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. 2021 Jan 21:11:629421.
doi: 10.3389/fphys.2020.629421. eCollection 2020.

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

Felix Wiedmann  1   2   3 , Christoph Beyersdorf  1   3 , Xiao-Bo Zhou  2   4 , Manuel Kraft  1   2   3 , Kathrin I Foerster  5 , Ibrahim El-Battrawy  2   4 , Siegfried Lang  2   4 , Martin Borggrefe  2   4 , Walter E Haefeli  5 , Norbert Frey  1   2   3 , Constanze Schmidt  1   2   3
Affiliations

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

Felix Wiedmann et al. Front Physiol. .

Abstract

Background: Upregulation of the two-pore-domain potassium channel TASK-1 (hK2 P 3.1) was recently described in patients suffering from atrial fibrillation (AF) and resulted in shortening of the atrial action potential. In the human heart, TASK-1 channels facilitate repolarization and are specifically expressed in the atria. In the present study, we tested the antiarrhythmic effects of the experimental ion channel inhibitor A293 that is highly affine for TASK-1 in a porcine large animal model of persistent AF.

Methods: Persistent AF was induced in German landrace pigs by right atrial burst stimulation via implanted pacemakers using a biofeedback algorithm over 14 days. Electrophysiological and echocardiographic investigations were performed before and after the pharmacological treatment period. A293 was intravenously administered once per day. After a treatment period of 14 days, atrial cardiomyocytes were isolated for patch clamp measurements of currents and atrial action potentials. Hemodynamic consequences of TASK-1 inhibition were measured upon acute A293 treatment.

Results: In animals with persistent AF, the A293 treatment significantly reduced the AF burden (6.5% vs. 95%; P < 0.001). Intracardiac electrophysiological investigations showed that the atrial effective refractory period was prolonged in A293 treated study animals, whereas, the QRS width, QT interval, and ventricular effective refractory periods remained unchanged. A293 treatment reduced the upregulation of the TASK-1 current as well as the shortening of the action potential duration caused by AF. No central nervous side effects were observed. A mild but significant increase in pulmonary artery pressure was observed upon acute TASK-1 inhibition.

Conclusion: Pharmacological inhibition of atrial TASK-1 currents exerts in vivo antiarrhythmic effects that can be employed for rhythm control in a porcine model of persistent AF. Care has to be taken as TASK-1 inhibition may increase pulmonary artery pressure levels.

Keywords: A293; KCNK3; TASK-1; antiarrhythmic pharmacotherapy; atrial fibrillation; cardioversion.

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Conflict of interest statement

FW and CS have filed a patent application for KCNK3-based gene therapy for cardiac arrhythmia. FW, WH, and CS have filed a patent application for pharmacological TASK-1 inhibition in treatment of atrial arrhythmia. A293-d8 was kindly gifted by Sanofi-Aventis Deutschland GmbH (Frankfurt, Germany). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Experimental protocol, surface electrocardiograms and echocardiography parameters. (A) Subsequent to an electrophysiological (EP) investigation and pacemaker (device) implantation, n = 15 pigs were randomized to atrial fibrillation (AF) induction or a sinus rhythm (SR) control group (n = 5). Pigs randomized to the AF group received AV-node ablations to prevent development of tachycardia-induced heart failure. The AF group was divided into subgroups receiving i.v. sham (NaCl 0.9%; n = 5) or A293 treatment (1 mg/kg bodyweight per day; n = 5). During the 14 days treatment period, pigs received daily sham or A293 treatments, and electrocardiogram (ECG) recordings and clinical investigations (CIV) were performed, and blood samples were taken. At the end of the observation period, electrophysiological investigations were repeated and atrial cardiomyocytes were subjected to patch clamp measurements. The protocol of burst-pacing, applied by the implanted pacemakers is visualized as insert. (B) Representative surface ECG measurements, recorded in a SR control pig at days 0 and 14, are shown in the upper part. No significant differences were observed between the 3 groups when comparing RR and PQ intervals, QRS durations, QT and QTc intervals at day 0 and day 14 with Wilcoxon matched pairs single rank tests. No PQ intervals could be measured in animals which underwent AV node ablation. (C) Values of left ventricular ejection fraction, quantified with echocardiography at day 0 and day 14 did not change significantly (means of n = 4–5 animals; error bars, SEM; scale bar, 200 ms). (D) Plasma levels of A293 (trough levels) during the 14 days period, measured by mass spectrometry. The chemical structure of A293 is provided as insert. Please note that blood clots in central vein catheters caused a relevant loss of follow up at some time points (means of n = 1–5 animals; error bars, SEM).
FIGURE 2
FIGURE 2
Electrophysiological studies. (A) Sinus node recovery times (SNRTs), corrected SNRTs (cSNRTs) and sinoatrial conduction times (SACT), measured according to Strauss et al. (1973) and Narula et al. (1978) compared among the three groups (means of n = 4–5 pigs). (B) Atrial effective refractory periods (AERPs) were significantly reduced in the atrial fibrillation (AF) induction group and could be partially restored by A293 (n = 4–5 pigs). (C) No significant differences in ventricular effective refractory periods (VERPs) were observed between the three groups (n = 4–5 pigs). (D) Left panel: Representative surface ECG recordings from all groups on day 14 (left side). Black dots indicate P waves (scale bar, 200 ms). Right panel: AF burden (i.e., diagnosis of AF in daily surface ECGs in relation to the cumulative number of surface ECGs, documented during the 14 days treatment period) was significantly reduced by A293 treatment (means of n = 4–5 animals; error bars, SEM; *P < 0.05 vs. SR; **P < 0.01 vs. SR; ***P < 0.001 vs. 14 days AF from Student’s t-tests).
FIGURE 3
FIGURE 3
Patch clamp recordings of atrial TASK-1 currents from SR and AF pigs, as well as AF pigs during A293 treatment. (A–C) Representative TASK-1 current recordings, performed in atrial cardiomyocytes isolated from atrial fibrillation (AF) or SR pigs at the end of the 14 days treatment period. TASK-1 currents were calculated as differences to background currents after administration of 200 nM A293. (D) Current-voltage relationships of isolated TASK-1 current densities for the treatment and control groups (n = 10–15 cells, from 4 different animals per group). (E) Comparison of average A293-sensitive current densities among the study groups, quantified at the end of a +20 mV pulse (insert: pulse protocols and scale bars; dotted lines, zero current levels; error bars, SEM; *P < 0.05 from Student’s t-tests).
FIGURE 4
FIGURE 4
Action potential recordings from isolated atrial cardiomyocytes. (A–C) Representative action potential (AP) recordings from atrial cardiomyocytes of the SR control group (A), the atrial fibrillation (AF) group receiving sham treatment (B), and the AF group receiving A293 (C). (D–F) Comparison of the corresponding mean AP durations at 20% (APD20, D), 50% (APD50, E) or 90% repolarization (APD90, F). (G,H) No statistically significant differences were observed among AP amplitude (G) or maximum AP upstroke velocity (H). (I) Similar cell capacities were recorded in all 3 study groups. Means of n = 4–13 cells isolated from 4 animals per group; error bars, SEM; dashed lines, zero potential levels; *P < 0.05 **P < 0.01 from Student’s t-tests.
FIGURE 5
FIGURE 5
Effects of TASK-1 inhibition on pulmonary artery pressure. (A,B) Systemic arterial (A) and pulmonary artery (B) blood pressure levels of n = 4 anesthetized pigs under control conditions (CTRL) and after intravenous application of A293 (1 mg/kg body weight). Means of n = 4 animals; error bars, SEM; *P < 0.05 from Student’s t-tests; dotted lines mark the normal range in humans.
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