impaired brachial artery flow-mediated dilation,344,347–349 which improves with exercise training.350–353 Dyslipidemia, diabetes mellitus, low-grade inflammation, and concomitant metabolic syndrome in obese children are linked with arterial dysfunction.354–356 Obesity-related peptides exert significant additional influence on the vasculature.357 Elevations in leptin have been shown to be associated with impaired arterial distensibility in healthy children358 and in children with type I diabetes.359 The effect of leptin on endothelial function in humans is, however, controversial.360 Plasma adiponectin, on the other hand, has been shown to correlate with the vasodilator response of the forearm microcirculation to reactive hyperemia.361,362 Children with heterozygous familial hypercholesterolemia have increased stiffness of the common carotid artery363,364 and modification of their aortic elastic properties.365 Impaired brachial artery flow-mediated dilation has also been shown in these children and in those as young as 6 years of age with familial combined hyperlipoproteinemia.251,366–368 Endothelial dysfunction is most pronounced in those with a positive family history of premature cardiovascular disease.369 Early statin and antioxidant vitamins C and E therapy may potentially restore endothelial dysfunction in these children toward normal.367,368,370 However, the relationship between flow-mediated dilation and low-density lipoprotein cholesterol levels is controversial.363,366,367 Nonetheless, in a population-based study, total and low-density lipoprotein cholesterol levels were found to relate inversely to brachial artery distensibility,371 suggesting the possibility that cholesterol levels in the general population during childhood may already be of relevance in the pathogenesis of arterial stiffening Children with type 1 diabetes have endothelial dysfunction,372–375 which is improved by folic acid.376 Arterial stiffening in these children is suggested by an increase in augmentation index,377 which is associated with nitric oxide synthase 3 polymorphism.378 Offspring of parents with type 2 diabetes have a high risk of developing diabetes and atherosclerotic complications Studies have shown increased aortic379 and carotid-radial380 pulse-wave velocity in normoglycemic adults who are offspring of parents with type 2 diabetes Intima-media thickening of the common carotid artery is found in children and adolescents with a parental history of premature myocardial infarction.381 In adults who are offspring of parents with premature cardiovascular disease, apart from intima-media thickening, impaired endothelial-dependent vasodilation of brachial artery has also been demonstrated.382,383 Habitual physical activity in children aged 5 to 10 years has been shown to correlate positively with flow-mediated dilation, suggesting that its cardiovascular protective effect may be mediated via the endothelium.384 In another cohort of 10-year-old children, physical activity was found to correlate inversely with arterial stiffness.385 Associations between increased baseline high-sensitivity C-reactive protein concentrations and the risks of developing cardiovascular disease in adults have been reported.386–388 In healthy children, serum high-sensitivity C-reactive protein concentrations have been found to have an inverse dose-dependent relationship with the magnitude of brachial artery flow-mediated dilation.389 Increased serum high-sensitivity C-reactive protein levels are found in obese adolescents.348,390 Analysis of the 1999 to 2000 National Health and Nutrition Examination Survey showed a strong independent association between body mass index and C-reactive protein level even in young children aged 3 to 17 years.391 However, in children and adolescents who do not have much of an atherosclerotic burden, whether high-sensitivity C-reactive protein is a risk factor or a risk marker requires further clarification In children with homozygous homocystinuria, impaired brachial artery flowmediated dilation has been demonstrated in those as young as 4 years.392 In the general pediatric population, findings of elevated homocysteine levels in children with a family history of premature cardiovascular disease are conflicting.393–395 Although hyperhomocysteinemia is a risk factor for endothelial dysfunction in middle-aged396 and elderly397 subjects, there are no data to suggest a link between arterial dysfunction and serum homocysteine levels in children Prenatal Growth Restriction It has been almost 3 decades since the report of associations between low birth weight and increased risk of cardiovascular disease.398 These findings, having been replicated in subsequent studies,399–401 have formed the basis of the fetal origins hypothesis, later termed developmental origins of disease,402 which implicates the origin of cardiovascular disease from adaptations to an adverse environment in utero There is now substantial evidence that individuals who are born small are at risk of vascular dysfunction in childhood and thereafter Arterial endothelial dysfunction has been found in term infants,277 children,403 and young adults404 with low birth weight Another study showed elevated uric acid in children with low birth weight and a graded inverse relationship between uric acid and flowmediated dilation.405 In children born at term, leanness at birth has been reported to correlate with the lowest endothelium-dependent microvascular responses and the highest carotid stiffness indexes.406 In infants with umbilical placental insufficiency before birth, the increase in afterload has been shown to result in a decrease in aortic distensibility during the neonatal period, suggesting an alteration of aortic wall structure.407 Furthermore, reduced compliance of the aorta and conduit arteries of the legs has been shown to occur in adults born small.408 The risk of arterial dysfunction for individuals who are born small as a result of prematurity is controversial.409,410 Nonetheless, preterm birth may attenuate the association between low birth weight and endothelial dysfunction.411 With regard to arterial stiffness, reduced aortic wall distensibility and whole-body compliance have been shown in premature infants with very low birth weight as early as the neonatal period.412 Other studies have demonstrated inverse relationships between systemic arterial stiffness and gestational age413 and birth weight standardized for gestational age.414 In monozygotic twins with twin-twin transfusion syndrome, peripheral conduit arterial stiffness has been shown to be increased during infancy in the growth-restricted donor twins.415 Such vascular programming can be ameliorated, albeit not completely abolished, by intrauterine endoscopic laser ablation of placental anastomoses.416 Even in monozygotic twins without twintwin transfusion syndrome, the twin with the lower birth weight has been found to have a higher systolic blood pressure and pulse pressure and impaired endothelial function in childhood.417 The mechanism whereby low birth weight is associated with increased arterial stiffness in childhood and adulthood remains unclear The reported endothelial dysfunction in individuals born preterm and small-for-gestational age277,403,406,408,410 suggests that functional alteration of arterial tone may contribute to an increase in systemic arterial stiffness Preferential perfusion of the upper part of the body in intrauterine growth retardation418 may affect the mechanical properties of the large arteries Hence selective carotid arterial atherosclerosis has been found to be more severe in elderly people with the ... In children with homozygous homocystinuria, impaired brachial artery flowmediated dilation has been demonstrated in those as young as 4 years.392 In the general pediatric population, findings of elevated homocysteine levels in children with a family history of premature cardiovascular disease are