Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Wiedmann, F; Beyersdorf, C; Zhou, XB; Kraft, M; Paasche, A; Jávorszky, N; Rinné, S; Sutanto, H; Büscher, A; Foerster, K; 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.
Treatment of atrial fibrillation with doxapram: TASK-1 potassium channel inhibition as a novel pharmacological strategy
CARDIOVASC RES. 2022; 118(7): 1728-1741.
Doi: 10.1093/cvr/cvab177
Web of Science
PubMed
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- Co-Autor*innen der Med Uni Graz
- Heijman Jordi
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- Abstract:
- 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. Aims TASK-1 (K(2P)3.1) 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.
- Find related publications in this database (Keywords)
- Antiarrhythmic pharmacotherapy
- Arrhythmia
- Atrial fibrillation
- Doxapram
- Electrical remodelling
- Potassium channel
- Rhythm control
- TASK-1