Mineralocorticoids and cardiac fibrosis: the decade in review.
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.
Funder
J
J
Baker Medical Research Institute, Prahran, Victoria, Australia. John.Funder@Baker.edu.au
D000450:Aldosterone / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002986:Clinical Trials as Topic; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008901:Mineralocorticoids / Q000096:biosynthesis / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D012965:Sodium Chloride / Q000378:metabolism / Q000494:pharmacology
D008901:Mineralocorticoids; D012965:Sodium Chloride; D000450:Aldosterone