ackground: Small conductance Ca2+ activated K+ (SK) channel inhibition has generating conflicting results in the setting of left ventricular dysfunction (LVD).

Objective: To evaluate the effect of the SK channel inhibitor AP14145 compared to dofetilide in LVD induced by atrial tachypacing (ATP) in pigs.

Methods: A total of 18 pigs were divided into an atrial fibrillation (AF) group and a control group. AF pigs were atrially tachypaced for 4–8 weeks until sustained vernakalant-resistant AF developed. Signs of remodeling were investigated by echocardiography (after cardioversion), biomarkers and tissue analysis. Effect of 20 mg/kg AP14145, given alone or before 0.1 mg/kg dofetilide, or vice versa, were compared in terms of short term variability (STV) of the QT and RR intervals.

Results: ATP resulted in a reduced ejection fraction (EF) (52±4 vs. 69±3%, p=0.003, AF vs. controls). This was accompanied by increased end diastolic and systolic LA volumes (50±8 vs. 29±2 ml, p=0.03 and 36±8 vs. 11±0.5 ml, p=0.0007) and LA area (18±2 vs. 11±0.5 cm2, p=0.0006). In pigs with AF, the STV of QT did not change when AP14145 was given alone or before dofetilide, but increased when dofetilide was given alone or after AP14145 (from 0.02±0.07 to 0.55±0.11, n=4, p=0.02). The baseline STV of RR was significantly reduced by AP14145 (from 0.31±0.14 to -0.33±0.11, n=4, p=0.01) and increased by dofetilide (1.5±0.16, n=4, p=0.04 and 0.01).

Conclusions: Atrial tachypacing induced AF with concomitantly lowered EF and increased LA volume and area. These findings show that structural remodeling developed, yet SK inhibition by AP14145 did not induce any pro-arrhythmic effects in the ventricles, in contrast to the positive control dofetilide.

Acknowledgement/Funding: Innovation Fund Denmark, the Carlsberg Foundation, the Wellcome Trust European Union's Horizon 2020 research and innovation programme