Early afterdepolarisation tendency as a simulated pro-arrhythmic risk indicator
Early afterdepolarisation tendency as a simulated pro-arrhythmic risk indicator
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DOI：
10.1039/c7tx00141j
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发表时间：
2017-11-01
影响因子：
2.1
通讯作者：
Mirams, Gary R.
中科院分区：
文献类型：
--
作者：
McMillan, Beth;Gavaghan, David J.;Mirams, Gary R.
药物诱导的尖端扭转型室性心动过速（TdP）心律失常是预测毒理学的主要兴趣。引起TdP的药物阻断hERG心脏钾通道。然而，并非所有阻断hERG的药物都会引起TdP。因此，需要进一步了解TdP的机制途径。早期后去极化（埃兹）是一种细胞水平的现象，其中心脏细胞的膜在复极化之前第二次去极化，并且在TdP期间在心脏中观察到埃兹。因此，我们提出了一种预测TdP的方法，使用诱导的埃兹结合多个离子通道阻滞在模拟中使用基于生物物理的数学模型的人类心室细胞电生理。使用基于已知引起埃兹的疾病的干预措施在心脏动作电位模型中诱导埃兹，包括：增加L型钙通道的传导，降低hERG通道的传导，以及移动快钠通道的失活曲线。使用引起EAD所需的干预阈值将药物分类为临床风险类别。使用L-型钙诱导的埃兹的度量是将药物分类为正确风险类别的最准确的EAD度量，并且当与动作电位持续时间测量相结合时，准确性增加。EAD指标都比单独的hERG阻滞更准确，但预测性不如模拟动作电位时程等更简单的指标。这可能是因为埃兹的不同途径代表了不同患者亚组的风险，目前难以评估。
Drug-induced Torsades de Pointes (TdP) arrhythmia is of major interest in predictive toxicology. Drugs which cause TdP block the hERG cardiac potassium channel. However, not all drugs that block hERG cause TdP. As such, further understanding of the mechanistic route to TdP is needed. Early afterdepolarisations (EADs) are a cell-level phenomenon in which the membrane of a cardiac cell depolarises a second time before repolarisation, and EADs are seen in hearts during TdP. Therefore, we propose a method of predicting TdP using induced EADs combined with multiple ion channel block in simulations using bio-physically-based mathematical models of human ventricular cell electrophysiology. EADs were induced in cardiac action potential models using interventions based on diseases that are known to cause EADs, including: increasing the conduction of the L-type calcium channel, decreasing the conduction of the hERG channel, and shifting the inactivation curve of the fast sodium channel. The threshold of intervention that was required to cause an EAD was used to classify drugs into clinical risk categories. The metric that used L-type calcium induced EADs was the most accurate of the EAD metrics at classifying drugs into the correct risk categories, and increased in accuracy when combined with action potential duration measurements. The EAD metrics were all more accurate than hERG block alone, but not as predictive as simpler measures such as simulated action potential duration. This may be because different routes to EADs represent risk well for different patient subgroups, something that is difficult to assess at present.