Abstract 2629: Flecainide Inhibits Arrhythmogenic Ca2+ Waves by Open State Block of Ryanodine Receptor Ca2+ Release Channels and Reduction of Ca2+ Spark Mass
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is linked to mutations in the cardiac ryanodine receptor (RyR2) or calsequestrin. We recently found that flecainide prevents CPVT in mice and humans by blocking RyR2 channels. Here we examine the mechanism of flecainide action by comparing the effects of flecainide and tetracaine, another RyR2 inhibitor that was ineffective in CPVT myocytes.
Methods: Measurement of single RyR2 channels incorporated in lipid bilayers and of spontaneous Ca sparks and Ca waves in ventricular myocytes lacking calsequestrin.
Results: Flecainide blocked RyR2 channels more potently than tetracaine (IC50 10 μM vs 50 μM, n=5 each, p<0.05), with a different mechanism of action: Flecainide acted by open state block, whereas tetracaine primarily acted on closed RyR2 channels. In myocytes, flecainide (6 μM) significantly reduced spark amplitude and spark width, resulting in a 51μ6% reduction in spark mass (n=461, p<0.001), but in a 71±19% increase in spark frequency (p<0.01). As a result, flecainide had no significant effect on spark-mediated SR Ca leak or SR Ca content and caused a sustained reduction of spontaneous Ca waves. In contrast, tetracaine (50 μM) had no significant effect on spark mass, but decreased spark frequency (−43±12%) and SR Ca leak (−68±5%, n=84, p<0.001), resulting in a significantly increased SR Ca content and resurgence of Ca waves.
Conclusions: The differences in RyR2 gating, spark mass and spark frequency likely explains why flecainide, unlike tetracaine, does not change the balance of SR Ca fluxes and causes a sustained suppression of arrhythmogenic Ca waves. Based on our findings with flecainide, RyR2 open state block should be considered as therapeutic strategy in SR Ca release-triggered arrhythmias, such as CPVT.
This research has received full or partial funding support from the American Heart Association, National Center.