[DOT 2021] Integrated Cardiac Proarrhythmic Risk Assessment Using Human-Induced Pluoripotent Stem Cell (hiPSC)-Derived Cardiomyocytes Assays for Proinflammatory Cytokines
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- DOT 2021
The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative is an effort to improve the accuracy of proarrhythmic risk assessment by reducing the focus on in vitro hERG channel assays and in vivo QT measurements. This novel approach includes the use of adult human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) to test compounds for potential cardiotoxic effects. hiPSC-CMs express ion channels that underlie action potentials and exhibit electrophysiological and mechanical characteristics of native human cardiomyocytes. Thus, hiPSC-CMs represent a more comprehensive and physiologically relevant preclinical
model for cardiac liability assessment.
Cardiac contraction is initiated by movement of sodium (Na+), potassium (K+), and Calcium (Ca2+) ions through ion channels, resulting in an action potential. Upon membrane depolarization, Ca2+ enters the cell through voltage-gated Ca2+ channels, stimulating the release of additional Ca2+ ions into the cytoplasm from the sarcoplasmic reticulum. Cytoplasmic Ca2+ binds to cardiac troponin-C, allowing myosin-actin cross-bridge formation, resulting in contraction. Upon release of Ca2+ from troponin-C, Ca2+ is translocated back into the sarcoplasmic reticulum, leading to relaxation. Thus, Ca2+ acts as a second messenger linking the electrochemical signals of the action potential to cardiomyocyte contraction. Changes in the activity of the action potential-inducing ion channels will therefore result in a changed shape and duration of the intracellular Ca2+ current. Consequently, the intracellular Ca2+ current may be used as a surrogate marker for examining compound effects on cardiac function. Eurofins DiscoverX has developed and validated a high-throughput assay in hiPSC-CMs to monitor intracellular Ca2+ transients in response to test compounds, which allows to assess the potential risk related to test compound-induced delayed ventricular repolarization and QT interval prolongation in humans.