Functional modulation of atrio-ventricular conduction by enhanced late sodium current and calcium-dependent mechanisms in Scn5a1798insD/+ mice

Mathilde R Rivaud; Gerard A Marchal; Rianne Wolswinkel; John A Jansen; Ingeborg van der Made; Leander Beekman; Adrián Ruiz-Villalba; Antonius Baartscheer; Sridharan Rajamani; Luiz Belardinelli; Toon A B van Veen; Cristina Basso; Gaetano Thiene; Esther E Creemers; Connie R Bezzina; Carol Ann Remme

doi:10.1093/europace/euaa127

Functional modulation of atrio-ventricular conduction by enhanced late sodium current and calcium-dependent mechanisms in Scn5a1798insD/+ mice

Mathilde R Rivaud, Gerard A Marchal, Rianne Wolswinkel, John A Jansen, Ingeborg van der Made, Leander Beekman, Adrián Ruiz-Villalba, Antonius Baartscheer, Sridharan Rajamani, Luiz Belardinelli, Toon A B van Veen, Cristina Basso, Gaetano Thiene, Esther E Creemers, Connie R Bezzina, Carol Ann Remme

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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/+ mutation. Langendorff-perfused Scn5a1798insD/+ 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/+ 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 Scn5a1798insD/+ hearts. Scn5a1798insD/+ mice from the 129P2 strain displayed more severe AV-conduction abnormalities than FVB/N-Scn5a1798insD/+ 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. Scn5a1798insD/+-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 Scn5a1798insD/+-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.

Original language	English
Pages (from-to)	1579-1589
Number of pages	11
Journal	Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology
Volume	22
Issue number	10
DOIs	https://doi.org/10.1093/europace/euaa127
Publication status	Published - 1 Oct 2020

Keywords

Atrio-ventricular block/conductionSCN5A
Calcium homeostasis
Late sodium current
mutations
Na 1.5

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Rivaud, M. R., Marchal, G. A., Wolswinkel, R., Jansen, J. A., van der Made, I., Beekman, L., Ruiz-Villalba, A., Baartscheer, A., Rajamani, S., Belardinelli, L., van Veen, T. A. B., Basso, C., Thiene, G., Creemers, E. E., Bezzina, C. R., & Remme, C. A. (2020). Functional modulation of atrio-ventricular conduction by enhanced late sodium current and calcium-dependent mechanisms in Scn5a1798insD/+ mice. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology, 22(10), 1579-1589. https://doi.org/10.1093/europace/euaa127

Rivaud, Mathilde R ; Marchal, Gerard A ; Wolswinkel, Rianne et al. / Functional modulation of atrio-ventricular conduction by enhanced late sodium current and calcium-dependent mechanisms in Scn5a1798insD/+ mice. In: Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2020 ; Vol. 22, No. 10. pp. 1579-1589.

@article{98fc464dbb28407387237bd56f6dd4c3,

title = "Functional modulation of atrio-ventricular conduction by enhanced late sodium current and calcium-dependent mechanisms in Scn5a1798insD/+ mice",

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/+ mutation. Langendorff-perfused Scn5a1798insD/+ 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/+ 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 Scn5a1798insD/+ hearts. Scn5a1798insD/+ mice from the 129P2 strain displayed more severe AV-conduction abnormalities than FVB/N-Scn5a1798insD/+ 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. Scn5a1798insD/+-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 Scn5a1798insD/+-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.",

keywords = "Atrio-ventricular block/conductionSCN5A, Calcium homeostasis, Late sodium current, mutations, Na 1.5",

author = "Rivaud, {Mathilde R} and Marchal, {Gerard A} and Rianne Wolswinkel and Jansen, {John A} and {van der Made}, Ingeborg and Leander Beekman and Adri{\'a}n Ruiz-Villalba and Antonius Baartscheer and Sridharan Rajamani and Luiz Belardinelli and {van Veen}, {Toon A B} and Cristina Basso and Gaetano Thiene and Creemers, {Esther E} and Bezzina, {Connie R} and Remme, {Carol Ann}",

note = "Publisher Copyright: {\textcopyright} 2020 The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2020",

month = oct,

day = "1",

doi = "10.1093/europace/euaa127",

language = "English",

volume = "22",

pages = "1579--1589",

number = "10",

}

Rivaud, MR, Marchal, GA, Wolswinkel, R, Jansen, JA, van der Made, I, Beekman, L, Ruiz-Villalba, A, Baartscheer, A, Rajamani, S, Belardinelli, L, van Veen, TAB, Basso, C, Thiene, G, Creemers, EE, Bezzina, CR & Remme, CA 2020, 'Functional modulation of atrio-ventricular conduction by enhanced late sodium current and calcium-dependent mechanisms in Scn5a1798insD/+ mice', Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology, vol. 22, no. 10, pp. 1579-1589. https://doi.org/10.1093/europace/euaa127

Functional modulation of atrio-ventricular conduction by enhanced late sodium current and calcium-dependent mechanisms in Scn5a1798insD/+ mice. / Rivaud, Mathilde R; Marchal, Gerard A; Wolswinkel, Rianne et al.
In: Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology, Vol. 22, No. 10, 01.10.2020, p. 1579-1589.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Functional modulation of atrio-ventricular conduction by enhanced late sodium current and calcium-dependent mechanisms in Scn5a1798insD/+ mice

AU - Rivaud, Mathilde R

AU - Marchal, Gerard A

AU - Wolswinkel, Rianne

AU - Jansen, John A

AU - van der Made, Ingeborg

AU - Beekman, Leander

AU - Ruiz-Villalba, Adrián

AU - Baartscheer, Antonius

AU - Rajamani, Sridharan

AU - Belardinelli, Luiz

AU - van Veen, Toon A B

AU - Basso, Cristina

AU - Thiene, Gaetano

AU - Creemers, Esther E

AU - Bezzina, Connie R

AU - Remme, Carol Ann

PY - 2020/10/1

Y1 - 2020/10/1

N2 - 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/+ mutation. Langendorff-perfused Scn5a1798insD/+ 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/+ 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 Scn5a1798insD/+ hearts. Scn5a1798insD/+ mice from the 129P2 strain displayed more severe AV-conduction abnormalities than FVB/N-Scn5a1798insD/+ 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. Scn5a1798insD/+-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 Scn5a1798insD/+-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.

AB - 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/+ mutation. Langendorff-perfused Scn5a1798insD/+ 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/+ 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 Scn5a1798insD/+ hearts. Scn5a1798insD/+ mice from the 129P2 strain displayed more severe AV-conduction abnormalities than FVB/N-Scn5a1798insD/+ 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. Scn5a1798insD/+-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 Scn5a1798insD/+-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.

KW - Atrio-ventricular block/conductionSCN5A

KW - Calcium homeostasis

KW - Late sodium current

KW - mutations

KW - Na 1.5

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U2 - 10.1093/europace/euaa127

DO - 10.1093/europace/euaa127

M3 - Article

C2 - 32778883

SN - 1099-5129

VL - 22

SP - 1579

EP - 1589

JO - Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology

JF - Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology

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Rivaud MR, Marchal GA, Wolswinkel R, Jansen JA, van der Made I, Beekman L et al. Functional modulation of atrio-ventricular conduction by enhanced late sodium current and calcium-dependent mechanisms in Scn5a1798insD/+ mice. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2020 Oct 1;22(10):1579-1589. doi: 10.1093/europace/euaa127

Functional modulation of atrio-ventricular conduction by enhanced late sodium current and calcium-dependent mechanisms in Scn5a1798insD/+ mice

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