Assessing drug-induced long QT and proarrhythmic risk using human stem cell-derived cardiomyocytes in a Ca2+ imaging assay: Evaluation of 28 CiPA compounds at three test sites

  • Publication Date :
  • Publication Type : Journal Article
  • Author(s) : Hua Rong Lu, Haoyu Zeng, Ralf Kettenhofen, Liang Guo, Ivan Kopljar, Karel van Ammel, Fetene Tekle, Ard Teisman, Jin Zhai, Holly Clouse, Jennifer Pierson, Michael Furniss, Armando Lagrutta, Frederick Sannajust, David J Gallacher
  • Journal Name : Toxicological Sciences

The goal of this research consortium including Janssen, MSD, Ncardia, FNCR/LBR and HESI was to evaluate the utility of an additional in vitro assay technology to detect potential drug-induced long QT and torsade de pointes (TdP) risk by monitoring cytosolic free Ca2+ transients in human stem cell-derived cardiomyocytes (hSC-CMs).

The potential proarrhythmic risks of the 28 CiPA drugs linked to low, intermediate, and high clinical TdP risk were evaluated in a blinded manner using Ca2+ -sensitive fluorescent dye assay recorded from a kinetic plate reader system (Hamamatsu FDSS/µCell and FDSS7000) in 2D cultures of two commercially available hSC-CM lines (Cor.4U® and CDI iCell® Cardiomyocytes) at three different test sites.

The Ca2+ transient assay, performed at the three sites using the two different hSC-CMs lines, correctly detected potential drug-induced QT prolongation among the 28 CIPA drugs and detected cellular arrhythmias-like/EAD in 7 of 8 high TdP-risk drugs (87.5%), 6 of 11 intermediate TdP risk drugs (54.5%) and 0 of 9 low/no TdP risk-drugs (0%). The results were comparable among the three sites and from two hSC-CM cell lines.

The Ca 2+ transient assay can serve as a user-friendly and higher throughput alternative to complement the micro-electrode array and voltage-sensing optical action potential recording assays used in the HESI-CiPA study for in vitro assessment of drug-induced long QT and TdP risk.

Link to full text.

Download PDF Link

Contact Us

Health and Environmental Sciences Institute (HESI)
Phone: +1-202-659-8404
Fax: +1-202-659-3859

740 15th Street NW, Suite 600
Washington, DC 20005

Stay Informed

Sign up for our monthly e-newsletter.