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

Figures

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  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…

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  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).

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  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).

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  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.

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  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.