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
  • 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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