Abstract 5454: Oxidative Stress is Associated with Arterial Dysfunction and Enhanced Intima-Media Thickness in Children with Hypercholesterolemia. Potential Role of Nadph Oxidase
Endothelial dysfunction and intima-media thickness (IMT) are precocious manifestations of hypercholesterolemia but the mechanism is unclear. The aim of the study was to analyse the interplay among endothelial dysfunction, IMT and oxidative stress in hypercholesterolemic children (HC). We performed a cross-sectional study comparing flow mediated dilation (FMD), IMT, lipid profile, urinary isoprostanes as markers of oxidative stress, and platelet expression of gp91phox, the catalytic unit of NADPH oxidase, in a population of 50 HC (mean age 10.0±3.7 years) and 50 normocholesterolemic children (NC) (mean age 9.2±3.5 years). Four children with hereditary deficiency of gp91phox were also studied. HC had reduced FMD (6.2±2.4 vs. 9.2±2.5%; p<0.001) and enhanced IMT (0.45±0.07 vs. 0.40±0.06 mm; p<0.002), urinary isoprostanes (86.9±51.6 vs. 45.9±25.6 pg/mg of creatinine; p<0.001) and gp91phox platelet expression (4.4±3.8 vs. 2.0±1.7 mean fluorescence; p<0.001) compared to controls. At bivariate analysis, FMD was correlated with LDL cholesterol (r= −0.448; p<0.001), IMT (r=−0.356; p=0.01), urinary isoprostanes (r=−0.388; p=0.005) and platelet gp91phox (r=−0.314; p=0.02). Stepwise multiple linear regression analysis showed that in HC, FMD and IMT were significantly associated with LDL cholesterol and urinary isoprostanes; also, gp91phox platelet expression was an independent predictor of urinary isoprostanes. Children with gp91phox hereditary deficiency showed down-regulation of platelet gp91phox and reduced urinary excretion of isoprostanes. The study suggests that gp91phox -mediated oxidative stress may have a pathogenic role in the anatomic and functional changes of the arterial wall occurring in children with premature atherosclerosis.