Abstracts

Introduction

Obesity is closely associated with cardiovascular diseases, since excess body fat may predispose the individual to multiple comorbidities, such as hypertension and dyslipidemia^{( 1}1. Ferreira HS, Florêncio TM, Fragoso MA, Melo FP, Silva TG. Hipertension, addominal obesity and short stature: aspects of nutritional transition within a shantytown in the city of Maceió (Northeastern Brazil). Rev Nutr 2005;18:209-18. ^{, 2}2. López de Fez CM, Gaztelu MT, Rubio T, Castaño A. Mechanisms of hypertension in obesity. An Sist Sanit Navar 2004;27:211-9. ⁾. Scientific evidence indicates that obesity is associated with a subclinical inflammatory process, as the adipose tissue secretes substances such as tumor necrosis factor-alpha (TNFα), interleukin 6 (IL-6), adiponectin, and resistin, acting on the vascular endothelium and metabolism of glucose and lipids, contributing to the pathophysiology of cardiovascular diseases^{( 3}3. Down JB, Zajacova A, Aiello AE. Predictors of inflammation in U.S. children aged 3-16 years. Am J Prev Med 2010;39:314-20. ^{, 4}4. Pickup JC. Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care 2004;27:813-23. ⁾.

The concentration of the C-reactive protein (CRP) has a direct relationship with the severity of obesity in childhood, being used as an inflammatory marker of accelerated progression of atherosclerosis^{( 5}5. Keavney B. C reactive protein and the risk of cardiovascular disease. BMJ 2011;342:d144. ⁾. The determination of ultra-sensitive CRP (us-CRP) is a relatively moderate predictor of cardiovascular events and hypertension, as it is associated with changes in fibrinolysis and components of the metabolic syndrome (MS), such as systemic arterial hypertension (SAH)^{( 6}6. Lande MB, Pearson TA, Vermilion RP, Auinger P, Fernandez ID. Elevated blood pressure, race/ethnicity, and C-reactive protein levels in children and adolescents. Pediatrics 2008;122:1252-7.

7. 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 2008;54:147-53. ^{- 8}8. Santos MG, Pegoraro M, Sandrini F, Macuco EC. Risk factors for the development of atherosclerosis in childhood and adolescence. Arq Bras Cardiol 2008;90:301-8. ⁾.

Few studies have evaluated the relationship between inflammatory biomarker levels (us-CRP) and high blood pressure (BP) in children and adolescents^{( 6}6. Lande MB, Pearson TA, Vermilion RP, Auinger P, Fernandez ID. Elevated blood pressure, race/ethnicity, and C-reactive protein levels in children and adolescents. Pediatrics 2008;122:1252-7. ⁾. High BP is considered an independent predictor of increased CRP levels, leading to the hypothesis that arterial hypertension in adults leads to atherosclerosis, partly due to chronic inflammatory diseases^{( 9}9. Campbell P, Blake GJ. C-reactive protein and hypertension. In: Ridker PM, Rifai N, editors. C-reactive protein and cardiovascular disease. St. Laurent: MediEdition Inc.; 2006. p.141-52. ⁾. Moreover, there is an association between family history of hypertension with HBP in children and those with hypertension or prehypertension have higher levels of subclinical inflammation, measured by CRP^{( 10}10. Aglony IM, Arnaiz GP, Acevedo BM, Barja YS, Márquez US, Guzmán AB et al. Blood pressure and family history of hypertension in children from Santiago, Chile. Rev Med Chil 2009;137:39-45. ⁾.

Due to the impact caused by high BP on health in a population and the observed association between CRP and hypertension - besides the limited understanding of this connection in childhood, especially in individuals who are overweight -, this study aimed to verify the relationship between the inflammatory biomarker (Us-CRP) and high BP in overweight children and adolescents from 2 to 18 years, treated at a Child Obesity Center.

Method

This was a cross-sectional study, with a quantitative approach, performed between April 2009 and April 2010, as part of a larger study entitled "Prevalence of cardiometabolic risk factors among obese or overweight children and adolescents" (Prevalência de fatores de risco cardiometabólicos entre crianças e adolescentes obesos ou com sobrepeso), approved by the Research Ethics Committee of Universidade Estadual da Paraíba, under n. 0040.0.133.000-08. The study was developed at the Child Obesity Center (COC), at Instituto de Saúde Elpídio de Almeida (ISEA), in the municipality of Campina Grande, state of Paraíba, specifically to meet the demands of this research. The Child Obesity Center is formed by researchers and a multidisciplinary team, composed of endocrinologists, nutritionists, psychologists, nurses, pharmacists, social workers, and physical instructor.

The sample was selected by convenience sampling and included children and adolescents from 2 to 18 years old who were overweight or obese. However, to verify the representativeness of the number, the ideal sample size was calculated with StatCalc with Epi-Info. Therefore, there was initially a population between 2 and 19 years registered in the Primary Care Information System (PCIS) in 2008, which amounted to 65,980^{( 11}11. Brasil - Instituto Brasileiro de Geografia e Estatística [homepage on the Internet]. População e domicílios: Censo 2000 com divisão territorial [cited 2008 Mar 17]. Available from: http://www.ibge.gov.br/cidadesat/topwindow.htm?1
Available from: http://www.ibge.g... ⁾. The prevalence of overweight and obesity was of 25%^{( 12}12. Da Silva RC, Miranda WL, Chacra AR, Dib SA. Metabolic syndrome and insulin resistance in normal glucose tolerant brazilian adolescents with family history of type 2 diabetes. Diabetes Care 2005;28:716-8. ⁾ and of systemic arterial hypertension (SAH), 37.5%^{( 13}13. Gomes Bda M, Alves JG. Prevalence of high blood pressure and associated factors in students from public schools in Greater Metropolitan Recife, Pernambuco State, Brazil, 2006. Cad Saude Publica 2009;25:375-81. ⁾. For 5% error, the sample size would result in 160 individuals. However, the study included a higher number, due to greater recruitment of subjects for the study.

Children and adolescents were recruited by the advertising of the research in the Basic Health Units in the municipality, performed by the Department of Health. Individuals who presented the inclusion criteria for the study were invited to participate and referred to the COC. In this period, 200 children and adolescents attended the Child Obesity Center, and those presenting one of the following complications were excluded: chronic disease, such as secondary hypertension, type 1 diabetes, inflammatory process, alcoholism, smoking, or using medications that interfered in lipid or glucose metabolism. Two individuals were excluded by the use of steroids and 14 by presenting values of us-CRP higher than 10mg/dL; then, a total of 184 individuals were analyzed. After explanation of the goals, METHODS and procedures to be followed, parents or guardians who agreed to participate in the study signed an informed consent form.

Initially, a form was administered with clinical (gender and age) and anthropometric (weight, height, body mass index - BMI, and waist circumference) variables, then BP was measured by previously trained students, and laboratory tests were scheduled to determine the concentrations of Us-CRP.

Anthropometric variables weight and height were collected in duplicate, based of the standardized criteria recommended by the World Health Organization (WHO). It was considered the mean of the two measures. To obtain weight, a Welmy digital scale (platform type) was used with a capacity of 150kg and accuracy of 0.1kg, children were barefoot, wearing light clothes and positioned in the center of the scale platform. Height was measured by stadiometer (Toneli), accurate to 0.1cm, with children barefoot, in upright position, arms at the sides, feet together, knees straight, head held in the Frankfurt plane, after deep inspiration^{( 14}14. World Health Organization. Physical status: the use and interpretation of anthropometry. Report of a WHO Expert Committee. [Technical Report Series n° 854]. Geneva: WHO; 1995. ⁾. Waist circumference was measured by an inelastic tape with accuracy of 0.5cm, at the midpoint between the top edge of the iliac crest and the last coastal rib, with the patient in upright position, unclothed, with arms positioned along the body and in the expiration phase of breathing^{( 15}15. No authors listed. Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser 2000;894:1-253. ⁾. Values above the 90th percentile were considered increased, but with a maximum limit of 88cm for girls and 102cm for boys, as recommended by the curve adopted by the National Cholesterol Education Program (NCEP)^{( 16}16. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) final report. Circulation 2002;106:3143-421. ⁾.

For the classification of nutritional status, BMI was calculated and, as recommended by the curve adopted by the Centers for Disease Control and Prevention (CDC)^{( 17}17. Center for Disease Control and Prevention [homepage on the Internet]. Body mass index-for-age (children) - 2002 [cited 2011 Jan 16]. Available from: http://www.cdc.gov/nccdphp/dnpa/bmi-for-age.htm
Available from: http://www.cdc.go... ⁾, individuals were classified into the following categories: overweight (BMI between percentile 85 and 95), obesity (BMI between percentile 95 and 97) and severe obesity (BMI ≥percentile 97).

BP was measured three times, with rest intervals of about 2 minutes, according to the method established in the V Brazilian Guidelines of Arterial Hypertension^{( 18}18. Sociedade Brasileira de Cardiologia-SBC; Sociedade Brasileira de Hipertensão-SBH; Sociedade Brasileira de Nefrologia-SBN. V Brazilian Guidelines in Arterial Hypertension. Arq Bras Cardiol. 2007 Sep;89(3):e24-79. ⁾, with a mercury sphygmomanometer (Tycos), using appropriate cuff sizes. The mean of the last two measurements was considered as systolic and diastolic blood pressure. Since BP was measured only once, and according to the recommendation of the V Brazilian Guidelines of Arterial Hypertension^{( 18}18. Sociedade Brasileira de Cardiologia-SBC; Sociedade Brasileira de Hipertensão-SBH; Sociedade Brasileira de Nefrologia-SBN. V Brazilian Guidelines in Arterial Hypertension. Arq Bras Cardiol. 2007 Sep;89(3):e24-79. ⁾ - to confirm the diagnosis of systemic arterial hypertension it is necessary to repeat the measurement of BP after 2 weeks in asymptomatic individuals -, we chose to adopt the nomenclature "high BP". Values of SBP or DBP for sex, age, and stature, were considered normal when <90th percentile, borderline between the 90th and 95th percentile, and high ≥95th percentile, according to the classification curve of BP for children and adolescents adopted at the V Brazilian Guidelines of Hypertension^{( 18}18. Sociedade Brasileira de Cardiologia-SBC; Sociedade Brasileira de Hipertensão-SBH; Sociedade Brasileira de Nefrologia-SBN. V Brazilian Guidelines in Arterial Hypertension. Arq Bras Cardiol. 2007 Sep;89(3):e24-79. ⁾, and re-categorized as normal BP, when <90th percentile, and abnormal, if ≥90th percentile for sex, age and height, for purposes of statistical analysis.

The us-CRP was assessed by chemiluminescence with automatic IMMULITE 1000 (SIEMENS^Â(r)). The individuals who presented values of CRP ≥10mg/dL were excluded, once, in these cases, it is recommended to repeat the exam^{( 6}6. Lande MB, Pearson TA, Vermilion RP, Auinger P, Fernandez ID. Elevated blood pressure, race/ethnicity, and C-reactive protein levels in children and adolescents. Pediatrics 2008;122:1252-7. ^{, 18}18. Sociedade Brasileira de Cardiologia-SBC; Sociedade Brasileira de Hipertensão-SBH; Sociedade Brasileira de Nefrologia-SBN. V Brazilian Guidelines in Arterial Hypertension. Arq Bras Cardiol. 2007 Sep;89(3):e24-79. ⁾. Values of CRP ≤3mg/L (low risk for cardiovascular events) and CRP >3mg/L (high risk for cardiovascular events) were considered as cutoff values^{( 6}6. Lande MB, Pearson TA, Vermilion RP, Auinger P, Fernandez ID. Elevated blood pressure, race/ethnicity, and C-reactive protein levels in children and adolescents. Pediatrics 2008;122:1252-7. ⁾.

Data were presented by means of proportion, mean, and standard-deviation (SD). The association between BP and the groups (age range, sex, and nutritional status) was verified by the Personsâ€(tm) chi-square test or Fisherâ€(tm)s exact test, as appropriate. For the comparison of means, the one-way ANOVA was used. All analyses were performed with the Statistical Package for the Social Sciences version 17.0 (SPSS Inc., Chicago, EUA). Significance was established at p<0.05.

Results

The present study analyzed 184 children and adolescents; 66.3% were female, 63.5% non-white, 64.1% had severe obesity and 78.3% had abnormal waist circumference (WC). Abnormal BP was present in 70.6% of the sample. There was no association of high BP, SBP and DBP with sex, age range, us-CRP, BMI and WC (Table 1).

Table 2 shows that abnormal CRP was associated with high WC (p<0.001) and severe obesity (BMI≥97) (p=0.005). The chance of having increased CRP levels was higher in the groups with high WC (Prevalence Ratio PR=8.08) and severe obesity (PR=2.70). The mean values of CRP were higher in the individuals who presented high SBP (p=0.013), a fact that was not observed in relation to DBP (Table 3). There was a significant association between increased CRP levels and high SBP (p=0.031) only in adolescents. Bivariate analysis between the outcomes high BP, SBP, and DBP and the studied factors was not statistically significant. Stratification by age group showed an association (p=0.013), indicating that adolescents with high CRP have twice the chance of presenting abnormal SBP than those with normal CRP [PR=2.35 (95%CI 1.07-5.14)] (Table 4).

Discussion

The importance of recognizing obesity as an inflammatory state is because of the possibility that inflammation may be one of the links among obesity and insulin resistance, hypertension, and cardiovascular disease^{( 19}19. Borges RL, Ribeiro-Filho FF, Carvalho KM, Zanella MT. Impact of weight loss on adipocytokines, C-reactive protein and insluin sensitivity in hypertensive women with central obesity. Arq Bras Cardiol 2007;89:409-14. ⁾.

In this study a high prevalence of high BP in overweight and obese children and adolescents was found. This is worrying, since the early risk for cardiovascular diseases may be enhanced at younger ages simply by the presence of excess body weight^{( 20}20. Howe LD, Tilling K, Benfield L, Logue J, Sattar N, Ness AR et al. Changes in ponderal index and body mass index across childhood and their associations with fat mass and cardiovascular risk factors at age 15. PLoS One 2010;5:e15186. ⁾. As obesity in childhood and adolescence predisposes to obesity in adult life, the high prevalence of high BP found in this research, in all age groups, represents an alert for the health conditions of these individuals^{( 21}21. Castro Burbano J, Fornasini M, Acosta M. Prevalencia y factores de riesgo de sobrepeso en colegialas de 12 a 19 años en una región semiurbana del Ecuador. Rev Panam Salud Publica 2003;13:277-84. ⁾.

The high BP was more prevalent in males, adolescents, and severely obese individuals, supporting the study performed by Costanzi et al ^{( 22}22. Costanzi CB, Halpern R, Rech RR, Bergmann ML, Alli LR, Mattos AP. Associated factors in high blood pressure among schoolchildren in a middle size city, southern Brazil. J Pediatr (Rio J) 2009;85:335-40. ⁾ with 1,413 children between 7 and 12 years old, students of public and private schools. In this study, there was a prevalence of high BP of 13.8%, being twice this value in those with obesity or overweight. In a study conducted in the state of Paraíba with 674 adolescents in public and private schools, the prevalence of high BP was of 7.4%, being higher in boys (10.2%) than in girls^{( 23}23. Silva KS, Farias Júnior JC. Risk factors associated with high blood pressure in adolescents. Rev Bras Med Esporte 2007;13:237-40. ⁾.

The risk of BP reaching high values varies according to the duration and intensity of obesity. One cannot say that the high BP increased with advanced age - since there was no longitudinal follow-up of patients, but it was more frequent in the older age group, i.e., in adolescence. It is also possible that the time period in which these individuals were exposed to excess adipose tissue may have contributed to the elevation in blood pressure values^{( 24}24. Ferreira JS. Interações entre variáveis antropométricas e valores pressóricos de crianças e adolescentes obesos de Campo Grande - MS [tese de mestrado]. Brasília (DF): UnB; 2006. ⁾.

In this study, there was no association between high BP and nutritional status or WC, as well as in a study conducted with Chilean children, in which no direct association was found between children with high blood pressure and the degree of obesity^{( 10}10. Aglony IM, Arnaiz GP, Acevedo BM, Barja YS, Márquez US, Guzmán AB et al. Blood pressure and family history of hypertension in children from Santiago, Chile. Rev Med Chil 2009;137:39-45. ⁾.

The measure of WC in adults is accepted as an important tool to assess the risk of diseases, especially atherosclerosis. In childhood and adolescence, however, the lack of long-term prospective studies does not allow the mere extrapolation of this knowledge. Furthermore, as this measure presents variation due to physical growth, it results in different cutoff points for each age range^{( 25}25. Wang J. Standardization of waist circumference reference data. Am J Clin Nutr 2006;83:3-4. ⁾.

Higher levels of us-CRP were found among individuals who were obese and in the preschool and school age ranges. The values of CRP rose as BMI increased, with severe obese having a prevalence of high CRP three times higher. The levels of high CRP were more frequent in individuals with high WC. Many studies performed with children and adolescents suggest that the concentration of us-CRP is strongly related to the ponderal index^{( 26}26. Acevedo M, Arnáiz P, Barja S, Bambs C, Berríos X, Guzmán B et al. Relationship of C-reactive protein to adiposity, cardiovascular risk factors, and subclinical atherosclerosis in healthy children. Rev Esp Cardiol 2007;60:1051-8. ⁾.

Junqueira, Romêo Filho and Junqueira^{( 27}27. Junqueira AS, Romêo Filho LJ, Junqueira Cde L. Evaluation of the degree of vascular inflammation in patients with metabolic syndrome. Arq Bras Cardiol 2009;93:360-6. ⁾ state that high levels of CRP are associated with the accumulation of visceral adipose tissue and metabolic syndrome components. These data suggest a possible role of the visceral adipose tissue in the pathogenesis of arteriosclerosis. Therefore, obesity, metabolic syndrome, and arteriosclerosis are closely related and can de determinants of a vascular inflammation increased response.

Because of the easy measurement of serum concentration, the low cost, and better clinical-epidemiological correlation when compared to other inflammatory markers such as IL-6 and TNFα, the CRP is of particular interest, given the possibility of elucidating new pathways for prevention and treatment of diseases of high prevalence, morbidity, and mortality^{( 28}28. Folsom AR, Pankow JS, Tracy RP, Arnett DK, Peacock JM, Hong Y et al. Association of C-reactive protein with markers of prevalent atherosclerotic disease. Am J Cardiol 2001;88:112-7. ⁾. Studies have shown that individuals with normal levels of us-CRP and BP have higher survival free from cardiovascular events compared to those with high levels^{( 28}28. Folsom AR, Pankow JS, Tracy RP, Arnett DK, Peacock JM, Hong Y et al. Association of C-reactive protein with markers of prevalent atherosclerotic disease. Am J Cardiol 2001;88:112-7. ⁾. These findings suggest that inflammation and hypertension may act together to promote atherosclerosis^{( 9}9. Campbell P, Blake GJ. C-reactive protein and hypertension. In: Ridker PM, Rifai N, editors. C-reactive protein and cardiovascular disease. St. Laurent: MediEdition Inc.; 2006. p.141-52. ⁾.

Studies from the National Health and Nutrition Examination Survey (NHANES) found that adiposity was the best predictor of high levels of us-CRP^{( 29}29. Ford ES, Giles WH, Myers GL, Rifai N, Ridker PM, Mannino DM. C-reactive protein concentration distribution among US children and young adults: findings from the National Health and Nutrition Examination Survey, 1999-2000. Clin Chem 2003;49:1353-7. ⁾. Thus, among those who were overweight, the higher the concentration of us-CRP, the greater the number of metabolic anomalies found^{( 30}30. De Ferranti SD, Gauvreau K, Ludwig DS, Newburger JW, Rifai N. Inflammation and changes in metabolic syndrome abnormalities in US adolescents: findings from the 1988-1994 and 1999-2000 National Health and Nutrition Examination Surveys. Clin Chem 2006;52:1325-30. ⁾. When analyzing SBP as a continuous variable, it was independently associated with the levels of us-CRP in girls from 12 to 17 years old. In the present study, there was association of abnormal SBP values and us-CRP in adolescence, and the CRP had a significantly higher mean value in those who presented high SAH.

Clinical and anatomopathological studies suggest that atherosclerosis can develop in adolescents, being more prevalent in those with high BP^{( 6}6. Lande MB, Pearson TA, Vermilion RP, Auinger P, Fernandez ID. Elevated blood pressure, race/ethnicity, and C-reactive protein levels in children and adolescents. Pediatrics 2008;122:1252-7. ⁾. Such findings, together with the role of chronic inflammation in the pathogenesis of atherosclerosis, have led researchers to study the relationship between high us-CRP, levels of BP, and other cardiovascular risk factors in children and adolescents. The measurement of us-CRP only in children and adolescents with excess weight and the cross-sectional design are limitations of this study; therefore, causality was unclear, which indicates that further studies with a longitudinal design are needed to better understand this relationship. A better understanding of the determinants of systemic inflammation at early ages may have important implications for primary prevention of many diseases related to chronic inflammation^{( 3}3. Down JB, Zajacova A, Aiello AE. Predictors of inflammation in U.S. children aged 3-16 years. Am J Prev Med 2010;39:314-20. ⁾.

Another limitation of the study was the measurement of BP in a single visit, which cannot be used to characterize arterial hypertension. This measure should be used as a risk indicator of hypertension for cross-sectional comparisons in epidemiological studies conducted with children and adolescents. The literature shows that the prevalence of high blood pressure can vary depending on the population studied, the cutoffs adopted (desirable or normal values), as well as educational, cultural, and genetic variables. These findings refer to a limitation of this study, which lies in the fact that the different criteria adopted, as well as the different populations studied hinder comparisons. However, it is important to highlight that no studies were found in the literature involving children and adolescents with excess weight that have included the number of cases and the wide age range that was analyzed in the present work.

Thus, the present study demonstrated a high prevalence of abnormal BP in children and adolescents who are overweight or obese, and a significant association of us-CRP with severe obesity, increased waist circumference, and SBP, so these markers can be used to identify children and adolescents with higher risk for development of atherosclerosis.

The prevention of obesity from an early age can prevent the metabolic/inflammatory unfavorable condition from remaining over the years, causing serious consequences in adulthood. Early treatment of children and adolescents with excess weight can decrease the incidence of comorbidities in adulthood. Further research is needed to demonstrate the association of inflammatory markers and comorbidities related to obesity in childhood and adolescence, which is currently one of the major public health problems.

References

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History