Cardiac Aldosterone Production: A Vascular Problem?

Abstract

Elevated circulating aldosterone level is associated with impaired cardiovascular function. As shown by RALES and EPHESUS clinical studies, aldosterone antagonists decrease total and cardiovascular mortality in heart failure and post-MI with left ventricular dysfunction. Aldosterone induces cardiac fibrosis in both experimental models and clinical conditions. Nevertheless, the pathophysiology of aldosterone-induced cardiac alterations remains in large part unclear. To resolve this issue we have explored the possibility that the heart may produce aldosterone. We found that there is in fact a myocardial production of the hormone which is regulated by the same physiological stimuli than in the adrenals. This local aldosterone production is increased in post-MI and is in part responsible for cardiac fibrosis. Then, transgenic mice that overexpress the terminal enzyme of aldosterone biosynthesis, aldosterone-synthase, AS, in the heart have been raised by gene targeting with the alpha-myosin heavy chain promoter. Aldosterone concentration was enhanced 1.7-fold in transgenic hearts with no evidences of either structural or functional myocardial alterations. In contrast, male transgenic mice displayed a major endothelium-independent alteration of the coronary vasodilatation. To conclude, a moderately increased local concentration in aldosterone results in a pronounced coronary dysfunction without other cardiac alterations, which is a newly identified effect of aldosterone. This aldosterone-induced decrease of coronary reserve may be a new risk factor for cardiovascular diseases.