesity and hypertension.
Pathophysiology and Pathogenesis
Simplistically, BP is the product of cardiac output and peripheral vascular resistance (BP = cardiac output × peripheral vascular resistance). Thus, variations in extracellular fluid volume, the contractile state of the heart, and vascular tone determine variation in BP level. The hemodynamic hallmark of established essential hypertension is elevated peripheral vascular resistance. An increase in cardiac output is occasionally noted early but is not a persistent finding. Hypertension can be viewed as the final outcome of a complex interaction between genetic and environmental factors that act on intermediate physiologic systems involved in BP regulation (i.e., those that influence fluid volume, heart contractility, and vascular tone).
A central hypothesis for the pathogenesis of essential hypertension involves an interaction between the high dietary sodium intake typical of industrial society and defects in renal sodium excretion. Evidence of a role for dietary sodium comes from animal studies and from epidemiologic and experimental studies in humans.26,27 Guyton hypothesized that hypertension develops when the kidneys require a higher BP to maintain extracellular volume within normal limits.28 This would occur in persons with impaired renal sodium excretion. Studies support the possibility of an inherited defect in renal sodium excretion as the basis of human essential hypertension. Most monogenic forms of hypertension discovered so far involve mutations that impair renal sodium excretion by increasing mineralocorticoid activity or by influencing tubular sodium transport systems.16 Moreover, renal sodium excretion can be influenced by variations in activity of both the renin-angiotensin-aldosterone system and the sympathetic nervous system. Angiotensin II enhances renal tubular sodium reabsorption directly and indirectly through stimulation of aldosterone release and the sympathetic nervous system. Additional mechanisms that may explain defective renal sodium excretion include an inherited reduction in the number of nephrons, as well as the presence of a subpopulation of so-called ischemic nephrons, which occur as a result of increased afferent renal artery tone and lead to increased renin activity.29,30 Extracellular volume expansion could lead to chronic increases in vascular resistance through mechanisms of organ autoregulation of blood flow (i.e., variation in the tone of vessels that occurs so as to regulate organ blood flow to meet metabolic needs). Some studies have suggested that volume expansion stimulates the release of a sodium-potassium-adenosine triphosphatase (Na+,K+-ATPase) inhibitor (i.e., an ouabainlike substance) that facilitates renal sodium excretion but increases vascular tone by interfering with sodium-calcium exchange in vascular smooth muscle cells.31
Other evidence suggests that increased sympathetic nervous system activity has a role in causing hypertension in some persons.32 These cases could be the result of a genetic tendency toward increased sympathetic activity interacting with repetitive psychogenic stress, obesity, or high sodium intake. Hypertension could also arise or be sustained by defects in baroreceptor function.33
Weight gain and obesity (especially abdominal fat accumulation) are associated with an increased risk of hypertension. A number of humoral factors may be responsible, including increased activity of the sympathetic nervous system and the renin-angiotensin system.34 In addition, obesity is associated with insulin resistance and hyperinsulinemia. Hyperinsulinemia may directly stimulate sympathetic activity, in addition to promoting vascular hypertrophy (increased vascular tone) and renal sodium retention.35 In addition, leptin levels are increased in obese individuals. Leptin may also increase BP by stimulation of the sympathetic nervous system.36
More general abnormalities of cell membranes or multiple ion transport systems acting across cell membranes could contribute to the development of hypertension. In addition to impairing sodium excretion in the kidneys, these defects could act in a variety of ways to influence vascular structure and tone.37 Vascular tone could also be influenced by variation in vascular endothelial function through an imbalance in the production of substances that cause vasodilation (e.g., nitric oxide) and those that cause vasoconstriction (e.g., endothelin).38
The role of progressive stiffness in the aorta and its major branches as a cause of the progressive rise in systolic BP with age has received increasing attention in recent years.39,40 In younger persons, the aorta is elastic, and expands as blood is ejected into it during systole. This retained blood is then transmitted to the periphery during diastole, supporting diastolic BP. As the aorta and its main branches stiffen, in association with aging and other factors, the aorta dilates less during systole. This leads to a higher systolic pressure. In addition, because more blood is forced into the periphery during systole, less is available during diastole, and diastolic pressure decreases. This causes the familiar widening of pulse pressure (i.e., the difference between systolic and diastolic BP) with age. Moreover, as blood is ejected into the aorta, a forward pressure wave is generated that travels along the vessel and into the periphery. The forward wave is partially reflected at points of vessel branching and by smaller vessels in the periphery. These reflections summate to form a composite reflected pressure wave that returns to the central aorta in late systole or early diastole and is referred to as the augmentation pressure. Forward pulse-wave velocity increases with progressive aortic stiffness. Consequently, the reflected wave (i.e., the augmentation pressure) arrives earlier at the central aorta, which further increases the peak central aortic pressure.41
The diagnosis of hypertension relies on multiple office measurements of BP performed in a rigorous manner with a validated and well-maintained mercury or aneroid sphygmomanometer and a cuff of appropriate size. Several expert groups have published guidelines for proper BP measurement; unfortunately, these guidelines are rarely complied with in most clinics [see Table 2].42,43 The diagnosis of hypertension requires findings of an elevated average BP on at least two office visits, with at least two standardized measures of BP made at each visit. For most patients, confirmation can occur over a 1- to 2-month period. If an initial BP is severely elevated, confirmation should occur over a shorter period. Self-measurements of BP outside the office setting can be used to distinguish sustained hypertension from isolated clinic hypertension; self-measurement has the further advantages of involving patients in the process of care (which often improves compliance) and aiding in the assessment of response to therapy. On average, home readings are lower than office readings; therefore, values above 135 mm Hg systolic or 85 mm Hg diastolic are considered elevated.8 BP devices for home use (aneroid or oscillometric) need to be validated twice yearly by the health care provider, and patients need to be educated in the technique of proper BP measurement [seeTable 2].
Table 2 Proper Blood Pressure Measurement Technique
AMBULATORY BLOOD PRESSURE MONITORING
Cross-sectional studies show that BP averages from ambulatory BP monitoring (ABPM) correlate better with the presence of target organ injury (especially left ventricular hypertrophy [LVH]) than office BP measurements.44 Also, prospective studies and population-based observational studies have shown that average BP derived from ABPM predicts additional risk for CV events after adjustment for clinic or office BP.45 This is true for both untreated as well as treated patients.46,47 ABPM is the best method of establishing the presence of isolated clinic hypertension (so-called white-coat hypertension), which is defined as an elevation in BP that occurs only in the clinic setting, with normal BP in all other settings, in the absence of evidence of target organ injury.8 Screening for white-coat hypertension is currently a reimbursable indication for ABPM by Medicare.48 The possibility of a white-coat effect should be considered in selected patients with resistant hypertension, in elderly patients with significant office systolic hypertension, and in some pregnant women. Although white-coat hypertension is associated with lower risk than sustained hypertension, it is a predictor of future sustained hypertension in some persons.49Other uses for ABPM include assessment of hypotensive symptoms, episodic hypertension, and suspected autonomic dysfunction in patients with postural hypotension.8 ABPM is also useful in the evaluation of the occasional patient with hypertensive target organ injury (e.g., LVH, stroke) whose office BP is normal. Some of these patients have so-called white-coat normotension, or masked hypertension; for these patients, BP is normal in the office but is elevated outside the office setting.50 This important group is often missed in routine practice unless target organ injury is manifested.
The initial evaluation of patients with elevated BP has four major objectives: (1) to identify lifestyle factors contributing to elevated BP and higher CV disease risk, (2) to identify associated modifiable CV risk factors, (3) to assess for target organ injury or clinical CV disease, and (4) to identify any secondary causes of hypertension.8 The second and third objectives are important for risk stratification, which defines the BP threshold for initiation of drug therapy and establishes the BP goal to achieve with therapy.51,52
The overall frequency of secondary hypertension is 5% to 10% in primary care practices. The classic picture of essential hypertension should be compared with the individual patient's presentation [see Table 3]. Secondary hypertension should be suspected on finding features that are not consistent with essential hypertension. Such features include age at onset younger than 30 or older than 50 years; BP higher than 180/110 mm Hg at diagnosis; significant target organ injury at diagnosis; hemorrhages and exudates on retinal examination; renal insufficiency; LVH; poor response to appropriate three-drug therapy; and the presentation of accelerated or malignant hypertension. Specific features that suggest secondary causes of hypertension vary with the individual condition [see Table 4].
Table 3 Classic Features of Essential Hypertension
Table 4 Features Suggesting Specific Causes of Secondary Hypertension
The clinician should inquire about a family history of hypertension, premature CV disease, and disorders that would increase the possibility of secondary hypertension (e.g., polycystic kidney disease or other renal disease, medullary cancer of the thyroid, hyperparathyroidism, or pheochromocytoma). The patient should be questioned about lifestyle habits that influence BP (e.g., level of physical activity, sodium intake, use of caffeine and alcohol, history of weight gain), and CV risk (e.g., tobacco use); in addition, the patient should be asked about symptoms suggesting target organ disease (e.g., angina, symptoms of heart failure, transient cerebral ischemia, or renal disease) or secondary hypertension (e.g., spells suggesting pheochromocytoma). A known history of dyslipidemia, diabetes, or cerebrovascular, heart, or renal disease also should be documented. In addition, a thorough medication review (including prescription and over-the-counter drugs, herbs and herbal compounds, and street drugs) is important to identify drugs that can raise BP or interfere with the antihypertensive effect of planned drug therapy [see Table 5].53 In patients with a history of hypertension, the physician should ascertain the duration of hypertension, the previous BP levels, and the specific drugs used for treatment, together with the efficacy of those drugs and the reasons for discontinuing them. Other comorbid conditions and their treatments need to be documented, because they may influence antihypertensive drug selection.
Table 5 Drugs That Can Increase Blood Pressure or Interfere with Antihypertensive Drug Efficacy
The examination should include at least two standardized measurements of BP with the subject in the seated position. Initially, BP should also be measured in the opposite arm (to identify arterial narrowing, which can cause an inaccurately low reading in one arm) and in the standing position, especially in diabetic patients and older patients (to identify orthostatic declines). Height and weight should be determined to permit calculation of body mass index, and waist circumference (a potential CV risk factor) should be recorded.
The physical examination is directed toward identifying target organ injury or features suggesting secondary hypertension [see Table 4]. Retinal examination should be performed, primarily to identify changes resultling from diabetes or severe hypertension (i.e., hemorrhages, exudates, papilledema). Arteriolar narrowing, focal constrictions, and arteriovenous nicking on retinal examination are more closely associated with atherosclerosis and are of limited value for predicting the severity of hypertension or assessing overall CV risk.52,54
Laboratory studies are performed to support the general goals of the initial evaluation [see Table 6]. In addition, they provide baseline information for monitoring in patients who are subsequently treated with antihypertensive drugs that can influence laboratory values (i.e., diuretics, beta blockers, ACE inhibitors, and angiotensin receptor blockers [ARBs]). Additional studies are not advised unless the history, physical examination, or initial laboratory studies are inconsistent with essential hypertension or suggest a specific secondary etiology.
Table 6 Laboratory Evaluation of Newly Diagnosed Hypertensive Patients
If the initial assessment suggests renal dysfunction, the patient should be evaluated for chronic kidney disease by measuring 24-hour urinary protein excretion and estimating glomerular filtration rate (GFR). Equations are available to estimate GFR [see Table 6].55,56 The Modification of Diet in Renal Disease (MDRD) equation requires measurement of blood urea nitrogen and serum albumin concentrations in addition to serum creatinine concentration. The estimate of GFR can also be calculated with an online tool (available atwww.hdcn.com/calcf/gfr.htm).
At any given level of BP, specific factors in an individual patient may result in deviations above or below the average CV risk observed in population studies. These factors are used to determine the BP threshold and timing of drug therapy and the BP goal for the individual patient. Individual specific factors that determine risk include the presence of other CV risk factors and the presence of injury to the target organs of hypertension or clinical CV disease.3 A simple and clinically useful scheme modified from the JNC 6 report separates patients into three levels of risk [see Table 7].51 This scheme suggests aggressive treatment and lower BP goals for patients at the highest level of risk and more conservative treatment and BP goals for patients at the lowest level of risk. For example, in a patient with diabetes, drug therapy is indicated initially (along with lifestyle changes) when BP exceeds 130/80 mm Hg. In contrast, in a young patient who has no other CV risk factors or evidence of target organ injury or CV disease, a 6- to 12-month trial of lifestyle changes rather than drugs is indicated as initial therapy unless BP is stage 2 (≥ 160 mm Hg systolic or ≥ 100 mm Hg diastolic). In these low-risk cases, the goal BP is less than 140/90 mm Hg. Guidelines from Europe provide an even more detailed approach to risk stratification.52
Table 7 Risk Stratification and Treatment in Hypertensive Patients8,51,52
Prevention of Hypertension
In many cases, the assessment will show BP in the prehypertensive range (i.e., 120 to 139/80 to 89 mm Hg); in the United States, 22% of adults, or approximately 45 million persons, fit this category. Preventive care is indicated in these patients.57
Multiple studies support the effectiveness of environmental manipulation in preventing or delaying the onset of hypertension.58,59,60,61,62,63Prevention of hypertension is important, given that treatment of established hypertension is only partly effective in reducing the associated morbidity and mortality.64 Furthermore, the relationship between BP level and CV morbidity and mortality is continuous and extends into nonhypertensive levels; approximately one third of the coronary artery disease deaths attributable to BP occur in persons whose BP is in the prehypertensive range. Prevention strategies that lower BP in prehypertensive patients extend the benefits of BP reduction to this large group.
Currently, the use of pharmacologic interventions for the treatment of prehypertension is limited to high-risk patients with diabetes or chronic kidney disease when BP exceeds 130/80 mm Hg. Pharmacologic treatment of prehypertension can delay the development of high blood pressure.65 However, use of drug therapy for all patients with prehypertension cannot be justified at this time.
The risk of developing hypertension is increased in African Americans and in all persons with prehypertension or a family history of hypertension. Reversible patient characteristics associated with an increased risk of developing hypertension include being overweight or obese; having a sedentary lifestyle; ingesting a high-sodium, low-potassium diet; using excessive amounts of alcohol; and manifesting the so-called metabolic syndrome. The metabolic syndrome is defined as three or more of the following conditions: abdominal obesity (waist circumference > 40 inches in men or > 35 inches in women), glucose intolerance (fasting blood glucose ≥ 110 mg/dl [or 100 mg/dl, depending on the organization]), BP of 130/85 mm Hg or higher, elevated triglycerides (≥ 150 mg/dl), or low high-density lipoprotein (HDL) cholesterol (< 40 mg/dl in men or < 50 mg/dl in women).66 Clinical trials support the efficacy of seven interventions in such people for the primary prevention of hypertension [see Table 8].57,58,59,61 Combining interventions is beneficial.67,68 For patients with the metabolic syndrome, in addition to intensive lifestyle modifications, drug therapy is recommended for management of each of its components when appropriate.
Table 8 Lifestyle Modifications for Hypertension Prevention and Management
The overall goal of treatment in hypertensive patients is to reduce the risk of CV morbidity and mortality by lowering BP and treating other modifiable risk factors. In general, the goal is to lower BP to below 140/90 mm Hg. In patients with heart failure, diabetes, or renal disease, the goal is to lower BP to below 130/80 mm Hg. In older patients with ISH, the goal is to lower systolic BP to below 140 mm Hg.
These goals are achieved through lifestyle modification and, in most cases, drug therapy [see Table 9]. In addition, comorbid conditions such as dyslipidemia or diabetes should be addressed.66 Low-dose aspirin should be considered once BP is controlled.69 Self-measurement of BP should be encouraged.43
Table 9 Antihypertensive Drugs
Observational studies have identified several environmental factors associated with hypertension, and prospective studies have demonstrated BP lowering with manipulation of these factors [see Table 8].58,59,61,67,68,70,71,72,73,74 In addition to lowering BP, lifestyle recommendations are designed to reduce overall CV risk. These measures should be advised for all patients with BP above the normal level. Tobacco use should be discouraged because, in addition to being a powerful CV risk factor, each cigarette smoked elevates BP for 15 to 30 minutes, and multiple cigarettes can raise BP for most of the day. A device that facilitates deep-breathing exercises (RESPeRATE) has been shown to lower BP and can be considered as an adjunct to lifestyle and drug treatments.75
The JNC 7 report recommends thiazide diuretics as initial drugs of choice for most patients; this recommendation is based on the totality of data from randomized trials, including the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).8,76,77,78Critics of diuretics have cited evidence suggesting that diuretic-based treatment does not provide protection from coronary artery disease events to the degree predicted from epidemiologic studies. The ALLHAT was designed to determine whether treatment with a diuretic would be inferior to treatment with an alpha blocker, a calcium antagonist, or an ACE inhibitor in preventing fatal and nonfatal coronary artery disease events in a high-risk group of adults with essential hypertension. The study showed no difference among the drugs for the outcome of fatal and nonfatal coronary artery disease or total mortality, regardless of the patient's race.79 Moreover, diuretic treatment was superior to alpha blocker, calcium antagonist, or ACE inhibitor treatment with some CV disease outcomes. The alpha-blocker arm of the trial was terminated early because of an almost twofold increase in the risk of heart failure compared with the diuretic group. On the basis of these results, alpha blockers are no longer considered an appropriate initial therapy for hypertension. Compared with the diuretic group, the calcium antagonist group also had a higher risk of heart failure. Compared with the diuretic group, the ACE inhibitor group had an increased risk of stroke and combined CV disease, but much of the increased risk occurred in blacks, in whom BP control with the ACE inhibitor was inferior to the control achieved with the diuretic. In addition, there was no evidence that calcium channel blockers or ACE inhibitors are superior to a thiazide diuretic as initial therapy in patients with diabetes mellitus or chronic kidney disease.80,81
Alternative medications should be considered if diuretics are contraindicated or are poorly tolerated or there is a compelling indication for a drug from a different class. Alternative drug choices are beta blockers, ACE inhibitors, ARBs, and calcium antagonists.
A subsequent study contradicted the results of ALLHAT and suggested that ACE inhibitors are superior to diuretics in older men.82 In truth, differences in outcomes by drug choice likely reflect differences in achieved BP rather than unique effects of specific agents.83 Therefore, achieving the BP goal is more important than the specific agents used to achieve it.
The role of beta blockers as an alternative initial treatment of uncomplicated primary hypertension is controversial. One meta-analysis found that the effect of beta blockers is less than optimum compared with that of other antihypertensive drugs, with an increased risk of stroke; these reviewers concluded that beta blockers should not remain a first-choice option in the treatment of primary hypertension.84 Another meta-analysis also found relatively increased risk, particularly of stroke, in patients 60 years of age and older, but concluded that in younger patients, beta blockers are associated with a significant reduction in cardiovascular morbidity and mortality.85
Randomized clinical trials suggest that the presence of certain comorbid conditions constitutes a so-called compelling indication for selection of specific drugs [see Table 10]. Other considerations that should influence drug selection include concomitant conditions for which some agents may be beneficial and others contraindicated [see Tables 10 and 11], potential drug-drug interactions, concerns about quality of life, and cost (generic formulations are available for diuretics, beta blockers, calcium antagonists, and ACE inhibitors). Finally, demographics should be considered: in general, older patients and blacks respond better to diuretics and calcium antagonists, whereas younger patients and whites respond better to beta blockers, ACE inhibitors, and ARBs. Blacks are more likely to sustain oxidative stress from endothelial dysfunction. Nebivolol, a new beta blocker that also has vasodilating and antioxidant properties, has proved especially effective in blacks; however, this agent is not yet available in the United States.86
Table 10 Patient Condition and Choice of Antihypertensive Drugs
Table 11 Contraindications to Antihypertensive Drugs
In general, the drug chosen should have a long half-life (once-daily dosing is preferable). It should be continued only if the patient tolerates it and is comfortable with its cost, because these are important factors in long-term compliance. To achieve currently recommended goal BP levels, many patients will require more than one drug; this possibility should be discussed at the outset with the patient. Regardless of the agent chosen, BP should be reassessed after 2 to 4 weeks of treatment [see Figure 1].
Figure 1. Overview of drug treatment for hypertension.
The JNC 7 report suggests initiation of therapy with two drugs (combination therapy) rather than a single agent if BP is more than 20 mm Hg systolic or 10 mm Hg diastolic above the treatment goal.8 Generally, a two-drug regimen should include a diuretic appropriate for the level of renal function. However, a 2005 study in high-risk hypertensive patients 40 to 79 years of age demonstrated that combination therapy with a calcium channel blocker and an ACE inhibitor prevented more major cardiovascular events and induced less diabetes than therapy with a beta blocker and a diuretic.87
An increasing number of antihypertensive combination products are available in a number of dosing options.8 Although combination products may be more convenient, it is often less expensive to use individual agents, because generic forms of the component drugs are frequently available. In addition, titration of doses of the two agents may be easier when the two drugs are prescribed separately. Once BP control is achieved with given doses of two agents, switching to the same therapy in combination form can be considered to enhance compliance, if cost is not prohibitive.
The advantages and disadvantages of using combination products have been reviewed.88 Caution is advised when using combination drugs as initial therapy in older persons and diabetic patients, because of the increased risk of precipitous declines in BP or aggravation of orthostatic hypotension.
Improving Control Rates
In general, significant progress has been made in lowering BP in patients with hypertension. Although the proportion of patients with BP lower than 160/95 mm Hg has increased significantly since the 1970s, the percentage of patients with controlled hypertension (defined as systolic BP maintained below 140 mm Hg and diastolic BP below 90 mm Hg) remains low. It is estimated that control of hypertension was accomplished in 31% of patients for the period from 1999 to 2000.9 This is well below the Healthy People 2010 goal of at least 50% of patients achieving control. It is commonly believed that the major factors responsible for lower control rates are lack of access to health care and patient noncompliance. It is also believed that the population of patients with uncontrolled hypertension comprises disproportionately large numbers of ethnic and racial minorities. However, studies suggest that other factors are also important. Analyses of the Third National Health and Nutrition Examination Survey (NHANES III) identified factors associated with the likelihood both of attaining control of hypertension and of failing to attain control.89 Factors associated with an increased likelihood of controlling hypertension included being married (greater social support), having private health insurance, visiting the same health care facility or having the same provider over time, having had BP measured within the previous 6 to 11 months, and using lifestyle modifications in the treatment program. On the other hand, factors associated with an increased likelihood of uncontrolled hypertension included being 65 years of age or older, being male, being black, and failing to see a physician in the preceding year. Interestingly, not having health insurance or not having a source of health care was not predictive of uncontrolled hypertension.
Most cases of uncontrolled hypertension occur in older persons and represent mild ISH (systolic BP, 140 to 160 mm Hg).90 In a study of self-reported treatment practices among primary care physicians, 43% of physicians would neither start drug therapy for a patient whose systolic BP is between 140 and 160 mm Hg nor intensify treatment for a patient whose systolic BP is 158 mm Hg.91 In this study, 41% of the caregivers were unfamiliar with national hypertension guidelines. Further analysis showed that providers who were familiar with the guidelines had a lower BP treatment threshold. Other studies of physician practices have shown similar results. Emerging from these studies is the realization that a major factor in continued poor control rates for hypertension is a tolerance by the health care provider of elevated systolic BP, especially in older patients. On the basis of these study results, health care providers should consider steps to improve control rates in their practice [see Table 12]. Familiarity with the epidemiology of uncontrolled hypertension may be useful in this regard.10
Table 12 Considerations for Improving Blood Pressure Control Rates
Studies conducted to determine what causes resistant hypertension have used different definitions of the term. In most studies, hypertension was considered resistant or refractory if control was not achieved with a combination of lifestyle modifications and the rational use of full therapeutic doses of two or three antihypertensive medications, one of which was a diuretic appropriate for the level of renal function. Studies suggest five issues to consider when evaluating patients with resistant hypertension51: noncompliance with therapy, interfering substances, an inappropriate drug regimen, office hypertension or pseudohypertension, and secondary hypertension. In most cases, causative factors will be identified if these five issues are given careful attention.
Lack of BP control often results from noncompliance with the drug regimen or diet. Common reasons for noncompliance with drug therapy include drug costs, side effects, complex dosing schedules, and inadequate follow-up. Patients are reluctant to admit noncompliance with drug treatment, so a high degree of vigilance is required. Asking an open-ended question such as, “Many people have problems remembering their drug schedule; do you?” is occasionally effective. Clues to noncompliance include failure to keep follow-up appointments or renew prescriptions, or complaints about the cost of drugs or side effects. Certain drugs are expected to cause effects observable on physical examination or laboratory evaluation. An absence of these findings may indicate noncompliance. Examples are slowing of the heart rate with beta blockers, electrolyte changes with diuretics, or dry mouth with clonidine. Noncompliance with a low-salt diet can also be important. A high-salt diet can interfere with the effectiveness of almost all of the currently used antihypertensive drugs.
Certain prescription drugs, over-the-counter medications, herbals, and street drugs can raise BP or interfere with the BP-lowering effect of antihypertensive drugs [see Table 5]. Taking a complete medication history and asking patients to bring in all their medication bottles is essential for identifying interfering substances. Alcohol abuse should also be considered, because in addition to its physiologic effects, alcohol abuse is often associated with poor compliance and lack of BP control.
Inappropriate Drug Regimens
The drug regimen should be carefully reviewed. Full therapeutic doses of drugs should be employed. In general, it is preferable to use drugs that have complementary actions and that work by interfering with different BP regulatory pathways. In compliant patients, inadequate control of extracellular volume is the most common cause of resistant hypertension.92 Extracellular volume expansion tends to occur as BP is lowered and is a secondary effect of some drugs (e.g., centrally acting sympatholytics in modest doses and some direct vasodilators). In patients with renal dysfunction, impaired renal excretion of sodium often is an important factor in raising BP. The filtered load of sodium declines in parallel with declining renal function. Because the thiazide diuretics impair reabsorption of sodium in the distal nephron, where only 7% of the filtered load of sodium is reabsorbed, they are often ineffective when serum creatinine is higher than 2.0 mg/dl or creatinine clearance is less than 30 ml/min. In such patients, loop diuretics are required; loop diuretics interfere with sodium reabsorption in the loop of Henle, where 30% of the filtered load of sodium is reabsorbed. For patients on multidrug regimens, the lack of a diuretic or the use of low doses of short-acting loop diuretics given only once daily may explain the resistant state. It should be noted that thiazide and loop diuretics are organic acids that gain access to their site of action in the kidney by active secretion into the proximal renal tubule. As renal function declines, less of an oral dose reaches the site of action, as a result of reduced renal blood flow and competition for secretory sites by accumulating endogenous organic acids. Thus, higher doses of diuretics are needed as renal function declines. In some patients with renal disease, combinations of loop agents and thiazide diuretics in adequate doses are required to control fluid volume.
Office measures of BP may overestimate the usual or average level [see Ambulatory BP Monitoring, above]. Before embarking on further evaluation, the clinician should consider using out-of-office BP readings or ABPM to exclude a white-coat effect. Patients with white-coat hypertension are more likely to be younger (although cases of white-coat ISH do occur in elderly patients), female, and of normal weight. They often have no target organ injury and complain of fatigue and weakness (which are symptoms of hypotension) when drug doses are increased. One study suggested that up to 50% of hypertensive patients deemed resistant by office determinations of BP in fact had controlled hypertension.93
Some elderly patients may have pseudohypertension—falsely elevated systolic and diastolic BP as determined by cuff measurement. Pseudohypertension results from atherosclerosis of the brachial artery. Because of the excessive stiffness of the vessel wall, higher cuff pressure must be applied to produce vascular occlusion. In addition, the accuracy of oscillometric devices is impaired under these circumstances. Such patients often have evidence of severe generalized atherosclerosis and remarkable elevations of systolic BP without concomitant symptoms. They may complain of weakness and fatigue with increases in drug doses. The ability to palpate the pulseless radial artery after cuff inflation (i.e., a positive Osler sign) increases the likelihood of pseudohypertension, but this is not a sensitive test.94Confirmation of pseudohypertension requires intra-arterial measures of BP.
Secondary forms of hypertension are relatively uncommon in the general hypertensive population but may account for a significant proportion of cases of resistant hypertension. Once the other considerations have been eliminated, patients with resistant hypertension should be considered for further evaluation of secondary causes [see Secondary Hypertension, below].
An acute and severe rise in BP is a serious medical concern. Prompt therapy may be lifesaving. Clinically, acute and severe increases in BP can be classified as either hypertensive urgencies or emergencies (crises).51
The term hypertensive emergency or hypertensive crisis is defined as severely elevated BP associated with acute injury to target organs (i.e., brain, heart, kidneys, vasculature, and retina). Prompt hospitalization and reduction of BP with parenteral therapy is required. Examples of hypertensive emergencies include malignant hypertension, hypertensive encephalopathy, aortic dissection, eclampsia, unstable angina or acute myocardial infarction, pulmonary edema, and acute renal failure.
Malignant hypertension is an old term that describes a clinical syndrome associated with acute severe elevation of BP that may be fatal if not promptly treated. It is associated with a marked increase in peripheral vascular resistance caused by systemic vasoconstrictors (e.g., angiotensin II) or locally generated vasoconstrictors (e.g., endothelin). Any form of hypertension can progress to the malignant phase. Clinical characteristics include severe hypertension (diastolic BP ≥ 130 mm Hg); hemorrhages, exudates, and papilledema on retinal examination; encephalopathy (i.e., headache, confusion, somnolence, stupor, visual loss, focal neurologic deficits, seizure, or coma); oliguria and azotemia; nausea, vomiting, and dyspnea; and physical findings of heart failure (e.g., rales, an S3 heart sound). Encephalopathy arises from the failure of cerebral autoregulation of blood flow at critically high pressures, which results in cerebral vasodilation, hyperperfusion, vascular leakage, and cerebral edema. The hallmark vascular lesion of malignant hypertension is fibrinoid necrosis of arterioles that, in turn, increases both ischemic injury and further vasoactive substance release, setting up a vicious cycle. Microangiopathic hemolytic anemia with fragmentation of red cells and intravascular coagulation may occur in the setting of fibrinoid necrosis.
Hypertensive urgency is defined as severe hypertension without evidence of acute target organ injury that requires BP reduction over 24 to 48 hours. Oral therapy in the outpatient setting is often adequate. Examples include severe hypertension in a patient with known coronary artery disease, an aortic aneurysm (or aneurysm at another site), or a history of heart failure. The term accelerated hypertension is often used to describe a state of acute, severe hypertension with hemorrhages and exudates on retinal examination (but not papilledema) but without other findings of acute organ injury. This condition can be managed with oral therapy but may progress to malignant hypertension if left untreated.
The causes of hypertensive urgencies and emergencies include neglected essential hypertension (approximately 7% of untreated hypertension can progress to the malignant phase), sudden discontinuance of drug therapy (especially multiple drug regimens or regimens containing clonidine or beta blockers), renovascular disease, collagen vascular disease (especially scleroderma), eclampsia, acute glomerulonephritis, and pheochromocytoma. Approximately 50% of hypertensive crises occur in patients with preexisting hypertension.
The goals of the initial evaluation are to assess for target organ injury and to define potential causes. The evaluation begins with a focused medical history and physical examination. In taking the history, the clinician must ask about compliance with prescribed antihypertensive medications and the use of drugs that can raise BP [see Table 5]. Retinal examination is a mandatory aspect of the physical examination. Immediate laboratory studies include a complete blood count (to check for anemia); blood smear (to look for fragmented red blood cells); serum creatinine and blood urea nitrogen assays; urinalysis; serum sodium, potassium, and glucose assays; a chest x-ray; and an electrocardiogram. In hypertensive crisis, evaluation for secondary hypertension should be deferred until the patient is stable. If a cause of the crisis is not apparent, such patients should eventually have an evaluation to exclude renal vascular disease, pheochromocytoma, scleroderma, and primary aldosteronism.
Patients with hypertensive crisis should be hospitalized in an intensive care unit. The challenge of treatment is to lower BP without aggravating ischemia to vital organs. Parenteral therapy should be used [see Table 13]. Sodium nitroprusside is generally the drug of choice. Diazoxide is considered obsolete, because of the availability of newer and safer drugs. Mean BP should be lowered by 20% in the first hour (diastolic BP should be reduced to 100 to 110 mm Hg). As BP is lowered, the patient should be monitored for evidence of worsening cerebral, renal, or cardiac function. If the patient is stable, BP should be further lowered over the next 24 hours. Oral therapy can be started, and parenteral therapy gradually discontinued.
Table 13 Parenteral Therapy for Hypertensive Crisis
TREATMENT FOR SPECIFIC PATIENT GROUPS
Approximately 60% to 70% of persons 60 years of age or older have hypertension.1 In this age group, systolic BP is the dominant predictor of adverse events, and ISH is the most common type of blood pressure disturbance.13,14 Treatment of hypertension in the elderly reduces CV disease event rates and lessens the risk of development and progression of cognitive dysfunction and dementia.7,95 The benefits of treatment have been shown for persons with either systolic-diastolic hypertension or ISH and for those older than 80 years. Although most elderly persons have primary hypertension, secondary forms of hypertension should be considered if the onset is recent or the hypertension is resistant.
There are special concerns regarding BP measurement in the elderly. Systolic BP is often quite variable, and the phenomenon of white-coat hypertension may be common in the elderly, especially in older women. Thus, readings of BP outside the office should be encouraged, as should selective use of ambulatory monitoring, especially if the patient has no target organ changes related to hypertension or complains of side effects that suggest hypotension with treatment. As noted, white-coat hypertension is an indication for ambulatory monitoring that is covered under Medicare.49 Orthostatic hypotension and postprandial hypotension are more common in the elderly, in most cases because of dysautonomia of aging. Systolic hypertension is a predictor of orthostatic hypotension, and diabetic patients are at greater risk because of autonomic neuropathy. Thus, BP measurement in the standing position is required in all elderly patients at all office visits. Pseudohypertension should be considered in elderly patients who have palpably stiff vessels, who lack significant target organ changes despite very high BP readings, and who complain of hypotensive symptoms with treatment. Such patients may require a direct intra-arterial measure of BP for clarification.
In general, treatment of hypertension in the elderly follows the same principles as treatment in younger patients. The BP goals are the same as for the general hypertensive population. However, because the benefit of treatment on longevity is less in most elderly patients, the costs of drugs, side effects, and quality of life are important considerations. Goal BP may be difficult to achieve in some patients with systolic hypertension, but any reduction is beneficial. Thus, in some patients, a higher systolic goal may be reasonable.
Modification of adverse lifestyle factors is beneficial in the elderly and should be encouraged.96 Salt sensitivity increases with age and with the reduction in renal function that is common in the elderly.97 In patients who require drugs, lower initial doses should be considered, especially in the presence of orthostatism or comorbid vascular diseases. However, many elderly patients ultimately require multiple drugs for BP control.
In the elderly with systolic-diastolic hypertension, placebo-controlled studies have shown that initial therapy with a diuretic or a beta blocker is beneficial. In one trial, treatment using newer drugs (calcium antagonists or ACE inhibitors) was not superior to treatment using diuretics and beta blockers.98 In another study, however, starting treatment with an ACE inhibitor rather than a diuretic was associated with better outcomes, particularly in men.82 Studies in patients with ISH have shown efficacy of thiazide diuretics and long-acting dihydropyridine calcium antagonists.7 In elderly patients with LVH, the LIFE (Losartan Intervention For Endpoint reduction in hypertension) trial demonstrated that, compared with therapy using a beta blocker (atenolol), use of an ARB (losartan) was associated with fewer CV events, including strokes.99 This observation was noted overall and in the subset of elderly patients with ISH. In elderly patients with a history of stroke or transient ischemic attack, the combination of indapamide and perindopril reduced the risk for subsequent stroke and progression to dementia.100 In many elderly patients, comorbid conditions will determine the use of specific drugs. Because of the problem of polypharmacy in the elderly, a goal should always be to keep the program as simple as possible.
Patients who have both hypertension and diabetes have twice the risk of CV disease as nondiabetic hypertensive patients. In addition, hypertension increases the risk of diabetic retinopathy and nephropathy.101 Epidemiologic and observational studies have shown that the risk of BP-related CV disease and mortality in diabetic patients begins to rise when BP exceeds 120/70 mm Hg.101,102 There does not appear to be a threshold value for risk associated with systolic BP in diabetic patients. In the Hypertension Optimal Treatment Trial (HOT), diabetic patients randomized to the lowest diastolic BP goal (≤ 80 mm Hg; the achieved diastolic BP was 82.6 mm Hg) had the best outcomes.69 In the United Kingdom Prospective Diabetes Study (UKPDS), a mean achieved diastolic BP of 82 mm Hg was beneficial, as compared with less aggressive BP reduction.103 On the basis of these data, the American Diabetes Association, the National Kidney Foundation, and the JNC 7 report recommend a goal BP of less than 130/80 mm Hg in hypertensive diabetic patients.8,102,104
All patients with diabetes should be encouraged to adopt lifestyle modifications [see Table 8]. Weight loss (if the patient is overweight or obese) and moderate exercise are especially beneficial in diabetic patients because in addition to lowering BP, these interventions improve insulin sensitivity and blood lipid levels. Many patients will require lifestyle modifications and three or more drugs to achieve the BP goals. Meeting these goals may be difficult in some patients. The clinician must balance benefit from lower BP with cost of medication, side effects, and risks associated with the lower goals in some patients. The American Diabetes Association recommends a trial of lifestyle modifications alone for up to 3 months if the initial systolic BP is 130 to 139 mm Hg or the diastolic BP is 80 to 89 mm Hg. Drug monotherapy should be considered initially along with lifestyle modifications if the initial systolic BP is 140 mm Hg or higher or if the diastolic BP is 90 mm Hg or higher.102 The JNC 7 report suggests that if the initial systolic BP is 150 mm Hg or higher or the initial diastolic BP is 90 mm Hg or higher, consideration should be given to starting therapy with a combination of two drugs, one of them a thiazide diuretic.8 Before initiating drug therapy, it is important to measure BP in the standing position to detect orthostatism, the presence of which may be a clue to autonomic neuropathy and would necessitate a modification to the treatment approach.
Placebo-controlled trials in diabetic patients have shown the efficacy of ACE inhibitors, ARBs, diuretics, and beta blockers as initial therapy. Although thiazides, ACE inhibitors, and calcium channel blockers provide equivalent cardiovascular benefit in this setting,80 numerous studies have shown the effectiveness of ACE inhibitors and ARBs in retarding progression of diabetic nephropathy.105,106 For diabetic patients with nephropathy, the American Diabetes Association guidelines recommend ACE inhibitors as initial drugs of choice in type 1 diabetes but ARBs in type 2 diabetes.102 It is unclear whether ARBs are as cardioprotective in diabetic patients as ACE inhibitors have been shown to be. In some studies, the incidence of cardiac events has been higher in diabetic patients treated with dihydropyridine calcium antagonists, as compared with ACE inhibitors.107 Beta blockers should be considered in the setting of coronary artery disease, a common comorbidity in patients with diabetes. On balance, treatment data suggest that reaching the goal BP in diabetic patients is probably more important than the choice of drugs used to achieve it.
Patients with Heart Disease
Ischemic heart disease is the most common cause of death in patients with hypertension. Poorly controlled hypertension also results in the development of LVH. Both LVH and ischemic injury lead to the development of heart failure from either systolic or diastolic dysfunction.108Hypertension is the most common antecedent of heart failure.109 Hypertensive effects on the heart also increase the risk for atrial fibrillation.
For asymptomatic patients with known coronary artery disease, an ACE inhibitor should be considered initially because some studies (but not all) suggest that their use may be associated with a reduced risk of cardiovascular events.110 An ACE inhibitor would also be the initial drug of choice for patients with concomitant reduced systolic function or concomitant diabetes with renal involvement.102,105,111 If there is a history of myocardial infarction, the first drug should be a beta blocker.112 For hypertensive patients with previous myocardial infarction and reduced left ventricular function, combination therapy with a beta blocker and an ACE inhibitor should be considered.113 In addition, the aldosterone antagonist eplerenone has been shown to be effective.114 If eplerenone is used, serum potassium levels should be monitored carefully, especially in patients with renal dysfunction or if ACE inhibitors or ARBs are used.
The drug of choice in hypertensive patients with stable angina, both to lower BP and to relieve symptoms and ischemia, is a beta blocker. Long-acting dihydropyridine or nondihydropyridine calcium antagonists have been shown to relieve symptoms and are alternative agents if beta blockers are contraindicated; these alternative agents are also suitable as additional therapy for BP or symptom control. Newer vasoselective, long-acting dihydropyridine calcium antagonists such as amlodipine or felodipine can be used safely to lower BP in patients with impaired left ventricular function. Nitrates can be used in combination with either beta blockers or calcium antagonists for symptomatic relief and may lower systolic BP. Beta blockers should be avoided in pure vasospastic angina, a disorder best managed with long-acting calcium antagonists or nitrates. Diuretics are safe antihypertensives for patients with coronary artery disease; they work well with other agents to lower BP. Hypokalemia should be avoided.
LVH is associated with a doubling of the risk of myocardial infarction and death in hypertensive patients.115 Effective BP control causes regression of LVH and improves prognosis. Weight loss and the use of antihypertensive drugs of all major classes have been shown to induce regression of LVH; however, increasing evidence suggests that ACE inhibitors and ARBs may be more effective than other agents.116
The goal of treating hypertension in patients with heart failure is a BP of less than 130/80 mm Hg. The American College of Cardiology and the American Heart Association have developed guidelines for the evaluation and management of heart failure in adults that encompass a staging system and evidence-based treatment recommendations for patients with heart failure [see I:II Heart Failure].
The goal of hypertension treatment in patients with coronary artery disease is also a BP of less than 130/80 mm Hg; however, concern has been raised that excessive decreases of diastolic BP may be associated with a paradoxical increase in morbidity and mortality (referred to as the J-curve hypothesis). A secondary analysis of a study of hypertensive patients with coronary artery disease demonstrated a progressively increased risk of all-cause death and myocardial infarction with low diastolic BP (< 84 mm Hg).117
Patients with Chronic Kidney Disease
Kidney disease is both a cause and a consequence of hypertension. Hypertension is the second most common cause of the development of end-stage kidney disease, and most people with kidney disease have hypertension. Aggressive control of elevated BP can slow the progression of renal damage and delay or prevent the development of end-stage disease.104,105,106,118,119 The currently recommended BP goal for patients with kidney disease is a level below 130/80 mm Hg. In addition to elevated BP, other modifiable CV risk factors require management, because patients with chronic kidney disease are also at high risk for CV morbidity and mortality. A study of hypertensive patients who were 55 years of age or older found that a low GFR was independently predictive of an increased risk of coronary artery disease; those patients with a reduced GFR proved more likely to develop coronary artery disease than to develop end-stage renal disease.120 In this study, neither a calcium channel blocker nor an ACE inhibitor proved superior to a thiazide diuretic in preventing coronary artery disease, stroke, or combined CV disease, and chlorthalidone was superior to both for preventing heart failure, independent of the level of renal function.
Chronic kidney disease is defined as either a GFR of less than 60 ml/min/1.73 m2 or the presence of albuminuria (> 300 mg/day or > 200 mg albumin per gram of creatinine).104 The GFR can be estimated using the Cockcroft-Gault or MDRD equation [see Table 6]. Determination of creatinine clearance using timed urine collections generally does not improve upon the estimates of GFR obtained using these equations.
ACE inhibitors and ARBs may be more effective than other drugs in slowing progression of proteinuric kidney disease. Whether these agents provide a specific advantage in the absence of proteinuria is less certain.104 Serum creatinine concentrations often increase acutely when these drugs are used, so serum creatinine and potassium should be measured within several days of initiating treatment. An increase in creatinine is not a reason to stop the drug unless it is excessive (> 30% from baseline) or associated with severe hyperkalemia (> 5.5 mEq/dl). Concomitant use of potassium-sparing diuretics, potassium supplements, or nonsteroidal anti-inflammatory drugs should be avoided. A persistent increase in creatinine with treatment raises the possibility of renal artery stenosis. Most patients with kidney disease will require a diuretic as part of the treatment regimen. If GFR is estimated to be less than 30 ml/min, thiazide diuretics are usually ineffective, and loop diuretics are required. Often, three or more drugs are required to control BP.
Patients with Acute Stroke
The majority of patients presenting with either acute ischemic or hemorrhagic stroke have hypertension.121 The temporal profile is that of an initial acute rise in BP in the first 24 hours, followed by a slow decline over the next several days. On the whole, observational studies show that high BP at stroke onset is associated with an increased risk of death or dependency.122 However, this association is not evident in some studies, especially studies in patients with ischemic stroke.123
Unfortunately, at present there is little evidence from clinical trials to provide clear recommendations for the appropriate management of BP during acute stroke. Currently, there is consensus that in patients with acute intracranial hemorrhage, BP should be lowered if it exceeds 200/120 mm Hg, to prevent growth of the hematoma or rebleeding. Lowering of BP by less than 20% is suggested in this setting.124Guidelines for BP management in acute ischemic stroke from the Stroke Council of the American Heart Association suggest that in patients who are not candidates for thrombolytic therapy, hypertension should be managed with observation alone if BP is less than 220 mm Hg systolic and 120 mm Hg diastolic, unless there is evidence of other acute target-organ injury (e.g., aortic dissection, acute myocardial infarction, pulmonary edema, hypertensive encephalopathy).125 For patients with systolic BP higher than 220 mm Hg or diastolic BP of 121 to 140 mm Hg, treatment with intravenous labetalol or nicardipine is recommended. Labetalol is given in a dosage of 10 to 20 mg over 1 to 2 minutes; the dose is repeated or doubled as needed every 10 minutes to a maximum dose of 300 mg. Nicardipine is given in an initial 5 mg/hr infusion and titrated to desired effect by increasing the dosage by 2.5 mg/hr every 5 minutes, to a maximum rate of 15 mg/hr. It is suggested that BP be lowered by 10% to 15%.
Nitroprusside is recommended if diastolic BP is higher than 140 mm Hg; the dose should be titrated to lower BP by 10% to 15%.
In patients who are eligible for thrombolytic therapy, the Stroke Council suggests lowering BP before initiating thrombolysis if the BP is higher than 185 mm Hg systolic or 110 mm Hg diastolic. Treatment with labetalol, 10 to 20 mg intravenously over 1 to 2 minutes, is advised. If needed, this dose can be repeated once; or nitroglycerin paste, 1 to 3 inches, can be applied. If antihypertensive treatment does not reduce BP to below 185/110 mm Hg, thrombolytic therapy is not advised. During and after thrombolytic treatment, BP should be monitored frequently (every 15 minutes for 2 hours, then every 30 minutes for 6 hours, and then every hour for 16 hours). During this period, treatment with nitroprusside is advised for diastolic BP higher than 140 mm Hg. For systolic BP higher than 180 mm Hg or diastolic BP of 105 to 140 mm Hg, intravenous labetalol in a dosage of 10 mg administered over 1 to 2 minutes is recommended; the dosage should be repeated or doubled every 10 minutes to a maximum of 300 mg, or a drip at a rate of 2 to 8 mg/min should be started.
Prospective cohort studies have shown that lower dietary intake of folate or increased intake of sugared or diet cola beverages is associated with an increased risk of hypertension in women; however, there was no association between caffeine consumption overall and risk of hypertension.126,127
It has long been recognized that the use of ACE inhibitors during the second and third trimesters of pregnancy increases the risk of fetal malformations. However, a 2006 case-control study found that the risk of fetal malformations—specifically, cardiovascular and central nervous system malformations—is also increased with ACE inhibitor use during the first trimester.128 For that reason, it would be prudent to avoid this class of drugs in women who may become pregnant. A larger body of evidence suggests, however, that the risk of inducing fetal anomalies is greatest when exposure is during the second or third trimesters. For this reason, exposure during the first trimester is not in itself an indication for elective termination of pregnancy.
In postmenopausal women who have hypertension, hormone therapy with a combination of drospirenone—a progestin with antialdosterone activity—and 17-β-estradiol (Angeliq) has been found to reduce BP without inducing significant increases in serum potassium. This product is approved for the treatment of moderate to severe vasomotor symptoms associated with menopause.129
Detection of secondary hypertension is important because, depending on the cause, it may be possible to cure the underlying condition or tailor therapy to achieve optimal BP control. Certain features suggest the presence of specific secondary forms of hypertension [see Table 4], which should then direct further testing [see Table 14].
Table 14 Screening and Diagnostic Options for Secondary Hypertension
Common reversible causes of hypertension include obesity, the use of drugs that raise BP [see Table 5], obstructive sleep apnea, and renal disease. Obstructive sleep apnea is prevalent in the population and is often associated with hypertension; treatment with continuous positive airway pressure can significantly lower both daytime and nighttime BP in these patients.130 Renal insufficiency from any etiology causes BP to rise. Elevated BP in turn accelerates loss of renal function, and a vicious cycle ensues. Traditional secondary causes of hypertension include renal vascular disease, coarctation of the aorta, the adrenal causes of primary aldosteronism, pheochromocytoma, and Cushing syndrome.
Renovascular hypertension is the most common form of potentially curable secondary hypertension. It probably occurs in 1% to 2% of the overall hypertensive population. The prevalence may be as high as 10% in patients with resistant hypertension, and 30% in patients with accelerated or malignant hypertension.
Stenosing lesions of the renal circulation cause hypertension through ischemia-mediated stimulation of the renin-angiotensin-aldosterone axis. Correcting renal ischemia eliminates excess renin production and improves or cures the hypertension. In unilateral disease, prolonged hypertension can cause nephrosclerosis in the nonischemic kidney; nephrosclerosis lessens the likelihood of benefit from correction of the renal vascular lesion.
Fibromuscular disease is the most common cause of renovascular hypertension in younger patients, especially women between 15 and 50 years of age131; it accounts for approximately 10% of cases of renovascular hypertension.132 Vascular lesions typically affect the middle and distal portions of the renal artery and often extend into branches. Three subtypes are defined on the basis of the layer of the vascular wall affected: (1) intimal hyperplasia (1% to 2% of cases), (2) medial fibromuscular dysplasia (95% of cases), and (3) periadventitial fibrosis (1% to 2% of cases). The most common subtype, medial fibromuscular dysplasia, presents as a classic string-of-beads (i.e., aneurysmal dilatations) on angiography; it progresses in 30% of cases. It is rarely associated with dissection or thrombosis. In contrast, the rarer forms can progress rapidly, and dissection and thrombosis are common. Fibromuscular dysplasia is a rare cause of renal artery occlusion.
Atheromatous disease is the most common cause of renovascular hypertension in middle-aged and older patients and accounts for approximately 90% of renovascular hypertension.132,133 Vascular lesions are usually in the proximal third of the renal arteries, often near or at the orifice. The prevalence of atheromatous renal artery disease increases with age and is common in older hypertensive patients, especially in those with diabetes or with atherosclerosis in other vascular beds. Most patients with atheromatous renal vascular disease and hypertension have essential hypertension and may not benefit from correction of the disorder. Sorting out the subset of patients with renovascular disease who have renovascular hypertension is a challenge. The disease is frequently bilateral (30%) and is often progressive. The likelihood of progression can be decreased by aggressive control of risk factors (e.g., dyslipidemia, cigarette smoking, and hypertension). Patients with atheromatous renal artery disease are at increased risk for cardiovascular morbidity and mortality, including stroke, congestive heart failure, and myocardial infarction.134 This increased risk can be explained in part by the observation that atheromatous renal artery disease is often a marker of more generalized atherosclerotic vascular disease. In addition, increased angiotensin II levels from a critical renal artery lesion may act in a variety of ways to accelerate the atherosclerotic process. Whether interventional therapy and correction of the underlying renal artery stenosis improves prognosis over optimum medical management in the majority of these patients is uncertain and is currently the subject of a major clinical trial.135
The presentations of hemodynamically significant bilateral renal artery disease (i.e., ischemic nephropathy) include the following: an acute decline in renal function with use of an ACE inhibitor or ARB or with a sudden decrease in blood pressure; acute hypertension and pulmonary edema (i.e., flash pulmonary edema); recurrent or resistant heart failure; or an unexplained subacute decline in renal function with or without worsening of hypertension.136 Bilateral atherosclerotic renal artery disease accounts for a small but increasing number of cases of end-stage renal disease in older persons.137
A variety of screening tests for renal artery disease are available [see Table 13]; however, duplex renal ultrasonography, magnetic resonance angiography (MRA), and spiral computed tomographic angiography are considered the initial screening tests of choice [see 10:VII Vascular Diseases of the Kidney]. In general, spiral CT and MRA have superior diagnostic accuracy compared with duplex ultrasonography. Duplex ultrasonography and MRA do not involve the use of iodinated contrast and therefore are safe in patients with chronic kidney disease. MRA is not highly sensitive for the identification of fibromuscular disease. The gold standard for diagnosis remains contrast angiography. In settings of renal disease, alternative contrast agents (e.g., CO2 or gadolinium) can be used.
For lesions from fibromuscular dysplasia, percutaneous intervention with balloon angioplasty is the treatment of choice. For lesions from atheromatous disease, stent-supported angioplasty is the treatment of choice. Surgery is employed for both types if the lesions are not amenable to angioplasty; for the rare subtypes of fibromuscular dysplasia that usually are unresponsive to angioplasty; and for atheromatous disease in settings where aortic replacement is required.
Atheroembolic renal disease can mimic renovascular hypertension and ischemic nephropathy, in that it may present as hypertension of acute onset or as a worsening of hypertension in conjunction with a subacute decline in renal function. Atheroembolic renal disease often occurs after angiography or vascular surgery. Physical findings include the presence of distal livido reticularis and peripheral emboli. Laboratory findings include an elevated erythrocyte sedimentation rate, anemia, hematuria, eosinophilia, and eosinophiluria.
The classic syndrome of primary aldosteronism consists of hypertension, hypokalemia from excessive renal excretion, alkalosis, suppressed plasma renin activity, and increased aldosterone secretion.138 Hypokalemia is the abnormality that most often raises suspicion of this disorder, but approximately 30% of patients with primary aldosteronism present with normal serum potassium levels.
Although several subtypes of primary aldosteronism have been identified, the most common are unilateral aldosterone-producing adenoma, which comprises 30% to 40% of cases; and bilateral adrenal zona glomerulosa hyperplasia (also known as idiopathic hyperaldosteronism [IHA]), which comprises 60% to 70% of cases. Rare subtypes include glucocorticoid-suppressible hyperplasia, unilateral hyperplasia, and aldosterone-producing cortical carcinoma. The prevalence of primary aldosteronism is probably around 2%, but studies have suggested the prevalence to be as high as 13% of the hypertensive population, which would make it the most common secondary form of hypertension.139The higher prevalence estimates reflect an increase in the number of patients being diagnosed with IHA, a condition that may be part of the spectrum of essential hypertension.
Patients for whom the diagnosis of primary aldosteronism should be considered include the following: all hypertensive patients with spontaneous hypokalemia of renal origin (for a hypokalemic patient, a 24-hour urinary potassium level higher than 30 mEq/L is consistent with renal potassium wasting); most patients with excessive hypokalemia who are receiving usual doses of diuretics (serum potassium < 3.0 mEq/L); most patients with resistant hypertension, even if normokalemic; all patients with hypertension and an adrenal mass; and patients receiving treatment with ACE inhibitors or ARBs, with or without concomitant diuretic therapy, who have hypokalemia or who require potassium supplements.
Screening is usually carried out by simultaneous measurement of plasma aldosterone concentration and plasma renin activity with calculation of the aldosterone-to-renin ratio [see Table 13]. Values that exceed 15 are suggestive of this disorder. This screening test has only fair diagnostic accuracy, with a sensitivity of 75% to 85% and a specificity of 75%.138 Because of the low specificity of the ratio test, confirmation testing is required for the diagnosis to be established. Confirmation is made by demonstrating an inability to suppress aldosterone production by extracellular volume expansion [see Table 13]. After the diagnosis is confirmed, the subtype is determined with CT imaging of the adrenal glands. Occasionally, adrenal vein sampling is required to confirm the presence of an aldosterone-producing adenoma. Treatment for an adenoma is usually with a laparoscopic adrenalectomy. Treatment of idiopathic hyperaldosteronism is pharmacologic and employs aldosterone antagonists, usually with additional drugs as needed for adequate BP control.
Pheochromocytomas are rare tumors of chromaffin cell origin that produce excess amounts of catecholamines, which leads to paroxysmal or sustained hypertension [see 3:IV The Adrenal]. The incidence in the general population is 2 to 8 cases per million persons per year. The prevalence is about 0.5% in patients with hypertension who have suggestive symptoms, and approximately 4% in hypertensive patients with an adrenal mass. Most tumors are benign, but approximately 10% are malignant. Symptomatic paroxysms occur in less than 50% of patients. Episodes are characterized by symptoms of headache, diaphoresis, palpitations, and pallor associated with increases in blood pressure.140 Such paroxysms are usually rapid in onset and offset and can be precipitated by a variety of activities (e.g., exercise, bending over, urination, defecation, induction of anesthesia, infusion of intravenous contrast media, smoking). A history of unintended weight loss is not uncommon, as is the presence of glucose intolerance. The hypertension may be associated with marked BP lability and orthostatic hypotension. Rarely, patients may present with catecholamine-induced cardiomyopathy, fever, or peripheral vasospasm. The hypertension can be severe and resistant to control.
Most pheochromocytomas are sporadic, but 10% are familial. The inheritance pattern for all familial cases is autosomal dominant, with variable penetrance. Familial syndromes include a simple form not associated with other abnormalities; the multiple endocrine neoplasias, in which the risk of pheochromocytoma is 50% (type IIA [medullary thyroid carcinoma, hyperparathyroidism] and type IIB [medullary thyroid carcinoma, mucosal neuromas, marfanoid habitus, thickened corneal nerves, intestinal gangliomatosis]); neurofibromatosis (risk of pheochromocytoma is 0.1% to 5.7%); the von Hippel-Lindau syndrome (retinal hemangiomatosis, cerebellar hemangioblastomas, renal cell carcinoma; risk of pheochromocytoma is 10% to 20%); and the familial paraganglioma syndrome (tumors of the head or neck [glomus tumors] or carotid body; risk of pheochromocytoma is 20%). Familial pheochromocytomas can be bilateral. Persons with suspected familial pheochromocytoma should undergo genetic testing.
Most pheochromocytomas (90%) are located in one or both adrenal glands. Extra-adrenal pheochromocytomas can occur anywhere along the sympathetic chain and, rarely, in other sites (i.e., the superior para-aortic region, the glomus jugulare, the inferior para-aortic region, the bladder, or the thorax). About 98% of pheochromocytomas are located in the abdomen.
Screening for pheochromocytoma should be selective and based on suggestive clinical features. Screening tests include measurement of catecholamines (i.e., epinephrine, norepinephrine, dopamine) and their metabolites (i.e., metanephrine, normetanephrine, and vanillylmandelic acid [VMA]) in the plasma and urine. Traditionally, most experts have considered measurement of 24-hour urinary catecholamines or catecholamine metabolites to be the screening tests of choice.140 However, studies now suggest that measurement of plasma free metanephrines is a much more sensitive screening test (for hereditary tumors, sensitivity is 97%, versus 60% for urinary metanephrines; for sporadic tumors, sensitivity is 99%, versus 88% for urinary metanephrines).141 Also, this screening test obviates the concerns associated with obtaining an adequate 24-hour urine collection. Although the sensitivity of the plasma screen is higher than that of urinary tests, its specificity is lower with regard to screening for sporadic tumors (for sporadic tumors, specificity is 82% with the plasma test versus 89% with the urinary test; in hereditary tumors, specificity is 96% with the plasma test versus 97% with the urinary test). Plasma metanephrine assay should be strongly considered as the screening test of choice if a hereditary form of pheochromocytoma is suspected; it should also be considered the test of choice for patients with a history of pheochromocytoma and for patients in whom the clinical suspicion is high. A negative result on either a plasma or urinary metanephrine test excludes the diagnosis in most cases. Measurement of catecholamines in the plasma or urine is quite insensitive and should not be used alone as a screening test.
Because of the low prevalence of pheochromocytomas in patients screened for this disorder, false positive results outnumber true positive results. This is of major concern because positive results from screening tests often lead to additional tests and anxiety on the part of the both the physician and the patient. There are three main factors associated with false positive results: diet, drugs, and physiologic stressors [see Table 15]. Specific dietary factors and drugs affect plasma screens and urinary metanephrine screens differently. Moreover, for urinary metanephrine screens, different drugs affect the results differently depending on the method of analysis used (i.e., high-pressure liquid chromatography [HPLC] versus mass spectrophotometry). Anticipation of these potential problems and proper preparation of the patient can prevent many false positive results.
Table 15 Causes for False Positive Screening Results for Plasma Free Metanephrines and 24-Hour Urinary Metanephrines
A positive screening test should prompt a search for the tumor if sources of a false positive result have been excluded. Abdominal imaging with CT or magnetic resonance imaging is the initial test of choice, given that 90% of pheochromocytomas are on the adrenal glands and 98% are in the abdomen. Additional studies may be required if a tumor is not found with initial imaging.142 Medical treatment is required before surgical intervention. The mainstay of treatment is alpha blockade with phenoxybenzamine. Beta blockers can be used to control the tachycardia that occasionally follows adequate alpha blockade. Because pheochromocytomas can recur in 10% of patients, long-term biochemical follow-up is required.
Cushing syndrome arises from excess production of glucocorticoids. It is rare: the incidence of the ectopic adrenocorticotropic hormone (ACTH) syndrome is about 660 cases per million population; in 50% of these cases, the underlying cause is small cell lung cancer. The incidence of adrenal tumors is one to five cases per million population per year. The incidence of pituitary ACTH-dependent disease is estimated to be five to 25 cases per million population per year. The signs and symptoms of Cushing syndrome arise from long-term exposure to excess glucocorticoids. They include central obesity, skin atrophy, striae, acne, slow wound healing, proximal muscle wasting and weakness, osteoporosis, menstrual irregularity, hyperpigmentation (ACTH dependent), glucose intolerance, hypokalemia, and hypertension. Clinical manifestations vary on the basis of the degree and duration of glucocorticoid excess, the presence or absence of androgen excess (in women, androgen excess produces hirsutism, decreased libido, virilization, and oily skin), and the cause of hypercortisolism (hyperpigmentation results from excessive ACTH; androgen excess is more common in adrenal carcinomas). States of pseudo-Cushing syndrome can result from significant stress, severe obesity, depression, and chronic alcoholism.143
Patients suspected of having Cushing syndrome should undergo measurement of 24-hour urinary free cortisol. Normal levels exclude the diagnosis, and levels higher than threefold normal confirm it. In patients with equivocal results, a low-dose dexamethasone suppression test can be used. For this test, the patient is given a 1 mg tablet at 11 P.M. Serum cortisol is measured on a specimen drawn the next morning at 8 A.M. A normal response is a serum cortisol level of less than 5 µg/dl. An alternative method is to give a 0.5 mg tablet every 6 hours for eight doses and to measure 24-hour urinary cortisol excretion on the second day. A normal response is a urinary cortisol excretion of less than 10 µg/24 hr and a serum cortisol level of less than 5 µg/dl.
COARCTATION OF THE AORTA
Congenital constriction of the aorta accounts for approximately 7% of congenital cardiovascular diseases. Coarctation can occur anywhere along the aorta but most often occurs just distal to the takeoff of the left subclavian artery. The disorder is usually detected in childhood, but occasionally it escapes detection until adulthood. Symptoms include headache, cold feet, and claudication. The classic feature of coarctation is elevated blood pressure in the arms and low or unobtainable blood pressure in the legs. This finding can be identified by direct measurement. The presence of weak femoral pulses or a delay in sensing the femoral pulse when simultaneously palpating the radial pulse is cause to suspect coarctation. Other findings include visible pulsations in the neck or chest wall and murmurs in the front and back of the chest from collateral vessels. Physical findings may be subtle. If the diagnosis is suspected, screening tests include transesophageal echocardiography or MRI or CT imaging of the aorta. Treatment is surgical in most cases [see 1:XII Diseases of the Aorta].
Left untreated, hypertension leads to premature death or disability from complications of CV diseases, especially atherosclerosis.3,4,5Hypertension affects blood vessels directly, inducing endothelial dysfunction, and acts in concert with other factors (e.g., smoking, hyperlipidemia, and diabetes) to promote the atherosclerotic process. Although the effect of hypertension on blood vessels is systemic, it expresses itself by characteristic effects on target organs—the heart, brain, kidneys, and eyes.
Hypertension increases the risk of myocardial infarction and sudden cardiac death twofold.3 It contributes to the risk of atrial fibrillation and is the single most important antecedent to the development of heart failure.108,109 These adverse effects of hypertension reflect both acceleration of atherosclerosis and the development of structural adaptation of the heart (LVH and left atrial enlargement) to increased afterload. The structural changes limit coronary reserve.
Heart failure can be the result of either systolic or diastolic dysfunction. Hypertension is commonly associated with abnormal diastolic relaxation, which can be demonstrated by echocardiography. Progression of these effects on the heart can lead to symptoms of heart failure with preserved systolic function, a condition known as diastolic heart failure [see 1:II Heart Failure]. In addition, long-standing hypertension leads to LVH and ventricular remodeling, which progresses to systolic dysfunction. This process is aggravated by myocardial infarction.
Hypertension is the single most important cause of stroke, which itself is the third leading cause of death in the United States.144Hypertension increases the risk of stroke by aggravating atherosclerosis in the aortic arch and carotid and cerebral arteries (causing thrombotic or embolic ischemic strokes) and by inducing arteriosclerosis in small, penetrating subcortical cerebral vessels, leading to leukoaraiosis (periventricular leukoenceophalopathy) and lacunar strokes. Severe hypertension is also associated with intraparenchymal and subarachnoid hemorrhage.
Hypertension in midlife is associated with an increased risk of cognitive dysfunction and dementia in later life.5 This may be a complication of multiple cerebral infarctions (multi-infarct dementia), but it also occurs in the absence of previous strokes. In some persons, cognitive dysfunction may arise from the effects of elevated BP on the small penetrating subcortical arterioles, leading to ischemic injury to white matter (visible as leukoaraiosis on brain imaging studies). Although vascular dementia in the elderly is strongly related to hypertension, the relationship between BP and cognition is less clear in persons older than 75 years. In some cases, an inverse relationship has been noted. This may reflect a shift in cerebral autoregulation to a higher range in patients with hypertension-induced small vessel disease, making these patients more vulnerable to further ischemic brain injury when BP is lowered.
Hypertension is a risk factor for abdominal aortic aneurysm. In addition, the majority of patients with aortic dissection have hypertension. Aortic dissection arises from the combined effects of accelerated aortic atherosclerosis and increased pulsatile stress on the aortic wall. Hypertension increases the risk of peripheral vascular disease, especially in cigarette smokers and diabetic patients.
Hypertension is the second leading cause of end-stage renal disease.137 Arteriosclerotic changes lead to ischemic injury and loss of glomeruli and tubular elements, ultimately leading to the shrunken kidney of nephrosclerosis. End-stage kidney disease from hypertension is much more common in blacks. Malignant hypertension induces fibrinoid necrosis of renal arterioles and can lead to acute renal failure.
Hypertension-related vascular disease causes loss of vision through a variety of mechanisms.145 Chronic hypertension causes arteriosclerosis of retinal vessels. These changes at the site of arterial-venous crossings can lead to branch retinal vein occlusion. Central retinal vein occlusion can also occur. Ischemic optic neuropathy can be a complication of chronic hypertension or acute severe hypertension. Acute, severe elevations in BP can also cause retinal hemorrhages, exudates, and papilledema. Hypertension accelerates atherosclerosis. Atherosclerotic emboli can occlude central or branch retinal arteries, with sudden and irreversible visual loss. Severe atherosclerosis can lead to venous stasis retinopathy as a result of a reduction in blood flow in the carotid or ophthalmic artery. Occlusive disease of retinal vessels can lead to cystoid macular edema, epiretinal membrane formation, and collateral vessel formation.
Effective treatment has a dramatic effect on the prognosis of patients with hypertension. Prospective treatment trials have established that BP reduction with drug therapy markedly reduces CV morbidity and mortality. Active treatment of hypertension lessens the tendency for BP to increase over time. For patients whose diastolic BP is 90 mm Hg or more or whose systolic BP is 160 mm Hg or more, drug intervention has been shown to reduce the risk of stroke by 35% to 40%; the risk of myocardial infarction is reduced by 20% to 25%; and the risk of heart failure is reduced by over 50%. In hypertensive patients with chronic kidney disease, drug intervention reduces the risk of progression to dialysis, transplantation, and death. However, even when BP is brought down to current recommended levels, hypertensive individuals remain at higher risk for CV disease events compared with normotensive individuals. Patients with target-organ disease remain at even higher risk, despite good BP control. These observations argue for application of public health and individual patient strategies to prevent the development of hypertension and for early detection and effective treatment of high BP.
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Editors: Dale, David C.; Federman, Daniel D.