Aldosterone, mineralocorticoid receptor activation, and cardiovascular remodeling.
Aldosterone, mineralocorticoid receptor activation, and cardiovascular remodeling.
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DOI：
10.1161/circulationaha.111.067918
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发表时间：
2011-11-01
期刊：
影响因子：
37.8
通讯作者：
Leopold JA
中科院分区：
文献类型：
--
作者：
Leopold JA
Large-scale clinical trials have established that mineralo-corticoid 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 III aminoterminal peptide (PIIINP), a marker of matrix synthesis, or tissue inhibitor of matrix metalloproteinase-1 (TIMP1) with hazard ratios of 1.47 (95% confidence interval, 1.11–1.96) and 1.72 (95% confidence interval, 1.30–2.27), respectively, for mortality risk. 7 On the basis of these observations, it is interesting to speculate that aldosterone may influence extracellular matrix remodeling, which is associated with adverse cardiovascular events, in an otherwise healthy population.By contrast, a series of studies performed in patients with left ventricular systolic dysfunction and heart failure clearly demonstrated the relationship between aldosterone/MR activation and extracellular matrix turnover. In a substudy from the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), MR antagonism with eplerenone resulted in a decrease in the levels of aminoterminal propeptide of collagen type I (PINP) and PIIINP after 6 months, with no apparent effect on TIMP1 or type I collagen telopeptide (ICTP). Thus, it is apparent that extracellular matrix remodeling is a dynamic process that is abrogated by MR antagonism. 8, 9 A second study of patients with New York Heart Association class II/III heart failure and left ventricular ejection fraction 35% randomized to eplerenone confirmed these findings. In that study, after 9 months, there was a greater decrease in PINP levels in patients treated with eplerenone than in control patients (6.72. 04 versus 2.41. 46 U, P 0.01). 10
