Atrial resting membrane potential confers sodium current sensitivity to propafenone, flecainide and dronedarone
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Atrial resting membrane potential confers sodium current sensitivity to propafenone, flecainide and dronedarone. / Holmes, Andrew P; Saxena, Priyanka; Kabir, S Nashitha; O'Shea, Christopher; Kuhlmann, Stefan M; Gupta, Suranjana; Fobian, Dannie; Apicella, Clara; O'Reilly, Molly; Syeda, Fahima; Reyat, Jasmeet S; Smith, Godfrey L; Workman, Antony J; Pavlovic, Davor; Fabritz, Larissa; Kirchhof, Paulus.
in: HEART RHYTHM, Jahrgang 18, Nr. 7, 07.2021, S. 1212-1220.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Atrial resting membrane potential confers sodium current sensitivity to propafenone, flecainide and dronedarone
AU - Holmes, Andrew P
AU - Saxena, Priyanka
AU - Kabir, S Nashitha
AU - O'Shea, Christopher
AU - Kuhlmann, Stefan M
AU - Gupta, Suranjana
AU - Fobian, Dannie
AU - Apicella, Clara
AU - O'Reilly, Molly
AU - Syeda, Fahima
AU - Reyat, Jasmeet S
AU - Smith, Godfrey L
AU - Workman, Antony J
AU - Pavlovic, Davor
AU - Fabritz, Larissa
AU - Kirchhof, Paulus
N1 - Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
PY - 2021/7
Y1 - 2021/7
N2 - BACKGROUND: Although atrial fibrillation ablation is increasingly used for rhythm control therapy, antiarrhythmic drugs (AADs) are commonly used, either alone or in combination with ablation. The effectiveness of AADs is highly variable. Previous work from our group suggests that alterations in atrial resting membrane potential (RMP) induced by low Pitx2 expression could explain the variable effect of flecainide.OBJECTIVE: The purpose of this study was to assess whether alterations in atrial/cardiac RMP modify the effectiveness of multiple clinically used AADs.METHODS: The sodium channel blocking effects of propafenone (300 nM, 1 μM), flecainide (1 μM), and dronedarone (5 μM, 10 μM) were measured in human stem cell-derived cardiac myocytes, HEK293 expressing human NaV1.5, primary murine atrial cardiac myocytes, and murine hearts with reduced Pitx2c.RESULTS: A more positive atrial RMP delayed INa recovery, slowed channel inactivation, and decreased peak action potential (AP) upstroke velocity. All 3 AADs displayed enhanced sodium channel block at more positive atrial RMPs. Dronedarone was the most sensitive to changes in atrial RMP. Dronedarone caused greater reductions in AP amplitude and peak AP upstroke velocity at more positive RMPs. Dronedarone evoked greater prolongation of the atrial effective refractory period and postrepolarization refractoriness in murine Langendorff-perfused Pitx2c+/- hearts, which have a more positive RMP compared to wild type.CONCLUSION: Atrial RMP modifies the effectiveness of several clinically used AADs. Dronedarone is more sensitive to changes in atrial RMP than flecainide or propafenone. Identifying and modifying atrial RMP may offer a novel approach to enhancing the effectiveness of AADs or personalizing AAD selection.
AB - BACKGROUND: Although atrial fibrillation ablation is increasingly used for rhythm control therapy, antiarrhythmic drugs (AADs) are commonly used, either alone or in combination with ablation. The effectiveness of AADs is highly variable. Previous work from our group suggests that alterations in atrial resting membrane potential (RMP) induced by low Pitx2 expression could explain the variable effect of flecainide.OBJECTIVE: The purpose of this study was to assess whether alterations in atrial/cardiac RMP modify the effectiveness of multiple clinically used AADs.METHODS: The sodium channel blocking effects of propafenone (300 nM, 1 μM), flecainide (1 μM), and dronedarone (5 μM, 10 μM) were measured in human stem cell-derived cardiac myocytes, HEK293 expressing human NaV1.5, primary murine atrial cardiac myocytes, and murine hearts with reduced Pitx2c.RESULTS: A more positive atrial RMP delayed INa recovery, slowed channel inactivation, and decreased peak action potential (AP) upstroke velocity. All 3 AADs displayed enhanced sodium channel block at more positive atrial RMPs. Dronedarone was the most sensitive to changes in atrial RMP. Dronedarone caused greater reductions in AP amplitude and peak AP upstroke velocity at more positive RMPs. Dronedarone evoked greater prolongation of the atrial effective refractory period and postrepolarization refractoriness in murine Langendorff-perfused Pitx2c+/- hearts, which have a more positive RMP compared to wild type.CONCLUSION: Atrial RMP modifies the effectiveness of several clinically used AADs. Dronedarone is more sensitive to changes in atrial RMP than flecainide or propafenone. Identifying and modifying atrial RMP may offer a novel approach to enhancing the effectiveness of AADs or personalizing AAD selection.
KW - Action Potentials/drug effects
KW - Animals
KW - Anti-Arrhythmia Agents/therapeutic use
KW - Atrial Fibrillation/drug therapy
KW - Disease Models, Animal
KW - Dronedarone/therapeutic use
KW - Female
KW - Flecainide/therapeutic use
KW - Heart Atria/metabolism
KW - Male
KW - Membrane Potentials/drug effects
KW - Mice
KW - Propafenone/therapeutic use
KW - Sodium/metabolism
KW - Voltage-Gated Sodium Channel Blockers/therapeutic use
U2 - 10.1016/j.hrthm.2021.03.016
DO - 10.1016/j.hrthm.2021.03.016
M3 - SCORING: Journal article
C2 - 33737232
VL - 18
SP - 1212
EP - 1220
JO - HEART RHYTHM
JF - HEART RHYTHM
SN - 1547-5271
IS - 7
ER -