Abstract 12552: Juxta-Purkinje Ventricular Myocytes Are the Cellular Trigger of Catecholaminergic Polymorphic Ventricular Tachycardia

Abstract

Introduction: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic arrhythmia syndrome caused by mutations that render intracellular calcium release channels hyperactive during adrenergic stress. Hyperactive calcium release has also been identified as a cause of ventricular arrhythmia in acquired heart diseases such as heart failure. What remains unknown is the cellular source of ventricular arrhythmia triggered by inappropriate calcium release – Purkinje cells in the cardiac conduction system or ventricular cardiomyocytes in the working myocardium. Methods: To investigate the cellular origin, we used a genetic approach in mice to knock out cardiac calsequestrin (Casq2) either in Purkinje cells or in ventricular cardiomyocytes (Panel A). Total loss of calsequestrin in the heart causes a severe CPVT phenotype in mice and humans. Immunostaining and western blotting were used to examine protein expression and arrhythmias were induced by administration of isoprenaline. Results: Loss of Casq2 only in ventricular myocytes produced a full-blown CPVT phenotype, whereas mice with loss of Casq2 only in Purkinje cells were comparable to wild-type mice (Panel B). Subendocardial chemical ablation or restoration of Casq2 expression in subendocardial cardiomyocytes neighboring Purkinje cells was sufficient to protect against catecholamine-induced arrhythmias (Panels C, D). Conclusion: Our data indicate that subendocardial ventricular myocytes juxtaposed to Purkinje fibers are the source of ventricular arrhythmias triggered by intracellular calcium release and hence identify a novel cellular target for arrhythmia prevention.