Role of Aldosterone in Heart Failure
Heart failure is a clinical syndrome characterized by the functional inability of the ventricle to provide adequate perfusion to meet the metabolic demands of the body resulting in symptoms of congestion or hypoperfusion. Heart failure is associated with impaired contractility (systolic dysfunction), impaired myocardial compliance (diastolic dysfunction), or both systolic and diastolic dysfunction,[7] which often result from coronary artery disease, hypertension, cardiomyopathy, or valvular disease.[1]
In heart failure, renal hypoperfusion occurs when cardiac output is reduced and blood is redistributed away from nonvital organs,[8] thereby activating the renin–angiotensin–aldosterone system (RAAS), which is intended to compensate for hypoperfusion (Figure 1). The endproducts of RAAS activation are angiotensin II and aldosterone. Angiotensin II causes direct vasoconstriction, stimulates catecholamine release from the adrenal medulla, increases centrally mediated sympathetic nervous system activity, and stimulates the release of aldosterone. Aldosterone is a mineralocorticoid produced in the adrenal cortex, heart, brain, and blood vessels.[10,11,12] It promotes sodium and water retention by inducing synthesis of the proteins that constitute the Na+,K+-ATPase pump in the cortical collecting ducts. The results are sodium and water retention and potassium secretion.[13]
The renin-angiotensin-aldosterone system. Angiotensinogen is produced by the liver. It is then cleaved by renin, which is secreted by the juxtaglomerular cells, forming angiotensin I. Angiotensin I is cleaved by angiotensin-converting enzyme (ACE) to form angiotensin II. Angiotensin II binds to the angiotensin receptors in the zona glomerulosa of the adrenal cortex to cause the release of aldosterone. Reprinted from reference 9, with permission.
This neurohormonal response to renal hypoperfusion increases ventricular preload, myocardial contractility, and heart rate.[8] Initially, the results are improved perfusion and a delay in heart failure symptoms. However, the compensatory mechanisms that delay these symptoms result in myocardial remodeling. The remodeling worsens ventricular function, perpetuating hypoperfusion. The result is an angiotensin II-induced hyperadrenergic, hyperaldosterone state that eventually leads to clinical heart failure. The neurohormonal pathology of heart failure is a significant contributor to the progressive morbidity and mortality asosciated with the disease.[14]
The effects of hyperaldosteronism extend beyond aldosterone's renal action. Mineralocorticoid receptors have also been isolated in the brain,[15] heart,[16] and blood vessels.[17] Human and animal models have established aldosterone's effects in the coronary vasculature and myocardial cells. Rocha and colleagues[18] demonstrated that hyperaldosteronism caused an inflammatory response in rat myocardium, characterized by severe coronary inflammatory lesions. The appearance of the lesions was preceded by myocardial expression and progressive upregulation of proinflammatory molecules, including cyclooxygenase-2, macrophage chemoattractant protein-1, and osteopontin. The effect appears to be mediated primarily through monocyte and macrophage infiltration, resulting in inflammatory damage to the coronary arteries,[18,19] cardiac hypertrophy,[20,21,22,23] myocardial fibrosis,[20,22,23,24,25] and ischemic and necrotic lesions.[18,19]
The pathology of aldosterone-induced fibrosis is not completely clear and likely multifactorial. Aldosterone has been shown to cause a dose-dependent increase in collagen synthesis by cardiac fibroblasts in rats.[26] Fibrosis has been hypothesized to be a result of the reparative process following myocardial necrosis.[21]
An association between aldosterone-induced fibrosis and angiotensin II is likely. Aldosterone has been shown to play a major role in angiotensin II-induced damage to coronary arteries.[19] Aldosterone increases both angiotensin II-receptor subtype 1 (AT1) mRNA accumulation and AT1- receptor density.[24] Similarly, very high dosages of losartan, an AT1-receptor antagonist, have been shown to prevent aldosterone-induced fibrosis. Ullian et al.[27] found that AT1-receptor binding increased in the presence of aldosterone. Aldosterone has also been shown to produce a synergistic effect with angiotensin II in increasing the expression of plasminogen activator inhibitor-1 (PAI-1),[25] further contributing to the development of fibrosis.[28]
Aldosterone may also induce ventricular arrhythmia in patients with heart failure. Ventricular arrhythmias often lead to sudden cardiac death, accounting for 40–50% of all patient deaths from heart failure.[7] The mechanism of aldosterone-induced ventricular arrhythmia is not clearly understood. It may be a result of myocardial fibrosis, increased arrhythmogenic response to catecholamines, magnesium or potassium deficiency, or depressed baroreceptor sensitivity.[29] The cardiovascular damage induced by these mechanisms leads to the progressive morbidity and the mortality commonly associated with heart failure.
Am J Health Syst Pharm. 2006;63(1):49-58. © 2006 American Society of Health-System Pharmacists
Cite this: Aldosterone Antagonists in the Treatment of Heart Failure - Medscape - Jan 01, 2006.
