PHYSIOLOGY IN MEDICINE: A SERIES OF ARTICLES LINKING MEDICINE WITH SCIENCE Physiology in Medicine Dennis A. Ausiello, MD, Editor; Dale J. Benos, PhD, Deputy Editor; Francois Abboud, MD, Associate Editor; Review William Koopman, MD, Associate Editor Annals of Internal Medicine Paul Epstein, MD, Series Editor Pathogenesis of Hypertension Suzanne Oparil, MD; M. Amin Zaman, MD; and David A. Calhoun, MD Clinical Principles Physiologic Principles A clearer understanding of the pathogenesis of hypertension More than 90% of cases of hypertension do not have a clear will probably lead to more highly targeted therapies and to cause. greater reduction in hypertension-related cardiovascular disease morbidity than can be achieved with current Hypertension clusters in families and results from a complex empirical treatment. interaction of genetic and environmental factors. The hypertension-related genes identified to date regulate renal salt and water handling. Major pathophysiologic mechanisms of hypertension include activation of the sympathetic nervous system and renin–angiotensin–aldosterone system. Endothelial dysfunction, increased vascular reactivity, and vascular remodeling may be causes, rather than consequences, of blood pressure elevation; increased vascular stiffness contributes to isolated systolic hypertension in the elderly. ssential hypertension, or hypertension of unknown sity; increased activity of vascular growth factors; alter- Ecause, accounts for more than 90% of cases of hyper- ations in adrenergic receptors that influence heart rate, ino- tension. It tends to cluster in families and represents a tropic properties of the heart, and vascular tone; and collection of genetically based diseases or syndromes with altered cellular ion transport (Figure 1) (2). The novel several resultant inherited biochemical abnormalities (1– concept that structural and functional abnormalities in the 4). The resulting phenotypes can be modulated by various vasculature, including endothelial dysfunction, increased environmental factors, thereby altering the severity of blood oxidative stress, vascular remodeling, and decreased com- pressure elevation and the timing of hypertension onset. pliance, may antedate hypertension and contribute to its Many pathophysiologic factors have been implicated pathogenesis has gained support in recent years. in the genesis of essential hypertension: increased sympathetic Although several factors clearly contribute to the nervous system activity, perhaps related to heightened ex- pathogenesis and maintenance of blood pressure elevation, posure or response to psychosocial stress; overproduction of renal mechanisms probably play a primary role, as hypoth- sodium-retaining hormones and vasoconstrictors; long-term esized by Guyton (5) and reinforced by extensive experi- high sodium intake; inadequate dietary intake of potassium mental and clinical data. As discussed in this paper, other and calcium; increased or inappropriate renin secretion mechanisms amplify (for example, sympathetic nervous with resultant increased production of angiotensin II and system activity and vascular remodeling) or buffer (for ex- aldosterone; deficiencies of vasodilators, such as prostacy- ample, increased natriuretic peptide or kallikrein–kinin ex- clin, nitric oxide (NO), and the natriuretic peptides; alter- pression) the pressor effects of renal salt and water reten- ations in expression of the kallikrein–kinin system that tion. These interacting pathways play major roles in both affect vascular tone and renal salt handling; abnormalities increasing blood pressure and mediating related target or- of resistance vessels, including selective lesions in the renal gan damage. Understanding these complex mechanisms microvasculature; diabetes mellitus; insulin resistance; obe- has important implications for the targeting of antihyper- Ann Intern Med. 2003;139:761-776. For author affiliations, see end of text. © 2003 American College of Physicians 761 Review Pathogenesis of Hypertension Figure 1. Pathophysiologic mechanisms of hypertension. AME ϭ apparent mineralocorticoid excess; CNS ϭ central nervous system; GRA ϭ glucocorticoid-remediable aldosteronism. Reproduced with permis- sion from Crawford and DiMarco (2). tensive therapy to achieve benefits beyond lowering blood factors. Improved techniques of genetic analysis, especially pressure. genome-wide linkage analysis, have enabled a search for genes that contribute to the development of primary hy- GENETICS pertension in the population. Application of these tech- Evidence for genetic influence on blood pressure niques has found statistically significant linkage of blood comes from various sources. Twin studies document pressure to several chromosomal regions, including regions greater concordance of blood pressures in monozygotic linked to familial combined hyperlipidemia (10–13). than dizygotic twins (6), and population studies show These findings suggest that there are many genetic loci, greater similarity in blood pressure within families than each with small effects on blood pressure in the general between families (7). The latter observation is not attrib- population. Overall, however, identifiable single-gene utable to only a shared environment since adoption studies causes of hypertension are uncommon, consistent with a demonstrate greater concordance of blood pressure among multifactorial cause of primary hypertension (14). biological siblings than adoptive siblings living in the same The candidate gene approach typically compares the household (8). Furthermore, single genes can have major prevalence of hypertension or the level of blood pressure effects on blood pressure, accounting for the rare Mende- among individuals of contrasting genotypes at candidate lian forms of high and low blood pressure (3). Although loci in pathways known to be involved in blood pressure identifiable single-gene mutations account for only a small regulation. The most promising findings of such studies percentage of hypertension cases, study of these rare disor- relate to genes of the renin–angiotensin–aldosterone sys- ders may elucidate pathophysiologic mechanisms that pre- tem, such as the M235T variant in the angiotensinogen dispose to more common forms of hypertension and may gene, which has been associated with increased circulat- suggest novel therapeutic approaches (3). Mutations in 10 ing angiotensinogen levels and blood pressure in many genes that cause Mendelian forms of human hypertension distinct populations (15–17), and a common variant in and 9 genes that cause hypotension have been described to the angiotensin-converting enzyme (ACE) gene that has date, as reviewed by Lifton and colleagues (3, 9) (Figure 2). been associated in some studies with blood pressure These mutations affect blood pressure by altering renal salt variation in men (18, 19). However, these variants seem handling, reinforcing the hypothesis of Guyton (5) that the to only modestly affect blood pressure, and other can- development of hypertension depends on genetically deter- didate genes have not shown consistent and reproduc- mined renal dysfunction with resultant salt and water re- ible associations with blood pressure or hypertension in tention (2). larger populations (3); thus, demonstration of common In most cases, hypertension results from a complex genetic causes of hypertension in the general population interaction of genetic, environmental, and demographic remains elusive (16, 20, 21). 762 4 November 2003 Annals of Internal Medicine Volume 139 • Number 9 www.annals.org Pathogenesis of Hypertension Review The best studied monogenic cause of hypertension is particularly in those resistant to conventional pharmaco- the Liddle syndrome, a rare but clinically important disor- logic therapies. der in which constitutive activation of the epithelial so- dium channel predisposes to severe, treatment-resistant hy- pertension (22). Epithelial sodium channel activation has INHERITED CARDIOVASCULAR RISK FACTORS been traced to mutations in the ␤ or ␥ subunits of the Cardiovascular risk factors, including hypertension, channel, resulting in inappropriate sodium retention at the tend to cosegregate more commonly than would be ex- renal collecting duct level. Patients with the Liddle syn- pected by chance. Approximately 40% of persons with es- drome typically present with volume-dependent, low- sential hypertension also have hypercholesterolemia. Ge- renin, and low-aldosterone hypertension. Screenings of netic studies have established a clear association between general hypertensive populations indicate that the Liddle hypertension and dyslipidemia (25). Hypertension and syndrome is rare and does not contribute substantially to type 2 diabetes mellitus also tend to coexist. Hypertension the development of hypertension in the general population is approximately twice as common in persons with diabetes (23). In selected groups, however, evidence suggests that as in persons without diabetes, and the association is even epithelial sodium channel activation might be a more com- stronger in African Americans and Mexican Americans mon cause of hypertension. Epithelial sodium channel ac- (26). The leading cause of death in patients with type 2 tivation, as evidenced by increased sodium conductance in diabetes is coronary heart disease, and diabetes increases peripheral lymphocytes, has been noted in 11 of 44 (25%) the risk for acute myocardial infarction as much as a pre- patients with resistant hypertension (blood pressure uncon-