Related Experiment Video
Updated: Mar 14, 2026
Evaluation of Cardiac Contractility Modulation Therapy in 2D Human Stem Cell-Derived Cardiomyocytes
Published on: December 16, 2022
Comprehensive in vitro cardiac safety assessment using human stem cell technology: Overview of CSAHi HEART initiative
Kiyoshi Takasuna1, Keiichi Asakura2, Seiichi Araki3
1Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan; Japan Pharmaceutical Manufacturers Association Drug Evaluation Committee, Non-Clinical Evaluation Expert Committee, TF2, Japan; Consortium for Safety Assessment using Human iPS Cells (CSAHi): HEART team, Japan.
Insights
Current drug safety tests for cardiac toxicity are insufficient. Human iPS cell-derived cardiomyocytes offer improved prediction of diverse cardiotoxicities, including arrhythmias and contractility dysfunction, via novel multi-parametric platforms.
Area of Science:
- Cardiovascular toxicology
- Stem cell biology
- Drug safety assessment
Background:
- Existing in vitro and in vivo assays for drug-induced cardiotoxicity, such as QT assays, have limitations in predicting Torsades de Pointes (TdP) and other arrhythmias (VT/VF).
- Current assays do not fully address cardiac safety liabilities like excitation-contraction coupling dysfunction (contractility) and cardiomyocyte structural damage, leading to significant drug attrition.
- The Consortium for Safety Assessment using Human iPS cells (CSAHi) was established to evaluate human induced pluripotent stem cell (hiPS)-derived cardiomyocytes for comprehensive drug safety assessment.
Purpose of the Study:
- To propose comprehensive screening strategies for predicting diverse cardiotoxicities using human iPS/ES cell-derived cardiomyocytes.
- To evaluate the strengths and weaknesses of recently introduced platforms: multi-electrode array (MEA), patch clamp, cellular impedance, motion field imaging (MFI), and Ca transient systems.
- To identify novel platforms that can predict a wider range of cardiac safety liabilities beyond current methods.
Main Methods:
- Utilizing human iPS cell-derived cardiomyocytes (hiPS-CMs) across various platforms including MEA, patch clamp, cellular impedance, MFI, and Ca transient systems.
- Comparing the pharmacological responses of hiPS-CMs in these platforms with existing assays like hERG, APD, and Langendorff.
- Investigating the potential of combining MEA, Ca transient, and MFI systems for simultaneous multi-parametric evaluation.
Main Results:
- hiPS-CMs demonstrate pharmacological responses more relevant to humans compared to traditional hERG, APD, or Langendorff assays.
- Platforms utilizing cellular impedance, MFI, and Ca transient systems, in addition to MEA, show potential for paradigm shifts in predicting drug-induced QT risk, arrhythmias, and contractile dysfunctions.
- The study identified strengths and weaknesses of individual platforms for predicting specific cardiotoxicities.
Conclusions:
- Human iPS/ES cell-derived cardiomyocytes integrated into advanced platforms offer a more predictive approach to cardiac safety assessment.
- Novel platforms, particularly multi-parametric systems combining MEA, Ca transient, and MFI, are crucial for predicting a broad spectrum of drug-induced cardiac toxicities.
- These comprehensive strategies are essential for reducing drug attrition due to unforeseen cardiac adverse events and improving drug development pipelines.
Abstract:
Recent increasing evidence suggests that the currently-used platforms in vitro IKr and APD, and/or in vivo QT assays are not fully predictive for TdP, and do not address potential arrhythmia (VT and/or VF) induced by diverse mechanisms of action. In addition, other cardiac safety liabilities such as functional dysfunction of excitation-contraction coupling (contractility) and structural damage (morphological damage to cardiomyocytes) are also major causes of drug attrition, but current in vitro assays do not cover all these liabilities. We organized the Consortium for Safety Assessment using Human iPS cells (CSAHi; http://csahi.org/en/), based on the Japan Pharmaceutical Manufacturers Association (JPMA), to verify the application of human iPS/ES cell-derived cardiomyocytes in drug safety evaluation. The main goal of the CSAHi HEART team has been to propose comprehensive screening strategies to predict a diverse range of cardiotoxicities by using recently introduced platforms (multi-electrode array (MEA), patch clamp, cellular impedance, motion field imaging [MFI], and Ca transient systems) while identifying the strengths and weaknesses of each. Our study shows that hiPS-CMs used in these platforms have pharmacological responses more relevant to humans in comparison with existent hERG, APD or Langendorff (MAPD/contraction) assays, and not only MEA but also other methods such as impedance, MFI, and Ca transient systems would offer paradigm changes of platforms for predicting drug-induced QT risk and/or arrhythmia or contractile dysfunctions. Furthermore, we propose a potential multi-parametric platform in which field potential (MEA)-Ca transient-contraction (MFI) could be evaluated simultaneously as an ideal novel platform for predicting a diversity of cardiac toxicities, namely whole effects on the excitation-contraction cascade.
More Related Videos
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
14:03High-Throughput Cardiotoxicity Screening Using Mature Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Monolayers
Published on: March 24, 2023