Chapter Twelve
Hypertension

Normal arterial blood pressure shows wide variation. The systolic pressure ranges from 100 to 140 mm Hg, and the diastolic pressure from 60 to 90 mm Hg. These upper and lower limits are derived from measurements of a large sampling of healthy persons. They cannot, however, be considered sharp cutoff points separating the healthy from those suffering from hypertension ("high blood pressure") or hypotension ("low blood pressure"). Hypertension is considered significant only if persistent and repeated readings of blood pressure above the norm, generally much higher than the maximum levels, are discovered. Both abnormally high and abnormally low blood pressure are clinical findings, not in themselves a disease. Abnormally elevated blood pressure occurs under certain circumstances in healthy persons; it can be a manifestation of disease elsewhere in the body (secondary hypertension ). But if persistent, it indicates primary disease. It is this primary disease (essential hypertension ) that is the principal subject of this chapter.

Disturbances of Regulation of
Blood Pressure

The regulatory mechanism for maintaining blood pressure at a constant level was presented in chapter 2. This barostatic mechanism (similar to temperature regulation by thermostats) is capable of regulating resistance to blood flow by opening and closing the arterioles to compensate for variation in cardiac output. This pressure regulatory center is located at the base of the brain, where it

receives and sends out signals via the autonomic nervous system. However, the response of the arterioles to these impulses can be either strengthened or weakened by chemical substances circulating in the blood. Thus disturbances of pressure regulation can be related to one of two mechanisms: either the barostatic center is set too high or too low, so that improper nervous impulses reach the arterioles (neurogenic mechanism ), or normal nervous impulses are improperly modified by the presence of chemical substances (humoral mechanism ). Chemical substances that raise blood pressure by sensitizing arteriolar responses to nervous impulses are called pressor substances; those that desensitize responses and lower blood pressure are called depressor . substances. Such pressor and depressor effects are the properties of many chemical substances—hormones normally produced in the body, hormones produced only under abnormal conditions, and drugs.

Disturbances of either the neurogenic or humoral mechanism may occur temporarily or permanently. For example, blood pressure may rise in healthy persons during periods of stress, anger, and excitement, presumably because of an excess of normal pressor hormones. Conversely, temporary falls in blood pressure may result from prolonged standing (fatigue of regulatory center), causing fainting. Furthermore, regulation of blood pressure may be imperfect, leading to abnormal drops in blood pressure when the person switches from a lying to a standing position (postural hypotension ). Permanent disturbances of blood pressure—hypertension or hypotension—may be caused secondarily by disturbances of other organs; however, only hypertension can be a primary, potentially serious disease. Hypotension is consistent with good health and is most frequently merely a variant of the norm, although occasionally it may be a sign of some systemic disease (long-standing wasting diseases such as cancer, tuberculosis, or Addison's disease).

The kidneys play an important role in the regulation of blood pressure. Special cells in the kidneys secrete renin , a chemical that combines with a protein circulating in the blood to produce angiotensin I . This compound has no significant effect on the circulation but is rapidly changed by an enzyme into angiotensin II , a powerful pressor hormone essential in regulating blood pressure. Furthermore, angiotensin II is the principal factor stimulating the adrenal

cortex to secrete aldosterone , which regulates salt and water content in the body. This reaction is referred to as the renin-angiotensin-aldosterone axis. Excess formation of renin may initiate the process leading to hypertension; furthermore, ingestion of salt (sodium) in the diet facilities the development of hypertension, whereas significant reduction of salt intake lowers blood pressure. The renin mechanism is directly involved in one type of secondary hypertension (renovascular hypertension) and may be implicated in some cases of essential hypertension.

The relationship between the kidneys and hypertension has been known since blood pressure measurements first became available at the turn of the century; in the 1930s high blood pressure was experimentally produced in an animal by interfering with the blood supply to the kidneys, thereby stimulating excessive production of renin. Stenosis of the renal artery (supplying the kidney) was experimentally induced, causing hypertension in the animal; relief of the stenosis brought the blood pressure back to normal.

Causes of Hypertension

Most patients with high blood pressure have essential hypertension (sometimes referred to as "idiopathic," since its cause is unknown). It accounts for about 95 percent of all cases of hypertension. Many patients with essential hypertension show increased activity of renin in the blood. This finding led to the hypothesis that disturbance of the renin-angiotensin-aldosterone axis is the cause of essential hypertension as well as of hypertension due to demonstrable abnormalities of renal blood supply. However, excess of these hormones could not be demonstrated consistently in patients with hypertension; thus the hypothesis has not been confirmed, although the renin mechanism plays a contributory role in many patients. There is some controversy as to whether hypertensive patients with high renin activity represent a subgroup with a different course and prognosis than those with low or normal renin activity. One feature of essential hypertension generally accepted, however, is its tendency to run in families, which indicates a hereditary factor.

Secondary hypertension (5 percent of all cases of hypertension) may occur in the course of many diseases. Some diseases of the

kidneys produce elevated blood pressure (renal hypertension ), though there is no definite relationship between impaired kidney function and hypertension. These include acute glomerulonephritis, chronic nephritis, pylonephritis, and polycystic kidney disease. Renovascular hypertension includes demonstrable abnormalities in the arterial blood supply to the kidney. Renal and renovascular hypertension account for about 80 percent of the cases of secondary hypertension. Endocrine hypertension is caused by tumors secreting an excess of hormones involved in pressure regulation or by abnormally increased hormone production in hyperactive glands. This category includes pheochromocytoma , a tumor secreting epinephrine or norepinephrine (normal hormones of the medulla of the adrenal glands); primary aldosteronism , an excess of the hormone of the adrenal cortex; and Cushing's syndrome , or hyperplasia of the pituitary gland. Hypertension may also be a secondary effect of coarctation of the aorta (see chap. 11), excess female hormones (such as in the abnormal reaction of some women to contraceptive pills and hypertension developing during pregnancy), and some disturbances of the central nervous system.

Consequences and Course
of Hypertension

Hypertension is not a well-defined disease but rather a nonspecific circulatory abnormality. It can be produced by several different mechanisms, and if it lasts long enough, it can be disabling or even shorten life. The characteristic feature of hypertension is that it does not produce symptoms in the vast majority of patients, who may remain unaware of any problem even when serious consequences of hypertension are already present. Some of the symptoms traditionally ascribed to hypertension, such as headache or dizziness, are relatively rare, and their relationship to elevated blood pressure is uncertain.

The question of when blood pressure should be considered abnormally high is still subject to debate. The accepted criterion in the United States is that normal pressure should not exceed 140 mm Hg systolic and 90 mm Hg diastolic. The World Health Organization accepts as normal blood pressure readings up to 160/95. The difficulty

in diagnosing hypertension is compounded by the wide variability of blood pressure in healthy persons; hence a single blood pressure reading is not a reliable basis for diagnosis. Normal variations are related to many factors, including responses to stimuli—stress, exercise, fear, or excitement. Physicians have long recognized that the blood pressure reading in a patient seen in the office for the first time is usually higher than subsequent readings, and the difference may be considerable. Some people always tense up in the doctor's office and show abnormally high blood pressure, although at other times their pressure may be normal; in the medical literature this condition is sometimes referred to as "white coat hypertension."

Proper diagnosis of hypertension must be based on repeated findings of abnormally high blood pressure. Often patients are taught to take their own blood pressure and are instructed to keep charts with periodic readings of blood pressure over several days. Portable automatic blood pressure monitors are also available; the patient wears the monitor for 12 or more hours, during which time frequent readings are registered.

Observations in patients with long-standing hypertension have revealed that the diastolic pressure is less variable than the systolic pressure. Hence the severity of hypertension is customarily classified according to diastolic pressure:

mild hypertension—90–104 mm Hg

moderate hypertension—105–119 mm Hg

severe hypertension—greater than 120 mm Hg

These levels represent averages of repeated readings rather than an isolated reading. One of the difficulties in evaluating the severity of hypertension is that many patients have unusually variable blood pressure, with grossly abnormal "overshoots" as well as normal pressures appearing periodically. Such patients are thought to have "labile," or unstable, hypertension, and the need for treatment has to be individually evaluated. Although variable, the systolic pressure level is closely related to the long-term consequences of hypertension.

Drug therapy for hypertension is relatively recent. The first drugs became available in the 1950s, but the full effect of successful

therapy is much more recent than that. To comprehend the dramatic effects of drug therapy, we need only review the course and prognosis of untreated hypertension before antihypertensive therapy was widely available. The principal consequences of severe hypertension for the cardiovascular system include the following:

increased workload on the left ventricle of the heart, producing its hypertrophy and eventual failure

acceleration of atherosclerotic damage to various organs due to the wear and tear of high pressure on the arteries

kidney damage, leading to kidney failure (uremia)

damage to the retina of the eye, leading to disturbances of vision

brain damage (stroke), including hemorrhage (often fatal)

complications directly related to high pressures in the arterial system, including aortic dissection (partial rupture of the aorta) and rupture of weakened areas in the arteries of the brain ("berry aneurysm," a small blisterlike outpouching of the wall of an artery), causing cerebral hemorrhage

The effect of hypertension on the heart is its commonest and most serious sequel. Left ventricular hypertrophy leads to heart failure, to accelerated coronary atherosclerosis, and to the risk of sudden death from arrhythmia. Atherosclerosis related to hypertension may also produce stroke and serious disabling disease of the arteries of the legs.

Hypertension induces damage to the small arteries of the kidneys (nephrosclerosis ), which may interfere with the principal function of the kidneys—excretion of waste products in the urine. The effect of hypertension on the retinal arteries in the back of the eye is of diagnostic importance since these small vessels are visible through an ophthalmoscope. Early changes produced by hypertension can be detected before any other consequences of high blood pressure are discovered. The severity of damage to the eye is classified according to the magnitude of detected abnormalities. However, vision is only affected in the last stage, when there is swelling in the critical portion of the eye (papilledema ).

Untreated essential hypertension typically progresses at a very slow pace, so that the consequent damage takes many years to develop.

It is often referred to as "benign hypertension," to distinguish it from a small subgroup of hypertension that progresses rapidly, "malignant hypertension." (If existing benign hypertension suddenly accelerates, the condition is called the "malignant phase.") Malignant hypertension may develop as a variant of either essential hypertension or some types of secondary hypertension. It is characterized by high blood pressure, particularly diastolic pressure, which may rise to 130–150 mm Hg. Severe damage to eye vessels affecting vision is common, as is kidney failure, in addition to its cardiac consequences. Some of these changes are irreversible, although aggressive therapy is capable of reversing and controlling malignant hypertension.

A rare complication of hypertension, most often found in malignant cases, is a hypertensive crisis, an acute event usually manifested as hypertensive encephalopathy . It is a life-threatening emergency consisting of an acute rise of blood pressure producing malfunction of the brain—confusion, loss of consciousness, and convulsions. When this complication develops in women afflicted with hypertension during pregnancy, it is known as eclampsia . Prompt aggressive therapy usually relieves the crisis and reverses its manifestations. Other complications of hypertension producing emergencies include acute pulmonary edema, myocardial infarction, and aortic dissection.

Untreated severe hypertension, though still encountered, is now uncommon, although milder degrees are very frequent in the general population, especially older people. The course of hypertension as it is seen today is entirely different because of effective drug therapy. Wide dissemination of knowledge regarding the importance of early treatment of high blood pressure has completely altered the course and natural history of hypertension. Yet since hypertension produces practically no symptoms, people occasionally carry this disease for a long time without being aware of it. Furthermore, some patients may neglect prescribed treatment, which requires some motivation and cooperation. But even poorly designed or sporadically pursued treatment exerts some effect by protecting against the most serious effects of this disease. Today poorly controlled hypertension is principally recognized as a risk factor in atherosclerosis, thus increasing the probability of myocardial infarction, stroke, and other atherosclerotic diseases.

Treatment of Hypertension

One of the more difficult decisions in medicine is how to treat hypertension. Though a potentially life-threatening—certainly a life-shortening—disease, in most patients hypertension is consistent with good general health. Yet a diagnosis of hypertension may require a commitment on the part of the patient to lifelong use of one or more drugs that frequently produce undesirable side effects—to put it bluntly, may make a well person sick. Consequently, before the initiation of antihypertensive therapy some questions need to be considered. Can the patient safely be left untreated? Could nonpharmacological treatment be effective? Could the patient have one of the rare curable varieties of hypertension that can be eliminated by a surgical intervention?

Differentiating between normal variations in blood pressure with unusual overshoots and true hypertension is difficult. This fact, together with observations showing that serious consequences of hypertension are mostly found in severe hypertension, has led to a controversy regarding the treatment of mild hypertension (diastolic pressure averaging less than 105 mm Hg). Some experts recommend treatment even in the mildest cases of hypertension; others favor postponing therapy, while maintaining careful supervision, unless the patient enters the stage of moderate hypertension. More often, however, early treatment of mild hypertension is advised. Antihypertensive therapy is tailored to each patient according to the degree of hypertension and the patient's motivation in adhering strictly to instructions involved in drug therapy.

Before starting therapy, the patient undergoes a careful evaluation to determine the extent of damage to body organs from the existing hypertension. If an abnormal electrocardiogram or echocardiogram demonstrates left ventricular hypertrophy, abnormalities of the vessels in the eye or impaired kidney function, aggressive therapy is mandatory, even if hypertension is only mild at the time of discovery. In cases of mild hypertension nonpharmacological therapy is tried first; such treatment is most successful in this group of patients. It includes reducing sodium (salt) in the diet, reducing body weight if the patient is overweight, avoiding stressful situations, engaging in recreational activities, and establishing a regular exercise program.

Only 2 percent of the cases of hypertension are curable. Certain screening tests may suggest such a possibility and justify more-elaborate studies. The search for reversible secondary hypertension is usually limited to cases in which unusual findings are present, such as severe or rapidly progressive hypertension in young persons; in addition, certain syndromes atypical of essential hypertension may point to some underlying disease responsible for the hypertension.

Most patients treated for hypertension are apparently healthy and asymptomatic persons with mild or moderate hypertension who are committed to prolonged drug therapy. Since the introduction of effective antihypertensive drugs in the 1950s, nearly 50 different drugs have been approved for treatment of hypertension, and the number of new drugs is constantly increasing.

Drugs are classified according to their effect on a specific function involved in regulating blood pressure. Most drugs in each class have similar—often identical—action and can be used interchangeably, although manufacturers often claim the superiority of one drug over the others. The important categories of antihypertensive drugs are

diuretics, which enhance salt excretion

drugs reducing or blocking vascular control exerted by the sympathetic nervous system

drugs dilating arterioles and thereby reducing resistance (and pressure)

drugs blocking the flow of calcium into cells

drugs inhibiting the angiotensin-converting enzyme

Antihypertensive therapy demands collaboration between physician and patient. To begin, one of the "first-line" antihypertensive agents least likely to have side effects is usually administered and the dose adjusted according to its effectiveness. Undesirable side effects may require switching to a drug from another class. Large doses of a single drug are often avoided in favor of adding a second drug. In severe hypertension or drug-resistant hypertension it may be necessary to use a combination of several drugs. Success in such therapy is gauged by the patient's tolerance for drugs and the

effective reduction of blood pressure. Patients who tolerate drugs poorly may have to settle for more-modest therapeutic goals, such as reducing moderate or severe hypertension to mild hypertension. Whereas in most cases effective and well-tolerated drugs can be found easily, in drug-resistant patients a prolonged period of drug testing by trial and error may be necessary.