An Automated Platform for Assessment of Congenital and Drug-Induced Arrhythmia with hiPSC-Derived Cardiomyocytes
Wesley L McKeithan1,2, Alex Savchenko1, Michael S Yu3,4
1Department of Medicine, Cardiovascular Institute, Stanford University, Stanford, CA, United States.
Insights
This study introduces a high-throughput, automated platform for analyzing human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). This innovation enables efficient modeling of heart diseases and drug-induced arrhythmias.
Area of Science:
- Cardiovascular Research
- Stem Cell Biology
- Drug Discovery
Background:
- Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer a powerful model for studying congenital heart diseases (CHDs) and drug-induced arrhythmias.
- Current methods for assessing cardiomyocyte action potential (AP) kinetics and arrhythmia phenotypes are often high-cost and low-throughput, hindering drug discovery applications.
Purpose of the Study:
- To develop and validate a large-scale, automated platform for analyzing hiPSC-CMs.
- To enable high-throughput assessment of AP kinetics and drug-induced proarrhythmia in hiPSC-CMs.
- To facilitate predictive modeling of drug safety and efficacy using patient-specific hiPSC-CMs.
Main Methods:
- Utilized a small molecule fluorescent voltage sensing probe (VoltageFluor2.1.Cl) for optical recording of cardiomyocyte activity.
- Integrated an automated high-throughput microscope with automated image analysis for rapid physiological measurements.
- Developed a statistically robust pipeline for analyzing AP kinetics and arrhythmia phenotypes in hiPSC-CMs.
Main Results:
- Successfully implemented the first fully automated, large-scale analysis of hiPSC-CM AP kinetics and drug-induced proarrhythmia.
- Demonstrated the platform's capability to rapidly generate physiological measurements from cardiomyocytes.
- Established a robust method for predicting proarrhythmic liabilities of drug candidates using hiPSC-CMs.
Conclusions:
- The developed automated platform overcomes previous throughput limitations in hiPSC-CM analysis.
- This technology provides a cost-effective and efficient solution for studying hiPSC-CM physiology.
- The platform is adaptable for broad application in drug discovery and personalized medicine for cardiovascular diseases.
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.
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