Determinants of arterial nitrate-mediated dilatation in children: role of oxidized low-density lipoprotein, endothelial function, and carotid intima-media thickness.

BACKGROUND Impaired arterial dilatation response to nitroglycerin has been observed in adults with risk factors for atherosclerosis and in patients with established atherosclerotic disease. This defect parallels changes in vascular endothelial function and may be attributed to increased oxidative stress. Because atherosclerosis begins in childhood, we examined the correlates of nitrate-mediated dilatation (NMD) in children, including brachial artery endothelial function, oxidized LDL, and carotid artery intima-media thickness (IMT). METHODS AND RESULTS Brachial artery flow-mediated endothelium-dependent dilatation (FMD) and nitrate-mediated smooth muscle function, IMT of the carotid bulb, and brachial artery and oxidized LDL were measured in 142 children (mean age, 11 years; range, 8 to 17 years), including 87 healthy children, 41 diabetic children, and 14 children with familial hypercholesterolemia. NMD correlated directly with FMD (r=0.46, P<0.001) and inversely with brachial artery baseline diameter (r=-0.36, P<0.001), age (r=-0.25, P=0.003), body mass index (r=-0.31, P<0.001), diabetes (r=-0.22, P=0.008), oxidized LDL (r=-0.18, P=0.045), and IMT (r=-0.33, P<0.001). In a multivariate regression model, the significant correlates for NMD were FMD response (beta=0.003, P<0.001), brachial artery diameter (beta=-0.03, P=0.01), oxidized LDL (beta=-0.07, P=0.02), and IMT (beta=-0.15, P=0.03). CONCLUSIONS Reduced endothelial function, increased oxidative stress, and preclinical carotid atherosclerosis are independent determinants of impaired NMD in children. These data thus suggest that primary nitrate tolerance occurs in children at risk for atherosclerosis.