Aldosterone, Mineralocorticoid Receptor Activation, and Cardiovascular Remodeling

Large-scale clinical trials have established that mineralocorticoid receptor (MR) blockade with spironolactone or eplerenone decreases morbidity and mortality in patients with chronic severe congestive heart failure and left ventricular systolic dysfunction (ejection fraction ≤35%),1 heart failure and left ventricular systolic dysfunction after an acute myocardial infarction,2 and chronic systolic heart failure with New York Heart Association class II (mild) symptoms.3 Although it was initially suggested that MR blockade with spironolactone improved outcomes in part by altering renal sodium or potassium handling or both, it was recognized that the mean dosage (26 mg/d) used in the Randomized Aldactone Evaluate Study (RALES) was not natriuretic, which indicates that other extrarenal effects of MR antagonism were more likely to prevent adverse cardiovascular events.1,4 Aldosterone and MR activation may also lead to dysregulation of local sodium, potassium, and water balance; promote autonomic dysfunction; impair vascular reactivity; and importantly, increase extracellular matrix turnover and fibrosis.5 In fact, there is now evidence to show that the hyperaldosteronism or enhanced MR activation contributes to (mal)adaptive ventricular structural and electric remodeling by stimulating extracellular matrix deposition and turnover.The association between aldosterone and left ventricular remodeling has been shown previously in a community-based sample. In 2119 participants in the Framingham Offspring Study, the aldosterone-renin ratio was positively associated with both concentric (odds ratio per SD increment 1.29; 95% confidence interval, 1.06–1.58) and eccentric (odds ratio per SD increment 1.20; 95% confidence interval, 1.05–1.37) left ventricular hypertrophy.6 Although the study did not measure circulating markers of extracellular matrix turnover, a follow-up study performed in the same community-based sample related elevated levels of procollagen type …