Pharmacologic TWIK‐Related Acid‐Sensitive K+ Channel (TASK‐1) Potassium Channel Inhibitor A293 Facilitates Acute Cardioversion of Paroxysmal Atrial Fibrillation in a Porcine Large Animal Model
Background The tandem of P domains in a weak inward rectifying K+ channel (TWIK)‐related acid‐sensitive K+ channel (TASK‐1; hK2P3.1) two‐pore–domain potassium channel was recently shown to regulate the atrial action potential duration. In the human heart, TASK‐1 channels are specifically expressed i...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-05-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.119.015751 |
| _version_ | 1828111431679082496 |
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| author | Felix Wiedmann Christoph Beyersdorf Xiaobo Zhou Antonius Büscher Manuel Kraft Jendrik Nietfeld Teo Puig Walz Laura A. Unger Axel Loewe Bastian Schmack Arjang Ruhparwar Matthias Karck Dierk Thomas Martin Borggrefe Gunnar Seemann Hugo A. Katus Constanze Schmidt |
| author_facet | Felix Wiedmann Christoph Beyersdorf Xiaobo Zhou Antonius Büscher Manuel Kraft Jendrik Nietfeld Teo Puig Walz Laura A. Unger Axel Loewe Bastian Schmack Arjang Ruhparwar Matthias Karck Dierk Thomas Martin Borggrefe Gunnar Seemann Hugo A. Katus Constanze Schmidt |
| author_sort | Felix Wiedmann |
| collection | DOAJ |
| description | Background The tandem of P domains in a weak inward rectifying K+ channel (TWIK)‐related acid‐sensitive K+ channel (TASK‐1; hK2P3.1) two‐pore–domain potassium channel was recently shown to regulate the atrial action potential duration. In the human heart, TASK‐1 channels are specifically expressed in the atria. Furthermore, upregulation of atrial TASK‐1 currents was described in patients suffering from atrial fibrillation (AF). We therefore hypothesized that TASK‐1 channels represent an ideal target for antiarrhythmic therapy of AF. In the present study, we tested the antiarrhythmic effects of the high‐affinity TASK‐1 inhibitor A293 on cardioversion in a porcine model of paroxysmal AF. Methods and Results Heterologously expressed human and porcine TASK‐1 channels are blocked by A293 to a similar extent. Patch clamp measurements from isolated human and porcine atrial cardiomyocytes showed comparable TASK‐1 currents. Computational modeling was used to investigate the conditions under which A293 would be antiarrhythmic. German landrace pigs underwent electrophysiological studies under general anesthesia. Paroxysmal AF was induced by right atrial burst stimulation. After induction of AF episodes, intravenous administration of A293 restored sinus rhythm within cardioversion times of 177±63 seconds. Intravenous administration of A293 resulted in significant prolongation of the atrial effective refractory period, measured at cycle lengths of 300, 400 and 500 ms, whereas the surface ECG parameters and the ventricular effective refractory period lengths remained unchanged. Conclusions Pharmacological inhibition of atrial TASK‐1 currents exerts antiarrhythmic effects in vivo as well as in silico, resulting in acute cardioversion of paroxysmal AF. Taken together, these experiments indicate the therapeutic potential of A293 for AF treatment. |
| first_indexed | 2024-04-11T11:35:52Z |
| format | Article |
| id | doaj.art-7d75362eb0664a31a7186e77361b2a01 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-04-11T11:35:52Z |
| publishDate | 2020-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-7d75362eb0664a31a7186e77361b2a012022-12-22T04:25:58ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802020-05-0191010.1161/JAHA.119.015751Pharmacologic TWIK‐Related Acid‐Sensitive K+ Channel (TASK‐1) Potassium Channel Inhibitor A293 Facilitates Acute Cardioversion of Paroxysmal Atrial Fibrillation in a Porcine Large Animal ModelFelix Wiedmann0Christoph Beyersdorf1Xiaobo Zhou2Antonius Büscher3Manuel Kraft4Jendrik Nietfeld5Teo Puig Walz6Laura A. Unger7Axel Loewe8Bastian Schmack9Arjang Ruhparwar10Matthias Karck11Dierk Thomas12Martin Borggrefe13Gunnar Seemann14Hugo A. Katus15Constanze Schmidt16Department of Cardiology University of Heidelberg GermanyDepartment of Cardiology University of Heidelberg GermanyDZHK (German Center for Cardiovascular Research) partner site Heidelberg /Mannheim University of Heidelberg GermanyDepartment of Cardiology University of Heidelberg GermanyDepartment of Cardiology University of Heidelberg GermanyDepartment of Cardiology University of Heidelberg GermanyInstitute for Experimental Cardiovascular Medicine University Heart Center Freiburg Bad Krozingen GermanyInstitute of Biomedical Engineering Karlsruhe Institute of Technology (KIT) Karlsruhe GermanyInstitute of Biomedical Engineering Karlsruhe Institute of Technology (KIT) Karlsruhe GermanyDepartment of Cardiac Surgery University Hospital Heidelberg GermanyDepartment of Cardiac Surgery University Hospital Essen GermanyDepartment of Cardiac Surgery University Hospital Heidelberg GermanyDepartment of Cardiology University of Heidelberg GermanyDZHK (German Center for Cardiovascular Research) partner site Heidelberg /Mannheim University of Heidelberg GermanyInstitute for Experimental Cardiovascular Medicine University Heart Center Freiburg Bad Krozingen GermanyDepartment of Cardiology University of Heidelberg GermanyDepartment of Cardiology University of Heidelberg GermanyBackground The tandem of P domains in a weak inward rectifying K+ channel (TWIK)‐related acid‐sensitive K+ channel (TASK‐1; hK2P3.1) two‐pore–domain potassium channel was recently shown to regulate the atrial action potential duration. In the human heart, TASK‐1 channels are specifically expressed in the atria. Furthermore, upregulation of atrial TASK‐1 currents was described in patients suffering from atrial fibrillation (AF). We therefore hypothesized that TASK‐1 channels represent an ideal target for antiarrhythmic therapy of AF. In the present study, we tested the antiarrhythmic effects of the high‐affinity TASK‐1 inhibitor A293 on cardioversion in a porcine model of paroxysmal AF. Methods and Results Heterologously expressed human and porcine TASK‐1 channels are blocked by A293 to a similar extent. Patch clamp measurements from isolated human and porcine atrial cardiomyocytes showed comparable TASK‐1 currents. Computational modeling was used to investigate the conditions under which A293 would be antiarrhythmic. German landrace pigs underwent electrophysiological studies under general anesthesia. Paroxysmal AF was induced by right atrial burst stimulation. After induction of AF episodes, intravenous administration of A293 restored sinus rhythm within cardioversion times of 177±63 seconds. Intravenous administration of A293 resulted in significant prolongation of the atrial effective refractory period, measured at cycle lengths of 300, 400 and 500 ms, whereas the surface ECG parameters and the ventricular effective refractory period lengths remained unchanged. Conclusions Pharmacological inhibition of atrial TASK‐1 currents exerts antiarrhythmic effects in vivo as well as in silico, resulting in acute cardioversion of paroxysmal AF. Taken together, these experiments indicate the therapeutic potential of A293 for AF treatment.https://www.ahajournals.org/doi/10.1161/JAHA.119.015751A293antiarrhythmic pharmacotherapyatrial fibrillationcardioversionK2P3.1TASK‐1 |
| spellingShingle | Felix Wiedmann Christoph Beyersdorf Xiaobo Zhou Antonius Büscher Manuel Kraft Jendrik Nietfeld Teo Puig Walz Laura A. Unger Axel Loewe Bastian Schmack Arjang Ruhparwar Matthias Karck Dierk Thomas Martin Borggrefe Gunnar Seemann Hugo A. Katus Constanze Schmidt Pharmacologic TWIK‐Related Acid‐Sensitive K+ Channel (TASK‐1) Potassium Channel Inhibitor A293 Facilitates Acute Cardioversion of Paroxysmal Atrial Fibrillation in a Porcine Large Animal Model Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease A293 antiarrhythmic pharmacotherapy atrial fibrillation cardioversion K2P3.1 TASK‐1 |
| title | Pharmacologic TWIK‐Related Acid‐Sensitive K+ Channel (TASK‐1) Potassium Channel Inhibitor A293 Facilitates Acute Cardioversion of Paroxysmal Atrial Fibrillation in a Porcine Large Animal Model |
| title_full | Pharmacologic TWIK‐Related Acid‐Sensitive K+ Channel (TASK‐1) Potassium Channel Inhibitor A293 Facilitates Acute Cardioversion of Paroxysmal Atrial Fibrillation in a Porcine Large Animal Model |
| title_fullStr | Pharmacologic TWIK‐Related Acid‐Sensitive K+ Channel (TASK‐1) Potassium Channel Inhibitor A293 Facilitates Acute Cardioversion of Paroxysmal Atrial Fibrillation in a Porcine Large Animal Model |
| title_full_unstemmed | Pharmacologic TWIK‐Related Acid‐Sensitive K+ Channel (TASK‐1) Potassium Channel Inhibitor A293 Facilitates Acute Cardioversion of Paroxysmal Atrial Fibrillation in a Porcine Large Animal Model |
| title_short | Pharmacologic TWIK‐Related Acid‐Sensitive K+ Channel (TASK‐1) Potassium Channel Inhibitor A293 Facilitates Acute Cardioversion of Paroxysmal Atrial Fibrillation in a Porcine Large Animal Model |
| title_sort | pharmacologic twik related acid sensitive k channel task 1 potassium channel inhibitor a293 facilitates acute cardioversion of paroxysmal atrial fibrillation in a porcine large animal model |
| topic | A293 antiarrhythmic pharmacotherapy atrial fibrillation cardioversion K2P3.1 TASK‐1 |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.119.015751 |
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