Comparison of zebrafish larvae and hiPSC cardiomyocytes for predicting drug-induced cardiotoxicity in humans

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• dc.contributor.author Dyballa, Sylvia, 1982-
• dc.contributor.author Miñana, Rafael
• dc.contributor.author Rubio-Brotons, Maria
• dc.contributor.author Cornet Bartolomé, Carles, 1991-
• dc.contributor.author Pederzani, Tiziana
• dc.contributor.author Escaramís, Geòrgia
• dc.contributor.author Garcia-Serna, Ricard
• dc.contributor.author Mestres i López, Jordi
• dc.contributor.author Terriente, Javier
• dc.date.accessioned 2023-01-24T07:17:28Z
• dc.date.available 2023-01-24T07:17:28Z
• dc.date.issued 2019
• dc.description.abstract Cardiovascular drug toxicity is responsible for 17% of drug withdrawals in clinical phases, half of post-marketed drug withdrawals and remains an important adverse effect of several marketed drugs. Early assessment of drug-induced cardiovascular toxicity is mandatory and typically done in cellular systems and mammals. Current in vitro screening methods allow high-throughput but are biologically reductionist. The use of mammal models, which allow a better translatability for predicting clinical outputs, is low-throughput, highly expensive, and ethically controversial. Given the analogies between the human and the zebrafish cardiovascular systems, we propose the use of zebrafish larvae during early drug discovery phases as a balanced model between biological translatability and screening throughput for addressing potential liabilities. To this end, we have developed a high-throughput screening platform that enables fully automatized in vivo image acquisition and analysis to extract a plethora of relevant cardiovascular parameters: heart rate, arrhythmia, AV blockage, ejection fraction, and blood flow, among others. We have used this platform to address the predictive power of zebrafish larvae for detecting potential cardiovascular liabilities in humans. We tested a chemical library of 92 compounds with known clinical cardiotoxicity profiles. The cross-comparison with clinical data and data acquired from human induced pluripotent stem cell cardiomyocytes calcium imaging showed that zebrafish larvae allow a more reliable prediction of cardiotoxicity than cellular systems. Interestingly, our analysis with zebrafish yields similar predictive performance as previous validation meta-studies performed with dogs, the standard regulatory preclinical model for predicting cardiotoxic liabilities prior to clinical phases.
• dc.format.mimetype application/pdf
• dc.identifier.citation Dyballa S, Miñana R, Rubio-Brotons M, Cornet C, Pederzani T, Escaramis G, et al. Comparison of zebrafish larvae and hiPSC cardiomyocytes for predicting drug-induced cardiotoxicity in humans. Toxicological Sciences. 2019 Oct;171(2):283-95. DOI: 10.1093/toxsci/kfz165
• dc.identifier.doi http://dx.doi.org/10.1093/toxsci/kfz165
• dc.identifier.issn 1096-6080
• dc.identifier.uri http://hdl.handle.net/10230/55408
• dc.language.iso eng
• dc.publisher Oxford University Press
• dc.relation.ispartof Toxicological Sciences. 2019 Oct;171(2):283-95
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/755988
• dc.rights © The Author(s) 2019. Published by Oxford University Press on behalf of the Society of Toxicology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Cardiovascular toxicity
• dc.subject.keyword Adverse effect
• dc.subject.keyword High-throughput
• dc.subject.keyword Drug screening
• dc.subject.keyword Zebrafish
• dc.subject.keyword hiPSC
• dc.subject.keyword ZeCardio
• dc.title Comparison of zebrafish larvae and hiPSC cardiomyocytes for predicting drug-induced cardiotoxicity in humans
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion