Abstract 17019: Two Distinct mechanisms by which Na+/Ca2+ dysregulation contributes to Arrhythmogenic Diastolic Ca2+ Release
Na+ and Ca2+ imbalance is associated with triggered arrhythmias resulting from diastolic Ca2+ release (DCR) from sarcoplasmic reticulum (SR). Recent evidence suggests Na+ channel blockade to be a promising therapy for pathologies, including catecholaminergic polymorphic ventricular tachycardia (CPVT). However, the specific mechanism(s) as to how Na+/Ca2+ dysregulation contribute to arrhythmias is unknown.
Confocal microscopy of ventricular myocytes isolated from CPVT mice lacking the cardiac calsequestrin was used to assess Ca2+ handling response to isoproterenol (Iso) and various pharmacological interventions, while electrocardiograms were acquired during catecholamine challenge to assess the roles of various pools of Na+ channels in CPVT.
We identify two pools of Na+ channels: one composed of cardiac-type Na+ channels localized to cell periphery, and a ‘local pool’ comprised of neuronal Na+ channels colocalizing with RyR2 in the T-tubules. Augmenting function of both Na+ channel pools with ATX-II in the presence Iso resulted in SR Ca2+ overload and activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII), which precipitated DCR. These, in turn, translated into frequent arrhythmias in CPVT mice. Selectively augmenting function of ‘local pool’ neuronal Na+ channels with β-Pompilidotoxin (β-PMTX) precipitated DCR on the cellular level causing frequent arrhythmias during catecholamine challenge in vivo. However, increasing local Na+ fluxes reduced SR Ca2+ load suggesting that local elevation in cytosolic Ca2+ rather than global SR Ca2+ overload underlies DCR and arrhythmias under such conditions.
These data suggest two distinct mechanisms for Na+/Ca2+ dysregulation-mediated arrhythmias. The first relies on SR Ca2+ overload and CaMKII activation and the other on local contribution of Na+-Ca2+ exchange to DCR. Consideration of these divergent mechanisms may enhance individualized approach to arrhythmia management.
Author Disclosures: P. Radwanski: None. R. Veeraraghavan: None. B. Knollmann: None. S. Györke: None.
- © 2014 by American Heart Association, Inc.