remain elusive In children and young adults with Marfan syndrome, LoeysDietz syndrome, and Ehlers-Danlos syndrome, the increase in aortic stiffness is associated with a higher rate of aortic root dilation and surgical root replacement on follow-up.465 Haploinsufficiency of the elastin gene is implicated in the arteriopathy of Williams syndrome.466 Despite a biologic basis for abnormal elastic fibers, the results of studies exploring arterial elastic properties in patients with Williams syndrome are controversial Studies have shown increased stiffness of the ascending aorta and aortic arch and implied that abnormal mechanical property of the arteries may contribute to systemic hypertension commonly found in patients with Williams syndrome.467,468 By contrast, paradoxical reduction of stiffness of the common carotid artery has also been reported.469,470 Systemic arterial abnormalities—including bicuspid aortic valve, coarctation of the aorta, and aneurysmal dilation of the aortic root—are common in Turner syndrome Although histologic evidence of cystic medial necrosis has been reported in Turner syndrome,471,472 these findings are not consistently present Functionally, the carotid augmentation index has been found to be increased, explainable in part by the short stature, whereas carotid-femoral pulse-wave velocity and brachial artery flow-mediated dilation remain normal in these patients.473,474 It is worthwhile to note, however, that an isolated bicuspid aortic valve is associated with progressive dilation of the ascending aorta in both children and adults475 and with increased aortic stiffness.476,477 Congenital Heart Disease Aortic medial abnormalities with elastic fiber fragmentation have been found in intraoperative biopsies and necropsy specimens of a variety of congenital heart disease in patients ranging from neonates to adults.478 These congenital heart lesions include tetralogy of Fallot with or without pulmonary atresia, common arterial trunk, complete transposition of the great arteries (TGA), coarctation of the aorta, double-outlet ventricles, and univentricular hearts Whether these abnormalities are inherent or acquired is, however, unknown In tetralogy of Fallot, these intrinsic histologic abnormalities have been implicated in the pathogenesis of progressive aortic root dilation despite surgical repair.479–481 In children and adults with repaired tetralogy of Fallot, increased aortic stiffness and reduced aortic strain have been documented and found to be related to aortic root dimensions.481 Preferential stiffening of the central over peripheral conduit arteries482 and a marked increase in the ascending but not descending aortic stiffness483 have been demonstrated Furthermore, the heartfemoral pulse-wave velocity and carotid augmentation index were found to be significant determinants of the size of sinotubular junction, suggesting that central arterial stiffening may contribute to progressive aortic root dilation in these patients.482 The fibrillin-1 gene variant has also been associated with an increased risk of aortic dilation in patients with repaired tetralogy of Fallot.484 In complete TGA, abnormal aorticopulmonary septation has been hypothesized to be associated with events in elastogenesis.485,486 In patients undergoing two-stage anatomic correction, decreased distensibility of the neoaorta has been thought to be related to pulmonary arterial banding.487 Nonetheless, even after a one-stage arterial switch operation, impaired distensibility of the neoaorta has similarly been found.488 Furthermore, reduced distensibility of the thoracic aorta at the level of the isthmus in addition to the neoaortic root has been documented.489 Upon submaximal bicycle stress testing, persistent elevation of aortic stiffening beyond the normal physiologic changes has been associated with a higher systolic blood pressure during exercise.490 Previous studies have also documented an increase in stiffness index of the carotid artery in patients after either atrial or arterial switch operations,486,491 suggesting that impaired elastogenesis may be an intrinsic component of this congenital anomaly Structural abnormalities of the aortic segment proximal to the site of aortic coarctation are characterized by an increase in collagen and a decrease in smooth muscle content.492 The finding of an increased ascending aortic stiffness index in neonates with coarctation before surgery supports that impairment of elastic properties of the prestenotic aorta is a primary abnormality.493 Despite successful surgical repair, functional impairments—including impaired flowmediated dilation, reduced nitroglycerine-induced vasodilation, and increased pulse-wave velocity of conduit arteries proximal to the site of coarctation— persist.494–496 Distensibility of the aortic arch has also been shown to be significantly lower than that of the distal thoracic aorta.497 Enhanced aortic pressure-wave reflection498 has been attributed to a major reflection point at the site of coarctation repair The finding of an inverse relationship between the magnitude of the brachial artery vasodilation response to nitroglycerine and 24hour systolic blood pressure implicates a possible role of reduced vascular reactivity in the development of systemic hypertension and left ventricular hypertrophy in patients despite successful repair of coarctation.496 The importance of early coarctation repair for the possible prevention of late vascular dysfunction is highlighted by the inverse relationships between age at repair and stiffness and vascular reactivity of the precoarctation arterial segments.495,497,499 In Fontan patients, magnetic resonance angiographic assessment has revealed a prevalence of 8.5% and 22% of severe dilation of the aortic root and ascending aorta, respectively.500 Importantly, dilation of the ascending aorta has been associated with an increase in the aortic stiffness index Increased central and peripheral arterial augmentation indexes have also been found in Fontan patients.501,502 Functionally, in adolescents and young adults, worse indexes of endothelial function and arterial stiffness are associated with lower exercise capacity, cardiac output, and physical activity and worse quality-of-life parameters.503 Endothelial dysfunction has also been associated with congenital cardiac anomalies In adults with cyanotic congenital heart disease, impaired forearm blood flow response to the intra-arterial infusion of acetylcholine has been shown.504 The cause is probably multifactorial, being related to reduced nitric oxide production,505 hypoxemia,506 and secondary erythrocytosis.507 Altered levels of biomarkers of endothelial activation have been shown in a small cohort of children and adolescents with univentricular hearts who have undergone cavopulmonary connection.508 In patients after the Fontan operation, reduced brachial artery flow-mediated dilation509,510 and, in a subset, impaired nitroglycerine-induced vasodilation510 have been demonstrated A negative correlation, albeit weak, was found in post-Fontan patients between flowmediated dilation and serum levels of the nitric oxide pathway inhibitors asymmetric and symmetric dimethlyarginine.509 Furthermore, patients on angiotensin-converting enzyme inhibitors tended to have better endothelial function Nonetheless the usefulness of angiotensin-converting enzyme inhibitors in the post-Fontan state remains debatable Systemic Diseases Rheumatoid arthritis and systemic lupus erythematosus provide clinical models for determining the relationship of chronic systemic inflammation to arterial dysfunction In children and young adults with juvenile idiopathic arthritis,