title: Cardiotoxicity screening: a review of rapid-throughput in vitro approaches.
abstract: Cardiac toxicity represents one of the leading causes of drug failure along different stages of drug development. Multiple very successful pharmaceuticals had to be pulled from the market or labeled with strict usage warnings due to adverse cardiac effects. In order to protect clinical trial participants and patients, the International Conference on Harmonization published guidelines to recommend that all new drugs to be tested preclinically for hERG (Kv11.1) channel sensitivity before submitting for regulatory reviews. However, extensive studies have demonstrated that measurement of hERG activity has limitations due to the multiple molecular targets of drug compound through which it may mitigate or abolish a potential arrhythmia, and therefore, a model measuring multiple ion channel effects is likely to be more predictive. Several phenotypic rapid-throughput methods have been developed to predict the potential cardiac toxic compounds in the early stages of drug development using embryonic stem cells- or human induced pluripotent stem cell-derived cardiomyocytes. These rapid-throughput methods include microelectrode array-based field potential assay, impedance-based or Ca(2+) dynamics-based cardiomyocytes contractility assays. This review aims to discuss advantages and limitations of these phenotypic assays for cardiac toxicity assessment.
authors.affiliation: State Key Laboratory of Natural Medicines and Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Development, China Pharmaceutical University, 639, Longmian Ave, Jiangning District, Nanjing, 211198, People's Republic of China.
authors.forename: Xichun
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, 95616, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China. binzhao@rcees.ac.cn.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Department of Neurology, University of California, Davis, Sacramento, CA, 95817, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Lossin
authors.affiliation: State Key Laboratory of Natural Medicines and Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Development, China Pharmaceutical University, 639, Longmian Ave, Jiangning District, Nanjing, 211198, People's Republic of China. zycao1999@hotmail.com.
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Cao
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D066126:Cardiotoxicity; D002317:Cardiovascular Agents / Q000633:toxicity*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D000072237:ERG1 Potassium Channel / Q000037:antagonists & inhibitors; D053595:Embryonic Stem Cells / Q000187:drug effects*; D057166:High-Throughput Screening Assays; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects*; D008839:Microelectrodes; D032383:Myocytes, Cardiac / Q000187:drug effects*; D056737:Safety-Based Drug Withdrawals
chemical_list: D002317:Cardiovascular Agents; D000072237:ERG1 Potassium Channel; C000606913:KCNH2 protein, human
keywords: Automated patch clamp; Cardiotoxicity; Fluorescence plate reader; Microelectrode array; Rapid throughput; hERG