High Throughput Measurement of Ca++ Dynamics in Human Stem Cell-Derived Cardiomyocytes by Kinetic Image Cytometery: A
Hua Rong Lu1, Ross Whittaker2, Jeffrey H Price2
1*Global Safety Pharmacology, Preclinical Development & Safety, Discovery Sciences, Janssen Pharmaceutical NV, B2340 Beerse, Belgium; hlu@its.jnj.com.
Insights
Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) and the Kinetic Image Cytometer (KIC) system effectively predict drug-induced cardiac risks. This approach aids early identification of compounds with arrhythmogenic liabilities in drug discovery.
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.
Abstract:
Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) are emerging as a powerful in vitro model for cardiac safety assessment which may allow for better identification of compounds with poor arrhythmogenic liability profiles early in the drug discovery process. Here, we describe our examination of the Kinetic Image Cytometer (KIC) system's ability to predict adverse compound effects using hiPS-CMs and a library of 53 compounds, the majority of which are known to be cardioactive compounds, and several negative controls. The KIC provides a high throughput method for analyzing intracellular calcium transients. In the cardiomyocyte, intracellular calcium transients integrate the electrochemical signals of the action potential (AP) with the molecular signaling pathways regulating contraction. Drug-induced alterations in the shape and duration of AP result in changes to the shape and duration of the intracellular calcium transient. By examining calcium transient dynamics in hiPS-CMs, KIC can be used as a phenotypic screen to assess compound effects across multiple ion channel types (MITs), detecting MITs, calcium handling and signaling effects. The results of this blinded study indicate that using hiPS-CMs, KIC is able to accurately detect drug-induced changes in Ca(2+) transient dynamics (ie, duration and beat rate) and therefore, may be useful in predicting drug-induced arrhythmogenic liabilities in early de-risking within the drug discovery phase.
