RyR2 inhibition with dantrolene is antiarrhythmic, antifibrotic, and improves cardiac function in chronic ischemic heart disease

Background Ventricular tachycardia (VT) is responsible for sudden death in chronic ischemic heart disease (CIHD) patients. The cardiac ryanodine receptor (RyR2) releases Ca2+ from the sarcoplasmic reticulum (SR) and links electrical excitation to contraction. RyR2 hyperactivity has been widely documented in CIHD and may contribute to VT risk and progressive LV remodeling. Objective To test the hypothesis that targeting RyR2 hyperactivity plays a mechanistic role in VT inducibility and progressive heart failure in CIHD that can be prevented by the RyR2 inhibitor dantrolene. Methods CIHD was induced in C57BL/6J mice by left coronary artery ligation. Four weeks later, mice were randomized to either acute or chronic (6 weeks via osmotic mini-pump) treatment with dantrolene or vehicle. VT inducibility was assessed by programmed stimulation in vivo and in isolated hearts. Electrical substrate remodeling was assessed by optical mapping. Ca2+ sparks and spontaneous Ca2+ releases were measured in isolated cardiomyocytes. Cardiac remodeling was assessed by histology and qRT-PCR. Cardiac function and contractility were assessed by echocardiography. Results Compared to vehicle, acute dantrolene treatment reduced VT inducibility and improved LV contractility in vivo . Optical mapping in isolated hearts demonstrated reentrant VT prevention by dantrolene, which normalized the shortened refractory period (VERP) and prolonged action potential duration (APD), preventing APD alternans. In single CIHD cardiomyocytes, dantrolene normalized RyR2 hyperactivity and prevented spontaneous SR Ca2+ release. Chronic dantrolene treatment reduced peripheral muscle strength but had no adverse effects on body weight or mortality. Chronic dantrolene not only reduced VT inducibility but also reduced peri-infarct fibrosis and prevented the progression of LV dysfunction in CIHD mice. Conclusion RyR2 hyperactivity plays a mechanistic role for VT risk, infarct remodeling, and contractile dysfunction in CIHD mice. Our data provide proof of concept for the anti-arrhythmic and anti-fibrotic efficacy of dantrolene in CIHD. What is New? Clinical Implications ### Competing Interest Statement The authors have declared no competing interest. * AF : Atrial Fibrillation APD : Action Potential Duration CIHD : Chronic Ischemic Heart Disease CPVT : catecholaminergic polymorphic ventricular tachycardia DAD : delayed afterdepolarization EMG : Electromyogram FS : Fractional shortening ICD : implantable cardioverter-defibrillator PSAX : parasternal short-axis PSLX : parasternal long-axis LV : Left ventricle/ventricular LVEDd : Left ventricular end-diastolic dimension LVESd : Left ventricular end-systolic dimension LVEF : Left ventricular ejection fraction MI : Myocardial Infarction mVcfc : mean velocity circumferential fiber shortening PES : Programmed electrical stimulation RV : Right ventricle/ventricular RyR2 : Ryanodine Receptor 2 SR : Sarcoplasmic reticulum SCD : Sudden cardiac death VT : Ventricular Tachycardia VF : Ventricular Fibrillation