Frommeyer Gerrit, Weller Jan, Ellermann Christian, Kaese Sven, Kochhäuser Simon, Lange Philipp S, Dechering Dirk G, Eckardt Lars
Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany.
Clin Exp Pharmacol Physiol. 2017 Sep;44(9):941-945. doi: 10.1111/1440-1681.12790.
The I channel inhibitor ivabradine is recommended for treatment of chronic heart failure. However, ivabradine also inhibits human ether-a-go-go (hERG) mediated potassium currents. The aim of the present study was to assess the electrophysiologic effects of ivabradine in an experimental model of short-QT-syndrome. Twelve rabbit hearts were isolated and Langendorff-perfused. After obtaining baseline data, pinacidil, an I channel opener, was infused (1 μmol/L). Eight endo- and epicardial monophasic action potentials and a 12-lead ECG showed a significant abbreviation of QT interval (-32 ms, P<.05) and shortening of action potential duration at 90% of repolarization (APD90; -22 ms, P<.05). The shortening of ventricular repolarization was accompanied by a reduction of effective refractory period (ERP; -20 ms, P<.05). Thereafter, hearts were additionally treated with ivabradine (5 μmol/L) leading to an increase of QT interval (+31 ms, P<.05), APD90 (+15 ms, P<.05) as well as of ERP (+38 ms, P<.05) and post-repolarization refractoriness (PRR, +33 ms, P<.05) as compared with sole pinacidil infusion. Under baseline conditions, ventricular fibrillation (VF) was inducible by a standardized pacing protocol including programmed stimulation and burst stimulation in 3 of 12 hearts (6 episodes). After application of 1 μmol/L pinacidil, 6 of 12 hearts were inducible (22 episodes). Additional infusion of 5 μmol/L ivabradine led to a significant suppression of VF. Only two episodes could be induced in 1 of 12 hearts. In the present study ivabradine reversed the electrophysiologic effects of pharmacologically simulated short-QT syndrome. Ivabradine demonstrated antiarrhythmic properties based on an increase of both ERP and PRR.
I 通道抑制剂伊伐布雷定被推荐用于治疗慢性心力衰竭。然而，伊伐布雷定也会抑制人醚 - 去极化相关基因（hERG）介导的钾电流。本研究的目的是评估伊伐布雷定在短 QT 综合征实验模型中的电生理效应。选取 12 只兔心脏进行离体 Langendorff 灌注。获取基线数据后，输注 I 通道开放剂匹那地尔（1 μmol/L）。8 个心内膜和心外膜单相动作电位以及 12 导联心电图显示 QT 间期显著缩短（-32 ms，P<0.05），复极化 90%时动作电位时程缩短（APD90；-22 ms，P<0.05）。心室复极化的缩短伴随着有效不应期的缩短（ERP；-20 ms，P<0.05）。此后，心脏再用伊伐布雷定（5 μmol/L）处理，与单独输注匹那地尔相比，QT 间期增加（+31 ms，P<0.05）、APD90 增加（+15 ms，P<0.05）、ERP 增加（+38 ms，P<0.05）以及复极化后不应期（PRR，+33 ms，P<0.05）。在基线条件下，12 只心脏中有 3 只（6 次发作）通过包括程序刺激和猝发刺激的标准化起搏方案可诱发出室颤（VF）。应用 1 μmol/L 匹那地尔后，12 只心脏中有 6 只可诱发（22 次发作）。额外输注 5 μmol/L 伊伐布雷定导致 VF 显著抑制。12 只心脏中只有 1 只诱发了 2 次发作。在本研究中，伊伐布雷定逆转了药理学模拟短 QT 综合征的电生理效应。伊伐布雷定基于 ERP 和 PRR 的增加显示出抗心律失常特性。
