Abstract 10950: Direct Renin Inhibition Improved Cardiac Remodeling and Survival in Mouse Model of Dilated Cardiomyopathy
Introduction: The renin-angiotensin system (RAS) is important during the pathogenesis of heart failure. Among inhibitors of RAS, direct renin inhibitors (DRIs) are promising for the treatment of heart failure, although little evidence has been reported.
Hypothesis: DRIs are effective for the treatment of heart failure due to dilated cardiomyopathy (DCM).
Methods: We used a knock-in mouse with a deletion mutant of cardiac troponin T (ΔK210), which causes human DCM (DCM mouse). Echocardiography was used to estimate the cardiac function in vivo. Histological examinations were performed to evaluate cardiac fibrosis using Masson's trichrome staining. To evaluate the intracellular Ca2+ transient (CaT) and tension, the aequorin method was applied to papillary muscle preparations.
Results: The DCM mice died within a few months after birth and a DRI (aliskiren, 50 mg/kg/day) significantly improved the survival (p<0.001, log rank test). The left ventricular chamber size was enlarged and the fractional shortening was reduced in the DCM mice. The DRI significantly reduced the left ventricular chamber size (diastolic dimension: from 4.2±0.2mm to 3.4±0.1mm, p<0.005; systolic dimension: from 3.0±0.1mm to 2.0±0.1mm, p<0.001) (n=4), and led to a significant recovery of the fractional shortening (from 27.7±1.1% to 40.4±2.1%, p<0.01) (n=4). Cardiac fibrosis increased in the DCM mouse heart, and it showed a significant improvement after treatment with the DRI (from 8.9±0.6% to 4.6±0.4%, p<0.001, n=12). The CaT increased while the tension decreased in the DCM mice, thus reflecting a decrease in the Ca2+ sensitivity. The DRI caused a recovery of the CaT (from 2.4±0.2μ M to 1.6±0.2μ M, p<0.05) and partially recovered the tension (from 1.0±0.3mN/mm2 to 1.2±0.3mN/mm2, p=0.63) (n=4), thus suggesting a partial recovery of the Ca2+ sensitivity.
Conclusion: These results suggest that the DRI improved cardiac remodeling, and this could help to improve the prognosis in DCM mice.
- © 2011 by American Heart Association, Inc.