title: An impedance-based cellular assay using human iPSC-derived cardiomyocytes to quantify modulators of cardiac contractility.
abstract: Cardiovascular toxicity, a prominent reason for late-stage failures in drug development, has resulted in a demand for in vitro assays that can predict this liability in early drug discovery. Current in vitro cardiovascular safety testing primarily focuses on ion channel modulation and low throughput cardiomyocyte (CM) contractility measurements. We evaluated both human induced pluripotent stem cell-derived CMs (hiPSC-CMs) and rat neonatal CMs (rat CMs) on the xCELLigence Cardio system which uses impedance technology to quantify CM beating properties in a 96-well format. Forty-nine compounds were tested in concentration-response mode to determine potency for modulation of CM beating, a surrogate biomarker for contractility. These compounds had previously been tested in vivo and in a low throughput in vitro optical-based contractility assay that measures sarcomere shortening in electrically paced dog CMs. In comparison with in vivo contractility effects, hiPSC-CM impedance had assay sensitivity, specificity, and accuracy values of 90%, 74%, and 82%, respectively. These values compared favorably to values reported for the dog CM optical assay (83%, 84%, and 82%) and were slightly better than impedance using rat CMs (77%, 74%, and 74%). The potency values from the hiPSC-CM and rat CM assays spanned four orders of magnitude and correlated with values from the dog CM optical assay (r(2 )= 0.76 and 0.70, respectively). The Cardio system assay has >5× higher throughput than the optical assay. Thus, hiPSC-CM impedance testing can help detect the human cardiotoxic potential of novel therapeutics early in drug discovery, and if a hazard is identified, has sufficient throughput to support the design-make-test-analyze cycle to mitigate this liability.
authors.affiliation: *Drug Safety and Metabolism, AstraZeneca Pharmaceuticals, Waltham, Massachusetts 02451, ACEA Biosciences Inc., San Diego, California 92121 and Drug Safety and Metabolism, AstraZeneca Pharmaceuticals, Alderley Park, SK10 4TG, UK clay.scott@astrazeneca.com.
authors.forename: Clay W
authors.initials: CW
authors.lastname: Scott
authors.affiliation: *Drug Safety and Metabolism, AstraZeneca Pharmaceuticals, Waltham, Massachusetts 02451, ACEA Biosciences Inc., San Diego, California 92121 and Drug Safety and Metabolism, AstraZeneca Pharmaceuticals, Alderley Park, SK10 4TG, UK.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: *Drug Safety and Metabolism, AstraZeneca Pharmaceuticals, Waltham, Massachusetts 02451, ACEA Biosciences Inc., San Diego, California 92121 and Drug Safety and Metabolism, AstraZeneca Pharmaceuticals, Alderley Park, SK10 4TG, UK.
authors.forename: Najah
authors.initials: N
authors.lastname: Abi-Gerges
authors.affiliation: *Drug Safety and Metabolism, AstraZeneca Pharmaceuticals, Waltham, Massachusetts 02451, ACEA Biosciences Inc., San Diego, California 92121 and Drug Safety and Metabolism, AstraZeneca Pharmaceuticals, Alderley Park, SK10 4TG, UK.
authors.forename: Sarah D
authors.initials: SD
authors.lastname: Lamore
authors.affiliation: *Drug Safety and Metabolism, AstraZeneca Pharmaceuticals, Waltham, Massachusetts 02451, ACEA Biosciences Inc., San Diego, California 92121 and Drug Safety and Metabolism, AstraZeneca Pharmaceuticals, Alderley Park, SK10 4TG, UK.
authors.forename: Yama A
authors.initials: YA
authors.lastname: Abassi
authors.affiliation: *Drug Safety and Metabolism, AstraZeneca Pharmaceuticals, Waltham, Massachusetts 02451, ACEA Biosciences Inc., San Diego, California 92121 and Drug Safety and Metabolism, AstraZeneca Pharmaceuticals, Alderley Park, SK10 4TG, UK.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Peters
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D066126:Cardiotoxicity; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology / Q000503:physiopathology; D017097:Electric Impedance; D057166:High-Throughput Screening Assays; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D004364:Pharmaceutical Preparations / Q000032:analysis*; D011237:Predictive Value of Tests; D051381:Rats; D012518:Sarcomeres / Q000187:drug effects / Q000473:pathology
chemical_list: D004364:Pharmaceutical Preparations
keywords: cardiac contractility; cardiomyocytes; human-induced pluripotent stem cells; impedance; label-free