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Despite the widespread knowledge that prenatal and postnatal drug exposure can lead to congenital abnormalities, the developmental toxicity of many FDA-approved drugs is rarely investigated. Therefore, to improve our understanding of drug side effects, we performed a high-content drug screen of 1,280 compounds using zebrafish as a model for cardiovascular analyses. Zebrafish are a well-established model for CVDs and developmental toxicity. However, flexible open-access tools to quantify cardiac phenotypes are lacking. Here, we provide <jats:italic>pyHeart4Fish<\/jats:italic>, a novel Python-based, platform-independent tool with a graphical user interface for automated quantification of cardiac chamber-specific parameters, such as heart rate (HR), contractility, arrhythmia score, and conduction score. In our study, about 10.5% of the tested drugs significantly affected HR at a concentration of 20\u00a0\u00b5M in zebrafish embryos at 2\u00a0days post-fertilization. Further, we provide insights into the effects of 13 compounds on the developing embryo, including the teratogenic effects of the steroid pregnenolone. In addition, analysis with <jats:italic>pyHeart4Fish<\/jats:italic> revealed multiple contractility defects induced by seven compounds. We also found implications for arrhythmias, such as atrioventricular block caused by chloropyramine HCl, as well as (R)-duloxetine HCl-induced atrial flutter. Taken together, our study presents a novel open-access tool for heart analysis and new data on potentially cardiotoxic compounds.<\/jats:p>","DOI":"10.3389\/fcell.2023.1143852","type":"journal-article","created":{"date-parts":[[2023,4,11]],"date-time":"2023-04-11T05:45:45Z","timestamp":1681191945000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["pyHeart4Fish: Chamber-specific heart phenotype quantification of zebrafish in high-content screens"],"prefix":"10.3389","volume":"11","author":[{"given":"Viviana L.","family":"Vedder","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Reinberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed M. 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