T-Type Ca 2+ Channel Blockade Prevents Sudden Death in Mice With Heart Failure

Abstract

Background— Pharmacological interventions for prevention of sudden arrhythmic death in patients with chronic heart failure remain limited. Accumulating evidence suggests increased ventricular expression of T-type Ca 2+ channels contributes to the progression of heart failure. The ability of T-type Ca 2+ channel blockade to prevent lethal arrhythmias associated with heart failure has never been tested, however. Methods and Results— We compared the effects of efonidipine and mibefradil, dual T- and L-type Ca 2+ channel blockers, with those of nitrendipine, a selective L-type Ca 2+ channel blocker, on survival and arrhythmogenicity in a cardiac-specific, dominant-negative form of neuron-restrictive silencer factor transgenic mice (dnNRSF-Tg), which is a useful mouse model of dilated cardiomyopathy leading to sudden death. Efonidipine, but not nitrendipine, substantially improved survival among dnNRSF-Tg mice. Arrhythmogenicity was dramatically reduced in dnNRSF-Tg mice treated with efonidipine or mibefradil. Efonidipine acted by reversing depolarization of the resting membrane potential otherwise seen in ventricular myocytes from dnNRSF-Tg mice and by correcting cardiac autonomic nervous system imbalance. Moreover, the R (−)-isomer of efonidipine, a recently identified, highly selective T-type Ca 2+ channel blocker, similarly improved survival among dnNRSF-Tg mice. Efonidipine also reduced the incidence of sudden death and arrhythmogenicity in mice with acute myocardial infarction. Conclusions— T-type Ca 2+ channel blockade reduced arrhythmias in a mouse model of dilated cardiomyopathy by repolarizing the resting membrane potential and improving cardiac autonomic nervous system imbalance. T-type Ca 2+ channel blockade also prevented sudden death in mice with myocardial infarction. Our findings suggest T-type Ca 2+ channel blockade is a potentially useful approach to preventing sudden death in patients with heart failure.