B-PO01-017 RYR2 HYPERACTIVITY PROMOTES SUSCEPTIBILITY TO VENTRICULAR TACHYCARDIA IN STRUCTURAL HEART DISEASE

Abstract

Ventricular tachycardia (VT) is responsible for sudden death in patients with ischemic cardiomyopathy after myocardial infarction (MI). However, antiarrhythmic drug therapy targeting ion channels on the cell surface has limited efficacy and high toxicity. The cardiac ryanodine receptor (RyR2) releases Ca from sarcoplasmic reticulum and links electrical excitation to contraction. RyR2 hyperactivity post-MI has been widely documented and may contribute to VT risk. To test the hypothesis that RyR2 hyperactivity plays a key role for VT inducibility post-MI and can be suppressed by RyR2 inhibitors. We used a coronary ligation-induced myocardial infarction (MI) mouse model. VT susceptibility and effective refractory period (ERP) was quantified by programmed stimulation 3-6 weeks post MI. The contribution of RyR2 hyperactivity for susceptibility of inducible VT was tested using the selective RyR2 inhibitors dantrolene and ent-verticilide. Compared to sham, MI mice had inducible VT (>3 ventricular beats), ectopy, impaired contractile function, and reduced survival. After catecholamine challenge with isoproterenol (ISO), 50% of MI mice exhibited inducible VT. VT burden was significantly reduced by treatment with RyR2 inhibitors (ISO: 6.1±2.5 vs ISO&dantrolene: 0.6±0.4, vs ISO&ent-verticilide: 0.3±0.2 sec; n=15; P=0.008, respectively). RyR2 inhibitors normalized the shortened ERP of MI mice (Fig), providing a possible mechanism of antiarrhythmic action of RyR2 inhibitors. Increased RyR2 activity post-MI contributes mechanistically to VT induction. RyR2 may be a therapeutic target for preventing VT post-MI.