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Association between serum resistin and carotid intima media thickness in hypertension patients
International Journal of Cardiology 125 (2008) 79 – 84 www.elsevier.com/locate/ijcard
Association between serum resistin and carotid intima media thickness in hypertension patients ☆ Hyun-Joon Shin a,1 , Sungha Park a,b,1 , Se-Jung Yoon a , Dae Shik Choi a , Deok-Kyu Cho c , Jung-Sun Kim a , Young-Guk Ko a , Donghoon Choi a,⁎, Yangsoo Jang a,b , Namsik Chung a a
Cardiology Division, Yonsei Cardiovascular Center, Yonsei University College of Medicine, SeodaemunGu 120-752, Seoul, Republic of Korea b Cardiovascular Genome Center, Yonsei Cardiovascular Center, Yonsei University College of Medicine, Seoul, Republic of Korea c Cardiovascular Center, Cardiology Division, Department of Internal Medicine, Myongji Hospital, Kwandong University College of Medicine, Goyang, Gyeonggi, Republic of Korea Received 22 August 2006; received in revised form 3 January 2007; accepted 17 February 2007 Available online 16 April 2007
Abstract Background: Resistin is an adipocytokine belonging to the family of cysteine rich secretory proteins. We sought to determine if a correlation between resistin levels and carotid atherosclerosis exists in hypertensive patients. Methods: This study consisted of 307 treated hypertensive patients. Subjects were grouped into tertiles according to their resistin level. Results: Carotid intima media thickness (IMT) was significantly highest in the third tertile. The first tertile had a mean carotid IMT and a mean of maximum carotid IMT of 0.63 ± 0.08 and 0.81 ± 0.10 mm, respectively. The 2nd tertile had measurements of 0.63 ± 0.08 and 0.81 ± 0.12 mm, and the 3rd tertile 0.67 ± 0.12 and 0.86 ± 0.11 for the same parameters. (p = 0.002). Resistin levels were independently associated with the carotid IMT (mean carotid IMT: R2 = 0.159, p b 0.001 and mean of maximum carotid IMT: R2 = 0.162, p b 0.001) after controlling for age, gender, HDL cholesterol, triglyceride, LDL cholesterol, smoking and DM. The tertile level of resistin was significantly associated with (odds ratio = 3.097, p = 0.004) risk of coronary artery disease after controlling for age, gender, HDL cholesterol, triglyceride, LDL cholesterol, smoking, DM and carotid IMT. Conclusion: Serum resistin is independently associated with increasing carotid IMT in treated hypertensive patients. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Resistin; Carotid intima media thickness; Hypertension
1. Introduction Inflammatory processes are important in hypertension pathophysiology and the subsequent development of cardiovascular complications [1–4]. Inflammatory markers such as CRP, cell adhesion molecules, MCP-1, Interleukin6 and TNF-α are known to be involved in the pathogenesis ☆
This work was supported by a grant from the ministry of Health and Welfare of the Republic of Korea (A000385) and by a grant of the Seoul R&BD program, Republic of Korea (10526). ⁎ Corresponding author. Tel.: +82 2 2228 8449; fax: +82 2 393 2041. E-mail address: [email protected] (D. Choi). 1 These authors contributed equally to this article. 0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2007.02.028
of hypertension and are present at increased levels in patients with cardiovascular disease [1,5–7]. Insulin resistance syndrome is observed in 30–50% of patients with hypertension and adipocytokines may be important inflammatory mediators in developing cardiovascular complications in hypertension patients [8]. Studies have demonstrated that adipocytokines, such as adiponectin, play a significant role in regulating vascular inflammation and atherogenesis [9,10]. Carotid intima media thickness (IMT) measurement is a marker of early atherosclerosis that is associated with traditional cardiovascular risk factors such as aging, obesity, hypertension, dyslipidemia, diabetes and smoking [11–14]. Also, studies have demonstrated that carotid IMT is an
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independent marker for future cardiovascular events such as myocardial infarction and stroke [15,16]. Hypertension is known to be a major factor on IMT via its effect on medial hypertrophy [11]. However, associated cardiovascular risk factors are likely to have a significant role in potentiating atherogenesis in hypertension. Among these factors, adipocytokines may have a significant role in potentiating vascular inflammation and atherogenesis. Resistin is an adipocytokine belonging to the family of cysteine rich secretory proteins [17]. Studies have shown it to have a role in regulating metabolism, adipogenesis and mediating vascular inflammation [18,19]. Unlike rodents, in which resistin is exclusively secreted from adipose tissue, human resistin is secreted not only by adipocytes but circulating mononuclear cells as well [20]. Studies have shown a potential role of resistin in atherogenesis and vascular inflammation [18,19,21,22]. However, studies regarding the role of resistin in the pathogenesis of atherosclerosis in hypertensive subjects have not been performed. In this study, we examined an association between serum resistin and carotid IMT, an index of early atherosclerosis, in 307 patients with essential hypertension. 2. Methods 2.1. Study population The study consisted of 307 hypertensive patients treated at the Yonsei Cardiovascular Hospital from October 2004 to March 2006. They were enrolled in the Cardiovascular Genome Center for a ministry of Health and Welfare sponsored genotypic study of cardiovascular disease. We recruited treated hypertensive patients based upon systolic blood pressure greater than 140 mm Hg and/or diastolic blood pressure greater than 90 mm Hg over three different visits prior to taking antihypertensive medication and/or patients taking anti-hypertensive medication for at least 3 months prior to enrollment. Patients with significant coronary artery disease [coronary artery disease (CAD) group; n = 76] were patients who had greater than 50% luminal narrowing in at least one coronary artery greater than 2 mm in diameter, as determined by coronary angiography. Smoking was classified as ever smoking versus never smoking. Amount of smoking was also considered. Past smokers who had smoked fewer than 100 cigarettes were classified as never smokers. Diabetes mellitus (DM) is defined as patients satisfying at least one of three criteria: 1) taking anti-diabetic medications, 2) fasting blood glucose level above 126 mg/dl and 3) random blood sugar above 200 mg/dl. The following conditions excluded patients from enrollment: valvular heart disease, peripheral vascular disease, significant systemic disease, history of inflammatory disease, a clinically significant atrioventricular conduction disturbance, history of atrial fibrillation or other serious arrhythmia, history of congestive heart failure, and severe hypertension (N 210/ 130 mm Hg), and serum creatinine greater than 1.4 mg/dl.
At the time of enrollment, patients underwent a complete physical examination, baseline electrocardiogram and laboratory assessment. After resting for at least five minutes in a sitting position, office blood pressure (BP) was measured using a sphygmomanometer with an appropriate cuff. Two measurements were taken at least five minutes apart and the mean was used for analysis. Blood chemistry [glucose, blood urea nitrogen (BUN), uric acid, total cholesterol, total bilirubin, alkaline phosphatase, AST, ALT, creatinine, Na, K, Triglyceride, highdensity lipoprotein (HDL), low-density lipoprotein (LDL)] and fasting serum insulin were assessed. The fasting serum insulin level was measured with an immunoradiometric assay and a gamma counter (Hewlett Packard, USA). Insulin resistance was measured using the homeostasis model assessment of insulin resistance index (HOMA index), with the following formula; HOMA index ¼ fasting insulinðAU=mlÞ fasting glycemia ðmmol=LÞ=22:5: Venous blood sampling was performed after an overnight fast, and the serum was immediately frozen at −70 °C for future analysis. Serum resistin levels were measured using the Quantikine human resistin immunoassay kit (R&D Systems, Minneapolis, MN, USA). The study group was divided according to the tertile level of resistin. Group 1 was patients with the 1st tertile level of resistin, group 2 was patients with 2nd tertile level of resistin and group 3 was patients with 3rd tertile level of resistin. This study was approved beforehand by the institutional ethics committee, and procedures followed were in accordance with the institutional guidelines. All patients gave informed consent prior to being enrolled. 2.2. Carotid IMT measurement Ultrasonographic scanning of the carotid artery was performed by a single operator, blind to subject details with a high-resolution real-time 8-MHz linear scanner (Sequoia C512, Acuson Co. Ltd.). Participants were scanned in the supine position with the neck hyperextended. An optimal longitudinal B mode image of both common carotid arteries proximal to the bifurcation was obtained and stored digitally. The mean and maximum CIMT (carotid intima media thickness) of the far wall of the common carotid arteries were measured offline with the highest quality end-diastolic frame, using the automated edge detection methodology program (M'ATH®, METRIS Co. FRANCE). The mean CIMT was defined as the average mean IMT of the right and left carotid arteries measured by the automated edge detection methodology. The mean of maximum CIMT was defined as the average of the maximum IMT value for both the right and left carotid arteries. 2.3. Statistical analysis The study population was divided into tertiles of serum resistin (Table 1). Continuous variables were compared using
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Table 1 Baseline characteristics
Resistin(ng/ml) Age (years) Mean of carotid IMT(mm) Mean of maximum carotid IMT(mm) Male (%) Official BP SBP (mm Hg) DBP (mm Hg) DM(%) Smoking (%) CAD (%) T. chol (mg/dl) TG (mg/dl) HDL (mg/dl) LDL (mg/dl) FBG(mg/dl) Insulin(mU/L) Waist(cm) Waist Hip Ratio BMI(kg/m2) Body weight(kg) HOMA White blood cell count (μl)
1st tertile(N = 102)
2nd tertile(N = 103)
3rd tertile(N = 102)
p-value⁎
3.77 ± 1.17(0.57–5.77) 56.3 ± 9.9(35–77) 0.63 ± 0.08(0.48–0.89) 0.81 ± 0.1(0.6–1.1) 55(53.9%)
7.87 ± 1.42(5.81–10.5) 55.4 ± 10.7(28–78) 0.63 ± 0.08(0.44–0.87) 0.81 ± 0.12(0.59–1.53) 56(54.4%)
17.17±6.11(10.55–44.42) 55.9 ± 11.1(25–77) 0.67±0.12(0.51–0.90) 0.86 ± 0.11(0.66–1.22) 51(50.0%)
b0.001 0.86 0.002 0.002 0.79
125 ± 14(92–160) 80 ± 11(60–110) 14(13.7%) 41(40.2.%) 17(16.7%) 191 ± 35(122–306) 157 ± 125(48–1020) 50 ± 13(28–93) 111 ± 32(45–225) 93± 22(70–204) 9.1 ± 4.0(2.2–28.6) 88.4 ± 7.9(60.9–104.0) 0.9 ± 0.07(0.65–1.03) 25.1 ± 2.6(19.22–33.48) 66.5 ± 10.8(45–94.5) 2.10 ± 1.06(0.42–8.18) 4634 ± 1242(2600–9300)
126 ± 15 (100–160) 80 ± 9(52–104) 14(13.6%) 44(42.7%) 22(21.4%) 185 ± 36(122–303) 153 ± 103(37–697) 48 ± 13(23–88) 106 ± 34(22–220) 94± 26(71–256) 10.7 ± 10.7(1.7–92.7) 88.5 ± 8.6(67.0–104.5) 0.91 ± 0.07(0.76–1.23) 25.6 ± 2.96(18.03–34.36) 67.5 ± 10.0(47.5–97.5) 2.54 ± 2.92(0.34–21.57) 5371 ± 1721(2700–13900)
126 ± 17(94–170) 80 ± 11(58–110) 19(18.6%) 37(36.3%) 37(36.3%) 189 ± 36(115–299) 155 ± 94(49–643) 49 ± 13 (25–86) 109 ± 35(36–220) 95± 23(66–218) 9.8 ± 4.2(4.0–32.8) 87.7 ± 7.7(68.0–108.0) 0.9 ± 0.6(0.77–1.08) 25.4 ± 2.7(18.44–32.13) 66.5 ± 10.8(47–96) 2.30 ± 1.17(0.91–6.96) 5472 ± 1611(2300–11800)
0.83 0.84 0.52 0.64 0.003 0.46 0.90 0.70 0.56 0.86 0.39 0.76 0.94 0.46 0.74 0.39 b0.001
Values are presented as n (%) or mean ± SD(range); IMT, intima media thickness; SBP, systolic blood pressure; DBP, diastolic blood pressure; DM, diabetes mellitus; CAD, coronary artery disease; TG, triglyceride; HDL, high-density lipoprotein; LDL, low-density lipoprotein; FBG, fasting blood glucose; BMI, body mass index; HOMA, homeostasis model assessment of insulin resistance index. ⁎ p-value b 0.05 is considered significant. Chi-square test was used for categorical variables. ANOVA was used for continuous variables.
analysis of variance (ANOVA). Categorical variables were compared using a Chi-squared analysis. The simple correlation between continuous variables was explored using the Pearson's correlation analysis. To normalize the distribution, a natural logarithmic transformation was applied to resistin levels, mean carotid IMT, mean of maximum carotid IMT, systolic blood pressure, diastolic blood pressure, triglyceride (TG), high-density lipoprotein (HDL) and HOMA index. In the multiple linear regression models, an association of log transformed resistin levels was assessed when controlled for age, TG, DM (yes, no), history of smoking (smoker, nonsmoker), low-density lipoprotein (LDL) cholesterol, HDL cholesterol and male gender(yes, no). Associations between resistin tertiles, age, TG, DM, smoking, LDL, HDL, male gender, mean carotid IMT and presence of CAD were evaluated by logistic regression analysis. Statistical significance is defined as a p-value b 0.05 on two-tailed testing. Statistical analysis was performed with SPSS 11.0 program (SPSS Inc., Chicago, IL, USA). 3. Results 3.1. Clinical characteristics The mean and median serum resistin concentration were 9.60 and 7.68 ng/ml respectively. Serum resistin concentration of females (mean/median: 9.59/8.02 ng/ml) and males(mean/ median: 9.60/7.70 ng/ml) did not differ significantly. Also, the
serum resistin concentration of metabolic syndrome patients defined according to the NCEPATP-III criteria (n = 159; mean/ median: 9.77/7.78 ng/ml) and non-metabolic syndrome patients (n = 148; mean/median: 9.23/7.33 ng/ml) was not significantly different. The three resistin tertiles did not differ for clinical variables such as age, gender and cardiovascular disease risk factors (Table 1). There were no significant differences in the proportion of patients taking ACE inhibitors, angiotensin receptor blockers, beta-blockers, calcium channel blockers, diuretics, statins, sulfonylureas or biguanides among the three tertiles. (Table 2) The mean carotid IMT and mean of maximum carotid IMT were both higher in the 3rd tertile Table 2 Medication history
ACE inhibitors (%) ARB (%) Beta-blockers (%) CCB (%) Diuretics (%) Statins (%) Sulfonylurea(%) Biguanide(%)
1st tertile (N = 102)
2nd tertile (N = 103)
3rd tertile (N = 102)
p-value⁎
18 (17.6%) 42(38.9%) 52 (51%) 81 (79.4%) 20 (19.6%) 30 (29.4%) 5(4.9%) 3(2.9%)
22 (21.4%) 37(34.3%) 52 (50.5%) 79 (76.7%) 18 (17.5%) 35 (34%) 3(2.9%) 4(3.9%)
25 (24.5%) 29(26.9%) 62 (60.8%) 77 (75.5%) 26 (25.5%) 32 (31.4%) 10(9.8%) 6(5.9%)
0.49 0.16 0.25 0.79 0.34 0.78 0.10 0.57
ACE, angiotensin-converting enzyme; ARB, angiotensin-converting enzyme receptor blocker; CCB, calcium channel blocker. ⁎ p-value b 0.05 is considered significant. Chi-square test was used for statistical analysis.
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Fig. 1. (a) Mean carotid IMT difference between the three resistin tertiles. (b) Mean of maximum carotid IMT difference between the three resistin tertiles. Error bar depicting mean ± standard error; ⁎, p b 0.01.
compared to the 1st tertile and the 2nd tertile (Table 1, Fig. 1). There was significant correlation between log transformed serum resistin and mean of mean IMT(r = 0.187, p = 0.001)
and mean of maximum IMT(r = 0.178, p = 0.002) by Pearson correlation analysis (Fig. 2). 3.2. Multivariate analysis for factors affecting carotid IMT Log transformed resistin levels are significantly associated with both mean carotid IMT (β = 0.189, p b 0.001) and mean of maximum carotid IMT (β = 0.182, p = 0.001) by multiple linear regression analysis (Table 3). In this model, correction was made for age, triglyceride, diabetes mellitus, history of smoking, HDL cholesterol, LDL cholesterol and male gender. In subgroup analysis according to the presence of DM, there was significant association of log transformed resistin with the mean carotid IMT (non-DM: β = 0.15, p = 0.01; DM: β = 0.37, p = 0.01) and mean of maximum carotid IMT. (non-DM: β = 0.17, p b 0.01; DM: β = 0.30, p = 0.03) in both non-DM(n = 260) and DM group(n = 47). Table 3 Multiple linear regression analysis for independent determinants of mean carotid IMT and mean of maximum carotid IMT
Fig. 2. (a) Correlation of log resistin with log mean of mean carotid IMT. (b) Correlation of log resistin with log mean of maximal carotid IMT.
Log mean IMT (R2 = 0.159) Age Log transformed resistin Log triglyceride Diabetes mellitus History of smoking LDL cholesterol Log HDL cholesterol Male gender Log maximum IMT(R2 = 0.162) Age Log transformed resistin Log triglyceride Diabetes mellitus History of smoking LDL cholesterol Log HDL cholesterol Male gender
T
Standardized coefficient
p-value
5.351 3.524 −0.447 2.945 −0.629 0.329 −1.466 −1.036
0.294 0.189 −0.027 0.163 −0.047 0.018 −0.09 −0.080
b0.001 b0.001 0.66 0.003 0.53 0.74 0.14 0.29
5.898 3.406 0.435 1.998 −1.379 0.1 −0.977 −0.688
0.324 0.182 0.026 0.110 −0.103 0.005 −0.06 −0.052
b0.001 0.001 0.66 0.047 0.17 0.92 0.33 0.49
HDL, high-density lipoprotein; LDL, low-density lipoprotein; R2, adjusted R2.
H.-J. Shin et al. / International Journal of Cardiology 125 (2008) 79–84 Table 4 Logistic regression analysis for independent determinants of CAD presence
Resistin 1st tertile Resistin 2nd tertile Resistin 3rd tertile Age Log triglyceride Diabetes mellitus History of smoking LDL cholesterol Log HDL cholesterol Male gender Log mean carotid IMT
Odds ratio
Confidence interval
p-value
1 1.334 3.097 1.046 0.656 3.174 1.307 0.990 0.221 1.646 9.868
0.606–2.936 1.438–6.669 1.014–1.079 0.329–1.310 1.486–6.777 0.555–3.080 0.980–1.000 0.052–0.939 0.681–3.979 0.763–127.573
0.47 0.004 0.004 0.23 0.003 0.54 0.04 0.04 0.27 0.08
HDL, high-density lipoprotein; LDL, low-density lipoprotein: IMT, intima media thickness.
3.3. Multivariate analysis for factors affecting presence of CAD We performed logistic regression analysis to investigate the association between resistin levels and CAD. In this model, correction was made for age, triglyceride, diabetes mellitus, history of smoking, LDL cholesterol, HDL cholesterol, mean carotid IMT and male gender. The results show more CAD in the highest resistin tertile (odds ratio = 3.097, p = 0.004; Table 4). 4. Discussion In this cross sectional study, we found that serum resistin levels are significantly and independently associated with increased IMT in hypertensive patients, even after controlling for other atherosclerosis risk factors. Studies have demonstrated a role for resistin in vascular inflammation and atherogenesis [18,19]. Resistin is known to induce MCP-1 and sVCAM-1 in vascular endothelial cells. In addition, it increases CD40 ligand expression by down regulating TNF receptor associated factor 3 [23,24]. Also, increased resistin expression has been seen in human carotid artery samples [15]. A recent study by Reilly et al. revealed, for the first time, a significant clinical association between serum resistin level and vascular inflammation markers, such as soluble TNF-α receptor 2, interleukin-6 and lipoprotein associated phospholipase A2 [18]. Notably, serum resistin was not significantly associated with markers of insulin resistance in that study, which is consistent with our results. Also, there were no significant differences in the adverse metabolic profiles such as triglyceride, HDL cholesterol or the HOMA index among serum resistin tertiles (Table 1). This finding is expected in humans, because it has been suggested that resistin is secreted by both monocytes and the adipose tissue. [22] Therefore, the association between resistin and insulin resistance markers may not be as prominent as it is in other well known adipocytokines. Rather, resistin may be an important systemic marker of vascular inflammation and atherogenesis.
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In this study, a significant association between resistin and white blood cell count was demonstrated. This finding is in concordance with a previous study that demonstrated significant correlation between plasma resistin and leukocyte count in a middle aged population cohort [25] and is most likely due to the fact that that resistins are strongly expressed in monocytes. This and the significant association of resistin with carotid IMT suggest a possibility for significant role of resistin in vascular inflammation and atherogenesis. The difference in the mean IMT between the highest resistin tertile and the others was 0.04mm, which is significant considering that the mean change in common CIMT is 0.0147 mm/year based on data from thirteen studies [26]. It is interesting to note that the highest resistin tertile contained significantly more patients with history of coronary artery disease, as demonstrated by coronary angiography, than 1 and 2 resistin tertiles. The presence of significantly higher levels of serum resistin in established coronary artery disease patients suggests a possible role for resistin in the pathogenesis of atherosclerosis. In a logistic regression analysis, there seems to be increasing CAD with lower LDL, but this may be an effect of increased statin use in the CAD group (n = 43/76; 56.6%) as compared with the non-CAD group (n = 54/231; 23.4%; p b 0.001 by Chisquared analysis). The results from this study are contradictory to the study by Kunnari et al., which did not demonstrate an independent association between resistin and early atherosclerosis [25]. The plausible reason for the discrepancy in findings may be that the study by Kunnari was performed on a relatively low risk, population based cohort, whereas this study was performed on a relatively high risk, hypertensive subjects. In this relatively high risk subjects, elevation of adipocytokines such as resistin may have a role in potentiating the risk of atherogenesis. However, because the study was performed in a relatively high risk hypertensive patients, the results from this study cannot be generalized to the general population. Also, while studies by Burnett and Pischon demonstrated significantly higher resistin level in patients with coronary artery disease, the significance was lost after controlling for variables such as microalbuminuria and hsCRP [23,27]. Because hsCRP was not assessed in this study, we cannot rule out the possibility that the association of resistin with atherogenesis is due to its association with concomitant inflammatory processes rather than a direct effect. Therefore, despite the significant association between resistin and atherogenesis that was demonstrated in this study, a direct causal relationship between resistin and atherogenesis cannot be concluded from the results. Since it has been suggested that resistin is primarily secreted by monocytes, the increase in resistin may merely be a reflection of increased monocyte activity in the vascular wall. Also, due to the cross sectional design of the study, we were not able to demonstrate a role for resistin in the progression of atherosclerosis. Further prospective studies
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are needed to elucidate this role. In conclusion, serum resistin level was significantly associated with carotid atherosclerosis and coronary artery disease, independent of age, gender, HDL cholesterol, triglyceride, LDL cholesterol, smoking and DM in treated, hypertensive patients. Acknowledgments The authors thank biostatistician, Chanmi Park for her invaluable assistance in statistical analysis and Woo Chul Chang for his assistance in the laboratory assays. This work was supported by grant (A000385) from the Ministry of Health and Welfare, Republic of Korea, and by a grant of the Seoul R&BD Program, Republic of Korea (10526). References [1] Savoia C, Schiffrin EL. Inflammation in hypertension. Curr Opin Nephrol Hypertens 2006;15:152–8. [2] Brasier AR, Recinos III A, Eledrisi MS. Vascular inflammation and the renin–angiotensin system. Arterioscler Thromb Vasc Biol 2002;22:1257–66. [3] Schiffrin EL, Touyz RM. From beside to bench to bedside: role of renin–angiotensin–aldosterone system in remodeling of resistance arteries in hypertension. Am J Physiol Heart Circ Physiol 2004;287: H435–46. [4] Touyz RM, Schiffrin EL. Reactive oxygen species in vascular biology: implications in hypertension. Histochem Cell Biol 2004;122:339–52. [5] Blake GJ, Ridker PM. Novel clinical markers of vascular wall inflammation. Circ Res 2001;89:763–71. [6] Nakashima Y, Raines EW, Plump AS, et al. Upregulation of VCAM-1 and ICAM-1 at atherosclerosis prone sites on the endothelium in the ApoE deficient mouse. Arterioscler Thromb Vasc Biol 1998;18:842–51. [7] Ballantyne CM, Entman ML. Soluble adhesion molecules and the search for biomarkers for atherosclerosis. Circulation 2002;106:766–7. [8] Lind L, Berne C, Lithell H. Prevalence of insulin resistance in essential hypertension. J Hypertens 1995;13:1457–62. [9] Fantuzzi G. Adipose tissue, adipocytokines, and inflammation. J Allergy Clin Immunol 2005;115:911–9. [10] Goldstein BJ, Scalia R. Adiponectin: a novel adipokine linking adipocytes and vascular function. J Clin Endocrinol Metab 2004;89: 2563–8. [11] Simon A, Gariepy J, Chironi G, Megnien JL, Levenson J. Intima-media thickness: a new tool for diagnosis and treatment of cardiovascular risk. J Hypertens 2002;20:159–69. [12] Ferrieres J, Elias A, Ruidavets JB, et al. Carotid intima-media thickness and coronary heart disease risk factors in low-risk population. J Hypertens 1999;17:743–8.
[13] Pannacciulli N, Rizzon P, De Pergola G, Giorgino F, Ciccone M, Giorgino R. Effect of family history of type 2 diabetes on the intimamedia thickness of the common carotid artery in normal weight, overweight, and obese glucose tolerant young adults. Diabetes Care 2003;26:1230–4. [14] Mannami T, Baba S, Ogata J. Strong and significant relationship between aggregation of major coronary risk factors and the acceleration of carotid atherosclerosis in the general population. Arch Intern Med 2001;160: 2297–303. [15] O'Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK. For the cardiovascular health study collaborative research group. N Engl J Med 1999;340:14–22. [16] Chambless LE, Folsom AR, Clegg LX, et al. Carotid wall thickness is predictive of incident clinical stroke: the Atherosclerosis Risk in Communities(ARIC) study. Am J Epidemiol 2000;151:478–87. [17] Steppan CM, Bailey ST, Bhat S, et al. The hormone resistin links obesity to diabetes. Nature 2001;409:307–12. [18] Reilly MP, Lehrke M, Wolfe ML, Rohatgi A, Lazar MA, Rader DJ. Resistin is an inflammatory marker of atherosclerosis in humans. Circulation 2005;111:932–9. [19] Steppan CM, Lazar MA. The current biology of resistin. J Intern Med 2004;255:439–47. [20] Savage DB, Sewter CP, Klenk ES, et al. Resistin/Fizz 3 expression in relation to obesity and peroxisome proliferators activated receptor gamma action in humans. Diabetes 2001;50:2199–202. [21] Burnett MS, Lee CW, Kinnaird TD, et al. The potential role of resistin in atherogenesis. Atherosclerosis 2005;182:241–8. [22] Jung HS, Park KH, Cho YM, et al. Resistin is secreted from macrophages in atheromas and promotes atherosclerosis. Cardiovasc Res 2006;69: 76–85. [23] Burnett MS, Devaney JM, Adenika RJ, Lindsay R, Howard BV. Cross sectional associations of resistin, coronary heart disease, and insulin resistance. J Clin Endocrinol Metab 2006;91:64–8. [24] Verma S, Li SH, Wang CH, et al. Resistin promotes endothelial cell activation: further evidence of adipocytokine-endothelial interactions. Circulation 2003;108:736–40. [25] Kunnari A, Ukkola O, Päivänsalo M, Kesäniemi YA. High plasma resistin level is associated with enhanced high sensitive C-reactive protein and leukocytes. J Clin Endocrinol Metab 2006;91:2755–60. [26] Bots ML, Evans GW, Riley WA, Grobbee DE. Carotid intima-media thickness measurements in intervention studies: design options, progression rates, and sample size considerations: a point of view. Stroke 2003;34:2985–94. [27] Pischon T, Bamberger CM, Kratzsch J, et al. Association of plasma resistin levels with coronary heart disease in women. Obes Res 2005;13 (10):1764–71.
Association between serum resistin and carotid intima media thickness in hypertension patients ☆ Hyun-Joon Shin a,1 , Sungha Park a,b,1 , Se-Jung Yoon a , Dae Shik Choi a , Deok-Kyu Cho c , Jung-Sun Kim a , Young-Guk Ko a , Donghoon Choi a,⁎, Yangsoo Jang a,b , Namsik Chung a a
Cardiology Division, Yonsei Cardiovascular Center, Yonsei University College of Medicine, SeodaemunGu 120-752, Seoul, Republic of Korea b Cardiovascular Genome Center, Yonsei Cardiovascular Center, Yonsei University College of Medicine, Seoul, Republic of Korea c Cardiovascular Center, Cardiology Division, Department of Internal Medicine, Myongji Hospital, Kwandong University College of Medicine, Goyang, Gyeonggi, Republic of Korea Received 22 August 2006; received in revised form 3 January 2007; accepted 17 February 2007 Available online 16 April 2007
Abstract Background: Resistin is an adipocytokine belonging to the family of cysteine rich secretory proteins. We sought to determine if a correlation between resistin levels and carotid atherosclerosis exists in hypertensive patients. Methods: This study consisted of 307 treated hypertensive patients. Subjects were grouped into tertiles according to their resistin level. Results: Carotid intima media thickness (IMT) was significantly highest in the third tertile. The first tertile had a mean carotid IMT and a mean of maximum carotid IMT of 0.63 ± 0.08 and 0.81 ± 0.10 mm, respectively. The 2nd tertile had measurements of 0.63 ± 0.08 and 0.81 ± 0.12 mm, and the 3rd tertile 0.67 ± 0.12 and 0.86 ± 0.11 for the same parameters. (p = 0.002). Resistin levels were independently associated with the carotid IMT (mean carotid IMT: R2 = 0.159, p b 0.001 and mean of maximum carotid IMT: R2 = 0.162, p b 0.001) after controlling for age, gender, HDL cholesterol, triglyceride, LDL cholesterol, smoking and DM. The tertile level of resistin was significantly associated with (odds ratio = 3.097, p = 0.004) risk of coronary artery disease after controlling for age, gender, HDL cholesterol, triglyceride, LDL cholesterol, smoking, DM and carotid IMT. Conclusion: Serum resistin is independently associated with increasing carotid IMT in treated hypertensive patients. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Resistin; Carotid intima media thickness; Hypertension
1. Introduction Inflammatory processes are important in hypertension pathophysiology and the subsequent development of cardiovascular complications [1–4]. Inflammatory markers such as CRP, cell adhesion molecules, MCP-1, Interleukin6 and TNF-α are known to be involved in the pathogenesis ☆
This work was supported by a grant from the ministry of Health and Welfare of the Republic of Korea (A000385) and by a grant of the Seoul R&BD program, Republic of Korea (10526). ⁎ Corresponding author. Tel.: +82 2 2228 8449; fax: +82 2 393 2041. E-mail address: [email protected] (D. Choi). 1 These authors contributed equally to this article. 0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2007.02.028
of hypertension and are present at increased levels in patients with cardiovascular disease [1,5–7]. Insulin resistance syndrome is observed in 30–50% of patients with hypertension and adipocytokines may be important inflammatory mediators in developing cardiovascular complications in hypertension patients [8]. Studies have demonstrated that adipocytokines, such as adiponectin, play a significant role in regulating vascular inflammation and atherogenesis [9,10]. Carotid intima media thickness (IMT) measurement is a marker of early atherosclerosis that is associated with traditional cardiovascular risk factors such as aging, obesity, hypertension, dyslipidemia, diabetes and smoking [11–14]. Also, studies have demonstrated that carotid IMT is an
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independent marker for future cardiovascular events such as myocardial infarction and stroke [15,16]. Hypertension is known to be a major factor on IMT via its effect on medial hypertrophy [11]. However, associated cardiovascular risk factors are likely to have a significant role in potentiating atherogenesis in hypertension. Among these factors, adipocytokines may have a significant role in potentiating vascular inflammation and atherogenesis. Resistin is an adipocytokine belonging to the family of cysteine rich secretory proteins [17]. Studies have shown it to have a role in regulating metabolism, adipogenesis and mediating vascular inflammation [18,19]. Unlike rodents, in which resistin is exclusively secreted from adipose tissue, human resistin is secreted not only by adipocytes but circulating mononuclear cells as well [20]. Studies have shown a potential role of resistin in atherogenesis and vascular inflammation [18,19,21,22]. However, studies regarding the role of resistin in the pathogenesis of atherosclerosis in hypertensive subjects have not been performed. In this study, we examined an association between serum resistin and carotid IMT, an index of early atherosclerosis, in 307 patients with essential hypertension. 2. Methods 2.1. Study population The study consisted of 307 hypertensive patients treated at the Yonsei Cardiovascular Hospital from October 2004 to March 2006. They were enrolled in the Cardiovascular Genome Center for a ministry of Health and Welfare sponsored genotypic study of cardiovascular disease. We recruited treated hypertensive patients based upon systolic blood pressure greater than 140 mm Hg and/or diastolic blood pressure greater than 90 mm Hg over three different visits prior to taking antihypertensive medication and/or patients taking anti-hypertensive medication for at least 3 months prior to enrollment. Patients with significant coronary artery disease [coronary artery disease (CAD) group; n = 76] were patients who had greater than 50% luminal narrowing in at least one coronary artery greater than 2 mm in diameter, as determined by coronary angiography. Smoking was classified as ever smoking versus never smoking. Amount of smoking was also considered. Past smokers who had smoked fewer than 100 cigarettes were classified as never smokers. Diabetes mellitus (DM) is defined as patients satisfying at least one of three criteria: 1) taking anti-diabetic medications, 2) fasting blood glucose level above 126 mg/dl and 3) random blood sugar above 200 mg/dl. The following conditions excluded patients from enrollment: valvular heart disease, peripheral vascular disease, significant systemic disease, history of inflammatory disease, a clinically significant atrioventricular conduction disturbance, history of atrial fibrillation or other serious arrhythmia, history of congestive heart failure, and severe hypertension (N 210/ 130 mm Hg), and serum creatinine greater than 1.4 mg/dl.
At the time of enrollment, patients underwent a complete physical examination, baseline electrocardiogram and laboratory assessment. After resting for at least five minutes in a sitting position, office blood pressure (BP) was measured using a sphygmomanometer with an appropriate cuff. Two measurements were taken at least five minutes apart and the mean was used for analysis. Blood chemistry [glucose, blood urea nitrogen (BUN), uric acid, total cholesterol, total bilirubin, alkaline phosphatase, AST, ALT, creatinine, Na, K, Triglyceride, highdensity lipoprotein (HDL), low-density lipoprotein (LDL)] and fasting serum insulin were assessed. The fasting serum insulin level was measured with an immunoradiometric assay and a gamma counter (Hewlett Packard, USA). Insulin resistance was measured using the homeostasis model assessment of insulin resistance index (HOMA index), with the following formula; HOMA index ¼ fasting insulinðAU=mlÞ fasting glycemia ðmmol=LÞ=22:5: Venous blood sampling was performed after an overnight fast, and the serum was immediately frozen at −70 °C for future analysis. Serum resistin levels were measured using the Quantikine human resistin immunoassay kit (R&D Systems, Minneapolis, MN, USA). The study group was divided according to the tertile level of resistin. Group 1 was patients with the 1st tertile level of resistin, group 2 was patients with 2nd tertile level of resistin and group 3 was patients with 3rd tertile level of resistin. This study was approved beforehand by the institutional ethics committee, and procedures followed were in accordance with the institutional guidelines. All patients gave informed consent prior to being enrolled. 2.2. Carotid IMT measurement Ultrasonographic scanning of the carotid artery was performed by a single operator, blind to subject details with a high-resolution real-time 8-MHz linear scanner (Sequoia C512, Acuson Co. Ltd.). Participants were scanned in the supine position with the neck hyperextended. An optimal longitudinal B mode image of both common carotid arteries proximal to the bifurcation was obtained and stored digitally. The mean and maximum CIMT (carotid intima media thickness) of the far wall of the common carotid arteries were measured offline with the highest quality end-diastolic frame, using the automated edge detection methodology program (M'ATH®, METRIS Co. FRANCE). The mean CIMT was defined as the average mean IMT of the right and left carotid arteries measured by the automated edge detection methodology. The mean of maximum CIMT was defined as the average of the maximum IMT value for both the right and left carotid arteries. 2.3. Statistical analysis The study population was divided into tertiles of serum resistin (Table 1). Continuous variables were compared using
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Table 1 Baseline characteristics
Resistin(ng/ml) Age (years) Mean of carotid IMT(mm) Mean of maximum carotid IMT(mm) Male (%) Official BP SBP (mm Hg) DBP (mm Hg) DM(%) Smoking (%) CAD (%) T. chol (mg/dl) TG (mg/dl) HDL (mg/dl) LDL (mg/dl) FBG(mg/dl) Insulin(mU/L) Waist(cm) Waist Hip Ratio BMI(kg/m2) Body weight(kg) HOMA White blood cell count (μl)
1st tertile(N = 102)
2nd tertile(N = 103)
3rd tertile(N = 102)
p-value⁎
3.77 ± 1.17(0.57–5.77) 56.3 ± 9.9(35–77) 0.63 ± 0.08(0.48–0.89) 0.81 ± 0.1(0.6–1.1) 55(53.9%)
7.87 ± 1.42(5.81–10.5) 55.4 ± 10.7(28–78) 0.63 ± 0.08(0.44–0.87) 0.81 ± 0.12(0.59–1.53) 56(54.4%)
17.17±6.11(10.55–44.42) 55.9 ± 11.1(25–77) 0.67±0.12(0.51–0.90) 0.86 ± 0.11(0.66–1.22) 51(50.0%)
b0.001 0.86 0.002 0.002 0.79
125 ± 14(92–160) 80 ± 11(60–110) 14(13.7%) 41(40.2.%) 17(16.7%) 191 ± 35(122–306) 157 ± 125(48–1020) 50 ± 13(28–93) 111 ± 32(45–225) 93± 22(70–204) 9.1 ± 4.0(2.2–28.6) 88.4 ± 7.9(60.9–104.0) 0.9 ± 0.07(0.65–1.03) 25.1 ± 2.6(19.22–33.48) 66.5 ± 10.8(45–94.5) 2.10 ± 1.06(0.42–8.18) 4634 ± 1242(2600–9300)
126 ± 15 (100–160) 80 ± 9(52–104) 14(13.6%) 44(42.7%) 22(21.4%) 185 ± 36(122–303) 153 ± 103(37–697) 48 ± 13(23–88) 106 ± 34(22–220) 94± 26(71–256) 10.7 ± 10.7(1.7–92.7) 88.5 ± 8.6(67.0–104.5) 0.91 ± 0.07(0.76–1.23) 25.6 ± 2.96(18.03–34.36) 67.5 ± 10.0(47.5–97.5) 2.54 ± 2.92(0.34–21.57) 5371 ± 1721(2700–13900)
126 ± 17(94–170) 80 ± 11(58–110) 19(18.6%) 37(36.3%) 37(36.3%) 189 ± 36(115–299) 155 ± 94(49–643) 49 ± 13 (25–86) 109 ± 35(36–220) 95± 23(66–218) 9.8 ± 4.2(4.0–32.8) 87.7 ± 7.7(68.0–108.0) 0.9 ± 0.6(0.77–1.08) 25.4 ± 2.7(18.44–32.13) 66.5 ± 10.8(47–96) 2.30 ± 1.17(0.91–6.96) 5472 ± 1611(2300–11800)
0.83 0.84 0.52 0.64 0.003 0.46 0.90 0.70 0.56 0.86 0.39 0.76 0.94 0.46 0.74 0.39 b0.001
Values are presented as n (%) or mean ± SD(range); IMT, intima media thickness; SBP, systolic blood pressure; DBP, diastolic blood pressure; DM, diabetes mellitus; CAD, coronary artery disease; TG, triglyceride; HDL, high-density lipoprotein; LDL, low-density lipoprotein; FBG, fasting blood glucose; BMI, body mass index; HOMA, homeostasis model assessment of insulin resistance index. ⁎ p-value b 0.05 is considered significant. Chi-square test was used for categorical variables. ANOVA was used for continuous variables.
analysis of variance (ANOVA). Categorical variables were compared using a Chi-squared analysis. The simple correlation between continuous variables was explored using the Pearson's correlation analysis. To normalize the distribution, a natural logarithmic transformation was applied to resistin levels, mean carotid IMT, mean of maximum carotid IMT, systolic blood pressure, diastolic blood pressure, triglyceride (TG), high-density lipoprotein (HDL) and HOMA index. In the multiple linear regression models, an association of log transformed resistin levels was assessed when controlled for age, TG, DM (yes, no), history of smoking (smoker, nonsmoker), low-density lipoprotein (LDL) cholesterol, HDL cholesterol and male gender(yes, no). Associations between resistin tertiles, age, TG, DM, smoking, LDL, HDL, male gender, mean carotid IMT and presence of CAD were evaluated by logistic regression analysis. Statistical significance is defined as a p-value b 0.05 on two-tailed testing. Statistical analysis was performed with SPSS 11.0 program (SPSS Inc., Chicago, IL, USA). 3. Results 3.1. Clinical characteristics The mean and median serum resistin concentration were 9.60 and 7.68 ng/ml respectively. Serum resistin concentration of females (mean/median: 9.59/8.02 ng/ml) and males(mean/ median: 9.60/7.70 ng/ml) did not differ significantly. Also, the
serum resistin concentration of metabolic syndrome patients defined according to the NCEPATP-III criteria (n = 159; mean/ median: 9.77/7.78 ng/ml) and non-metabolic syndrome patients (n = 148; mean/median: 9.23/7.33 ng/ml) was not significantly different. The three resistin tertiles did not differ for clinical variables such as age, gender and cardiovascular disease risk factors (Table 1). There were no significant differences in the proportion of patients taking ACE inhibitors, angiotensin receptor blockers, beta-blockers, calcium channel blockers, diuretics, statins, sulfonylureas or biguanides among the three tertiles. (Table 2) The mean carotid IMT and mean of maximum carotid IMT were both higher in the 3rd tertile Table 2 Medication history
ACE inhibitors (%) ARB (%) Beta-blockers (%) CCB (%) Diuretics (%) Statins (%) Sulfonylurea(%) Biguanide(%)
1st tertile (N = 102)
2nd tertile (N = 103)
3rd tertile (N = 102)
p-value⁎
18 (17.6%) 42(38.9%) 52 (51%) 81 (79.4%) 20 (19.6%) 30 (29.4%) 5(4.9%) 3(2.9%)
22 (21.4%) 37(34.3%) 52 (50.5%) 79 (76.7%) 18 (17.5%) 35 (34%) 3(2.9%) 4(3.9%)
25 (24.5%) 29(26.9%) 62 (60.8%) 77 (75.5%) 26 (25.5%) 32 (31.4%) 10(9.8%) 6(5.9%)
0.49 0.16 0.25 0.79 0.34 0.78 0.10 0.57
ACE, angiotensin-converting enzyme; ARB, angiotensin-converting enzyme receptor blocker; CCB, calcium channel blocker. ⁎ p-value b 0.05 is considered significant. Chi-square test was used for statistical analysis.
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Fig. 1. (a) Mean carotid IMT difference between the three resistin tertiles. (b) Mean of maximum carotid IMT difference between the three resistin tertiles. Error bar depicting mean ± standard error; ⁎, p b 0.01.
compared to the 1st tertile and the 2nd tertile (Table 1, Fig. 1). There was significant correlation between log transformed serum resistin and mean of mean IMT(r = 0.187, p = 0.001)
and mean of maximum IMT(r = 0.178, p = 0.002) by Pearson correlation analysis (Fig. 2). 3.2. Multivariate analysis for factors affecting carotid IMT Log transformed resistin levels are significantly associated with both mean carotid IMT (β = 0.189, p b 0.001) and mean of maximum carotid IMT (β = 0.182, p = 0.001) by multiple linear regression analysis (Table 3). In this model, correction was made for age, triglyceride, diabetes mellitus, history of smoking, HDL cholesterol, LDL cholesterol and male gender. In subgroup analysis according to the presence of DM, there was significant association of log transformed resistin with the mean carotid IMT (non-DM: β = 0.15, p = 0.01; DM: β = 0.37, p = 0.01) and mean of maximum carotid IMT. (non-DM: β = 0.17, p b 0.01; DM: β = 0.30, p = 0.03) in both non-DM(n = 260) and DM group(n = 47). Table 3 Multiple linear regression analysis for independent determinants of mean carotid IMT and mean of maximum carotid IMT
Fig. 2. (a) Correlation of log resistin with log mean of mean carotid IMT. (b) Correlation of log resistin with log mean of maximal carotid IMT.
Log mean IMT (R2 = 0.159) Age Log transformed resistin Log triglyceride Diabetes mellitus History of smoking LDL cholesterol Log HDL cholesterol Male gender Log maximum IMT(R2 = 0.162) Age Log transformed resistin Log triglyceride Diabetes mellitus History of smoking LDL cholesterol Log HDL cholesterol Male gender
T
Standardized coefficient
p-value
5.351 3.524 −0.447 2.945 −0.629 0.329 −1.466 −1.036
0.294 0.189 −0.027 0.163 −0.047 0.018 −0.09 −0.080
b0.001 b0.001 0.66 0.003 0.53 0.74 0.14 0.29
5.898 3.406 0.435 1.998 −1.379 0.1 −0.977 −0.688
0.324 0.182 0.026 0.110 −0.103 0.005 −0.06 −0.052
b0.001 0.001 0.66 0.047 0.17 0.92 0.33 0.49
HDL, high-density lipoprotein; LDL, low-density lipoprotein; R2, adjusted R2.
H.-J. Shin et al. / International Journal of Cardiology 125 (2008) 79–84 Table 4 Logistic regression analysis for independent determinants of CAD presence
Resistin 1st tertile Resistin 2nd tertile Resistin 3rd tertile Age Log triglyceride Diabetes mellitus History of smoking LDL cholesterol Log HDL cholesterol Male gender Log mean carotid IMT
Odds ratio
Confidence interval
p-value
1 1.334 3.097 1.046 0.656 3.174 1.307 0.990 0.221 1.646 9.868
0.606–2.936 1.438–6.669 1.014–1.079 0.329–1.310 1.486–6.777 0.555–3.080 0.980–1.000 0.052–0.939 0.681–3.979 0.763–127.573
0.47 0.004 0.004 0.23 0.003 0.54 0.04 0.04 0.27 0.08
HDL, high-density lipoprotein; LDL, low-density lipoprotein: IMT, intima media thickness.
3.3. Multivariate analysis for factors affecting presence of CAD We performed logistic regression analysis to investigate the association between resistin levels and CAD. In this model, correction was made for age, triglyceride, diabetes mellitus, history of smoking, LDL cholesterol, HDL cholesterol, mean carotid IMT and male gender. The results show more CAD in the highest resistin tertile (odds ratio = 3.097, p = 0.004; Table 4). 4. Discussion In this cross sectional study, we found that serum resistin levels are significantly and independently associated with increased IMT in hypertensive patients, even after controlling for other atherosclerosis risk factors. Studies have demonstrated a role for resistin in vascular inflammation and atherogenesis [18,19]. Resistin is known to induce MCP-1 and sVCAM-1 in vascular endothelial cells. In addition, it increases CD40 ligand expression by down regulating TNF receptor associated factor 3 [23,24]. Also, increased resistin expression has been seen in human carotid artery samples [15]. A recent study by Reilly et al. revealed, for the first time, a significant clinical association between serum resistin level and vascular inflammation markers, such as soluble TNF-α receptor 2, interleukin-6 and lipoprotein associated phospholipase A2 [18]. Notably, serum resistin was not significantly associated with markers of insulin resistance in that study, which is consistent with our results. Also, there were no significant differences in the adverse metabolic profiles such as triglyceride, HDL cholesterol or the HOMA index among serum resistin tertiles (Table 1). This finding is expected in humans, because it has been suggested that resistin is secreted by both monocytes and the adipose tissue. [22] Therefore, the association between resistin and insulin resistance markers may not be as prominent as it is in other well known adipocytokines. Rather, resistin may be an important systemic marker of vascular inflammation and atherogenesis.
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In this study, a significant association between resistin and white blood cell count was demonstrated. This finding is in concordance with a previous study that demonstrated significant correlation between plasma resistin and leukocyte count in a middle aged population cohort [25] and is most likely due to the fact that that resistins are strongly expressed in monocytes. This and the significant association of resistin with carotid IMT suggest a possibility for significant role of resistin in vascular inflammation and atherogenesis. The difference in the mean IMT between the highest resistin tertile and the others was 0.04mm, which is significant considering that the mean change in common CIMT is 0.0147 mm/year based on data from thirteen studies [26]. It is interesting to note that the highest resistin tertile contained significantly more patients with history of coronary artery disease, as demonstrated by coronary angiography, than 1 and 2 resistin tertiles. The presence of significantly higher levels of serum resistin in established coronary artery disease patients suggests a possible role for resistin in the pathogenesis of atherosclerosis. In a logistic regression analysis, there seems to be increasing CAD with lower LDL, but this may be an effect of increased statin use in the CAD group (n = 43/76; 56.6%) as compared with the non-CAD group (n = 54/231; 23.4%; p b 0.001 by Chisquared analysis). The results from this study are contradictory to the study by Kunnari et al., which did not demonstrate an independent association between resistin and early atherosclerosis [25]. The plausible reason for the discrepancy in findings may be that the study by Kunnari was performed on a relatively low risk, population based cohort, whereas this study was performed on a relatively high risk, hypertensive subjects. In this relatively high risk subjects, elevation of adipocytokines such as resistin may have a role in potentiating the risk of atherogenesis. However, because the study was performed in a relatively high risk hypertensive patients, the results from this study cannot be generalized to the general population. Also, while studies by Burnett and Pischon demonstrated significantly higher resistin level in patients with coronary artery disease, the significance was lost after controlling for variables such as microalbuminuria and hsCRP [23,27]. Because hsCRP was not assessed in this study, we cannot rule out the possibility that the association of resistin with atherogenesis is due to its association with concomitant inflammatory processes rather than a direct effect. Therefore, despite the significant association between resistin and atherogenesis that was demonstrated in this study, a direct causal relationship between resistin and atherogenesis cannot be concluded from the results. Since it has been suggested that resistin is primarily secreted by monocytes, the increase in resistin may merely be a reflection of increased monocyte activity in the vascular wall. Also, due to the cross sectional design of the study, we were not able to demonstrate a role for resistin in the progression of atherosclerosis. Further prospective studies
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are needed to elucidate this role. In conclusion, serum resistin level was significantly associated with carotid atherosclerosis and coronary artery disease, independent of age, gender, HDL cholesterol, triglyceride, LDL cholesterol, smoking and DM in treated, hypertensive patients. Acknowledgments The authors thank biostatistician, Chanmi Park for her invaluable assistance in statistical analysis and Woo Chul Chang for his assistance in the laboratory assays. This work was supported by grant (A000385) from the Ministry of Health and Welfare, Republic of Korea, and by a grant of the Seoul R&BD Program, Republic of Korea (10526). References [1] Savoia C, Schiffrin EL. Inflammation in hypertension. Curr Opin Nephrol Hypertens 2006;15:152–8. [2] Brasier AR, Recinos III A, Eledrisi MS. Vascular inflammation and the renin–angiotensin system. Arterioscler Thromb Vasc Biol 2002;22:1257–66. [3] Schiffrin EL, Touyz RM. From beside to bench to bedside: role of renin–angiotensin–aldosterone system in remodeling of resistance arteries in hypertension. Am J Physiol Heart Circ Physiol 2004;287: H435–46. [4] Touyz RM, Schiffrin EL. Reactive oxygen species in vascular biology: implications in hypertension. Histochem Cell Biol 2004;122:339–52. [5] Blake GJ, Ridker PM. Novel clinical markers of vascular wall inflammation. Circ Res 2001;89:763–71. [6] Nakashima Y, Raines EW, Plump AS, et al. Upregulation of VCAM-1 and ICAM-1 at atherosclerosis prone sites on the endothelium in the ApoE deficient mouse. Arterioscler Thromb Vasc Biol 1998;18:842–51. [7] Ballantyne CM, Entman ML. Soluble adhesion molecules and the search for biomarkers for atherosclerosis. Circulation 2002;106:766–7. [8] Lind L, Berne C, Lithell H. Prevalence of insulin resistance in essential hypertension. J Hypertens 1995;13:1457–62. [9] Fantuzzi G. Adipose tissue, adipocytokines, and inflammation. J Allergy Clin Immunol 2005;115:911–9. [10] Goldstein BJ, Scalia R. Adiponectin: a novel adipokine linking adipocytes and vascular function. J Clin Endocrinol Metab 2004;89: 2563–8. [11] Simon A, Gariepy J, Chironi G, Megnien JL, Levenson J. Intima-media thickness: a new tool for diagnosis and treatment of cardiovascular risk. J Hypertens 2002;20:159–69. [12] Ferrieres J, Elias A, Ruidavets JB, et al. Carotid intima-media thickness and coronary heart disease risk factors in low-risk population. J Hypertens 1999;17:743–8.
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