genes encoding factors involved in the regulation of nitric oxide synthesis have been implicated in endothelial dysfunction,564 further studies are warranted before any conclusions can be drawn Clinical Implications The prognostic implications of arterial dysfunction in adults have been alluded to earlier Whether arterial stiffening and endothelial dysfunction represent genuine cardiovascular risk factors and can predict future cardiovascular events in children and adolescents is unclear Nevertheless it appears unrealistic to assess the prognostic value of indexes of arterial function in childhood only in terms of endpoints as cardiovascular morbidity and mortality The use of carotid intima-media thickness (see earlier) as a structural surrogate measure of atherosclerosis is a potentially useful alternative Increased carotid intima-media thickness is documented in several of the aforementioned pediatric conditions including childhood obesity,565 familial hypercholesterolemia,566–568 type 1 diabetes,372,568 hypertension,569,570 metabolic syndrome,571 family history of premature myocardial infarction,381 children born small for gestational age,572,573 children infected with human immunodeficiency virus on antiretroviral therapy,574 Kawasaki disease,446–448 chronic renal disease,575,576 and thalassemia major.536 Early identification of arterial dysfunction that potentially precedes and induces atherosclerotic changes provides a window for early intervention The potential beneficial effects on endothelial function of folic acid in children with renal failure,529,530 antioxidant vitamins and statins in those with familial hypercholesterolemia,367,368,370 vitamin C and statins in those with Kawasaki disease,432,447 and exercise training in obese children384,577 have been discussed Furthermore, in patients with Marfan syndrome, β-blocker therapy,455 and angiotensin-converting enzyme inhibition,462 and losartan463,464 appear to reduce aortic stiffness, albeit with uncertain effects on aortic dilation itself However, intuitive longitudinal studies are required to determine whether therapeutic intervention to improve arterial function will be translated into clinical benefits or whether lifestyle and dietary modifications in healthy children may prevent arterial dysfunction in later life Nonetheless this is a rich area for research, with potentially huge benefits at an individual and societal level Given that the systemic arterial system receives and distributes output from the systemic ventricle, satisfactory performance of the systemic ventricular pump depends not only on its intrinsic properties but also on its optimal interaction with the systemic circulation Dysfunction of either of the components of the cardiovascular system would inevitably affect performance of the other This issue of ventriculoarterial interaction is discussed in the following section Ventriculoarterial Interaction Impact of Arterial Dysfunction on Ventricular Function From the cardiac perspective, arterial dysfunction exerts its influence on systemic ventricular afterload, myocardial energetic efficiency, coronary artery perfusion, and cardiac structure and function Ventricular afterload is increased in the presence of systemic arterial stiffening and endothelial dysfunction, the latter through modulation of vascular tone To generate the same stroke volume against a stiffened arterial tree, the systemic ventricle has to generate a higher end-systolic pressure As the pressure developed during systole is a major determinant of myocardial oxygen consumption, greater energy expenditure of the heart is required as afterload increases.578,579 The phasic coronary flow pattern is also altered by arterial stiffening.578,580 Early return of the reflected pressure wave augments the systolic pressure and lowers the diastolic coronary perfusion pressure As the reliance on systolic coronary perfusion increases,580 the fall in systolic pressure with worsening of ventricular systolic performance would lead to more pronounced effects than expected on the basis of the size of the ischemic bed and ventricular function.581 Structural adaptation of the left ventricle occurs in the presence of arterial stiffening In a rat model of aortic elastocalcinosis, isolated increased aortic stiffness but without changes in mean arterial blood pressure has been associated with left ventricular hypertrophy.582 In an otherwise healthy population of adults, measures of arterial function have been shown to be significant determinants of left ventricular mass when blood pressure is removed from the statistical model.583 In adolescents and young adults, increased arterial stiffness has also been associated with left ventricular mass independent of traditional cardiovascular risk factors.584 The afterload dependence of cardiac relaxation is well recognized.585–587 In adults with hypertension588–591 and diabetes mellitus,589,591,592 arterial stiffness is associated with left ventricular diastolic dysfunction Increased myocardial oxygen consumption, left ventricular hypertrophy, and decreased diastolic coronary perfusion pressure predispose the myocardium to subendocardial