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

Abstract

Background The tandem of P domains in a weak inward rectifying K+ channel (TWIK)‐related acid‐sensitive K + channel (TASK‐1; hK 2P 3.1) 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.

The Experimental TASK-1 Potassium Channel Inhibitor A293 Can Be Employed for Rhythm Control of Persistent Atrial Fibrillation in a Translational Large Animal Model

“…Membrane currents were evoked by application of 400 ms voltage steps between −60 and +60 mV in 10 mV increments from a holding potential of −50 mV and measured using the whole cell configuration. TASK-1 current densities were calculated by subtracting background potassium currents before and after administration of 200 nM A293 as described earlier ( Limberg et al, 2011 ; Schmidt et al, 2014 , 2019 ; Wiedmann et al, 2020a ). To assess the effects of altered background potassium currents on atrial actions potentials (APs), isolated atrial cardiomyocytes were studied using the patch clamp technique under current clamp conditions.…”

“…The high-affinity TASK-1 inhibitor A293 was evaluated as an experimental anti-arrhythmic treatment. This aromatic carbonamide represents an experimental compound that is active in the nanomolar to micromolar range ( Putzke et al, 2007b ; Kiper et al, 2015 ; Schmidt et al, 2015 ; Wiedmann et al, 2019 , 2020a ). As TASK-1 channels are expressed in pulmonary artery (PA) smooth muscle cells where they might contribute to regulation of the vascular tone ( Olschewski et al, 2006 ), hemodynamic effects of TASK-1 inhibition were studied upon acute TASK-1 channel inhibition.…”

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

“…In chronic AF, but not in paroxysmal AF, atrial TASK-1mediated K 2P 3.1 current expression is upregulated and causes action potential shortening (Schmidt et al, 2015). 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).…”

“…The next milestone came from the revolutionary insights of the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) ( Wyse et al, 2002 ; Corley et al, 2004 ), the largest randomized controlled clinical trial at the time ( n = 4,060 AF patients; 4-years follow up). The goal of the AFFIRM trial was to address the controversy of anticoagulated rhythm control vs. anticoagulated rate control as the main long-term therapeutic strategy with superior survival benefits.…”

“…Amiodarone, an iodinated benzofuran derivative, is the most widely used off-label antiarrhythmic for AF due to its superior efficacy in both cardioversion ( Khan et al, 2003 ) and particularly sinus rhythm maintenance ( Roy et al, 2000 ; Wyse et al, 2002 ; Singh et al, 2005 ; Freemantle et al, 2011 ). Amiodarone displays properties of all four Vaughan Williams classes, but is classified as class III due to its major potency in blocking K + channels to prolong cardiac action potential and refractoriness.…”