Hypertension is one of the most common worldwide diseases afflicting humans. Because of the associated morbidity and mortality and the cost to society, hypertension is an important public health challenge. Over the past several decades, extensive research, widespread patient education, and a concerted effort on the part of health care professionals have led to decreased mortality and morbidity rates from the multiple organ damage arising from years of untreated hypertension.

Hypertension is the most important modifiable risk factor for coronary heart disease (the leading cause of death in North America), stroke (the third leading cause), congestive heart failure, end-stage renal disease, and peripheral vascular disease. Therefore, health care professionals must not only identify and treat patients with hypertension but also promote a healthy lifestyle and preventive strategies to decrease the prevalence of hypertension in the general population.

Historical perspectives

Blood pressure was measured for the first time by Stephen Hales in 1773. Hales also described the importance of blood volume in blood pressure regulation. The contribution of peripheral arterioles in maintaining blood pressure, described as "tone," was first described by Lower in 1669 and subsequently by Sénac in 1783. The role of vasomotor nerves in the regulation of blood pressure was observed by such eminent investigators as Claude Bernard, Charles E. Edouard, Charles Brown-Séquard, and Augustus Waller. William Dayliss advanced this concept in a monograph published in 1923. Cannon and Rosenblueth developed the concept of humoral control of blood pressure and investigated pharmacologic effects of epinephrine. Three contributors who advanced the knowledge of humoral mechanisms of blood pressure control are TR Elliott, Sir Henry Dale, and Otto Loew.

Richard Bright, a physician who practiced in the first half of the 19th century, observed the changes of hypertension on the cardiovascular system in patients with chronic renal disease. George Johnson in 1868 postulated that the cause of left ventricular hypertrophy (LVH) in Bright disease was the presence of muscular hypertrophy in the smaller arteries throughout the body. Further clinical pathologic studies by Sir William Gull and HG Sutton (1872) led to further description of the cardiovascular changes of hypertension. Frederick Mahomed was one of the first physicians to systematically incorporate blood pressure measurement as a part of a clinical evaluation.

The recognition of primary, or essential, hypertension is credited to the work of Huchard, Vonbasch, and Albutt. Observations of Janeway and Walhard led to the recognition of target organ damage, which branded hypertension as the "silent killer." The concepts of renin, angiotensin, and aldosterone were advanced by several investigators in the late 19th and early 20th centuries. The names of Irwine, Page, van Slyke, Goldblatt, Laragh, and Tuttle prominently appear throughout the hypertension literature, and their work enhances our understanding of the biochemical basis of essential hypertension. Cushman and Ondetti developed an orally acting converting enzyme inhibitor from snake venom peptides and are credited with the successful synthesis of the modern antihypertensive captopril.


Defining abnormally high blood pressure is extremely difficult and arbitrary. Furthermore, the relationship between systemic arterial pressure and morbidity appears to be quantitative rather than qualitative. A level for high blood pressure must be agreed upon in clinical practice for screening patients with hypertension and for instituting diagnostic evaluation and initiating therapy. Because the risk to an individual patient may correlate with the severity of hypertension, a classification system is essential for making decisions about aggressiveness of treatment or therapeutic interventions.

Based on recommendations of the Seventh Report of the Joint National Committee of Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII), the classification of blood pressure (expressed in mm Hg) for adults aged 18 years or older is as follows*:1

  • Normal† - Systolic lower than 120, diastolic lower than 80
  • Prehypertension - Systolic 120-139, diastolic 80-99
  • Stage 1 - Systolic 140-159, diastolic 90-99
  • Stage 2 - Systolic equal to or more than 160, diastolic equal to or more than 100

*Based on the average of 2 or more readings taken at each of 2 or more visits after initial screening

†Normal blood pressure with respect to cardiovascular risk is less than 120/80 mm Hg. However, unusually low readings should be evaluated for clinical significance.

Prehypertension, a new category designated in the JNC VII report, emphasizes that patients with prehypertension are at risk for progression to hypertension and that lifestyle modifications are important preventive strategies.

Hypertension may be either essential or secondary. Essential hypertension is diagnosed in the absence of an identifiable secondary cause. Approximately 95% of the 50 million American adults with hypertension have essential hypertension, while secondary hypertension accounts for fewer than 5% of the cases. However secondary forms of hypertension, such as primary hyperaldosteronism, account for 20% of resistant hypertension (hypertension that requires 4 or more medications to control).


Arterial blood pressure is a product of cardiac output and systemic vascular resistance. Therefore, determinants of blood pressure include factors that affect cardiac output and arteriolar vascular physiology. Blood viscosity, vascular wall sheer conditions (rate and stress), and blood flow velocity (mean and pulsatile components) have potential relevance with regard to the regulation of blood pressure in humans by vascular and endothelial function. Furthermore, changes in vascular wall thickness affect the amplification of peripheral vascular resistance in hypertensive patients and result in reflection of waves back to the aorta, increasing systolic blood pressure. Circulating blood volume is regulated by renal salt and water handling, a phenomenon that plays a particularly important role in salt-sensitive hypertension.

Regulation of blood pressure

Regulation of normal blood pressure is a complex process. Although a function of cardiac output and peripheral vascular resistance, both of these variables are influenced by multiple factors.

The factors affecting cardiac output include sodium intake, renal function, and mineralocorticoids; the inotropic effects occur via extracellular fluid volume augmentation and an increase in heart rate and contractility. Peripheral vascular resistance is dependent upon the sympathetic nervous system, humoral factors, and local autoregulation. The sympathetic nervous system produces its effects via the vasoconstrictor alpha effect or the vasodilator beta effect. The humoral actions on peripheral resistance are also mediated by other mediators such as vasoconstrictors (angiotensin and catecholamines) or vasodilators (prostaglandins and kinins).

Autoregulation of blood pressure occurs by way of intravascular volume contraction and expansion regulated by the kidney, as well as via transfer of transcapillary fluid. Through the mechanism of pressure natriuresis, salt and water balance is achieved at heightened systemic pressure, as proposed by Guyton. Interactions between cardiac output and peripheral resistance are autoregulated to maintain a set blood pressure in an individual. For example, constriction of the arterioles elevates arterial pressure by increasing total peripheral resistance, whereas venular constriction leads to redistribution of the peripheral intravascular volume to the central circulation, thereby increasing preload and cardiac output.

Pathogenesis of hypertension

The pathogenesis of essential hypertension is multifactorial and highly complex. Multiple factors modulate the blood pressure for adequate tissue perfusion and include humoral mediators, vascular reactivity, circulating blood volume, vascular caliber, blood viscosity, cardiac output, blood vessel elasticity, and neural stimulation. A possible pathogenesis of essential hypertension has been proposed in which multiple factors, including genetic predisposition, excess dietary salt intake, and adrenergic tone, may interact to produce hypertension. Although genetics appears to contribute to essential hypertension, the exact mechanism has not been established.

The natural history of essential hypertension evolves from occasional to established hypertension. After a long invariable asymptomatic period, persistent hypertension develops into complicated hypertension, in which target organ damage to the aorta and small arteries, heart, kidneys, retina, and central nervous system is evident. The progression begins with prehypertension in persons aged 10-30 years (by increased cardiac output) to early hypertension in persons aged 20-40 years (in which increased peripheral resistance is prominent) to established hypertension in persons aged 30-50 years, and, finally, to complicated hypertension in persons aged 40-60 years.

One mechanism of hypertension has been described as high-output hypertension. High-output hypertension results from decreased peripheral vascular resistance and concomitant cardiac stimulation by adrenergic hyperactivity and altered calcium homeostasis. A second mechanism manifests with normal or reduced cardiac output and elevated systemic vascular resistance due to increased vasoreactivity. Another (and overlapping) mechanism is increased salt and water reabsorption (salt sensitivity) by the kidney, which increases circulating blood volume.

The vasoreactivity of the vascular bed, an important phenomenon mediating changes of hypertension, is influenced by the activity of vasoactive factors, reactivity of the smooth muscle cells, and structural changes in the vessel wall and vessel caliber, expressed by a lumen-to-wall ratio. Patients who develop hypertension are known to develop a systemic hypertensive response secondary to vasoconstrictive stimuli. Alterations in structural and physical properties of resistance arteries, as well as changes in endothelial function, are probably responsible for this abnormal behavior of vasculature. Furthermore, vascular remodeling occurs over the years as hypertension evolves, thereby maintaining increased vascular resistance irrespective of the initial hemodynamic pattern.

Genetic factors

Hypertension develops secondary to environmental factors, as well as to multiple genes, whose inheritance appears to be complex.2,3 Very rare secondary causes are related to single genes and include Liddle syndrome, glucocorticoid remediable hyperaldosteronism, 11 beta-hydroxylase and 17 alpha-hydroxylase deficiencies, the syndrome of apparent mineralocorticoid excess, and pseudohypoaldosteronism type II.

Role of the vascular endothelium

The vascular endothelium is presently considered a vital organ, where synthesis of various vasodilating and constricting mediators occurs. The interaction of autocrine and paracrine factors takes place in the vascular endothelium, leading to growth and remodeling of the vessel wall and to the hemodynamic regulation of blood pressure.

Numerous hormonal, humeral vasoactive, and growth and regulating peptides are produced in the vascular endothelium. These mediators include angiotensin II, bradykinin, endothelin, nitric oxide, and several other growth factors. Endothelin is a potent vasoconstrictor and growth factor that likely plays a major role in the pathogenesis of hypertension. Angiotensin II is a potent vasoconstrictor synthesized from angiotensin I with the help of an angiotensin-converting enzyme (ACE). Another vasoactive substance manufactured in the endothelium is nitric oxide. Nitric oxide is an extremely potent vasodilator that influences local autoregulation and other vital organ functions. Additionally, several growth factors are manufactured in the vascular endothelium; each of these plays an important role in atherogenesis and target organ damage. These factors include platelet-derived growth factor, fibroblast growth factor, insulin growth factor, and many others.

Pathophysiology of target organ damage

Hypertension and the cardiovascular system

Cardiac involvement in hypertension manifests as LVH, left atrial enlargement, aortic root dilatation, atrial and ventricular arrhythmias, systolic and diastolic heart failure, and ischemic heart disease. LVH is associated with an increased risk of premature death and morbidity. A higher frequency of cardiac atrial and ventricular dysrhythmias and sudden cardiac death may exist. Possibly, increased coronary arteriolar resistance leads to reduced blood flow to the hypertrophied myocardium, resulting in angina despite clean coronary arteries. Hypertension, along with reduced oxygen supply and other risk factors, accelerates the process of atherogenesis, thereby further reducing oxygen delivery to the myocardium.

Hypertension remains the most common cause of congestive heart failure. Antihypertensive therapy has been demonstrated to significantly reduce the risk of death from stroke and coronary heart disease. Two published meta-analyses have shown 14% and 26% reductions in cardiovascular mortality rates.

Left ventricular hypertrophy

The myocardium undergoes structural changes in response to increased afterload. Cardiac myocytes respond by hypertrophy, allowing the heart to pump more strongly against the elevated pressure. However, the contractile function of the left ventricle remains normal until later stages. Eventually, LVH lessens the chamber lumen, limiting diastolic filling and stroke volume. The left ventricular diastolic function is markedly compromised in long-standing hypertension.

The mechanisms of diastolic dysfunction have been elucidated only recently. An aberration in the passive relaxation of the left ventricle during diastole appears to exist. Over time, fibrosis may occur, further contributing to the poor compliance of the ventricle. As the left ventricle does not relax during early diastole, left ventricular end-diastolic pressure increases, further increasing left atrial pressure in late diastole. The exact determinants of left ventricular diastolic dysfunction have not been well studied; possibly, the abnormality is governed by abnormal calcium kinetics.

The central nervous system

Long-standing hypertension may manifest as hemorrhagic and atheroembolic stroke or encephalopathy. Both the high systolic and diastolic pressures are harmful; a diastolic pressure of more than 100 mm Hg and a systolic pressure of more than 160 mm Hg have led to a significant incidence of strokes. Other cerebrovascular manifestations of complicated hypertension include hypertensive hemorrhage, hypertensive encephalopathy, lacunar-type infarctions, and dementia.

Renal disease

Despite widespread treatment of hypertension in the United States, the incidence of end-stage renal disease continues to rise. The explanation for this rise may be concomitant diabetes mellitus, the progressive nature of hypertensive renal disease despite therapy, or a failure to reduce blood pressure to a protective level. A reduction in renal blood flow in conjunction with elevated afferent glomerular arteriolar resistance increases glomerular hydrostatic pressure secondary to efferent glomerular arteriolar constriction. The result is glomerular hyperfiltration, followed by development of glomerulosclerosis and further impairment of renal function.

Two studies have demonstrated that a reduction in blood pressure may result in improved renal function. Therefore, earlier detection of hypertensive nephrosclerosis using means to detect microalbuminuria and aggressive therapeutic interventions, particularly with ACE inhibitor drugs, may prevent progression to end-stage renal disease.4

Nephrosclerosis is one of the possible complications of long-standing hypertension. The risk of hypertension-induced end-stage renal disease is higher in black patients, even when blood pressure is under good control. Furthermore, patients with diabetic nephropathy who are hypertensive are also at high risk for developing end-stage renal disease.

The renin-angiotensin system activity influences the progression of renal disease. Angiotensin II acts at the afferent and the efferent arterioles, but more so on the efferent arteriole, which leads to an increase of the intraglomerular pressure. The excess glomerular pressure leads to microalbuminuria. Reducing intraglomerular pressure using an ACE inhibitor has been shown to be beneficial in patients with diabetic nephropathy, even in those who are not hypertensive. The beneficial effect of ACE inhibitors on the progression of renal insufficiency in patients who are nondiabetic is less clear. The benefit of ACE inhibitors is greater in patients with more pronounced proteinuria.

Hypertension in renal disease

Hypertension is commonly observed in patients with kidney disease. Volume expansion is the main cause of hypertension in patients with glomerular disease (nephrotic and nephritic syndrome). Hypertension in patients with vascular disease is the result of the activation of the renin-angiotensin system, which is often secondary to ischemia. Most patients with chronic renal failure are hypertensive (80-90%). The combination of volume expansion and the activation of the renin-angiotensin system is believed to be the main factor behind hypertension in patients with chronic renal failure.

Metabolic syndrome

The metabolic syndrome is an assemblage of metabolic risk factors that directly promote the development of atherosclerotic cardiovascular disease.5,6 Dyslipidemia, hypertension, and hyperglycemia are the most widely recognized metabolic risk factors. The combination of these risk factors leads to a prothrombotic, proinflammatory state in humans and identifies individuals who are at elevated risk for atherosclerotic cardiovascular disease.

The predominant underlying risk factors for the metabolic syndrome appear to be abdominal obesity and insulin resistance. Other associated conditions are physical inactivity, aging, hormonal imbalance, and atherogenic diet. Insulin resistance, an essential cause of the metabolic syndrome, predisposes to hyperglycemia and type 2 diabetes mellitus. Individuals who insulin resistant may not be clinically obese, but they commonly have an abnormal fat distribution that is characterized by predominant upper body fat. Upper body obesity can occur either intraperitoneally (visceral fat) or subcutaneously, both of which correlate strongly with insulin resistance and the metabolic syndrome.

The rising prevalence of the metabolic syndrome is secondary to the increasing burden of obesity in our society. The adipose tissue in people who are obese is insulin resistant, raises nonesterified fatty acid levels, alters hepatic metabolism, and produces several adipokines. These include increased production of inflammatory cytokines, plasminogen activator inhibitor-1, and other bioactive products, while the synthesis of potentially protective adipokine, adiponectin, is reduced. This syndrome has been noted to be associated with a state of chronic, low-grade inflammation. Although the metabolic syndrome unequivocally predisposes to type 2 diabetes mellitus, this syndrome is multidimensional risk factor for atherosclerotic cardiovascular disease.


United States

Forty-three million people are estimated to have hypertension, defined by a systolic blood pressure of 140 mm Hg or greater and/or diastolic blood pressure of 90 mm Hg or greater or defined as those taking antihypertensive medications. The age-adjusted prevalence of hypertension varies from 18-32%, according to data from the National Health Examination Surveys. According to the National Center for Health Statistic Surveys, the awareness for hypertension increased from 53% in 1960-1962 to 89% in 1988-1991. The percentage of patients engaged in hypertension treatment increased from 35% to 79% during this period.7

  • The National High Blood Pressure Education Program (NHBPEP) has reported estimates of hypertension prevalence in United States.8 The hypertension survey was conducted from 1989-1994, and actual blood pressure and self-reported information was used. Hypertension was defined as systolic blood pressure equal to or more than 140 mm Hg, diastolic blood pressure equal or more than 90 mm Hg, or taking medication for hypertension. The data estimated 43.3 million adults with hypertension in November 1991. The prevalence according to age group, sex, and race is shown in Table 1.
Table 1. Prevalence (%) of Hypertension in the United States, 1989-1994*