Mineralocorticoids and Cardiac Fibrosis: The Decade in Review

Abstract

1. Over the past decade, aldosterone has been shown to have direct extra-epithelial actions and substantial (patho)physiological roles in the cardiovascular system in the context of inappropriate salt status. In experimental studies on uninephrectomized rats given 0.9% NaCl solution to drink, these include blood pressure elevation via activation of circumventricular mineralocorticoid receptors in the central nervous system and production of pressure-independent cardiac hypertrophy and fibrosis by a direct effect on the heart. 2. In the Randomized Aldactone Evaluation Study (RALES) trial, patients with severe congestive heart failure (CHF) were continued on their current therapy (angiotensin-converting enzyme inhibitor, diuretic etc.) and given either placebo or spironolactone at an average dose of 26 mg/day. Mineralocorticoid receptor inhibition was accompanied by a 30% improvement in mortality and 35% less hospitalization, striking confirmation of a pathophysiological role for aldosterone in CHF. 3. Although the current basic and clinical studies are conflicting, there is evidence both for aldosterone synthesis by the failing human heart and for substantial cardiac metabolism of aldosterone. The extent to which this potential paracrine source for aldosterone may be involved in cardiac hypertrophy and cardiac fibrosis remains to be established. 4. Belatedly, aldosterone-induced proteins (e.g. serum and glucocorticoid-regulated kinase (SGK)) have been identified in epithelial mineralocorticoid target tissue. Studies are currently in progress on the cellular and molecular mechanisms involved in the coronary vasculitis provoked early in the mineralocorticoid/salt model, which, in turn, appears to trigger the subsequent perivascular and interstitial fibrotic response.

Mechanisms for Aldosterone and Spironolactone-Induced Positive Inotropic Actions in the Rat Heart

“…1 This study, along with many translational reports, strongly developed the concept that aldosterone may play an important, deleterious effect in human congestive heart failure. [2][3][4][5] In addition, we have previously observed that aldosterone has rapid, inotropic effects in the isolated perfused rat heart; 6 however, rapid, inotropic effects were observed as early as the 1960s. 7,8 This rapid, inotropic effect of aldosterone almost certainly occurs through nongenomic mechanism(s).…”

c-Src–Dependent Nongenomic Signaling Responses to Aldosterone Are Increased in Vascular Myocytes From Spontaneously Hypertensive Rats

“…Several studies have shown vascular and target-organ protective effects of aldosterone receptor antagonism. [1][2][3][4] In aldosteroneinfused rats, spironolactone or the more specific antagonist eplerenone prevents inflammation and fibrosis in the heart, blood vessels, and kidney; improves endothelial function; and reduces activation of NAD(P)H oxidase. [5][6][7][8][9] In animal models of hypertension, such as stroke-prone spontaneously hypertensive rats, aldosterone receptor antagonism also reduced vascular remodeling and renal damage, particularly in the presence of high salt.…”

Mineralocorticoid Receptor Antagonism Prevents the Electrical Remodeling That Precedes Cellular Hypertrophy After Myocardial Infarction

“…The mechanisms of this action in cardiac remodeling are not fully understood. The antiarrhythmogenic benefits of MR antagonists might be linked to their role in ameliorating reactive fibrosis 8,9 and/or, alternatively, to their electrophysiological effects. Recently, we showed that aldosterone treatment of isolated myocytes mimics the electrophysiological changes that occur during cardiac remodeling.…”