Related Experiment Video
Updated: Jul 10, 2025
Technical Applications of Microelectrode Array and Patch Clamp Recordings on Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Published on: August 4, 2022
In-depth mechanistic analysis including high-throughput RNA sequencing in the prediction of functional and structural
Alicia Rosell-Hidalgo1, Christopher Bruhn2, Emma Shardlow1
1Cyprotex Discovery Ltd UK, Macclesfield, UK.
Background:
Cardiotoxicity remains one of the most reported adverse drug reactions that lead to drug attrition during pre-clinical and clinical drug development. Drug-induced cardiotoxicity may develop as a functional change in cardiac electrophysiology (acute alteration of the mechanical function of the myocardium) and/or as a structural change, resulting in loss of viability and morphological damage to cardiac tissue.
Research Design And Methods:
Non-clinical models with better predictive value need to be established to improve cardiac safety pharmacology. To this end, high-throughput RNA sequencing (ScreenSeq) was combined with high-content imaging (HCI) and Ca2+ transience (CaT) to analyze compound-treated human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).
Results:
Analysis of hiPSC-CMs treated with 33 cardiotoxicants and 9 non-cardiotoxicants of mixed therapeutic indications facilitated compound clustering by mechanism of action, scoring of pathway activities related to cardiomyocyte contractility, mitochondrial integrity, metabolic state, diverse stress responses and the prediction of cardiotoxicity risk. The combination of ScreenSeq, HCI and CaT provided a high cardiotoxicity prediction performance with 89% specificity, 91% sensitivity and 90% accuracy.
Conclusions:
Overall, this study introduces mechanism-driven risk assessment approach combining structural, functional and molecular high-throughput methods for pre-clinical risk assessment of novel compounds.
Insights
Developing new drugs requires accurate prediction of cardiotoxicity. This study combined high-throughput RNA sequencing, imaging, and calcium transient analysis in human-induced pluripotent stem cell-derived cardiomyocytes to predict drug-induced heart damage.
Area of Science:
- Pharmacology
- Cardiology
- Biotechnology
Background:
- Drug-induced cardiotoxicity is a major cause of drug attrition in development.
- It manifests as functional (electrophysiological, mechanical) or structural cardiac damage.
- Improved non-clinical models are crucial for cardiac safety pharmacology.
Purpose of the Study:
- To establish a predictive non-clinical model for drug-induced cardiotoxicity.
- To integrate multiple high-throughput assays for comprehensive cardiac safety assessment.
- To enable mechanism-driven risk assessment of novel compounds.
Main Methods:
- Utilized human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).
- Combined high-throughput RNA sequencing (ScreenSeq), high-content imaging (HCI), and Ca2+ transience (CaT) assays.
- Analyzed responses to 33 cardiotoxicants and 9 non-cardiotoxicants.
Main Results:
- Enabled compound clustering by mechanism of action.
- Scored pathway activities (contractility, mitochondrial integrity, metabolism, stress).
- Achieved high prediction performance: 89% specificity, 91% sensitivity, 90% accuracy.
Conclusions:
- Introduced a novel, mechanism-driven risk assessment approach.
- Integrated structural, functional, and molecular high-throughput methods.
- Demonstrated a robust strategy for pre-clinical cardiotoxicity risk assessment.
More Related Videos
14:03High-Throughput Cardiotoxicity Screening Using Mature Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Monolayers
Published on: March 24, 2023
08:03Hybrid Cell Analysis System to Assess Structural and Contractile Changes of Human iPSC-Derived Cardiomyocytes for Preclinical Cardiac Risk Evaluation
Published on: October 20, 2022