SWATH-MS for discovery of early biomarkers of drug-induced cardiotoxicity using an animal doxorubicin model

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Abstract Background Clinical use of anthracyclines is limited by cumulative dose-dependent cardiotoxicity, though the mechanisms responsible for this are complex and incompletely understood. Existing biomarkers of anthracycline-related cardiotoxicity, such as troponin and NT-proBNP, lack sensitivity for the earliest stages of cardiotoxicity, therefore limiting scope to switch to alternative, safer treatment. As such, a reliable early biomarker of anthracycline-related cardiotoxicity remains a key unmet research need. Methods We investigated the rat myocardial proteome to identify novel biomarkers of anthracycline-related cardiotoxicity warranting further investigation for routine clinical application. Six groups of 8 Han-Wistar rats were dosed weekly for 1-7 doses with either doxorubicin 1.25mg/kg or saline control, followed by terminal bleeds. Sequential window acquisition of all theoretical mass spectra (SWATH-MS) was used to compare the rat myocardial proteome at serial timepoints and between doxorubicin- and saline-treated animals. A shortlist of candidate biomarkers was generated by identifying proteins with significant log 2 fold changes at early/mid timepoint dysregulation, sustained to later timepoints. Pathway analysis for human ortholog proteins was undertaken using the Uniprot database and STRING. Results Three proteins were differentially expressed at early, mid- and late timepoints (myosin light chain 3, desmin and cysteine-rich protein 2). A further 10 proteins were differentially expressed at mid- and late timepoints. Pathway analysis identified biological processes enriched within the myocardial proteome, predominantly related to muscle, metal ion, haemostasis, lipid and inflammation processes. A candidate biomarker shortlist of 34 proteins was derived for future study. Conclusion We used a rat anthracycline dosing schedule to recapitulate the development of cardiotoxicity observed in humans. We describe a shortlist of 34 proteins with promise as candidate biomarkers of the earliest stages of anthracycline-related cardiotoxicity and summarise pathway analysis of functionally enriched biological processes within the rat myocardial proteome during anthracycline treatment. Further study is underway to explore these shortlisted proteins in rat plasma, with a human study planned to validate best-performing biomarkers.

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