A new paradigm for drug-induced torsadogenic risk assessment using human iPS cell-derived cardiomyocytes
A new paradigm for drug-induced torsadogenic risk assessment using human iPS cell-derived cardiomyocytes
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DOI：
10.1016/j.vascn.2016.12.003
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发表时间：
2017-03-01
影响因子：
1.9
通讯作者：
Sekino, Yuko
中科院分区：
文献类型：
--
作者：
Ando, Hiroyuki;Yoshinaga, Takashi;Sekino, Yuko
简介：人诱导多能干细胞衍生的心肌细胞（hiPSC-CM）预计将成为一个有用的工具，进行心律失常风险评估的候选药物。然而，使用hiPSC-CMs的扭转性室性心动过速风险预测范式尚未完全建立。方法：使用多电极阵列（MEA）系统记录hiPSC-CMs的细胞外场电位（Hs）。用60种药物评价了对FP的影响，其中包括57种具有各种临床致扭转型室性心动过速风险的药物。使用快速平衡透析装置的平衡透析方法测量培养基中的实际药物浓度。根据FP持续时间延长和早期后除极发生的程度，确定每种药物的相对尖端扭转型室性心动过速（TdP）评分。根据培养基中的游离浓度和游离有效治疗血浆浓度计算界值。每种药物的结果绘制在一个二维地图上的相对TdP风险分数与margins.Results：每种药物被归类为高，中，或低风险的基础上，其位置在预定义的区域内的二维地图。我们将19种药物归类为高风险，18种为中等风险，17种为低风险。我们检查了我们对CreclibleMeds中的高风险和低风险药物的分类与致氯沙痛风险分类之间的一致性。结论：本系统具有较高的一致性，敏感性为81%，特异性为87%，准确性为83%。在这里，我们提出了一种新的药物诱导的扭转型室性心动过速的风险分类系统，使用hiPSC-CM和MEA系统。(C)2016年6月，作者。由Elsevier Inc发布这是CC BY-NC-ND许可下的开放获取文章
Introduction: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) arc anticipated to be a useful tool for conducting proarrhythmia risk assessments of drug candidates. However, a torsadogenic risk prediction paradigm using hiPSC-CMs has not yet been fully established.Methods: Extracellular field potentials (Hs) were recorded from hiPSC-CMs using the multi-electrode array (MEA) system. The effects on FPs were evaluated with 60 drugs, including 57 with various clinical torsadogenic risks. Actual drug concentrations in medium were measured using the equilibrium dialysis method with a Rapid Equilibrium Dialysis device. Relative torsade de pointes (TdP) scores were determined for each drug according to the degree of FP duration prolongation and early afterdepolarization occurrence. The margins were calculated from the free concentration in medium and free effective therapeutic plasma concentration. Each drug's results were plotted on a two-dimensional map of relative TdP risk scores versus margins.Results: Each drug was categorised as high, intermediate, or low risk based on its location within predefined areas of the two-dimensional map. We categorised 19 drugs as high risk; 18 as intermediate risk; and 17 as low risk. We examined the concordance between our categorisation of high and low risk drugs against the lorsadogenic risk categorisation in CreclibleMeds. Our system demonstrated high concordance, as reflected in a sensitivity of 81%, specificity of 87%, and accuracy of 83%.Discussion: These results indicate that our lorsadogenic risk assessment is reliable and has a potential lo replace the hERG assay for torsaclogenic risk prediction, however, this system needs to be improved for the accurate of prediction of clinical TdP risk. Here, we propose a novel drug induced torsadogenic risk categorising system using hiPSC-CMs and the MEA system. (C) 2016 The Authors. Published by Elsevier Inc This is an open access article under the CC BY-NC-ND license