Abstract 17350: Neuronal Na+ Channels Serve as a Trigger for Atrial Arrhythmias
Background: Triggered arrhythmias including catecholaminergic polymorphic ventricular tachycardia (CPVT) and often accompanying atrial fibrillation (AF) are associated with diastolic Ca2+ release. Despite the Ca2+-dependent nature of these maladies, Na+ channel blockade often proves to be a successful intervention. This would suggest a Na+/Ca2+ imbalance; however, the specific mechanism as to how Na+/Ca2+ dysregulation contributes to AF remains elusive.
Methods and Results: To address this issue we used two mouse models of Ca2+-dependent disorders, one a ryanodine receptor (RyR2) “knock-in” (RyR2-V2475F) and the other calsequestrin-associated CPVT (R33Q). We performed confocal microscopy, recorded cellular Na+ currents (INa) and electrocardiograms in vivo. Immunocytochemistry experiments revealed that a subpopulation of Na+ channels (neuronal Na+ channels; nNav) localize with RyR2 and the Na+/Ca2+ exchanger (NCX). Furthermore, isolated isoproterenol (100nM)-treated atrial myocytes from both CPVT mice exhibited enhanced nNav-mediated late INa that was coupled to repetitive Ca2+ oscillations. Both were abolished by acute exposure to nNav (100nM tetrodotoxin or 10μM riluzole; Fig 1a) or NCX inhibitors (1mM NiCl2 or 1μM SEA0400). Reduction of arrhythmogenic parameters with nNav blockers translated into reduced AF in both CPVT models upon catecholamine challenge or intra-cardiac atrial rapid pacing. Conversely, in wild type mice, augmentation of nNav-mediated late INa with β-Pompilidotoxin (β-PMTX; Fig 1b-d) during concomitant exposure to catecholamines triggered Ca2+ oscillations on the cellular level and atrial arrhythmias in vivo.
Conclusion: These data suggest that cross-talk between nNav, NCX and RyR2 form the structural bases for the triggered, self-sustained Ca2+ oscillations that underlie AF. Therefore, disruption of the cross-talk between these key factors by nNav blockade can serve as a potential antiarrhythmic therapy.
Author Disclosures: P.B. Radwanski: None. Q. Lou: Employment; Significant; Current employment: CardioInsight, Inc. M. Koleske: None. R. Ramos Mondragon: None. S. Priori: None. P. Volpe: None. H.H. Valdivia: None. S. Gyorke: None.
- © 2016 by American Heart Association, Inc.