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

Abstract

BackgroundVentricular 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. ObjectiveTo 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. MethodsCIHD 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. ResultsCompared 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. ConclusionRyR2 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. Clinical PerspectiveO_ST_ABSWhat is New?C_ST_ABSO_LIThe mouse CIHD model is a more clinically relevant model in which treatment is started late after infarction, when heart failure is already established. C_LIO_LIAcute and chronic dantrolene treatment suppresses VT inducibility by restoring myocyte APD, terminating APD alternans and normalizing VERP. C_LIO_LIChronic dantrolene treatment prevents pathological remodeling and peri-infarct fibrosis, the substrate for reentry VT. Cardiac function is improved with chronic dantrolene therapy. C_LI Clinical ImplicationsO_LITreatment with dantrolene, which is already approved for clinical use, is a promising therapy in patients with ischemic heart disease, in whom other antiarrhythmic drugs are contraindicated. C_LIO_LIDantrolene inhibition of RyR2 not only suppresses VT but also improves cardiac function in chronic ischemic heart disease. C_LI