Functional cardiotoxicity profiling and screening using the xCELLigence RTCA Cardio System

Area of Science:

• Cardiovascular pharmacology
• Drug discovery and development
• Biomedical engineering

Background:

• Preclinical cardiac safety assessment is crucial for new drug candidates.
• Identifying compounds causing Torsades de Pointes (a fatal arrhythmia) is a key challenge.
• Existing methods may lack real-time kinetic information.

Purpose of the Study:

• To introduce and validate an innovative label-free, real-time system for monitoring cardiomyocyte contractility.
• To assess the system's utility in identifying pro-arrhythmic drug candidates.
• To evaluate the potential of impedance-based measurements for mechanistic toxicity information.

Main Methods:

• Development of the xCELLigence RTCA Cardio System utilizing impedance measurement.
• Assay performed in microtiter plates with integrated gold microelectrodes.
• Validation using various cardiomyocyte models (mouse ESC-derived, human iPSC-derived, rat neonatal primary) and known compounds.

Main Results:

• The system successfully monitored cardiomyocyte contractility in real-time.
• Assay time resolution provided valuable insights into compound action kinetics.
• Impedance-based beating profiles offered mechanistic toxicity information and flagged pro-arrhythmic compounds.

Conclusions:

• The xCELLigence RTCA Cardio System offers a real-time, kinetic approach to cardiomyocyte contractility assessment.
• Beat-to-beat measurement capabilities enhance preclinical cardiac safety evaluation.
• This technology is a valuable addition to the drug discovery and development toolkit for cardiac liability assessment.