Full metadata record
DC FieldValueLanguage
dc.creatorRivaud, M.R. (Mathilde R.)-
dc.creatorMarchal, G.A. (Gerard A.)-
dc.creatorWolswinkel, R. (Rianne)-
dc.creatorJansen, J.A. (John A.)-
dc.creatorvan-der-Made, I. (Ingeborg)-
dc.creatorBeekman, L. (Leander)-
dc.creatorRuiz-Villalba, A. (Adrián)-
dc.creatorBaartscheer, A. (Antonius)-
dc.creatorRajamani, S. (Sridharan)-
dc.creatorBelardinelli, L. (Luiz)-
dc.creatorvan-Veen, T.A.B. (Toon A.B.)-
dc.creatorBasso, C. (Cristina)-
dc.creatorThiene, G. (Gaetano)-
dc.creatorCreemers, E.E. (Ester E.)-
dc.creatorBezzina, C.R. (Connie R.)-
dc.creatorRemme, C.A. (Carol Ann)-
dc.identifier.citationRivaud, M.R. (Mathilde R.); Marchal, G.A. (Gerard A.); Wolswinkel, R. (Rianne); et al. "Functional modulation of atrio-ventricular conduction by enhanced late sodium current and calcium-dependent mechanisms in Scn5a1798insD/þ mice". Europace. 22 (10), 2020, 1579 - 1589es_ES
dc.description.abstractAims SCN5A mutations are associated with arrhythmia syndromes, including Brugada syndrome, long QT syndrome type 3 (LQT3), and cardiac conduction disease. Long QT syndrome type 3 patients display atrio-ventricular (AV) conduction slowing which may contribute to arrhythmogenesis. We here investigated the as yet unknown underlying mechanisms. Methods and results We assessed electrophysiological and molecular alterations underlying AV-conduction abnormalities in mice carrying the Scn5a1798insD/þ mutation. Langendorff-perfused Scn5a1798insD/þ hearts showed prolonged AV-conduction compared to wild type (WT) without changes in atrial and His-ventricular (HV) conduction. The late sodium current (INa,L) inhibitor ranolazine (RAN) normalized AV-conduction in Scn5a1798insD/þ mice, likely by preventing the mutation-induced increase in intracellular sodium ([Naþ]i ) and calcium ([Ca2þ]i ) concentrations. Indeed, further enhancement of [Naþ]i and [Ca2þ]i by the Naþ/Kþ-ATPase inhibitor ouabain caused excessive increase in AV-conduction time in Scn5a1798insD/þ hearts. Scn5a1798insD/þ mice from the 129P2 strain displayed more severe AV-conduction abnormalities than FVB/N-Scn5a1798insD/þ mice, in line with their larger mutation-induced INa,L. Transverse aortic constriction (TAC) caused excessive prolongation of AV-conduction in FVB/N-Scn5a1798insD/þ mice (while HV-intervals remained unchanged), which was prevented by chronic RAN treatment. Scn5a1798insD/þTAC hearts showed decreased mRNA levels of conduction genes in the AV-nodal region, but no structural changes in the AV-node or His bundle. In Scn5a1798insD/þ-TAC mice deficient for the transcription factor Nfatc2 (effector of the calcium-calcineurin pathway), AV-conduction and conduction gene expression were restored to WT levels. Conclusions Our findings indicate a detrimental role for enhanced INa,L and consequent calcium dysregulation on AVconduction in Scn5a1798insD/þ mice, providing evidence for a functional mechanism underlying AV-conduction disturbances secondary to gain-of-function SCN5A mutations.es_ES
dc.description.sponsorshipInnovational Research Incentives Scheme Vidi grant from the Netherlands Organisation for Health Research and Development (ZonMw; 91714371 to C.A.R.); the Netherlands CardioVascular Research Initiative CVON (Dutch Heart Foundation, Dutch Federation of University Medical Centres, ZonMw, and the Royal Netherlands Academy of Sciences; projects PREDICT CVON2012-10, e-DETECT CVON2015-12, and PREDICT2 CVON2018-30 to C.R.B., T.A.B.vV, and C.A.R.); and the Dutch Heart Foundation (NHS2010/B201 to C.A.R.); the Registry for Cardio-cerebro-vascular Pathology, Veneto Region, Venice, Italy (to C.B and G.T); Veneto Region Target Research 933/2015, Venice, Italy (to C.B. and G.T.); Foundation Leducq (16CVD02 RHYTHM); CardioNeT, the EU FP7-Marie Curie-ITN actions ITN-GA2011–289600, and Juan de la Cierva-Incorporacio´n programme, from Ministerio de Ciencias, Innovacion y Universidades (Spain) grants (to A.R.V).es_ES
dc.subjectAtrio-ventricular block/conductionSCN5Aes_ES
dc.subjectLate sodium currentes_ES
dc.subjectCalcium homeostasises_ES
dc.titleFunctional modulation of atrio-ventricular conduction by enhanced late sodium current and calcium-dependent mechanisms in Scn5a1798insD/þ micees_ES
dc.description.noteThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comes_ES

Files in This Item:
1.54 MB
Adobe PDF

Statistics and impact

Items in Dadun are protected by copyright, with all rights reserved, unless otherwise indicated.