The 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

Research output: Contribution to journalArticlepeer-review


BACKGROUND: Although atrial fibrillation (AF) 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. Prior work from our group suggests that alterations in the atrial resting membrane potential (RMP) induced by low Pitx2 expression could explain the variable effect of flecainide.

OBJECTIVE: This study assessed whether alterations in the atrial/cardiac RMP modify the effectiveness of multiple clinically used AADs.

METHODS: The sodium channel blocking effects of propafenone (300nM, 1μM), flecainide (1μM) and dronedarone (5μM, 10μM) 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 the peak AP upstroke velocity. All three AADs displayed enhanced sodium channel block at more positive atrial RMPs. Dronedarone was the most sensitive to changes in the 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 post-repolarisation refractoriness in murine Langendorff-perfused Pitx2c+/- hearts, which have a more positive RMP compared to wild-type.

CONCLUSION: The 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 the atrial RMP may offer a novel approach to enhancing the effectiveness of AADs or personalizing AAD selection.

Original languageEnglish
Pages (from-to)1-37
JournalHeart Rhythm
Issue number00
Early online date16 Mar 2021
Publication statusE-pub ahead of print - 16 Mar 2021


  • resting membrane potential
  • propafenone
  • dronedarone
  • flecainide
  • atrial fibrillation
  • PITX2
  • atrial action potential


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