High Throughput Measurement of Ca++ Dynamics in Human Stem Cell-Derived Cardiomyocytes by Kinetic Image Cytometery: A...

Area of Science:

• Cardiovascular pharmacology
• Stem cell biology
• Drug safety assessment

Background:

• Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) offer a promising in vitro model for cardiac safety evaluation.
• Early identification of cardiotoxic drug candidates is crucial in the drug discovery process to mitigate risks.

Purpose of the Study:

• To evaluate the Kinetic Image Cytometer (KIC) system's capability in predicting adverse compound effects using hiPS-CMs.
• To assess the KIC system's utility in detecting drug-induced changes in cardiomyocyte function and predicting arrhythmogenic liabilities.

Main Methods:

• Utilized hiPS-CMs and a library of 53 compounds, including known cardioactive agents and negative controls.
• Employed the KIC system for high-throughput analysis of intracellular calcium transients in hiPS-CMs.
• Examined drug-induced alterations in calcium transient dynamics, including duration and beat rate, as indicators of compound effects.

Main Results:

• The KIC system accurately detected drug-induced changes in Ca(2+) transient dynamics in hiPS-CMs.
• The study demonstrated the KIC's ability to assess compound effects across multiple ion channel types (MITs) and calcium handling pathways.
• Results from this blinded study suggest a strong correlation between observed calcium transient changes and potential arrhythmogenic liabilities.

Conclusions:

• The KIC system, in conjunction with hiPS-CMs, shows significant potential for predicting drug-induced arrhythmogenic liabilities.
• This approach can serve as an effective phenotypic screen for early de-risking in the drug discovery pipeline.
• Utilizing hiPS-CMs and KIC facilitates a more accurate and timely assessment of cardiac safety profiles for novel compounds.