Central obesity as a major determinant of increased high-sensitivity C-reactive protein in metabolic syndrome

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1 (2005) 29, & 2005 Nature Publishing Group All rights reserved /05 $30.00 PAPER Central obesity as a major determinant of increased high-sensitivity C-reactive protein in metabolic syndrome A-C Santos 1 *, C Lopes 1, JT Guimarães 2 and H Barros 1 1 Department of Hygiene and Epidemiology, University of Porto Medical School, Alameda Professor Hernani Monteiro, Porto, Portugal; and 2 Departments of Biochemistry and Clinical Pathology, University of Porto Medical School and São João Hospital, Porto, Portugal INTRODUCTION: Traditional cardiovascular risk factors such as central obesity, high blood pressure and insulin resistance, all constituents of metabolic syndrome, have been associated with increased levels of C-reactive protein (CRP). Therefore, this marker of low-grade inflammation may play a major role in the pathogenesis of cardiovascular diseases. In this study, data from a representative sample of urban adults was used to evaluate the association between CRP and metabolic syndrome, accounting for the type and number of its constituents. METHODS: Using random digit dialing, 1022 participants, aged y, were selected. All participants completed a structured questionnaire comprising of information on social, demographic, behavioral and clinical aspects. Anthropometrics and blood pressure were recorded and a fasting blood sample collected. Metabolic syndrome was defined, according to the Third Report of the Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults, as the presence of three or more of the following characteristics: waist circumference greater than 102 cm in men and 88 cm in women; triglyceride levels Z150 mg/dl; high-density lipoprotein cholesterol levels o40 mg/dl in men and o50 mg/dl in women; blood pressure Z130/ 85 mm Hg; and serum glucose Z110 mg/dl. High-sensitivity CRP was assessed by immunonephelometric assay. After excluding 65 participants with CRP Z10 mg/l, 957 subjects (599 women and 358 men) remained for analysis. Geometric means were compared after adjustment for age, sex, alcohol consumption and smoking. RESULTS: Higher mean levels of CRP (2.34 vs 1.36, Po0.001) were observed when metabolic syndrome was present. Also, mean CRP levels were significantly higher in the presence of central obesity (2.45 vs 1.24, Po0.001), high blood pressure (1.76 vs 1.12, Po0.001), hypertriglyceridemia (2.17 vs 1.32, Po0.001) and high fasting glucose (1.96 vs 1.46, P ¼ 0.032). We found a significant increasing trend (Po0.001) in mean levels of CRP as the number of features of metabolic syndrome increased. The major contributing features for high CRP levels were central obesity and high blood pressure. CONCLUSIONS: Present data show that increasing severity of metabolic syndrome is associated with increasing CRP. Additionally, we found that central obesity and high blood pressure are the most important determinants of the low-grade chronic inflammation present in metabolic syndrome. (2005) 29, doi: /sj.ijo ; published online 2 August 2005 Keywords: inflammation; C-reactive protein; metabolic syndrome; blood pressure *Correspondence: Dr A-C Santos, Department of Hygiene and Epidemiology, University of Porto Medical School, Alameda Professor Hernani Monteiro, Porto , Portugal. acsantos@med.up.pt Received 4 August 2004; revised 21 February 2005; accepted 26 February 2005; published online 2 August 2005 Introduction The close association between type II diabetes and cardiovascular disease raised the hypothesis of a common antecedent, and led to the description of a new clinical entity, currently designated metabolic syndrome, 1 which is characterized by the co-occurrence of obesity, dyslipidemia, hyperglycemia and hypertension. Some of these abnormalities are linked to insulin resistance, a metabolic disturbance accompanied by an increased acute-phase response. 2 Crosssectional studies 3 5 have described metabolic syndrome as a common condition associated with increased CRP levels and prospective evaluations have shown that high CRP levels predict the development of the syndrome. 6 With varying magnitude, individual constituents of metabolic syndrome have been associated with increased CRP levels. 7 9 However, abnormal levels of these features that define the syndrome tend to cluster, making it difficult to

2 establish any independent association between the constituent and the CRP level. The identification of this individual contribution could provide useful information for therapeutic and preventive decisions. 10,11 When considering metabolic syndrome features, blood pressure is more loosely associated than other constituents 11,12 and also tends to present a weaker association with CRP. However, as CRP has been associated with the development of hypertension, it is possible to consider it an inflammatory disorder. 13 High-sensitivity (hs) assays made it possible to investigate the function of low-grade inflammation in the occurrence of cardiovascular disease at normal plasma C-reactive protein (CRP) range Although the mechanisms underlying the described relations remain poorly understood, CRP has been identified as a strong independent predictor of cardiovascular events in healthy individuals 7,17,18 and in diabetic men, as well as a predictor of adverse outcomes in patients sustaining an acute coronary syndrome In a representative sample of urban adults, we evaluated the association between hs-crp and metabolic syndrome, taking into account the type and the number of syndrome-related components. Participants and methods As part of an ongoing health and nutrition survey, 23 residents in Porto, Portugal, were selected using random digit dialing. In every identified household, residents were characterized according to age and sex. One adult was selected by simple random sampling and was invited to visit the Department of Hygiene and Epidemiology at the University of Porto Medical School for an interview and examination. If there was a refusal, replacement was not allowed. The participation rate was 70%. 24 The local institutional ethics committee approved the study and all participants gave written informed consent. Trained interviewers collected information using a structured questionnaire. Data were obtained on social, demographic, personal and family medical history, as well as on behavioral characteristics comprising of diet, physical activity, smoking and alcohol intake. The Mini-Mental State Examination 25 was used for the evaluation of cognitive impairments in individuals aged over 64 y. In all, 23 interviewees who scored less than 24 were considered unable to provide reliable information. Data on alcohol, smoking and physical activity were not considered for those participants. Participants who engaged in any leisure time physical activity, performed on a repeated basis and for at least 30 min a week, were considered to undertake regular physical exercise. Anthropometrics were obtained by registered nutritionists, with the participant in light clothing, no footwear and after 12 h fasting. Body weight was measured to the nearest 0.1 kg using a digital scale, and height was measured to the nearest centimeter, in the standing position, using a wall stadiometer. Waist and hip circumference were measured to the nearest centimeter with a flexible and nondistendable tape, avoiding exertion of pressure on the tissues and with the subject standing. The waist circumference was measured midway between the lower limit of the rib cage and the iliac crest. The hip circumference was measured as the maximal circumference over the femoral trochanters. Physicians measured blood pressure on a single occasion using the American Heart Association recommendations. 26 A standard mercury sphygmomanometer with the cuff on the right upper arm was used. Two blood pressure readings were taken with the participant seated, resting for 10 min, and the mean of the two readings was calculated. Blood was sampled after a 12-h overnight fast and it was the first procedure undertaken after arriving at the Department. hs-crp levels were determined by means of particle-enhanced immunonephelometry using a BNt II nephelometer (Dade Bhering). Glucose, cholesterol (total, high-density lipoprotein (HDL), low-density lipoprotein) and triglycerides were measured using standard enzymatic methods. Metabolic syndrome was defined according to the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (ATPIII). 27 It was considered present when at least three of the following characteristics were detected: waist circumference 4102 cm in men and 488 cm in women; triglycerides Z150 mg/dl; HDL cholesterol o40 mg/dl in men and o50 mg/dl in women; blood pressure Z130/85 mmhg; and fasting glucose Z110 mg/dl. For the purpose of this study, we evaluated 1022 participants, including the 23 participants, with no data for smoking, alcohol intake and physical activity. In the analysis, we excluded 65 (6.4%) participants in whom CRP levels were above 10 mg/l, which might indicate other clinically relevant inflammatory conditions. 16 The remaining 957 subjects were comprised of 599 women (mean age y) and 358 men ( y old). Statistical analysis Data were analyzed using SPSS, release Proportions were compared using the w 2 -test. As CRP distribution was highly skewed, a natural logarithmic transformation was performed, and the geometric mean and the respective 95% confidence intervals (95% CI) were calculated. All mean values were adjusted for sex, age, smoking status (current, former or never smoker) and alcohol consumption (current, former or never drinker). Statistical significance for a trend was assessed using linear regression. Results In our study sample, the prevalence of metabolic syndrome was higher in females (17.2%) than in males (16.0%, Po0.001). Females also presented a significantly higher crude 1453

3 1454 Table 1 Crude prevalence of metabolic syndrome and mean CRP Table 2 Mean adjusted values of CRP n CRP geometric mean (95% CI) Metabolic syndrome (%) n CRP mean (95% CI) a P-value w Gender* Male ( ) 16.0 Female ( ) 17.2 Age (y)* ( ) ( ) ( ) ( ) ( ) 30.5 Z ( ) 19.2 Education (y)* r ( ) ( ) 13.4 Z ( ) 10.6 Smoking a Current ( ) 13.3 Never ( ) 18.5 Former ( ) 15.5 Alcohol consumption a Current ( ) 17.0 Never ( ) 11.7 Former ( ) 25.0 Regular physical exercise a Yes ( ) 14.2 No ( ) 18.1 *Po0.05 for the comparison of CRP geometric mean values across data. a No information on behavioral characteristics was collected for 23 participants due to low Mini-Mental State Examination scores. mean CRP level. Table 1 summarizes the crude prevalence of metabolic syndrome and the crude mean plasma CRP concentrations according to participants demographic and behavioral characteristics. Older subjects, those less educated, nonsmokers, former alcohol drinkers and those reporting no regular practice of exercise presented a higher prevalence of metabolic syndrome and higher levels of CRP. CRP mean levels, adjusted for sex, age, alcohol consumption and smoking status, are presented in Table 2 according to each individual feature of metabolic syndrome. Significantly higher mean CRP levels were found in subjects with central obesity (2.45 vs 1.24 mg/l, Po0.001), hypertriglyceridemia (2.17 vs 1.32 mg/l, Po0.001), high fasting glucose (1.96 vs 1.46 mg/l, P ¼ 0.032) and high blood pressure (1.76 vs 1.12 mg/l, Po0.001). Also, participants with low HDL cholesterol presented higher levels of CRP (1.64 vs 1.45 mg/l, P ¼ 0.190), although these differences did not reach statistical significance. Participants with metabolic syndrome, defined as an aggregate of any three or more of these features, presented with significantly higher adjusted mean levels of CRP (2.34 vs 1.36 mg/l, Po0.001). An increasing number of abnormal metabolic syndrome features was associated with an increase in CRP mean levels from 0.97 to 3.18 mg/l (Table 2). Waist circumference 4102 cm in men and 88 cm in women r102 cm in men and 88 cm in women ( ) o ( ) Triglycerides (mg/dl) Z ( ) o0.001 o ( ) HDL cholesterol o40 mg/dl in men and 50 mg/dl in women Z40 mg/dl in men and 50 mg/dl in women ( ) ( ) Blood pressure (mmhg) Z130/ ( ) o0.001 o130/ ( ) Fasting glucose (mg/dl) Z ( ) o ( ) Number of features ( ) o0.001** ( ) ( ) ( ) ( ) ( ) Metabolic syndrome (Z3 features) Yes ( ) o0.001 No ( ) a Geometric mean adjusted for sex, age, alcohol consumption and smoking status. w Difference of the mean. **P for trend. In Table 3 the mean CRP levels, adjusted for sex, age, alcohol consumption and smoking status, of the participants with normal levels for all five constitutive variables of metabolic syndrome, are compared with the mean CRP levels of those presenting one or more abnormal value. Those only presenting high blood pressure (1.25 vs 0.97 mg/l) or central obesity (1.64 vs 0.97 mg/l) did not have significantly different CRP levels compared to the reference group. However, when these two major cardiovascular risk factors were both present, the mean levels of CRP increased twofold, from 0.97 mg/l (reference) to 2.28 mg/l. The presence of an additional abnormal metabolic syndrome feature had no apparent significant effect on CRP. Discussion Recent studies provide evidence that inflammation might play a role in the occurrence of cardiovascular disease, 9,22,28 with inflammatory markers being regarded as indicators of atherothrombotic disease. 29,30 CRP is released by the liver

4 Table 3 Geometric mean of CRP levels 1455 CRP levels Mean (95% CI) a None (n ¼ 210) 0.97 ( ) Central obesity, only (n ¼ 23) 1.64 ( ) High blood pressure, only (n ¼ 226) 1.25 ( ) Central obesity+high blood pressure (n ¼ 104) 2.28 ( ) Central obesity+high blood pressure+high fasting glucose (n ¼ 8) 2.14 ( ) Central obesity+high blood pressure+low HDL cholesterol (n ¼ 20) 2.27 ( ) Central obesity+high blood pressure+high triglycerides (n ¼ 37) 2.70 ( ) a Geometric mean adjusted for sex, age, alcohol consumption and smoking status. following stimulation by interleukin 6, and is also locally produced in atheromatous lesions. 31 Although we relied on a single measurement of CRP, this is not expected to affect our results, as CRP levels have been shown to be stable with little or no diurnal variation, 15,32 making CRP the most commonly used and best standardized inflammatory marker of cardiovascular and metabolic disorders. 11,16,33 In previous studies, positive correlations were found between levels of CRP and glucose, triglycerides and body mass index, and negative correlations were found with HDL cholesterol. 6,7,8,10 A linear increase in CRP with an increasing number of abnormal metabolic features was also observed in previous studies. 2,7,10 Although these results were interpreted as favoring the hypothesis that CRP participates in the development and progression of atherosclerosis, 2,9,34 it is also possible to view higher CRP just as the consequence of disease severity without playing any etiologic role. In our sample, we found a higher mean concentration of CRP in participants with metabolic syndrome, and a significant positive linear trend with the number of abnormal features. Abnormal levels of any of the five metabolic syndrome components were associated with significantly higher mean CRP concentrations independent of sex, age, alcohol consumption and smoking status. As previously described in our population, 35 high blood pressure and central obesity are the two most prevalent features of metabolic syndrome. Results presented in Table 3 show that high blood pressure in itself was not significantly associated with an increased CRP level. On the other hand, the single presence of central obesity significantly increased CRP, as described previously. 8,9,36 In addition, when these two features of metabolic syndrome were present, a greater than two-fold increase in CRP occurred. Furthermore, adding other individual features resulted in no significant CRP increase, suggesting that central obesity and high blood pressure are the most important factors associated with inflammation. It is possible, that the clustering of cardiovascular risk factors, typically encountered in subjects with metabolic syndrome, might lead to cardiovascular disease and to elevated CRP, solely as the result of pre-existing atherosclerosis. It is now well recognized that atherosclerosis starts early in life; 37 therefore, it is likely to prevail in the healthy middle-aged population, particularly in those with features of metabolic syndrome. There is also evidence that cigarette smoking increases CRP, 17 therefore possibly acting as a confounder. Regarding alcohol consumption, recent studies suggest that moderate drinkers have lower CRP concentrations when compared to nondrinkers or heavy drinkers. 38,39 We adjusted the results for smoking status and alcohol consumption because of those known associations with inflammation, even without finding a statistically significant contribution in our sample. However, the point estimates were not affected by adjustment. As previously shown, treatment of several components of metabolic syndrome (obesity, dyslipidemia, hypertension, insulin resistance) may have beneficial effects in preventing cardiovascular disease. 17 Therefore, if subclinical inflammation is indeed another aspect of metabolic syndrome, antiinflammatory treatment could be sought. Additionally, the advantages of nonpharmacological interventions, such as weight reduction or regular practice of exercise, may be translated into lower CRP levels due to reduced inflammation, thus providing benefits that go beyond solely decreasing glucose levels or obesity prevalence. 40 Acknowledgements This study was funded by the Fundac-ão para a Ciência e Tecnologia, Praxis 2/2.1/SAU/1332/95, POCTI/ESP/35767/99 and POCTI/ESP/42361/2001. References 1 Alberti K, Zimmet P. Definition, diagnosis and classification of diabetes mellitus and its complications. Part I: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabetes Med 1998; 15: Festa A, D Agostino R, Howard G, Mykkänen L, Tracy R, Haffner S. Chronic subclinical inflammation as part of the insulin resistance syndrome. The Insulin Resistance Atherosclerosis Study (IRAS). Circulation 2000; 102: Ford E. 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