Circulating microRNAs and myocardial damage in paediatric cancer patients receiving anthracycline therapy

Abstract

Introduction: We investigated whether circulating heart-associated microRNAs (miRNAs) and the conventional cardiac biomarker, cardiac troponin T as detected by a highly senstive assay (hs-cTnT), are increased in paediatric cancer patients receiving anthracycline therapy and whether the increased levels reflect myocardial damage. Methods: The in vitro study utilized a human embryonic stem cell-derived cardiomyocyte cell model of anthracycline cardiotoxicity. A prospective patient cohort study was completed in 20 children diagnosed to have acute leukaemia with serial echocardiographic speckle tracking assessment of left ventricular (LV) myocardial deformation and quantification of circulating heart-associated microRNAs and plasma hs-cTnT at five time points during and after completion of anthracycline-based chemotherapy. Results: In vitro study showed that heart-associated miRNAs including miR-1, miR-133a, miR-208a, miR-208b, and miR-499 are released from the cells into the culture medium in a time- and dose-dependent manner on exposure to doxorubicin. In patients, significant reduction of LV global longitudinal systolic strain, systolic strain rate, and early and late diastolic strain rate (all p<0.05) were found at the third time point, which is within 1 week after completion of anthracycline therapy in the induction phase of treatment. Of the five miRNAs, only miR-1 showed significant increase in fold changes, which was most significant at similarly the third time point. Plasma hs-cTnT level was also significantly higher than baseline at this time point and within 1 week after completion of all anthracycline treatment. Receiver operating characteristic curve analysis revealed that plasma hs-cTnT, compared with miR-1, had a greater area under the curve (0.82 vs 0.42) for detection of early impairment (>10% reduction of global systolic strain) of LV myocardial deformation. Conclusions: Circulating miR-1 and hs-cTnT showed significant increase during anthracycline-based therapy in children with leukaemias. Plasma hs-cTnT level may, however, be better than circulating miR-1 as a biomarker of early subclinical myocardial impairment.