Show simple item record

dc.contributor.authorSalvage, Samanthaen
dc.contributor.authorKing, JHen
dc.contributor.authorChandrasekharan, KHen
dc.contributor.authorJafferji, DIGen
dc.contributor.authorGuzadhur, Len
dc.contributor.authorMatthews, Hughen
dc.contributor.authorHuang, Christopheren
dc.contributor.authorFraser, Jamesen
dc.date.accessioned2015-05-29T09:51:54Z
dc.date.available2015-05-29T09:51:54Z
dc.date.issued2015-04-23en
dc.identifier.citationSalvage et al. Acta Physiologica (2015) Vol. 214, Issue 3, pp. 361-375. DOI: 10.1111/apha.12505en
dc.identifier.issn1748-1708
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/248079
dc.description.abstractAims 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.
dc.description.sponsorshipThis 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.
dc.languageEnglishen
dc.language.isoenen
dc.publisherWiley
dc.rightsAttribution 2.0 UK: England & Wales*
dc.rights.urihttp://creativecommons.org/licenses/by/2.0/uk/*
dc.subjectatrial arrhythmiaen
dc.subjectconduction velocityen
dc.subjectCPVTen
dc.subjectflecainideen
dc.subjectNa+ currentsen
dc.subjectryanodine receptoren
dc.titleFlecainide exerts paradoxical effects on sodium currents and atrial arrhythmia in murine RyR2-P2328S heartsen
dc.typeArticle
dc.description.versionThis is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1111/apha.12505en
prism.endingPage375
prism.publicationDate2015en
prism.publicationNameActa Physiologicaen
prism.startingPage361
prism.volume214en
dc.rioxxterms.funderBBSRC
dc.rioxxterms.funderWellcome Trust
dc.rioxxterms.projectidBB/FO23863/1
dcterms.dateAccepted2015-04-01en
rioxxterms.versionofrecord10.1111/apha.12505en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2015-04-23en
dc.contributor.orcidSalvage, Samantha [0000-0002-5793-2349]
dc.contributor.orcidHuang, Christopher [0000-0001-9553-6112]
dc.contributor.orcidFraser, James [0000-0002-6505-1883]
dc.identifier.eissn1748-1716
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWELLCOME TRUST (105727/Z/14/Z)
pubs.funder-project-idMRC (MR/M001288/1)
pubs.funder-project-idBritish Heart Foundation (PG/14/79/31102)
pubs.funder-project-idBBSRC (BB/F023863/1)


Files in this item

Thumbnail
Thumbnail

This item appears in the following Collection(s)

Show simple item record

Attribution 2.0 UK: England & Wales
Except where otherwise noted, this item's licence is described as Attribution 2.0 UK: England & Wales