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Circulation
Year: 2009  |  Volume: 120  |  Issue: 9  |  Page No.: 743 - 752

T-Type Ca2+ Channel Blockade Prevents Sudden Death in Mice With Heart Failure

H Kinoshita, K Kuwahara, M Takano, Y Arai, Y Kuwabara, S Yasuno, Y Nakagawa, M Nakanishi, M Harada, M Fujiwara, M Murakami, K Ueshima and K. Nakao    

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 Ca2+ channels contributes to the progression of heart failure. The ability of T-type Ca2+ 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 Ca2+ channel blockers, with those of nitrendipine, a selective L-type Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ channel blockade also prevented sudden death in mice with myocardial infarction. Our findings suggest T-type Ca2+ channel blockade is a potentially useful approach to preventing sudden death in patients with heart failure.

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