Abstract
Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic syndrome due to cardiac Ca2+ release channel (RYR2) or cardiac calsequestrin (CASQ2) mutations. VT is caused by spontaneous Ca2+-release from the sarcoplasmic reticulum (SR) that generates after-depolarizations and triggered beats during catecholamine surge. We recently found that flecainide, a class 1c Na+ channel blocker, suppressed ventricular arrhythmia in Casq2 null (Casq−/−) mice, a model of CPVT. Here, we investigated the effect of flecainide on on cardiac Ca2+ handling in Casq2−/− myocytes loaded with Fura-2 AM, and on sheep RyR2 RyR2 channels reconstituted in lipid bilayers.Results: In isoproterenol-stimulated Casq2−/− myocytes, flecainide (6 μmol/l) reduced triggered beats by over 70% (p<0.001). Unexpected for a Na+ channel blocker, flecainide also reduced SR Ca2+ leak (Ca2+ fluorescence ratio: vehicle: 0.12±0.01 vs. flecainide: 0.08±0.01, n=54 per group, p=0.02) and suppressed the rate of spontaneous Ca2+ releases (SCRs) from the SR (SCRs/min: vehicle: 48±5 vs. flecainide: 29±5, n=45 per group, p=0.006), suggesting flecainide directly inhibits SR Ca2+ release. Lipid bilayer experiments confirmed a direct action of flecainide on RyR2 SR Ca2+ release channels: Flecainide induced brief partial closures of channels to a substate with a conductance equal to 20% of the fully open state. On average, flecainide as low as 5 μmol/L caused a 4-fold increase in the frequency of closed events and caused a significant reduction in the open probability from control levels. The effect of flecainide was concentration dependent (IC50 ∼ 50 μmol/l) and fully-reversible upon washout. Flecainide also inhibited RyR2 channels activated by high luminal Ca2+.Conclusion: We report a heretofore unrecognized inhibitory action of flecainide on RyR2 channels, which together with flecainide's inhibition of Na+ channels may explain flecainide's effectiveness in preventing CPVT.Supported by R01-HL88635.
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