The initiation period of a combination therapy (spironolactone, lisinopril and atenolol) after myocardial infarction plays a major role on the kinetics of heart failure in rats

Abstract

Myocardial infarction (MI) induces severe structural and functionnal changes of the left ventricle (LV) leading to heart failure (HF). The gold-standard treatment in HF patients with reduced ejection fraction (HFrEF) combines aldosterone antagonists such as spironolactone (SPI), ACE-inhibitors such as lisinopril (LIS) and β-blockers such as atenolol (ATE), to improve cardiac function and reduce morbi-mortality. Despite its beneficial effects, the initiation period of such treatment seems to play a major role on the kinetics of heart failure following MI. We evaluated the cardiac outcomes of a combination therapy introduced at 2 time points on rats presenting MI. After MI, treated rats [SPI (10 mg.kg-1.d-1), LIS (1 mg.kg-1.d-1) and ATE (1 mg.kg-1.d-1)] were divided into 2 groups: treatment started either 1 day (early) or 1 month (late) after MI. Longitudinal follow-up of LV remodeling and function was assessed by Echocardiography-Doppler every month during 4 months. LV fibrosis was quantified with picrosirius red staining. Early treatment did not induce beneficial cardiac effects, whereas late treatment significantly improved cardiac function from 2 months, as shown by the increased EF (+19%), and persists over time. It was associated after 3 months with a significant beneficial decrease in the E/A ratio (−44%), a marker of diastolic function. Compared with MI, late combination therapy also prevented LV remodeling, as shown by a significant decreased LV dilation (−7%) and cardiac fibrosis (−30%). Only late management of MI by combination therapy had a cardioprotective effect on cardiac function and remodeling. These findings raise the pivotal role of early adaptive cardiac remodeling following MI.