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

Sian O' Brien; Andrew P. Holmes; Daniel M. Johnson; S. Nashitha Kabir; Christopher O' Shea; Molly O' Reilly; Adelisa Avezzu; Jasmeet S. 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 O' Brien, Andrew P. Holmes, Daniel M. Johnson, S. Nashitha Kabir, Christopher O' Shea, Molly O' Reilly, Adelisa Avezzu, Jasmeet S. Reyat, Amelia W. Hall, Clara Apicella, Patrick T. Ellinor, Steven Niederer, Nathan R. Tucker, Larissa Fabritz, Paulus Kirchhof, Davor Pavlovic^*

^*Corresponding author for this work

Biomedical Engineering Department

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

14 Citations (Scopus)

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 (I_Na), leading to reduced maximum upstroke velocity of action potential and slower conduction, in left atria compared to ventricle. Reduced atrial I_Na is only detected at physiological membrane potentials and is driven by alterations in sodium channel biophysical properties and not by Na_V1.5 protein expression. Flecainide displayed greater inhibition of atrial I_Na, 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
DOIs	https://doi.org/10.1016/j.yjmcc.2022.01.009
Publication status	Published - May 2022

Keywords

Atria
Conduction
Flecainide
Sodium channels
Ventricles

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.yjmcc.2022.01.009

Cite this

O' Brien, S., Holmes, A. P., Johnson, D. M., Kabir, S. N., O' Shea, C., O' Reilly, M., Avezzu, A., Reyat, J. S., 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

@article{9aa04c10e14c45d2a8a27662e4660f5d,

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 = "{O' Brien}, Sian and Holmes, {Andrew P.} and Johnson, {Daniel M.} and Kabir, {S. Nashitha} and {O' Shea}, Christopher and {O' Reilly}, Molly and Adelisa Avezzu and Reyat, {Jasmeet S.} 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",

note = "Publisher Copyright: {\textcopyright} 2022 Elsevier Ltd",

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",

publisher = "ACADEMIC PRESS INC",

}

O' Brien, S, Holmes, AP, Johnson, DM, Kabir, SN, O' Shea, C, O' Reilly, M, Avezzu, A, Reyat, JS, 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

AU - Holmes, Andrew P.

AU - Johnson, Daniel M.

AU - Kabir, S. Nashitha

AU - O' Shea, Christopher

AU - O' Reilly, Molly

AU - Avezzu, Adelisa

AU - Reyat, Jasmeet S.

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

UR - http://www.scopus.com/inward/record.url?scp=85124236806&partnerID=8YFLogxK

U2 - 10.1016/j.yjmcc.2022.01.009

DO - 10.1016/j.yjmcc.2022.01.009

M3 - Article

C2 - 35114252

AN - SCOPUS:85124236806

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

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this