Abstract 10945: Calsequestrin 2 Deletion Causes Abnormal Atrial Automaticity and Conduction Associated With Degenerative Fibrosis of the Sinoatrial Node Pacemaker Complex
Introduction: Loss of function mutations in Calsequestrin 2 (Casq2) is associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). Moreover, CPVT patients exhibit bradycardia and atrial arrhythmias, the underlying mechanism of which remains unknown.
Methods: In vivo ECG monitoring, in vitro high-resolution optical mapping and 3D histological and immunohistological (Cx43 and HCN4) analyses were performed to characterize sinoatrial node (SAN) function and structure in young (3 months) and old (12-14 months) wild type (WT) and Casq2-null (Casq2-/-) mice.
Results: Casq2-/- mice showed SAN dysfunction including bradycardia, slowed SAN conduction, and prolonged SAN recovery time both at rest and during autonomic stimulation by isoproterenol and acetylcholine. In Casq2-/- mice, bradycardia was associated with enhanced atrial ectopic activity accompanied by a shift of the leading pacemaker outside the SAN towards either inter-atrial septum or other latent pacemakers with positive HCN4 expression. Furthermore, in Casq2-/- mice, aging led to increased fibrosis within the SAN pacemaker complex (22±5% vs. 35±7% in old WT vs. old Casq2-/-, p<0.01) and more pronounced bradycardia, enhanced ectopy, and atrial reentrant arrhythmias, suggesting that fibrosis worsens SAN function. Simultaneous voltage (V) and calcium (Ca) imaging of the intact heart confirmed the presence of calcium induced triggered activity and CPVT in the ventricles, but not in atria during atrial ectopy and arrhythmias in old Casq2-/- mice (Figure). Atrial Ca2+ transient upstrokes followed action potential upstrokes with delay of 8.7±1.5 ms and 7.5±0.7 ms in old Casq2-/- and WT respectively (p=NS).
Conclusions: Loss of Casq2 causes pathological remodeling of the SAN pacemaker complex which is responsible for the bradycardic phenotype of Casq2-/- mice. Fibrosis further enhances atrial ectopy and local conduction blocks provoking atrial flutter and fibrillation.
- © 2012 by American Heart Association, Inc.