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.
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.
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.
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.
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.
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).
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 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 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).
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).
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.
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.
1. Grundy SM, Cleeman JI, Daniels SR, et al.. Diagnosis and management of the metabolic syndrome
. An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Executive summary. Cardiol Rev. 2005; 13 (6): 322–327.
2. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the 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). JAMA. 2001; 285: 2486–2497.
3. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome
among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA. 2002; 287 (3): 356–359.
4. Nishida M, Moriyama T, Ishii K, et al.. Effects of IL-6, adiponectin
, CRP and metabolic syndrome
on subclinical atherosclerosis. Clin Chim Acta. 2007; 384 (1–2): 99–104.
5. Festa A, Dr’Agostino R Jr, Howard G, Mykkanen L, Tracy RP, Haffner SM. Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation. 2000; 102 (1): 42–47.
6. Rutter MK, Meigs JB, Sullivan LM, Dr’Agostino RB Sr, Wilson PW. C-reactive protein
, the metabolic syndrome
, and prediction of cardiovascular events in the Framingham Offspring Study. Circulation. 2004; 110 (4): 380–385.
7. Yun JE, Kimm H, Jo J, Jee SH. Serum leptin is associated with metabolic syndrome
in obese and nonobese Korean populations. Metabolism. 2010; 59 (3): 424–429.
8. Park HT, Cho SH, Cho GJ, et al.. Relationship between serum adipocytokine levels and metabolic syndrome
in menopausal women. Gynecol Endocrinol. 2009; 25 (1): 27–31.
9. Aquilante CL, Kosmiski LA, Knutsen SD, Zineh I. Relationship between plasma resistin concentrations, inflammatory chemokines, and components of the metabolic syndrome
in adults. Metabolism. 2008; 57 (4): 494–501.
10. Gilardini L, McTernan PG, Girola A, et al.. Adiponectin
is a candidate marker of metabolic syndrome
in obese children and adolescents. Atherosclerosis. 2006; 189 (2): 401–407.
11. Abdullah AR, Hasan HA, Raigangar VL. Analysis of the relationship of leptin, high-sensitivity C-reactive protein
, insulin, and uric acid to metabolic syndrome
in lean, overweight, and obese young females. Metab Syndr Relat Disord. 2009; 7 (1): 17–22.
12. Okamoto Y, Kihara S, Funahashi T, Matsuzawa Y, Libby P. Adiponectin
: a key adipocytokine in metabolic syndrome
. Clin Sci (Lond). 2006; 110 (3): 267–278.
13. Isomaa B, Almgren P, Tuomi T, et al.. Cardiovascular morbidity and mortality associated with the metabolic syndrome
. Diabetes Care. 2001; 24 (4): 683–689.
14. Lee WL, Lee WJ, Chen YT, et al.. The presence of metabolic syndrome
is independently associated with elevated serum CD40 ligand and disease severity in patients with symptomatic coronary artery disease. Metabolism. 2006; 55 (8): 1029–1034.
15. Okosun IS. Metabolic syndrome
and C-reactive protein
in American adults: the impact of abdominal obesity. Metab Syndr Relat Disord. 2008; 6 (4): 289–297.
16. Ahonen T, Saltevo J, Laakso M, Kautiainen H, Kumpusalo E, Vanhala M. Gender differences relating to metabolic syndrome
and proinflammation in Finnish subjects with elevated blood pressure. Mediators Inflamm. 2009. http://http://www.ncbi.nlm.nih.gov
/pmc/articles/PMC2730476/?tool=pubmed. DOI: 10.1155/2009/959281.
17. Lai MM, Li CI, Kardia SL, et al. Sex difference in the association of metabolic syndrome
with high sensitivity C-reactive protein
in a Taiwanese population. BMC Public Health
18. Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein
, the metabolic syndrome
, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation. 2003; 107 (3): 391–397.
19. Pearson TA, Mensah GA, Alexander RW, et al.. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003; 107 (3): 499–511.
20. Ridker PM, Cook N. Clinical usefulness of very high and very low levels of C-reactive protein
across the full range of Framingham risk scores. Circulation. 2004; 109 (16): 1955–1959.
21. Kumada M, Kihara S, Sumitsuji S, et al.. Association of hypoadiponectinemia with coronary artery disease in men. Arterioscler Thromb Vasc Biol. 2003; 23 (1): 85–89.
22. Schuur M, Henneman P, van Swieten JC, et al.. Insulin-resistance and metabolic syndrome
are related to executive function in women in a large family-based study. Eur J Epidemiol. 2010; 25 (8): 561–568.
23. King GA, Deemer SE, Thompson DL. Adiponectin
is associated with risk of the metabolic syndrome
and insulin resistance in women. Acta Diabetol. 2010;Online published.
24. Salvi P, Safar ME, Labat C, Borghi C, Lacolley P, Benetos A. Heart disease and changes in pulse wave velocity and pulse pressure amplification in the elderly over 80 years: the PARTAGE Study. J Hypertens. 2010; 28 (10): 2127–2133.
25. Gomez-Marcos MA, Recio-Rodriguez JI, Rodriguez-Sanchez E, et al.. Central blood pressure and pulse wave velocity: relationship to target organ damage and cardiovascular morbidity-mortality in diabetic patients or metabolic syndrome
. An observational prospective study. LOD-DIABETES study protocol. BMC Public Health. 2010; 18 (10): 143.
26. Holewijn S, den Heijer M, Swinkels DW, Stalenhoef AF, de Graaf J. The metabolic syndrome
and its traits as risk factors for subclinical atherosclerosis. J Clin Endocrinol Metab. 2009; 94 (8): 2893–2899.
27. Pischon T, Hu FB, Rexrode KM, Girman CJ, Manson JE, Rimm EB. Inflammation, the metabolic syndrome
, and risk of coronary heart disease in women and men. Atherosclerosis. 2008; 197 (1): 392–399.
28. Lakoski SG, Cushman M, Criqui M, et al.. Gender and C-reactive protein
: data from the Multiethnic Study of Atherosclerosis (MESA) cohort. Am Heart J. 2006; 152 (3): 593–598.
29. Lin HF, Liu CK, Liao YC, Lin RT, Chen CS, Juo SH. The risk of the metabolic syndrome
on carotid thickness and stiffness: sex and age specific effects. Atherosclerosis. 2010; 210 (1): 155–159.
30. Oh EG, Bang SY, Hyun SS, et al.. Effects of a 6-month lifestyle modification intervention on the cardiometabolic risk factors and health-related qualities of life in women with metabolic syndrome
. Metabolism. 2010; 59 (7): 1035–1043.
31. Grundy SM, Cleeman JI, Daniels SR, et al.. Diagnosis and management of the metabolic syndrome
: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005; 112: 2735–2752.
32. Tan CE, Ma S, Wai D, Chew SK, Tai ES. Can we apply the national cholesterol education program adult treatment panel definition of the metabolic syndrome
to Asians. Diabetes Care. 2004; 27: 1182–1186.
33. Ohnishi H, Saitoh S, Takagi S, et al.. Pulse wave velocity as an indicator of atherosclerosis in impaired fasting glucose: the Tanno and Sobetsu study. Diabetes Care. 2003; 26 (2): 437–440.
34. Sung SH, Chuang SY, Sheu WH, Lee WJ, Chou P, Chen CH. Relation of adiponectin
and high-sensitivity C-reactive protein
to pulse-wave velocity and N-terminal pro–B-type natriuretic peptide in the general population. Am J Cardiol. 2009; 103 (10): 1411–1416.
35. Nagano M, Nakamura M, Sato K, Tanaka F, Segawa T, Hiramori K. Association between serum C-reactive protein
levels and pulse wave velocity: a population-based cross-sectional study in a general population. Atherosclerosis. 2005; 180 (1): 189–195.
36. Komatsu M, Ohfusa H, Aizawa T, Hashizume K. Adiponectin
inversely correlates with high sensitive C-reactive protein
and triglycerides, but not with insulin sensitivity, in apparently healthy Japanese men. Endocr J. 2007; 54 (4): 553–558.
37. Nam JS, Park JS, Cho MH, et al.. The association between pulse wave velocity and metabolic syndrome
in patients with impaired fasting glucose: cardiovascular risks and adiponectin
in IFG. Diabetes Res Clin Pract. 2009; 84 (2): 145–151.
38. Mahmud A, Feely J. Adiponectin
and arterial stiffness
. Am J Hypertens. 2005; 18 (12 pt 1): 1543–1548.
39. Koh SB, Park JK, Yoon JH, et al.. Preliminary report: a serious link between adiponectin
levels and metabolic syndrome
in a Korean nondiabetic population. Metabolism. 2010; 59 (3): 333–337.
40. Yu RH, Ho SC, Lam CW, Woo JL, Ho SS. Distribution of C-reactive protein
and its association with subclinical atherosclerosis in asymptomatic postmenopausal Chinese women. Metabolism. 2010; 59 (11): 1672–1679.
41. Kim YK. Impact of the metabolic syndrome
and its components on pulse wave velocity. Korean J Intern Med. 2006; 21 (2): 109–115.
42. Roes SD, Alizadeh Dehnavi R, Westenberg JJ, et al.. Assessment of aortic pulse wave velocity and cardiac diastolic function in subjects with and without the metabolic syndrome
: HDL cholesterol is independently associated with cardiovascular function. Diabetes Care. 2008; 31 (7): 1442–1444.
43. Mahmud A, Feely J. Reduction in arterial stiffness
with angiotensin II antagonist is comparable with and additive to ACE inhibition. Am J Hypertens. 2002; 15 (4 pt 1): 321–325.
44. Takeda T, Hoshida S, Nishino M, Tanouchi J, Otsu K, Hori M. Relationship between effects of statins, aspirin and angiotensin II modulators on high-sensitive C-reactive protein
levels. Atherosclerosis. 2003; 169 (1): 155–158.
45. Albert MA, Glynn RJ, Buring J, Ridker PM. C-reactive protein
levels among women of various ethnic groups living in the United States (from the Womenr’s Health Study). Am J Cardiol. 2004; 93 (10): 1238–1242.
46. Matthews KA, Sowers MF, Derby CA, et al.. Ethnic differences in cardiovascular risk factor burden among middle-aged women: Study of Womenr’s Health Across the Nation (SWAN). Am Heart J. 2005; 149 (6): 1066–1073.
47. Mattace-Raso FU, van der Cammen TJ, van der Meer IM, et al.. C-reactive protein
and arterial stiffness
in older adults: the Rotterdam Study. Atherosclerosis. 2004; 176 (1): 111–116.
48. Kullo IJ, Seward JB, Bailey KR, et al.. C-reactive protein
is related to arterial wave reflection and stiffness in asymptomatic subjects from the community. Am J Hypertens. 2005; 18 (8): 1123–1129.
49. Yasmin, McEniery CM, Wallace S, Mackenzie IS, Cockcroft JR, Wilkinson IC. C-reactive protein
is associated with arterial stiffness
in apparently healthy individuals. Arterioscler Thromb Vasc Biol. 2004; 24 (5): 969–974.
50. Venugopal SK, Devaraj S, Yuhanna I, Shaul P, Jialal I. Demonstration that C-reactive protein
decreases eNOS expression and bioactivity in human aortic endothelial cells. Circulation. 2002; 106 (12): 1439–1441.
51. Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein
on human endothelial cells. Circulation. 2000; 102 (18): 2165–2168.
52. Pasceri V, Cheng JS, Willerson JT, Yeh ET. Modulation of C-reactive protein
-mediated monocyte chemoattractant protein-1 induction in human endothelial cells by anti-atherosclerosis drugs. Circulation. 2001; 103 (21): 2531–2534.