Short Communication: Flecainide Exerts an Antiarrhythmic Effect in a Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia by Increasing the Threshold for Triggered Activity
Rationale: Flecainide prevents arrhythmias in catecholaminergic polymorphic ventricular tachycardia, but the antiarrhythmic mechanism remains unresolved. It is possible for flecainide to directly affect the cardiac ryanodine receptor (RyR2); however, an extracellular site of action is suggested because of the hydrophilic nature of flecainide.
Objective: To investigate the mechanism for the antiarrhythmic action of flecainide in a RyR2R4496C+/− knock-in mouse model of catecholaminergic polymorphic ventricular tachycardia.
Methods and Results: Flecainide prevented catecholamine-induced sustained ventricular tachycardia in RyR2R4496C+/− mice. Cellular studies were performed with isolated RyR2R4496C+/− myocytes. Isoproterenol caused the appearance of spontaneous Ca2+ transients, which were unaffected by flecainide (6 μmol/L). Flecainide did not affect Ca2+ transient amplitude, decay, or sarcoplasmic reticulum Ca2+ content. Moreover, it did not affect the frequency of spontaneous Ca2+ sparks in permeabilized myocytes. In contrast, flecainide effectively prevented triggered activity induced by isoproterenol. The threshold for action potential induction was increased significantly (P<0.01), which suggests a primary extracellular antiarrhythmic effect mediated by Na+ channel blockade.
Conclusions: Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in RyR2R4496C+/− mice; however, at variance with previous reports, we observed minimal effects on intracellular Ca2+ homeostasis. Our data suggest that the antiarrhythmic activity of the drug is caused by reduction of Na+ channel availability and by an increase in the threshold for triggered activity.
- Received January 22, 2011.
- Revision received May 24, 2011.
- Accepted June 2, 2011.
- © 2011 American Heart Association, Inc.