Flecainide exerts paradoxical effects on sodium currents and atrial arrhythmia in murine RyR2-P2328S hearts
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Salvage, S., King, J., Chandrasekharan, K., Jafferji, D., Guzadhur, L., Matthews, H., Huang, C., & et al. (2015). Flecainide exerts paradoxical effects on sodium currents and atrial arrhythmia in murine RyR2-P2328S hearts. Acta Physiologica, 214 361-375. https://doi.org/10.1111/apha.12505
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 Nav1.5 currents in homozygous RyR2-P2328S (RyR2S/S) mice with slowed conduction and increased arrhythmogenicity. Yet clinically, and in murine models, the Nav1.5 blocker flecainide reduces ventricular arrhythmogenicity in CPVT. We aimed to determine whether, and how, flecainide influences atrial arrhythmogenicity in RyR2S/S mice and their wild-type (WT) littermates. Methods We explored effects of 1 μm flecainide on WT and RyR2S/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 RyR2S/S showed more frequent atrial arrhythmias, slower CV, reduced INa and unchanged AERP compared to WT. Flecainide was anti-arrhythmic in RyR2S/S but pro-arrhythmic in WT. It increased INa in RyR2S/S atria, whereas it reduced INa as expected in WT. It increased AERP while sparing CV in RyR2S/S, but reduced CV while sparing AERP in WT. Thus, RyR2S/S hearts have low λ relative to WT; flecainide then increases λ in RyR2S/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 Ca2+ release. This contrasts with the increased arrhythmic incidence and reduced INa and λ with flecainide in WT.
atrial arrhythmia, conduction velocity, CPVT, flecainide, Na+ currents, ryanodine receptor
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.
WELLCOME TRUST (105727/Z/14/Z)
British Heart Foundation (PG/14/79/31102)
External DOI: https://doi.org/10.1111/apha.12505
This record's URL: https://www.repository.cam.ac.uk/handle/1810/248079
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/
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