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

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 LoonIbrahim Akin, Martin Borggrefe, Stefan Kallenberger, Jordi Heijman, Walter E Haefeli, Hugo A Katus, Constanze Schmidt^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

10 Citations (Web of Science)

Abstract

AIMS: TASK-1 (K2P3.1) two-pore domain potassium channels are atrial-specific and significantly upregulated 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 the present 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 d 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 d 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.

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

TRANSLATIONAL PERSPECTIVE: Pharmacological suppression of atrial TASK 1 potassium currents prolongs atrial refractoriness with no effects on ventricular repolarization, resulting in atrial-specific class III antiarrhythmic effects. In our preclinical pilot study the respiratory stimulant doxapram was successfully administered for cardioversion of acute AF as well as rhythm control of persistent AF in a clinically relevant porcine animal model.

Original language	English
Pages (from-to)	1728-1741
Number of pages	14
Journal	Cardiovascular Research
Volume	118
Issue number	7
Early online date	24 May 2021
DOIs	https://doi.org/10.1093/cvr/cvab177
Publication status	Published - 22 Jun 2022

Keywords

Antiarrhythmic pharmacotherapy
Arrhythmia
Atrial fibrillation
Doxapram
Electrical remodelling
Potassium channel
Rhythm control
TASK-1
ACTION-POTENTIAL DURATION
SINOATRIAL CONDUCTION
K+ CHANNEL
LEAK
MECHANISMS

Access to Document

10.1093/cvr/cvab177

Cite this

Wiedmann, F., Beyersdorf, C., Zhou, X-B., Kraft, M., Paasche, A., Jávorszky, N., Rinné, S., Sutanto, H., Büscher, A., Foerster, K. I., Blank, A., El-Battrawy, I., Li, X., Lang, S., Tochtermann, U., Kremer, J., Arif, R., Karck, M., Decher, N., ... Schmidt, C. (2022). Treatment of atrial fibrillation with doxapram: TASK-1 potassium channel inhibition as a novel pharmacological strategy. Cardiovascular Research, 118(7), 1728-1741. https://doi.org/10.1093/cvr/cvab177

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

abstract = "AIMS: TASK-1 (K2P3.1) two-pore domain potassium channels are atrial-specific and significantly upregulated 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 the present 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 d 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 d 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.CONCLUSIONS: Repurposing doxapram might yield a promising new antiarrhythmic drug to treat AF in patients.TRANSLATIONAL PERSPECTIVE: Pharmacological suppression of atrial TASK 1 potassium currents prolongs atrial refractoriness with no effects on ventricular repolarization, resulting in atrial-specific class III antiarrhythmic effects. In our preclinical pilot study the respiratory stimulant doxapram was successfully administered for cardioversion of acute AF as well as rhythm control of persistent AF in a clinically relevant porcine animal model.",

keywords = "Antiarrhythmic pharmacotherapy, Arrhythmia, Atrial fibrillation, Doxapram, Electrical remodelling, Potassium channel, Rhythm control, TASK-1, ACTION-POTENTIAL DURATION, SINOATRIAL CONDUCTION, K+ CHANNEL, LEAK, MECHANISMS",

author = "Felix Wiedmann and Christoph Beyersdorf and Xiao-Bo Zhou and Manuel Kraft and Amelie Paasche and Natasa J{\'a}vorszky and Susanne Rinn{\'e} and Henry Sutanto and Antonius B{\"u}scher and Foerster, {Kathrin I} and Antje Blank and Ibrahim El-Battrawy and Xin Li and Siegfried Lang and Ursula Tochtermann and Jamila Kremer and Rawa Arif and Matthias Karck and Niels Decher and {van Loon}, Gunther and Ibrahim Akin and Martin Borggrefe and Stefan Kallenberger and Jordi Heijman and Haefeli, {Walter E} and Katus, {Hugo A} and Constanze Schmidt",

year = "2022",

month = jun,

day = "22",

doi = "10.1093/cvr/cvab177",

language = "English",

volume = "118",

pages = "1728--1741",

journal = "Cardiovascular Research",

issn = "0008-6363",

publisher = "Oxford University Press",

number = "7",

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Wiedmann, F, Beyersdorf, C, Zhou, X-B, Kraft, M, Paasche, A, Jávorszky, N, Rinné, S, Sutanto, H, Büscher, A, Foerster, KI, Blank, A, El-Battrawy, I, Li, X, Lang, S, Tochtermann, U, Kremer, J, Arif, R, Karck, M, Decher, N, van Loon, G, Akin, I, Borggrefe, M, Kallenberger, S, Heijman, J, Haefeli, WE, Katus, HA & Schmidt, C 2022, 'Treatment of atrial fibrillation with doxapram: TASK-1 potassium channel inhibition as a novel pharmacological strategy', Cardiovascular Research, vol. 118, no. 7, pp. 1728-1741. https://doi.org/10.1093/cvr/cvab177

TY - JOUR

T1 - Treatment of atrial fibrillation with doxapram

T2 - TASK-1 potassium channel inhibition as a novel pharmacological strategy

AU - Wiedmann, Felix

AU - Beyersdorf, Christoph

AU - Zhou, Xiao-Bo

AU - Kraft, Manuel

AU - Paasche, Amelie

AU - Jávorszky, Natasa

AU - Rinné, Susanne

AU - Sutanto, Henry

AU - Büscher, Antonius

AU - Foerster, Kathrin I

AU - Blank, Antje

AU - El-Battrawy, Ibrahim

AU - Li, Xin

AU - Lang, Siegfried

AU - Tochtermann, Ursula

AU - Kremer, Jamila

AU - Arif, Rawa

AU - Karck, Matthias

AU - Decher, Niels

AU - van Loon, Gunther

AU - Akin, Ibrahim

AU - Borggrefe, Martin

AU - Kallenberger, Stefan

AU - Heijman, Jordi

AU - Haefeli, Walter E

AU - Katus, Hugo A

AU - Schmidt, Constanze

PY - 2022/6/22

Y1 - 2022/6/22

N2 - AIMS: TASK-1 (K2P3.1) two-pore domain potassium channels are atrial-specific and significantly upregulated 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 the present 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 d 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 d 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.CONCLUSIONS: Repurposing doxapram might yield a promising new antiarrhythmic drug to treat AF in patients.TRANSLATIONAL PERSPECTIVE: Pharmacological suppression of atrial TASK 1 potassium currents prolongs atrial refractoriness with no effects on ventricular repolarization, resulting in atrial-specific class III antiarrhythmic effects. In our preclinical pilot study the respiratory stimulant doxapram was successfully administered for cardioversion of acute AF as well as rhythm control of persistent AF in a clinically relevant porcine animal model.

AB - AIMS: TASK-1 (K2P3.1) two-pore domain potassium channels are atrial-specific and significantly upregulated 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 the present 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 d 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 d 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.CONCLUSIONS: Repurposing doxapram might yield a promising new antiarrhythmic drug to treat AF in patients.TRANSLATIONAL PERSPECTIVE: Pharmacological suppression of atrial TASK 1 potassium currents prolongs atrial refractoriness with no effects on ventricular repolarization, resulting in atrial-specific class III antiarrhythmic effects. In our preclinical pilot study the respiratory stimulant doxapram was successfully administered for cardioversion of acute AF as well as rhythm control of persistent AF in a clinically relevant porcine animal model.

KW - Antiarrhythmic pharmacotherapy

KW - Arrhythmia

KW - Atrial fibrillation

KW - Doxapram

KW - Electrical remodelling

KW - Potassium channel

KW - Rhythm control

KW - TASK-1

KW - ACTION-POTENTIAL DURATION

KW - SINOATRIAL CONDUCTION

KW - K+ CHANNEL

KW - LEAK

KW - MECHANISMS

U2 - 10.1093/cvr/cvab177

DO - 10.1093/cvr/cvab177

M3 - Article

C2 - 34028533

SN - 0008-6363

VL - 118

SP - 1728

EP - 1741

JO - Cardiovascular Research

JF - Cardiovascular Research

IS - 7

ER -