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

BACKGROUND

The dual Na and cardiac Ca-release channel inhibitor, Flecainide (FLEC) is effective in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), a disease caused by mutations in cardiac Ca-release channels (RyR2), calsequestrin (Casq2), or calmodulin. FLEC suppresses spontaneous Ca waves in Casq2-knockout (Casq2) cardiomyocytes, a CPVT model. However, a report failed to find FLEC efficacy against Ca waves in another CPVT model, RyR2-R4496C heterozygous mice (RyR2), raising the possibility that FLEC efficacy may be mutation dependent.

OBJECTIVE

To address this controversy, we compared FLEC in Casq2 and RyR2 cardiomyocytes and mice under identical conditions.

METHODS

After 30 min exposure to FLEC (6 μM) or vehicle (VEH), spontaneous Ca 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 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]. At 2 mM [Ca], only Casq2 myocytes exhibited Ca waves, which were strongly suppressed by FLEC. At 3 mM [Ca] both groups exhibited Ca waves that were suppressed by FLEC. At 4 mM [Ca], FLEC no longer suppressed Ca waves in both groups. Analogous to the results in myocytes, RyR2 mice ( = 12) had significantly lower arrhythmia scores than Casq2 mice ( = 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 waves in RyR2 cardiomyocytes, indicating that RyR2 channel block by FLEC is not mutation-specific. However, FLEC efficacy is reduced by Ca overload or by high dose catecholamine challenge , which could explain conflicting literature reports.