title: Functional cardiotoxicity profiling and screening using the xCELLigence RTCA Cardio System.
abstract: Cardiac safety testing of lead drug candidates is an important part of the drug discovery and development process. All new chemical entities need to be subjected to extensive preclinical assessment for cardiac liability, especially for a potentially fatal form of ventricular arrhythmia referred to as Torsades de Pointes. We have developed an innovative label-free, real-time system, the xCELLigence RTCA Cardio System, which is designed to monitor contractility of cardiomyocytes based on impedance measurement. The assay is performed using specially designed microtiter plates that are integrated with gold microelectrodes. The system was validated using mouse embryonic stem cell-derived cardiomyocytes, human-induced pluripotent stem cell-derived cardiomyocytes, and rat neonatal primary cardiomyocytes by applying a variety of tool compounds and drugs with known mechanisms of action. Our data show that the time resolution in the assay can provide important information about compound action. Furthermore, the impedance-based beating profile in response to compound treatment can provide mechanistic toxicity information regarding the target being modulated and may be able to flag pro-arrhythmic compounds. We believe the real-time and kinetic aspect of this technology combined with beat-to-beat measurement of cardiomyocyte contraction would make this instrument an important part of preclinical cardiac safety assessment.
authors.affiliation: ACEA Biosciences, Inc., San Diego, CA 92121, USA. bxi@aceabio.com
authors.forename: Biao
authors.initials: B
authors.lastname: Xi
authors.forename: Tianxing
authors.initials: T
authors.lastname: Wang
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Ouyang
authors.forename: William
authors.initials: W
authors.lastname: Zhang
authors.forename: Jieying
authors.initials: J
authors.lastname: Wu
authors.forename: Xiao
authors.initials: X
authors.lastname: Xu
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Wang
authors.forename: Yama A
authors.initials: YA
authors.lastname: Abassi
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002460:Cell Line; D004353:Drug Evaluation, Preclinical / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D022062:Electrophysiologic Techniques, Cardiac / Q000295:instrumentation / Q000379:methods; D005240:Feasibility Studies; D006801:Humans; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats