Abstract 18111: Flecainide Exerts its Antiarrhythmic Action in CPVT Through Blockade of Neuronal Na+ channel-mediated Arrhythmogenic Diastolic Ca2+ Release
Background: Flecaininde is an effective antiarrhythmic in management of CPVT. Its antiarrhythmic action has been attributed to direct effect on RyR2 and reduced cellular excitability through the inhibition of cardiac-type Na+ channels. Recently we demonstrated that neuronal Na+ channels (nNavs) colocalize with the ryanodine receptors (RyR2) Ca2+ release channels on the sarcoplasmic reticulum. Here we explore a novel mechanism that may contribute to the antiarrhythmic effect of flecainide, mainly uncoupling of aberrant Na+/Ca2+ signaling through nNav inhibition.
Methods: To study the effects of flecainide on Ca2+ signaling we used a murine model of cardiac calsequestrin-associated CPVT. We performed confocal microscopy in intact isolated ventricular myocytes to assess Ca2+ handling and recorded late Na+ current (INa) during various pharmacological interventions. Surface electrocardiograms were performed during catecholamine challenge to monitor arrhythmic activity in vivo.
Results: During catecholamine stimulation with isoproterenol (Iso; 100 nM) disruption of the cross-talk between nNavs and RyR2 by nNav blockade with 100nM tetrodotoxin (TTX) and riluzole (10μM) as well as flecainide (2.5μM) reduced Iso-promoted late INa and DCR in isolated intact CPVT cardiomyocytes. To further examine the role of nNav-mediated late INa in genesis of DCR we augmented nNav channel activity with β-Pompilidotoxin (β-PMTX, 40μM). Effects of β-PMTX in CPVT cardiomyocytes were reversed by nNav blockade with TTX and riluzole as well as flecainide. This reduction in late INa and DCR frequency with riluzole and flecainide in the presence of β-PMTX on cellular level translated to decreased ventricular arrhythmias in CPVT mice.
Conclusion: These data suggest that disruption of nNav-mediated late INa can prevent arrhythmogenic DCR in CPVT. Importantly, the antiarrhythmic effects of flecainide can be attributed, at least in part, to its nNav blocking properties.
Author Disclosures: P. Radwanski: None. H. Ho: None. B. Knollmann: None. A. Belevych: None. S. Györke: None.
- © 2015 by American Heart Association, Inc.