Citerni Carlotta, Kirchhoff Jeppe, Olsen Lisbeth Høier, Sattler Stefan Michael, Grunnet Morten, Edvardsson Nils, Bentzen Bo Hjorth, Diness Jonas Goldin
Biomedical Institute, University of Copenhagen, Copenhagen, Denmark.
Acesion Pharma, Copenhagen, Denmark.
Front Pharmacol. 2020 May 6;11:556. doi: 10.3389/fphar.2020.00556. eCollection 2020.
Inhibition of K2 channels, conducting I, can convert atrial fibrillation (AF) to sinus rhythm and protect against its induction. I inhibition has been shown to possess functional atrial selectivity with minor effects on ventricles. Under pathophysiological conditions with ventricular remodeling, however, inhibiting I can exhibit both proarrhythmic and antiarrhythmic ventricular effects. The aim of this study was to evaluate the effects of the I inhibitor AP14145, when given before or after the I blocker dofetilide, on cardiac function and ventricular proarrhythmia markers in pigs with or without left ventricular dysfunction (LVD).
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) and RR (STV) 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.
I inhibition by AP14145 did not increase STV or STV in any of the pigs. I inhibition by dofetilide markedly increased STV 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.
I 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. K2 channel inhibition did not affect cardiac function, implying that K2 inhibitors can be administered safely also in the presence of LV dysfunction.
抑制介导I电流的K2通道可将心房颤动（AF）转为窦性心律并预防其诱发。已表明抑制I电流具有功能性心房选择性，对心室影响较小。然而，在伴有心室重构的病理生理条件下，抑制I电流可表现出促心律失常和抗心律失常的心室效应。本研究的目的是评估I电流抑制剂AP14145在I电流阻滞剂多非利特之前或之后给药时，对伴有或不伴有左心室功能障碍（LVD）的猪的心脏功能和心室促心律失常标志物的影响。
长白猪被随机分为AF组（n = 6）和两个对照组：假手术组1（SHAM1，n = 8）和假手术组2（SHAM2，n = 4）。AF组猪进行心房快速起搏（A-TP）43±4天，直至发生持续性AF和LVD。A-TP组和SHAM1组猪先接受20 mg/kg AP14145，随后接受100 μg/kg多非利特，而SHAM2组猪以相反顺序接受相同药物。在基线和给药后测量促心律失常标志物，如QT间期（STV）和RR间期（STV）的短期变异性以及室性早搏（PVC）的数量。通过测量心输出量、每搏输出量和相关超声心动图参数评估对心脏功能的影响。
AP14145抑制I电流在任何猪中均未增加STV或STV。多非利特抑制I电流使A-TP组猪的STV显著增加，但在假手术组猪中未增加。在基线后和多非利特给药后输注AP14145时PVC数量均减少或保持不变。相反，输注多非利特时PVC数量增加或保持不变。AP14145和多非利特均未影响任何组的相关超声心动图参数、心输出量或每搏输出量。
在健康猪或因A-TP导致LVD的情况下，用AP14145抑制I电流不会引起促心律失常。在已接受100 μg/kg多非利特挑战的猪中，输注20 mg/kg AP14145时没有促心律失常的迹象。抑制K2通道不影响心脏功能，这意味着在存在左心室功能障碍的情况下也可安全使用K2抑制剂。
