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Nat Protoc. 2018 Dec;13(12):3018-3041. doi: 10.1038/s41596-018-0076-8.

Use of human induced pluripotent stem cell-derived cardiomyocytes to assess drug cardiotoxicity.

Author information

1
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
2
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
3
Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
4
Department of Mechanical and Aerospace Engineering, University of California, San Diego, San Diego, CA, USA.
5
Department of Pharmacology and Center for Pharmacogenomics, Northwestern University School of Medicine, Chicago, IL, USA.
6
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA. joewu@stanford.edu.
7
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. joewu@stanford.edu.
8
Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. joewu@stanford.edu.

Abstract

Cardiotoxicity has historically been a major cause of drug removal from the pharmaceutical market. Several chemotherapeutic compounds have been noted for their propensities to induce dangerous cardiac-specific side effects such as arrhythmias or cardiomyocyte apoptosis. However, improved preclinical screening methodologies have enabled cardiotoxic compounds to be identified earlier in the drug development pipeline. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can be used to screen for drug-induced alterations in cardiac cellular contractility, electrophysiology, and viability. We previously established a novel 'cardiac safety index' (CSI) as a metric that can evaluate potential cardiotoxic drugs via high-throughput screening of hiPSC-CMs. This metric quantitatively examines drug-induced alterations in CM function, using several in vitro readouts, and normalizes the resulting toxicity values to the in vivo maximum drug blood plasma concentration seen in preclinical or clinical pharmacokinetic models. In this ~1-month-long protocol, we describe how to differentiate hiPSCs into hiPSC-CMs and subsequently implement contractility and cytotoxicity assays that can evaluate drug-induced cardiotoxicity in hiPSC-CMs. We also describe how to carry out the calculations needed to generate the CSI metric from these quantitative toxicity measurements.

PMID:
30413796
PMCID:
PMC6502639
[Available on 2019-12-01]
DOI:
10.1038/s41596-018-0076-8
[Indexed for MEDLINE]

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