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 2ϩ channels contributes to the progression of heart failure. The ability of T-type Ca 2ϩ 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 2ϩ channel blockers, with those of nitrendipine, a selective L-type Ca 2ϩ 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(Ϫ)-isomer of efonidipine, a recently identified, highly selective T-type Ca 2ϩ 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 Ca2ϩ 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 2ϩ channel blockade also prevented sudden death in mice with myocardial infarction. Our findings suggest T-type Ca 2ϩ channel blockade is a potentially useful approach to preventing sudden death in patients with heart failure. Key Words: ion channels Ⅲ nervous system, autonomic Ⅲ heart failure Ⅲ calcium Ⅲ arrhythmia A s many as 50% of deaths among heart failure patients are sudden and unexpected, presumably the result of lethal arrhythmias. 1 Despite recent progress in nonpharmacological therapy, pharmacological interventions for the treatment and prevention of lethal arrhythmias associated with chronic heart failure remain limited. A prerequisite for the development of new pharmacological approaches is to identify potential targets based on knowledge of the molecular basis of arrhythmogenesis in failing hearts. Clinical Perspective on p 752Compelling evidence implicates T-type Ca 2ϩ channels in the progression of heart failure. 2,3 During development, T-type Ca 2ϩ channels are abundantly expressed in the embryonic ventricle, but their expression is suppressed in the adult ventricle, so that it is restricted to the conduction system. 4,5 However, T-type Ca 2ϩ channels are reexpressed in hypertrophied and failing ventricles, 4,6 -9 and the resultant T-type Ca 2ϩ currents (I Ca,T ) are thought to be involved in the pathologica...

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