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J Appl Physiol 105: 325-333, 2008. First published May 1, 2008; doi:10.1152/japplphysiol.00001.2008
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INVITED REVIEW

HIGHLIGHTED TOPIC
Biology of Physical Activity in Youth

Arterial function in youth: window into cardiovascular risk

Bo Fernhall and Stamatis Agiovlasitis

Exercise and Cardiovascular Research Laboratory, Kinesiology and Community Health Department, College of Applied Health Sciences, University of Illinois at Urbana-Champaign, Champaign, Illiois


   ABSTRACT
TOP
 ABSTRACT
MEASURING ARTERIAL STRUCTURE AND...
 DEVELOPMENTAL ASPECTS OF...
 INFLUENCE OF CARDIOVASCULAR RISK...
 EFFECTS OF INTERVENTIONS
 CONCLUSIONS AND FUTURE...
 REFERENCES
 
Noninvasive measures of arterial function, such as intima-media thickness (IMT), endothelial function, and arterial stiffness are associated with and are prognostic of cardiovascular events in adults. Postmortem evidence, however, has established that the atherosclerotic process starts in childhood. Furthermore, cardiovascular morbidities in childhood disrupt arterial health and may lead to adverse outcomes in adulthood. Thus it is important to examine the developmental changes in IMT, endothelial function, and arterial stiffness in healthy youth in contrast to the arterial health profile of youth with cardiovascular morbidities and to examine the effect of lifestyle interventions. In healthy youth, IMT may increase slightly, arterial stiffness increases, but there is no change in endothelial function from 5 to 20 years of age. In youth with cardiovascular risk factors there are larger increases in IMT and arterial stiffness, and reductions in endothelial function compared with healthy youth. The reduced arterial function in youth with cardiovascular risk factors may be related to the atherosclerotic process. Exercise and physical activity appear to exert a protective effect on arterial function, and exercise training can improve arterial function in children with cardiovascular risk factors. Furthermore, although diet alone can improve arterial function in children, the combination of exercise and diet appears to be more effective than either intervention alone. Future studies need to focus on the mechanism by which exercise and diet improve arterial function, the most effective types of diet and exercise, and if intervening in childhood leads to favorable outcomes in adulthood.

children; intima-media thickness; endothelial function; arterial stiffness

CONSIDERING THE LONG LATENT PHASE of atherosclerotic progression before symptoms are manifested, the ability to evaluate arterial function before the development of angiographically measurable atherosclerotic plaque is an important aspect of early detection and risk classification (17, 20, 70). Several noninvasive and, thus, easy to obtain measures of arterial structure and function have been shown to be clinically useful, including measurement of carotid intima-medial thickness (IMT), endothelial function, and arterial compliance (13, 14, 37, 86, 91, 102).

Carotid IMT, a subclinical marker of atherosclerosis, is a strong marker of cardiovascular disease burden and is related to coronary artery disease, stroke, and cardiovascular mortality in adults (54, 69). Decreases in endothelial function have been associated with and shown to be prognostic of increased cardiovascular events (86, 91). Decreased endothelial function may also adversely affect peripheral blood delivery and metabolism during exercise (49). Similarly, arterial stiffness has been associated with adverse cardiovascular outcomes (11, 51, 59, 102). In addition, arterial stiffness may negatively affect myocardial performance due to increased afterload and potentially lead to decreased coronary flow (49, 50, 70). Furthermore, arterial stiffness has been hypothesized to lead to microvascular disease, which may cause additional end-organ damage such as stroke or renal failure (70). Consequently, the markers of arterial structure and function discussed above are associated with adverse outcomes in adults.

Atherosclerosis starts in childhood, and postmortem studies have identified fatty streaks in the intima of large arteries in children and adolescents (66). Early manifestation of atherosclerosis is related to traditional risk factors (9). In fact, traditional cardiovascular risk factors that are present in childhood predict cardiovascular disease risk in adulthood (4, 8, 9). Furthermore, recent studies suggest that risk factors such as hypertension, elevated low-density lipoprotein (LDL)-cholesterol, low high-density lipoprotein (HDL)-cholesterol, and obesity can predict the development of increased arterial stiffness and decreased arterial compliance in adulthood (45, 56). These findings are consistent with data showing that children with traditional risk factors also exhibit reduced arterial function (2, 89). This review will briefly describe arterial structure and function findings in healthy children. We will then review the effect of cardiovascular risk factors and the impact of interventions, such as exercise and nutrition, on arterial function in children.


   MEASURING ARTERIAL STRUCTURE AND FUNCTION
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 ABSTRACT
 MEASURING ARTERIAL STRUCTURE AND...
DEVELOPMENTAL ASPECTS OF...
 INFLUENCE OF CARDIOVASCULAR RISK...
 EFFECTS OF INTERVENTIONS
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IMT.   IMT can be reliably measured using high-resolution ultrasound. It is often measured at the common carotid artery, since IMT at this site is related to adverse cardiovascular events (54, 69). Several measures of the far wall are made over a distance of 1 cm and about 1–2 cm proximal to the bifurcation, and a mean value for the selected area is provided, using automated wall-tracking software (13, 69). Measures are made from the leading edge of the lumen-intima interface to the media-adventitia interface (44). Some researchers prefer to measure IMT at the femoral artery, because IMT at this site appears to be more readily impacted by interventions such as exercise (27, 62). However, femoral IMT has not been empirically evaluated as thoroughly as carotid IMT. Although IMT measurements are highly reliable, the resolution of the ultrasound images can be a significant limitation, as differences between groups and changes in IMT are often less than 5/100 mm.

Endothelial function.   The endothelium produces nitric oxide (NO), mediated by the enzyme endothelial NO synthase (eNOS). NO induces potent vasodilation through relaxation of the vascular smooth muscle (15–17, 20, 83). Endothelial function can be evaluated by measuring the arterial response to infused vasoactive substances, such as acetylcholine, which increases NO production (16, 83). However, the invasive nature of this approach is generally not considered ethically appropriate for use in healthy children. Endothelial function can be assessed noninvasively using flow-mediated dilation (FMD). By inducing a hyperemic stimulus, the artery dilates as a result of NO release produced by shear stress. The amount of dilation can be accurately measured using high-resolution ultrasound, thus providing an index of endothelial function (16, 17, 20, 99).

Conduit-artery endothelial function is usually evaluated in the brachial artery. The artery is visualized by ultrasound in the longitudinal plane above the antecubital fossa. Following a resting image, a blood pressure (BP) cuff is typically placed on the forearm and inflated to 250 mmHg, or to at least 50 mmHg above systolic pressure, for 4–5 min. Alternately, the cuff could be placed on the upper arm, although upper-arm placement may induce a vasodilatory response that probably reflects vasodilatory mechanisms other than NO (10). Following release of cuff pressure, the artery is continually imaged for 2 min and evaluated for percent maximal dilation from baseline, using automatic edge-detection software. However, recent data indicate that, for some populations, an imaging time longer than 2 min, and as much as 5 min, may be needed (12). The hyperemic response is also typically evaluated during the first 15–30 s following cuff release, using pulsed Doppler, and is then often used as an index of the vasodilatory stimulus. Recent evidence, however, suggests that the vasodilatory response needs to be adjusted for shear rate to accurately evaluate endothelial function (12). Following measures of FMD (and a 10-min rest period), the endothelium-independent vasodilatory response is often evaluated following administration on nitroglycerine. The artery is visualized continuously for 4–5 min after administration. The nitroglycerin-induced vasodilation is considered an index of smooth muscle function (20). Although smooth muscle function is sometimes reduced in clinical populations (37), it is not as sensitive an indicator of cardiovascular risk as endothelial function and is often not prognostic of future events (77). Since many factors affect endothelial function, it is important to control for as many factors as possible, including time of day, medication, caffeine, antioxidants, high-fat foods, smoking, alcohol, exercise, and menstrual status. [For a more complete description of the specific methodology, see Corretti et al. (20), Celermajer et al. (17), and Black et al. (12).] It should be noted that, even with careful control and appropriate measurements, the day-to-day variability of endothelial function often exceeds measured differences between groups.

Arterial compliance.   Arterial compliance is evaluated using noninvasive methods such as high-resolution ultrasound or pulse wave velocity (PWV). Ultrasound measurements of the carotid artery or the aorta are usually obtained, but peripheral measurements can also be made, such as of the brachial artery. These measures provide information on the amount of change in lumen size from diastole to systole, by evaluating the increase in lumen diameter during systole. Since compliance is dependent on local distending pressure, it is important to measure local BP. For this purpose, an estimate of the contralateral carotid artery BP is commonly obtained, using handheld applanation tonometry (2, 72). Other variables commonly used include the beta (β) stiffness index, a measure of arterial stiffness shown to be relatively independent of BP (81), and the incremental elastic modulus (Ep). Ep is a measure of the intrinsic elastic properties of the arterial wall material and is influenced less by vessel geometry (44). Ultrasound measurements of arterial compliance are reasonably reliable, but day-to-day variability can exceed commonly reported group differences, and, frequently, measurements are limited by a lack of direct BP measurements of the imaged artery.

PWV is a measure of the speed of the arterial pressure wave propagation and is an index of arterial wall stiffness (2, 21). The arterial pulse wave is noninvasively recorded using pressure-sensitive transducers or Doppler ultrasound, and a simultaneously recorded electrocardiogram is often used as a timing marker. Measurements are typically made from the carotid to the femoral artery (central stiffness) or from the femoral to the dorsalis pedis artery (peripheral stiffness). However, carotid-to-radial artery measurements are also common (whole body compliance). The time delay from the proximal to the peripheral artery is measured and then divided by the distance between the measurement sites to calculate the velocity (21). A higher velocity indicates a stiffer artery. Muscular peripheral arteries are stiffer than less muscular central arteries; thus PWV is higher in peripheral arteries. Since BP significantly influences PWV, it is important to measure PWV and BP simultaneously. Only central PWV has been a consistent predictor of clinical outcomes, even though peripheral and whole body PWV are commonly reported.


   DEVELOPMENTAL ASPECTS OF ARTERIAL STRUCTURE AND FUNCTION IN HEALTHY CHILDREN
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INFLUENCE OF CARDIOVASCULAR RISK...
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IMT.   The developmental changes of IMT during the developmental years have not been clearly elucidated. Some studies have shown carotid IMT to increase linearly with age in children (35, 44), but this finding has not been consistent, as others have found little change in IMT during childhood (55, 84). These different findings are probably related to the very small changes observed in IMT between 7 and 18 yr of age. Jourdan et al. (44) showed that median carotid IMT increased linearly from 0.384 to 0.400 mm between 10 and 20 yr of age, but when splitting their sample into three age groups, this trend was less clear. Thus, if carotid IMT changes throughout childhood, these changes are very small (16/1,000 mm) and their clinical or functional relevance questionable. Changes in femoral IMT have been more consistent, showing a small linear increase with age in children (44, 84), but again the clinical or functional relevance of these changes is unknown.

These changes in both carotid and femoral IMT are accompanied by increases in arterial size, including luminal diameter (44, 84), suggesting that the increase in IMT may be a function of increased overall arterial size. Postmortem studies of the aortas of children have shown that both intimal and medial thickness and density increase from birth throughout childhood (30, 96). The density changes were primarily a function of increased "packing" of the elastic fibers, suggesting that changes in IMT in children might also impact functional arterial properties.

Endothelial function.   Unlike IMT and arterial compliance (see below), endothelial function, as measured by FMD, does not appear to change throughout childhood in normal, healthy, nonobese children (46, 60, 94, 104). Regardless of age, the mean FMD in healthy nonobese children is typically between 8% and 11% (Fig. 1). However, the range of a normal FMD response is very large, with the 95% confidence interval reportedly between 4 and 18% among healthy children (94, 104). This response is similar to that of healthy young and middle-aged adults (17, 20). However, it is unclear if this large range of normal values is due to normal biological variability or due to measurement error, making comparisons of data between studies very difficult. Thus, even though FMD is reduced in both children and adults with cardiovascular risk factors (2, 17, 20, 89), it is difficult to make individual determinations of what constitutes an "abnormal" FMD response in children. Furthermore, the clinical implications of low FMD in children are unknown.


Figure 1
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  		Fig. 1. Reported mean and SD of flow-mediated dilation in healthy youth and youth with obesity, hyperlipidemia, and Type 1 diabetes. Reference numbers appear above each bar. A repeating reference number implies multiple subsamples within the study.

 
Arterial compliance.   Both aortic and carotid compliance decrease throughout childhood and adolescence (3, 44, 55, 88), with the fastest decline observed during the first few years of life. Interestingly, aortic capacitance (flow at a given pressure) increases throughout childhood, primarily as a function of increased arterial size (3, 88), whereas the distensibility of the arterial wall actually decreases (3, 88). Carotid compliance decreases by 10–28% between 5 and 20 yr of age, coupled with increases in Ep and β-stiffness of 9–30%. Thus, although the trend for an increase in arterial wall stiffness is clear, the amount of change appears to be variable between studies.

The increase in arterial capacitance suggests that arterial buffering capacity (the ability of the aorta to facilitate increased blood flow with minimal changes in BP) increases independently from changes in arterial wall elasticity in children, since both EP and β-stiffness continually increase throughout childhood (88). Thus the increase in arterial size appears to offset the increase in wall stiffness, preventing an increase in afterload that could adversely affect ventricular performance (49, 50, 70). This is different from the effect of aging in adults, where arterial capacitance decreases concomitant with an increase in arterial wall stiffness (6, 7). The age-associated increase in arterial wall stiffness in children is also supported by several studies showing increases in both aortic and peripheral PWV from childhood through puberty (6, 7, 18, 19, 67). The increases in arterial stiffness are usually observed in both boys and girls without any sex differences (44, 55, 67). However, Ahimastos et al. (3) demonstrated that, in males, both central and peripheral PWV increased with age, whereas the reverse was true in females whose central PWV was lower postpuberty compared with prepuberty, suggesting that large vessels are more distensible postpuberty.

Although the mechanism of the age-associated increase in arterial wall stiffness in children is not clear, it is often assumed to be associated with changes in elastin and collagen in the media. However, this association is primarily based on studies in adults (85), although some evidence exists in children (30, 96). It has been suggested that the degeneration of the arterial wall begins in childhood, causing decreases in elastin, increases in collagen, and ultimately the beginning of the atherosclerotic process (8, 66, 67). This proposition appears to be plausible when considering that risk factors such as BP, body mass index (BMI), physical inactivity, and high dietary fat intake are related to arterial stiffness in healthy children (44, 87).


   INFLUENCE OF CARDIOVASCULAR RISK FACTORS ON ARTERIAL FUNCTION IN CHILDREN
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Childhood obesity is associated with arterial dysfunction from adolescence through adulthood (107). Although the carotid distensibility was reduced and stiffness increased with increasing BMI at any age, these changes were especially pronounced at a young age (107). Obesity in children has also been associated with increased carotid IMT (60, 105). Carotid IMT has been found to be 9–25% higher and directly correlated to BMI in obese children, with the increased IMT being independent of vessel size. However, not all studies (94) have found increased IMT in obese children. Interestingly, the higher IMT was found in overweight and mildly obese children, whereas Tounian et al. (94) found no difference in carotid IMT between severely obese children and normal-weight controls. Nevertheless, all of these studies showed a decrease in endothelial function in the obese or overweight children, with mean FMD of 5–6% in the obese cohorts compared with ~10% in normal-weight controls. Endothelium-independent vasodilation was also significantly lower in the severely obese children, but not in the mildly obese/overweight children, suggesting severe obesity may directly impact smooth muscle function. In addition, arterial stiffness is commonly much higher in obese compared with normal-weight children (40, 41, 94). For example, the aortic stiffness index was 38% higher, the elastic modulus 58% higher (40), and the carotid Ep 75% higher (94) in obese compared with control children.

Metabolic syndrome in children, defined according to the Third National Health and Nutrition Examination Survey (NHANES III) criteria (22), appears to further deteriorate arterial structure and function. Obese children with metabolic syndrome had not only greater IMT, but also greater systolic and diastolic arterial diameter, coupled with a greater cross-sectional area of the intima-media complex compared with healthy control children (38). This suggests that children with metabolic syndrome exhibit evidence for early arterial remodeling. However, since this study did not compare the children with metabolic syndrome to obese children without metabolic syndrome, the unique effects of metabolic syndrome could not be determined. Iannuzzi et al. (39), however, did show that carotid stiffness was higher in children with metabolic syndrome compared with obese children (with a similar BMI) without metabolic syndrome, suggesting that arterial function is indeed further deteriorated in the presence of metabolic syndrome compared with obesity alone.

The mechanisms through which obesity impacts arterial structure and function are unclear at this time. Endothelial dysfunction and arterial stiffness may be related to increased low-level inflammation, as obese children consistently exhibit higher levels of C-reactive protein (CRP) compared with nonobese children (38, 39, 60). However, BMI alone has been shown to contribute to endothelial dysfunction, even when controlling for CRP, suggesting an inflammation-independent but obesity-dependent factor. Higher leptin levels in obese individuals may be involved, since a dose-response relationship exists between leptin and atherosclerosis (68, 89). Furthermore, leptin has been associated with arterial stiffness independent of inflammation and insulin resistance (90). Other factors that may have a role are insulin resistance, increased blood lipids, and BP (38, 39, 60, 94). However, most of these metabolic factors have not been related to arterial stiffness, suggesting a different mechanism for this variable. It is likely that arterial wall remodeling is involved, but the specific changes that may occur are unknown. It is also possible that autonomic dysfunction may contribute, as vagal tone is related to FMD and arterial stiffness following exercise (36, 46).

Increased carotid IMT is a common finding among children with familial hypercholesterolemia (52, 73, 98). These changes in IMT are often accompanied by endothelial dysfunction (2, 17, 23). Arterial stiffness may also be increased in hypercholesterolemic children (2, 53), although this is not a universal finding (42). The exact mechanisms for these changes in arterial structure and function are not clear but are probably related to detrimental effects of hypercholesterolemia on the arterial wall that lead to increased expression of adhesion molecules, LDL infiltration and oxidation, and increased inflammation (82). However, LDL-cholesterol has not always been associated with decreased arterial structure and function (52, 73, 87), suggesting a more complex interactive process.

Hypertension is related to arterial dysfunction in adults, but little information exists in children with essential hypertension. Ep was increased in children with both elevated BP and elevated cholesterol (80). Others have shown that offspring of hypertensive parents have increased aortic and carotid stiffness (26, 58), suggesting a genetic link. Furthermore, BP is strongly related to PWV in children (87), and it is a strong determinant of the increased carotid IMT in obese children (38). Consequently, even though evidence for the direct impact of hypertension on arterial function is lacking, increased BP appears to be related to increased arterial stiffness and IMT in children.

Several studies have shown an increase in carotid IMT among Type 1 diabetic children and adults (43, 63, 64, 92). This increase in IMT has been related to higher insulin dose, suggesting that high levels of insulin may have a detrimental influence on the arterial wall. However, recent data in adults showed that progression of IMT thickness was reduced in subjects receiving intensive diabetes treatment (65). Therefore, it is likely that a more complex relationship exists between insulin and IMT.

Children with Type 1 diabetes also exhibit lower FMD compared with controls (43, 74, 92). The reduced FMD has been attributed to increased inflammatory status (71) or a combination of inflammation and expression of human leukocyte antigen, suggesting a genetic influence as well. Others have shown a relationship between FMD and LDL-cholesterol (43), suggesting an influence of lipid status, but this is not a universal finding (92). Folate status has also been related to FMD, which implies a potential influence of homocysteine levels on FMD in children with Type 1 diabetes (74). Recent evidence (32) also suggest increased arterial stiffness in children with Type 1 diabetes. These findings show that Type 1 diabetes in childhood is clearly associated with decrements in arterial structure and function.


   EFFECTS OF INTERVENTIONS
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 ABSTRACT
 MEASURING ARTERIAL STRUCTURE AND...
 DEVELOPMENTAL ASPECTS OF...
 INFLUENCE OF CARDIOVASCULAR RISK...
 EFFECTS OF INTERVENTIONS
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Lifestyle interventions, using aerobic exercise training, weight loss, or dietary modifications, have been successful in improving arterial health and in treating arterial dysfunction associated with morbidity in adults (93). This positive response has led to a speculation that lifestyle modifications in childhood may lead to improved arterial health in adulthood. Recent work (see Fig. 2) has shown that various intervention strategies, such as physical activity, diet, and supplementation with antioxidants, can improve arterial function in youth with and without cardiovascular morbidities (23–25, 60, 61, 76, 94, 103, 106).


Figure 2
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  		Fig. 2. Reported mean flow-mediated dilation before (Pre) and after (Post) various interventions in youth with obesity, hyperlipidemia, and Type 1 diabetes. Reference numbers appear above each bar. Repeating reference number implies multiple subsamples within the study. E, exercise; D, diet; DE, diet + exercise; A, antioxidant therapy; DA, diet + antioxidant therapy; DDH, diet + docosahexaenoic acid; B6, vitamin B6; F, folate; B6F, vitamin B6 + folate. *Nonsignificant effect.

 
Limited work on the relationship between physical activity and arterial health in healthy children has provided contradictory findings. Abbott et al. (1) found that habitual physical activity levels as measured with doubly labeled water independently predicted brachial FMD among 5- to 11-yr-old children. Follow-up tertile analysis showed that the most active children had significantly greater FMD compared with their least active peers. Similarly, Schack-Nielsen et al. (87) showed that the amount of time 10-yr-old children spend in play or sport participation is inversely related and independently contributes to the arterial stiffness of both the aorto-radial and the aorto-femoral segments. In contrast, Reed and coworkers (79) found no significant relationship between the total amount of physical activity, estimated with a 7-day questionnaire, and arterial compliance in 9- to 11-yr-old children. These disparate results may reflect a weak relationship between physical activity and arterial function in healthy children or known difficulties in accurately estimating physical activity levels. To reach definitive conclusions, however, considerably more work is needed.

Limited cross-sectional research suggests that aerobic fitness may contribute to improved endothelial function in healthy children (79, 95). In one study, aerobic fitness explained 23% of the variance in femoral FMD among children aged 11–14 yr (95). Similarly, performance on a 20-m shuttle-run appears to contribute to large- and small-artery compliance (15% and 7%, respectively), with children who show the highest performance score also showing higher arterial compliance than those with the lowest performance scores (79). In contrast, 12-yr-old boys who had undertaken swim training (8–10 h/wk) for at least 4 yr have demonstrated higher upper-limb PWV and lower pressure-corrected index of distension compared with age- and sex-matched nonswimmers (97). Furthermore, the child swimmers showed PWV values similar to those of adults, suggesting an early detrimental effect of high-volume swim training on upper-limb arterial stiffness in children. These findings underscore the importance of considering the type of exercise stimulus in evaluating the effect of exercise training on arterial function in youth. It is also evident that the mode, volume, and duration of exercise training that may improve arterial stiffness and endothelial function in healthy children remain largely unknown.

The seemingly favorable response of the arterial system of healthy children to physical activity and exercise is probably related to increased NO bioavailability. This is thought to result from the upregulation of eNOS gene expression in response to vascular wall shear stress caused by exercise-related increases in systemic blood flow (31, 33, 34). Since basal NO levels also contribute to arterial compliance, this may also partially explain the positive effect of physical activity on PWV.

Similar to physical activity, an 11-yr-long dietary intervention (low saturated fat) was shown to have long-term beneficial effects on endothelial function in boys, but not in girls (78). The intervention, which was initiated in infancy, improved brachial FMD in boys at age 11 yr compared with controls. This effect was nonsignificant after adjustment for cholesterol levels at age 3 yr, suggesting that the relationship between endothelial function and diet was mediated by changes in cholesterol levels.

There is more information available on the effect of various interventions on the arterial function in youth with morbidities that may contribute to early atherosclerosis, such as obesity, Type 1 diabetes, and hyperlipidemia, probably because children with these conditions show disrupted endothelial function (Fig. 1) (23–25, 60, 61, 76, 94, 103, 106). Recent evidence suggests that this unfavorable profile may be reversed to a certain extent by various intervention strategies. Notably, endothelial function is nearly normalized following several types of interventions in various populations of children with risk factors (Fig. 2).

Among overweight and obese children and adolescents, arterial health may improve following short-term lifestyle interventions, using either exercise training or dietary modification, or a combination of exercise and diet (47, 48, 100, 101, 104). Exercise training alone improves and nearly normalizes brachial FMD in obese children and adolescents (48, 100, 101). This positive outcome appears to result after only 6–8 wk of exercise training conducted three to four times per week and incorporating either 60 min of sport and play activities (101) or 30–50 min of progressively increased aerobic exercise at 50–80% of the age-predicted maximum heart rate (48), or a combination of aerobic and resistance exercise training (100). Interestingly, the exercise-induced improvement in endothelial function was reversed after only 6 wk of inactivity (100), thus justifying a recommendation for continuous exercise training (100, 104).

Six weeks of a dietary intervention, consisting of a well-balanced hypocaloric diet, improved endothelial function in overweight and obese children aged 9–12 yr (104). Analogous short-term benefits have been obtained from combinations of dietary modification and exercise training (47, 104), potentially surpassing those of diet alone (104). In contrast, carotid IMT (104) has not been shown to be responsive to short-term lifestyle interventions in this population of children.

The rapid improvement in endothelial function to short-term interventions suggests that exercise and/or dietary intervention improves NO-mediated vasodilator function, probably through both direct and indirect effects (31). It is likely that shear stress-mediated improvement in NO availability occurs as well as possible changes in the effect of free radical degradation of NO availability (31). However, short-term interventions appear to have little effect on vascular remodeling, suggesting functional changes precede structural changes.

Longer-term interventions have demonstrated improvements both in carotid IMT and in endothelial function of overweight or obese youth (60, 104, 106). Six months of exercise training improved FMD and carotid IMT in obese youth aged 11–16 yr compared with age-matched controls (60). Similar results have been documented in 9- to 12-yr-old children following 12-mo-long regimens of either dieting alone or diet and exercise, with the latter showing greater benefits than the former (104). However, a 12-mo-long intervention in obese prepubescents that included exercise training, nutrition education, and behavior therapy showed improvements in brachial FMD and reduced carotid IMT only in those children who experienced substantial weight loss (106). Although only one of the three aforementioned studies included a control group, thus making definitive inferences difficult, it does appear that long-term lifestyle modifications hold promise in reversing the impaired arterial health and atherosclerotic profile of youth with obesity.

Although the physiological mechanisms responsible for the above favorable outcomes in children with obesity remain speculative, they are likely multiple given the multidimensional nature of interventions. Exercise-induced upregulation of eNOS is one possible mechanism for the improvements in the atherogenic risk profiles in youth with obesity. However, changes in proinflammatory markers may also contribute to this favorable effect (89). Accordingly, increases in FMD and reductions in IMT following lifestyle interventions have been accompanied by reductions in proinflammatory markers (47, 60, 106). These reductions in inflammation may be mediated by accompanying weight loss and/or decreases in abdominal fat (92). Furthermore, acute inflammation increases arterial stiffness (70), also suggesting an inflammatory link to improvements in arterial compliance.

The potential for improving arterial health through exercise and diet in children with Type 1 diabetes has not been explored. However, 8 wk of supplementation with either folic acid or vitamin B6, or a combination of the two, improved endothelium-dependent dilation of the brachial artery compared with placebo in this population (57, 74). This effect occurs rapidly within 2 h of treatment, and it is maintained over an 8-wk supplementation period (57). One possible mechanism responsible for the improved endothelial function following folic acid therapy relates to an improvement in eNOS regulation and to prevention of peroxynitrite-mediated BH4 oxidation (5). Furthermore, the inflammatory and blood lipid profiles of youth with Type 1 diabetes may favor a positive response of endothelial function to folic acid. FMD does not appear to respond to folic acid supplementation in obese youth (75) who have higher levels of inflammation and blood lipids than children with Type 1 diabetes (76). It is, thus, possible that folic acid may improve endothelial function only at lower levels of inflammation and lipid irregularities. The positive effects, however, of folic acid supplementation in children with Type 1 diabetes appear reversible within 8 wk of withdrawal from therapy (74), thus suggesting a need for continuous therapy.

Promising results have also been obtained in children and adolescents with familial hyperlipidemia (24, 25, 28, 29, 61). Short-term supplementation with docosahexaenoic acid (DHA), an omega-3 fatty acid found in fish oil, combined with a diet in accordance with the National Cholesterol Education Program Step II, increased brachial artery FMD compared with both diet alone and diet plus placebo (28). This favorable adaptation was hypothesized to result from possible improvements in eNOS regulation or production induced by DHA (28). Similar results were reported when the same diet was used in conjunction with antioxidant vitamin C and E supplementation (29). Interestingly, short-term dieting alone did not induce any appreciable changes in FMD (28, 29). Conversely, 6 wk of antioxidant therapy alone, using tocopherol and vitamin C, induced marked improvements in the brachial FMD of children with hyperlipidemia compared with controls (61). Antioxidants are thought to reduce inflammation and inactivation of eNOS caused by free oxygen radicals, thus increasing NO availability and improving endothelial function.


   CONCLUSIONS AND FUTURE DIRECTIONS
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 MEASURING ARTERIAL STRUCTURE AND...
 DEVELOPMENTAL ASPECTS OF...
 INFLUENCE OF CARDIOVASCULAR RISK...
 EFFECTS OF INTERVENTIONS
 CONCLUSIONS AND FUTURE...
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The normal development of IMT, endothelial function, and arterial stiffness among healthy children and adolescents is reasonably well described in the literature. There are very small increases in IMT during childhood, endothelial function does not appear to be different between children and adults, and arterial stiffness increases linearly from 5 to 20 yr of age. Cardiovascular risk factors such as obesity, metabolic syndrome, hyperlipemia, hypertension, and Type 1 diabetes can negatively impact IMT and endothelial function at an early age, although it is currently unknown if the changes in arterial function in children have the same pathophysiological implications as in adults. Nevertheless, exercise training, dietary intervention, or vitamin and folic acid supplementation can partially or almost completely offset the alterations in IMT and endothelial function that accompany cardiovascular morbidities. However, any improvements appear to be rapidly reversed with cessation of the interventions.

Little is known regarding the mechanisms that cause the alterations in arterial structure and function in youth with cardiovascular risk factors. There is also little empirical information regarding the mechanisms that produce the improvements seen in arterial structure and function following exercise, diet, vitamin C, or folate supplementation. Furthermore, the most effective way to intervene and improve arterial structure and function in youth with cardiovascular risk factors remains speculative. In particular, the most appropriate exercise prescription, type of diet, supplementation regimen, or combination thereof have not been fully described. Also, there is no information to date on the effect of Type 2 diabetes on arterial structure and function in children, which may be of considerable concern considering the rapid increase in the prevalence of this condition during the past several years. Most important, the effect reduced arterial function in childhood has on arterial function and risk of cardiovascular disease in adulthood has not been elucidated to date. We also do not know if reducing the risk factors in childhood, leading to improvement in arterial structure and function, will affect the risk for cardiovascular events in adulthood. To provide these answers, well-designed empirical work must be conducted in the years ahead.


   FOOTNOTES
 

Address for reprint requests and other correspondence: B. Fernhall, 1206 South Fourth St., Rm. 110, MC-586, Champaign, IL (e-mail: fernhall{at}uiuc.edu)


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 ABSTRACT
 MEASURING ARTERIAL STRUCTURE AND...
 DEVELOPMENTAL ASPECTS OF...
 INFLUENCE OF CARDIOVASCULAR RISK...
 EFFECTS OF INTERVENTIONS
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  1. Abbott RA, Harkness MA, Davies PS. Correlation of habitual physical activity levels with flow-mediated dilation of the brachial artery in 5–10 year old children. Atherosclerosis 160: 233–239, 2002.[CrossRef][Web of Science][Medline]
  2. Aggoun Y, Szezepanski I, Bonnet D. Noninvasive assessment of arterial stiffness and risk of atherosclerotic events in children. Pediatr Res 58: 173–178, 2005.[CrossRef][Web of Science][Medline]
  3. Ahimastos AA, Formosa M, Dart AM, Kingwell BA. Gender differences in large artery stiffness pre- and postpuberty. J Clin Endocrinol Metab 88: 5375–5380, 2003.[Abstract/Free Full Text]
  4. Akerblom HK, Uhari M, Pesonen E, Dahl M, Kaprio EA, Nuutinen EM, Pietikainen M, Salo MK, Aromaa A, Kannas L, et al. Cardiovascular risk in young Finns. Ann Med 23: 35–39, 1991.[Web of Science][Medline]
  5. Antoniades C, Shirodaria C, Warrick N, Cai S, de Bono J, Lee J, Leeson P, Neubauer S, Ratnatunga C, Pillai R, Refsum H, Channon KM. 5-Methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels: effects on vascular tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling. Circulation 114: 1193–1201, 2006.[Abstract/Free Full Text]
  6. Avolio AP, Chen SG, Wang RP, Zhang CL, Li MF, O'Rourke MF. Effects of aging on changing arterial compliance and left ventricular load in a northern Chinese urban community. Circulation 68: 50–58, 1983.[Abstract/Free Full Text]
  7. Avolio AP, Deng FQ, Li WQ, Luo YF, Huang ZD, Xing LF, O'Rourke MF. Effects of aging on arterial distensibility in populations with high and low prevalence of hypertension: comparison between urban and rural communities in China. Circulation 71: 202–210, 1985.[Abstract/Free Full Text]
  8. Berenson GS. Childhood risk factors predict adult risk associated with subclinical cardiovascular disease. The Bogalusa Heart Study. Am J Cardiol 90: 3L–7L, 2002.[CrossRef][Web of Science][Medline]
  9. Berenson GS, Srinivasan SR, Bao W, Newman WP 3rd, Tracy RE, Wattigney WA. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. N Engl J Med 338: 1650–1656, 1998.[Abstract/Free Full Text]
  10. Betik AC, Luckham VB, Hughson RL. Flow-mediated dilation in human brachial artery after different circulatory occlusion conditions. Am J Physiol Heart Circ Physiol 286: H442–H448, 2004.[Abstract/Free Full Text]
  11. Blacher J, Guerin AP, Pannier B, Marchais SJ, London GM. Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension 38: 938–942, 2001.[Abstract/Free Full Text]
  12. Black MA, Cable NT, Thijssen DH, Green DJ. Importance of measuring the time course of flow-mediated dilatation in humans. Hypertension 51: 203–210, 2008.[Abstract/Free Full Text]
  13. Bots ML, Hoes AW, Hofman A, Witteman JC, Grobbee DE. Cross-sectionally assessed carotid intima-media thickness relates to long-term risk of stroke, coronary heart disease and death as estimated by available risk functions. J Intern Med 245: 269–276, 1999.[CrossRef][Web of Science][Medline]
  14. Boutouyrie P, Bussy C, Lacolley P, Girerd X, Laloux B, Laurent S. Association between local pulse pressure, mean blood pressure, and large-artery remodeling. Circulation 100: 1387–1393, 1999.[Abstract/Free Full Text]
  15. Celermajer DS. Endothelial dysfunction: does it matter? Is it reversible? J Am Coll Cardiol 30: 325–333, 1997.[Abstract]
  16. Celermajer DS. Testing endothelial function using ultrasound. J Cardiovasc Pharmacol 32, Suppl 3: S29–S32, 1998.[CrossRef][Web of Science][Medline]
  17. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, Lloyd JK, Deanfield JE. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 340: 1111–1115, 1992.[CrossRef][Web of Science][Medline]
  18. Cheung YF, Brogan PA, Pilla CB, Dillon MJ, Redington AN. Arterial distensibility in children and teenagers: normal evolution and the effect of childhood vasculitis. Arch Dis Child 87: 348–351, 2002.[Abstract/Free Full Text]
  19. Cheung YF, Wong KY, Lam BC, Tsoi NS. Relation of arterial stiffness with gestational age and birth weight. Arch Dis Child 89: 217–221, 2004.[Abstract/Free Full Text]
  20. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, Deanfield J, Drexler H, Gerhard-Herman M, Herrington D, Vallance P, Vita J, Vogel R. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 39: 257–265, 2002.[Abstract/Free Full Text]
  21. Davies JI, Struthers AD. Pulse wave analysis and pulse wave velocity: a critical review of their strengths and weaknesses. J Hypertens 21: 463–472, 2003.[CrossRef][Web of Science][Medline]
  22. de Ferranti SD, Gauvreau K, Ludwig DS, Neufeld EJ, Newburger JW, Rifai N. Prevalence of the metabolic syndrome in American adolescents: findings from the Third National Health and Nutrition Examination Survey. Circulation 110: 2494–2497, 2004.[Abstract/Free Full Text]
  23. de Jongh S, Lilien MR, Bakker HD, Hutten BA, Kastelein JJ, Stroes ES. Family history of cardiovascular events and endothelial dysfunction in children with familial hypercholesterolemia. Atherosclerosis 163: 193–197, 2002.[CrossRef][Web of Science][Medline]
  24. de Jongh S, Lilien MR, op't Roodt J, Stroes ES, Bakker HD, Kastelein JJ. Early statin therapy restores endothelial function in children with familial hypercholesterolemia. J Am Coll Cardiol 40: 2117–2121, 2002.[Abstract/Free Full Text]
  25. de Jongh S, Ose L, Szamosi T, Gagne C, Lambert M, Scott R, Perron P, Dobbelaere D, Saborio M, Tuohy MB, Stepanavage M, Sapre A, Gumbiner B, Mercuri M, van Trotsenburg AS, Bakker HD, Kastelein JJ. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized, double-blind, placebo-controlled trial with simvastatin. Circulation 106: 2231–2237, 2002.[Abstract/Free Full Text]
  26. Dernellis J, Panaretou M. Aortic stiffness in children of parents with hypertension. J Hum Hypertens 20: 225–226, 2006.[CrossRef][Web of Science][Medline]
  27. Dinenno FA, Tanaka H, Monahan KD, Clevenger CM, Eskurza I, DeSouza CA, Seals DR. Regular endurance exercise induces expansive arterial remodelling in the trained limbs of healthy men. J Physiol 534: 287–295, 2001.[Abstract/Free Full Text]
  28. Engler MM, Engler MB, Malloy M, Chiu E, Besio D, Paul S, Stuehlinger M, Morrow J, Ridker P, Rifai N, Mietus-Snyder M. Docosahexaenoic acid restores endothelial function in children with hyperlipidemia: results from the EARLY study. Int J Clin Pharmacol Ther 42: 672–679, 2004.[Web of Science][Medline]
  29. Engler MM, Engler MB, Malloy MJ, Chiu EY, Schloetter MC, Paul SM, Stuehlinger M, Lin KY, Cooke JP, Morrow JD, Ridker PM, Rifai N, Miller E, Witztum JL, Mietus-Snyder M. Antioxidant vitamins C and E improve endothelial function in children with hyperlipidemia: Endothelial Assessment of Risk from Lipids in Youth (EARLY) Trial. Circulation 108: 1059–1063, 2003.[Abstract/Free Full Text]
  30. Glukhova MA, Frid MG, Koteliansky VE. Phenotypic changes of human aortic smooth muscle cells during development and in the adult vessel. Am J Physiol Suppl 261 (4): 78–80, 1991.
  31. Green DJ, Maiorana A, O'Driscoll G, Taylor R. Effect of exercise training on endothelium-derived nitric oxide function in humans. J Physiol 561: 1–25, 2004.[Abstract/Free Full Text]
  32. Haller MJ, Samyn M, Nichols WW, Brusko T, Wasserfall C, Schwartz RF, Atkinson M, Shuster JJ, Pierce GL, Silverstein JH. Radial artery tonometry demonstrates arterial stiffness in children with type 1 diabetes. Diabetes Care 27: 2911–2917, 2004.[Abstract/Free Full Text]
  33. Hambrecht R, Adams V, Erbs S, Linke A, Krankel N, Shu Y, Baither Y, Gielen S, Thiele H, Gummert JF, Mohr FW, Schuler G. Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase. Circulation 107: 3152–3158, 2003.[Abstract/Free Full Text]
  34. Hambrecht R, Fiehn E, Weigl C, Gielen S, Hamann C, Kaiser R, Yu J, Adams V, Niebauer J, Schuler G. Regular physical exercise corrects endothelial dysfunction and improves exercise capacity in patients with chronic heart failure. Circulation 98: 2709–2715, 1998.[Abstract/Free Full Text]
  35. Hansen F, Mangell P, Sonesson B, Lanne T. Diameter and compliance in the human common carotid artery—variations with age and sex. Ultrasound Med Biol 21: 1–9, 1995.[Web of Science][Medline]
  36. Heffernan KS, Collier SR, Kelly EE, Jae SY, Fernhall B. Arterial stiffness and baroreflex sensitivity following bouts of aerobic and resistance exercise. Int J Sports Med 6: 6, 2006.
  37. Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 104: 2673–2678, 2001.[Abstract/Free Full Text]
  38. Iannuzzi A, Licenziati MR, Acampora C, De Michele M, Iannuzzo G, Chiariello G, Covetti G, Bresciani A, Romano L, Panico S, Rubba P. Carotid artery wall hypertrophy in children with metabolic syndrome. J Hum Hypertens 22: 83–88, 2008.[CrossRef][Web of Science][Medline]
  39. Iannuzzi A, Licenziati MR, Acampora C, Renis M, Agrusta M, Romano L, Valerio G, Panico S, Trevisan M. Carotid artery stiffness in obese children with the metabolic syndrome. Am J Cardiol 97: 528–531, 2006.[CrossRef][Web of Science][Medline]
  40. Iannuzzi A, Licenziati MR, Acampora C, Salvatore V, Auriemma L, Romano ML, Panico S, Rubba P, Trevisan M. Increased carotid intima-media thickness and stiffness in obese children. Diabetes Care 27: 2506–2508, 2004.[Free Full Text]
  41. Iannuzzi A, Licenziati MR, Acampora C, Salvatore V, De Marco D, Mayer MC, De Michele M, Russo V. Preclinical changes in the mechanical properties of abdominal aorta in obese children. Metabolism 53: 1243–1246, 2004.[CrossRef][Web of Science][Medline]
  42. Iannuzzi A, Rubba P, Pauciullo P, Celentano E, Capano G, Sartorio R, Mercuri M, Bond MG. Stiffness of the aortic wall in hypercholesterolemic children. Metabolism 48: 55–59, 1999.[CrossRef][Web of Science][Medline]
  43. Jarvisalo MJ, Raitakari M, Toikka JO, Putto-Laurila A, Rontu R, Laine S, Lehtimaki T, Ronnemaa T, Viikari J, Raitakari OT. Endothelial dysfunction and increased arterial intima-media thickness in children with type 1 diabetes. Circulation 109: 1750–1755, 2004.[Abstract/Free Full Text]
  44. Jourdan C, Wuhl E, Litwin M, Fahr K, Trelewicz J, Jobs K, Schenk JP, Grenda R, Mehls O, Troger J, Schaefer F. Normative values for intima-media thickness and distensibility of large arteries in healthy adolescents. J Hypertens 23: 1707–1715, 2005.[Web of Science][Medline]
  45. Juonala M, Jarvisalo MJ, Maki-Torkko N, Kahonen M, Viikari JS, Raitakari OT. Risk factors identified in childhood and decreased carotid artery elasticity in adulthood: the Cardiovascular Risk in Young Finns Study. Circulation 112: 1486–1493, 2005.[Abstract/Free Full Text]
  46. Kaufman CL, Kaiser DR, Steinberger J, Dengel DR. Relationships between heart rate variability, vascular function, and adiposity in children. Clin Auton Res 17: 165–171, 2007.[CrossRef][Web of Science][Medline]
  47. Kelishadi R, Hashemi M, Mohammadifard N, Asgary S, Khavarian N. Association of changes in oxidative and proinflammatory states with changes in vascular function after a lifestyle modification trial among obese children. Clin Chem 54: 147–153, 2008.[Abstract/Free Full Text]
  48. Kelly AS, Wetzsteon RJ, Kaiser DR, Steinberger J, Bank AJ, Dengel DR. Inflammation, insulin, and endothelial function in overweight children and adolescents: the role of exercise. J Pediatr 145: 731–736, 2004.[CrossRef][Web of Science][Medline]
  49. Kingwell BA. Nitric oxide as a metabolic regulator during exercise: effects of training in health and disease. Clin Exp Pharmacol Physiol 27: 239–250, 2000.[CrossRef][Web of Science][Medline]
  50. Kingwell BA, Berry KL, Cameron JD, Jennings GL, Dart AM. Arterial compliance increases after moderate-intensity cycling. Am J Physiol Heart Circ Physiol 273: H2186–H2191, 1997.[Abstract/Free Full Text]
  51. Laurent S, Katsahian S, Fassot C, Tropeano AI, Gautier I, Laloux B, Boutouyrie P. Aortic stiffness is an independent predictor of fatal stroke in essential hypertension. Stroke 34: 1203–1206, 2003.[Abstract/Free Full Text]
  52. Lavrencic A, Kosmina B, Keber I, Videcnik V, Keber D. Carotid intima-media thickness in young patients with familial hypercholesterolaemia. Heart 76: 321–325, 1996.[Abstract/Free Full Text]
  53. Leeson CP, Whincup PH, Cook DG, Mullen MJ, Donald AE, Seymour CA, Deanfield JE. Cholesterol and arterial distensibility in the first decade of life: a population-based study. Circulation 101: 1533–1538, 2000.[Abstract/Free Full Text]
  54. Lemne C, Jogestrand T, de Faire U. Carotid intima-media thickness and plaque in borderline hypertension. Stroke 26: 34–39, 1995.[Abstract/Free Full Text]
  55. Lenard Z, Studinger P, Mersich B, Kocsis L, Kollai M. Maturation of cardiovagal autonomic function from childhood to young adult age. Circulation 110: 2307–2312, 2004.[Abstract/Free Full Text]
  56. Li S, Chen W, Srinivasan SR, Berenson GS. Childhood blood pressure as a predictor of arterial stiffness in young adults: the Bogalusa Heart Study. Hypertension 43: 541–546, 2004.[Abstract/Free Full Text]
  57. MacKenzie KE, Wiltshire EJ, Gent R, Hirte C, Piotto L, Couper JJ. Folate and vitamin B6 rapidly normalize endothelial dysfunction in children with type 1 diabetes mellitus. Pediatrics 118: 242–253, 2006.[Abstract/Free Full Text]
  58. Meaney E, Samaniego V, Alva F, Valdovinos RA, Marrufo R, Vela A, Allen T, Misra A, Madsen R. Increased arterial stiffness in children with a parental history of hypertension. Pediatr Cardiol 20: 203–205, 1999.[CrossRef][Web of Science][Medline]
  59. Meaume S, Benetos A, Henry OF, Rudnichi A, Safar ME. Aortic pulse wave velocity predicts cardiovascular mortality in subjects >70 years of age. Arterioscler Thromb Vasc Biol 21: 2046–2050, 2001.[Abstract/Free Full Text]
  60. Meyer AA, Kundt G, Lenschow U, Schuff-Werner P, Kienast W. Improvement of early vascular changes and cardiovascular risk factors in obese children after a six-month exercise program. J Am Coll Cardiol 48: 1865–1870, 2006.[Abstract/Free Full Text]
  61. Mietus-Snyder M, Malloy MJ. Endothelial dysfunction occurs in children with two genetic hyperlipidemias: improvement with antioxidant vitamin therapy. J Pediatr 133: 35–40, 1998.[CrossRef][Web of Science][Medline]
  62. Moreau KL, Silver AE, Dinenno FA, Seals DR. Habitual aerobic exercise is associated with smaller femoral artery intima-media thickness with age in healthy men and women. Eur J Cardiovasc Prev Rehabil 13: 805–811, 2006.[CrossRef][Medline]
  63. Muis MJ, Bots ML, Bilo HJ, Hoogma RP, Hoekstra JB, Grobbee DE, Stolk RP. High cumulative insulin exposure: a risk factor of atherosclerosis in type 1 diabetes? Atherosclerosis 181: 185–192, 2005.[CrossRef][Web of Science][Medline]
  64. Muis MJ, Bots ML, Grobbee DE, Stolk RP. Insulin treatment and cardiovascular disease: friend or foe? A point of view. Diabet Med 22: 118–126, 2005.[CrossRef][Web of Science][Medline]
  65. Nathan DM, Lachin J, Cleary P, Orchard T, Brillon DJ, Backlund JY, O'Leary DH, Genuth S. Intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus. N Engl J Med 348: 2294–2303, 2003.[Abstract/Free Full Text]
  66. Newman WP, 3rd Wattigney W, Berenson GS. Autopsy studies in United States children and adolescents. Relationship of risk factors to atherosclerotic lesions. Ann NY Acad Sci 623: 16–25, 1991.[Web of Science][Medline]
  67. Niboshi A, Hamaoka K, Sakata K, Inoue F. Characteristics of brachial-ankle pulse wave velocity in Japanese children. Eur J Pediatr 165: 625–629, 2006.[CrossRef][Web of Science][Medline]
  68. Nishina PM, Naggert JK, Verstuyft J, Paigen B. Atherosclerosis in genetically obese mice: the mutants obese, diabetes, fat, tubby, and lethal yellow. Metabolism 43: 554–558, 1994.[CrossRef][Web of Science][Medline]
  69. O'Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 340: 14–22, 1999.[Abstract/Free Full Text]
  70. O'Rourke MF, Safar ME. Relationship between aortic stiffening and microvascular disease in brain and kidney: cause and logic of therapy. Hypertension 46: 200–204, 2005.[Abstract/Free Full Text]
  71. Odermarsky M, Nilsson A, Lernmark A, Sjoblad S, Liuba P. Atherogenic vascular and lipid phenotypes in young patients with Type 1 diabetes are associated with diabetes high-risk HLA genotype. Am J Physiol Heart Circ Physiol 293: H3175–H3179, 2007.[Abstract/Free Full Text]
  72. Oliver JJ, Webb DJ. Noninvasive assessment of arterial stiffness and risk of atherosclerotic events. Arterioscler Thromb Vasc Biol 23: 554–566, 2003.[Abstract/Free Full Text]
  73. Pauciullo P, Iannuzzi A, Sartorio R, Irace C, Covetti G, Di Costanzo A, Rubba P. Increased intima-media thickness of the common carotid artery in hypercholesterolemic children. Arterioscler Thromb 14: 1075–1079, 1994.[Abstract/Free Full Text]
  74. Pena AS, Wiltshire E, Gent R, Hirte C, Couper J. Folic acid improves endothelial function in children and adolescents with type 1 diabetes. J Pediatr 144: 500–504, 2004.[CrossRef][Web of Science][Medline]
  75. Pena AS, Wiltshire E, Gent R, Piotto L, Hirte C, Couper J. Folic acid does not improve endothelial function in obese children and adolescents. Diabetes Care 30: 2122–2127, 2007.[Abstract/Free Full Text]
  76. Pena AS, Wiltshire E, MacKenzie K, Gent R, Piotto L, Hirte C, Couper J. Vascular endothelial and smooth muscle function relates to body mass index and glucose in obese and nonobese children. J Clin Endocrinol Metab 91: 4467–4471, 2006.[Abstract/Free Full Text]
  77. Perticone F, Ceravolo R, Pujia A, Ventura G, Iacopino S, Scozzafava A, Ferraro A, Chello M, Mastroroberto P, Verdecchia P, Schillaci G. Prognostic significance of endothelial dysfunction in hypertensive patients. Circulation 104: 191–196, 2001.[Abstract/Free Full Text]
  78. Raitakari OT, Ronnemaa T, Jarvisalo MJ, Kaitosaari T, Volanen I, Kallio K, Lagstrom H, Jokinen E, Niinikoski H, Viikari JS, Simell O. Endothelial function in healthy 11-year-old children after dietary intervention with onset in infancy: the Special Turku Coronary Risk Factor Intervention Project for children (STRIP). Circulation 112: 3786–3794, 2005.[Abstract/Free Full Text]
  79. Reed KE, Warburton DE, Lewanczuk RZ, Haykowsky MJ, Scott JM, Whitney CL, McGavock JM, McKay HA. Arterial compliance in young children: the role of aerobic fitness. Eur J Cardiovasc Prev Rehabil 12: 492–497, 2005.[CrossRef][Medline]
  80. Riley WA, Freedman DS, Higgs NA, Barnes RW, Zinkgraf SA, Berenson GS. Decreased arterial elasticity associated with cardiovascular disease risk factors in the young. Bogalusa Heart Study. Arteriosclerosis 6: 378–386, 1986.[Abstract/Free Full Text]
  81. Roman MJ, Pini R, Pickering TG, Devereux RB. Non-invasive measurements of arterial compliance in hypertensive compared with normotensive adults. J Hypertens Suppl 10: S115–S118, 1992.[Medline]
  82. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362: 801–809, 1993.[CrossRef][Web of Science][Medline]
  83. Sader MA, Celermajer DS. Endothelial function, vascular reactivity and gender differences in the cardiovascular system. Cardiovasc Res 53: 597–604, 2002.[Free Full Text]
  84. Sass C, Herbeth B, Chapet O, Siest G, Visvikis S, Zannad F. Intima-media thickness and diameter of carotid and femoral arteries in children, adolescents and adults from the Stanislas cohort: effect of age, sex, anthropometry and blood pressure. J Hypertens 16: 1593–1602, 1998.[CrossRef][Web of Science][Medline]
  85. Sawabe M, Takahashi R, Matsushita S, Ozawa T, Arai T, Hamamatsu A, Nakahara K, Chida K, Yamanouchi H, Murayama S, Tanaka N. Aortic pulse wave velocity and the degree of atherosclerosis in the elderly: a pathological study based on 304 autopsy cases. Atherosclerosis 179: 345–351, 2005.[CrossRef][Web of Science][Medline]
  86. Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 101: 1899–1906, 2000.[Abstract/Free Full Text]
  87. Schack-Nielsen L, Molgaard C, Larsen D, Martyn C, Michaelsen KF. Arterial stiffness in 10-year-old children: current and early determinants. Br J Nutr 94: 1004–1011, 2005.[CrossRef][Web of Science][Medline]
  88. Senzaki H, Akagi M, Hishi T, Ishizawa A, Yanagisawa M, Masutani S, Kobayashi T, Awa S. Age-associated changes in arterial elastic properties in children. Eur J Pediatr 161: 547–551, 2002.[CrossRef][Web of Science][Medline]
  89. Singhal A. Endothelial dysfunction: role in obesity-related disorders and the early origins of CVD. Proc Nutr Soc 64: 15–22., 2005.[CrossRef][Web of Science][Medline]
  90. Singhal A, Farooqi IS, Cole TJ, O'Rahilly S, Fewtrell M, Kattenhorn M, Lucas A, Deanfield J. Influence of leptin on arterial distensibility: a novel link between obesity and cardiovascular disease? Circulation 106: 1919–1924, 2002.[Abstract/Free Full Text]
  91. Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR Jr, Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 101: 948–954, 2000.[Abstract/Free Full Text]
  92. Suys B, de Beeck LO, Rooman R, Kransfeld S, Heuten H, Goovaerts I, Vrints C, de Wolf D, Matthys D, Manuel-y-Keenoy B. Impact of oxidative stress on the endothelial dysfunction of children and adolescents with type 1 diabetes mellitus: protection by superoxide dismutase? Pediatr Res 62: 456–461, 2007.[Web of Science][Medline]
  93. Tanaka H, Safar ME. Influence of lifestyle modification on arterial stiffness and wave reflections. Am J Hypertens 18: 137–144, 2005.[CrossRef][Web of Science][Medline]
  94. Tounian P, Aggoun Y, Dubern B, Varille V, Guy-Grand B, Sidi D, Girardet JP, Bonnet D. Presence of increased stiffness of the common carotid artery and endothelial dysfunction in severely obese children: a prospective study. Lancet 358: 1400–1404, 2001.[CrossRef][Web of Science][Medline]
  95. Treiber F, Papavassiliou D, Gutin B, Malpass D, Yi W, Islam S, Davis H, Strong W. Determinants of endothelium-dependent femoral artery vasodilation in youth. Psychosom Med 59: 376–381, 1997.[Abstract/Free Full Text]
  96. van Meurs-van Woezik H, Klein HW, Markus-Silvis L, Krediet P. Comparison of the growth of the tunica media of the ascending aorta, aortic isthmus and descending aorta in infants and children. J Anat 136: 273–281, 1983.[Web of Science][Medline]
  97. Vinet A, Nottin S, Beck L, Perez-Martin A, Dauzat M, Obert P. Effect of maturational status and training on upper limb pulse wave velocity. Eur J Pediatr 164: 197–201, 2005.[CrossRef][Web of Science][Medline]
  98. Virkola K, Pesonen E, Akerblom HK, Siimes MA. Cholesterol and carotid artery wall in children and adolescents with familial hypercholesterolaemia: a controlled study by ultrasound. Acta Paediatr 86: 1203–1207, 1997.[Web of Science][Medline]
  99. Vita JA. Nitric oxide and vascular reactivity in African American patients with hypertension. J Card Fail 9: S199–S204; discussion S205, 2003.[CrossRef][Web of Science][Medline]
  100. Watts K, Beye P, Siafarikas A, Davis EA, Jones TW, O'Driscoll G, Green DJ. Exercise training normalizes vascular dysfunction and improves central adiposity in obese adolescents. J Am Coll Cardiol 43: 1823–1827, 2004.[Abstract/Free Full Text]
  101. Watts K, Beye P, Siafarikas A, O'Driscoll G, Jones TW, Davis EA, Green DJ. Effects of exercise training on vascular function in obese children. J Pediatr 144: 620–625, 2004.[CrossRef][Web of Science][Medline]
  102. Weber T, Auer J, O'Rourke MF, Kvas E, Lassnig E, Berent R, Eber B. Arterial stiffness, wave reflections, and the risk of coronary artery disease. Circulation 109: 184–189, 2004.[Abstract/Free Full Text]
  103. Wiltshire EJ, Gent R, Hirte C, Pena A, Thomas DW, Couper JJ. Endothelial dysfunction relates to folate status in children and adolescents with type 1 diabetes. Diabetes 51: 2282–2286, 2002.[Abstract/Free Full Text]
  104. Woo KS, Chook P, Yu CW, Sung RY, Qiao M, Leung SS, Lam CW, Metreweli C, Celermajer DS. Effects of diet and exercise on obesity-related vascular dysfunction in children. Circulation 109: 1981–1986, 2004.[Abstract/Free Full Text]
  105. Woo KS, Chook P, Yu CW, Sung RY, Qiao M, Leung SS, Lam CW, Metreweli C, Celermajer DS. Overweight in children is associated with arterial endothelial dysfunction and intima-media thickening. Int J Obes Relat Metab Disord 28: 852–857, 2004.[CrossRef][Web of Science][Medline]
  106. Wunsch R, de Sousa G, Toschke AM, Reinehr T. Intima-media thickness in obese children before and after weight loss. Pediatrics 118: 2334–2340, 2006.[Abstract/Free Full Text]
  107. Zebekakis PE, Nawrot T, Thijs L, Balkestein EJ, van der Heijden-Spek J, Van Bortel LM, Struijker-Boudier HA, Safar ME, Staessen JA. Obesity is associated with increased arterial stiffness from adolescence until old age. J Hypertens 23: 1839–1846, 2005.[Web of Science][Medline]



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