title: Proarrhythmia Risk Assessment in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Using the Maestro MEA Platform.
abstract: Evaluation of stem cell-derived cardiomyocytes (SC-CM) using multi-electrode array (MEA) has attracted attention as a novel model to detect drug-induced arrhythmia. An experiment was conducted to determine if MEA recording from human induced pluripotent SC-CM (hiPSC-CM) could assess proarrhythmic risk. Ten hERG blockers, 4 Na(+) blockers, and 1 IKs blocker were evaluated blindly. Eight drugs are associated with Torsades de Pointes (TdP) and 4 are not. Multiple parameters, including field potential duration (FPD), Na(+) slope, Na(+) amplitude, beat rate (BR), and early after-depolarization (EAD) were recorded. Minimum effective concentrations (MEC) that elicited a significant change were calculated. Our results determined that FPD and EAD were unable to distinguish torsadogenic from benign compounds, Na(+) slope and amplitude could not differentiate Na(+) channel blockade from hERG blockade, BR had an inconsistent response to pharmacological treatment, and that hiPSC-CM were, in general, insensitive to IKs inhibition. A ratio was calculated that relates MEC for evoking FPD prolongation, or triggering EAD, to the human therapeutic unbound Cmax (MEC/Cmax). The key finding was that the ratio was sensitive, but specificity was low. Consistently, the ratio had high positive predictive value and low negative predictive value. In conclusion, MEA recordings of hiPSC-CM were sensitive for FPD and EAD detection, but unable to distinguish agents with low- and high-risk for TdPs. Although some published reports suggested great potential for MEA recordings in hSC-CM to assess preclinical cardiac toxicity, the current evaluation implies that this model would have a high false-positive rate in regard to proarrhythmic risk.
authors.affiliation: Integrated Discovery and Safety Pharmacology, Amgen Inc., Thousand Oaks, California 91320 yqu@amgen.com.
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Integrated Discovery and Safety Pharmacology, Amgen Inc., Thousand Oaks, California 91320.
authors.forename: Hugo M
authors.initials: HM
authors.lastname: Vargas
mesh_terms: D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects*; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D008839:Microelectrodes; D032383:Myocytes, Cardiac / Q000187:drug effects*; D026902:Potassium Channel Blockers / Q000633:toxicity; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D018570:Risk Assessment; D026941:Sodium Channel Blockers / Q000633:toxicity; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D026902:Potassium Channel Blockers; D026941:Sodium Channel Blockers
keywords: Torsades de Pointes; cardiac myocytes; early after-depolarization; field potential; human induced pluripotent stem cells; minimal effective concentrations; multi-electrode array; proarrhythmia