Hypertension: Pathophysiology
The Hypertensive State
Irrespective of the underlying cause, when a patient becomes hypertensive there is an increase in cardiac output and peripheral resistance, and the body systems responsible for regulating blood pressure (i.e., the sympathetic nervous system, the renin-angiotensin-aldosterone system, and natriuresis) attempt to compensate. Vicious cycles become established as the control systems fail and the relationship between renal blood flow and arterial blood pressure is upset because of the narrowing of the renal blood vessele. Sustained increases in blood pressure increase the load on both the heart and the blood vessels, resulting in hypertrophy of the myocardium and the vascular smooth-muscle cells in the blood vessels. Although hypertrophy strengthens the heart and blood vessels, it also reduces compliance, ultimately reducing the heart’s ability to respond to increased or variable loads and reducing the arteries’ ability to vasodilate. Important characteristics of the hypertensive state include sustained endothelial dysfunction and hypercoagulability. Figure 6 provides an overview of the pathogenesis of hypertension.
Sustained Endothelial Dysfunction
The vascular endofhelium, a mono-layer of cells providing the inner lining of the blood vessel wall, plays a major role in vascular regulation by releasing a plethora of vasoactive mediators such as the potent vasoconstrictor endothelin-1 and vasodilators, including NO and prostacyclin. Dysfunction of this cell layer has long been implicated in the development of hypertension. Studies have demonstrated that treatment with certain antihypertensive pharmacotherapy (calcium-channel blockers and angiotensin-converting enzyme inhibitors) can restore to some extent NO bioavailability; however, such therapies do not appear to improve vascular responses to endothelial agonists (e.g., acetylcholine) and so cannot reverse endothelial damage.
FIGURE. Schematic diagram of hypertension pathogenesis
Hypercoagulability
In addition to altered endothelial cell function, patients with hypertension possess abnormalities in terms of blood constituents (e.g., increased platelet activation and abnormally high levels of clotting factors) and blood flow (e.g., altered viscosity). These abnormalities suggest that hypertension confers a prothrombotic state in the vasculature; this state of hypercoagulability is thought to be related to disease progression and target organ damage. Treatment with antihypertensive agents has been shown to temper this prothrombotic environment.
Uncomplicated and Complicated Hypertension
Patients with uncomplicated hypertension have high blood pressure only; patients with complicated hypertension have comorbidities and/or additional risk factors, such as diabetes or dyslipidemia. Alterations in the properties of the blood vessels exacerbate disturbances in blood flow inside the large vessels and can lead to sustained dysfunction of the endothelium (as previously outlined), which can foster the development of progressive atherosclerosis and complications such as angina, myocardial infarction, peripheral arterial disease (PAD), and stroke. Risk factors such as smoking and dyslipidemia increase the likelihood of endothelial dysfunction and the progression of atherosclerosis. In addition, vascular remodeling that occurs during hypertension can cause target organ damage, such as nephropathy of the kidneys and retinopathy of the eye.
Hypertension and Cardiovascular Risk
Studies such as the Framingham Heart Study (FHS) first determined that people with hypertension are at greater risk than the general population for cardiovascular disease. Because hypertension can be asymptomatic for long periods (10-20 years or longer), it is often described as a “silent killer.” Frequently, its first manifestation is a complication of hypertension, such as myocardial infarction, stroke, or renal disease.
Historically, elevated diastolic blood pressure has been associated with increased cardiovascular risk, but more recent epidemiological data stress the importance of systolic blood pressure as a cardiovascular risk factor, particularly in patients older than 50 years. The Multiple Risk Factor Intervention Trial (MRFIT) was a 12-year follow-up investigating cardiovascular risk in 316,000 middle-aged men. In this study, death from coronary heart disease was almost linearly related to systolic blood pressure, at all levels of diastolic blood pressure.
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