Mineralocorticoid Accelerates Transition to Heart Failure With Preserved Ejection Fraction Via “Nongenomic Effects”

Abstract

Background-Mechanisms promoting the transition from hypertensive heart disease to heart failure with preserved ejection fraction are poorly understood. When inappropriate for salt status, mineralocorticoid (deoxycorticosterone acetate) excess causes hypertrophy, fibrosis, and diastolic dysfunction. Because cardiac mineralocorticoid receptors are protected from mineralocorticoid binding by the absence of 11-␤ hydroxysteroid dehydrogenase, salt-mineralocorticoid-induced inflammation is postulated to cause oxidative stress and to mediate cardiac effects. Although previous studies have focused on salt/nephrectomy in accelerating mineralocorticoid-induced cardiac effects, we hypothesized that hypertensive heart disease is associated with oxidative stress and sensitizes the heart to mineralocorticoid, accelerating hypertrophy, fibrosis, and diastolic dysfunction. Methods and Results-Cardiac structure and function, oxidative stress, and mineralocorticoid receptor-dependent gene transcription were measured in sham-operated and transverse aortic constriction (studied 2 weeks later) mice without and with deoxycorticosterone acetate administration, all in the setting of normal-salt diet. Compared with sham mice, sham plus deoxycorticosterone acetate mice had mild hypertrophy without fibrosis or diastolic dysfunction. Transverse aortic constriction mice displayed compensated hypertensive heart disease with hypertrophy, increased oxidative stress (osteopontin and NOX4 gene expression), and normal systolic function, filling pressures, and diastolic stiffness. Compared with transverse aortic constriction mice, transverse aortic constriction plus deoxycorticosterone acetate mice had similar left ventricular systolic pressure and fractional shortening but more hypertrophy, fibrosis, and diastolic dysfunction with increased lung weights, consistent with heart failure with preserved ejection fraction. There was progressive activation of markers of oxidative stress across the groups but no evidence of classic mineralocorticoid receptor-dependent gene transcription. Conclusions-Pressure-overload hypertrophy sensitizes the heart to mineralocorticoid excess, which promotes the transition to heart failure with preserved ejection fraction independently of classic mineralocorticoid receptordependent gene transcription. (Circulation. 2010;122:370-378.)

Mineralocorticoid receptor blockade improves diastolic function independent of blood pressure reduction in a transgenic model of RAAS overexpression

“…function with MR blockade independently of effects on blood pressure (15,17,18). Although previous work on blood pressure-independent effects of MR antagonism and diastolic function have supported an essential role for salt and/or nephrectomy in promoting MR-dependent cardiac fibrosis and diastolic dysfunction (2,15,17,18,29,31,38), this is the first such study in a RAAS-dependent model. Because we began treatment before the onset of diastolic dysfunction, our data further suggest that low-dose Sp treatment is effective at preventing the development of diastolic dysfunction through improvements in myocardial fibrosis and oxidant stress in young transgenic rats.…”

“…Both cardiac myocytes and fibroblasts express MRs with a high affinity for aldosterone (17,32,38). However, the development of interstitial fibrosis and diastolic dysfunction by aldosterone actions on the MR occur when the renin-angiotensin-aldosterone system (RAAS) is inappropriately activated relative to salt intake, i.e., in the absence of salt deprivation (30,32).Inappropriate activation of the RAAS through aldosterone actions on the MR have been shown to promote the development of diastolic dysfunction through putative nongenomic actions including the generation of oxidative stress in models of chronic pressure overload (18,22,38). Oxidative stress is known to impair metabolic signaling pathways that regulate cardiac remodeling, LV hypertrophy (LVH), and diastolic dysfunction through interstitial fibrosis (16).…”

“…Inappropriate activation of the RAAS through aldosterone actions on the MR have been shown to promote the development of diastolic dysfunction through putative nongenomic actions including the generation of oxidative stress in models of chronic pressure overload (18,22,38). Oxidative stress is known to impair metabolic signaling pathways that regulate cardiac remodeling, LV hypertrophy (LVH), and diastolic dysfunction through interstitial fibrosis (16).…”

“…In this context, increases in aldosterone levels are associated with increased heart failure mortality (9,22), and blockade of mineralcorticoid receptors (MRs) improves morbidity and mortality (22,25,26), including those with preserved ejection fraction (EF), e.g., diastolic dysfunction (15,18). Both cardiac myocytes and fibroblasts express MRs with a high affinity for aldosterone (17,32,38).…”

Benidipine reduces ischemia reperfusion-induced systemic oxidative stress through suppression of aldosterone production in mice

“…28,29 An excess of mineralocorticoid causes cardiac hypertrophy, fibrosis and diastolic dysfunction. 30,31 In this study, we found for the first time that the plasma concentration of aldosterone increased after I/R partially through the upregulation of plasma renin activity and that benidipine treatment effectively inhibited this response in vivo. Aldosterone is produced mainly by the adrenal cortex in response to increased potassium or angiotensin II.…”