reduced arterial elasticity, increased aortic pulse-wave velocity, decreased flowmediated dilation, and increased carotid intima-media thickness have been reported.511 In an interventional study, the use an antiinflammatory medication for a year has been shown to decrease carotid intima-media thickness.512 Few studies have evaluated arterial function in children with systemic lupus erythematosus In women with systemic lupus erythematosus, brachial artery flow-mediated dilation has been found to be impaired513,514 and carotid arterial stiffness increased.515,516 In adolescents and young adults with lupus of pediatric onset, endothelial function has been found to be normal.517 However, another study demonstrated increased carotid artery stiffness associated with left ventricular hypertrophy and subclinical left ventricular dysfunction.518 Acute exposure to extrinsic inflammatory insult in children who had an acute infection or are convalescing from an infection in the previous 2 weeks has also been shown to cause transient impairment of brachial artery flow-mediated dilation.519 The endothelial dysfunction was found to recover in most but not all of the children studied at follow-up 1 year later Possible mechanisms include a direct effect of virus520 or an indirect effect through inflammatory cytokines on endothelial function Apart from common acute childhood infections, chronic infection with human immunodeficiency virus in children has been associated with arterial dysfunction The functional alteration is characterized by impaired brachial artery flow-mediated dilation521,522 and increased elastic modulus of the carotid arterial wall.521 Additionally, endothelial dysfunction was found to be more pronounced in children receiving protease inhibitor therapy.522 In adults with chronic renal failure, premature atherosclerosis is a major cause of morbidity and mortality There is evidence to suggest that children with endstage renal failure are similarly predisposed to an increased risk of cardiovascular disease.523 Increased aortic pulse-wave velocity and carotid artery stiffness are independent predictors of cardiovascular mortality in adults with end-stage renal failure.163,164,524 In children on hemodialysis, increased carotid-femoral pulse-wave velocity and augmentation index have also been demonstrated.525 Even after successful pediatric renal transplantation, carotid artery stiffness remains elevated and is associated with a higher daytime systolic blood pressure load and receipt of cadaveric kidney.526 Apart from arterial stiffening, endothelial dysfunction has been demonstrated in children with chronic renal failure even in the absence of classic cardiovascular risk factors527 and in those after transplantation.528 Limited evidence suggests that oral folic acid, but not L-arginine, may improve endothelial function in children with chronic renal failure by lowering the homocysteine level and increasing the resistance of low-density lipoprotein to oxidation.529,530 Increased iron storage has been linked with the risk of atherosclerosis.531 Iron overloading in patients with β-thalassemia major results in alterations of arterial structures with disruption of elastic tissue and calcification.532,533 In adolescent and adult patients with β-thalassemia major, increased stiffness of the carotid artery, brachioradial artery, and aorta has been shown in vivo.534,535 Importantly, systemic arterial stiffening is inversely related to brachial artery flow-mediated dilation and positively with left ventricular mass and carotid intima-media thickness.534,536 Furthermore, elevated pulsatile and static afterload was found in patients with β-thalassemia major.537 Apart from oxidative damage related to iron overload, the cell-free hemoglobin in hemolytic disease has also been implicated in mediating vascular dysfunction by limiting the availability of nitric oxide.538 Sleep-related disorders are common in children and may affect arterial function In children with primary snoring, higher daytime systemic blood pressure, increased brachioradial artery stiffness, and reduced flow-mediated dilation of the brachial artery independent of obesity have been reported.539,540 In adults with obstructive sleep apnea, increased carotid-femoral pulse-wave velocity and brachial-ankle pulse-wave velocity have been reported.541,542 Pediatric data in this regard are lacking On the other hand, nonobese children with obstructive sleep apnea were found to have endothelial function,543,544 which could be reversed after adenotonsillectomy.544 Children with obstructive sleep apnea and altered endothelial function have been found to have reduced circulatory endothelial progenitor cells.543 On the other hand, the levels of circulating microparticles were found to be increased and, in particular, plateletderived microparticles were found to be associated with vascular dysfunction.545 Recent studies also suggest possible involvement of a triggering receptor expressed on myeloid cells-1,546 pentraxin-3,546 adropin,547 and nicotinamide adenine dinucleotide phosphate oxidase548 in causing endothelial dysfunction in children with obstructive sleep apnea In children with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS), the level of L-arginine has been found to be significantly lower during stroke-like episodes and associated with reduced brachial artery flowmediated dilation.549–551 Prolonged L-arginine supplementation has been shown to reduce the stroke-like episodes and to normalize endothelial dysfunction.550,551 In vitro studies have demonstrated the toxic effects of anthracyclines on endothelial cells.552 Finally, in survivors of childhood cancers, increased aortic stiffness and reduced carotid distensibility have recently been reported.553,554 Genetic Considerations The genetic aspect of arterial stiffness is increasingly being unveiled The phenomenon of arterial stiffening in genetic syndromes associated with the mutation or deletion of genes encoding structural proteins of the arterial wall has been alluded to earlier Studies have demonstrated moderate to substantial heritability of common carotid artery stiffness, augmentation index, and carotidfemoral pulse-wave velocity in different ethnic populations.555–558 Genome-wide association studies, linkage analysis, and candidate gene polymorphism association studies have revealed different groups of genes that may contribute to arterial stiffening.559 These genes are involved in the renin-angiotensinaldosterone system, matrix components and metalloproteinases, and the nitric oxide pathway Other important gene variants include β-adrenergic receptors, endothelin receptors, and inflammatory molecules, which are implicated in the pathophysiology of arterial stiffness Genome-wide association studies have identified additional genes that have no apparent relationship to mechanisms of arterial stiffness but which may target transcriptional pathways controlling gene expression, differentiation of vascular smooth muscle cells, apoptosis of endothelial cells, or the immune response within the vascular wall Detailed discussion on the genetics of arterial stiffness is beyond the scope of this chapter; however, interested readers are referred to recently published reviews.559,560 The genetics of endothelial dysfunction are less clear Potential genetic contribution is evidenced by studies demonstrating that young individuals with a family history of cardiovascular disease have impaired endothelial function382,383 and that polymorphisms of angiotensin-converting enzyme561 and endothelial nitric oxide synthase genes562 may influence endothelial function In children, endothelial dysfunction is found in single-gene disorders including homocystinuria392 and familial hypercholesterolemia.251,366–368 In a large community-based sample, the estimated heritability of brachial artery flowmediated dilation has been shown to be modest.563 Although polymorphisms of ... In adults with obstructive sleep apnea, increased carotid-femoral pulse-wave velocity and brachial-ankle pulse-wave velocity have been reported.541,542 Pediatric data in this regard are lacking On the other hand, nonobese children with obstructive sleep apnea were found to have endothelial function,543,544