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oai:recercat.cat:10256/181932024-06-18T11:12:49Zcom_2072_452955com_2072_2054col_2072_452964

2024-06-18T11:12:48Z urn:hdl:10256/18193 Comparison of Zebrafish Larvae and hiPSC Cardiomyocytes for Predicting Drug-Induced Cardiotoxicity in Humans Dyballa, Sylvia Minana, Rafael Rubio Brotons, Maria Cornet, Carles Pederzani, Tiziana Escaramís Babiano, Geòrgia Garcia Serna, Ricard Mestres i López, Jordi Terriente, Javier Toxicologia cardiovascular Cardiovascular toxicology Models lineals (Estadística) Linear models (Statistics) Toxicologia cardiovascular -- Models matemàtics Cardiovascular toxicology -- Mathematical models 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 2024-06-18T11:12:48Z 2024-06-18T11:12:48Z 2019-07-30 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion peer-reviewed http://hdl.handle.net/10256/18193 info:eu-repo/semantics/altIdentifier/doi/10.1093/toxsci/kfz165 info:eu-repo/semantics/altIdentifier/issn/1096-6080 info:eu-repo/semantics/altIdentifier/eissn/1096-0929 Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess Oxford University Press (OUP) Toxicological Sciences, 2019, vol. 171, núm. 2, p. 283-295 Articles publicats (D-EC)