Genetic ablation of TASK-1 (tandem of P domains in a weak inward rectifying K+ channel-related acid-sensitive K+ channel-1) (K2P3.1) K+ channels suppresses atrial fibrillation and prevents electrical remodeling
Background:Despite an increasing understanding of atrial fibrillation (AF) pathophysiology, translation into mechanism-based treatment options is lacking. In atrial cardiomyocytes of patients with chronic AF, expression, and function of tandem of P domains in a weak inward rectifying TASK-1 (K+ chan...
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| Hauptverfasser: | , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
September 13, 2019
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| In: |
Circulation. Arrhythmia and electrophysiology
Year: 2019, Jahrgang: 12, Heft: 9, Pages: e007465 |
| ISSN: | 1941-3084 |
| DOI: | 10.1161/CIRCEP.119.007465 |
| Online-Zugang: | Verlag, Volltext: https://doi.org/10.1161/CIRCEP.119.007465 Verlag: https://www.ahajournals.org/doi/10.1161/CIRCEP.119.007465 
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| Verfasserangaben: | Constanze Schmidt, MD, Felix Wiedmann, MD, Christoph Beyersdorf, BS, Zhi-han Zhao, MSc, Ibrahim El-Battrawy, MD, Huan Lan, MD, Gabor Szabo, MD, Xin Li, MSc, Siegfried Lang, PhD, Sevil Korkmaz-Icöz, MD, Kleopatra Rapti, PhD, Andreas Jungmann, PhD, Antonius Ratte, MD, Oliver J. Müller, MD, Matthias Karck, MD, Gunnar Seemann, PhD, Ibrahim Akin, MD, Martin Borggrefe, MD, Xiao-Bo Zhou, MD, Hugo A. Katus, MD, Dierk Thomas, MD |
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| 245 | 1 | 0 | |a Genetic ablation of TASK-1 (tandem of P domains in a weak inward rectifying K+ channel-related acid-sensitive K+ channel-1) (K2P3.1) K+ channels suppresses atrial fibrillation and prevents electrical remodeling |c Constanze Schmidt, MD, Felix Wiedmann, MD, Christoph Beyersdorf, BS, Zhi-han Zhao, MSc, Ibrahim El-Battrawy, MD, Huan Lan, MD, Gabor Szabo, MD, Xin Li, MSc, Siegfried Lang, PhD, Sevil Korkmaz-Icöz, MD, Kleopatra Rapti, PhD, Andreas Jungmann, PhD, Antonius Ratte, MD, Oliver J. Müller, MD, Matthias Karck, MD, Gunnar Seemann, PhD, Ibrahim Akin, MD, Martin Borggrefe, MD, Xiao-Bo Zhou, MD, Hugo A. Katus, MD, Dierk Thomas, MD |
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| 520 | |a Background:Despite an increasing understanding of atrial fibrillation (AF) pathophysiology, translation into mechanism-based treatment options is lacking. In atrial cardiomyocytes of patients with chronic AF, expression, and function of tandem of P domains in a weak inward rectifying TASK-1 (K+ channel-related acid-sensitive K+ channel-1) (K2P3.1) atrial-specific 2-pore domain potassium channels is enhanced, resulting in action potential duration shortening. TASK-1 channel inhibition prevents action potential duration shortening to maintain values observed among sinus rhythm subjects. The present preclinical study used a porcine AF model to evaluate the antiarrhythmic efficacy of TASK-1 inhibition by adeno-associated viral anti-TASK-1-siRNA (small interfering RNA) gene transfer.Methods:AF was induced in domestic pigs by atrial burst stimulation via implanted pacemakers. Adeno-associated viral vectors carrying anti-TASK-1-siRNA were injected into both atria to suppress TASK-1 channel expression. After the 14-day follow-up period, porcine cardiomyocytes were isolated from right and left atrium, followed by electrophysiological and molecular characterization.Results:AF was associated with increased TASK-1 transcript, protein and ion current levels leading to shortened action potential duration in atrial cardiomyocytes compared to sinus rhythm controls, similar to previous findings in humans. Anti-TASK-1 adeno-associated viral application significantly reduced AF burden in comparison to untreated AF pigs. Antiarrhythmic effects of anti-TASK-1-siRNA were associated with reduction of TASK-1 currents and prolongation of action potential durations in atrial cardiomyocytes to sinus rhythm values.ConclusionsAdeno-associated viral-based anti-TASK-1 gene therapy suppressed AF and corrected cellular electrophysiological remodeling in a porcine model of AF. Suppression of AF through selective reduction of TASK-1 currents represents a new option for antiarrhythmic therapy. | ||
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