Global Optimization of Ventricular Myocyte Model to Multi-Variable Objective Improves Predictions of Drug-Induced Torsades de Pointes.
Global Optimization of Ventricular Myocyte Model to Multi-Variable Objective Improves Predictions of Drug-Induced Torsades de Pointes.
复制标题
DOI：
10.3389/fphys.2017.01059
复制
发表时间：
2017
影响因子：
4
通讯作者：
Christini DJ
中科院分区：
文献类型：
--
作者：
Krogh-Madsen T;Jacobson AF;Ortega FA;Christini DJ
计算机心肌细胞模型为药物安全性测试和预测离子通道突变的表型后果提供了强大的工具，但其准确性有时有限。例如，描述人类心室电生理学的几个模型在模拟长QT突变的影响时表现不佳。模型优化代表了获得具有更强预测能力的模型的一种方式。使用最近的人心室肌细胞模型，我们证明了模型优化临床长QT数据，结合细胞内钙和钠浓度的生理基础的界限，更好地约束模型参数。为了确定针对先天性长QT数据进行优化的模型是否能更好地预测药物诱导的长QT间期发生风险，特别是尖端扭转型室性心动过速风险，我们针对已知致心律失常和非致心律失常离子通道阻滞剂的数据库对优化模型进行了检测。在这样做时，优化模型提供了改进的风险评估。特别是，我们证明了消除假阳性结果产生的基线模型，其中模拟的非扭转型室性心动过速药物，特别是维拉帕米，预测动作电位延长。我们的研究结果强调了电流的重要性，超出了那些直接影响的药物块在确定扭转型室速的风险。我们的研究还强调了在心肌细胞模型优化中需要丰富的数据，并证实了这种优化是一种生成具有更高准确性的药物诱导的心脏毒性预测模型的方法。
In silico cardiac myocyte models present powerful tools for drug safety testing and for predicting phenotypical consequences of ion channel mutations, but their accuracy is sometimes limited. For example, several models describing human ventricular electrophysiology perform poorly when simulating effects of long QT mutations. Model optimization represents one way of obtaining models with stronger predictive power. Using a recent human ventricular myocyte model, we demonstrate that model optimization to clinical long QT data, in conjunction with physiologically-based bounds on intracellular calcium and sodium concentrations, better constrains model parameters. To determine if the model optimized to congenital long QT data better predicts risk of drug-induced long QT arrhythmogenesis, in particular Torsades de Pointes risk, we tested the optimized model against a database of known arrhythmogenic and non-arrhythmogenic ion channel blockers. When doing so, the optimized model provided an improved risk assessment. In particular, we demonstrate an elimination of false-positive outcomes generated by the baseline model, in which simulations of non-torsadogenic drugs, in particular verapamil, predict action potential prolongation. Our results underscore the importance of currents beyond those directly impacted by a drug block in determining torsadogenic risk. Our study also highlights the need for rich data in cardiac myocyte model optimization and substantiates such optimization as a method to generate models with higher accuracy of predictions of drug-induced cardiotoxicity.
登录
查看更多内容
DOI：
10.1152/ajpheart.00808.2011
发表时间：
2012-04-01
影响因子：
4.8
作者：
Davies, M. R.;Mistry, H. B.;Abi-Gerges, N.
通讯作者：
Abi-Gerges, N.
在脑膜心律失常风险评估中优化硅心细胞模型。
影响因子：
4
作者：
Dutta S;Chang KC;Beattie KA;Sheng J;Tran PN;Wu WW;Wu M;Strauss DG;Colatsky T;Li Z
通讯作者：
Li Z
支持向量机和计算生物学的内核。
影响因子：
4.3
作者：
Ben-Hur, Asa;Ong, Cheng Soon;Sonnenburg, Soeren;Schoelkopf, Bernhard;Raetsch, Gunnar
通讯作者：
Raetsch, Gunnar
影响因子：
3.7
作者：
Kaur J;Nygren A;Vigmond EJ
通讯作者：
Vigmond EJ
影响因子：
4
作者：
Passini E;Britton OJ;Lu HR;Rohrbacher J;Hermans AN;Gallacher DJ;Greig RJH;Bueno-Orovio A;Rodriguez B
通讯作者：
Rodriguez B