Key result
Flecainide's principal action on RyR2 involves the partial block of ion flow in the cytoplasm-to-lumen direction, inhibiting RyR2-mediated sarcoplasmic reticulum countercurrent.
Why the study?
Although flecainide treats CPVT via complex ion channel effects, the exact mechanism of RyR2 block remains debated given bidirectional ion fluxes across the sarcoplasmic reticulum membrane.
This review proposes a paradigm shift in understanding flecainide's mechanism in CPVT, suggesting it primarily blocks RyR2-mediated SR countercurrent rather than lumen-to-cytoplasm Ca2+ release.
Flecainide use in CPVT requires mechanistic caution; review leaves open disease-state effects on multiple channels.
Flecainide is used to treat catecholaminergic polymorphic ventricular tachycardia (CPVT), an arrhythmia caused by disrupted cellular Ca 2+ handling following β‐adrenergic stimulation. The clinical efficacy of flecainide in this context involves complex effects on multiple ion channels that may be influenced by the disease state. A compelling narrative has been constructed around flecainide's nonselective block of sarcoplasmic reticulum (SR) lumen‐to‐cytoplasm Ca 2+ release through intracellular calcium release channels (RyR2). However, ion fluxes across the SR membrane during heart contraction are bidirectional , and here, we review experimental evidence that flecainide's principal action on RyR2 involves the partial block of ion flow in the cytoplasm‐to‐lumen direction (i.e., flecainide inhibits RyR2‐mediated SR ‘countercurrent’). Experimental approaches that could advance new knowledge on the mechanism of RyR2 block by flecainide are proposed. Some impediments to progress in this area, that must be overcome to enable the development of superior drugs to treat CPVT, are also considered.
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Bannister et al. (2021) conducted a review in Catecholaminergic polymorphic ventricular tachycardia (CPVT). Flecainide was evaluated. Flecainide's principal action on RyR2 involves the partial block of ion flow in the cytoplasm-to-lumen direction, inhibiting RyR2-mediated sarcoplasmic reticulum countercurrent.
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