Is the Debate on the Flecainide Action on the RYR2 in CPVT Closed?

Abstract

The class IC antiarrhythmic agent flecainide, developed in the 70s as a more stable local anesthetic by incorporating of fluorine, is nowadays recommended as one of the first-line rhythm control therapeutic options in patients without significant structural heart disease or severe hemodynamic instability. Flecainide appears to be effective for managing arrhythmias via blocking Na+ channel but also acts on voltage-gated K+ and Ca2+ channels1 and thus can also be classified as class IVb antiarrhythmic.2 More recently, flecainide has drawn renewed interest on its precise mechanisms of action stimulated from a landmark study3 demonstrating that flecainide may also block the intracellular Ca2+ release channel—the RyR2 (ryanodine receptor) and suppress ventricular arrhythmias in both murine models and patients with catecholaminergic polymorphic ventricular tachycardia (CPVT). This life-threatening inherited arrhythmia is caused by mutations in the RyR2 gene but also to a far lesser extent from RyR2 modulators, such as CasQ2 (calsequestrin-2), CALM (calmodulin), and TRDN (triadin). Mutations in TECRL (trans-2,3-enoyl-CoA reductase-like protein) and other ion channels (Kir2.1-inward-rectifier potassium channel, KCNJ2 and Na+ channel, SCN5A) have also been linked to some CPVT.4 The participation of a direct effect on the RyR2 has been challenged, although the beneficial effect of flecainide in patients with CPVT,5 as well as other RyR2 dysfunction-linked inherited arrhythmias6–9 is largely accepted. Objections mainly claim that flecainide only blocks RyR2 at not physiological positive potential, and blunt sarcoplasmic reticulum (SR) cation influx (cytosolic to SR luminal flux) but not SR efflux. Others claim that the main flecainide mechanism of action preventing CPVT arrhythmias is due to the blockade of Na+ channels, which increases the threshold for triggered activity10 and results in preventing elevated intracellular Ca2+ levels via the Na+/Ca2+ exchanger to decrease inappropriate postdepolarization.11,12 To add complexity, it has been shown that flecainide might prevent Na+ current modulation by RyR2 in CPVT atria.13 As many scientists debate, the conflicting reports look like a ping-pong game where the opponents use different paddles (techniques), balls (dose and application time of flecainide), and play on a different table (normal versus CPVT model), jeopardizing the reconciliation. Whatever the root cause of the discrepancies, and even if a more definitive proof could come with [3H]-ryanodine binding assay to see how flecainide affect RyR2 channel activity, the contrasting studies agree on the fact that flecainide is an open RyR2 channel blocker, altering Ca2+ sparks, the elementary RyR2-mediated SR Ca2+ release.