Evaluation of endothelial function in childhood standard risk acute lymphoblastic leukemia survivors: role of subclinical markers and identification of preventable factors

Background: Adult survivors from childhood malignancy are prone to accelerated atherogenesis and cardiovascular (CV) complications. In this population reliable tools are needed to detect preclinical onset of CV disease. Aim: To assess subclinical markers of inflammation and endothelial dysfunction in young survivors from acute lymphoblastic leukemia (ALL) treated with chemotherapy without cranial irradiation (AIEOP 2000 and 2009 standard risk protocols). Methods: Anthropometric parameters [height (H), body mass index (BMI), waist circumference (WC), hip circumference (HC), WC/H and WC/HC ratio], blood pressure, glucose and lipid profile, serum CV markers [Interleukin 6 (IL-6), Vascular Cell Adhesion Molecule (VCAM), Intercellular Adhesion Molecule (ICAM), Tumor Necrosis Factor-alfa (TNF-α), endogenous secretory Receptor for Advanced Glycation Endproducts (Es-RAGE)] and ultrasound parameters of endothelial function (carotid intima–media thickness, c-IMT) were assessed in 28 ALL survivors (71% male, 18% prepubertal, aged 15.98±4.41 years) at least two years after the end of chemotherapy (mean follow-up 8.57±3.14 years) and in 22 sex- and age-matched controls (64% male, aged 16.59±5.60 years). Results: ALL survivors exhibited low levels of Es-RAGE than controls (0.18±0.07 vs. 0.27±0.08 ng/ml, p<0.001). No other differences in serum CV markers were detected between survivors and controls. Among survivors, Es-RAGE values significantly correlated with BMI-SDS off-therapy (R2-0.42), WC/H ratio (R2-0.41), WC/HC ratio (R2-0.38) and with low-density-lipoprotein cholesterol (LDL-c; R2-0.43). IL-6 and TNF-α levels directly correlated with WC/H ratio (R20.41), WC/HC ratio (R20.51), triglycerides values (R20.40) and with diastolic blood pressure (DBP; R20.50), respectively. Moreover, in ALL survivors, mean c-IMT was within the normal range for age (0.55±0.14 mm, range 0.4-0.85) and correlated with systolic blood pressure (SBP; R20.56), DBP (R20.66) and LDL-c levels (R20.56). According to Weiss’ definition, metabolic syndrome (MetS) was fully detected only in one ALL survivor. Nevertheless, 18% ALL survivors presented more than one MetS diagnostic criteria: 14% showed insulin-resistance, 25% dyslipidemia and 17.8% hypertension. Conclusions: We demonstrated that in ALL survivors, as in general population, all the investigated CV markers correlate with modifiable clinical and biochemical parameters. Therefore, a healthy lifestyle should be encouraged soon after chemotherapy. The detection of low levels of Es-RAGE in ALL survivors could be due to their consumption in a chronic endothelial inflammatory condition that seems to be only partially reversible after chemotherapy.