Increased atrial effectiveness of flecainide conferred by altered biophysical properties of sodium channels
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Increased atrial effectiveness of flecainide conferred by altered biophysical properties of sodium channels. / O' Brien, Sian; Holmes, Andrew P; Johnson, Daniel M; Kabir, S Nashitha; O' Shea, Christopher; O' Reilly, Molly; Avezzu, Adelisa; Reyat, Jasmeet S; Hall, Amelia W; Apicella, Clara; Ellinor, Patrick T; Niederer, Steven; Tucker, Nathan R; Fabritz, Larissa; Kirchhof, Paulus; Pavlovic, Davor.
in: J MOL CELL CARDIOL, Jahrgang 166, 05.2022, S. 23-35.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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
N1 - Copyright © 2022 Elsevier Ltd. All rights reserved.
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 - Action Potentials
KW - Aged
KW - Anti-Arrhythmia Agents/pharmacology
KW - Atrial Fibrillation/metabolism
KW - Flecainide/metabolism
KW - Heart Atria/metabolism
KW - Humans
KW - Sodium/metabolism
KW - Sodium Channel Blockers/pharmacology
KW - Sodium Channels/metabolism
U2 - 10.1016/j.yjmcc.2022.01.009
DO - 10.1016/j.yjmcc.2022.01.009
M3 - SCORING: Journal article
C2 - 35114252
VL - 166
SP - 23
EP - 35
JO - J MOL CELL CARDIOL
JF - J MOL CELL CARDIOL
SN - 0022-2828
ER -