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

• DOI: 10.7554/elife.88638
• Publication Date: 2023-07-12T15:31:57Z
• Authors: Pooja Joshi; Shanea Estes; Deeptankar DeMazu...; Bjorn C Knollmann; Swati Dey
• Keywords: Sudden Death

Sudden cardiac death (SCD) from ventricular tachycardia/fibrillation (VT/VF) is 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) Ca2+ release the downstream effectors underexplored in this context. Recent evidence implicates reactive oxygen species (ROS)-mediated oxidation and hyperactivity RyR2s pathophysiology We tested hypothesis that RyR2 inhibition failing arrhythmogenic hearts reduces sarcoplasmic leak repolarization lability, mitigates VT/VF/SCD improves contractile function. used guinea pig model replicates key clinical aspects human nonischemic HF, such as prolonged QT interval, high prevalence spontaneous arrhythmic SCD, profound via hyperactive RyR2. HF animals were randomized to receive dantrolene (DS) or placebo early chronic HF. assessed incidence VT/VF SCD (primary outcome), ECG heart rate variability, echocardiographic left (LV) structure function, immunohistochemical LV fibrosis, oxidation. DS treatment prevented by decreasing dispersion arrhythmias. Compared placebo, lowered resting rate, preserved chronotropic competency during transient β-adrenergic challenge, improved variability Inhibition with vicious cycle leak-induced increases diastolic ROS-mediated oxidation, thereby reducing lability protecting against VT/VF/SCD. Moreover, consequent increase load These potentially life-saving effects warrant further investigation, studies repurposing potential new therapy failure and/or