Efficacy of Flecainide in Catecholaminergic Polymorphic Ventricular Tachycardia Is Mutation-Independent but Reduced by Calcium Overload

BACKGROUND: The dual Na(+) and cardiac Ca(2+)-release channel inhibitor, Flecainide (FLEC) is effective in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), a disease caused by mutations in cardiac Ca(2+)-release channels (RyR2), calsequestrin (Casq2), or calmodulin. FLEC suppresses spontaneous Ca(2+) waves in Casq2-knockout (Casq2(−/−)) cardiomyocytes, a CPVT model. However, a report failed to find FLEC efficacy against Ca(2+) waves in another CPVT model, RyR2-R4496C heterozygous mice (RyR2(R4496C+/−)), raising the possibility that FLEC efficacy may be mutation dependent. OBJECTIVE: To address this controversy, we compared FLEC in Casq2(−/−) and RyR2(R4496C+/−) cardiomyocytes and mice under identical conditions. METHODS: After 30 min exposure to FLEC (6 μM) or vehicle (VEH), spontaneous Ca(2+) waves were quantified during a 40 s pause after 1 Hz pacing train in the presence of isoproterenol (ISO, 1 μM). FLEC efficacy was also tested in vivo using a low dose (LOW: 3 mg/kg ISO + 60 mg/kg caffeine) or a high dose catecholamine challenge (HIGH: 3 mg/kg ISO + 120 mg/kg caffeine). RESULTS: In cardiomyocytes, FLEC efficacy was dependent on extracellular [Ca(2+)]. At 2 mM [Ca(2+)], only Casq2(−/−) myocytes exhibited Ca(2+) waves, which were strongly suppressed by FLEC. At 3 mM [Ca(2+)] both groups exhibited Ca(2+) waves that were suppressed by FLEC. At 4 mM [Ca(2+)], FLEC no longer suppressed Ca(2+) waves in both groups. Analogous to the results in myocytes, RyR2(R4496C+/−) mice (n = 12) had significantly lower arrhythmia scores than Casq2(−/−) mice (n = 9), but the pattern of FLEC efficacy was similar in both groups (i.e., reduced FLEC efficacy after HIGH dose catecholamine challenge). CONCLUSION: FLEC inhibits Ca(2+) waves in RyR2(R4496C+/−) cardiomyocytes, indicating that RyR2 channel block by FLEC is not mutation-specific. However, FLEC efficacy is reduced by Ca(2+) overload in vitro or by high dose catecholamine challenge in vivo, which could explain conflicting literature reports.