An additional finding from our studies was that the association between body composition and arterial compliance differed between boys and girls (Fig. 3). As a group, boys had higher compliance values than girls, but this difference primarily was attributable to differences between boys and girls in the normal–body weight range. Within the subgroup of normal-weight children, the sex difference in arterial compliance was best explained by the higher lean body mass in boys. Fat mass was a positive predictor of small and large artery compliance in normal-weight girls but was not associated with arterial compliance in normal-weight boys. In contrast, within the subgroups of obese boys and girls, there was no difference between sexes for lean mass, fat mass, or arterial compliance, and the relationship between fat mass and arterial compliance was similar for boys and girls. Thus, the sex differences in body composition, particularly body fat, and arterial compliance that were present in normal-weight children were not present in obese children. As shown in the summary in Figure 3, arterial compliance was correlated positively with total body fat, measured by dual-energy x-ray absorptiometry, across the range of measured values in girls. However, that relationship was only present for boys with more than 24 kg of fat mass; below the 24-kg threshold, fat mass and arterial compliance were not significantly associated in boys. The mechanism that explains this relationship is not yet clear, but it is possible that the vascularity of adipose tissue or the secretion of vasoactive compounds from adipose tissue must reach a higher level in boys than girls before arterial compliance is affected.
Other studies also have reported that obese children have increased arterial compliance. Chalmers and colleagues (7) used diastolic pulse wave contour analysis and showed that large artery compliance was 38% higher and small artery compliance was 20% higher in obese versus normal-weight children (mean age, 13 yr) even after controlling for height, blood pressure, sex, and Tanner stage. In agreement, Dangardt and colleagues (9) reported that carotid-radial pulse wave velocity was 11% lower (indicating increased arterial compliance) in obese adolescent girls than in girls within the normal range for BMI. In a large cohort of prepubertal children, aged approximately 9 to 12 yr, in the United Kingdom, Donald and colleagues (11) reported that BMI was correlated negatively with pulse wave velocity and correlated positively with brachial artery distensibility coefficient (a measure of arterial elasticity), which could contribute to a higher arterial compliance in children with elevated BMI. They also reported that flow-mediated brachial artery dilation (a measure of vascular function in response to vessel occlusion and resumption of blood flow) also was positively correlated with BMI. Flow-mediated dilation typically is reduced in the presence of obesity or diabetes in adults and some studies of children (34). Although the three separate measures of vascular function reported by Donald and colleagues (11) were not well correlated with one another, they each suggest that children with a higher BMI display changes in arterial structure and/or function that are not typical for studies of obese adults. Whether this reflects adaptive processes or early pathology in obese children is not yet clear. Donald et al. (11) reported that brachial artery diameter was a significant predictor for each of the vascular outcomes in their study. Thus, although the studies cited (7,9,11) were not designed to identify the underlying mechanism that explains why obese children may have the unexpected vascular differences observed, they suggest a potential role for vessel size that should be considered in future studies.
In contrast to the studies described above, there are reports that central arterial compliance is reduced in obese children. For example, Tounian and colleagues (28) showed that severely obese children, median age approximately 12 yr, had 7% lower central compliance and 14% lower vessel distensibility, measured at the carotid artery with ultrasound techniques, compared with a normal-weight control group. Urbina and colleagues (33) performed carotid ultrasonographic assessments on 446 children and young adults (age range, 10–24 yr; mean age, 17.8 yr) and found that obese participants had approximately 20% stiffer arteries than their normal-weight peers. In that study, carotid stiffness was associated positively with age and blood pressure. Similarly, Sakuragi and colleagues found that BMI and total body fat measured by dual-energy x-ray absorptiometry were associated positively with pulse wave velocity measured by applanation tonometry of the carotid and femoral arteries in 573 Japanese children aged 9 to 10 yr (25). It is not yet clear what factors, whether methodological or characteristics of the study populations, account for the differences among the studies that have measured the effect of obesity on arterial compliance. Some possibilities are considered in a later section.
ARTERIAL COMPLIANCE IN CHILDREN WITH T2D
To our knowledge, there have been only three published studies that described the effect of T2D on arterial compliance in children. We found that children with T2D (who were all overweight or obese) had, like obese children without T2D, higher arterial compliance compared with normal-weight controls (31). In our sample of 10- to 18-yr-olds with T2D (average duration of diagnosis, 1.9 ± 1.7 yr), small artery compliance was 24% higher than age-matched normal-weight youth but not different from obese peers (Fig. 1). The difference in small artery compliance between the T2D and normal-weight groups was most evident in children 15 to 16 yr old. Small artery compliance in the T2D group was associated positively with total lean body mass, systolic blood pressure, and fasting glucose. In contrast, large artery compliance in the T2D group was not different from either normal-weight or obese children. A notable finding was that large artery compliance in the T2D group increased with age from ages 10 to 16 yr and then declined significantly in 17- to 18-yr-olds; small artery compliance followed a similar, albeit nonstatistically significant, pattern (Fig. 1). Although a larger follow-up study that includes young adults is required for confirmation, our data support the hypothesis that children with T2D follow a pattern of elevated arterial compliance at younger ages that is similar to obese children but start to show signs of declining compliance earlier than expected for normal-weight or obese peers (Fig. 2).
In contrast to our findings, Gungor and colleagues (16) reported that pulse wave velocity, and, therefore, arterial stiffness, measured with ultrasonography at the carotid artery in children with T2D (average duration, 1.7 yr) was 55% greater than normal-weight and 32% greater than obese comparison groups of similar age (aged ~15 yr). Urbina and colleagues (33) also found that carotid artery stiffness was increased in children and young adults (age range, 10–24 yr) with T2D. Beta stiffness and Young elastic modulus values were 12% to 20% higher in the T2D group compared with a normal-weight group but not different compared with an obese group with the same average BMI (33).
INTERPRETATIONS AND POTENTIAL MECHANISMS
It is not yet clear why there is a lack of consensus on the effects of obesity and T2D on arterial compliance in children and adolescents. There are differences among studies in the ages and clinical features of the study participants, methodology used to measure vascular parameters, and approaches used to analyze data that may contribute to the different outcomes. There also is the challenge of drawing conclusions from the relatively few studies published so far.
Variations in the age, maturation, race/ethnicity, and/or clinical history of the participants may to contribute to differences among studies. In our studies, for example, arterial compliance varied with age, in addition to the effects of obesity and diabetes (Fig. 1). The value of presenting an age-related pattern of arterial compliance is that it reveals potential differences among groups that may be missed if analysis is limited to aggregate statistics. Notably, we found that arterial compliance had a stronger association with chronological age than Tanner maturation score. Our data suggest that, for youth with T2D, arterial compliance may be increased in younger participants but decreased in older cohorts (Fig. 2). In the study by Urbina and colleagues (33), the average age of the participants was 18 yr, and people up to 24 yr old were included. It is, therefore, possible that the reduced arterial compliance in the T2D group in that study was attributable to more pronounced effects of T2D in the older participants or that the carotid artery was already dilated, which resulted in less smooth muscle relaxation and lower distensibility in older children and young adults. Analyses of participants with T2D also may be challenging if the duration of diabetes or medication use is not known or not presented. In the study by Gungor et al. (16), some of the participants were on multiple medications; it is possible that those participants had a higher level of cardiometabolic dysfunction that contributed to their reduced arterial compliance at the time of measurement. By comparison, participants with T2D in our investigation were only using lifestyle approaches or metformin to manage their blood glucose and were not using other medications, such as insulin, thiazolidinediones, or lipid-lowering agents, with known cardiovascular or metabolic effects (31). In addition to the effects of age, our data analyses revealed that variations in body composition and sexual maturation predict differences in arterial compliance and that data analyses may need to account for interactions between the effects of body size and sex (29,30).
Methodological differences also may contribute to the different outcomes reported. There are several methodological approaches that have been used to measure arterial compliance in children and adults. All approaches have strengths and limitations and provide different insights about vascular function, as reviewed elsewhere (34); this variation may complicate comparisons among studies that use different methods. Our studies (29,31) and others that have recently reported that arterial compliance was increased in obese children used techniques with measurements made at the radial artery (7,9). In studies in which arterial compliance was reduced in children with obesity or T2D, the measurements were made at the carotid and/or femoral artery and provided a measure of central compliance (16,25,28,33). Whether this reveals that obesity exerts differential effects in different parts of the vascular tree in children or is a reflection of the strengths and limitations of each method is not yet clear. Peripheral vessels such as the radial artery may be more dilated and compliant than central vessels in obese children, but comparison studies are required to confirm this possibility.
Among the potentially important covariates that have been understudied so far are diet, physical activity, and physical fitness. Of the studies in children in which arterial compliance was compared in normal-weight and obese children, physical activity was measured using accelerometry in only two reports (7,25). In both of those studies, however, physical activity was not a significant predictor of arterial compliance after controlling for variables such as age, sex, and blood pressure. None of the studies examining obesity in children reported data on dietary history and only one reported a measure of aerobic fitness (25). In the latter study, aerobic fitness was measured in children 8 to 12 yr old using a 20-m shuttle run and was found to be a positive predictor of arterial compliance. Because a physically active lifestyle is associated with better vascular function, such as higher arterial compliance in adults (26), aerobic fitness and physical activity require more attention as modifying variables in studies of children, particularly those designed to assess the specific effects of obesity, diabetes, or metabolic syndrome.
The implications of our findings, as depicted in Figure 2, are that childhood obesity may result in earlier attainment of peak values for arterial compliance but also may drive an earlier decline during adulthood. T2D may further accelerate that decline. A potential explanation for why obese or T2D children do not have a more pronounced reduction in arterial compliance at earlier ages is the relatively lower development of atherosclerotic changes. Obese adults have more atherosclerosis compared with obese children (10,13,17), which attenuates vascular smooth muscle relaxation. The increased luminal pressure in atherosclerotic vessels in older obese people caused by atherosclerosis and decreased elastin in the vascular wall is expected to result in decreased arterial compliance (26). However, a premature reduction in vascular function, as depicted in Figure 2, is consistent with the earlier development of cardiovascular disease risk in people who were obese during childhood (38). As already noted, some (7,9,11,29), although not all (25,28,33), studies suggest that, during childhood, there is an ability to accommodate the negative impact of obesity on the vascular system (i.e., arterial compliance is not reduced and may be increased), although new evidence demonstrates that the consequences of obesity likely emerge in children who remain obese (8). Dangardt and colleagues (8) recently published a 5-yr follow-up to their initial study in which they reported that obese children had lower arterial stiffness at age approximately 13.8 yr compared with a group of normal-weight children. In the follow-up, when the participants were approximately 18 to 19 yr old, arterial stiffness was higher in the obese group compared with the normal-weight group. This reversal occurred because, during the 5-yr interim, pulse wave velocity increased 25% in the obese group but only 3% in the normal-weight group. Furthermore, there were parallel changes in diastolic blood pressure, and changes in arterial stiffness were associated with changes in arterial vessel diameter. These data suggest that obese children have a capacity to increase arterial compliance as an adaptive response but, under the pressure of ongoing obesity, this adaptation is temporary, and eventually, the established pattern of reduced arterial compliance that has been observed in obese adults will become apparent in obese youth. Thus, the data collected cross sectionally (25,28,29,31,33) and the longitudinal data of Dangardt et al. (8) highlight the need to monitor cardiovascular health of obese children and develop strategies to avoid the development of an elevated risk during the transition to adulthood.
The mechanisms that account for how early maturation and excess adiposity result in higher arterial compliance in obese children are not yet clear. In studies by Donald et al. (11) and Dangardt et al. (8), arterial diameter was reported to play an important role in the compliance of the vessel. Therefore, in the obese child, it is possible that the vascular system accommodates an increase in blood volume through systemic vasodilation. In our studies, we found that fat mass and lean mass were each associated positively with arterial compliance in obese children (29,30). Thus, it is possible that differences in arterial structure and function in obese children can be attributed to, in part, their larger stature and larger vascular network, which is attained at an earlier age because of faster maturation (Fig. 4). The overall vascular tone is mediated through several mechanisms. First, the endothelium provides vascular control through the actions of nitric oxide (NO) and endothelin. NO released from the endothelium via sheer stress results in the relaxation of the adjacent smooth muscle, thereby resulting in vasodilation. Opposing the action of NO is endothelin, which causes smooth muscle contraction and vasoconstriction. The autonomic nervous system also plays a role maintaining vascular tone. Neurohormonal mechanisms, such as the renin-angiotensin-aldosterone system, also affect vascular tone (15). In addition, because it is established that adipocytes and skeletal muscle communicate with other tissues by secreting several hormones and cytokines, it is possible that compounds released from either fat depots or lean tissues act on the vasculature to increase arterial compliance (Fig. 4). Compounds that stimulate the production of NO synthase (eNOS) in vascular endothelial cells could lead to increased NO release, greater smooth muscle relaxation, and increased arterial compliance (37). At least two hormones, insulin and visfatin, that are elevated in obesity are known to increase eNOS (20,24). In adults, both eNOS protein and mRNA content are higher in the subcutaneous fat of obese individuals relative to that of normal-weight controls (12). Although infusion of insulin promotes eNOS activity and vasodilatation (36), insulin resistance is associated with lower eNOS mRNA expression and activity in adults (18). In our analyses, fasting insulin and calculated insulin resistance indices were not correlated with vascular compliance (29). Our interpretation was that insulin per se is unlikely to be a primary mediator of the differences in arterial compliance in children, but other vasoactive compounds, including those produced by adipose tissue, may play a role.
Ongoing exposure to obesity, particularly if accompanied by T2D, is expected to result in premature reduction in arterial compliance and increased cardiovascular disease risk, even in youth. For adolescents with T2D, we observed higher fasting glucose, insulin resistance, hypertriglyceridemia, inflammation, and systolic blood pressure compared with normal-weight or obese peers (31). These features all have been shown in adults to be associated with cardiovascular disease risk and are, therefore, expected to contribute to a decline of arterial compliance at an earlier age than in obese youth (Fig. 4). In particular, glycemic variability in people with diabetes is likely to cause oxidative and osmotic stress on the vasculature (22).
Because there have been few investigations on arterial compliance in youth, additional confirmation studies are needed, especially those that include a wide age range of participants, compare outcomes from different methods of assessing vascular function, and account for potential modifying variables such as sex, body composition, aerobic fitness, and lifestyle factors such as diet and physical activity. Longitudinal studies, similar to those presented by Dangardt et al. (8) would be particularly useful to follow trends in the development of arterial compliance from childhood into adulthood because the majority of current data are based on cross-sectional comparisons. Recent trends for obesity in children suggest that the number of obese adults will continue to increase for the foreseeable future, which could contribute to higher cardiovascular disease risk. Obviously, individual-, family-, and community-based interventions to curtail the rise in obesity could have a major impact but require significant resources to be successful. Interventions that emphasize physical activity are essential. Although the effect of exercise training on arterial compliance in obese or T2D children has, to our knowledge, not been reported, other components of vascular function such as endothelial-dependent flow-mediated dilation have been reported to improve in response to exercise training in obese children (21,35). These strategies could help counter the effects of obesity, independent of weight loss.
The presence of obesity and T2D in children and adolescents may be associated with an increased arterial compliance that appears to be attributable to earlier maturation and increased fat and lean tissue masses. Based on our data (29,31) and that of others (7–9,11), we hypothesize that obese and T2D children may attain their peak potential for arterial compliance earlier in life than normal-weight children but also may experience an earlier decline in vascular health, and, therefore, increased cardiovascular risk, in adulthood (Fig. 2). Additional confirmation of this proposal, along with lifestyle interventions that address the cardiometabolic disease risk of obese and T2D youth, is the next step.
Acknowledgment: Funding for the authors’ work was provided by the Endocrine Fellows Foundation, the Marilyn Fishman Grant for Diabetes Research, the Lawson Wilkins Pediatric Endocrine Society Clinical Scholars Award, the University of Oklahoma Health Sciences Center Department of Pediatric Diabetes and Endocrinology, and National Institutes of Health Grant P20 RR 024215 from the COBRE Program of the National Center for Research Resources.
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Keywords:© 2014 American College of Sports Medicine
arterial compliance; arterial stiffness; vascular health; adolescents; maturation