Identifying metabolic adaptations characteristic of cardiotoxicity using paired transcriptomics and metabolomics data integrated with a computational model of heart metabolism

Improvements in the diagnosis and treatment of cancer have revealed long-term side effects of chemotherapeutics, particularly cardiotoxicity. Here, we present paired transcriptomics and metabolomics data characterizing in vitro cardiotoxicity to three compounds: 5-fluorouracil, acetaminophen, and doxorubicin. Standard gene enrichment and metabolomics approaches identify some commonly affected pathways and metabolites but are not able to readily identify metabolic adaptations in response to cardiotoxicity. The paired data was integrated with a genome-scale metabolic network reconstruction of the heart to identify shifted metabolic functions, unique metabolic reactions, and changes in flux in metabolic reactions in response to these compounds. Using this approach, we confirm previously seen changes in the p53 pathway by doxorubicin and RNA synthesis by 5-fluorouracil, we find evidence for an increase in phospholipid metabolism in response to acetaminophen, and we see a shift in central carbon metabolism suggesting an increase in metabolic demand after treatment with doxorubicin and 5-fluorouracil. Improvements in the diagnosis and treatment of cancer have revealed long-term side effects of chemotherapeutics, particularly cardiotoxicity. Here, we compare the cardiotoxic effects of 3 drugs, 5-fluorouracil, acetaminophen, and doxorubicin, using transcriptomic and metabolomic data. By integrating these data into a genome-scale metabolic network reconstruction of the heart, we were able to identify metabolic adaptations in response to cardiotoxicity that avoided detection in traditional gene enrichment and metabolomic techniques. Using this approach, we confirm known mechanisms of doxorubicin-induced cardiotoxicity and provide hypotheses and potential mechanisms for metabolic adaptations in cardiotoxicity for 5-fluorouracil, doxorubicin, and acetaminophen. We hope future work using our novel paired transcriptomic and metabolic characterization of in vitro cardiotoxicity can help improve the current network heart model and further characterize the role of chemotherapeutics in cardiotoxicity.