© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Aldosterone receptor blockade improves left ventricular remodeling and increases ventricular fibrillation threshold in experimental heart failure
aDepartment of Internal Medicine and Cardiovascular Sciences, University Federico II, Naples, Italy
bResearch Center for Endocrinology and Metabolism, Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden
cMedizinische Universitätsklinik Würzburg, Würzburg, Germany
dGiEnne Pharma, Milan, Italy
cittadin{at}unina.it
* Corresponding author. Medicina Interna, Via Pansini 5 (Ed. 18), University Federico II, 80131 Naples, Italy. Tel.: +39-081-746-4375; fax: +39-081-746-3199.
Objectives: To investigate the effects of aldosterone receptor blockade in postinfarction heart failure. Methods: Eighty-seven rats with moderate myocardial infarction were randomized to receive either no drug or canrenone, the active metabolite of spironolactone, 20 mg/kg/day, or ramipril, 1 mg/kg/day, or a combination of the two drugs. Treatment was initiated 1 month after coronary ligation and lasted 4 weeks. Echocardiography was performed at baseline and after 4 weeks. LV catheterization, isolated heart studies, morphometric histology, myocardial norepinephrine and SERCA-2 mRNA were assessed at the end of the treatment period. Results: Infarct sizes were 33±3, 32±3, 34±3, and 34±4% in the placebo, canrenone, ramipril, and combination groups, respectively. Canrenone attenuated LV remodeling, improved LV systolic and diastolic function, and markedly reduced interstitial and perivascular fibrosis. These effects were increased by concomitant ramipril therapy. Moreover, myocardial norepinephrine content was decreased while ventricular fibrillation threshold significantly augmented by canrenone. SERCA-2 levels remained unchanged. Conclusions: Canrenone attenuated LV dilation and interstitial remodeling, and improved LV filling dynamics and systolic function in the rat model of postinfarction heart failure. Addition of ramipril conferred further cardioprotection. Canrenone also reduced myocardial norepinephrine content and increased ventricular fibrillation threshold. The data provide a potential explanation for the decreased sudden death observed in the RALES study.
The mechanisms of action of aldosterone inhibition are still poorly understood, despite its proven efficacy in heart failure. Rats with postinfarction heart failure were randomized to receive for 1 month either no drug or canrenone, or ramipril, or a combination of canrenone and ramipril. Canrenone treatment was associated with a significant attenuation of LV dilation, better LV diastolic and systolic dynamics, and a marked reduction of reactive fibrosis. These effects were enhanced by concomitant ramipril therapy. Moreover, canrenone increased ventricular fibrillation threshold and reduced myocardial norepinephrine content. The data may explain the reduced mortality demonstrated by the RALES.
KEYWORDS Antagonists; Connective tissue; Fibrosis; Heart failure; Ventricular arrhythmias
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