Familial atrial fibrillation mutation M1875T-SCN5A increases early sodium current and dampens the effect of flecainide

Molly O'Reilly; Laura C Sommerfeld; C O'Shea; S Broadway-Stringer; S Andaleeb; J S Reyat; S N Kabir; D Stastny; A Malinova; D Delbue; L Fortmueller; K Gehmlich; D Pavlovic; B V Skryabin; A P Holmes; P Kirchhof; L Fabritz

doi:10.1093/europace/euac218

Familial atrial fibrillation mutation M1875T-SCN5A increases early sodium current and dampens the effect of flecainide

Molly O'Reilly, Laura C Sommerfeld, C O'Shea, S Broadway-Stringer, S Andaleeb, J S Reyat, S N Kabir, D Stastny, A Malinova, D Delbue, L Fortmueller, K Gehmlich, D Pavlovic, B V Skryabin, A P Holmes, P Kirchhof, L Fabritz^*

^*Corresponding author for this work

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

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Abstract

AIMS: Atrial fibrillation (AF) is the most common cardiac arrhythmia. Pathogenic variants in genes encoding ion channels are associated with familial AF. The point mutation M1875T in the SCN5A gene, which encodes the α-subunit of the cardiac sodium channel Nav1.5, has been associated with increased atrial excitability and familial AF in patients.

METHODS AND RESULTS: We designed a new murine model carrying the Scn5a-M1875T mutation enabling us to study the effects of the Nav1.5 mutation in detail in vivo and in vitro using patch clamp and microelectrode recording of atrial cardiomyocytes, optical mapping, electrocardiogram, echocardiography, gravimetry, histology, and biochemistry. Atrial cardiomyocytes from newly generated adult Scn5a-M1875T+/- mice showed a selective increase in the early (peak) cardiac sodium current, larger action potential amplitude, and a faster peak upstroke velocity. Conduction slowing caused by the sodium channel blocker flecainide was less pronounced in Scn5a-M1875T+/- compared to wildtype atria. Overt hypertrophy or heart failure in Scn5a-M1875T+/- mice could be excluded.

CONCLUSION: The Scn5a-M1875T point mutation causes gain-of-function of the cardiac sodium channel. Our results suggest increased atrial peak sodium current as a potential trigger for increased atrial excitability.

Original language	English
Article number	euac218
Journal	EP Europace
Early online date	12 Dec 2022
DOIs	https://doi.org/10.1093/europace/euac218
Publication status	E-pub ahead of print - 12 Dec 2022

Bibliographical note

Keywords

Sodium channel
Channelopathy
Atrial electrophysiology
Sodium channel blocker

Access to Document

10.1093/europace/euac218Licence: Creative Commons: Attribution (CC BY)

OReillyM2022FamilialFinal published version, 2.01 MBLicence: Creative Commons: Attribution (CC BY)

2 Active
6 Finished

Development of novel computational approaches for human cardiac mapping data - Improving understanding and treatment of atrialfibrillation
O'Shea, C. (Principal Investigator)
The Wellcome Trust
1/05/21 → 1/01/26
Project: Research
MAESTRIA: Machine Learning Artificial Intelligence Early Detection Stroke Atrial Fibrillation
Kirchhof, P. (Researcher), Gkoutos, G. (Principal Investigator) & Fabritz, L. (Researcher)
European Commission
1/03/21 → 28/02/26
Project: EU
The interactions between filamin C and small heat shock proteins in cardiac mechanosignalling
Gehmlich, K. (Principal Investigator)
Medical Research Council
1/06/21 → 30/11/24
Project: Research Councils
Defining clusters of patients with atrial fibrillation at risk of heart failure and death
Kirchhof, P. (Principal Investigator) & Gkoutos, G. (Researcher)
British Heart Foundation
1/07/20 → 30/06/21
Project: Research
The contribution of stretch-signalling pathways to the pathogenesis of Hypertrophic Cardiomyopathy
Gehmlich, K. (Principal Investigator)
British Heart Foundation
1/10/19 → 30/11/20
Project: Research
Impact of chronic intermittent hypoxia on atrial resting membrane potential and Na 1.5 channel function: A new mechanism for causing atrial fibrillation
Kirchhof, P. (Principal Investigator) & Holmes, A. (Co-Investigator)
British Heart Foundation
1/10/17 → 18/07/21
Project: Research
H2020_COLLAB_CATCH ME_(LEAD)
Kirchhof, P. (Principal Investigator), Fabritz, L. (Co-Investigator), Hemming, K. (Co-Investigator) & Deeks, J. (Co-Investigator)
European Commission
1/05/15 → 30/04/19
Project: EU

Cite this

O'Reilly, M., Sommerfeld, L. C., O'Shea, C., Broadway-Stringer, S., Andaleeb, S., Reyat, J. S., Kabir, S. N., Stastny, D., Malinova, A., Delbue, D., Fortmueller, L., Gehmlich, K., Pavlovic, D., Skryabin, B. V., Holmes, A. P., Kirchhof, P., & Fabritz, L. (2022). Familial atrial fibrillation mutation M1875T-SCN5A increases early sodium current and dampens the effect of flecainide. EP Europace, Article euac218. Advance online publication. https://doi.org/10.1093/europace/euac218

@article{f2bcd617593948cba106f15accda37db,

title = "Familial atrial fibrillation mutation M1875T-SCN5A increases early sodium current and dampens the effect of flecainide",

abstract = "AIMS: Atrial fibrillation (AF) is the most common cardiac arrhythmia. Pathogenic variants in genes encoding ion channels are associated with familial AF. The point mutation M1875T in the SCN5A gene, which encodes the α-subunit of the cardiac sodium channel Nav1.5, has been associated with increased atrial excitability and familial AF in patients.METHODS AND RESULTS: We designed a new murine model carrying the Scn5a-M1875T mutation enabling us to study the effects of the Nav1.5 mutation in detail in vivo and in vitro using patch clamp and microelectrode recording of atrial cardiomyocytes, optical mapping, electrocardiogram, echocardiography, gravimetry, histology, and biochemistry. Atrial cardiomyocytes from newly generated adult Scn5a-M1875T+/- mice showed a selective increase in the early (peak) cardiac sodium current, larger action potential amplitude, and a faster peak upstroke velocity. Conduction slowing caused by the sodium channel blocker flecainide was less pronounced in Scn5a-M1875T+/- compared to wildtype atria. Overt hypertrophy or heart failure in Scn5a-M1875T+/- mice could be excluded.CONCLUSION: The Scn5a-M1875T point mutation causes gain-of-function of the cardiac sodium channel. Our results suggest increased atrial peak sodium current as a potential trigger for increased atrial excitability.",

keywords = "Sodium channel, Channelopathy, Atrial electrophysiology, Sodium channel blocker",

author = "Molly O'Reilly and Sommerfeld, {Laura C} and C O'Shea and S Broadway-Stringer and S Andaleeb and Reyat, {J S} and Kabir, {S N} and D Stastny and A Malinova and D Delbue and L Fortmueller and K Gehmlich and D Pavlovic and Skryabin, {B V} and Holmes, {A P} and P Kirchhof and L Fabritz",

note = "{\textcopyright} The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.",

year = "2022",

month = dec,

day = "12",

doi = "10.1093/europace/euac218",

language = "English",

journal = "EP Europace",

issn = "1099-5129",

publisher = "Oxford University Press",

}

O'Reilly, M, Sommerfeld, LC, O'Shea, C , Broadway-Stringer, S, Andaleeb, S, Reyat, JS, Kabir, SN, Stastny, D, Malinova, A, Delbue, D, Fortmueller, L, Gehmlich, K , Pavlovic, D, Skryabin, BV, Holmes, AP , Kirchhof, P & Fabritz, L 2022, 'Familial atrial fibrillation mutation M1875T-SCN5A increases early sodium current and dampens the effect of flecainide', EP Europace. https://doi.org/10.1093/europace/euac218

TY - JOUR

T1 - Familial atrial fibrillation mutation M1875T-SCN5A increases early sodium current and dampens the effect of flecainide

AU - O'Reilly, Molly

AU - Sommerfeld, Laura C

AU - O'Shea, C

AU - Broadway-Stringer, S

AU - Andaleeb, S

AU - Reyat, J S

AU - Kabir, S N

AU - Stastny, D

AU - Malinova, A

AU - Delbue, D

AU - Fortmueller, L

AU - Gehmlich, K

AU - Pavlovic, D

AU - Skryabin, B V

AU - Holmes, A P

AU - Kirchhof, P

AU - Fabritz, L

PY - 2022/12/12

Y1 - 2022/12/12

N2 - AIMS: Atrial fibrillation (AF) is the most common cardiac arrhythmia. Pathogenic variants in genes encoding ion channels are associated with familial AF. The point mutation M1875T in the SCN5A gene, which encodes the α-subunit of the cardiac sodium channel Nav1.5, has been associated with increased atrial excitability and familial AF in patients.METHODS AND RESULTS: We designed a new murine model carrying the Scn5a-M1875T mutation enabling us to study the effects of the Nav1.5 mutation in detail in vivo and in vitro using patch clamp and microelectrode recording of atrial cardiomyocytes, optical mapping, electrocardiogram, echocardiography, gravimetry, histology, and biochemistry. Atrial cardiomyocytes from newly generated adult Scn5a-M1875T+/- mice showed a selective increase in the early (peak) cardiac sodium current, larger action potential amplitude, and a faster peak upstroke velocity. Conduction slowing caused by the sodium channel blocker flecainide was less pronounced in Scn5a-M1875T+/- compared to wildtype atria. Overt hypertrophy or heart failure in Scn5a-M1875T+/- mice could be excluded.CONCLUSION: The Scn5a-M1875T point mutation causes gain-of-function of the cardiac sodium channel. Our results suggest increased atrial peak sodium current as a potential trigger for increased atrial excitability.

AB - AIMS: Atrial fibrillation (AF) is the most common cardiac arrhythmia. Pathogenic variants in genes encoding ion channels are associated with familial AF. The point mutation M1875T in the SCN5A gene, which encodes the α-subunit of the cardiac sodium channel Nav1.5, has been associated with increased atrial excitability and familial AF in patients.METHODS AND RESULTS: We designed a new murine model carrying the Scn5a-M1875T mutation enabling us to study the effects of the Nav1.5 mutation in detail in vivo and in vitro using patch clamp and microelectrode recording of atrial cardiomyocytes, optical mapping, electrocardiogram, echocardiography, gravimetry, histology, and biochemistry. Atrial cardiomyocytes from newly generated adult Scn5a-M1875T+/- mice showed a selective increase in the early (peak) cardiac sodium current, larger action potential amplitude, and a faster peak upstroke velocity. Conduction slowing caused by the sodium channel blocker flecainide was less pronounced in Scn5a-M1875T+/- compared to wildtype atria. Overt hypertrophy or heart failure in Scn5a-M1875T+/- mice could be excluded.CONCLUSION: The Scn5a-M1875T point mutation causes gain-of-function of the cardiac sodium channel. Our results suggest increased atrial peak sodium current as a potential trigger for increased atrial excitability.

KW - Sodium channel

KW - Channelopathy

KW - Atrial electrophysiology

KW - Sodium channel blocker

U2 - 10.1093/europace/euac218

DO - 10.1093/europace/euac218

M3 - Article

C2 - 36504385

SN - 1099-5129

JO - EP Europace

JF - EP Europace

M1 - euac218

ER -

Familial atrial fibrillation mutation M1875T-SCN5A increases early sodium current and dampens the effect of flecainide

Abstract

Bibliographical note

Keywords

Access to Document

Fingerprint

Projects

Development of novel computational approaches for human cardiac mapping data - Improving understanding and treatment of atrialfibrillation

MAESTRIA: Machine Learning Artificial Intelligence Early Detection Stroke Atrial Fibrillation

The interactions between filamin C and small heat shock proteins in cardiac mechanosignalling

Defining clusters of patients with atrial fibrillation at risk of heart failure and death

The contribution of stretch-signalling pathways to the pathogenesis of Hypertrophic Cardiomyopathy

Impact of chronic intermittent hypoxia on atrial resting membrane potential and Na 1.5 channel function: A new mechanism for causing atrial fibrillation

H2020_COLLAB_CATCH ME_(LEAD)

Cite this