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

Standard

Familial atrial fibrillation mutation M1875T-SCN5A increases early sodium current and dampens the effect of flecainide. / O’Reilly, Molly; Sommerfeld, Laura 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.

In: EUROPACE, Vol. 25, No. 3, 30.03.2023, p. 1152-1161.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

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 2023, 'Familial atrial fibrillation mutation M1875T-SCN5A increases early sodium current and dampens the effect of flecainide', EUROPACE, vol. 25, no. 3, pp. 1152-1161. https://doi.org/10.1093/europace/euac218

APA

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. (2023). Familial atrial fibrillation mutation M1875T-SCN5A increases early sodium current and dampens the effect of flecainide. EUROPACE, 25(3), 1152-1161. https://doi.org/10.1093/europace/euac218

Vancouver

O’Reilly M, Sommerfeld LC, O’Shea C, Broadway-Stringer S, Andaleeb S, Reyat JS et al. Familial atrial fibrillation mutation M1875T-SCN5A increases early sodium current and dampens the effect of flecainide. EUROPACE. 2023 Mar 30;25(3):1152-1161. https://doi.org/10.1093/europace/euac218

Bibtex

@article{d283ce7fe9c5439588a0110a70028a25,
title = "Familial atrial fibrillation mutation M1875T-SCN5A increases early sodium current and dampens the effect of flecainide",
abstract = "AimsAtrial 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 resultsWe 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.ConclusionThe 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.",
author = "Molly O{\textquoteright}Reilly and Sommerfeld, {Laura C} and C O{\textquoteright}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",
year = "2023",
month = mar,
day = "30",
doi = "10.1093/europace/euac218",
language = "English",
volume = "25",
pages = "1152--1161",
journal = "EUROPACE",
issn = "1099-5129",
publisher = "Oxford University Press",
number = "3",

}

RIS

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 - 2023/3/30

Y1 - 2023/3/30

N2 - AimsAtrial 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 resultsWe 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.ConclusionThe 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 - AimsAtrial 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 resultsWe 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.ConclusionThe 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.

U2 - 10.1093/europace/euac218

DO - 10.1093/europace/euac218

M3 - SCORING: Journal article

C2 - 36504385

VL - 25

SP - 1152

EP - 1161

JO - EUROPACE

JF - EUROPACE

SN - 1099-5129

IS - 3

ER -