Abstract
Objective: metabolic syndrome (MetS) is known to be associated with an increased risk for cerebro- as well as cardio-vascular disease. Prediction of carotid atherosclerosis by components of MetS, serum C-reactive protein, aging and related factors was conducted for Japanese inhabitants. Methods: A total of 887 subjects (761 males, 126 females) were included in the present study. Early atherosclerosis was assessed by measurement of the intima-media thickness of the common carotid arteries. Results: The carotid arterial intima-media thickness on both the right and left sides significantly increased as the number of components of MetS increased. The maximum intima-media thickness values in the right (left) carotid arteries in the male and female subjects who fulfilled the criteria for MetS were 0.65 ± 0.18 (0.66 ± 0.17) mm and 0.58 ± 0.12 (0.59 ± 0.11) mm, respectively. After adjustment for several factors, the intima-media thickness related significantly with aging, some components of MetS and serum C-reactive protein by multiple regression analysis. β-coefficient of age was largest, presenting 0.457 in right side and 0.479 in left side. Conclusions: Aging, metabolic components and serum C-reactive protein are independent predictors of intima-media thickness in subjects.
Introduction
Metabolic syndrome (MetS) is a known risk factor for cardio- and cerebro-vascular disease [1,2], especially for men [3,4]. The definition of MetS was first proposed by the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III [5], and slight modifications of this definition are used in different nations and areas of clinical practice and in various epidemiological studies [6,7].
The maximum intima-media thickness (IMT) of the common carotid artery (CCA), as measured by carotid artery ultrasound, has been widely used as a marker of early atherosclerosis [8–10] and has been recognized as a predictor of stroke and coronary events [11,12]. These associations were confirmed in a meta-analysis conducted by Lorenz et al. [13]. Furthermore, an elevated serum high-sensitive C-reactive protein (CRP) level has been demonstrated to be associated with the low-grade inflammation underlying the development of atherosclerosis [14,15]. Furthermore, the serum CRP has been shown to increase linearly with the carotid IMT [16,17], although conflicting findings have also been reported [18,19]. Endorsing the demonstrated associations, increased serum CRP has been found to be associated with MetS, and been shown to be a predictor of increased carotid IMT and related pathological changes [20,21]. Population-based studies have demonstrated that both CRP and MetS are independent risk factors for cardiovascular disease [22]. However, the combined use of MetS components and the serum CRP as predictors of subclinical atherosclerosis has not yet been well established.
In this community-based study, the authors investigated the role of CRP, components of MetS, and aging in the early changes of the carotid arterial wall, as assessed by the IMT of the CCA.
Methods
Study subjects
The 944 subjects consisted of 804 males (aged 28–87 years) and 144 females (32–78 years) who were inhabitants or workers undergoing intensive health checkups. Subjects with coronary heart disease (22 males and 8 females) and/or cerebrovascular disease (13 males and 2 females) were excluded from this study. We also excluded subjects (n = 15) with serum high-sensitive CRP levels ≥10 mg/L, to rule out acute inflammatory disorders. In contrast, subjects who were receiving treatment for hypertension, diabetes mellitus and/or dyslipidemia were included in this study. Thus, the study population included 34 patients who were receiving medication for diabetes mellitus (32 men, 2 women), 138 subjects were receiving medication for hypertension (121 men, 17 women), and 93 subjects were receiving medication for dyslipidemia (79 men, 14 women). Finally, 887 subjects (761 men, 126 women) were included in the database. At baseline, all participants were subjected to a screening protocol, including a questionnaire survey on personal health practices, physical examination, and determination of anthropometric and biochemical parameters, including carotid artery ultrasound. Informed consent was obtained from all the participants. This study was with the approval of the Institutional Review Board at Ota General Hospital, Gunma Prefecture, Japan (July 17, 2010).
Health examination data
Venous blood was collected after the patients had fasted overnight. Serum levels of triglycerides, high-density lipoprotein cholesterol (HDLC) and CRP, and also the fasting blood glucose were determined (AU2700, Olympus Co. Ltd., Japan). The lower detection limit of the serum CRP determination was 0.1 mg/L, and the intra-assay coefficient of variation was under 5%. Values of serum CRP under the detection limit were recorded as 0.05 mg/L. The blood pressure was measured twice in all the participants (Nippon COLIN BP-103i, Japan) and the lower values were adopted for the analysis. Waist circumference was measured at the level midway between the iliac crest and the 12th rib.
Definitions of lifestyle-related variables and MetS
Self-reported Information was collected on lifestyle-related variables. Smoking habit was categorized as current smoking or no smoking. Drinking habit was categorized as daily drinking or no daily drinking (including no drinking). Physical activity was categorized as habitual exercise presence of the exercise habit (≥ 2 times per week for more than 1 year) or absence of exercise habit.
In accordance with the criteria of Joint Scientific Statement [23], MetS was diagnosed when 3 or more of the following criteria were fulfilled: fasting blood glucose ≥ 100 mg/dL (5.6 mmol/L) or receiving treatment for diabetes mellitus, blood pressure ≥ 130/85 mm Hg (either value) or receiving antihypertensive drug treatment, plasma triglycerides ≥ 150 mg/dL (1.7 mmol/L) or receiving treatment for dyslipidemia, plasma HDLC <40 mg/dL (1.0 mmol/L) in men and <50 mg/dL (1.3 mmol/L)in women, and waist circumference ≥85 cm in men and ≥80 cm in women.
Ultrasonography
At baseline, the presence of carotid atherosclerosis was determined by B-mode carotid ultrasound (Aplio SSA-700A, TOSHIBA co. Ltd., Japan). Measurements were performed and interpreted by experienced ultrasound operators who were blinded to all clinical and laboratory characteristics of the patients. The protocol included multiple longitudinal and transverse imaging of the CCA (8 mm proximal to the bifurcation) at the height of the flow divider, and within the proximal 8 mm of the internal carotid artery. The end-diastolic IMT was measured as the distance from the leading edge of the first bright line on the far wall to the leading edge of the second bright line. The maximal IMT values of the right and left CCAs were used for the statistical analyses.
Statistical analysis
Analyses were performed using the SPSS 16.0 statistical package (SPSS Inc., Japan). The results are expressed as means and SDs, except for parameters with a skewed distribution to the left. Multiple regression analysis was performed to analyze the association of the maximum IMT with each component of MetS and the serum CRP, controlling for sex and age.
Results
The characteristics of the study participants are presented in Tables I andII. MetS was present in 213 of the 761 men (28.0%) and 24 of the 126 women (19.0%). Significant differences (p < 0.05) were found between subjects with and without MetS (controls) in the distribution of the components of MetS, as well as in the age and serum uric acid and CRP levels. There was no significant difference in the prevalence of current smoking or daily drinking between the subjects with and without MetS. Among the men with MetS, 130 (17.1%) men had 3 components of MetS, 53 (7.0%) men had 4 components, and 30 (3.9%) men had all 5 components of MetS. The corresponding numbers (and percentages within parentheses) among the women with MetS were 14 (11.1%), 10 (7.9%) and 0 (0%).
Table I. Characteristics of subjects (mean and standard deviation) stratified by sex and the presence/absence of metabolic syndrome (MetS).
Table II. Characteristics of subjects (percentage) stratified by sex and the presence/absence of metabolic syndrome (MetS).
The distribution of the maximum IMT in the subjects is presented in Figure 1. Significantly higher maximum IMT values were observed in the subjects with MetS. Namely, the mean and standard deviation of the right/left maximum carotid IMT in the male subjects with MetS were 0.65 ± 0.18 and 0.66 ± 0.17 mm, and those in the male control subjects were 0.56 ± 0.14 and 0.57 ± 0.14 mm (p < 0.05). There were no such significant differences in the female subjects. The mean and standard deviation of the right/left maximum carotid IMT in the female subjects with MetS was 0.58 ± 0.12 and 0.59 ± 0.11 mm, and those in the female control subjects were 0.54 ± 0.12 and 0.55 ± 0.13 mm. In addition, both the right/left maximum IMT increased significantly as the number of MetS components increased in the male subjects (p < 0.05, Dunnett’s multiple comparison); the same trend was noted in the female subjects, although the result did not reach statistical significance (Figure 2). The association between the right and left maximum carotid IMT was strong even after controlling for sex and age, with a partial correlation coefficient of 0.627.
Published online:
04 February 2012Figure 1. Distribution of the maximum intima-media thickness of the common carotid artery.
![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/itam20/2012/itam20.v015.i01/13685538.2011.593656/20150509/images/medium/itam_a_593656_f0001_b.gif"})
Figure 1. Distribution of the maximum intima-media thickness of the common carotid artery.
Published online:
04 February 2012Figure 2. Means and standard deviations of the maximum intima-media thickness stratified by the number of components of metabolic syndrome. Dunnett’s multiple comparison revealed a significant difference in the male subjects when the group with no components of metabolic syndrome was set as a control group (* p < 0.05). The same trend was observed in the female subjects, although the difference did not reach statistical significance.
![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/itam20/2012/itam20.v015.i01/13685538.2011.593656/20150509/images/medium/itam_a_593656_f0002_b.gif"})
Figure 2. Means and standard deviations of the maximum intima-media thickness stratified by the number of components of metabolic syndrome. Dunnett’s multiple comparison revealed a significant difference in the male subjects when the group with no components of metabolic syndrome was set as a control group (* p < 0.05). The same trend was observed in the female subjects, although the difference did not reach statistical significance.
Using stepwise multiple regression analysis, factors influencing the maximum IMT were analyzed (Table III). Adjusted multiple regression coefficients to predict the maximum IMT of the right and left carotid arteries were 0.301 and 0.303, respectively. As common significant variables, the age, sex, waist circumference, hypertension, and Log10 (CRP) were selected as covariates to identify the predictors of the maximum IMT of the right and left carotid arteries. HDLC and smoking were selected as showing significant independent relationship to the maximum IMT of the right and left carotid arteries, respectively. The standardized coefficient of age was the most significantly predictive variable of the maximum IMT of both the right and left carotid arteries.
Table III. Multiple regression analysis to identify determinants of the right and left maximum intima-media thickness (IMT) by all components of metabolic syndrome, sex, age, serum uric acid and log-transformed serum C-reactive protein level.
Discussion
The authors assessed the combination of serum CRP, the components of MetS and aging for predicting early carotid atherosclerosis. Aging, an elevated level of the serum CRP and presence of some components of MetS significantly predicted the maximum IMT of the carotid artery. General population studies have shown the existence of an association between the serum CRP and the IMT of the carotid artery in women [18,19], and the results of a multivariate analysis in our cross-sectional study revealed the existence of an association of IMT with the presence of some metabolic components of MetS and the serum CRP in men. The NCEP-III criteria were selected for the diagnosis of MetS, although the waist circumference was modified for Asian people. In the past, associations between IMT of the carotid artery and cerebro- and cardiovascular diseases have been reported; however, no consensus had been established to suggest that IMT of the carotid artery could also be a surrogate marker of systemic vascular disease [13,24,25]. Our results here indicated that IMT of the carotid artery was significantly associated with both some components of MetS and a systemic inflammatory marker in male subjects. However, aging male was the highest risk population for predicting early carotid atherosclerosis.
Some reports have suggested that evaluation of carotid artery atherosclerosis by ultrasound can be used to differentiate between early and advanced atherosclerosis [26,27]. Increased IMT of the CCA has been shown to reflect the early changes in the arterial wall associated with dyslipidemia and hypertension [9,27]. On the other hand, plaque formation is likely to reflect advanced atherosclerosis [28]. As only the IMT of the CCA was used, with no evaluation of carotid plaques in this study, the authors want to conclude that the results are valid for the early stage atherosclerosis.
One study has suggested the existence of a significant association between IMT of the carotid artery IMT and the presence of MetS [29], although it has been shown that the presence of components of MetS other than hypertension does not increase the risk of carotid atherosclerosis [30]. In our study, hypertension as a component of MetS was shown by multivariate analysis to be significantly associated with increase of the carotid IMT, even after adjustment for the related factors.
With respect to MetS, it has been suggested that MetS has a strong association with early carotid atherosclerosis in postmenopausal women [31], explained by the lack of estrogen and higher insulin resistance [32]. Because of the limited sample size, the absence of any significant outcome in the female subjects in our study should be interpreted with caution. There are other limitations in this study. Among the several lifestyle factors, no smoking was significantly associated with lower value of left IMT by multiple regression analysis. There is also laterality (right-left difference) of HDLC on carotid atherosclerosis. There are significant associations between carotid atherosclerosis and smoking cessation or HDLC [33,34], concluding that smoking and HDLC were strong predictors of carotid atherosclerosis. The laterality of two variables on carotid atherosclerosis is difficult to be explained, and the authors want to conduct additional survey to make validation for these variables. At the same time, information on the medication of hypertension, diabetes mellitus and/or dyslipidemia should be asked.
The authors conclude that the presence of some MetS components and higher serum CRP exert significant impact on the development early carotid atherosclerosis, particularly in men. In other words, the serum CRP levels and some components of MetS can be considered as markers of early atherosclerosis, although no cause-effect relationship could be concluded in this cross-sectional study.
| Variables | Male subjects | Female subjects | ||
|---|---|---|---|---|
| MetS + n = 213 | MetS − n = 548 | MetS + n = 24 | MetS − n = 102 | |
| Age | 50.1, 9.1 | 46.9, 8.9 | 56.7, 8.4 | 50.7, 9.0 |
| FPG | 112.1, 28.9 | 97.3, 11.6 | 101.5, 12.6 | 93.3, 9.4 |
| WC | 91.2, 7.2 | 82.2, 7.8 | 90.5, 9.7 | 79.3, 8.1 |
| SBP | 129.3, 15.4 | 117.3, 14.1 | 124.0, 16.5 | 107.4, 13.3 |
| DBP | 77.1, 10.0 | 69.7, 10.0 | 72.4, 10.2 | 61.9, 9.1 |
| TG | 176.7, 1.70 | 99.9, 1.59 | 123.3, 1.63 | 75.0, 1.53 |
| HDLC | 49.5, 11.9 | 58.8, 13.0 | 56.4, 12.1 | 69.8, 13.7 |
| Uric acid | 6.3, 1.2 | 5.9, 1.1 | 5.0, 1.2 | 4.2, 1.0 |
| CRP | 0.67, 2.65 | 0.37, 2.87 | 0.54, 2.65 | 0.32, 3.00 |
| Right IMT | 0.65, 0.18 | 0.56, 0.14 | 0.58, 0.12 | 0.54, 0.12 |
| Left IMT | 0.66, 0.17 | 0.57, 0.14 | 0.59, 0.11 | 0.55, 0.13 |
SD, Standard deviation; FPG, Fasting Plasma glucose; WC, Waist circumference; SBP, Systolic blood pressure; DBP, Diastolic blood pressure; TG, Triglyceride; HDLC, High-density lipoprotein cholesterol; CRP, high-sensitive C-reactive protein; IMT, maximum intima-media thickness of common carotid artery. Geometric mean and geometric standard deviation was used for triglyceride and CRP. Mann–Whitney test was used for the analysis. There were significant differences in the mean values stratified by the existence of MetS except IMT in female subjects.
| Variables | Male subjects | Female subjects | ||
|---|---|---|---|---|
| MetS + n = 213 | MetS − n = 548 | MetS + n = 24 | MetS − n = 102 | |
| Smoking | 35.2% (n = 75) | 34.9% (n = 191) | 8.3% (n = 2) | 9.8% (n = 10) |
| Drinking | 45.1% (n = 96) | 40.7% (n = 223) | 12.5% (n = 3) | 12.7% (n = 13) |
| Exercise | 20.2% (n = 43) | 23.7% (n = 130) | 33.3% (n = 8) | 18.6% (n = 19) |
Fisher’s exact test was used for the analysis. There were no significant differences in the percentages stratified by the existence of MetS both in male and female subjects. Smoking, prevalence of current smoking; Drinking, prevalence of everyday drinking; Exercise, prevalence of habitual exercise with more than twice per week for more than one year.
| Dependent variable Independent variable | B | SE | βcoefficient | Significance |
|---|---|---|---|---|
| Right IMT (0.301) | ||||
| Age | 0.008 | <0.001 | 0.457 | <0.001 |
| Sex | −0.060 | 0.013 | −0.135 | <0.001 |
| Waist circumference | 0.039 | 0.009 | 0.126 | <0.001 |
| Blood pressure | 0.039 | 0.010 | 0.116 | <0.001 |
| HDLC | 0.029 | 0.012 | 0.070 | <0.05 |
| Log10(CRP) | 0.022 | 0.010 | 0.066 | <0.05 |
| Left IMT (0.303) | ||||
| Age | 0.008 | <0.001 | 0.479 | <0.001 |
| Sex | −0.054 | 0.013 | −0.125 | <0.001 |
| Waist circumference | 0.045 | 0.009 | 0.150 | <0.001 |
| Blood pressure | 0.026 | 0.010 | 0.079 | <0.01 |
| Log10(CRP) | 0.034 | 0.009 | 0.104 | <0.001 |
| No current smoking | −0.030 | 0.009 | −0.093 | <0.01 |
SE, Standard error; other abbreviations were listed in Table I. Positive metabolic component of waist circumference, blood pressure and HDLC were coded as 1 and control was coded as 0. Male and female subjects were coded as 1 and 2, respectively. Adjusted square values of multiple regression coefficient were listed in parenthesis after dependent variable.
Acknowledgments
We wish to express our appreciation to the study participants.
Declaration of interest:This work was supported partly by Grant-in-Aid for Scientific Research (C) (20590616), which was given by the Japan Society for the Promotion of Science.
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