Key result
Flecainide paradoxically increased the open probability of low-activity RyR2 channels (Po < 0.08) at concentrations of 0.5 to 10 µM (WT) or 0.5 to 50 µM (P2328S), while inhibiting more active channels.
Why the study?
Reported actions of flecainide on cardiac sodium currents from mice carrying the pro-arrhythmic homozygotic RyR2-P2328S mutation prompted investigation into the effects of flecainide on their RyR2 channels.
Flecainide exhibits a paradoxical pro-arrhythmic activation of cardiac RyR2 channels under low activity conditions, which may explain occasional treatment failures in CPVT.
Answers are grounded in this paper and cite their sources.
Flecainide may directly modulate mutant RyR2; leaves open its role in CPVT/AF therapy beyond Na-channel blockade.
Cardiac ryanodine receptor (RyR2) mutations are implicated in the potentially fatal catecholaminergic polymorphic ventricular tachycardia (CPVT) and in atrial fibrillation. CPVT has been successfully treated with flecainide monotherapy, with occasional notable exceptions. Reported actions of flecainide on cardiac sodium currents from mice carrying the pro-arrhythmic homozygotic RyR2-P2328S mutation prompted our explorations of the effects of flecainide on their RyR2 channels. Lipid bilayer electrophysiology techniques demonstrated a novel, paradoxical increase in RyR2 activity. Preceding flecainide exposure, channels were mildly activated by 1 mM luminal Ca2+ and 1 µM cytoplasmic Ca2+, with open probabilities (Po) of 0.03 ± 0.01 (wild type, WT) or 0.096 ± 0.024 (P2328S). Open probability (Po) increased within 0.5 to 3 min of exposure to 0.5 to 5.0 µM cytoplasmic flecainide, then declined with higher concentrations of flecainide. There were no such increases in a subset of high Po channels with Po ≥ 0.08, although Po then declined with ≥5 µM (WT) or ≥50 µM flecainide (P2328S). On average, channels with Po < 0.08 were significantly activated by 0.5 to 10 µM of flecainide (WT) or 0.5 to 50 µM of flecainide (P2328S). These results suggest that flecainide can bind to separate activation and inhibition sites on RyR2, with activation dominating in lower activity channels and inhibition dominating in more active channels.
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Salvage et al. (2021) studied Catecholaminergic polymorphic ventricular tachycardia (CPVT). Flecainide vs. Baseline (preceding flecainide exposure) was evaluated on Open probability (Po) of RyR2 channels. Flecainide paradoxically increased the open probability of low-activity RyR2 channels (Po < 0.08) at concentrations of 0.5 to 10 µM (WT) or 0.5 to 50 µM (P2328S), while inhibiting more active channels.
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