Atrial resting membrane potential confers sodium current sensitivity to propafenone, flecainide and dronedarone

Andrew P. Holmes*, Priyanka Saxena, S. Nashitha Kabir, Christopher O'Shea, Stefan M Kuhlmann, Suranjana Gupta, Dannie Fobian, Clara Apicella, Molly O'Reilly, Fahima Syeda, Jasmeet S Reyat, Godfrey L Smith, Antony J Workman, Davor Pavlovic, Larissa Fabritz, Paulus Kirchhof

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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 Na V1.5, primary murine atrial cardiac myocytes, and murine hearts with reduced Pitx2c.

Results: A more positive atrial RMP delayed I Na 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.

Original languageEnglish
Pages (from-to)1212-1220
Number of pages9
JournalHeart Rhythm
Volume18
Issue number7
Early online date16 Mar 2021
DOIs
Publication statusPublished - Jul 2021

Bibliographical note

Funding Information:
Funding sources: This work was supported by a Medical Research Council Confidence in Concept Award to Dr Holmes, Professor Kirchhof, and Dr Syeda; the European Union (Grant Agreement No. 633196 [CATCH ME]) to Professors Kirchhof and Fabritz; the British Heart Foundation (PG/17/30/32961 to Professor Kirchhof and Dr Holmes; FS/13/43/30324 and AA/18/2/34218 to Professors Kirchhof and Fabritz; PG/20/22/35093 to Professor Kirchhof; PG/17/55/33087, RG/17/15/33106, FS/19/12/34204, and FS/19/16/34169 to Dr Pavlovic; PG/16/42/32142 to Dr Workman and Professor Smith); a Wellcome Trust Seed Award Grant (109604/Z/15/Z) to Dr Pavlovic; the German Centre for Cardiovascular Research supported by the German Ministry of Education and Research (DZHK) via a grant to AFNET to Professor Kirchhof; the Leducq Foundation to Professor Kirchhof; and the University of Birmingham India Institute Fellowship scheme to Dr Gupta. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director, NIH and NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Disclosures: Professor Kirchhof receives support from several drug and device companies active in atrial fibrillation; and has received honoraria from several such companies but independent of the current work. Professor Fabritz has received institutional research grants and nonfinancial support from European Union, British Heart Foundation, Medical Research Council (UK), and several biomedical companies. Professors Kirchhof, Fabritz, and Dr Syeda are listed as inventors on 2 patents held by the University of Birmingham (WO 2015140571, WO 2016012783). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Publisher Copyright:
© 2021 Heart Rhythm Society

Keywords

  • resting membrane potential
  • propafenone
  • dronedarone
  • flecainide
  • atrial fibrillation
  • PITX2
  • atrial action potential
  • Atrial action potential
  • Atrial fibrillation
  • Dronedarone
  • Resting membrane potential
  • Flecainide
  • Propafenone

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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