Human stem cell-derived cardiomyocytes in cellular impedance assays: bringing cardiotoxicity screening to the front
Matthew F Peters1, Sarah D Lamore, Liang Guo
1Department of Discovery Safety and Metabolism, AstraZeneca Pharmaceutical, 35 Gatehouse Park Drive, Waltham, MA, USA, matt.f.peters@gmail.com.
Abstract:
Cardiovascular (CV) toxicity is a leading cause of drug attrition and withdrawal. Introducing in vitro assays with higher throughput should permit earlier CV hazard identification and enable medicinal chemists to design-out liabilities. Heretofore, development of in vitro CV assays has been limited by the challenge of replicating integrated cardiovascular physiology while achieving the throughput and consistency required for screening. These challenges appear to be met with a combination of human stem cell-derived cardiomyocytes (CM) which beat spontaneously and monitoring the response with technology that can assess drug-induced changes in voltage dependent contraction such as cellular impedance which has been validated with excellent predictivity for drug-induced arrhythmia and contractility. Here, we review advances in cardiomyocyte impedance with emphasis on stem cell-derived cardiomyocyte models for toxicity screening. Key perspectives include: the electrical principles of impedance technology, impedance detection of cardiomyocyte beating, beat parameter selection/analysis, validation in toxicity and drug discovery, and future directions. As a conclusion, an in vitro screening cascade is proffered using the downstream, inclusive detection of CM impedance assays as a primary screen followed by complementary CM assays chosen to enable mechanism-appropriate follow-up. The combined approach will enhance testing for CV liabilities prior to traditional in vivo models.
Insights
New in vitro assays using human stem cell-derived cardiomyocytes (CM) and cellular impedance technology can identify cardiovascular (CV) drug toxicity earlier. This approach improves drug safety and reduces late-stage failures.
Area of Science:
- Biomedical Engineering
- Cardiovascular Pharmacology
- Drug Discovery
Background:
- Cardiovascular (CV) toxicity is a major reason for drug development failure.
- Current in vitro assays struggle to replicate complex cardiovascular physiology for effective toxicity screening.
- High-throughput, reliable methods are needed for early identification of drug-induced CV liabilities.
Purpose of the Study:
- To review advances in cardiomyocyte impedance technology for in vitro cardiovascular toxicity screening.
- To highlight the use of stem cell-derived cardiomyocytes (CM) in conjunction with impedance monitoring.
- To propose an in vitro screening cascade for enhanced cardiovascular safety assessment.
Main Methods:
- Utilizing human stem cell-derived cardiomyocytes (CM) that exhibit spontaneous beating.
- Employing cellular impedance technology to monitor drug-induced changes in cardiomyocyte contraction.
- Analyzing beat parameters derived from impedance measurements for toxicity assessment.
Main Results:
- Cellular impedance assays using CM have demonstrated excellent predictivity for drug-induced arrhythmia and contractility changes.
- This technology offers a high-throughput and consistent method for assessing cardiovascular hazards.
- The approach facilitates earlier identification of potential drug liabilities compared to traditional methods.
Conclusions:
- A screening cascade integrating CM impedance assays as a primary screen is proposed.
- Complementary CM assays can provide mechanism-specific follow-up for identified CV liabilities.
- This combined in vitro strategy enhances cardiovascular safety testing before in vivo studies.
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