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High-Sensitivity C-Reactive Protein Is Independently Associated With Arterial Stiffness in Women With Metabolic Syndrome

Oh, Eui Geum PhD, RN; Kim, Soo Hyun PhD, RN; Bang, So Youn PhD, RN; Hyun, Sa Saeng PhD, RN; Im, Jee-Aee PhD; Lee, Jung Eun MS, RN; Yoo, Jae Yong MS, RN

The Journal of Cardiovascular Nursing: January/February 2012 - Volume 27 - Issue 1 - p 61–67
doi: 10.1097/JCN.0b013e31820e5a91
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Background: Metabolic syndrome (MetS) is associated with higher incidences of cardiovascular events and with increased mortality from coronary heart disease. There is increasing evidence that MetS presents as a proinflammatory and prothrombotic state.

Objectives: The purposes of this study were to investigate the relationships among adiponectin (a marker for adipocytokines), high-sensitivity C-reactive protein (hs-CRP, a marker for inflammation), and brachial-ankle pulse-wave velocity (ba-PWV, a marker for arterial stiffness) in MetS and to identify predictors of ba-PWV, which indicates subclinical atherosclerosis.

Methods: The present study is a cross-sectional, secondary analysis of data collected as part of a longitudinal, randomized controlled trial that tested the effectiveness of a therapeutic lifestyle modification for Korean women with MetS (N = 52). We used the definition for MetS suggested by the National Cholesterol Education Program Adult Treatment Panel III.

Results: Adiponectin was negatively correlated with hs-CRP (r = −0.316, P = .027) and ba-PWV (r = −0.284, P = .048), and hs-CRP was positively correlated with ba-PWV (r = 0.341, P = .016). Women with high hs-CRP and low adiponectin levels also had greater ba-PWV levels (P = .041). Levels of hs-CRP were independently associated with ba-PWV after adjusting for age, body mass index, and number of MetS components, whereas no independent association was identified for adiponectin.

Conclusion: Levels of hs-CRP may provide important prognostic information in terms of future cardiovascular risk in women with MetS.

Eui Geum Oh, PhD, RN Professor, College of Nursing, Nursing Policy and Research Institution, Yonsei University, Seoul, Republic of Korea.

Soo Hyun Kim, PhD, RN Assistant Professor, Department of Nursing, Inha University College of Nursing, Incheon, Republic of Korea.

So Youn Bang, PhD, RN Assistant Professor, Department of Nursing, Youngdong University, Chungbuk, Republic of Korea.

Sa Saeng Hyun, PhD, RN Community Health Practitioner, Galsan Community Health Center, Chungju, Republic of Korea.

Jee-Aee Im, PhD Sports and Medicine Research Center, INTOTO, Inc, Seoul, Republic of Korea.

Jung Eun Lee, MS, RN Teaching Assistant, College of Nursing, Nursing Policy and Research Institution, Yonsei University, Seoul, Republic of Korea.

Jae Yong Yoo, MS, RN Teaching Assistant, College of Nursing, Nursing Policy and Research Institution, Yonsei University, Seoul, Republic of Korea.

This work was supported by the Korean Science and Engineering Foundation (R01-2006-000-11333-0). The authors have no conflicts of interest to disclose.

Correspondence Soo Hyun Kim, PhD, RN, Department of Nursing, Inha University, 253 Yonghyun-dong, Nam-gu, Incheon, Korea 401-752 (soohyun@inha.ac.kr).

Metabolic syndrome (MetS), a constellation of coronary heart disease risk factors, includes atherogenic dyslipidemia (increased triglyceride [TG] and decreased high-density lipoprotein cholesterol [HDL-C] levels), hypertension, abdominal obesity, hyperglycemia, and insulin resistance.1,2 Metabolic syndrome is associated with higher incidences of cardiovascular disease (CVD) and with increased mortality from coronary heart disease.3,4 There is increasing evidence that MetS presents as a proinflammatory and prothrombotic state.5,6 By identifying the underlying mechanisms of the proinflammatory and prothrombotic characteristics of MetS, disease burden from CVD can be reduced.

Recent research suggests that the presence of MetS is significantly associated with inflammatory cytokines, adipokines, and other important predictors of cardiovascular events. Parameters that have been examined include adipocytokines such as adiponectin, tumor necrosis factor α, and resistin7–12; the inflammatory markers high-sensitivity C-reactive protein (hs-CRP) and CD40L11,13–18; and the inflammatory cytokines leptin and IL-6.11 As an inflammatory marker, hs-CRP has been well established as an independent predictor of CVD.19,20 It has also been reported that hypoadiponectinemia has also been associated with MetS and has been found to be a predictor of CVD.16,21–23 However, the associations among these biomarkers and the presence of MetS have not yet been consistently replicated in clinical studies. Furthermore, few data exist on the association among biomarkers that indicate endothelial dysfunction and those signaling the presence of MetS.4 Because atherosclerosis is an important pathological factor in CVD, it is important to elucidate the factors closely associated with subclinical arterial alterations to ensure the prevention of CVD.4 Recently, pulse-wave velocity (PWV) has been widely used as an indication of subclinical arterial alterations and has been shown to be a predictor of CVD.24–26

Metabolic syndrome appears to be a stronger predictor of CVD in women than in men,27 although there are limited data on sex differences with respect to CVD and risk factors of CVD in people with MetS. Women with MetS have higher levels of proinflammatory markers, lower adiponectin levels, and stiffer arteries compared with those of men.16,17,22,28,29 Furthermore, absolute differences in adiponectin and hs-CRP levels in those with MetS are greater in women than they are in men.16 These data suggest that inflammatory processes may be of particular importance in the pathogenesis of MetS in women.

In 2008, a longitudinal, randomized controlled trial (RCT) that tested the effectiveness of a therapeutic lifestyle modification in women with MetS was conducted in Korea.30 The present study is a secondary analysis of data from the RCT30 that investigated relationships among adiponectin (a marker for adipocytokines), hs-CRP (a marker for inflammation), and brachial-ankle PWV (ba-PWV, a marker for arterial stiffness) in women with MetS.

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Methods

Study Design

The study was a cross-sectional study that utilized data from the RCT described above.30 We used only baseline data to identify the relationships among adipocytokines, inflammatory markers, and arterial stiffness in MetS.

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Subjects

Participants were recruited from 3 public health centers. Inclusion criteria were women 20 years or older who had a confirmed MetS diagnosis. Participants were excluded from the study if they had underlying diseases that prevented them from exercising (eg, uncontrolled congestive heart failure, angina or recent myocardial, or breathing difficulties requiring oxygen therapy) or if they were not able to participate in the intervention because of work commitments. Data from a total of 52 women with MetS were analyzed in the current study.

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Definition of Metabolic Syndrome

In the present study, a diagnosis of MetS was defined as a subject presenting at least 3 of the 5 factors for MetS described by the National Cholesterol Education Program Adult Treatment Panel III.2,31 However, waist circumference cutoffs were modified for Asian populations.32 The following factors were used to define MetS: (1) abdominal obesity (waist circumference ≥80 cm for women); (2) TG level 150 mg/dL or greater; (3) HDL-C less than 50 mg/dL; (4) systolic/diastolic blood pressure 130/85 mm Hg or greater or use of antihypertensive medication; and (5) a fasting plasma glucose (FPG) 100 mg/dL or greater or use of antidiabetic medication.

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Anthropometric and Biochemical Measurements

Body weight was measured with a high-precision scale (InBody 220; Biospace, Seoul, Korea), and body mass index (BMI) was calculated as weight (in kilograms) divided by height (in meters squared). Waist circumference was measured midway between the lowest rib and the iliac crest. Blood pressure was measured with an automatic digital sphygmomanometer (OMROM T4; Tokyo, Japan), with the subject in a seated position after 15 minutes of rest. The average of 2 measurements taken 2 or 3 minutes apart was used for analysis.

Blood samples from participants were obtained from the antecubital vein following an overnight fast. Venous blood was drawn and centrifuged, and serum and plasma were frozen immediately at −80°C. Serum levels of FPG, total cholesterol, low-density lipoprotein cholesterol, HDL-C, and TG were assayed using an ADVIA 1650 Chemistry system (Hitachi, Tokyo, Japan). Insulin levels were measured using a radioimmunoassay. Insulin resistance was estimated using the homeostasis model assessment (HOMA). The HOMA insulin resistance index was calculated using the following formula: FPG (in milligrams per deciliter) × fasting plasma insulin (in milli–international units per milliliter) / 405.

Serum levels of cytokines were measured using enzyme-linked immunosorbent assay kits according to the manufacturer’s instructions (adiponectin; AdipoGen, Seoul, Korea). Levels of hs-CRP were measured via a latex-enhanced immunoturbidimetric assay using an ADVIA 1650 Chemistry system (Siemens, Tarrytown, New York). Intra-assay and interassay coefficients of variance for adiponectin were less than 4.6% and less than 5.0%, respectively, and those for hs-CRP were less than 4.9% and less than 4.1 %, respectively.

Brachial-ankle pulse-wave velocity was measured using a volume plethysmographic instrument (PWV/ABI; Colin Co, Komaki, Japan) that records the phonocardiograms, electrocardiograms, volume pulse forms, and arterial blood pressures at the left and right brachial arteries and ankles. Brachial-ankle pulse-wave velocity was calculated using time-phase analysis between the right brachial and volume waveforms in both ankles. The distance between the right brachium and ankle was estimated based on body height. In addition, because there was significant correlation between the right and left ba-PWVs,33 we used the mean ba-PWV for analysis. The interobserver and intraobserver variation coefficients were 8.4 and 10.0%, respectively.

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Statistical Analyses

Descriptive data are presented as number and percentage and mean and SD for normally distributed variables and median and 25%–75% percentile for non–normally distributed variables. Because of skewed distributions, log transformations were performed for waist circumference, FPG, HOMA, TG, adiponectin, and hs-CRP prior to Pearson correlation coefficient and multivariate linear regression analyses. Pearson correlation coefficients were used to analyze relationships among variables, accounting for age. Brachial-ankle pulse-wave velocities in groups of subjects with adiponectin and hs-CRP levels that had been defined using the median were compared using a multivariate general linear model. This analysis was adjusted for age, BMI, and blood pressure, which have the potential to affect PWV.34,35 For this analysis, participants were divided into the following 4 groups: (1) high adiponectin and low hs-CRP (n = 16), (2) low adiponectin and high hs-CRP (n = 16), (3) high adiponectin and high hs-CRP (n = 10), and (4) low adiponectin and low hs-CRP (n = 10). High or low cutoffs were median values of adiponectin and hs-CRP because of their skewed distributions. We selected only 2 clinically meaningful groups (ie, high adiponectin and low hs-CRP group, and low adiponectin and high hs-CRP group) to examine the relationships between high or low adiponectin and hs-CRP with ba-PWV (n = 32). Finally, independent determinants of ba-PWV were analyzed using multivariate linear regression. All results were considered significant at a 2-tailed threshold of P < .05. Analyses were performed using SPSS version 15.0 (SPSS Inc, Chicago, Illinois).

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Results

Demographic and cardiovascular characteristics of the participants are presented in Table 1. The mean participant age was 62.7 (SD, 9.0) years, and the mean BMI was 26.0 (SD, 3.1) kg/m2. Twenty-eight women (53.8%) had 3 components of MetS, 20 women (38.5%) had 4 components, and only 4 women had all components. Among the 5 indices, waist circumference was the most frequent diagnostic indicator in our sample. Sixty-nine percent of women were diagnosed with hypertension, and 23.1% had diabetes.

TABLE 1

TABLE 1

Table 2 displays the relationships among the metabolic biomarkers, adiponectin, hs-CRP, and ba-PWV. Adiponectin, hs-CRP, and ba-PWV did not show significant correlations with most metabolic biomarkers. After adjusting for age, hs-CRP was positively correlated with BMI (r = 0.285, P = .047) and with HDL-C (r = 0.389, P = .006). Brachial-ankle pulse-wave velocity was positively correlated with FPG (r = 0.375, P = .008). Adiponectin was not associated with any metabolic biomarkers. There was significant negative association between adiponectin and hs-CRP (r = −0.316, P = .027); ba-PWV was also negatively correlated with adiponectin (r = −0.284, P = .048) and positively correlated with hs-CRP (r = 0.341, P = .016; Table 2).

TABLE 2

TABLE 2

Table 3 shows the relationships of high or low adiponectin level and hs-CRP with ba-PWV after adjusting for age, BMI, and blood pressure. Women with low adiponectin and high hs-CRP had higher ba-PWVs than did those with high adiponectin and low hs-CRP (P = .041).

TABLE 3

TABLE 3

In the multiple linear regression analysis, adiponectin was not related to ba-PWV after controlling for age, BMI, and number of MetS components (P = .108). In contrast, hs-CRP was independently associated with ba-PWV after adjusting for the same parameters. Also, hs-CRP remained significantly associated with ba-PWV with further adjustment for adiponectin (P = .006 and P = .018, respectively; Table 4).

TABLE 4

TABLE 4

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Discussion

To our knowledge, this is the first study to examine relationships among metabolic parameters and adiponectin, hs-CRP, and ba-PWV in women with MetS. Previous studies included only normal, healthy populations4,34–36; patients with impaired fasting glucose37; or hypertensive patients.38 This study has demonstrated that significant relationships exist among adiponectin, hs-CRP, and ba-PWV in women with MetS and that hs-CRP is an independent predictor of arterial stiffness in MetS. These results indicate that hs-CRP may be a prognostic determinant for the development of atherosclerosis in women with MetS.

Unexpectedly, most metabolic biomarkers were not related to adiponectin, hs-CRP, or ba-PWV. Hypoadiponectinemia has been associated with MetS and CVD and is a predictor of CVD.16,22,23 Adiponectin, an anti-inflammatory and antiatherogenic adipocytokine, has been found to be more strongly associated with MetS parameters8,16,22,34,39; however, it did not correlate with any of the MetS parameters in our study. High-sensitivity C-reactive protein is a sensitive marker of systemic inflammation and is also reportedly related to MetS16,17,22,40; however, only BMI and HDL-C were significantly related to hs-CRP in this study. Furthermore, it is difficult to explain why hs-CRP positively correlated with HDL-C. A marker for arterial stiffness, ba-PWV has been found to be related to some MetS-related biomarkers.33,41 However, in our study, only fasting glucose was significantly related to ba-PWV.

One of the reasons for these unexpected findings may be that the clinical characteristics of participants in this study differed from those in earlier studies. In previous studies, the mean level of hs-CRP in subjects with MetS ranged from 2.0 to 2.7mg/L,16,40,42 whereas that of our participants was 1.2 mg/L. This suggests that the mean subclinical inflammation status of our participants was relatively low. This might be due to the fact that many of the subjects were taking medications; 67.3% of the subjects were using antihypertensive drugs, 23.1% were using antidiabetic agents, and 21.2% were using nonsteroidal anti-inflammatory agents. Of particular interest are those medications that regulate the renin-angiotensin system, as they decrease PWV as well as serum CRP level.43,44 Thus, it is possible that the hs-CRP and ba-PWV levels in subjects taking such drugs may have been underestimated. Another possible reason may be related to the health behavior characteristics of our participants. Forty-two percent of the subjects reported engaging in regular exercise, and almost all (n = 49) were nonsmokers. Furthermore, the Korean diet is plant based, which lowers CVD risk. This pattern of positive health behaviors may have affected the clinical characteristics of our sample. Furthermore, low levels of hs-CRP may also be due to ethnic differences. C-reactive protein levels vary among different populations, and in particular, it has been reported that Asian women have significantly lower levels.45,46 Finally, a small sample size may be a possible explanation for our unexpected findings.

The present study found significant relationships among adiponectin, hs-CRP, and ba-PWV. Although there have been no previous studies that have examined these relationships in people with MetS, previous studies of healthy populations or patients with impaired fasting glucose support such relationships.34,36,47–49 For instance, Sung et al34 have also found significant associations between adiponectin and hs-CRP and adiponectin and ba-PWV, but they did not find a significant relationship between hs-CRP and ba-PWV. Interestingly, adiponectin, but not hs-CRP, was independently related to ba-PWV in their study, different from the results of our study. We found that a high ba-PWV was mainly determined by high hs-CRP, and no significant additive effect of low adiponectin on ba-PWV was observed. This difference may be due to participant characteristics. Sung et al34 included both sexes, but our sample included only women. According to Nishida et al,4 adiponectin is an important risk factor for arterial alteration in men, but not in women. Thus, there may be sex differences in the associations among adiponectin, arterial stiffness, and hs-CRP. In women with MetS, other factors such as endothelial dysfunction and oxidative stress may contribute more strongly to arterial stiffness than does adiponectin.

High-sensitivity C-reactive protein has been reported to inhibit endothelial nitric oxide synthase and to induce the expressions of monocyte chemoattractant protein 1 and adhesion molecules in human endothelial cells.50–52 Because this type of endothelial dysregulation may promote arterial vasoconstriction, smooth muscle cell proliferation, and vascular inflammation, an increase in CRP level may increase vascular stiffness and promote further vascular inflammation. Thus, this acute-reactant protein may not be merely a marker of inflammation, but may also have modulatory functions that contribute to the progression and evolution of atherosclerosis and increased arterial stiffness.35 However, extant data are mixed regarding the relationships between inflammatory markers and arterial stiffness. In a study by Nishida et al,4 serum IL-6 concentrations were more sensitive than that of hs-CRP in the determination of subclinical atherosclerosis in patients with type 2 diabetes mellitus. Therefore, further research regarding sensitive predictors of arterial stiffness is needed.

Several limitations of this study should be considered. First, a cross-sectional design does not allow for the establishment of any causal relationship. Second, the small sample size limits our power to detect statistical significance. Third, the study population was composed of women with MetS living in a rural area of Korea; thus, the study population may have been significantly different from the general population of Korean women or from women of other ethnicities.

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Conclusions

We demonstrated that, in women with MetS, the arterial stiffness marker ba-PWV is independently correlated with serum hs-CRP level, after adjusting for other established cardiovascular risks factors. Future studies should focus on the identification of the adipocytokines or inflammatory markers that are responsible for the increase in ba-PWV seen in MetS because these parameters may lead to the development of a therapeutic blueprint for the prevention of atherosclerosis and cardiovascular risk in this population.

Table

Table

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Keywords:

adiponectin; arterial stiffness; C-reactive protein; metabolic syndrome

© 2012 Lippincott Williams & Wilkins, Inc.