Full metadata record
DC Field | Value | Language |
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dc.creator | Rivaud, M.R. (Mathilde R.) | - |
dc.creator | Marchal, G.A. (Gerard A.) | - |
dc.creator | Wolswinkel, R. (Rianne) | - |
dc.creator | Jansen, J.A. (John A.) | - |
dc.creator | van-der-Made, I. (Ingeborg) | - |
dc.creator | Beekman, L. (Leander) | - |
dc.creator | Ruiz-Villalba, A. (Adrián) | - |
dc.creator | Baartscheer, A. (Antonius) | - |
dc.creator | Rajamani, S. (Sridharan) | - |
dc.creator | Belardinelli, L. (Luiz) | - |
dc.creator | van-Veen, T.A.B. (Toon A.B.) | - |
dc.creator | Basso, C. (Cristina) | - |
dc.creator | Thiene, G. (Gaetano) | - |
dc.creator | Creemers, E.E. (Ester E.) | - |
dc.creator | Bezzina, C.R. (Connie R.) | - |
dc.creator | Remme, C.A. (Carol Ann) | - |
dc.date.accessioned | 2023-05-23T07:23:27Z | - |
dc.date.available | 2023-05-23T07:23:27Z | - |
dc.date.issued | 2020 | - |
dc.identifier.citation | Rivaud, 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 - 1589 | es_ES |
dc.identifier.issn | 1099-5129 | - |
dc.identifier.uri | https://hdl.handle.net/10171/66321 | - |
dc.description.abstract | Aims 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.sponsorship | Innovational 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.language.iso | eng | es_ES |
dc.relation | info:eu-repo/grantAgreement/EC/FP7/289600/EU | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.subject | Atrio-ventricular block/conductionSCN5A | es_ES |
dc.subject | Mutations | es_ES |
dc.subject | NaV1.5 | es_ES |
dc.subject | Late sodium current | es_ES |
dc.subject | Calcium homeostasis | es_ES |
dc.title | Functional modulation of atrio-ventricular conduction by enhanced late sodium current and calcium-dependent mechanisms in Scn5a1798insD/þ mice | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.publisher.place | Oxford | es_ES |
dc.description.note | This 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.com | es_ES |
dc.identifier.doi | 10.1093/europace/euaa127 | - |
dadun.citation.endingPage | 1589 | es_ES |
dadun.citation.number | 10 | es_ES |
dadun.citation.publicationName | Europace | es_ES |
dadun.citation.startingPage | 1579 | es_ES |
dadun.citation.volume | 22 | es_ES |
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