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Essential Hypertension
Part I: Definition and Etiology
Oscar A. Carretero, MD; Suzanne Oparil, MD
heart failure have also increased. A major contributor to these systolic hypertension is defined as systolic BP 140 mm Hg
trends is inadequate control of BP in the hypertensive and diastolic BP 90 mm Hg. Individuals with high normal
population. This review of current concepts regarding the BP tend to maintain pressures that are above average for the
definition, etiology, and treatment of essential hypertension is general population and are at greater risk for development of
intended to aid the clinician in identifying those individuals at definite hypertension and cardiovascular events than the
high risk who need to undergo evaluation and treatment, as general population. With the use of these definitions, it is
well as in selecting optimal treatment strategies for hyperten- estimated that 43 million people in the United States have
sive patients with comorbid conditions and/or target organ hypertension or are taking antihypertensive medication,
damage. The part of the review that deals with the genetic which is 24% of the adult population. This proportion
basis of hypertension and the gene/environment interaction changes with (1) race, being higher in blacks (32.4%) and
that may lead to elevated BP is still a work in progress. lower in whites (23.3%) and Mexican Americans (22.6%);
Information gained from the Human Genome Project and (2) age, because in industrialized countries systolic BP rises
from ongoing studies of the genetic basis of hypertension throughout life, whereas diastolic BP rises until age 55 to 60
both in animal models and human populations may revolu- years and thus the greater increase in prevalence of hyper-
tionize the treatment of hypertension by replacing current tension among the elderly is mainly due to systolic hyperten-
empirical therapy with more effective, targeted treatments sion; (3) geographic patterns, because hypertension is more
based on the genotype of the patient. Concepts introduced in prevalent in the southeastern United States; (4) gender,
this review form the basis for such pharmacogenomic because hypertension is more prevalent in men (though
approaches to antihypertensive therapy. menopause tends to abolish this difference); and (5) socio-
economic status, which is an indicator of lifestyle attributes
Definition of Essential or and is inversely related to the prevalence, morbidity, and
Primary Hypertension mortality rates of hypertension.
BP is a quantitative trait that is highly variable1; in population Essential, primary, or idiopathic hypertension is defined as
studies, BP has a normal distribution that is slightly skewed to high BP in which secondary causes such as renovascular
the right. There is a strong positive and continuous correlation disease, renal failure, pheochromocytoma, aldosteronism, or
between BP and the risk of CVD (stroke, myocardial infarc- other causes of secondary hypertension or mendelian forms
tion, heart failure), renal disease, and mortality, even in the (monogenic) are not present. Essential hypertension accounts
normotensive range. This correlation is more robust with for 95% of all cases of hypertension. Essential hypertension is
systolic than with diastolic BP.2 There is no specific level of a heterogeneous disorder, with different patients having
BP where cardiovascular and renal complications start to different causal factors that lead to high BP. Essential
occur; thus the definition of hypertension is arbitrary but hypertension needs to be separated into various
This is Part I of a 2-part article. Part II of this article will be published in the February 1, 2000 issue of Circulation.
From the Hypertension and Vascular Research Division, Heart and Vascular Institute, Henry Ford Hospital, Detroit, Mich (O.A.C.), and the Division
of Cardiovascular Disease, Vascular Biology and Hypertension Program, University of Alabama School of Medicine, Birmingham (S.O.).
Correspondence to Oscar A. Carretero, MD, Hypertension and Vascular Research Division, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI
48202. E-mail ocarret1@hfhs.org
(Circulation. 2000;101:329-335.)
2000 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
329
330 Circulation January 25, 2000
syndromes because the causes of high BP in most patients or high normal inherited BP become hypertensive stage 1 when
BP is increased by a hypertensinogenic factor. In patients with
presently classified as having essential hypertension can be
inherited hypertension in stages 1 to 3, their hypertension
recognized. becomes more severe when hypertensinogenic factors are
added.
Known Etiological Factors in
Essential Hypertension hypertensive range (140/90 mm Hg) (Figure 1, third 2
Although it has frequently been indicated that the causes of columns); and (4) patients who have inherited BP in the
essential hypertension are not known, this is only partially hypertensive range; addition of 1 or more hypertensinogenic
true because we have little information on genetic variations factors will make hypertension more severe, changing it from
or genes that are overexpressed or underexpressed as well as stage 1 to stage 2 or 3 (Figure 1, fourth to sixth 2 columns).
the intermediary phenotypes that they regulate to cause high Theoretically, in a population unaffected by hypertensino-
BP.4 A number of factors increase BP, including (1) obesity, genic factors, BP will have a normal distribution; it will be
(2) insulin resistance, (3) high alcohol intake, (4) high salt skewed to the right and will have a narrow base or less
intake (in salt-sensitive patients), (5) aging and perhaps (6) variance (Figure 2, continuous line). When 1 hypertensino-
sedentary lifestyle, (7) stress, (8) low potassium intake, and genic factor is added to this population, such as increased
(9) low calcium intake.5,6 Furthermore, many of these factors body mass, one would expect the normal distribution curve to
are additive, such as obesity and alcohol intake. be further skewed to the right; consequently the base will be
In this review, variations in BP that are genetically deter- wider (more variance) and the curve will be flatter (Figure 2,
mined will be called inherited BP, although we do not broken line). If a second hypertensinogenic factor such as
know which genes cause BP to vary; we know from family alcohol intake is added to increased body mass, the curve will
studies that inherited BP can range from low normal BP to be skewed more to the right and the variance will increase
severe hypertension. Factors that increase BP, such as obesity further, with more subjects classified as hypertensive (Figure
and high alcohol and salt intake, will be called hyperten- 2, dotted line).
sinogenic factors. Some of these factors have inherited, Discovering which genetic variations place BP on the left
behavioral, and environmental components. Inherited BP or right side of the distribution curve is of both theoretical and
could be considered core BP, whereas hypertensinogenic practical importance because it could help the physician to
factors cause BP to increase above the range of inherited BPs, better treat or cure hypertension.7 Recognition of the hyper-
thus creating 4 main possibilities: (1) patients who have tensinogenic factors may allow nonpharmacological preven-
inherited BP in the optimal category (120/80 mm Hg); if tion, treatment, or cure of hypertension. Hypertensinogenic
1 or more hypertensinogenic factors are added, BP would factors such as obesity, insulin resistance, or high alcohol
probably increase but remain in the normal range (135/ intake also have an important genetic component. Further-
85 mm Hg) (Figure 1, first 2 columns); (2) patients who more, there are interactions between genetic and environmen-
have inherited BP in the normal category (130/ tal factors (Figure 2) that influence intermediary phenotypes
85 mm Hg); if 1 or more hypertensinogenic factors are such as sympathetic nerve activity, the renin-angiotensin-
added, BP will probably increase to the high normal range aldosterone and renal kallikrein-kinin systems, and endothe-
(130 to 139/85 to 89 mm Hg) or to stage 1 of the hypertensive lial factors, which in turn influence other intermediary phe-
category (140 to 159/90 to 99 mm Hg) (Figure 1, second 2 notypes such as sodium excretion, vascular reactivity, and
columns); (3) patients who have inherited BP in the high cardiac contractility. These and many other intermediary
normal category (130 to 139/85 to 89 mm Hg); if 1 or more phenotypes determine total vascular resistance and cardiac
hypertensinogenic factors are added, BP will increase to the output and, consequently, BP. Recognition of the hypertensi-
Carretero and Oparil Essential Hypertension 331
nogenic factor(s) and establishing that the patients hyperten- Thus there are many genes that could participate in the
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sion is the result of obesity (either alone or combined with development of hypertension.
other factors such as insulin resistance or high alcohol intake) The influence of genes on BP has been suggested by family
or old age instead of essential hypertension may help the studies demonstrating associations of BP among siblings and
physician as well as the patient and his or her family to between parents and children. There is a better association
modify or eliminate these hypertensinogenic and CVD risk among BP values in biological children than in adopted
factors when possible, which may cure the hypertension or at children and in identical as opposed to nonidentical twins. BP
least facilitate control of BP. When the hypertensinogenic variability attributed to all genetic factors varies from 25% in
factor cannot be reduced or eliminated, as with systolic pedigree studies to 65% in twin studies. Furthermore, genetic
hypertension induced by aging (arteriosclerosis), recognition factors also influence behavioral patterns, which might lead
of the underlying cause of high BP will emphasize the need to BP elevation. For example, a tendency toward obesity or
for (1) further studies to determine whether the patient has alcoholism will be influenced by both genetic and environ-
arteriosclerosis and/or atherosclerosis, the magnitude of the mental factors; thus the proportion of BP variability caused
disease, and whether there are occlusive lesions; (2) treatment by inheritance is difficult to determine and may vary in
of the atherosclerosis with lifestyle and dietary changes and different populations.
lipid-lowering agents if necessary; and (3) pharmacological Mutations in at least 10 genes have been shown to raise or
treatment of systolic hypertension to decrease passive stiff- lower BP through a common pathway by increasing or
ness (arteriosclerosis) of the major central elastic arteries and decreasing salt and water reabsorption by the nephron.13,14
decrease morbidity and mortality rates. Thus recognition of The genetic mutations responsible for 3 rare forms of men-
factors that induce hypertension is not only of theoretical but delian (monogenic) hypertensive syndromesglucocorticoid-
also of practical importance. In conclusion, as stated by remediable aldosteronism (GRA), Liddles syndrome, and
Beilin,8 it is no longer appropriate to define essential apparent mineralocorticoid excesshave been identified,
hypertension as a rise in blood pressure without cause, since whereas in a fourth, autosomal dominant hypertension with
a number of causes can be clearly identified in most cases of brachydactyly, the gene is not yet identified but has been
so-called essential hypertension. As discussed later in more mapped to chromosome 12 (12p). Subtle variations in one of
detail, there is clear evidence that changes in lifestyle, these genes may also cause some forms of essential
including dietary changes that reduce body weight, fat, and hypertension. For a review of the mutations that cause a
alcohol intake and increase potassium and calcium intake,9 as decrease in BP, see Lifton.13
well as exercise,10,11 reduce or normalize BP in many
patients. Glucocorticoid-Remediable Aldosteronism
This is an autosomal dominant form of monogenic hyperten-
Inherited BP sion in which aldosterone secretion is regulated by adreno-
The identification of variant (allelic) genes that contribute to corticotropic hormone. Glucocorticoid treatment causes BP to
the development of hypertension is complicated by the fact decrease and gives the syndrome its name. The genetic
that the 2 phenotypes that determine BP, cardiac output and mutation that causes GRA has been identified by Lifton14 as
total peripheral resistance, are controlled by intermediary a chimeric gene fusing nucleotide sequences of the promoter-
phenotypes, including the autonomic nervous system, vaso- regulatory region of 11-hydroxylase (controlled by adreno-
pressor/vasodepressor hormones, the structure of the cardio- corticotropic hormone) and the structural portion of the
vascular system, body fluid volume and renal function, and aldosterone synthase gene. The chimeric gene results from a
many others. Furthermore, these intermediary phenotypes are meiotic mismatch and unequal crossing over. The patients are
also controlled by complex mechanisms including BP itself.12 usually thought to have primary aldosteronism because they
332 Circulation January 25, 2000
exhibit volume expansion, metabolic alkalosis with hypoka- chromosome 12 (12p) in a large Turkish kindred. Two other
lemia, low plasma renin, and high aldosterone. Most of the families with this syndrome have been reported, 1 in Canada
patients first described as having GRA showed severe hyper- and 1 in the United States. In addition, the study of a Japanese
tension and died prematurely from stroke. However, with the child with hypertension and type E brachydactyly has al-
development of direct genetic testing, the BP of patients with lowed the area on 12p containing the gene mutation to be
this syndrome was found to cover a wide range, including pinpointed further, although the gene responsible for this
normotensive levels.15,16 In patients with GRA and normal syndrome has not yet been cloned. Unlike the other 3
BP, expression of the chimeric gene may be variable, but autosomal forms of hypertension, BP is not affected by
because steroid levels are similar in patients with severe and volume expansion and the underlying mechanism is not
mild hypertension, this seems unlikely. It is also possible that known. Thus identification of the gene responsible may help
the genetic background of the trait (other than the chimeric clarify some of the genetic alterations in essential
mutation), such as high renal kallikrein, places the inherited hypertension.
BP of these subjects in the low or ideal normal range and the
mutation causes BP to increase to high normal or hyperten- Essential or Primary Hypertension
sive stage 1. Thus the final BP would be the combined result The genetic alterations responsible for inherited essential
of the inherited BP (including the genetic mutation) and the hypertension remain largely unknown.4 Results from family
increase in BP caused by hypertensinogenic factors such as studies suggest several possible intermediary phenotypes
salt. (genetic traits) that may be related to inherited high BP, such
as high sodium-lithium countertransport, low urinary kal-
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Essential Hypertension: Part I: Definition and Etiology
Oscar A. Carretero and Suzanne Oparil
Circulation. 2000;101:329-335
doi: 10.1161/01.CIR.101.3.329
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
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