Ryanodine Receptor Inhibition with Dantrolene Prevents Ventricular Tachycardia Induction in Patients with Structural Heart Disease - A Randomized Controlled Trial.

Despite clinical need, no new drugs for treating ventricular tachycardia (VT) have emerged for over 20 years. In structural heart disease, posttranslational modifications render intracellular ryanodine receptor-2 (RyR2) calcium release channels leaky, which increases VT risk. Treatment with dantrolene, an RyR2 inhibitor, prevents VT in animal models. Here, we test Dantrolene in a randomized, double-blinded, placebo-controlled clinical trial of 51 patients with structural heart disease undergoing catheter ablation for ventricular arrhythmias. Cardiac electrophysiologic parameters, hemodynamics and VT inducibility were assessed at baseline and after IV administration of dantrolene (29 patients) or placebo (22 patients). Approximately half of study participants were inducible at baseline. Dantrolene reduced inducible VT by 66% whereas placebo had no effect (odds ratio 0.23, 95% CI 0.06-0.90, P=0.034). Dantrolene had no significant effects on conduction velocity, effective refractory periods, heart rate, ECG intervals, blood pressure, or cardiac function. We conclude that Dantrolene reduced VT inducibility in high-risk patients with a favorable safety profile. These findings support the safety and efficacy of targeting RyR2 for arrhythmia prevention in humans. Clinicaltrials.gov NCT04134845 .