Additive amelioration of left ventricular remodeling and molecular alterations by combined aldosterone and angiotensin receptor blockade after myocardial infarction

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Abstract
Objectives: The mechanisms underlying the clinical benefits of mineralocorticoid receptor antagonism in patients with left ventricular (LV) dysfunction and heart failure (CHF) after myocardial infarction (MI) are poorly understood. Methods: We investigated whether long-term (9 weeks) aldosterone antagonism with eplerenone (100 mg/kg/day) provides additional benefit to angiotensin II type 1 (AT1) receptor inhibition with irbesartan (50 mg/kg/day) on cardiac remodeling after MI in rats. Results: Eplerenone monotherapy, like AT1 receptor blockade, significantly reduced LV end-diastolic pressure (LVEDP), end-systolic volume (LVESV) and end-diastolic volume (LVEDV) compared to placebo. Improvement of LV dilation by aldosterone antagonism was associated with a significant reduction of increased AT1 receptor, angiotensin-converting enzyme (ACE) and endothelin-1 gene expression in the noninfarcted LV myocardium. Combination therapy with irbesartan led to a substantial further leftward shift of the LV pressure–volume curve and decrease in LVEDP, LVESV and LVEDV. Moreover, combination therapy significantly improved LV systolic and diastolic function and reversed LV alterations of α- and β-myosin heavy-chain isoforms, ANF and SERCA2 ATPase expression more effectively than monotherapies. LV collagen type I and type III expression as well as interstitial fibrosis were substantially increased in placebo CHF rats, similarly decreased by eplerenone and irbesartan, and further reduced by eplerenone/irbesartan. However, no additive effects of eplerenone/irbesartan on myocardial AT1 receptor, ACE and endothelin-1 mRNAs were observed. Conclusions: Aldosterone receptor antagonism provides additional benefit to AT1 receptor blockade on LV function and remodeling associated with improvement of molecular alterations responsible for progressive contractile dysfunction post-MI.

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