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

Authors
  • Wiedmann, Felix1, 2, 3
  • Beyersdorf, Christoph1, 3
  • Zhou, Xiao Bo2, 4
  • Kraft, Manuel1, 2, 3
  • Paasche, Amelie1, 3
  • Jávorszky, Natasa1, 3
  • Rinné, Susanne5
  • Sutanto, Henry6
  • Büscher, Antonius1, 2, 3
  • Foerster, Kathrin I7
  • Blank, Antje7
  • El-Battrawy, Ibrahim2, 4
  • Li, Xin4
  • Lang, Siegfried2, 4
  • Tochtermann, Ursula8
  • Kremer, Jamila8
  • Arif, Rawa8
  • Karck, Matthias8
  • Decher, Niels9
  • van Loon, Gunther10
  • And 7 more
  • 1 Department of Cardiology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. , (Germany)
  • 2 Partner site Heidelberg /Mannheim, DZHK (German Center for Cardiovascular Research), Potsdamer Straße 58, 10785 Berlin, Germany. , (Germany)
  • 3 HCR, Heidelberg Center for Heart Rhythm Disorders, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. , (Germany)
  • 4 First Department of Medicine, University Medical Center Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. , (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. , (Germany)
  • 6 Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands. , (Netherlands)
  • 7 Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. , (Germany)
  • 8 Department of Cardiac Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany. , (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. , (Germany)
  • 10 Department of Large Animal Internal Medicine, Equine Cardioteam, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820 Merelbeke, Belgium. , (Belgium)
  • 11 Digital Health Center, Berlin Institute of Health (BIH), Anna-Louisa-Karsch-Straße 2, 10178 Berlin, Germany. , (Germany)
  • 12 Health Data Science Unit, BioQuant, Faculty of Medicine, University of Heidelberg, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany. , (Germany)
Type
Published Article
Journal
Cardiovascular Research
Publisher
Oxford University Press
Publication Date
Jun 22, 2022
Volume
118
Issue
7
Pages
1728–1741
Identifiers
DOI: 10.1093/cvr/cvab177
PMID: 34028533
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. 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. Repurposing doxapram might yield a promising new antiarrhythmic drug to treat AF in patients. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

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