Screening system for drug-induced arrhythmogenic risk combining a patch clamp and heart simulator.
Screening system for drug-induced arrhythmogenic risk combining a patch clamp and heart simulator.
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DOI：
10.1126/sciadv.1400142
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发表时间：
2015-05
期刊：
影响因子：
13.6
通讯作者：
Hisada T
中科院分区：
文献类型：
--
作者：
Okada J;Yoshinaga T;Kurokawa J;Washio T;Furukawa T;Sawada K;Sugiura S;Hisada T
寻找沉默跳过的心跳：使用高通量混合心脏模拟器预测引起心律失常的药物。为了节省药物发现的时间和成本，需要在心脏毒性测试中进行范式转变。我们介绍了一种新的筛选系统，结合体外药理学试验和多尺度心脏模拟器的药物诱导的致瘤风险。对于12种被报道具有不同心脏毒性风险的药物，使用自动膜片钳系统测定了6种离子通道的剂量-抑制曲线。通过操纵由2000多万个肌细胞模型组成的心脏模拟器中实现的通道模型，我们模拟了各种药物剂量下的标准心电图（ECG）。当药物浓度从治疗水平增加时，每种药物均诱导浓度依赖性特征性类型的室性心律失常，而在已知安全的药物的任何剂量下均未观察到心律失常。我们已经证明，我们的系统结合体外和计算机技术可以可靠有效地预测药物诱导的致癌风险。
Finding the silent skipped beat: Predicting arrhythmia-causing drugs using a high-throughput hybrid heart simulator. To save time and cost for drug discovery, a paradigm shift in cardiotoxicity testing is required. We introduce a novel screening system for drug-induced arrhythmogenic risk that combines in vitro pharmacological assays and a multiscale heart simulator. For 12 drugs reported to have varying cardiotoxicity risks, dose-inhibition curves were determined for six ion channels using automated patch clamp systems. By manipulating the channel models implemented in a heart simulator consisting of more than 20 million myocyte models, we simulated a standard electrocardiogram (ECG) under various doses of drugs. When the drug concentrations were increased from therapeutic levels, each drug induced a concentration-dependent characteristic type of ventricular arrhythmia, whereas no arrhythmias were observed at any dose with drugs known to be safe. We have shown that our system combining in vitro and in silico technologies can predict drug-induced arrhythmogenic risk reliably and efficiently.