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. 2019 Sep;12(9):e007465.
doi: 10.1161/CIRCEP.119.007465. Epub 2019 Sep 13.

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

Constanze Schmidt  1   2   3 , Felix Wiedmann  1   2   3 , Christoph Beyersdorf  1   2   3 , Zhihan Zhao  2   4 , Ibrahim El-Battrawy  2   4 , Huan Lan  2   4 , Gabor Szabo  5 , Xin Li  4 , Siegfried Lang  2   4 , Sevil Korkmaz-Icöz  5 , Kleopatra Rapti  1   2 , Andreas Jungmann  1   2 , Antonius Ratte  1   2   3 , Oliver J Müller  6   7 , Matthias Karck  5 , Gunnar Seemann  8   9 , Ibrahim Akin  2   4 , Martin Borggrefe  2   4 , Xiao-Bo Zhou  2   4 , Hugo A Katus  1   2   3 , Dierk Thomas  1   2
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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

Constanze Schmidt et al. Circ Arrhythm Electrophysiol. 2019 Sep.

Abstract

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. Conclusions Adeno-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.

Keywords: action potential; atrial fibrillation; catheter ablation; potassium; risk factor.

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