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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, Vol. 18, No. 7, 07.2021, p. 1212-1220.

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

Harvard

Holmes, AP, Saxena, P, Kabir, SN, O'Shea, C, Kuhlmann, SM, Gupta, S, Fobian, D, Apicella, C, O'Reilly, M, Syeda, F, Reyat, JS, Smith, GL, Workman, AJ, Pavlovic, D, Fabritz, L & Kirchhof, P 2021, 'Atrial resting membrane potential confers sodium current sensitivity to propafenone, flecainide and dronedarone', HEART RHYTHM, vol. 18, no. 7, pp. 1212-1220. https://doi.org/10.1016/j.hrthm.2021.03.016

APA

Holmes, A. P., Saxena, P., Kabir, S. N., O'Shea, C., Kuhlmann, S. M., Gupta, S., Fobian, D., Apicella, C., O'Reilly, M., Syeda, F., Reyat, J. S., Smith, G. L., Workman, A. J., Pavlovic, D., Fabritz, L., & Kirchhof, P. (2021). Atrial resting membrane potential confers sodium current sensitivity to propafenone, flecainide and dronedarone. HEART RHYTHM, 18(7), 1212-1220. https://doi.org/10.1016/j.hrthm.2021.03.016

Vancouver

Holmes AP, Saxena P, Kabir SN, O'Shea C, Kuhlmann SM, Gupta S et al. Atrial resting membrane potential confers sodium current sensitivity to propafenone, flecainide and dronedarone. HEART RHYTHM. 2021 Jul;18(7):1212-1220. https://doi.org/10.1016/j.hrthm.2021.03.016

Bibtex

@article{82ee89edf6ab4834b7b72efe02e724c2,
title = "Atrial resting membrane potential confers sodium current sensitivity to propafenone, flecainide and dronedarone",
abstract = "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.",
keywords = "Action Potentials/drug effects, Animals, Anti-Arrhythmia Agents/therapeutic use, Atrial Fibrillation/drug therapy, Disease Models, Animal, Dronedarone/therapeutic use, Female, Flecainide/therapeutic use, Heart Atria/metabolism, Male, Membrane Potentials/drug effects, Mice, Propafenone/therapeutic use, Sodium/metabolism, Voltage-Gated Sodium Channel Blockers/therapeutic use",
author = "Holmes, {Andrew P} and Priyanka Saxena and Kabir, {S Nashitha} and Christopher O'Shea and Kuhlmann, {Stefan M} and Suranjana Gupta and Dannie Fobian and Clara Apicella and Molly O'Reilly and Fahima Syeda and Reyat, {Jasmeet S} and Smith, {Godfrey L} and Workman, {Antony J} and Davor Pavlovic and Larissa Fabritz and Paulus Kirchhof",
note = "Copyright {\textcopyright} 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.",
year = "2021",
month = jul,
doi = "10.1016/j.hrthm.2021.03.016",
language = "English",
volume = "18",
pages = "1212--1220",
journal = "HEART RHYTHM",
issn = "1547-5271",
publisher = "Elsevier",
number = "7",

}

RIS

TY - JOUR

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 -