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

Felix Wiedmann; Christoph Beyersdorf; Xiao Bo Zhou; Manuel Kraft; Amelie Paasche; Natasa Jávorszky; Susanne Rinné; Henry Sutanto; Antonius Büscher; Kathrin I Foerster; Antje Blank; Ibrahim El-Battrawy; Xin Li; Siegfried Lang; Ursula Tochtermann; Jamila Kremer; Rawa Arif; Matthias Karck; Niels Decher; Gunther van Loon; Ibrahim Akin; Martin Borggrefe; Stefan Kallenberger; Jordi Heijman; Walter E Haefeli; Hugo A Katus; Constanze Schmidt

doi:10.1093/cvr/cvab177

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.

Authors

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 Rinné⁵, Henry Sutanto⁶, Antonius Büscher^{1

2

3}, Kathrin I Foerster⁷, Antje Blank⁷, Ibrahim El-Battrawy^{2

4}, Xin Li⁴, Siegfried Lang^{2

4}, Ursula Tochtermann⁸, Jamila Kremer⁸, Rawa Arif⁸, Matthias Karck⁸, Niels Decher⁹, Gunther van Loon¹⁰, Ibrahim Akin^{2

4}, Martin Borggrefe^{2

4}, Stefan Kallenberger^{11

12}, Jordi Heijman⁶, Walter E Haefeli⁷, 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Arrhythmia Agents / pharmacology
Anti-Arrhythmia Agents / therapeutic use
Atrial Fibrillation* / drug therapy
Doxapram / therapeutic use
Heart Atria / metabolism
Humans
Nerve Tissue Proteins / metabolism
Potassium Channel Blockers / pharmacology*
Potassium Channels, Tandem Pore Domain* / antagonists & inhibitors
Swine

Substances

Anti-Arrhythmia Agents
Nerve Tissue Proteins
Potassium Channel Blockers
Potassium Channels, Tandem Pore Domain
Doxapram