Losartan reduces mortality in a model of heart failure

Abstract

Calsequestrin (CSQ) is the main Ca2+ store in the cardiac sarcoplasmic reticulum (SR). Overexpression of CSQ selectively in the heart of transgenic mice (TG) under the control of the alpha myosin heavy chain promoter leads to hypertrophy, fibrosis, heart failure, cardiac arrhythmias and ultimately premature death compared to littermate controls (WT). We hypothesized that losartan, an inhibitor of angiotensin II receptors, may be able to abrogate these detrimental effects. Hence, TG and WT were treated for about 2 or 5 months perorally with losartan (5 mg/Kg body weight) or solvent alone. Under control conditions (solvent alone), none of the WT died within the observation period whereas all TG died within 9 months. In the treatment group the mortality of TG was significantly reduced: mean life span was raised from 116 d to 192.5 d (n=18). Likewise, the degree of fibrosis was reduced. Hemodynamic parameters (pressure; dp/dt) were improved. However, the relative heart weight remained unchanged. Likewise, the expression of CSQ in the heart was unchanged by losartan treatment. In conclusion, the renin angiotensin system is apparently involved in heart failure due to CSQ overexpression, because its blockade improves survival (supported by the DFG).