Triple mode of action of flecainide in catecholaminergic polymorphic ventricular tachycardia: reply

We thank Steele et al . for their interest and comments regarding our recent study focusing on the effects of INa reduction on spontaneous sarcoplasmic reticulum (SR) Ca2+ release.1 In the context of the authors' previous publications regarding the mechanism of action of flecainide at the cardiac ryanodine receptor (RyR2),2–4 it appears they have interpreted our study as an attempt to infer that flecainide has no effect on RyR2. We would like to clarify this misinterpretation. Our work demonstrates that a reduction in Na+ influx into the cardiomyocyte can, via the enhancement of Ca2+ efflux through the Na+/Ca2+ exchanger, reduce [Ca2+]i in the vicinity of the RyR2 and thus reduce the frequency of spontaneous SR Ca2+ release events. We demonstrate that this is a class effect of INa blockers, and that flecainide causes no reduction in SR Ca2+ leak when INa is eliminated by altering the holding potential via voltage clamp. This mechanism also appears to be relevant in whole-heart models of arrhythmia induced by increased SR Ca2+ release as evidenced by recent data from Radwanski et al .5 Our data should not be taken as a dismissal of the effects of flecainide at RyR2. We merely conclude that, under our experimental conditions, INa blockade confers a greater reduction in spontaneous SR Ca2+ release than effects at the RyR2. Flecainide has been …