Mineralocorticoids and cardiovascular diseases. Status of knowledge from experimental and clinical studies

Abstract

Although results of randomized trials have demonstrated the beneficial effects of ACE-inhibitors, mortality and morbidity remain high in patients with heart failure and myocardial infarction. In fact, there are data suggesting that aldosterone production may occur despite ACE-inhibitor treatment. There is recent evidence that aldosterone exerts a pro-fibrotic effect, via the mineralocorticoid receptors in cardiovascular tissues resulting in partial aldosterone production during ACE-inhibitor treatment. Mineralocorticoids have also been identified within the cardiovascular system and they may determine increased collagen synthesis which within fibroblasts is largely controlled by locally generated aldosterone. Cardiovascular tissue also expresses genes which are responsible for the late stages of aldosterone and corticosterone formation. Cardiac and vascular tissues elaborate the aforementioned steroids, with the result that aldosterone is more concentrated in the cardiovascular tissue rather than in the circulation. It is probable that locally, while not contributing to the coronary circulation, aldosterone plays an autocrine and/or paracrine role within the tissue of origin. Such roles may relate to local modulation of vessel tonicity and structure, with consequent effects on blood pressure, and repair of damaged tissue through a possible up-regulation of collagen deposition. The ability of the cardiovascular system to elaborate aldosterone opens a vast new area of study since it is becoming increasingly apparent that this local production of mineralocorticoids results in high levels of steroids within the cells of origin and those in the immediate vicinity. The recent RALES trial has shown a significant reduction in mortality, non-fatal hospitalization and sudden death. The fact that patients were on ACE-inhibitors, and accordingly circulating aldosterone levels were presumably reduced, presents the intriguing possibility that spironolactone may block the autocrine and paracrine effects of locally generated aldosterone. This trial has contributed to better understand the pathophysiology of heart failure and its therapeutic strategies. Further studies are required to address this treatment in patients with other heart diseases (hypertension, post-myocardial infarction) and in lower heart failure classes.