title: Human stem cell-derived cardiomyocytes in cellular impedance assays: bringing cardiotoxicity screening to the front line.
abstract: Cardiovascular (CV) toxicity is a leading cause of drug attrition and withdrawal. Introducing in vitro assays with higher throughput should permit earlier CV hazard identification and enable medicinal chemists to design-out liabilities. Heretofore, development of in vitro CV assays has been limited by the challenge of replicating integrated cardiovascular physiology while achieving the throughput and consistency required for screening. These challenges appear to be met with a combination of human stem cell-derived cardiomyocytes (CM) which beat spontaneously and monitoring the response with technology that can assess drug-induced changes in voltage dependent contraction such as cellular impedance which has been validated with excellent predictivity for drug-induced arrhythmia and contractility. Here, we review advances in cardiomyocyte impedance with emphasis on stem cell-derived cardiomyocyte models for toxicity screening. Key perspectives include: the electrical principles of impedance technology, impedance detection of cardiomyocyte beating, beat parameter selection/analysis, validation in toxicity and drug discovery, and future directions. As a conclusion, an in vitro screening cascade is proffered using the downstream, inclusive detection of CM impedance assays as a primary screen followed by complementary CM assays chosen to enable mechanism-appropriate follow-up. The combined approach will enhance testing for CV liabilities prior to traditional in vivo models.
authors.affiliation: Department of Discovery Safety and Metabolism, AstraZeneca Pharmaceutical, 35 Gatehouse Park Drive, Waltham, MA, USA, matt.f.peters@gmail.com.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Peters
authors.forename: Sarah D
authors.initials: SD
authors.lastname: Lamore
authors.forename: Liang
authors.initials: L
authors.lastname: Guo
authors.forename: Clay W
authors.initials: CW
authors.lastname: Scott
authors.forename: Kyle L
authors.initials: KL
authors.lastname: Kolaja
mesh_terms: D000818:Animals; D066126:Cardiotoxicity / Q000175:diagnosis / Q000473:pathology; D054715:Cardiotoxins / Q000633:toxicity*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D017097:Electric Impedance; D006801:Humans; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D013234:Stem Cells / Q000187:drug effects* / Q000473:pathology / Q000502:physiology
chemical_list: D054715:Cardiotoxins