Abstract 17054: N-Type Ca2+ Channel Blocker is Effective to Prevent Sudden Cardiac Death in Mice with Heart Failure
Background - Increased sympathetic nerve activity is involved in the increased arrhythmogenicity seen in patients with chronic heart failure. N-type Ca2+ 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 Ca2+ channel blocker, with those of nitrendipine (Nit), a selective L-type Ca2+ 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. 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. In addition to the pharmacological blockade, we also assessed the effect of genetic titration of NCC by crossing dnNRSF-Tg mice with the mice lacking CACNA1B encoding α1B subunit of NCC. In dnNRSF-Tg;CACNA1B+/- mice, survival rate was significantly improved compared with that in dnNRSF-Tg;CACNA1B+/+ mice (p=0.001).
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.
- © 2011 by American Heart Association, Inc.