Rajamani, S. (Sridharan)

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    Functional modulation of atrio-ventricular conduction by enhanced late sodium current and calcium-dependent mechanisms in Scn5a1798insD/þ mice
    (2020) Remme, C.A. (Carol Ann); Rajamani, S. (Sridharan); Rivaud, M.R. (Mathilde R.); van-Veen, T.A.B. (Toon A.B.); van-der-Made, I. (Ingeborg); Beekman, L. (Leander); Ruiz-Villalba, A. (Adrián); Belardinelli, L. (Luiz); Basso, C. (Cristina); Marchal, G.A. (Gerard A.); Wolswinkel, R. (Rianne); Creemers, E.E. (Ester E.); Baartscheer, A. (Antonius); Jansen, J.A. (John A.); Bezzina, C.R. (Connie R.); Thiene, G. (Gaetano)
    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.