Felix Wiedmann1,2,3, Christoph Beyersdorf1,3, Xiao Bo Zhou2,4, Manuel Kraft1,2,3, Amelie Paasche1,3, Natasa Jávorszky1,3, Susanne Rinné5, Henry Sutanto6, Antonius Büscher1,2,3, Kathrin I Foerster7, Antje Blank7, Ibrahim El-Battrawy2,4, Xin Li4, Siegfried Lang2,4, Ursula Tochtermann8, Jamila Kremer8, Rawa Arif8, Matthias Karck8, Niels Decher9, Gunther van Loon10, Ibrahim Akin2,4, Martin Borggrefe2,4, Stefan Kallenberger11,12, Jordi Heijman6, Walter E Haefeli7, Hugo A Katus1,2,3, Constanze Schmidt1,2,3. 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.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Sotirios Nedios; Frank Lindemann; Jordi Heijman; Harry J G M Crijns; Andreas Bollmann; Gerhard Hindricks Journal: Herz Date: 2021-07-05 Impact factor: 1.443
Authors: Manuel Kraft; Kathrin I Foerster; Felix Wiedmann; Max Sauter; Amelie Paasche; Pablo L Blochberger; Baran Yesilgöz; Yannick L'hoste; Norbert Frey; Walter E Haefeli; Jürgen Burhenne; Constanze Schmidt Journal: Pharmaceutics Date: 2022-03-31 Impact factor: 6.321