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首页> 外文期刊>PLoS Computational Biology >Computational prediction of drug response in short QT syndrome type 1 based on measurements of compound effect in stem cell-derived cardiomyocytes
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Computational prediction of drug response in short QT syndrome type 1 based on measurements of compound effect in stem cell-derived cardiomyocytes

机译：基于干细胞衍生心肌细胞的复合作用测量的短QT综合征1型药物反应的计算预测

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Short QT (SQT) syndrome is a genetic cardiac disorder characterized by an abbreviated QT interval of the patient’s electrocardiogram. The syndrome is associated with increased risk of arrhythmia and sudden cardiac death and can arise from a number of ion channel mutations. Cardiomyocytes derived from induced pluripotent stem cells generated from SQT patients (SQT hiPSC-CMs) provide promising platforms for testing pharmacological treatments directly in human cardiac cells exhibiting mutations specific for the syndrome. However, a difficulty is posed by the relative immaturity of hiPSC-CMs, with the possibility that drug effects observed in SQT hiPSC-CMs could be very different from the corresponding drug effect in vivo. In this paper, we apply a multistep computational procedure for translating measured drug effects from these cells to human QT response. This process first detects drug effects on individual ion channels based on measurements of SQT hiPSCCMs and then uses these results to estimate the drug effects on ventricular action potentials and QT intervals of adult SQT patients. We find that the procedure is able to identify IC50 values in line with measured values for the four drugs quinidine, ivabradine, ajmaline and mexiletine. In addition, the predicted effect of quinidine on the adult QT interval is in good agreement with measured effects of quinidine for adult patients. Consequently, the computational procedure appears to be a useful tool for helping predicting adult drug responses from pure in vitro measurements of patient derived cell lines.
机译：短QT（SQT）综合征是一种遗传心脏障碍，其特征在于患者心电图的缩写QT间隔。该综合征与心律失常的风险增加和心脏猝死的风险增加，并且可以从许多离子通道突变产生。来自SQT患者（SQT HIPSC-CMS）产生的诱导多能干细胞的心肌细胞提供了有希望的平台，用于在表现出对综合征特异的突变的人体心脏细胞中进行药理学治疗。然而，困难是通过HIPSC-CMS的相对不成熟来构成的，并且在SQT HIPSC-CMS中观察到的药物效应可能与体内相应的药物作用非常不同。在本文中，我们应用了多步骤计算程序，以将测量的药物效应从这些细胞转化为人QT响应。该方法首先基于SQT Hipscm的测量检测对单个离子通道的药物影响，然后使用这些结果来估计对健心室作用电位和成人SQT患者的QT间隔的药物影响。我们发现该程序能够以四种药物奎尼丁，Ivabradine，Ajmaline和梅西汀的测量值识别IC50值。此外，奎尼丁对成年QT间歇的预测作用与成年患者奎尼丁的测量效果吻合良好。因此，计算过程似乎是有用的工具，用于帮助预测患者衍生细胞系的纯度体外测量的成人药物反应。

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