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Front Physiol. 2017 Oct 11;8:766. doi: 10.3389/fphys.2017.00766. eCollection 2017.

An Automated Platform for Assessment of Congenital and Drug-Induced Arrhythmia with hiPSC-Derived Cardiomyocytes.

Author information

1
Department of Medicine, Cardiovascular Institute, Stanford University, Stanford, CA, United States.
2
Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States.
3
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States.
4
Department of Bioengineering, University of California, San Diego, San Diego, CA, United States.
5
Vala Sciences, San Diego, CA, United States.
6
Departments of Chemistry, Molecular and Cell Biology, Helen Wills Neuroscience, University of California, Berkeley, Berkeley, CA, United States.
7
Human BioMolecular Research Institute, San Diego, CA, United States.

Abstract

The ability to produce unlimited numbers of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) harboring disease and patient-specific gene variants creates a new paradigm for modeling congenital heart diseases (CHDs) and predicting proarrhythmic liabilities of drug candidates. However, a major roadblock to implementing hiPSC-CM technology in drug discovery is that conventional methods for monitoring action potential (AP) kinetics and arrhythmia phenotypes in vitro have been too costly or technically challenging to execute in high throughput. Herein, we describe the first large-scale, fully automated and statistically robust analysis of AP kinetics and drug-induced proarrhythmia in hiPSC-CMs. The platform combines the optical recording of a small molecule fluorescent voltage sensing probe (VoltageFluor2.1.Cl), an automated high throughput microscope and automated image analysis to rapidly generate physiological measurements of cardiomyocytes (CMs). The technique can be readily adapted on any high content imager to study hiPSC-CM physiology and predict the proarrhythmic effects of drug candidates.

KEYWORDS:

CiPA; cardiomyocyte; cardiotoxicity; drug development; high throughput screening; induced pluripotent stem cells; voltage sensitive probe

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