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

The dual Na⁺ and cardiac Ca²⁺-release channel inhibitor, Flecainide (FLEC) is effective in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), a disease caused by mutations in cardiac Ca²⁺-release channels (RyR2), calsequestrin (Casq2), or calmodulin. FLEC suppresses spontaneous Ca²⁺ waves in Casq2-knockout (Casq2^-/-) cardiomyocytes, a CPVT model. However, a report failed to find FLEC efficacy against Ca²⁺ waves in another CPVT model, RyR2-R4496C heterozygous mice (RyR2^R4496C+/-), raising the possibility that FLEC efficacy may be mutation dependent.

To address this controversy, we compared FLEC in Casq2^-/- and RyR2^R4496C+/- cardiomyocytes and mice under identical conditions.

After 30 min exposure to FLEC (6 μM) or vehicle (VEH), spontaneous Ca²⁺ 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).

In cardiomyocytes, FLEC efficacy was dependent on extracellular [Ca²⁺]. At 2 mM [Ca²⁺], only Casq2^-/- myocytes exhibited Ca²⁺ waves, which were strongly suppressed by FLEC. At 3 mM [Ca²⁺] both groups exhibited Ca²⁺ waves that were suppressed by FLEC. At 4 mM [Ca²⁺], FLEC no longer suppressed Ca²⁺ 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).

FLEC inhibits Ca²⁺ waves in RyR2^R4496C+/- cardiomyocytes, indicating that RyR2 channel block by FLEC is not mutation-specific. However, FLEC efficacy is reduced by Ca²⁺ overload in vitro or by high dose catecholamine challenge in vivo, which could explain conflicting literature reports.