Aldosterone Receptor Antagonists in the Medical Management of Chronic Heart Failure

Abstract

The benefits of aldosterone receptor antagonists (spironolactone and eplerenone) for patients with heart failure were shown in 2 recent randomized controlled trials. Some of the proposed mechanisms of action of aldosterone antagonists are (1) inhibition of myocardial and vascular remodeling, (2) blood pressure reduction, (3) decreased collagen deposition, (4) decreased myocardial stiffness, (5) prevention of hypokalemia and arrhythmia, (6) modulation of nitric oxide synthesis, and (7) immunomodulation. Like many hormone receptors, the aldosterone receptor can be either nuclear or membrane bound. Most of the activities of the aldosterone receptor are subserved by the nuclear receptors and often lead to alterations in gene transcription. Although these agents are well tolerated in carefully selected patient populations that meet the inclusion criteria of large clinical trials, their use in unselected elderly patients with heart failure and multiple comorbidities has been associated with a significant risk of hyperkalemia and renal failure. Although no convincing data exist to predict which individual patients will respond to aldosterone inhibition, patients with more severe heart failure and those with acute myocardial infarction with concomitant heart failure or left ventricular dysfunction are most likely to respond. Theoretically, aldosterone receptor antagonists may also be beneficial in patients with more mild to moderate systolic heart failure or even in those with diastolic heart failure, although direct evidence is still lacking.

Diabetic cardiomyopathy: understanding the molecular and cellular basis to progress in diagnosis and treatment

“…Evidence also suggests a beneficial effect of aldosterone antagonism in diastolic heart failure by virtue of their beneficial effects on cardiac hypertrophy and fibrosis [148,198]. These findings underscore the critical importance of inhibiting the RAAS in diabetic patients, especially when diastolic dysfunction is present and the process is, at least, partially reversible.…”

Eplerenone Survival Benefits in Heart Failure Patients Post-Myocardial Infarction Are Independent From its Diuretic and Potassium-Sparing Effects

“…In addition to a variety of pleiotropic effects (5), eplerenone may exert a diuretic, as well as a potassium (K)-sparing effect. The aim of the present study was to determine whether a diuretic and/or a K-sparing effect could be detected in patients treated with eplerenone in an EPHESUS substudy and, if any, whether these effects influenced cardiovascular outcomes.…”

Therapeutic approaches to diastolic dysfunction

“…It has also improved outcomes in patients after myocardial infarction, in those with hypertension, and in those with other highrisk vascular disease-populations that are thought to be at risk for HF-PEF. Inhibitors of the RAAS have been shown to blunt neurohormonal activation in patients with systolic heart failure [40] and thereby decrease salt and water retention, which contributes to symptoms of dyspnea and effort intolerance in patients with heart failure. In an experimental model of hypertension and compensated LVH, it was demonstrated that the blockade of the AT 1 receptor can prevent the development of heart failure [41].…”