This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Studies in humans have indicated that aldosterone excess induces left ventricular (LV) hypertrophy independent of hypertension. Ultrasonographic studies further suggest myocardial hypertrophy due to hyperaldosteronism occurs concomitantly with myocardial fibrosis. The importance of these findings is highlighted by our resent observation that primary aldosteronism (PA) is several times more prevalent in patients with resistant hypertension than previously thought. Interestingly, in patients with resistant hypertension, chronic blockade of the rennin-angiotensis system (RAS) does not attenuate LV hypertrophy in PA patients relative to non-PA patients despite a similar blood pressure reduction. The central role of aldosterone in promoting perivascular inflammation and fibrosis in the heart independent of blood pressure has been confirmed in experimental models of hyperaldosteronism. The pro-fibrotic action is blocked not only by mineral corticoid receptor antagonism but also by a low-salt diet. This important observation as well as the general relation between NaC1 and aldosterone to LV remodeling remains to be elucidated m humans. We hypothesize that adosterone-induced myocardial fibrosis is primarily an inflammatory process that depends highly on the dietary salt status. To test this hypothesis we will:
Specific Aim 1) To show that in humans, aldosterone excess causes LV hypertrophy and fibrosis through inflammatory pathways, we will relate markers of inflammation and oxidative stress to LV hypertrophy and fibrosis in PA patients;
Specific Aim 2 ) We expect that spironolactone will reverse cardiac hypertrophy in PA patients. However, in this aim, we will examine if spironolactone -dependentent reverse-LV remodeling relates to markers of inflammation and/or cardiac fibrosis in these patients;
Specific Aim 3) Show that salt restriction reduces myocardial fibrosis , inflammation, and oxidative stress in patients with PA;
Specific Aim 4) Using genetic models and pharmacologic approaches, show a cause-and-effect relation between aldosterone-induced inflammation and subsequent cardiac fibrosis. If these proposed studies show that inappropriately high aldosterone secretion relative to dietary salt ingestion causes adverse cardiac remodeling, a new paradigm would be created in which the 'aldosterone-salt product' predicts cardiovascular risk.
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