Abstract 14157: Direct Renin Inhibitor Strongly Prevents Ventricular Arrhythmogenic Remodeling and Sudden Cardiac Death in Mice with Dilated Cardiomyopathy
Background Progression of left ventricular (LV) remodeling including fibrosis contributes to the occurrence of lethal ventricular arrhythmias and sudden cardiac death. Hypothesis Renin-angiotensin system (RAS) contributes to the generation of substrate for arrhythmogenicity in chronic heart failure (CHF).
Methods We used cardiac-specific dominant-negative form of neuron-restrictive silencer factor transgenic mice (dnNRSF-Tg), which exhibit progressive dilated cardiomyopathy with lethal arrhythmias beginning at 12 weeks of age and 60% of which die suddenly by 30 weeks. Direct renin inhibitor (DRI) (aliskiren, 22 mg/kg/day) was administered via osmotic mini-pumps to dnNRSF-Tg in early (from 12 to 18 weeks of age) and late (from 16 to 28 weeks of age) stages of CHF. We measured blood pressure and performed echocardiographic analyses. In late stage we analyzed survival rate, histological fibrosis, ventricular expression of remodeling-related genes, hemodynamic LV parameters with a catheter-tip micromanometer and arrhythmogenicity by in vivo intracardiac electrophysiological study.
Results Without reducing blood pressure, DRI significantly improved LV ejection fraction not only in early stage (41 ± 2 % to 52 ± 4 %; vehicle (n=7) vs. DRI (n=4), p<0.03) but also in late stage (35 ± 4 % to 56 ± 4 %; vehicle (n=5) vs. DRI (n=8), p<0.005), and dP/dt in late stage (vehicle (n=3) vs. DRI (n=3), p<0.03) in dnNRSF-Tg. DRI decreased histological LV fibrosis-to-total area ratios (vehicle (n=4) vs. DRI (n=4), p<0.03) and attenuated the increase in ventricular mRNA expression of atrial natriuretic peptide, β-myosin heavy chain, transforming growth factor-β1, -β3, tissue inhibitor of metalloproteinase-1 and angiotensin converting enzyme in dnNRSF-Tg (vehicle (n=5) vs. DRI (n=8), all p<0.05). DRI strongly reduced induction rate of ventricular tachycardia during electrophysiological study (83% to 0%; vehicle (n=6) vs. DRI (n=5), p<0.03) and improved survival (vehicle (n=11) vs. DRI (n=11), p<0.05 by log-rank test).
Conclusions DRI ameliorated pathological LV remodeling and prevented lethal arrhythmias and sudden cardiac death in dnNRSF-Tg. We concluded RAS contributes to the generation of arrhythmogenic substrate during the progression of CHF.
- © 2012 by American Heart Association, Inc.