Abstract
Introduction: Current therapies for preventing sudden cardiac death (SCD) are limited. Prior studies have shown that cardiac stress-induced ryanodine receptor (RyR2) hyperactivity increases sarcoplasmic calcium leak, leading to ventricular tachyarrythmias (VT) and SCD. We hypothesized that inhibition of RyR2 with dantrolene sodium (DS) reduces Ca 2+ leak and mitigates VT and SCD risk in pressure-overloaded arrhythmogenic hearts. Methods: We used an established guinea pig model that uniquely recapitulates key features of human SCD, including a high incidence of spontaneous VT in freely ambulating animals, randomized to placebo vs. DS treatment. We performed in vivo (e.g., VT/SCD incidence, ECG heart rate and QT variability, echocardiographic measures of cardiac function) and ex vivo (e.g., pressure-volume, electrophysiology) studies. We performed intention to treat analysis for 4-week VT-free survival. Results: About half the animals receiving placebo had SCD by 4 weeks. By contrast, dantrolene treatment reduced SCD incidence by 50%. Compared to placebo, dantrolene treatment preserved chronotropic competency during transient β-adrenergic challenge, and improved heart rate variability (SDNN: 11±1.1 vs 17±2.8 ms, p<0.05), reduced QT variability (0.52±0.13 vs 0.19±0.08 (log, ms, p<0.05), and improved cardiac function (fractional shortening: 26±1.9 vs 45±4.5 %, p<0.05). In perfused excised hearts, dantrolene treatment mitigated VT (induced by isoproterenol or burst pacing). Conclusion: Inhibition of RyR2 hyperactivity by dantrolene treatment prevents VT and SCD by increasing cardiac repolarization reserve. Dantrolene also improved overall cardiac electromechanical function in stressed arrhythmogenic hearts. Targeted inhibition of RyR2 hyperactivity may be an effective therapeutic strategy for preventing VT and SCD.
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