69 Hypertension

Arterial hypertension is a condition characterized by abnormally high systolic and/or diastolic blood pressure levels. Systolic and diastolic blood pressure levels are usually estimated indirectly by use of an inflatable rubber bladder to compress the artery in the upper arm.

Although longitudinal research studies such as the one in Framingham, Massachusetts, and the life insurance industry have noted that even slight elevations of blood pressure are associated with in­creased risk of premature death, the World Health Organization has recommended that the following blood pressure levels be used to classify adults (blood pressure levels defining juvenile hyperten­sion are under review):

Hypertensive: Greater than or equal to 160 millime­ters of mercury (mmHg) systolic and/or greater than or equal to 95 mmHg diastolic.

Normotensive: Less than or equal to 140 mmHg sys­tolic and less than or equal to 90 mmHg diastolic.

Borderline Hypertensive: Between hypertensive and normotensive.

The condition is also divided etiologically into two types: secondary and primary or essential hyperten­sion. Secondary hypertension, resulting from some known cause (including diseases of the kidney or the adrenal glands), represents less than 10 percent of all the cases of the disease. Essential hypertension, occurring in over 90 percent of the cases, is defined as high blood pressure without evident cause.

Distribution and Incidence

In most societies the average blood pressure levels and the diseases associated with higher blood pres­sure increase as people get older. However, blood pressure does not increase with age in all popula­tions. Indeed, the disease appears to be totally ab­sent from societies described as “stone age.” In such societies, blood pressure does not rise with age, and hypertension is extremely rare. However, a 1988 World Health Organization literature survey on high blood pressure in less developed countries re­vealed that the prevalence of hypertension there is increasing.

A recent international survey, the INTERSALT study, highlights the wide geographic variability of hypertension throughout the world. INTERSALT, a 52-center, 32-country study, found that the preva­lence Ofhypertension (hypertensives were defined as anyone having greater than 140 mmHg systolic or greater than 90 mmHg diastolic or of persons on antihypertensive medication) between the ages of 20 and 59 ranged from zero percent in the Yanomamo Indians of northern Brazil to over 33 percent in an African-American population in Jackson, Missis­sippi. There was a significant within-continent vari­ability as well (see Table VIII.69.1). It is likely that this wide variability in the prevalence of hyperten­sion is due to differences in both environmental and genetic factors.

Etiology and Epidemiology

Many have hypothesized that environmental factors are primarily responsible for the development of high blood pressure. Principal evidence for this view consists of reports that Unacculturated or “primi­tive” populations are virtually free of hypertension, but when members of these populations migrate to urban areas their blood pressures rise. There are conflicting interpretations of this phenomenon: Some postulate that the change in diet (especially salt intake) and/or the weight gain that often accom­pany the move to a modern area are the primary reasons for the development of high blood pressure in populations that were previously free from it.

Table VIΠ.69.1 (cont.)

Note: At each site the investigators randomly chose about 200 individuals from population-based registries from 4 equally sized age groups between the ages of 20 and 59 years.

Source: INTERSALT (1988).

chosocial stress is the culprit. Still others surmise that those who experienced the greatest rise in blood pressure may have inherited a genetic predisposi­tion to the disease that is sparked by some environ­mental phenomena such as dietary salt or psychoso­cial stress. Interestingly, salt and stress have been assumed to be related to the disease for eons. A Chinese physician stated over 4,000 years ago that “if too much salt is used in food, the pulse hardens [and] when rebellious emotions rise to Heaven, the pulse expires and leaves the body.”

A gain in body weight as a result of a generalized increase in food intake is most definitely associated with high blood pressure, and a sustained reduction in body weight is one of the most effective methods of lowering blood pressure.

Specific dietary factors that may affect blood pres­sure include salt (sodium chloride), potassium, mag­nesium, calcium, fat, and even licorice. Most interest has centered around salt - more specifically, the so­dium portion of the molecule. The most compelling evidence for the influence of salt on blood pressure is the fact that every low-salt-intake population ever studied has manifested very low blood pressure that does not rise with age. Significantly, INTERSALT reported a positive and statistically significant rela­tionship between salt intake and blood pressure in their 52-center study.

Psychosocial stress is also believed to be associated with hypertension. In some population surveys, inves­tigators have reported that societies under high stress also have higher mean blood pressure levels than those under low stress. Unfortunately, stress has been a difficult phenomenon to measure, and the association between stress and blood pressure has been difficult to demonstrate in human populations.

Heredity is known to be an important contributor to blood pressure regulation, and hence to abnor­mally elevated blood pressure or hypertension. Like many quantitative genetic traits such as height, lev­els of blood pressure tend to run in families; some have higher blood pressure, some have lower blood pressure. Other evidence of genetic influence is re­vealed by the concordance of hypertension in sib­lings, especially identical, or monozygotic (MZ), twins: If one member of a set of MZ twins has hyper­tension, there is a strong likelihood that the other will have the disease as well. Genetic influences on arterial pressure have also been demonstrated in inbred strains of rats, mice, and other animals. The hereditary mediators of these genetic influences on blood pressure are not known but probably reside in genetic influences on the major blood pressure con­trol systems.

Many investigators believe that neither genetic nor environmental factors act alone, that in fact there is an interactive relationship between genes and environment. A compelling example of this is the simple breeding experiments in rats carried out by L. K. DahI and colleagues in the early 1960s. By selective breeding they were able, in a very few generations, to develop two strains of rats: One, ex­tremely sensitive to the blood pressure-raising ef­fects of salt in the diet, was called “salt sensitive”; the other, resistant to the blood pressure-raising ef­fects of salt, was termed “salt resistant.” Humans manifest similar differences, in that some are “salt sensitive” and others are not, and the Dahl model may be applicable to understanding the evolution of “salt sensitivity” in human populations as well.

In former times, as isolated populations diverged and migrated into different ecological systems, they may also have experienced different “selection pres­sures” related to salt metabolism. These included different temperatures, salt intake, and mortality from salt-depletive diseases such as diarrhea and fe­ver. These “selection pressures” may have resulted in a new genotype that enhanced survival in the new ecology environment by protecting against prema­ture mortality from salt-depletive conditions. If this protective genotype included an enhanced ability to conserve sodium, then it is likely that these adapta­tions predispose to salt-sensitive hypertension today. It is argued that this may have occurred when many sub-Saharan Africans were forced to migrate to the Western Hemisphere. Mortality rates were very high from salt-depletive diseases, and it is surmised that those with the superior salt-retaining abilities sur­vived and passed their genes on to present-day Afri­can Americans. This enhanced genetically based abil­ity to conserve salt may, therefore, be found in greater frequency in Western Hemisphere blacks than in West African blacks, and may be part of the reason the former group today has a higher prevalence of hypertension than does the latter.

Clinical Manifestations

Although in the past a “hard pulse” or “dropsical swellings” (edema) may have signaled hypertension, today the only acceptable way to detect the condition is through the use of the blood pressure cuff (sphyg­momanometer). Because the disease is usually asymptomatic, essential hypertension has been ap­propriately termed the “silent killer.” Undetected and uncontrolled, it can damage the arteries, the kidneys, and the heart, and, as several important long-term studies revealed, hypertension is a precur­sor to premature death from coronary heart disease, stroke, congestive heart failure, kidney (renal) fail­ure, and atherosclerosis.

History

For centuries, the only way to assess “blood pres­sure” was to feel the pulse, and interpreting its force and rhythm proved to be a useful predictor of disease and death. In about 2500 B.C., for example, a Chi­nese physician remarked: “[W]hen the pulse is abun­dant but tense and hard like a cord, there are dropsi­cal swellings.”

More than 4,000 years later, in 1827, the British physician Richard Bright suggested that the dropsi­cal swellings he encountered in a patient were due to obstruction in the kidney’s circulatory system. Bright’s argument was so persuasive that through­out the remainder of the nineteenth century most physicians considered a strong or tense pulse a symp­tom of kidney disease.

By the late nineteenth century, the earlier discover­ies on the measurement of systolic blood pressure by Stephen Hales, Samuel von Basch, and others led to the invention of the sphygmomanometer (blood pres­sure cuff). Coupled with the 1905 description of diastolic blood pressure by N. Korotkoff, this device effectively replaced diagnosis by “pulse,” and its wide­spread use led observers to the realization that most patients with elevated arterial pressure did not have a kidney disorder. This newly discovered condition was given various names including angiosclerosis, presclerosis, hyperpiesis, primary hypertensive car­diovascular disease, and essential hypertension. The condition was soon recognized as one of the most common types of cardiovascular disorders. Insurance companies led the way in quantifying the association between this new disease and premature death.

In the 1910s, the medical director of the North­western Mutual Life Insurance Company, J. W. Fisher, reported the results of several years of study of the relationship between blood pressure levels and premature death. Table VIII.69.2 provides a brief summary of the findings.

It was obvious to Fisher that the higher the sys­tolic blood pressure, the greater the risk of death. Those with systolic blood pressure levels above 160 mmHg had a probability of premature death about 2.5 times greater than those with a systolic blood pressure of about 140 mmHg. In recommending that any insurance application with a persistent blood pressure of “15 mm Hg above the average for his or her age” should be investigated further, Fisher was probably the first to offer a quantifiable definition of “high blood pressure” (see Table VIII.69.3).

The scientific world was interested in what caused this newly discovered, deadly, and extremely preva­lent disease. During the 1930s and 1940s, research­ers conducted detailed examinations on the influence of the sympathetic nervous system, the endocrine system, and the renal system on arterial pressure, and were successful in cataloging several types of

Table VIΠ.69.2. Relationship between blood pressure and mortality: Northwestern Mutual Life Insurance Company, 1907-14

Note: Expected deaths = expected deaths in company (80% of M.A. table in source); systolic BP = systolic blood pressure; observed deaths = observed deaths of those with noted systolic blood pressure.

Source: Adapted from Fisher (1914).

secondary hypertension. Pheochromocytoma was first reported in 1929, Cushing’s syndrome in 1932, pyelonephritis in 1937, renal artery stenosis in 1938, and Conn’s syndrome (primary aldosteronism) in 1955. In very few cases these “secondary” causes of high blood pressure were cured through surgery, but in the great majority of cases - those with essential hypertension - the ultimate determinant of elevated arterial pressure remained a mystery. One very im­portant breakthrough in understanding the patho­physiology of essential hypertension occurred among investigators working in animal physiology.

In the 1920s, Harry Goldblatt progressively con­stricted blood flow to the kidney in a dog, which produced a rapidly developing high blood pressure that resulted in death due to heart failure. The ex­periment, said by T. A. Stamey to have “stimulated more medical research than any single experiment in medical history,” sparked a worldwide search for a kidney (renal)-based pressor substance that pro­duced hypertension. By the end of the 1930s, two

Table VIII.69.3. “Normal” and “unacceptable” systolic blood pressures by age: Northwestern Mutual Life Insurance Company, 1914

Source: Adapted from Fisher (1914).

teams, one in the United States and one in Argen­tina, simultaneously discovered that the blood from a “Goldblatt kidney” contained a substance that caused vasoconstriction (squeezing of the arteries). The American group called their substance “angio- tonin,” while the Argentine group christened the compound “hypertensin.” These two teams met and, deciding they were working on the same substance, combined their two names for the compound; the substance became angiotensin. These discoveries led to extensive biochemical research into the neural, cellular, and hemodynamic systems that control blood pressure, and eventually to the development of the most widely prescribed antihypertensive medica­tions today. The discovery and elucidation of the biochemical mechanisms controlling blood pressure were extremely important in understanding and con­trolling high blood pressure, but researchers were still a long way from finding the ultimate cause of the disease.

In the 1950s and 1960s, an important debate oc­curred between two British physicians over the influ­ence of heredity on high blood pressure in humans. Robert Platt argued that essential hypertension was a “qualitative” disease, controlled by a single gene, with a bimodal population distribution. George Pick­ering, on the other hand, reasoned that what was termed “hypertension” was only the upper end of a continuous unimodal distribution of blood pressure levels. He thought that hypertension was a “quanti­tative” disease and was controlled by multiple genes in combination with environmental influences. The debate was never resolved by the two participants. Epidemiological research since then has tended to favor Pickering’s quantitative definition; however, in 1983 the analysis of a biostatistician showed the bimodal distribution of blood pressure values in a very large sample from Norway.

Today, both environmental and genetic factors are under intense study as possible etiologic factors at the individual level and the population level. How­ever, it is still the case that the cause of abnormally elevated blood pressure in over 90 percent of the cases remains unknown. Fortunately, however, suc­cessful efforts are being made to lower blood pres­sure through diet, stress reduction, exercise, weight control, medication, and other means, in the hope that the frequency of premature deaths from hyper­tension will be reduced throughout the world.

Thomas W. Wilson and Clarence E. Grim

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