2026-05-31T06:54:31Zhttps://riuma.uma.es/rest/oai/request

oai:riuma.uma.es:10630/337022026-02-03T11:23:24Zcom_10630_2254col_10630_37953

Rivaud, Mathilde R Marchal, Gerard A Wolswinkel, Rianne Jansen, John A van der Made, Ingeborg Beekman, Leander Ruiz-Villalba, Adrián Baartscheer, Antonius Rajamani, Sridharan Belardinelli, Luiz van Veen, Toon A B Basso, Cristina Thiene, Gaetano Creemers, Esther E Bezzina, Connie R Remme, Carol Ann 2024-09-27T11:08:28Z 2024-09-27T11:08:28Z 2020 https://hdl.handle.net/10630/33702 10.1093/europace/euaa127 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. Methods/Results: We assessed electrophysiological and molecular alterations underlying AV-conduction abnormalities in mice carrying the Scn5a1798insD/+ mutation (mutants). Langendorff-perfused mutants 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 mutants mice, likely by preventing the mutation-induced increase in intracellular sodium ([Na+]i) and calcium ([Ca2+]i) concentrations. Indeed, further enhancement of [Na+]i and [Ca2+]i by the Na+/K+-ATPase inhibitor ouabain caused excessive increase in AV-conduction time in mutants hearts. Mutants mice from the 129P2 strain displayed more severe AV-conduction abnormalities than FVB/N-mutants mice, in line with their larger mutation-induced INa,L. Transverse aortic constriction (TAC) caused excessive prolongation of AV-conduction in FVB/N-Scn5a1798insD/+ mice (while HV-intervals remained unchanged), which was prevented by chronic RAN treatment. Mutants-TAC 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 mutants-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 AV-conduction in Scn5a1798insD/+ mice, providing evidence for a functional mechanism underlying AV-conduction disturbances secondary to gain-of-function SCN5A mutations. eng open access Functional modulation of atrio-ventricular conduction by enhanced late sodium current and calcium-dependent mechanisms in Scn5a1798insD/+ mice journal article