Inhibition of KCa2 and Kv11.1 Channels in Pigs With Left Ventricular Dysfunction

Background: Inhibition of K_CA2 channels, conducting I_KCa, can convert atrial fibrillation (AF) to sinus rhythm and protect against its induction. I_KCa inhibition has been shown to possess functional atrial selectivity with minor effects on ventricles. Under pathophysiological conditions with ventricular remodeling, however, inhibiting I_KCa can exhibit both proarrhythmic and antiarrhythmic ventricular effects. The aim of this study was to evaluate the effects of the I_KCa inhibitor AP14145, when given before or after the I_Kr blocker dofetilide, on cardiac function and ventricular proarrhythmia markers in pigs with or without left ventricular dysfunction (LVD).

Methods: Landrace pigs were randomized into an AF group (n = 6) and two control groups: SHAM1 (n = 8) and SHAM2 (n = 4). AF pigs were atrially tachypaced (A-TP) for 43 ± 4 days until sustained AF and LVD developed. A-TP and SHAM1 pigs received 20 mg/kg AP14145 followed by 100 µg/kg dofetilide whereas SHAM2 pigs received the same drugs in the opposite order. Proarrhythmic markers such as short-term variability of QT (STV_QT) and RR (STV_RR) intervals, and the number of premature ventricular complexes (PVCs) were measured at baseline and after administration of drugs. The influence on cardiac function was assessed by measuring cardiac output, stroke volume, and relevant echocardiographic parameters.

Results: I_KCa inhibition by AP14145 did not increase STV_QT or STV_RR in any of the pigs. I_Kr inhibition by dofetilide markedly increased STV_QT in the A-TP pigs, but not in SHAM operated pigs. Upon infusion of AP14145 the number of PVCs decreased or remained unchanged both when AP14145 was infused after baseline and after dofetilide. Conversely, the number of PVCs increased or remained unchanged upon dofetilide infusion. Neither AP14145 nor dofetilide affected relevant echocardiographic parameters, cardiac output, or stroke volume in any of the groups.

Conclusion: I_KCa inhibition with AP14145 was not proarrhythmic in healthy pigs, or in the presence of LVD resulting from A-TP. In pigs already challenged with 100 µg/kg dofetilide there were no signs of proarrhythmia when 20 mg/kg AP14145 were infused. K_CA2 channel inhibition did not affect cardiac function, implying that K_CA2 inhibitors can be administered safely also in the presence of LV dysfunction.

KCa2 channels; atrial fibrillation; dofetilide; pig model; small-conductance Ca2+-activated K+ channels; ventricular dysfunction.