Ryanodine receptor 2 inhibition reduces dispersion of cardiac repolarization, improves contractile function and prevents sudden arrhythmic death in failing hearts.

Introduction: Sudden cardiac death (SCD) from ventricular tachycardia/fibrillation (VT/VF) are a leading cause of death, but current therapies are limited. Despite extensive research on drugs targeting sarcolemmal ion channels, none have proven sufficiently effective for preventing SCD. Sarcoplasmic ryanodine receptor 2 (RyR2) Ca Objective: To test the hypothesis that RyR2 inhibition of failing arrhythmogenic hearts reduces sarcoplasmic Ca Methods: We used a guinea pig model that replicates key clinical aspects of human nonischemic HF, such as a prolonged QT interval, a high prevalence of spontaneous arrhythmic SCD, and profound Ca Results: DS treatment prevented VT/VF and SCD by decreasing dispersion of repolarization and ventricular arrhythmias. Compared to placebo, DS lowered resting heart rate, preserved chronotropic competency during transient β-adrenergic challenge, and improved heart rate variability and cardiac function. Conclusion: Inhibition of RyR2 hyperactivity with dantrolene mitigates the vicious cycle of sarcoplasmic Ca