Abstract 17971: Flecainide's Anti-arrhythmic Efficacy in CPVT Mice is Mutation-independent but Reduced by Calcium Overload
Background: The dual Na and RyR2 Ca release channel inhibitor Flecainide (FLEC) appears effective in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), a disease caused by mutations in cardiac Ca-release channels (RyR2) or calsequestrin (Casq2). FLEC suppresses spontaneous Ca waves in Casq2-knockout (KO) myocytes, a CPVT model. However, a recent report failed to find FLEC efficacy against Ca waves in another CPVT model, RyR2-R4496C heterozygous mice, raising the possibility that FLEC efficacy may be mutation dependent. To address this controversy, we compared FLEC in Casq2-KO and RyR2-R4496C myocytes and mice under identical conditions.
Methods: After 30min exposure to FLEC (6μ M) or vehicle (VEH), spontaneous Ca waves were quantified during a 40s pause after 1Hz pacing train in presence of isoproterenol (ISO, 1μ M). FLEC efficacy was also tested in vivo using a low dose (LOW: 3mg/kg ISO + 60mg/kg caffeine) or a high dose catecholamine challenge (HIGH: 3mg/kg ISO + 120mg/kg caffeine).
Results: In myocytes (Figures A&B), FLEC efficacy was strongly dependent on extracellular [Ca]. At 2mM Ca, only Casq2-KO myocytes exhibited Ca waves, which were strongly suppressed by FLEC. At 3mM Ca, both groups had frequent Ca waves. FLEC had reduced efficacy in Casq2-KO but was effective in RyR2-R4496C myocytes. Analogous to the results in myocytes, RyR2-R4496C mice (n=12) had significantly lower arrhythmia scores than Casq2 KO mice (N=9, Figures C & D), but pattern of FLEC efficacy was similar in both groups (i.e., reduced FLEC efficacy after high dose catecholamine challenge).
Conclusion: FLEC inhibits Ca waves in RyR2-R4496C myocytes, indicating that RyR2 channel block by FLEC is not mutation-specific. However, FLEC efficacy in myocytes and in vivo is reduced by Ca overload (extracellular [Ca] or Caffeine-induced), which could explain divergent literature reports.
- Arrhythmias, treatment of
- Myocyte electrophysiology
- Sudden cardiac death
- Ventricular tachycardia
- © 2012 by American Heart Association, Inc.