Abstract
Background
We investigated whether plasma high-sensitivity cardiac troponin T (hs-cTnT) and circulating heart-associated microRNA (miRs) are increased in children with leukaemias during anthracycline-based chemotherapeutic treatment.
Methods
In vitro human pluripotent stem cell (hPSC)-derived cardiomyocyte model showed that miR-1, miR-133a, miR-208a, miR-208b, and miR-499 are released from cells into culture medium in a time- and dose-dependent manner on doxorubicin exposure. Left ventricular (LV) myocardial deformation and circulating heart-associated miRs and plasma hs-cTnT during and after completion of chemotherapy were determined in 40 children with newly diagnosed acute leukaemia.
Results
Significant reduction of LV global longitudinal strain and strain rates were found within 1 week after completion of anthracycline therapy in the induction phase of treatment (all p < 0.05). Hs-cTnT level peaked and miR-1 increased significantly at this time point. Log-transformed hs-cTnT correlated negatively with LV global systolic longitudinal strain (r = −0.38, p < 0.001). Receiver operating characteristic analysis revealed that area under the curve for changes in plasma hs-cTnT from baseline and plasma miR-1 levels in detecting a reduction in ≥20% of global longitudinal strain were respectively 0.62 (95% CI 0.38−0.87) and 0.62 (95% CI 0.40−0.84).
Conclusion
Plasma hs-cTnT and circulating miR-1 may be useful markers of myocardial damage during chemotherapy in children with leukaemias.
Impact
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Heart-associated miRNAs including miR-1, miR-133a, miR-208a, miR-208b,and miR-499 were increased in the culture medium upon exposure of hPSC-derived cardiomyocytes to doxorubicin.
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Only miR-1 increased significantly during anthracycline-based therapy in paediatric leukaemic patients.
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In paediatric leukaemic patients, plasma hs-cTnT and circulating level of miR-1 showed the most significant increase within 1 week after completion of anthracycline therapy in the induction treatment phase.
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The study provides the first evidence of progressive increase in circulating miR-1 and plasma hs-cTnT levels during the course of anthracycline-based therapy in children with leukaemias, with hs-cTnT level also associated with changes in LV myocardial deformation.
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Acknowledgements
This study was supported by the Health and Health Services Research Fund, Food and Health Bureau, Hong Kong SAR Government (01121546).
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Y.-f.C. conceptualized the study, analysed the echocardiographic data and wrote the manuscript. V.W.-y.L. and C.T.-m.L. recruited the patients, acquired echocardiographic data and analysed the echocardiographic data. V.Y.S. and A.K. performed the circulating microRNA measurements and analysed laboratory results. W.K. and R.A.L. performed experiments on human pluripotent stem cell-derived cardiomyocytes and interpreted the in vitro data. D.K.-l.C. and G.C.-f.C. helped to recruit patients and analysed the clinical data. All of the authors had critically reviewed the manuscript, provided their intellectual input, and approved the final version of the manuscript.
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Informed written consent was obtained from parents of all patients for this clinical study, which was approved by the Institutional Review Board and performed in accordance with the relevant guidelines and regulations.
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Cheung, Yf., Li, V.Wy., Lai, C.Tm. et al. Circulating high-sensitivity troponin T and microRNAs as markers of myocardial damage during childhood leukaemia treatment. Pediatr Res 89, 1245–1252 (2021). https://doi.org/10.1038/s41390-020-1049-5
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DOI: https://doi.org/10.1038/s41390-020-1049-5
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