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Departments of Internal Medicine and Public Health (G.D., M.C.M., V.C., G.C., G.P., S.N., C.F.) and Experimental Medicine (M.D.S., T.R., M.L.I.), University of l’Aquila, 67100 L’Aquila, Italy; and Department of Pediatrics (L.I.), University of Modena and Reggio Emilia, 41100 Modena, Italy
Address all correspondence and requests for reprints to: Giovambattista Desideri, M.D., University of L’Aquila Department of Internal Medicine and Public Health, Piazzale Salvatore Tommasi n.1, 67100, Coppito, L’Aquila, Italy. E-mail: giovambattista.desideri{at}cc.univaq.it.
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Abstract |
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were evaluated because of their ability to promote vascular endothelial cell and platelet activation. Circulating levels of all of the assessed markers were higher in obese than in nonobese children (sICAM-1, +38.8 ± 13.3%; sVCAM-1, +26.5 ± 13.7%; sE-selectin, +31.3 ± 17.3%; sP-selectin, +31.7 ± 16.9%; sCD40 ligand, +36.9 ± 22.1%; total 8-iso-PGF2, +24.0 ± 20.2%; hs-CRP, +76.6 ± 12.9%; P < 0.0001). Significant correlations (P < 0.004) between plasma total 8-iso-PGF2 levels and circulating sICAM-1 (r = 0.485), sVCAM-1 (r = 0.506), sP-selectin (r = 0.449), sCD40 ligand (r = 0.498), and hs-CRP (r = 0.520) concentrations were found in obese children. In conclusion, an early activation of vascular endothelial cells and platelets was present in obese children. Increased lipid peroxidation was also present in these children and likely contributed to the observed proinflammatory phenotype. |
Introduction |
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Although the presence of additional risk factors could be relevant in increasing the individual cardiovascular risk profile, recent data suggest that obesity in children per se could worsen cardiovascular prognosis later in life. In this regard, central obesity has been demonstrated to be combined with more extensive fatty streaks at the aortic level and raised lesions in the right coronary arteries of male children and young adults (8). In addition, severe obesity in children is independently associated with endothelial dysfunction and arterial wall thickening (9). In turn, such detrimental obesity-related vascular abnormalities are partially reversible with diet (alone or combined with exercise training) (10). Thus, obesity per se has the potential to promote atherosclerotic plaque formation since the earliest phases of life. Even more interesting, obesity at adolescence is a strong predictor of coronary heart disease during adulthood (11, 12), independent of the persistence of obesity (11). Therefore, obesity in childhood might represent the trigger for the development of permanent vascular abnormalities that, in turn, increase cardiovascular risk in adulthood.
Up-regulation of endothelial adhesion molecules plays a pivotal role during the earliest phases of atherogenesis by allowing leukocyte and monocyte adhesion to the endothelial cell surface and their transendothelial migration (13, 14). Activated platelets also participate in such early steps of atherogenesis by modulating chemotactic and adhesive properties of endothelial cells (15). In addition, activated platelets release a trimeric transmembrane protein of the TNF family, soluble CD40 ligand (sCD40L), which further amplifies atherogenesis by promoting inflammatory cytokine release and circulating cell adhesion to the vascular endothelium (16).
Therefore, it is tempting to hypothesize that obesity-related activation of vascular endothelial cells and platelets may occur during childhood and contribute to increased cardiovascular risk later in life. However, to the best of our knowledge, no studies have tested this possibility. To assess this topic, we evaluated circulating levels of soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and sE-selectin, as indices of endothelial activation (17) in obese children. Plasma concentrations of sP-selectin (17) and sCD40L (16), as markers of platelet activation, were also assessed in the same patients. In addition, because oxidative stress is involved in both vascular endothelial cell (18) and platelet activation (19), we evaluated circulating levels of the lipid peroxidation product 8-iso-prostaglandin (PG)F2, i.e. a well recognized marker of oxidative stress (20). Finally, because C-reactive protein (CRP) deeply affects vascular biology by favoring a proinflammatory and proatherosclerotic phenotype (14), we evaluated the relationship between circulating levels of highly sensitive (hs)-CRP and soluble markers of vascular endothelial cell and platelet activation in our study population.
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Subjects and Methods |
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The study population consisted of 40 obese Caucasian school children (21 males; mean age, 10.3 ± 2.5 yr) who were referred to our Outpatient Unit at the Center of the Control of Growth Disorders of our University Pediatric Clinic and 40 nonobese children (21 males; mean age, 10.3 ± 2.3 yr) who served as controls. Obese children were consecutively selected among those who were referred to the Outpatient Unit for obesity between 2001 and 2002 according to the following exclusion criteria: presence of concomitant diseases, i.e. renal, liver, and/or cardiovascular diseases; hypertension; metabolic and/or endocrine disorders, including dyslipidemia and diabetes; and genetic syndromes. In addition, obese children were requested to have no personal histories of chronic allergies involving either type I or type II immune responses. No patient had acute infectious or inflammatory diseases during the last 3 months preceding the study. No patient was treated with any kind of drug (including vitamins, etc.) or experienced a weight reduction program during the last 12 months.
Nonobese, control children were consecutively recruited among healthy children referred for a routine clinical check to the Outpatient Unit of our University Pediatric Clinic. Apart from obesity, inclusion/exclusion criteria and evaluated variables were identical to those used for the obese group. Informed consent was obtained from the parents and children.
Body composition and definition of obesity
Body weight was measured to the nearest 0.1 kg with a balance scale and height was measured to the nearest 0.1 cm with Harpenden’s stadiometer with subjects lightly dressed and without shoes. Waist circumference was measured midway between the lower rib margin and the iliac crest and hip circumference was measured at the widest point over the great trochanters. Both circumferences were measured in the standing position and at the end of a gentle expiration. The waist-to-hip ratio (WHR) was calculated to assess body fat distribution. Body mass index (BMI) was calculated for each subject using the formula weight (kilograms)/height (meters2). Obesity was defined as a BMI higher than the 95th percentile for age and sex, whereas normal weight was defined as a BMI lower than the 85th percentile for age and sex (21). The BMI percentiles reported by Must et al. (22) were used as a reference. To express the weight excess as a continuous variable, obesity was also defined as relative BMI (relBMI) greater than 120%, where relBMI was obtained using the formula (BMI/BMI at 50th percentile for age and gender) x 100. The relBMI was calculated again by using the BMI percentiles of Must et al. (22).
Blood pressure
Blood pressure was measured in all children according to the American Heart Association guidelines, by using a standard Riva-Rocci sphygmomanometer with an appropriate size cuff and a stethoscope (23). Subjects were classified as hypertensive if their systolic or diastolic blood pressure was higher than the 95th percentile for age after adjustment for height (23).
Procedures and laboratory measurements
After admission to the Clinic, obese subjects were placed on a 3-d weight-maintaining diet that provided 50% of calories as carbohydrate, 30% as fat, and 20% as protein. An oral glucose tolerance test was then performed in these subjects after an overnight fast using a glucose load of 1.75 g/kg body weight. The maximum administered dose of glucose was 75 g. The categorization of glucose tolerance status was made using the World Health Organization criteria (24). The areas under the plasma insulin and glucose concentration time curve from 0–120 min (AUC0–120ins and AUC0–120glu, respectively) after oral glucose load were calculated. To ascertain the insulin resistance status, the homeostasis model assessment of insulin resistance (HOMAIR) was calculated according to the following formula: [fasting insulin (µU/ml) x fasting glucose (mmol/liter)]/22.5.
After an overnight fast, blood samples were taken in obese children and in control subjects to measure serum total cholesterol, HDL cholesterol, LDL cholesterol, and triglyceride concentrations.
Plasma aliquots were stored at –80 C in polypropylene tubes immediately after centrifugation (15 min at 4 C at 3000 rpm) of blood samples and subsequently used to assess circulating levels of sICAM-1, sVCAM-1, sE-selectin, sP-selectin, sCD40L, hs-CRP, and total 8-iso-PGF2. Circulating sVCAM-1, sICAM-1, sE-selectin, sP-selectin, and sCD40L concentrations were measured by an immunoenzymatic method (R&D Systems, Minneapolis, MN). Plasma total 8-iso-PGF2 levels were assessed by enzyme immunoassay (Assay Design Inc., Ann Arbor, MI). The hs-CRP levels were measured using the Integra-Immunoturbidimetric method (Cobas Integra 700; Roche Diagnostics, Indianapolis, IN). The method is sensitive to 0.3 mg/liter.
Sample power and statistical analysis
Statistical analysis and power calculation was performed by PC and the SAS statistical software (version 8.12, 2000; SAS Institute, Inc., Cary, NC). The size of the sample necessary to achieve 80% statistical power at a two-sided significance level of 0.05 was calculated starting from previous data on vascular inflammatory markers in obese populations (25, 26). On the basis of the assumption that a difference of about 15% of soluble adhesins was expected to occur in obese compared with nonobese subjects, two matched groups of 40 subjects were studied.
The AUC0–120ins and AUC0–120glu were determined using the trapezoidal rule. The distribution of values for each variable studied was analyzed by the Shapiro-Wilk normality test. Obese and nonobese children were compared with a t test for independent samples for variables that were normally distributed. When necessary, a nonparametric test (Mann-Whitney U test) was used. For analytical purposes, obese children were stratified into quartiles on the basis of their relBMI, HOMAIR, AUC0–120ins, and AUC0–120glu. Differences in mean values of the evaluated variables among the four quartiles were assessed by one-way ANOVA. Post hoc comparisons were performed by Tukey’s Studentized range, honestly significant difference, test. Plasma insulin and glucose concentrations during the oral glucose tolerance test were compared by ANOVA for repeated measurements. Spearman nonparametric correlation was used to evaluate correlations between variables. Multiple linear regression with stepwise procedure was used to evaluate the relative weight and persistence of the relationship among variables. Unless otherwise stated, data are given as mean ± 1 SD. Only p values equal to or lower than 0.05 were regarded as statistically significant.
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Results |
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The physical characteristics and the main laboratory variables for both obese and nonobese children are given in Table 1
. According to the adopted inclusion criteria, compared with control subjects, obese children had similar systolic and diastolic blood pressure levels, serum lipid profile, and glucose concentrations. In contrast, fasting insulin concentrations were higher in obese than in nonobese children (Table 1). Concordant to this, a significant degree of insulin resistance was present in obese children who manifested with higher HOMAIR when compared with nonobese children (Table 1). Mean plasma glucose and insulin excursions vs. time after oral glucose load are shown in Table 2. None of the obese children manifested with impaired fasting glucose, whereas one among them had glucose intolerance (2-h plasma glucose level, 8.05 mmol/liter).
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Obese children showed higher plasma levels of sICAM-1 (206.4 ± 33.6 vs. 122.8 ± 16.0 µg/liter; P < 0.001), sVCAM-1 (402.6 ± 75.7 vs. 289.5 ± 44.8.0 µg/liter; P < 0.001), and sE-selectin (84.0 ± 20.0 vs. 55.3 ± 10.6 µg/liter; P < 0.001) when compared with nonobese subjects (Fig. 1). Similarly, significant platelet activation was present in obese children as indicated by their higher plasma levels of sP-selectin (73.2 ± 11.2 vs. 48.5 ± 8.9 µg/liter; P < 0.001) and sCD40L (3.3 ± 0.6 vs. 2.0 ± 0.5 ng/ml; P < 0.001) in comparison with nonobese children (Fig. 1).
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). Similarly, when obese children were stratified into quartiles on the basis of HOMAIR, AUC0–120ins, and AUC0–120glu, all the assessed parameters were found to be similar among the four subgroups (data not shown).
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Soluble markers of lipid peroxidation and systemic inflammation
A significant degree of lipid peroxidation was present in obese children as indicated by the increased circulating levels of total 8-iso-PGF2 (332.7 ± 69.2 vs. 243.5 ± 45.4 pg/liter; P < 0.001) (Fig. 1
). Circulating levels of hs-CRP were also significantly higher in obese children than in nonobese ones (2.3 ± 0.7 vs. 0.5 ± 0.2 mg/liter; P < 0.001). When the obese population was divided into quartiles on the basis of relBMI, circulating levels of total 8-iso-PGF2 and hs-CRP levels were found to be quite similar among quartiles (Table 3). Similar findings were observed when obese children were stratified into quartiles on the basis of HOMAIR, AUC0–120ins, and AUC0–120glu (data not shown).
Relationships between soluble markers of vascular endothelial cell and platelet activation, lipid peroxidation, and systemic inflammation
Circulating levels of sICAM-1 (r = 0.485; P = 0.0015), sVCAM-1 (r = 0.506; P = 0.0009), sP-selectin (r = 0.449; P = 0.0037), and sCD40L (r= 0.498; P = 0.0011) were directly correlated with plasma total 8-iso-PGF2 concentrations (Fig. 2). These latter also correlate with circulating hs-CRP levels (r = 0.520; P = 0.0006) in obese children (Fig. 3). Significant correlations between circulating hs-CRP levels and plasma concentrations of sCD40L (r = 0.379; P = 0.0159) and sICAM-1 (r = 0.708; P < 0.0001) were also found in obese children (Fig. 3). Plasma sP-selectin levels negatively correlated with serum HDL cholesterol concentrations (r = –0.419; P = 0.007) but directly correlated with plasma sICAM-1 (r = 0.509; P = 0.0008) and sCD40L (r = 0.634; P < 0.0001) levels in obese children.
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, and hs-CRP and anthropometric measurements in both obese and nonobese children (data not shown). Spearman nonparametric correlation found a weak but significant relationship between AUC0–120ins and plasma total 8-iso-PGF2 concentrations (r = 0.310; P = 0.05). In a multivariate regression analysis with a stepwise approach, AUC0–120ins explained 11% of the total 8-iso-PGF2 variance. No significant relationships were found between AUC0–120ins and AUC0–120glu and soluble markers of vascular endothelial cell and platelet activation in obese children (data not shown). |
Discussion |
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In this context, our study provides clear evidence that obesity in children is combined with increased circulating levels of sICAM-1, sVCAM-1, and sE-selectin, thereby suggesting the presence of vascular endothelial cell activation (17). Obese children also manifested with increased plasma sP-selectin and sCD40L concentrations, demonstrating that platelet activation was also present (16, 17). Of note, our study population was carefully selected to avoid confounding conditions such as hypertension, diabetes, dyslipidemia, or allergic diseases. Thus, adipose tissue accumulation likely represented the main factor responsible for the activation of vascular endothelium and platelets that we observed in obese children.
In contrast to this data interpretation, we failed to find significant correlations between soluble indices of vascular endothelial cell and platelet activation and either the degree of overweight, as evaluated by BMI and relBMI assessment, or visceral fat distribution, as evaluated by WHR, in obese children. Even more perplexing, we have previously described a direct correlation between circulating levels of sE-selectin (25) and BMI and between plasma sCD40L and WHR (26) in obese adults without additional cardiovascular risk factors. The lack of any correlation between soluble adhesion molecule and sCD40L levels and BMI or WHR in obese children could reflect the limits of these surrogate anthropometric indices of body fatness and visceral fat distribution when they are used in children. Indeed, it has been well established that both BMI and WHR could be misleading in infancy and childhood (29). A more intriguing explanation for the above findings is that the presence of obesity per se rather than the degree of body fatness or visceral fat distribution could have played a critical role in the activation of vascular endothelial cells and platelets in our obese children, i.e. as when a threshold effect does exist. In agreement with such data interpretation, when obese children were stratified into quartiles on the basis of their relBMI, no significant differences in circulating levels of soluble markers of vascular endothelial cell and platelet activation were found among the four subgroups, despite significant differences in regard to the degree of weight excess. The lack of correlation between degrees of endothelial dysfunction and either body weight or android/gynoid fat-mass ratio recently described by Tounian et al. (9) in severely obese children also agrees with our data interpretation. However, children enrolled in our study were requested to have a BMI either higher than 95th (obese) or lower than 85th (control) percentile for age and sex. Thus, we cannot completely exclude that the relatively narrow range of BMI in our study population could have made us unable to find relationships between degrees of obesity and activation of vascular endothelial cells and platelets. On the other hand, the same patient selection did not allow us to verify whether or not a lower degree of body fatness (i.e. a BMI higher than 85th and lower than 95th percentile for age and sex) could be able to trigger off the proatherogenic inflammation in children.
As far as the reasons underlying vascular endothelial cell and platelet activation, several feed-forward mechanisms likely cooperate in uncovering the proinflammatory and proatherosclerotic phenotype observed in obese children.
First, obese children showed increased circulating levels of total 8-iso-PGF2. Although we cannot completely exclude that a reduced antioxidant intake could have contributed, at least in part, to the above finding, it is likely that circulating levels of total 8-iso-PGF2 were elevated because of enhanced oxidative stress (20). Indeed, F2-isoprostanes are generated from arachidonic acid through a process of nonenzymatic free radical-catalyzed lipid peroxidation (20). Because circulating levels of total 8-iso-PGF2 and hs-CRP were directly correlated in obese children, it is conceivable that the increased circulating levels of total 8-iso-PGF2 observed in these subjects were a result of a low-grade systemic inflammation (30) leading to increased lipid peroxidation (31). F2-isoprostanes, in turn, further amplify vascular wall inflammation because of their ability to promote several proatherogenic responses, including sustained vasoconstriction (20) and inflammatory gene expression (32).
In this context, circulating levels of total 8-iso-PGF2 also directly correlated with soluble markers of vascular endothelial cell and platelet activation in obese children. Interestingly, we have previously described similar correlations between increased plasma total 8-iso-PGF2 and soluble endothelial adhesion molecule levels in hypercholesterolemic patients (33). Furthermore, we have also observed a significant correlation between increased plasma total 8-iso-PGF2 and sCD40L levels in low-risk obese adults (26). In our opinion, these data suggest a link between lipid peroxidation and activation of vascular endothelial cells and platelets. Consistent with our hypothesis, experimental models clearly demonstrated the ability of lipid peroxidation products to promote platelet activation (34) and endothelium-leukocyte interaction (35).
Second, obese children manifested with increased circulating levels of hs-CRP, suggesting the presence of a low-grade systemic inflammation (30). In this regard, adipocytes represent a source of the inflammatory cytokine IL-6 (36), which powerfully stimulates the liver to produce acute-phase protein, including CRP (14, 36). This latter, in turn, directly promotes several inflammatory responses on both vascular endothelial and vascular smooth muscle cells, including up-regulation of adhesion molecules, production of chemoattractant chemokines, and generation of reactive oxygen species (14). Thus, it is likely that an obesity-related low-grade inflammation could have contributed to the activation of endothelial cells and platelets that we have observed in obese children. According to this, circulating levels of hs-CRP were directly correlated with plasma concentrations of sCD40L and sICAM-1 in obese children.
Finally, it is possible that metabolic factors could have taken a part in activating vascular endothelial cells and platelets in our obese children. In this regard, it worth mentioning that obese children were found to be insulin resistant and hyperinsulinemic, as indicated by the higher HOMAIR value in comparison with nonobese children and the hyperinsulinemic response to oral glucose load. Insulin resistance and hyperinsulinemia represent major cardiovascular risk factors that have the biological potential to affect endothelial functions as well as proatherogenic inflammation independently of obesity. According to this, endothelial dysfunction has been previously demonstrated to be related to indices of insulin resistance in obese children (9) and to represent an independent predictor of circulating CRP concentrations in insulin-resistant obese individuals (37). In our study, we failed to find any correlation between HOMAIR, AUC0–120ins, and AUC0–120glu and circulating levels of soluble adhesion molecules and CD40L. These findings seem to exclude a direct role for insulin and glucose in promoting the activation of vascular endothelial cells and platelets in our obese children. In accord with this, we have previously demonstrated that hyperinsulinemia does not affect circulating levels of sVCAM-1, at least in type 2 diabetic patients (38). However, it was interesting to observe a weak but significant correlation between AUC0–120ins and plasma total 8-iso-PGF2 concentrations in obese children. This finding agrees with previous studies demonstrating a relationship between oxidative stress and insulin resistance in obese subjects (39) and the ability of insulin to stimulate hydrogen peroxide generation in human fat cells (40). Although correlation does not prove causation, it is likely that hyperinsulinemia could have contributed to the increased lipid peroxidation that we have found in obese children.
With regard to lipid profile, circulating levels of HDL cholesterol, although normal, were found to be inversely correlated with circulating sP-selectin concentrations. These findings agree with experimental data demonstrating a role for HDL cholesterol in modulating P-selectin expression (41) and suggest that the lipid profile could have contributed to the up-regulation of P-selectin in obese children.
Thus, several feed-forward mechanisms are likely to amplify and sustain vascular endothelial cell and platelet activation in obese children and lead to persistent vascular wall inflammation. The latter, in the long run, has the potential to affect the prognosis by producing advanced atherosclerotic lesions and favoring their acute complications (13, 42).
Study limitation
To avoid confounding, we carefully excluded obese children with comorbidities and/or conditions that are known to affect vascular endothelial cell and platelet activation. This selection strongly supports the hypothesis that obesity was the main determinant of the vascular endothelial cell and platelet activation that we have observed in obese children. On the other hand, the same patient selection limits the generalization of our data to obese children as a whole.
In conclusion, our study provides clear evidence that obesity in children is associated with increased circulating levels of soluble markers of vascular endothelial cell and platelet activation. As we have previously described in low-risk obese adults (26), increased lipid peroxidation likely represents the main link between obesity and vascular endothelial cell and platelet activation also in obese children. Whether or not such inflammatory phenotype could set the stage for the development of atherosclerosis and affect cardiovascular prognosis later in life remains to be demonstrated by prospective studies.
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Footnotes |
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First Published Online March 8, 2005
Abbreviations: AUC, Area under the curve; BMI, body mass index; CD40L, CD40 ligand; CRP, C-reactive protein; HDL, high-density lipoprotein; HOMAIR, homeostasis model assessment of insulin resistance; hs, highly sensitive; ICAM-1, intercellular adhesion molecule-1; LDL, low-density lipoprotein; PG, prostaglandin; relBMI, relative BMI; s, soluble; VCAM-1, vascular cell adhesion molecule-1; WHR, waist-to-hip ratio.
Received September 3, 2004.
Accepted February 25, 2005.
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increases platelet adhesion and reduces the antiadhesive and antiaggregatory effects of NO. Arterioscler Thromb Vasc Biol 8:1248–1256
induces ß2-integrin-mediated rapid adhesion of human polymorphonuclear neutrophils: a link between oxidative stress and ischemia/reperfusion injury. Arterioscler Thromb Vasc Biol 21:55–60This article has been cited by other articles:
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  Y. Aggoun, N. J. Farpour-Lambert, L. M. Marchand, E. Golay, A. B.R. Maggio, and M. Beghetti Impaired endothelial and smooth muscle functions and arterial stiffness appear before puberty in obese children and are associated with elevated ambulatory blood pressure Eur. Heart J., March 2, 2008; 29(6): 792 - 799. [Abstract] [Full Text] [PDF]
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 A. E. Caballero, K. Bousquet-Santos, L. Robles-Osorio, V. Montagnani, G. Soodini, S. Porramatikul, O. Hamdy, A. C.L. Nobrega, and E. S. Horton Overweight Latino Children and Adolescents Have Marked Endothelial Dysfunction and Subclinical Vascular Inflammation in Association With Excess Body Fat and Insulin Resistance Diabetes Care, March 1, 2008; 31(3): 576 - 582. [Abstract] [Full Text] [PDF]
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 M. V. Jimenez, R. M. Estepa, R. M. Camacho, R. C. Estrada, F. G. Luna, and F. B. Guitarte Endothelial dysfunction is related to insulin resistance and inflammatory biomarker levels in obese prepubertal children Eur. J. Endocrinol., April 1, 2007; 156(4): 497 - 502. [Abstract] [Full Text] [PDF]
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 A. A. Meyer, G. Kundt, M. Steiner, P. Schuff-Werner, and W. Kienast Impaired Flow-Mediated Vasodilation, Carotid Artery Intima-Media Thickening, and Elevated Endothelial Plasma Markers in Obese Children: The Impact of Cardiovascular Risk Factors Pediatrics, May 1, 2006; 117(5): 1560 - 1567. [Abstract] [Full Text] [PDF]
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