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Cardiotoxicity screening: a review of rapid-throughput in vitro approaches

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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 Ca2+ dynamics-based cardiomyocytes contractility assays. This review aims to discuss advantages and limitations of these phenotypic assays for cardiac toxicity assessment.

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Abbreviations

AP:

Action potential

APC:

Automated patch clamping

ESC:

Embryonic stem cell

FPD:

Field potential duration

FLIPR:

Fluorescent imaging plate reader

iPSC:

Induced pluripotent stem cell

IC50 :

Half-maximal inhibitory concentration

Kv :

Voltage-gated potassium channels

LQTs:

Long-QT syndrome

MEA:

Microelectrode array

Nav :

Voltage-gated sodium channels

RTCA:

The real-time cell analyzer

TdP:

Torsade de pointes

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Acknowledgments

This research was supported by the Natural Science Foundation of China [Grant 81473539, 21525730, 21177150], the Jiangsu Provincial Natural Science Foundation [Grant BK20141357], Strategic Priority Research Program of the Chinese Academy of Sciences [Grant XDB14030401] and the Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University [Grant SKLNMZZJQ201402].

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Authors and Affiliations

  1. 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

    Xichun Li & Zhengyu Cao

  2. Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, 95616, USA

    Rui Zhang

  3. Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China

    Bin Zhao

  4. Department of Neurology, University of California, Davis, Sacramento, CA, 95817, USA

    Christoph Lossin

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  1. Xichun Li
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  2. Rui Zhang
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  3. Bin Zhao
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  4. Christoph Lossin
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  5. Zhengyu Cao
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Correspondence to Bin Zhao or Zhengyu Cao.

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Li, X., Zhang, R., Zhao, B. et al. Cardiotoxicity screening: a review of rapid-throughput in vitro approaches. Arch Toxicol 90, 1803–1816 (2016). https://doi.org/10.1007/s00204-015-1651-1

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