Mechanism of Antiarrhythmic Effects of Flecainide in Catecholaminergic Polymorphic Ventricular Tachycardia

Abstract

We read with interest the recent article by Liu et al, in Circulation Research, on the mechanism underlying the antiarrhythmic effects of flecainide in catecholaminergic polymorphic ventricular tachycardia (CPVT). 1 They conclude that Na ϩ channel block but not inhibition of the cardiac ryanodine receptor (RyR2) has a key role in the antiarrhythmic effects of flecainide in CPVT, because they found flecainide suppresses triggered activity without a reduction of Ca 2ϩ waves in RyR2R4496Cϩ/Ϫ mice. However, we have previously reported that flecainide directly inhibits RYR2 and thereby prevents CPVT. 2 Evidence that flecainide reduces the frequency of triggered beats to a greater extent than that of spontaneous Ca 2ϩ waves in cardiac calsequestrin Casq2 null (Casq2 Ϫ/Ϫ ) mice, another model of CPVT, led us to propose a dual mode of flecainide action in CPVT: suppression of spontaneous Ca 2ϩ release from sarcoplasmic reticulum by RyR2 inhibition and suppression of triggered beats by Na ϩ channel block. 2 Our studies with a range of sodium channel blockers support a role for RyR2 block in this setting. In our first report, we found that lidocaine, which does not inhibit RyR2, fails to suppress CPVT at a dose that produces similar Na ϩ channel block to a dose of flecainide that completely suppresses CPVT, 2 which supports a direct role for RyR2 inhibition in this setting. The importance of RyR2 inhibition is further corroborated by our recent study, which tested the effects of all class I antiarrhythmic drugs clinically available in the Unites States in Casq2 Ϫ/Ϫ mice. 3 We found that RyR2 inhibition and Ca 2ϩ wave suppression in vitro determined the antiarrhythmic efficacy against CPVT in vivo. 3 The importance of RyR2 inhibition for preventing CPVT has also been confirmed by the recent report of the Chen group. 4 One of the points of difference between the data of Liu et al and our work is the effect of flecainide on sarcoplasmic reticulum Ca 2ϩ sparks: no apparent effect in RyR2 R4496Cϩ/Ϫ cells in the study by Liu et al 1 and an increase in Ca 2ϩ spark frequency and reduction of spark amplitude, width, and overall spark mass in mouse and rat myocytes in our studies. 5,6 The discrepancy may relate to experimental conditions, because the basal Ca 2ϩ spark frequency in the experiments by Liu et al is several fold higher than that of our experiments. 1,5 If Ca 2ϩ spark frequency is already very high, it may be difficult to detect any further increases caused by flecainide.Another possible explanation for the reported discrepancy is that flecainide may be less effective against mutant RyR2R4496Cϩ/Ϫ channels than wild-type RyR2 channels in the setting of Casq2 deletion. However, the Fishman group 7 has reported that flecainide is effective in suppressing Ca 2ϩ waves in Purkinje cells from the same RyR2R4496Cϩ/Ϫ mouse model studied by Liu et al. 1 Furthermore, we reported that flecainide and propafenone (which also blocks RyR2 channels) were effective in CPVT patients carrying mutations in RYR2, 2,3 whereas other sodium cha...

Patient-Specific Drug Screening Using a Human Induced Pluripotent Stem Cell Model of Catecholaminergic Polymorphic Ventricular Tachycardia Type 2

“…21,[38][39][40][41][42][43][44] Our results support this concept by showing that flecainide, at clinically relevant concentrations, could significantly suppress baseline Ca 2+ -cycling abnormalities and protect against isoproterenol-induced arrhythmogenicity in the CPVT2-hiPSC-CMs. Finally, riluzole, a neuronal Na + channel blocker used for treatment of amyotrophic lateral sclerosis, which was recently shown to be antiarrhythmic in a mouse model of CPVT, 45 was also found beneficial in our CPVT2-hiPSC-CMs model.…”

“…21,[38][39][40][41][42][43][44] This was also manifested in our CPVT2 model ( Figure 3D), as application of flecainide significantly suppressed baseline arrhythmic activity in the CPVT2-hiPSC-CMs. Overall, flecainide (1 and 6 µmol/L) abolished Ca 2+ -cycling abnormalities in 26% and 57% of previously arrhythmic CPVT2-hiPSC-CMs, respectively ( Figures 3D and 4A).…”

“…Two main mechanisms were suggested (1) flecainide may increase triggered-activity threshold by directly blocking Na + channels 39,44,46 or (2) flecainide may stabilize SR thereby decreasing diastolic Ca 2+ leak. 38,40,[42][43][44] To provide mechanistic insights into the antiarrhythmic action of the tested pharmacological agents, we initially evaluated their ability to alter SOICR incidence in the CPVT2-hiPSC-CMs as a surrogate for SR stabilization. To provide additional information on their capacity to alter excitability or stabilize the SR, we also evaluated their effects on triggered activity and diastolic Ca 2+ -release events after pacing.…”

New antiarrhythmic targets to control intracellular calcium handling

“…Mutations in RyR can enhance the susceptibility for Ca 2+ leak, especially under conditions with an increased adrenergic drive. Flecainide, a well-established class-Ic antiarrhythmic, showed additional and remarkable efficacy to suppress these arrhythmias both in mice and humans through enhancement of the threshold for triggered activity [40, 41]. It remains to be discussed what the exact contribution is of sodium channel block and RyR inhibition in this preventive effect.…”

Standard Antiarrhythmic Drugs

“…As sodium channel block slows RyR2 channels leading to delayed afterdepolarizations (DADs), triggered activity, and bidirectional/polymorphic VT. 23 Although ICDs are recommended for the prevention of SCD in patients with CPVT, 24 painful shocks can trigger further adrenergic stress and arrhythmias; deaths have occurred despite appropriate ICD shocks. If the heart rate is increased, there is less time for dissociation, so that channel block is enhanced.…”