Metabolic Syndrome and C-reactive Protein among Cardiology Patients

Archives of Medical Research 38 (2007) 783e788

ORIGINAL ARTICLE

Metabolic Syndrome and C-reactive Protein among Cardiology Patients Gulnara Chapidze,a Nino Dolidze,a Daniel A. Enquobahrie,b,c,d Simon Kapanadze,a Nino Latsabidze,a and Michelle A. Williamsb,d a

Emergency Cardiology Center, Tbilisi, Republic of Georgia Multidisciplinary International Research Training Program, cCardiovascular Health Research Unit, dDepartment of Epidemiology, University of Washington School of Public Health and Community Medicine, Seattle, Washington

b

Received for publication January 3, 2007; accepted March 14, 2007 (ARCMED-D-07-00007).

Background. Associations between inflammation, metabolic syndrome (MetS), and cardiovascular disease have been reported. Limited information, however, is available on the prevalence of MetS and its relation to inflammation among Georgian cardiology patients. We investigated MetS components (elevated blood pressure, abdominal obesity, elevated triglyceride concentrations, decreased HDL-cholesterol concentrations, and elevated fasting glucose) and their relationships with C-reactive protein (CRP) concentrations in this population. Methods. A total of 167 patients (mean age 53.1 years, 54% male) who attended an Emergency Cardiology Center in Tbilisi, Republic of Georgia were enrolled in this cross-sectional study. In-person interviews and clinical exams, as well as laboratory studies, were conducted to characterize MetS (using the ATP III criteria) and cardiac conditions in the study population. CRP concentrations were determined using standardized immunoassays. Results. Overall prevalence of MetS was 40.7%. Patients with coronary heart disease (CHD) had higher CRP concentrations compared with non-CHD patients. A linear relationship between increase in number of MetS components and CRP concentrations was observed among females ( p value for linear trend !0.05), but not males. Further, among females, all components of MetS except HDL-C concentrations were correlated with CRP concentrations after adjustment for age and body mass index (all p values !0.05). However, among males, only abdominal obesity was significantly correlated with CRP. Conclusions. MetS is prevalent among Georgian cardiology patients. CRP concentrations are positively associated with MetS. Further prospective studies are required to determine whether combining MetS and CRP data may have utility in the assessment of risk for developing future cardiovascular events in both males and females. Ó 2007 IMSS. Published by Elsevier Inc. Key Words: Metabolic syndrome, C-reactive protein, Cardiovascular disease, Inflammation.

Introduction Metabolic syndrome (MetS) has generated a great deal of interest during the past few years. It consists of several interrelated risk factors of metabolic origin that appear to

Address reprint requests to: Nino Dolidze, Emergency Cardiology Center, 4 Lubliana Street, Digomi, 0159 Tbilisi, Republic of Georgia 995; E-mail: [email protected]

directly promote the development of atherosclerotic cardiovascular diseases (1). The relation between MetS and inflammation has been previously investigated (2e7). Creactive protein (CRP), an easily measured inflammatory biomarker, has been proven to be a strong, independent predictor of incident cardiovascular diseases (8e11). Several studies have demonstrated relationships between CRP and individual components of MetS in subjects with or without coronary atherosclerosis. Notably, most studies stressed the

0188-4409/07 $esee front matter. Copyright Ó 2007 IMSS. Published by Elsevier Inc. doi: 10.1016/j.arcmed.2007.03.011

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importance of identifying individuals with MetS and elevated levels of CRP as those at particularly high risk of developing future cardiovascular events (2e7). Nontraditional risk factors for coronary atherosclerosis including elevated level of CRP have previously been investigated at the Emergency Cardiology Center, Tbilisi, Republic of Georgia (12e13). However, MetS and its association with elevated CRP concentrations have not been examined. The presence of these two potentially independent risk indicators together may further increase the risk for developing recurrent cardiovascular events in our population. This may necessitate more aggressive treatment of such a high-risk category of patients. Hence, we sought to evaluate the prevalence of MetS and its components, as well as the potential cross-sectional relationships between MetS and CRP among cardiology patients attending our center.

Subjects and Methods Study Setting This cross-sectional study was conducted among 250 consecutive patients who either visited or were admitted to the intensive care unit, cardiology, cardiosurgical, and secondary coronary prevention departments of the Emergency Cardiology Center in Tbilisi, Georgia from May 2005 to November 2005. The study was approved by the Ethics Committee of the Center. Each patient provided written informed consent prior to enrollment. Data Collection Center cardiologists took a detailed clinical history and examined each patient at the time of visit or admission. A preventive cardiologist interviewed each patient and completed questionnaires with information concerning sociodemographic characteristics and physical and anthropometric measurements. All participants provided blood specimens for investigation after the interview and physical examination. Patients with CRP concentrations O10 mg/L (57 males and 24 females) were excluded to minimize the effect of any acute disease process. Two patients were excluded from further study because their blood samples were hemolyzed. A total of 167 patients (90 males and 77 females) remained for analysis. Coronary heart disease (CHD) was defined as the presence of a history of myocardial infarction, myocardial revascularization, coronary angiography, or typical chest pain with a positive stress test. Cardiomyopathy and valvular heart disease were diagnosed by echocardiography and patient’s clinical status. Cardiac syndrome X was diagnosed on the basis of chest pain, a positive stress test and normal coronary vessels on coronary angiograms. Hypertension was defined as an average systolic blood pressure $140 mmHg or diastolic blood pressure $90 mmHg on three separate occasions or the

history of use of antihypertensive medications. Diagnosis of MetS was established when three or more of the following attributes were present: (a) blood pressure $135/85 mmHg; (b) abdominal obesity (waist circumference): men O102 cm, women O88 cm; (c) high-density lipoprotein cholesterol (HDL-C): men !40 mg/dL; women 50 mg/ dL; (d) triglycerides (TGs) $150 mg/dL; (e) fasting glucose $110 mg /dL (14). Waist circumference was measured at the center point between the lower border of the rib cage and the upper border of the iliac crest to the nearest 0.1 cm and was used as an indicator of abdominal obesity. Laboratory Analysis Fasting blood samples were obtained from all 167 patients. Total cholesterol (TC), HDL-C, and TGs were measured enzymatically using standardized assays (Humana Kits; Humana, Wiesbaden, Germany). Low-density lipoprotein cholesterol (LDL-C) was calculated using the Friedewald equation (15). High-sensitive CRP measurements were determined using an ELISA kit (IBL, Hamburg, Germany). Fasting glucose was measured on capillary blood using Finetest (Infopia Co. Ltd, Anyang, South Korea). Statistical Analysis In the descriptive analysis, continuous variables were expressed as mean  SD, whereas categorical variables were expressed as number (percentages). All continuous variables were assessed for skewness. CRP, which was skewed, was log-transformed to obtain an approximate normal distribution. Significant differences in continuous variables among groups (classified by type of heart disease) were assessed using Student’s t-test. Differences in categorical variables among groups were assessed using Pearson chisquare tests. Linear test for trend evaluated incremental associations of number of MetS components with CRP concentrations. Partial CRP and MetS components pairwise correlations (adjusted for age, body mass index, and current smoking) were computed to assess independent associations. All statistical analyses were conducted using STATA version 8.2 (College Station, TX).

Results Sociodemographic and metabolic characteristics of the study population are summarized in Table 1. The mean age of patients was 53.1  13.4 years (range, 15e87 years). Approximately 54% (n 5 90) of participants were male. Most patients (54.4%) had a history of smoking. Among males, 86.7% were smokers, whereas among females only 16.8% were smokers. Overall, mean systolic blood pressure was high and almost identical between males and females. Males had higher abdominal obesity (waist circumference measure) as compared with their female counterparts. Male

Metabolic Syndrome and C-reactive Protein

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Table 1. Characteristics of study population according to metabolic syndrome (MetS) status (Tbilisi, Republic of Georgia) Male Characteristics Age (years)* Education ($ secondary) Married/living together Current smokers (in last month) Smokers (O5 packs in lifetime) Mean systolic blood pressure (mmHg)* Mean diastolic blood pressure (mmHg)* Waist circumference (cm)* Fasting plasma glucose (mg/dL)* Plasma lipids (mg/dL)* Total cholesterol Low-density lipoprotein cholesterol High-density lipoprotein cholesterol Triglycerides C-reactive protein (mg/L)* Metabolic syndrome (MetS)

Female

Total

n 5 90

% (SD)

n 5 77

% (SD)

n 5 167

% (SD)

53.8 62 79 23 78 151.7 91.0 109.1 112.8

11.9 68.9 87.8 26.1 86.7 35.2 21.0 14.9 32.3

52.2 57 45 7 13 150.6 87.0 92.4 102.9

15.0 74.0 58.4 9.7 16.8 40.0 22.9 13.4 28.5

53.1 119 124 30 91 151.2 89.1 101.4 108.2

13.4 71.2 74.3 18.9 54.4 37.3 21.9 16.5 30.9

219.3 141.2 43.8 176.8 4.0 39

52.8 46.1 9.0 96.4 2.8 43.4

232.3 147.7 54.3 150.9 3.7 29

56.2 48.1 11.0 76.0 3.0 37.7

225.3 144.2 48.6 164.7 3.9 68

54.7 47.0 11.2 88.2 2.9 40.7

*Mean  SD, otherwise number (%).

patients tended to have higher fasting glucose values than females. Overall, mean levels of TC, LDL-C, and TGs were elevated in both males and females. However, HDL-C concentrations were within normal limits in both males and females, although concentrations tended to be higher in female patients. Mean concentrations of CRP were similar between males and females. MetS was present in 40.7% of patients overall with a higher frequency among male (43.4%) vs. female (37.7%) patients. Most patients (n 5 98) had CHD (Table 2). Of these, 21 had unstable angina, whereas 77 had stable angina. Among CHD patients, 51 had a history of previous myocardial infarction and/or had undergone myocardial revascularization. Other cardiac pathologies were as follows: cardiomyopathy (n 5 7), cardiac syndrome X (n 5 4), and valvular heart disease (n 5 3). A total of 55 patients were identified as being hypertensive. Generally, higher mean CRP concentrations were observed among CHD patients compared with non-CHD patients. Patients with unstable angina had the highest mean CRP concentration (6.42  3.66 mg/L), which was also significantly different when compared with patients diagnosed with stable angina ( p !0.05). Patients with recurrent coronary events had higher, though statistically insignificant, mean CRP concentrations when compared with patients admitted to the hospital following first coronary episodes. Overall, MetS was more common among patients with CHD as compared with those patients without CHD. Distributions of MetS components among the study population are shown in Figure 1. Elevated blood pressure was the most frequent feature of MetS in the total population (64%) as well as in men and women separately (65.6% and 62.3%, respectively). All MetS components appeared to be more common among males than females. Figure 2

displays mean CRP concentrations among men and women according to the presence of 0, $1, $2, $3, $4, and 5 components of MetS. Among females, mean CRP concentrations increased as the number of MetS components increased ( p value for linear trend 5 0.025). However, in males, this linear trend of association was not observed ( p value for linear trend 5 0.528). Correlations between MetS components and CRP levels are presented in Table 3. Among female participants, CRP

Table 2. Plasma C-reactive protein concentrations and frequency of prevalence of metabolic syndrome (MetS) according to patients’ diagnostic status (Tbilisi, Republic of Georgia) Metabolic syndrome (%) (n 5 68) Cardiovascular diseases

C-reactive protein (mg/L) Number

CHD (n 5 98) Unstable angina (n 5 21) Stable angina (n 5 77) First-ever coronary events (n 5 47) Recurrent coronary events (n 5 51) Non-CHD (n 5 69) Cardiomyopathy (n 5 7) Cardiac syndrome X (n 5 4) Valvular heart disease (n 5 3) Hypertension (n 5 55)

5.26 6.42 4.11 4.54

   

47 14 33 22

48.0* 66.7 42.9 46.8

5.98  3.57

26

51.0

   

1.85 2.12 1.68 2.81

21 6 3 0

30.4 85.7 75.0 0.0

2.38  2.07

12

21.8

2.71 3.09 2.25 3.12

2.82* 3.66x 2.73 2.91

(%)

*p value statistically significant (!0.05) comparing coronary heart disease (CHD) to non-coronary heart disease (non-CHD). x p value statistically significant (!0.05) comparing unstable angina to stable angina.

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Metabolic syndrome components 70 Male 60

Female All

50

(%)

40 30 20 10 0

High blood pressure

Abdominal obesity

Elevated triglycerides

Decreased HDL-C

Fasting hyperglycemia

Figure 1. Prevalence of each component of metabolic syndrome by gender among study patients (Tbilisi, Republic of Georgia).

concentrations were positively correlated with MetS components except HDL-C ( p values !0.05). HDL-C was inversely correlated with CRP concentrations, although the correlations were not statistically significant. Among male patients, the only statistically significant correlation was the positive correlation between waist circumference and CRP concentrations. Overall, compared to other MetS components, abdominal obesity (as measured using waist circumference) was highly correlated to CRP concentrations in both males and females (partial correlation coefficients; 0.3377 and 0.4258, respectively).

Discussion Our current study demonstrated a high prevalence of MetS (40.7%) among cardiology patients. Notably, only a small minority of participants was free of all five components

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Table 3. Pearson partial correlation coefficients of C-reactive protein with individual components of metabolic syndrome (MetS) (Tbilisi, Republic of Georgia)

Male Female

Characteristics*

5

Mean CRP

of MetS (13.2%). The prevalence of MetS was higher among patients with CHD (48.0%) as compared with patients without CHD (30.4%). Overall, CRP concentrations were correlated with several MetS components. For instance, abdominal obesity was highly correlated with CRP concentrations among both male and female patients. Generally, our study has shown a much higher prevalence of MetS than previously shown in other crosssectional surveys (4,5,16,17). This may be due to the fact that, in our study, most subjects had established CHD, whereas many prior studies were population based and included higher proportions of healthy individuals. In studies conducted among patients with known CHD (2,14,16e19), similar to our study, the prevalence of MetS was high. In some previous cross-sectional studies, CRP concentrations were positively correlated with central adiposity, systolic

4 3 2 1 0 4+ 0 1+ 2+ 3+ (M=71, (M=39, (M=25, (M=8, (M=76, F=44) F=29) F=17) F=14) F=59) Number of metabolic syndrome components*

5 (M=4, F=4)

Figure 2. Mean C-reactive protein (CRP) concentrations (mg/L) according to number of components of metabolic syndrome by gender among cardiology patients (Tbilisi, Republic of Georgia).

Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Waist circumference (cm) High-density lipoprotein cholesterol (mg/dL) Triglycerides (mg/dL) Fasting plasma glucose (mg/dL)

Male correlation

Female correlation

Total correlation

0.1207

0.3920b

0.2679b

0.1264

0.3610a

0.2577b

0.4903b 0.1523

0.4258b 0.1236

0.4074b 0.3532a

0.2707b 0.2564b

0.3377a 0.0039 0.1467 0.1511

*Partial pairwise correlation between log (CRP) and each metabolic syndrome (MetS) component adjusted for age, BMI, and current smoking; a p !0.01. b p !0.001.

Metabolic Syndrome and C-reactive Protein

and diastolic elevated blood pressure, triglycerides, and fasting glucose concentrations (4,20). CRP concentrations have been inversely correlated with HDL-C concentrations (4,20). Hence, CRP is associated with all key measured components of the ATP III diagnostic criteria of MetS (4,20). On the basis of several observations, Ridker and colleagues have suggested that CRP should be added as a clinical criterion for MetS (21). Our results, indicating association between CHD, MetS, and CRP, are consistent with the proposal put forth by Ridker and colleagues (21). Notably, patients with CHD had higher mean CRP concentrations than those patients without CHD, and a similar pattern was observed in frequency of MetS. Inflammation is known to play an important role in atherosclerosis (4,20). Elevated CRP is increasingly being recognized as an independent risk factor for CHD, as it is a marker and/or mediator of the inflammatory atherosclerotic process (11,22e24). Several studies of CHD and CRP have shown CRP to be positively associated with CHD incidence (10,25,26). CRP as an acute-phase reactant markedly increases during acute myocardial infarction (8,26) and elevated levels of CRP predict recurrent coronary events in patients with unstable angina even after successful myocardial revascularization (27). These observations are in agreement with our findings. Abdominal obesity was strongly related to CRP concentrations independent of gender. Among all five components of MetS, abdominal obesity was the only one that showed significant positive correlations with CRP in the total sample as well as in both genders separately. Further, the magnitudes of correlations were the highest between abdominal obesity and CRP compared to CRP and other MetS variables. This is in accordance with findings of the Oxford and Collaborators Health Check Study (25), in which a significant association of CRP with obesity was demonstrated, but no associations were found between CRP and other features of MetS. In the Bogalusa Heart Study (3), CRP was better correlated with obesity measures than with other MetS variables. It can be hypothesized that abdominal obesity may be a mediator of excess CRP seen in MetS. As a major source of pro-inflammatory cytokines, adipose tissue produces tumor necrosis factor a and interleukin 6, which are considered as the main stimulators of CRP synthesis in the liver (28,29). In support of this thesis, investigations of the central role for abdominal obesity in the pathogenesis of insulin resistance, the underlying risk factor for MetS (1), have shown that relationship between inflammatory markers including CRP and the risk of developing diabetes is attenuated after adjustment for obesity (30,31). Overall, CRP concentrations were strongly related to individual components of the ATP III MetS components except for HDL-C, which showed insignificant inverse relationships to CRP. This may be explained by the fact that most study participants had normal HDL-C concentrations

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and there was a limited HDL-C variation among the study population. We found that CRP values clearly increased with increase in the number of MetS components among females and the highest mean CRP level was observed among participants with all five components. However, this was not observed among males. Such gender-specific difference between CRP and MetS components was also demonstrated in the Mexico City Diabetes Study in which CRP levels were more strongly associated with insulin resistance and features of MetS among females (7). Three more previous reports showed that in cross-sectional analysis, markers of inflammation including CRP were more strongly related to insulin resistance and ATP III MetS among females than males (5,32,33). It is possible that endogenous estrogen in females is responsible for such a gender difference. However, not all studies reported the same results. In the Bogalusa Heart Study conducted among biracial adults, CRP was significantly correlated with all MetS variables in men as well as in white women. In addition, mean CRP levels increased with increasing number of risk factors in both genders (3). We acknowledge a number of limitations of our study. First, the final sample size of our study was relatively small. A larger study is needed to corroborate our findings. Second, previous treatment (both medical and surgical) was not taken into account. More specifically, some antiatherogenic preparations (e.g., statins) administered to patients that may affect both CRP and lipid profile parameters were not taken into account. Finally, the current study is both observational and cross-sectional in nature and, therefore, cannot prove but only suggest causality of described relationships. Prospective studies conducted among Georgian patients are needed to address these important limitations. In summary, a high prevalence of MetS was observed among cardiology patients, particularly among those with clinical manifestation of coronary atherosclerosis (i.e., CHD). Elevated CRP concentrations were present with the presence of acute coronary syndrome. Among all MetS components, abdominal obesity was most strongly correlated with CRP concentrations. Although all measures of secondary prevention should be instituted in all patients with CHD who are known to be at high risk for recurrent cardiovascular events, the presence of MetS and elevated CRP may identify particularly high-risk group of patients, which may benefit from more aggressive treatment. Further prospective studies are required to determine whether including elevated CRP as a criterion for MetS will have utility in assessing the risk for developing recurrent cardiovascular events in cardiology patients.

Acknowledgments The authors wish to thank the staff of the Emergency Cardiology Center, Tbilisi, Republic of Georgia, for their assistance in data collection and Mr. Bizu Gelaye for his skillful technical assistance.

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