Department of Anesthesiology, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan.
Department of Anesthesiology, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan.
Eur J Pharmacol. 2020 Sep 15;883:173378. doi: 10.1016/j.ejphar.2020.173378. Epub 2020 Jul 22.
The slowly and rapidly activating delayed rectifier K channels (I and I, respectively) contribute to the repolarization of ventricular action potential in human heart and thereby determine QT interval on an electrocardiogram. Loss-of-function mutations in genes encoding I and I cause type 1 and type 2 long QT syndrome (LQT1 and LQT2, respectively), accompanied by a high risk of malignant ventricular arrhythmias and sudden cardiac death. This study was designed to investigate which cardiac electrophysiological conditions exaggerate QT-prolonging and arrhythmogenic effects of sevoflurane. We used the O'Hara-Rudy dynamic model to reconstruct human ventricular action potential and a pseudo-electrocardiogram, and simulated LQT1 and LQT2 phenotypes by decreasing conductances of I and I, respectively. Sevoflurane, but not propofol, prolonged ventricular action potential duration and QT interval in wild-type, LQT1 and LQT2 models. The QT-prolonging effect of sevoflurane was more profound in LQT2 than in wild-type and LQT1 models. The potent inhibitory effect of sevoflurane on I was primarily responsible for its QT-prolonging effect. In LQT2 model, I was considerably enhanced during excessive prolongation of ventricular action potential duration by reduction of I and relative contribution of I to ventricular repolarization was markedly elevated, which appears to underlie more pronounced QT-prolonging effect of sevoflurane in LQT2 model, compared with wild-type and LQT1 models. This simulation study clearly elucidates the electrophysiological basis underlying the difference in QT-prolonging effect of sevoflurane among wild-type, LQT1 and LQT2 models, and may provide important information for developing anesthetic strategies for patients with long QT syndrome in clinical settings.
缓慢激活延迟整流钾通道（I 和 I，分别）有助于人类心脏心室动作电位的复极，从而决定心电图上的 QT 间期。编码 I 和 I 的基因突变导致 1 型和 2 型长 QT 综合征（LQT1 和 LQT2，分别），伴有恶性室性心律失常和心脏性猝死的高风险。本研究旨在探讨哪些心脏电生理条件会夸大七氟醚的 QT 延长和致心律失常作用。我们使用 O'Hara-Rudy 动力学模型重建人类心室动作电位和假性心电图，并通过分别降低 I 和 I 的电导来模拟 LQT1 和 LQT2 表型。七氟醚而不是异丙酚延长了野生型、LQT1 和 LQT2 模型中的心室动作电位持续时间和 QT 间期。与野生型和 LQT1 模型相比，LQT2 模型中七氟醚的 QT 延长作用更为明显。七氟醚对 I 的强烈抑制作用是其 QT 延长作用的主要原因。在 LQT2 模型中，I 在 I 减少导致心室动作电位持续时间过度延长期间得到显著增强，I 对心室复极的相对贡献明显升高，这似乎是 LQT2 模型中七氟醚 QT 延长作用比野生型和 LQT1 模型更为明显的基础。这项模拟研究清楚地阐明了七氟醚在野生型、LQT1 和 LQT2 模型中 QT 延长作用差异的电生理基础，并可为临床长 QT 综合征患者制定麻醉策略提供重要信息。
