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In this study, a metabolic biomarker-based assay was developed that predicts the cardiotoxicity potential of a drug based on changes in the metabolism and viability of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). Assay development and testing was conducted in 2 phases: (1) biomarker identification and (2) targeted assay development. In the first phase, metabolomic data from hiPSC-CM spent media following exposure to 66 drugs were used to identify biomarkers that identified both functional and structural cardiotoxicants. Four metabolites that represent different metabolic pathways (arachidonic acid, lactic acid, 2\u2032-deoxycytidine, and thymidine) were identified as indicators of cardiotoxicity. In phase 2, a targeted, exposure-based biomarker assay was developed that measured these metabolites and hiPSC-CM viability across an 8-point concentration curve. Metabolite-specific predictive thresholds for identifying the cardiotoxicity potential of a drug were established and optimized for balanced accuracy or sensitivity. When predictive thresholds were optimized for balanced accuracy, the assay predicted the cardiotoxicity potential of 81 drugs with 86% balanced accuracy, 83% sensitivity, and 90% specificity. Alternatively, optimizing the thresholds for sensitivity yields a balanced accuracy of 85%, 90% sensitivity, and 79% specificity. This new hiPSC-CM-based assay provides a paradigm that can identify structural and functional cardiotoxic drugs that could be used in conjunction with other endpoints to provide a more comprehensive evaluation of a drug\u2019s cardiotoxicity potential.<\/jats:p>","DOI":"10.1093\/toxsci\/kfaa015","type":"journal-article","created":{"date-parts":[[2020,1,23]],"date-time":"2020-01-23T20:10:26Z","timestamp":1579810226000},"page":"218-240","source":"Crossref","is-referenced-by-count":36,"title":["A Targeted Metabolomics-Based Assay Using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Identifies Structural and Functional Cardiotoxicity Potential"],"prefix":"10.1093","volume":"174","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7373-4118","authenticated-orcid":false,"given":"Jessica A","family":"Palmer","sequence":"first","affiliation":[{"name":"Stemina Biomarker Discovery, Inc, Madison, Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan M","family":"Smith","sequence":"first","affiliation":[{"name":"Stemina Biomarker Discovery, Inc, Madison, Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vitalina","family":"Gryshkova","sequence":"first","affiliation":[{"name":"UCB Biopharma SPRL, Investigative Toxicology, Development Science, B-1420 Braine L\u2019Alleud, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth L R","family":"Donley","sequence":"first","affiliation":[{"name":"Stemina Biomarker Discovery, Inc, Madison, Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Pierre","family":"Valentin","sequence":"first","affiliation":[{"name":"UCB Biopharma SPRL, Investigative Toxicology, Development Science, B-1420 Braine L\u2019Alleud, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert E","family":"Burrier","sequence":"first","affiliation":[{"name":"Stemina Biomarker Discovery, Inc, Madison, Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,2,10]]},"reference":[{"key":"2020032609575435900_kfaa015-B1","volume-title":"DailyMed [Internet]","year":"2017"},{"key":"2020032609575435900_kfaa015-B2","volume-title":"DailyMed [Internet]","year":"2019"},{"key":"2020032609575435900_kfaa015-B3","volume-title":"DailyMed [Internet]","year":"2019"},{"key":"2020032609575435900_kfaa015-B4","volume-title":"DailyMed [Internet]","year":"2019"},{"key":"2020032609575435900_kfaa015-B5","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1124\/dmd.115.063776","article-title":"Early changes in cytochrome P450s and their associated arachidonic acid metabolites play a crucial role in the initiation of cardiac hypertrophy induced by isoproterenol","volume":"43","author":"Althurwi","year":"2015","journal-title":"Drug Metab. 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