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

Abstract

BackgroundUpregulation of the two-pore-domain potassium channel TASK-1 (hK2P3.1) 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.MethodsPersistent 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.ResultsIn 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.ConclusionPharmacological 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.

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

“…Similar results could be observed in an animal model of persistent AF (Wiedmann et al, 2021). To sum up, blockage of TASK-1 currents by A293 leads to anti-arrhythmic effects and acute cardioversion in vivo (Wiedmann et al, 2020(Wiedmann et al, , 2021.…”

“…We have also been able to restore sinus rhythm after elicitation of AF episodes by application of A293 with cardioversion times of about 3 min (Wiedmann et al, 2020). Similar results could be observed in an animal model of persistent AF (Wiedmann et al, 2021). To sum up, blockage of TASK-1 currents by A293 leads to anti-arrhythmic effects and acute cardioversion in vivo (Wiedmann et al, 2020(Wiedmann et al, , 2021.…”

“…Whether pharmacological inhibition of TASK-1 can also lead to PH is still not finally clarified (Olschewski et al, 2016;Schmidt et al, 2016;Wiedmann et al, 2021). Olschewski et al (2016) give for consideration that endothelin-1, a strong endogenous inhibitor of the TASK-1 channel, can induce PH as well as dasatinib, a src tyrosine kinase inhibitor that inactivates the TASK-1 channel (Tang et al, 2009;Montani et al, 2012;Seyler et al, 2012;Nagaraj et al, 2013).…”

“…Very recently, however, our group published some preliminary data on the hemodynamic effect of TASK-1 inhibition in a pig model. A mild increase in pulmonary artery pressure was observed upon acute TASK-1 inhibition (Wiedmann et al, 2021). Therefore, this potential side effect has to be considered in the development of TASK-1 inhibitors for future treatment of AF (Schmidt et al, 2016).…”

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

“…The authors report in a porcine model of persistent atrial fibrillation (AF) that long term in vivo pharmacological inhibition of TASK-1 potassium channels with A293 compound (1 mg/kg/day) has antiarrhythmic effects, suggesting that TASK-1 inhibition can be used to counteract rhythm abnormalities in AF patients (Wiedmann et al, 2020b). Previously, the same group, using in vitro experiments described an upregulation of TASK-1 in patients with AF, which was associated with a shortening of the human atrial action potential (Schmidt et al, 2015).…”