Cardiovascular signaling proteins as predictors of the cardiac effects of doxorubicin treatment in children with acute lymphoblastic leukemia

BACKGROUND: Cardiac signaling proteins sensitive to changes in cardiac status may help predict the cardiac effects of doxorubicin in children with acute lymphoblastic leukemia (ALL). We determined the relationship between these proteins and biomarkers of cardiac injury and echocardiographic characteristics. METHODS: Cardiotrophin-1 (CT-1), interleukin-6 (IL-6), neuregulin-1 (NRG-1), and vascular endothelial growth factor (VEGF) concentrations were measured in 83 children on Dana-Farber Cancer Institute ALL Protocol 95 - 01 before, during (T1: 0-50 days, T2: 51-100 days, T3: 151-300 days), and after treatment and compared to existing data for cardiac troponin-T (cTnT), N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hsCRP), and echocardiograms. RESULTS: Compared to baseline, mean IL-6 concentrations were lower during doxorubicin treatment (P < 0.01 for all) and after (P = 0.03). Mean NRG-1 and CT-1 concentrations were significantly lower beginning at T2 and thereafter (P < 0.001 for all). Mean VEGF concentrations were significantly elevated from baseline at all on-treatment time points (P ≤ 0.02 for all). Lower odds of abnormal cTnT were marginally associated with increased NRG-1. Higher odds of abnormal NT-proBNP were associated with CT-1 concentrations (P = 0.03) and marginally associated with increased IL-6 and NRG-1 concentrations. Increased hsCRP concentrations were associated with increased IL-6, NRG-1, and CT-1 (P < 0.001 for all). No echocardiographic measurements were associated with signaling proteins. CONCLUSIONS: Decreased concentrations CT-1 and NRG-1 during doxorubicin treatment may increase cardiomyocyte death. Changes in IL-6 and VEGF suggest doxorubicin-related inflammation and angiogenesis. These markers may help identify children at greatest risk of long-term adverse outcomes.