Increased atrial effectiveness of flecainide conferred by altered biophysical properties of sodium channels

Sian-Marie O'Brien; Andy Holmes; Daniel Johnson; Syeeda Nashitha Kabir; Christopher O'Shea; Molly O'Reilly; Adelisa Avezzu; Jasmeet Reyat; Amelia W. Hall; Clara Apicella; Patrick T.  Ellinor; Steven Niederer; Nathan R.  Tucker; Larissa Fabritz; Paulus Kirchhof; Davor Pavlovic

doi:10.1016/j.yjmcc.2022.01.009

Increased atrial effectiveness of flecainide conferred by altered biophysical properties of sodium channels

Sian-Marie O'Brien, Andy Holmes, Daniel Johnson, Syeeda Nashitha Kabir, Christopher O'Shea, Molly O'Reilly, Adelisa Avezzu, Jasmeet Reyat, Amelia W. Hall, Clara Apicella, Patrick T. Ellinor, Steven Niederer, Nathan R. Tucker, Larissa Fabritz, Paulus Kirchhof, Davor Pavlovic

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Abstract

Atrial fibrillation (AF) affects over 1% of the population and is a leading cause of stroke and heart failure in the elderly. A feared side effect of sodium channel blocker therapy, ventricular pro-arrhythmia, appears to be relatively rare in patients with AF. The biophysical reasons for this relative safety of sodium blockers are not known.

Our data demonstrates intrinsic differences between atrial and ventricular cardiac voltage-gated sodium currents (INa), leading to reduced maximum upstroke velocity of action potential and slower conduction, in left atria compared to ventricle. Reduced atrial INa is only detected at physiological membrane potentials and is driven by alterations in sodium channel biophysical properties and not by NaV1.5 protein expression. Flecainide displayed greater inhibition of atrial INa, greater reduction of maximum upstroke velocity of action potential, and slowed conduction in atrial cells and tissue.

Our work highlights differences in biophysical properties of sodium channels in left atria and ventricles and their response to flecainide. These differences can explain the relative safety of sodium channel blocker therapy in patients with atrial fibrillation.

Original language	English
Pages (from-to)	23-35
Number of pages	13
Journal	Journal of Molecular and Cellular Cardiology
Volume	166
Early online date	1 Feb 2022
DOIs	https://doi.org/10.1016/j.yjmcc.2022.01.009
Publication status	Published - May 2022

Keywords

Atria
Conduction
Flecainide
Sodium channels
Ventricles

ASJC Scopus subject areas

Molecular Biology
Cardiology and Cardiovascular Medicine

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10.1016/j.yjmcc.2022.01.009Licence: Creative Commons: Attribution (CC BY)

1-s2.0-S0022282822000207-mainFinal published version, 7.08 MBLicence: Creative Commons: Attribution (CC BY)

Cardiotonic steroids in patients with atrial fibrillation and heart failure: Quantification, functional effects and personalisation of digoxin therapy
Arlt, W., Pavlovic, D., Taylor, A., Kotecha, D. & Kirchhof, P.
British Heart Foundation
1/06/18 → 30/05/21
Project: Research

Cite this

O'Brien, S.-M., Holmes, A., Johnson, D., Kabir, S. N., O'Shea, C., O'Reilly, M., Avezzu, A., Reyat, J., Hall, A. W., Apicella, C., Ellinor, P. T., Niederer, S., Tucker, N. R., Fabritz, L., Kirchhof, P., & Pavlovic, D. (2022). Increased atrial effectiveness of flecainide conferred by altered biophysical properties of sodium channels. Journal of Molecular and Cellular Cardiology, 166, 23-35. https://doi.org/10.1016/j.yjmcc.2022.01.009

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title = "Increased atrial effectiveness of flecainide conferred by altered biophysical properties of sodium channels",

abstract = "Atrial fibrillation (AF) affects over 1% of the population and is a leading cause of stroke and heart failure in the elderly. A feared side effect of sodium channel blocker therapy, ventricular pro-arrhythmia, appears to be relatively rare in patients with AF. The biophysical reasons for this relative safety of sodium blockers are not known.Our data demonstrates intrinsic differences between atrial and ventricular cardiac voltage-gated sodium currents (INa), leading to reduced maximum upstroke velocity of action potential and slower conduction, in left atria compared to ventricle. Reduced atrial INa is only detected at physiological membrane potentials and is driven by alterations in sodium channel biophysical properties and not by NaV1.5 protein expression. Flecainide displayed greater inhibition of atrial INa, greater reduction of maximum upstroke velocity of action potential, and slowed conduction in atrial cells and tissue.Our work highlights differences in biophysical properties of sodium channels in left atria and ventricles and their response to flecainide. These differences can explain the relative safety of sodium channel blocker therapy in patients with atrial fibrillation.",

keywords = "Atria, Conduction, Flecainide, Sodium channels, Ventricles",

author = "Sian-Marie O'Brien and Andy Holmes and Daniel Johnson and Kabir, {Syeeda Nashitha} and Christopher O'Shea and Molly O'Reilly and Adelisa Avezzu and Jasmeet Reyat and Hall, {Amelia W.} and Clara Apicella and Ellinor, {Patrick T.} and Steven Niederer and Tucker, {Nathan R.} and Larissa Fabritz and Paulus Kirchhof and Davor Pavlovic",

year = "2022",

month = may,

doi = "10.1016/j.yjmcc.2022.01.009",

language = "English",

volume = "166",

pages = "23--35",

journal = "Journal of Molecular and Cellular Cardiology",

issn = "0022-2828",

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O'Brien, S-M, Holmes, A, Johnson, D, Kabir, SN, O'Shea, C, O'Reilly, M, Avezzu, A, Reyat, J, Hall, AW, Apicella, C, Ellinor, PT, Niederer, S, Tucker, NR, Fabritz, L , Kirchhof, P & Pavlovic, D 2022, 'Increased atrial effectiveness of flecainide conferred by altered biophysical properties of sodium channels', Journal of Molecular and Cellular Cardiology, vol. 166, pp. 23-35. https://doi.org/10.1016/j.yjmcc.2022.01.009

TY - JOUR

T1 - Increased atrial effectiveness of flecainide conferred by altered biophysical properties of sodium channels

AU - O'Brien, Sian-Marie

AU - Holmes, Andy

AU - Johnson, Daniel

AU - Kabir, Syeeda Nashitha

AU - O'Shea, Christopher

AU - O'Reilly, Molly

AU - Avezzu, Adelisa

AU - Reyat, Jasmeet

AU - Hall, Amelia W.

AU - Apicella, Clara

AU - Ellinor, Patrick T.

AU - Niederer, Steven

AU - Tucker, Nathan R.

AU - Fabritz, Larissa

AU - Kirchhof, Paulus

AU - Pavlovic, Davor

PY - 2022/5

Y1 - 2022/5

N2 - Atrial fibrillation (AF) affects over 1% of the population and is a leading cause of stroke and heart failure in the elderly. A feared side effect of sodium channel blocker therapy, ventricular pro-arrhythmia, appears to be relatively rare in patients with AF. The biophysical reasons for this relative safety of sodium blockers are not known.Our data demonstrates intrinsic differences between atrial and ventricular cardiac voltage-gated sodium currents (INa), leading to reduced maximum upstroke velocity of action potential and slower conduction, in left atria compared to ventricle. Reduced atrial INa is only detected at physiological membrane potentials and is driven by alterations in sodium channel biophysical properties and not by NaV1.5 protein expression. Flecainide displayed greater inhibition of atrial INa, greater reduction of maximum upstroke velocity of action potential, and slowed conduction in atrial cells and tissue.Our work highlights differences in biophysical properties of sodium channels in left atria and ventricles and their response to flecainide. These differences can explain the relative safety of sodium channel blocker therapy in patients with atrial fibrillation.

AB - Atrial fibrillation (AF) affects over 1% of the population and is a leading cause of stroke and heart failure in the elderly. A feared side effect of sodium channel blocker therapy, ventricular pro-arrhythmia, appears to be relatively rare in patients with AF. The biophysical reasons for this relative safety of sodium blockers are not known.Our data demonstrates intrinsic differences between atrial and ventricular cardiac voltage-gated sodium currents (INa), leading to reduced maximum upstroke velocity of action potential and slower conduction, in left atria compared to ventricle. Reduced atrial INa is only detected at physiological membrane potentials and is driven by alterations in sodium channel biophysical properties and not by NaV1.5 protein expression. Flecainide displayed greater inhibition of atrial INa, greater reduction of maximum upstroke velocity of action potential, and slowed conduction in atrial cells and tissue.Our work highlights differences in biophysical properties of sodium channels in left atria and ventricles and their response to flecainide. These differences can explain the relative safety of sodium channel blocker therapy in patients with atrial fibrillation.

KW - Atria

KW - Conduction

KW - Flecainide

KW - Sodium channels

KW - Ventricles

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U2 - 10.1016/j.yjmcc.2022.01.009

DO - 10.1016/j.yjmcc.2022.01.009

M3 - Article

C2 - 35114252

SN - 0022-2828

VL - 166

SP - 23

EP - 35

JO - Journal of Molecular and Cellular Cardiology

JF - Journal of Molecular and Cellular Cardiology

ER -

Increased atrial effectiveness of flecainide conferred by altered biophysical properties of sodium channels

Abstract

Keywords

ASJC Scopus subject areas

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Cardiotonic steroids in patients with atrial fibrillation and heart failure: Quantification, functional effects and personalisation of digoxin therapy

Cite this