Abstract 16183: Inhibition of Hcn Overexpression in Failing Heart of Dilated Cardiomyopathy Mouse Model by Ivabradine Prevents Sudden Arrhythmic Death
Growing evidence demonstrates that the hyperpolarization-activated cyclic nucleotide-gated channels (HCN) expression is increased in failing hearts and potentially involved in the increased arrythmogenicity. The ability of HCN inhibition to prevent lethal arrhythmias associated with heart failure remained untested, however. Transgenic mice expressing a dominant-negative mutant of neuron-restrictive silencer factor specifically in the heart (dnNRSF-Tg) exhibit dilated cardiomyopathy and sudden arrhythmic death, accompanied with the increased ventricular HCN2 and HCN4 expression. We examined effects of ivabradine (Iva), a specific HCN inhibitor, on survival and arrhtthmogenicity in dnNRSF-Tg. Administration of 7mg/kg/day of Iva from 8 weeks of age, significantly improved the survival among dnNRSF-Tg without affecting heart rates (%survival at 32 weeks of age; 75.3% with Iva, vs. 36.1% without Iva; p<0.05). Though echocardiographic, hemodynamic, and histological analysis showed no significant difference between dnNRSF-Tg mice with and without Iva, ECG telemetric monitoring showed the reduction of arrhythmias in dnNRSF-Tg mice treated with Iva compared to those without Iva (VT; 19/hr with Iva (n=7) vs. 92/h without Iva (n=7), p<0.05), suggesting that Iva improved the survival by preventing lethal arrhythmias. Indeed, Iva prevented isoproterenol (Isp, 0.3μM)-induced increased in spontaneous action potentials in ventricular myocytes from dnNRSF-Tg. To further investigate the effect of increased expression of HCN on arrhythmogenicity in ventricular myocytes, we generated the transgenic mice overexpressing HCN2 specifically in the heart (HCN2-Tg). Thought there was no difference in heart rate, cardiac structure and cardiac systolic function between HCN2-Tg and wild type mice, HCN2-Tg showed high susceptibility to arrhythmias induced by chronic β-adrenergic stimulation using osmotic pump infusion. Isolated ventricular myocytes from HCN2-Tg were highly susceptible to Isp stimulation-induced increase in abnormal automaticity (0.3μM), which was inhibited by Iva (3μM). Collectively, our findings demonstrate a novel therapeutic role of HCN inhibition with Iva in preventing lethal arrhythmias associated with heart failure.
- © 2011 by American Heart Association, Inc.