Subcellular Origin and Tissue-Wide Synchronization of Abnormal Ca Release in the Genesis of Ca-Dependent Atrial Arrhythmia

Abstract

Introduction. Abnormal diastolic Ca release (DCR) from the sarcoplasmic reticulum has been implicated in both ventricular as well as atrial fibrillation (AF). Atrial cells lack the extensive T-tubule network that facilitates Ca signaling in ventricular myocytes. How the distinct structural organization of atrial cells affects the genesis of AF is currently unknown.Methods and Results. We used rapid 2D confocal imaging to map Ca changes in atrial single myocytes and tissue preparations derived from CASQ2 knock-out (CASQ2.KO) mice manifesting Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). Isolated CASQ2.KO atrial cells showed frequent local and cell-wide DCR events when exposed to isoproterenol. DCR predominantly originated nearly simultaneously at several “eager” sites localized at cell periphery. The distribution of latencies to local DCR events in CASQ2.KO cells displayed a left-ward shift consistent with abbreviated RyR2 refractoriness associated with CPVT. This abbreviated RyR2 refractoriness translated into highly synchronous spontaneous Ca oscillations across the intact atrial tissue. Conditional overexpression of SERCA2a in CASQ.KO mice exacerbated proarrhythmic Ca oscillations by increasing the proportion of interior eager release sites and enhancing DCR synchronicity in both isolated atrial cells and atrial tissue preparations.Conclusions. Our results suggest that aberrant DCR involves a certain set of eager Ca release sites that 1) only in part coincide with sites involved in normal EC coupling at cell periphery and 2) act as pacemakers for spontaneous Ca oscillations present in atrial cells. Due to abbreviated release site refractoriness, DCR is synchronized between neighboring cells thereby leading to tissue-wide Ca oscillations that may form basis for AF. SERCA2a overexpression exacerbates arrhythmic Ca oscillations by further enhancing DCR synchronicity.