Conditional Up-Regulation of SERCA2a Exacerbates Ventricular and Atrial Arrhythmias in the Setting of Catecholaminergic Polymorphic Ventricular Tachycardia

Abstract

SERCA2a gene transfer is an emerging therapy for treating contractile dysfunction in heart failure. While improving contractile performance, SERCA2a overexpression has been shown to exacerbate arrhythmias, although beneficial effects of SERCA2a up-regulation on cardiac rhythm have also been reported. To examine the role of SERCA2a and the consequences of its acute up-regulation in arrhythmogenesis, we conditionally overexpressed SERCA2a in a genetic mouse model featuring catecholaminergic polymorphic ventricular tachycardia (CPVT) due to loss of calsequestrin 2 (CASQ2). CASQ2 knock-out (KO) mice were crossbred with doxycycline (DOX)-inducible SERCA2a transgenic mice to generate KO-TG mice. In-vivo ECG studies showed that uninduced KO-TG (DOX-) mice developed both ventricular and atrial arrhythmias in response to catecholamine challenge (isoproterenol, ISO or a combination of ISO and caffeine). Induction of SERCA2a (DOX+) markedly exacerbated both ventricular and atrial arrhythmias in response to ISO. Besides ventricular bigeminy, KO-TG (DOX+) also displayed frequent bursts of sustained ventricular ectopic beats that were not present in KO-TG (DOX-). Moreover, episodes of atrial rhythm disturbances in KO-TG (DOX+) mice occurred even under baseline conditions (no ISO). ISO further promoted atrial tachy- and brady-arrhythmias in the KO-TG (DOX+) mice. Consistent with the in-vivo studies, confocal Ca imaging in both ventricular and atrial myocytes demonstrated that acute SERCA2a overexpression significantly increased the rate of occurrence of diastolic spontaneous and triggered Ca release events. Thus, our results suggest that acute overexpression of SERCA2a exacerbates both ventricular and atrial arrhythmias in settings of CPVT by further elevating diastolic Ca release.