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  3. Treatment of atrial fibrillation with doxapram: TASK-1 potassium channel inhibition as a novel pharmacological strategy

Treatment of atrial fibrillation with doxapram: TASK-1 potassium channel inhibition as a novel pharmacological strategy

  • Cardiovasc Res. 2022 Jun 22;118(7):1728-1741. doi: 10.1093/cvr/cvab177.
Felix Wiedmann 1 2 3,  Christoph Beyersdorf 1 3,  Xiao Bo Zhou 2 4,  Manuel Kraft 1 2 3,  Amelie Paasche 1 3,  Natasa Jávorszky 1 3,  Susanne Rinné 5,  Henry Sutanto 6,  Antonius Büscher 1 2 3,  Kathrin I Foerster 7,  Antje Blank 7,  Ibrahim El-Battrawy 2 4,  Xin Li 4,  Siegfried Lang 2 4,  Ursula Tochtermann 8,  Jamila Kremer 8,  Rawa Arif 8,  Matthias Karck 8,  Niels Decher 9,  Gunther van Loon 10,  Ibrahim Akin 2 4,  Martin Borggrefe 2 4,  Stefan Kallenberger 11 12,  Jordi Heijman 6,  Walter E Haefeli 7,  Hugo A Katus 1 2 3,  Constanze Schmidt 1 2 3
Affiliations

Affiliations

  • 1 Department of Cardiology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
  • 2 Partner site Heidelberg /Mannheim, DZHK (German Center for Cardiovascular Research), Potsdamer Straße 58, 10785 Berlin, Germany.
  • 3 HCR, Heidelberg Center for Heart Rhythm Disorders, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
  • 4 First Department of Medicine, University Medical Center Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
  • 5 Institute for Physiology and Pathophysiology, Vegetative Physiology and Marburg Center for Mind, Brain and Behavior MCMBB, University of Marburg, Deutschhausstrasse 1-2, 35037 Marburg, Germany.
  • 6 Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.
  • 7 Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
  • 8 Department of Cardiac Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany.
  • 9 Institute for Physiology and Pathophysiology, Vegetative Physiology and Marburg Center for Mind, Brain and behavior MCMBB, University of Marburg, Deutschhausstrasse 1-2, 35037 Marburg, Germany.
  • 10 Department of Large Animal Internal Medicine, Equine Cardioteam, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820 Merelbeke, Belgium.
  • 11 Digital Health Center, Berlin Institute of Health (BIH), Anna-Louisa-Karsch-Straße 2, 10178 Berlin, Germany.
  • 12 Health Data Science Unit, BioQuant, Faculty of Medicine, University of Heidelberg, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany.
PMID: 34028533 DOI: 10.1093/cvr/cvab177
Abstract

Aims: TASK-1 (K2P3.1) two-pore-domain potassium channels are atrial-specific and significantly up-regulated in atrial fibrillation (AF) patients, contributing to AF-related electrical remodelling. Inhibition of TASK-1 in cardiomyocytes of AF patients was shown to counteract AF-related action potential duration shortening. Doxapram was identified as a potent inhibitor of the TASK-1 channel. In this study, we investigated the antiarrhythmic efficacy of doxapram in a porcine model of AF.

Methods and results: Doxapram successfully cardioverted pigs with artificially induced episodes of AF. We established a porcine model of persistent AF in domestic pigs via intermittent atrial burst stimulation using implanted pacemakers. All pigs underwent catheter-based electrophysiological investigations prior to and after 14 days of doxapram treatment. Pigs in the treatment group received intravenous administration of doxapram once per day. In doxapram-treated AF pigs, the AF burden was significantly reduced. After 14 days of treatment with doxapram, TASK-1 currents were still similar to values of sinus rhythm Animals. Doxapram significantly suppressed AF episodes and normalized cellular electrophysiology by inhibition of the TASK-1 channel. Patch-clamp experiments on human atrial cardiomyocytes, isolated from patients with and without AF could reproduce the TASK-1 inhibitory effect of doxapram.

Conclusion: Repurposing doxapram might yield a promising new antiarrhythmic drug to treat AF in patients.

Keywords

Antiarrhythmic pharmacotherapy; Arrhythmia; Atrial fibrillation; Doxapram; Electrical remodelling; Potassium channel; Rhythm control; TASK-1.

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