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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

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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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Main Authors: Schmidt, Constanze (Author) , Wiedmann, Felix Tobias (Author) , El-Battrawy, Ibrahim (Author) , Lan, Huan (Author) , Szabó, Gábor (Author) , Lang, Siegfried (Author) , Rapti, Kleopatra (Author) , Ratte, Antonius (Author) , Karck, Matthias (Author) , Akın, Ibrahim (Author) , Borggrefe, Martin (Author) , Zhou, Xiao-Bo (Author) , Katus, Hugo (Author) , Thomas, Dierk (Author)
Format: Article (Journal)
Language:English
Published: September 13, 2019
In: Circulation. Arrhythmia and electrophysiology
Year: 2019, Volume: 12, Issue: 9, Pages: e007465
ISSN:1941-3084
DOI:10.1161/CIRCEP.119.007465
Online Access: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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Author Notes: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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Summary: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.
Item Description:Gesehen am 05.12.2019
Physical Description:Online Resource
ISSN:1941-3084
DOI:10.1161/CIRCEP.119.007465

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