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Flecainide exerts paradoxical effects on sodium currents and atrial arrhythmia in murine RyR2-P2328S hearts.


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Authors

Salvage, SC 
King, JH 
Chandrasekharan, KH 
Jafferji, DIG 
Guzadhur, L 

Abstract

AIMS: Cardiac ryanodine receptor mutations are associated with catecholaminergic polymorphic ventricular tachycardia (CPVT), and some, including RyR2-P2328S, also predispose to atrial fibrillation. Recent work associates reduced atrial Nav 1.5 currents in homozygous RyR2-P2328S (RyR2(S/S) ) mice with slowed conduction and increased arrhythmogenicity. Yet clinically, and in murine models, the Nav 1.5 blocker flecainide reduces ventricular arrhythmogenicity in CPVT. We aimed to determine whether, and how, flecainide influences atrial arrhythmogenicity in RyR2(S/S) mice and their wild-type (WT) littermates. METHODS: We explored effects of 1 μm flecainide on WT and RyR2(S/S) atria. Arrhythmic incidence, action potential (AP) conduction velocity (CV), atrial effective refractory period (AERP) and AP wavelength (λ = CV × AERP) were measured using multi-electrode array recordings in Langendorff-perfused hearts; Na(+) currents (INa ) were recorded using loose patch clamping of superfused atria. RESULTS: RyR2(S/S) showed more frequent atrial arrhythmias, slower CV, reduced INa and unchanged AERP compared to WT. Flecainide was anti-arrhythmic in RyR2(S/S) but pro-arrhythmic in WT. It increased INa in RyR2(S/S) atria, whereas it reduced INa as expected in WT. It increased AERP while sparing CV in RyR2(S/S) , but reduced CV while sparing AERP in WT. Thus, RyR2(S/S) hearts have low λ relative to WT; flecainide then increases λ in RyR2(S/S) but decreases λ in WT. CONCLUSIONS: Flecainide (1 μm) rescues the RyR2-P2328S atrial arrhythmogenic phenotype by restoring compromised INa and λ, changes recently attributed to increased sarcoplasmic reticular Ca(2+) release. This contrasts with the increased arrhythmic incidence and reduced INa and λ with flecainide in WT.

Description

Keywords

CPVT, Na+ currents, atrial arrhythmia, conduction velocity, flecainide, ryanodine receptor, Animals, Anti-Arrhythmia Agents, Atrial Fibrillation, Flecainide, Ion Channel Gating, Membrane Potentials, Mice, Mutation, NAV1.5 Voltage-Gated Sodium Channel, Ryanodine Receptor Calcium Release Channel, Sodium, Treatment Outcome, Voltage-Gated Sodium Channel Blockers

Journal Title

Acta Physiol (Oxf)

Conference Name

Journal ISSN

1748-1708
1748-1716

Volume Title

214

Publisher

Blackwell Publishing Ltd
Sponsorship
Biotechnology and Biological Sciences Research Council (BB/F023863/1)
Wellcome Trust (105727/Z/14/Z)
Medical Research Council (MR/M001288/1)
British Heart Foundation (None)
This work was supported by the Biotechnology and Biological Sciences Research Council (BBSRC, UK) under a David Phillips Fellowship held by JAF (BB/FO23863/1) and by the Isaac Newton Trust/Wellcome Trust ISSF/University of Cambridge Joint Research Grants Scheme.