Proarrhythmia Risk Assessment Using Electro-Mechanical Window in Human iPS Cell-Derived Cardiomyocytes

Area of Science:

• Cardiovascular Pharmacology
• Stem Cell Biology
• Drug Safety Assessment

Background:

• Drug-induced cardiotoxicity, particularly torsade de pointes (TdP), poses a significant challenge in drug development.
• Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are increasingly utilized for predicting TdP risk.
• Previous studies, including the Comprehensive in vitro Proarrhythmia Assay (CiPA), suggest hiPSC-CMs offer improved accuracy over traditional methods, yet some drug outliers remain.

Purpose of the Study:

• To evaluate the utility of the electromechanical (E-M) window in hiPSC-CMs for classifying drug-induced TdP risk.
• To assess specific CiPA compounds, including known high-risk (dofetilide, bepridil) and low-risk (aspirin, mexiletine, ranolazine) drugs, using the E-M window assay.

Main Methods:

• Utilized hiPSC-CMs for drug testing.
• Employed multi-electrode array assay and motion analysis to measure the E-M window.
• Assessed the effects of dofetilide (positive control), aspirin (negative control), and CiPA compounds (bepridil, mexiletine, ranolazine).

Main Results:

• Dofetilide, a high TdP risk drug, significantly decreased the E-M window in hiPSC-CMs.
• Aspirin, a low TdP risk drug, showed minimal effect on the E-M window.
• Bepridil (high TdP risk) decreased the E-M window, while mexiletine and ranolazine (low TdP risk) had minimal to slight effects, aligning with their known risk profiles.

Conclusions:

• The E-M window assay in hiPSC-CMs demonstrates effectiveness in differentiating between high and low TdP risk drugs.
• This assay provides a valuable tool for improving the prediction of drug-induced cardiotoxicity and TdP risk.
• The findings support the broader application of hiPSC-CMs and the E-M window for preclinical drug safety evaluations.