Abstract P160: N-Type Ca 2+ Channel Blockade Prevents Sudden Death in Mice with Heart Failure

Abstract

Background - Increased sympathetic nerve activity is involved in the increased arrhythmogenicity seen in patients with chronic heart failure. N-type Ca 2+ channel (NCC) modulates sympathetic nerve activity by regulating calcium entry at sympathetic nerve terminal, which triggers the release of the neurotransmitter noradrenalin. The ability of NCC blockade to prevent lethal arrhythmias associated with heart failure has never been tested, however. Methods and Results - We compared effects of cilnidipine (Cil), dual N-and L-type Ca 2+ channel blocker, with those of nitrendipine (Nit), a selective L-type Ca 2+ channel blocker, in a cardiac-specific, dominant-negative form of neuron-restrictive silencer factor transgenic mice (dnNRSF-Tg), a mouse model of dilated cardiomyopathy leading to sudden arrhythmic death. Hemodynamic and echocardiographic analyses showed no significant difference among the control, Cil, and Nit groups. In contrast, Cil dramatically improved the survival rate (p<0.001) and reduced ventricular arrhythmia (p<0.05) among dnNRSF-Tg mice, compared with control vehicle or Nit (n=22 for WT, n=20 for Tg without drugs, n=22 for Tg with Cil, n=23 for Tg with Nit). Cil improved the imbalance in autonomic nerve activity assessed by heart rate valiability, and also reduced the increased urinary excretion of noradrenalin seen in dnNRSF-Tg, whereas Nit did not. Conclusions - NCC blockade ameliorated disturbed autonomic nerve function and improved survival in a mouse model of dilated cardiomyopathy and sudden death. Our findings suggest NCC blockade is a potentially useful approach to preventing sudden cardiac death in patients with heart failure.