Abstract
BackgroundAnthracycline induced cardiomyopathy is a major cause of mortality and morbidity among pediatric cancer survivors. It has been postulated that oxidative stress induction and inflammation may play a role in the pathogenesis of this process. Accordingly, the present study performed an assessment of biomarker profiles and functional imaging parameters focused upon potential early determinants of anthracycline induced cardiomyopathy.MethodsPatients (10–22 years) were prospectively enrolled between January 2013 and November 2014. Thirteen subjects completed the study and underwent serial cardiac magnetic resonance imaging and plasma biomarker profiling performed 24–48 h after the first anthracycline dose and at set dose intervals. In addition, we collected plasma samples from 62 healthy controls to examine normal plasma biomarker profiles.ResultsLeft ventricular ejection fraction (LVEF) decreased from 64.3 ± 6.2 at the first visit to 57.5 ± 3.3 (p = 0.004) 1 year after chemotherapy. A decline in longitudinal strain magnitude occurred at lower cumulative doses. A differential inflammatory/matrix signature emerged in anthracycline induced cardiomyopathy patients compared to normal including increased interleukin-8 and MMP levels. With longer periods of anthracycline dosing, MMP-7, a marker of macrophage proteolytic activation, increased by 165 ± 54% whereas interleukin-10 an anti-inflammatory marker decreased by 75 ± 13% (both p < 0.05). MMP7 correlated with time dependent changes in EF.ConclusionsAsymptomatic pediatric patients exposed to anthracycline therapy develop abnormal strain parameters at lower cumulative doses when compared to changes in EF. A differential biomarker signature containing both inflammatory and matrix domains occur early in anthracycline treatment. Dynamic changes in these domains occur with increased anthracycline doses and progression to anthracycline induced cardiomyopathy. These findings provide potential prognostic and mechanistic insights into the natural history of anthracycline induced cardiomyopathy.Trial registration numberNCT03211520 Date of Registration February 13, 2017, retrospectively registered.
Highlights
Anthracycline induced cardiomyopathy is a major cause of mortality and morbidity among pediatric cancer survivors
Shifts in the steady-state expression of matrix metalloproteinases (MMPs) and Inhibitors of metalloproteinase (TIMP) have been identified to occur with inflammation and cytokine release as well as with oxidative stress, [24, 25] both of which are operative in the context of Anthracycline induced cardiomyopathy (AIC) [18, 26,27,28]
We demonstrate an increase in MMP-2, MMP-7 and MMP9, and detectable levels of TIMP-3 and TIMP-4 in the anthracycline group (p < 0.05) (Fig. 3)
Summary
Anthracycline induced cardiomyopathy is a major cause of mortality and morbidity among pediatric cancer survivors. The present study performed an assessment of biomarker profiles and functional imaging parameters focused upon potential early determinants of anthracycline induced cardiomyopathy. Shifts in the steady-state expression of MMPs and TIMPs have been identified to occur with inflammation and cytokine release as well as with oxidative stress, [24, 25] both of which are operative in the context of AIC [18, 26,27,28]. The primary objective of this study was to examine MMP/TIMP and cytokine plasma levels in pediatric cancer patients undergoing anthracycline (AC) therapy and perform a comparative analysis with age matched reference control subjects
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