Genetic Ablation of TASK-1 (Tandem of P Domains in a Weak Inward Rectifying K ⁺ Channel–Related Acid-Sensitive K ⁺ Channel-1) (K _2P 3.1) K ⁺ Channels Suppresses Atrial Fibrillation and Prevents Electrical Remodeling

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) (K 2P 3.1) 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.

Current Drug Treatment Strategies for Atrial Fibrillation and TASK-1 Inhibition as an Emerging Novel Therapy Option

“…Pigs were treated with an adeno-associated viral vector carrying anti-TASK-1-siRNA which was injected in both atria and led to a reduced expression of TASK-1. This treatment led to a prolongation of the APD and reduction of TASK-1 current in the siRNA group compared to AF control pigs and to a significant reduction in AF burden (Schmidt et al, 2019b). Liang et al (2014) showed that loss-of-function mutations of TASK-1 lead to increased susceptibility to develop AF in the presence of pro-arrhythmic stimuli and Harleton et al (2015Harleton et al ( , 2013 observed a phosphorylation dependent TASK-1 dysregulation in a canine model of AF, further underlining its role in AF.…”

Recent Advances in Gene Therapy for Atrial Fibrillation

“…78 Genetic suppression of TASK-1 (Tandem of P Domains in a Weak Inward Rectifying K+ Channel-Related Acid-Sensitive K+ Channel-1; K2P3.1) through transfection of AAV containing atrial anti-TASK-1 siRNA lead to reduction of expression of TASK-1 and prolongation of atrial APD and refractoriness. 79 Ca 2+ handling proteins Abnormal sarcoplasmic reticulum (SR) Ca 2+ leak via the ryanodine receptor type 2 (RyR2) has been described in atrial cardiomyocytes from AF patients and in various AF models. 80,81 This disruption in calcium handling contributes to ectopic atrial activity and is implicated in the progression from paroxysmal to persistent AF.…”

Revisiting Antiarrhythmic Drug Therapy for Atrial Fibrillation: Reviewing Lessons Learned and Redefining Therapeutic Paradigms

“…In a preclinical trial with an AF pig model, inhibition of atrial-specific K 2P 3.1 current using the TASK-1 channel blocker A293 reverses pathologic AF-related atrial action potential shortening and significantly prolongs atrial ERP without causing ventricular arrhythmias (Wiedmann et al, 2020). In another more recent pig preclinical trial, K 2P 3.1 current inhibition by genetic ablation of TASK-1 channels using small interfering RNA (siRNA) prevents atrial electrical remodeling and suppresses AF (Schmidt et al, 2019). However, an important caveat is that in chronic-AF patients with heart failure due to left ventricular dysfunction, atrial K 2P 3.1 expression is downregulated instead of upregulated, making it unlikely for I K2P blockers to be an efficient anti-AF approach in patients with structurally remodeled atria (Schmidt et al, 2017).…”

“…For example, the Controlled Study of Rate vs. Rhythm Control in Patients with Chronic AF and Heart Failure (CAFÉ-II) found that the rhythm-control strategy, even when achieved by an antiarrhythmic drug such as amiodarone, was associated with greater symptomatic relief and improved quality of life as compared to the rate-control strategy ( Shelton et al, 2009 ).…”