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

Holmes, A. P. et al. (2021) The atrial resting membrane potential confers sodium current sensitivity to propafenone, flecainide and dronedarone. Heart Rhythm, 18(7), pp. 1212-1220. (doi: 10.1016/j.hrthm.2021.03.016) (PMID:33737232)

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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.

Item Type:Articles
Additional Information:This work was supported by a Medical Research Council Confidence in Concept Award to APH, PK and FS; and the European Union [grant agreement No 633196 [CATCH ME] to PK and LF]; and the British Heart Foundation [PG/17/30/32961 to PK and APH, FS/13/43/30324 to PK and LF, AA/18/2/34218 to PK and LF, PG/20/22/35093 to PK, PG/17/55/33087 to DP, RG/17/15/33106 to DP, FS/19/12/34204 to DP, FS/19/16/34169 to DP, PG/16/42/32142 to AJW and GLS]; and a Wellcome Trust Seed Award Grant [109604/Z/15/Z to DP]; and the German Centre for Cardiovascular Research supported by the German Ministry of Education and Research (DZHK, via a grant to AFNET to PK); and the Leducq Foundation to PK; and the University of Birmingham India Institute Fellowship scheme to SG.
Glasgow Author(s) Enlighten ID:Smith, Professor Godfrey and Workman, Dr Antony and Saxena, Dr Priyanka
Authors: 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., and Kirchhof, P.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Heart Rhythm
ISSN (Online):1556-3871
Published Online:16 March 2021
Copyright Holders:Copyright © 2021 Heart Rhythm Sciety
First Published:First published in Heart Rhythm 18(7): 1212-1220
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
173444Adrenoceptor-subtype antagonism profiles with anti-arrhythmic potential in human atrial myocytesAntony WorkmanBritish Heart Foundation (BHF)PG/16/42/32142Institute of Cardiovascular & Medical Sciences