PEDIATRICS Vol. 117 No. 5 May 2006, pp. 1560-1567 (doi:10.1542/peds.2005-2140)
Impaired Flow-Mediated Vasodilation, Carotid Artery Intima-Media Thickening, and Elevated Endothelial Plasma Markers in Obese Children: The Impact of Cardiovascular Risk Factors
a Division of Pediatric Cardiology, Children's Hospital
b Institute of Medical Informatics and Biometry and
c Institute of Clinical Chemistry and Laboratory Medicine, University of Rostock, Rostock, Germany
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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OBJECTIVES. Childhood obesity contributes to the development of adult obesity and subsequent cardiovascular disease. The present study aimed to assess vascular status (flow-mediated vasodilation [FMD], intima-media thickness [IMT]) and to analyze plasma surrogate endothelial markers (von Willebrand factor [vWf], E-selectin, and thrombomodulin) in obese children as compared with controls. Associations between early morphologic and functional vascular changes, surrogate soluble markers of early atherosclerosis, and the cardiovascular risk profile were determined.
METHODS. We examined 32 obese children versus 20 control subjects. All of the children underwent identical screening, comprehensive risk factor assessment, and measurements of E-selectin, vWf, thrombomodulin, FMD, and IMT.
RESULTS. Compared with controls, obese children demonstrated significantly impaired FMD and increased IMT. Concentrations of soluble E-selectin and thrombomodulin were significantly elevated in obese children, whereas vWf showed no significant differences between obese children and controls. FMD, IMT, E-selectin, and thrombomodulin were significantly associated with various risk factors, including the extent of obesity, arterial hypertension, fibrinogen, C-reactive protein, and low physical fitness.
CONCLUSIONS. The present study documented increased IMT, impaired endothelial function, and elevated plasma markers of endothelial activation and injury in obese children. Morbid obesity, arterial hypertension, subclinical inflammation, and low physical fitness formed a risk profile associated with the risk of early atherosclerosis in these children. Sonographic assessment of vascular status and the estimation of soluble endothelial plasma markers, combined with comprehensive risk factor screening, may form a rationale to identify high-risk children susceptible to early atherosclerotic disease and to monitor vascular changes during follow-up studies and therapeutic measures.
Key Words: atherosclerosis • children • obesity • risk factors
Abbreviations: FMD—flow-mediated vasodilation • IMT—intima-media thickness • vWf:Ag—von Willebrand factor antigen • BP—blood pressure • HDL—high-density lipoprotein • LDL—low-density lipoprotein
Child and adolescent obesity demonstrates a strong relation to the early development of atherosclerosis and is a major risk determinator of obesity-related cardiovascular disease.1 Both genetic and environmental factors (nutrition and lifestyle) constitute a risk factor profile modifying the extent of childhood obesity. Recent data have shown that obesity is independently associated with coronary atherosclerosis in young adults.2 The development of cardiovascular disease begins in childhood,3 and obesity is considered a nutritional disease accelerating its progression.4
Obese children present a number of additional risk factors that are associated with atherosclerotic disease during middle and late life.5 However, the mechanisms of how a given cluster of risk factors influences the early development of vascular pathology in children are incompletely understood. Improved treatment, including early intervention and prevention strategies, rely on a better understanding of which risk factor(s) are strongly linked to early atherosclerosis in obese children, thereby allowing for the identification of children at high risk.6
It is universally accepted that disturbed endothelial cell biology, variably including activation, injury, damage, and dysfunction,7 forms part of the early pathogenesis of atherosclerosis.8 Therefore, the assessment of endothelial dysfunction by either noninvasive or invasive means may represent a clinically relevant tool to predict the overall vascular risk.9
Using high-resolution vascular ultrasound-based tests of endothelial function, including the vasodilator response to increased blood flow (flow-mediated vasodilation [FMD]) and the analysis of carotid artery intima-media thickness (IMT), the detection of early stage vascular changes can now be accomplished.10,11 Both FMD and IMT were associated with several cardiovascular risk factors.12–14
Quantitative analysis of endothelium-derived soluble markers in plasma would be another diagnostic and/or prognostic approach. The endothelium synthesizes a large number of molecules, part of which can reliably be demonstrated in plasma. However, only a few of them are specific to the vascular endothelium. The plasma concentration of von Willebrand factor antigen (vWf:Ag) is the most extensively studied endothelial marker,15 and its concentrations were shown to be increased in a number of clinical settings where endothelial function and integrity are impaired, including atherosclerosis.16,17 E-selectin is an endothelial cell-specific adhesion molecule regulating adhesive interactions between blood cells and the endothelium. A soluble form has been proposed as a surrogate marker of endothelial cell activation, and raised plasma concentrations have been found in cardiovascular disease. However, its place in the overall assessment of cardiovascular risk remains controversial.17 Thrombomodulin is a transmembrane thrombin receptor molecule located at the luminal endothelial cell surface. Its soluble form results from cleavage or shedding and is thought to reflect endothelial cell injury rather than activation.18 Increased soluble thrombomodulin has been reported in established atherosclerosis.19 The aim of this study was to investigate whether obese children present evidence of impaired endothelial function and whether this would be related to traditional and newer cardiovascular disease risk factors.
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METHODS |
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Study Design
We recruited 32 consecutive obese children (age range: 9–16 years) when they presented to an established university outpatient department of pediatric endocrinology and cardiology. Obesity was defined as a BMI in excess of the 97th percentile for the German pediatric population.20
The control group consisted of children (n = 20) without appreciable cardiovascular risk factors and was selected among children presenting at the same institution for diagnostic workup of dizziness and minor orthostatic complaints. Children with structural or functional cardiovascular abnormalities were excluded from the control group. All of the patients underwent an identical 2-day screening program based on a multiple risk factor approach. Pubertal development based on Tanner stages was assessed by physical examination. We ensured comparability of the 2 groups by frequency matching21 for major baseline characteristics, including family history of atherosclerotic disease, risk behavior (smoking), gender, and Tanner stages based on the assumption that significant differences between the 2 groups in these variables would have an impact on the study conclusions.
The study complied with the Declaration of Helsinki. The study plan was approved by the local ethics committee, and written informed consent was obtained from the parents after a detailed interview.
Measurement of Risk Factors
Anamnestic and anthropometric data were reviewed during a 2-day hospital stay. Body fat was assessed by bioelectrical impedance22 (Data Input Inc, Frankfurt/Main, Germany) and was expressed as percentage of body weight. A venous blood sample was collected after overnight fasting. Insulin resistance was calculated using the homeostasis model assessment,23 and insulin sensitivity was determined using data of an oral glucose tolerance test (insulin sensitivity index).
Resting blood pressure (BP) was measured at all of the extremities by an automatic oscillometric cuff device (Dinamap, Critikon Inc, Tampa, FL). The 24-hour ambulatory BP was measured on the right arm (Space Labs Inc, Issaquah, WA). BP data were automatically recorded every 15 minutes from 8:00 AM to 8:00 PM (daytime BP), and every 30 minutes from 8:00 PM to 8:00 AM (nighttime BP). BP studies were not considered meaningful and were excluded from analysis if there was an interval of invalid or absent measurements >2 hours. Hypertension was defined as 24-hour systolic and/or diastolic BP above the 95th percentile of the reference values according to Soergel et al.24
The spiroergometric equipment Oxycon Alpha (Jaeger, Würzburg, Germany) was used for the evaluation of exercise parameters. All of the children underwent a cycle exercise test using a modified Bruce protocol with continuously raised strain loads and were exercised to the point of exhaustion. Parameters of physical fitness were maximal Watt per kilogram and ventilatory anaerobic threshold. Hypertension during exercise was arbitrarily defined as a BP >180 mmHg when measured at 2 Watt/kg strain.
Echocardiography and vascular measurements were taken with a Hewlett-Packard Sonos system (Sonos 5500; Philips, Int, Hamburg, Germany). Left ventricular measurements were derived from two-dimensional guided M-mode tracings, as recommended by the American Society of Echocardiography.25 Left ventricular mass was calculated using the Devereux-modified American Society of Echocardiography cube equation.26
Vascular Measurements
All of the children were examined in a quiet, temperature-controlled room. The procedure was conducted between 7:00 AM and 8:00 AM after a fasting period of 12 hours.
For FMD, endothelium-dependent responses of the right radial artery were measured for each patient subject to the guidelines of the International Brachial Artery Reactivity Task Force.27 Subjects were in the supine position with their forearm comfortably placed and fixed in a semiopen splint. The high-frequency (15 MHz) vascular transducer (15–6 L ultraband linear Advanced Technology Laboratories [Hamburg, Germany]) was fixed with a stereotactic probe-holding device. The radial artery was imaged 5 cm distally from the antecubital fossa in the longitudinal plane. A small BP cuff was placed on the wrist to create a flow stimulus by reactive hyperemia. A baseline rest image was acquired, and the blood flow velocity was estimated by time averaging the Doppler signal from a midartery sample volume. After a 5-minute interval of ischemia, cuff deflation was followed by a brief high-flow state. The image of the artery and the Doppler signal were recorded alternatively in 20-second intervals for 
5 minutes after cuff deflation. Images were stored on a magnet-optical disk and analyzed after the procedure. Distance measurements of the artery were taken at maximum systolic extension. FMD analyses were performed by a trained and board-certified pediatrician. The intraobserver variability expressed as median absolute difference in the measurements of FMD was 1.03 ± 0.28%. The results of the measurements of the arterial diameter were highly reproducible with a mean difference of 0.034 ± 0.076
For IMT, a high-frequency (15 MHz) vascular linear transducer was used for imaging the carotid arteries. Patients were examined in the supine position, with the head turned 45° away from the side being scanned. Two segments were identified on each side: the distal 1 cm of the common carotid artery and the bifurcation itself. Five measurements were taken at 2-mm intervals at near and far wall (distance from the transducer) in each of the 2 segments. Maximum and mean IMT were calculated separately for each side of each segment. Sonography and reading were performed by trained and board-certified sonographers. Intraobserver and interobserver variability (mean bias) were 0.2% and 1.2%, respectively.
Measurement of Plasma Endothelial Markers
Fasting plasma samples were obtained from citrate-anticoagulated venous blood samples after centrifugation (3000 rpm, 15 minutes). Aliquots were snap frozen, stored at –80°C, and thawed only once immediately before analyses, which were performed in 1 batch.
vWF:Ag was determined by an immunoturbidimetric assay with antibody-coated polystyrene beads using a Behring coagulation analyzer (Dade Behring, Marburg, Germany). Soluble thrombomodulin was assayed using a sandwich enzyme immunoassay (Diagnostica Stago, Asnieres-Sur-Seine, France). Thrombomodulin recognized by a mouse monoclonal antibody coated on a solid support was revealed by a secondary monoclonal antibody labeled with horseradish peroxidase. The bound enzyme was detected by colorimetry and read at 492 nm. Soluble E-selectin was quantitated using a sandwich enzyme immunoassay (R&D Systems, Wiesbaden-Nordenstadt, Germany) with a monoclonal antibody coated onto a microplate, followed by a secondary enzyme-labeled monoclonal antibody. Color development was measured at 450 nm.
Statistical Methods
Data were stored and analyzed using the SPSS 12.0 statistical package (SPSS Inc, Chicago, IL). Descriptive statistics were computed for variables of interest and included mean values and SDs of continuous variables and absolute and relative frequencies of categorical factors.
Testing for differences of continuous variables between the study groups was accomplished by the 2-sample t test for independent samples or the Mann-Whitney U test, as appropriate. Test selection was based on evaluating the variables for normal distribution using the Kolmogorov-Smirnov test. For categorial factors, comparisons between groups were performed by Fisher's exact test. All of the P values resulted from 2-sided statistical tests, and P .05 was considered to be significant.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Assessment of Risk Profile
Compared with controls, obese children demonstrated significant differences for a number of risk factors, including BMI, body fat content, BP, laboratory parameters (insulin, insulin resistance, triglycerides, HDL cholesterol, LDL/HDL ratio, fibrinogen, and C-reactive protein), echocardiographic measurements, and physical fitness (Table 1). In contrast, no significant differences were obtained for smoking, time of television viewing, gender, and Tanner stages. Similarly, no significant differences were observed for additional laboratory measures, including the concentrations of total cholesterol; LDL cholesterol; lipoprotein(a); homocysteine; and apolipoproteins A1, A2, B, and HbA1c (data not shown).
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Vascular Measurements and Plasma Endothelial Markers
Obese children presented with significantly reduced FMD compared with controls (Table 2). Time to maximum dilation was between 40 and 80 seconds after cuff release. There was no correlation between maximum FMD and time to maximum dilation (r = 0.07) and no significant difference of time to maximum dilation between the 2 groups.
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The measurements of IMT were adequate for all of the children in the segments of the common carotid artery and the carotid bifurcation. In these segments, there were significant differences for near and far walls between obese and control children (P < .001).
E-selectin and thrombomodulin were significantly elevated in obese children. In contrast, vWf:Ag showed no significant difference between obese and control children (Table 2).
Risk Factor Profile in Children With Impaired Vascular Status or Increased Plasma Endothelial Markers
The control population presented with FMD 9.29% ± 1.87% and IMT 0.39 ± 0.05 mm. Both sets of data were normally distributed, leading to a definition of impaired vascular status in the presence of FMD values 5.55% (mean – 1.96 SD) and for IMT values (common carotid artery) 
0.48 mm (mean + 1.96 SD). Similarly, plasma endothelial markers were defined as increased in the presence of soluble E-selectin 51 ng/mL and soluble thrombomodulin 44 ng/mL.
We assessed children with impaired vascular status according to their cardiovascular risk profile. Children with impaired FMD demonstrated significant differences in a number of risk factors, including BMI, body fat content, concentrations of triglycerides, HDL cholesterol, fibrinogen, LDL/HDL ratio, and physical fitness. In addition, a greater proportion of children with hypertension in the ambulatory measurement and during exercise was noted in the group of subjects with impaired FMD (Table 3). Children with elevated IMT had significantly higher BMI, lower physical fitness parameters, and were more likely to have hypertension (Table 4).
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Children with increased plasma concentrations of soluble thrombomodulin presented with significantly elevated BP and reduced indices of physical fitness (Table 5). In addition to more prevalent and low physical fitness, children with increased concentrations of soluble E-selectin demonstrated elevated concentrations of fibrinogen and C-reactive protein (Table 6). Risk assessment according to normal or increased plasma concentrations of vWF:Ag did not reveal meaningful differences in additional laboratory parameters or vascular indices (data not shown).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Childhood obesity has reached pandemic dimensions and represents a major public health problem in Western countries. Being a strong risk factor for adult atherosclerotic disease, it threatens the achievements over the past decades in terms of reducing cardiovascular morbidity and mortality.28 Obesity-related vascular abnormalities form part of a cluster of risk factors in overweight children, putting them at high risk for the development of premature atherosclerotic disease.
The aim of the present study in obese children was twofold. Two independent vascular measures were used to document early functional and morphologic arterial changes in obese children, and plasma endothelial markers were used to assess endothelial cell function and integrity. In addition, a more detailed risk factor analysis was performed in children demonstrating pathologic data for functional or biochemical vascular measures.
Ultrasound evaluation of brachial artery FMD and carotid artery intima-medial thickening is increasingly being used for pediatric cardiovascular risk assessment.29 In children, impaired FMD is known to be present in conditions predisposing to atherosclerosis, including familial hypercholesterolemia, type I diabetes, and morbid obesity.5,30 In the study population, obese children presented remarkably impaired FMD. Increased IMT has been reported in hypercholesterolemic and diabetic children.13,31 The present study revealed increased IMT in obese children as compared with control children. IMT in obese children is a matter of ongoing debate. A study of severely obese children obtained no evidence of significant differences in carotid IMT as compared with control subjects.32 In contrast, data from the present study lend support to results from a larger study demonstrating increased carotid IMT in obese children.33 Moreover, our ultrasound technique-based data confirm results from several studies performed in children at risk for early onset atherosclerosis and controls.11–13,34
Obesity-related activation of endothelial cells may contribute to early atherogenesis during childhood and to increased cardiovascular risk later in life.35 The vascular endothelium remains a difficult organ to study, and the use of surrogate plasma endothelial markers, reflecting either endothelial cell activation or injury, has attracted much attention.36 In the present study, obese children demonstrated elevated concentrations of the plasma endothelial markers soluble E-selectin and thrombomodulin, whereas those of vWf:Ag showed no significant differences between obese and control children.
E-selectin in an endothelial cell-specific adhesion molecule. The mechanisms of the generation of its soluble form have not been well established. Increased concentrations of soluble E-selectin have been repeatedly reported for obese adults.37,38 However, increased soluble E-selectin in obese children, as an indicator of early vascular endothelial cell activation, has only very recently been reported for the first time.39 Experimental studies have provided firm evidence that soluble E-selectin was increased after endothelial cell activation by cytokines.40 Accordingly, in our study population, an association of elevated levels of soluble E-selectin with indicators of a low-grade proinflammatory phenotype (fibrinogen and C-reactive protein) was established. The finding of reduced physical fitness among obese children with elevated soluble E-selectin has not been reported previously and deserves additional investigation, including follow-up studies, while applying measures to improve physical fitness.
Soluble thrombomodulin likely reflects endothelial injury.19 However, studies on soluble thrombomodulin in atherosclerotic disease yielded conflicting results. Although increased concentrations of soluble thrombomodulin were related to clinical events in atherosclerotic patients,17 another study reported that lower levels were associated with ischemic events.41 This controversy notwithstanding, we provide, for the first time, data on increased concentrations of soluble thrombomodulin in obese children. Detailed risk factor analysis in children with elevated thrombomodulin revealed evidence that their physical fitness was remarkably reduced. Furthermore, they were more likely to be hypertensive, supporting the emerging concept that, in adults, increased soluble thrombomodulin is related to latent progression of atherosclerosis in hypertensive patients.42
Increased vWF:Ag concentrations have been repeatedly demonstrated in hypertensive and obese adults. However, its prognostic impact in asymptomatic patients with regard to subsequently developing strokes and other atherosclerotic manifestations is a matter of ongoing controversy.43 Interpretation in individual subjects must be cautious, because vWF:Ag concentrations are influenced by various physiologic stimuli, including vasopressin, thrombin, and proinflammatory cytokines.44 Accordingly, its reliability as a marker of early atherosclerotic disease development in children has yet to be proven.
In addition to impaired endothelial indices, obese children demonstrated significant differences in the general laboratory risk profile, BP during rest and exercise, echocardiographic data, and physical fitness parameters. A number of these risk factors showed significant influences on vascular status in univariate regression analyses. Increased insulin resistance, high triglyceride and lower HDL cholesterol concentrations, and higher LDL/HDL ratio were related to anthropometric data and to impaired FMD, indicating that the extent and distribution of childhood obesity is linked to the overall cardiovascular risk.
FMD was associated with a number of risk factors and negatively correlated with IMT (R = –0.394; P = .006). In contrast, no association could be established with plasma endothelial markers. This finding indicates that different estimates of vascular wall changes may reflect different expressions of early atherosclerotic disease development.
Sedentary lifestyles and reduced physical fitness are major risk factors for the development of cardiovascular disease.45 In our population, obese children presented lower values of maximal Watt per kilogram and reduced anaerobic threshold. These indicators of reduced physical fitness were associated with morphologic and biochemical parameters, reflecting early stage vascular changes. Therefore, improvement of physical fitness remains a cornerstone in the management of cardiovascular risk in obese children.46
The most important finding of the present study was that early functional (FMD) and structural (IMT) vascular wall changes and increased plasma markers of endothelial activation and injury are detectable in obese children. Extending data from previous studies describing vascular abnormalities in obese children,32,47 a number of the obesity-related risk factors were shown to be correlated with both FMD and IMT measurements in our study population.
Among obese children, a particularly high risk of early atherosclerosis seems to be associated with extreme obesity and the presence of additional risk factors, including hypertension, ongoing low-grade inflammation, and a state of reduced physical fitness.48 This detrimental combination of interacting obesity-related risk factors makes a clinically meaningful risk prediction of atherosclerotic disease in obese children a challenging issue. The present study provides evidence that a number of parameters may be used for disclosing those children at high risk. FMD and IMT measurements and the analysis of soluble E-selectin and thrombomodulin may reflect the overall influence of different risk factors on the early development of atherosclerosis.
From a clinical point of view, weight control and the support of physical fitness will remain the cornerstones in the management of obese children at risk of early atherosclerotic disease. In contrast, noninvasive assessment of endothelial integrity is a research tool to document the vascular effects of weight control and therapeutic measures.
Limitations of the present study relate to the control population consisting of children suspected of having minor orthostatic symptoms or dizziness. Although morphologic and functional cardiovascular abnormalities had been ruled out in the control group, it is only partly representative of the general healthy pediatric population. It should also be noted that there are no accepted definitions for arterial hypertension during exercise. The definition used throughout the study was a BP >180 mmHg at 2 Watt/kg strain, which represented a strain level that could be achieved by most of our patients.
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ACKNOWLEDGMENTS |
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This study was supported by a University of Rostock Medical Faculty research program grant.
We acknowledge Dr Christine Burstein, Dr Ute Lenschow, Dr Jutta Muscheites, Barbara Heiseler, and Heide Hamp for ongoing support and expert technical assistance.
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FOOTNOTES |
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Accepted Oct 17, 2005.
Address correspondence to Andreas Alexander Meyer, MD, Division of Pediatric Cardiology, Childrens Hospital, University of Rostock, Rembrandtstrasse 16-17, D-18055 Rostock, Germany. E-mail: andreas-alexander.meyer{at}medizin.uni-rostock.de
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics
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