A computational analysis of the effect of sevoflurane in a human ventricular cell model of long QT syndrome: Importance of repolarization reserve in the QT-prolonging effect of sevoflurane
A computational analysis of the effect of sevoflurane in a human ventricular cell model of long QT syndrome: Importance of repolarization reserve in the QT-prolonging effect of sevoflurane
复制标题
七氟醚在长 QT 综合征心室细胞模型中作用的计算分析：复极储备在七氟醚 QT 延长作用中的重要性
DOI：
10.1016/j.ejphar.2020.173378
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发表时间：
2020
影响因子：
5
通讯作者：
Matsuura Hiroshi
中科院分区：
文献类型：
--
作者：
Kojima Akiko;Fukushima Yutaka;Itoh Hideki;Imoto Keiji;Matsuura Hiroshi
缓慢和快速激活的延迟整流钾离子通道（IKr和IKk）对心室动作电位的复极起作用，从而决定心电图上的QT间期。编码IKK和IKR的基因的功能缺失突变导致1型和2型长QT综合征（分别为LQT 1和LQT 2），伴有恶性室性心律失常和心源性猝死的高风险。本研究旨在研究哪些心脏电生理条件会加重七氟烷的QT延长和致心律失常作用。我们使用O 'Hara-Rudy动力学模型重建人心室动作电位和伪心电图，并分别通过降低IK和IKr的电导来模拟LQT 1和LQT 2表型。在野生型、LQT 1和LQT 2模型中，七氟烷延长心室动作电位时程和QT间期，但丙泊酚不延长。七氟烷在LQT 2模型中的QT延长作用比野生型和LQT 1模型中更显著。七氟醚对IKs的强抑制作用是其QT延长作用的主要原因。在LQT 2模型中，通过降低IK而过度延长心室动作电位时程，IK显著增强，并且IK对心室复极的相对贡献显著增加，这似乎是七氟烷在LQT 2模型中比野生型和LQT 1模型更显著的QT延长作用的基础。这项模拟研究清楚地阐明了七氟烷在野生型、LQT 1和LQT 2模型中QT延长效应差异的电生理基础，并可能为临床环境中长QT综合征患者制定麻醉策略提供重要信息。
The slowly and rapidly activating delayed rectifier K+channels (IKsandIKr, 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 encodingIKsandIKrcause 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 ofIKsandIKr, 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 onIKswas primarily responsible for its QT-prolonging effect. In LQT2 model, IKswas considerably enhanced during excessive prolongation of ventricular action potential duration by reduction ofIKrand relative contribution ofIKsto 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.