The association of metabolic syndrome and its components with brachial-ankle pulse wave velocity in south China

Atherosclerosis 240 (2015) 345e350

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The association of metabolic syndrome and its components with brachial-ankle pulse wave velocity in south China Liying Chen a, Wenhua Zhu a, Linhe Mai b, Lizheng Fang a, Kejing Ying a, * a b

Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, No. 3 Qingchun East Road, Hangzhou 310016, PR China Shajing People's Hospital, Shenzhen, No. 3 Shajing Street, Baoan District, Shenzhen 518104, PR China

a r t i c l e i n f o

a b s t r a c t

Article history: Received 4 January 2015 Received in revised form 5 March 2015 Accepted 18 March 2015 Available online 20 March 2015

Background: Brachial-ankle pulse wave velocity (baPWV) can reflect both central and peripheral arterial stiffness. Metabolic syndrome (MS) and its components may increase arterial stiffness and the risks of cardiovascular diseases. However, the correlation of MS and its components with arterial stiffness has not been not well studied. The aim of this study was to investigate the correlation between MS/its components and arterial stiffness by the measurement of baPWV in south China population. Methods: A total of 8599 subjects were selected from those who underwent health examination in our hospital. MS was defined by Joint Scientific Statement. BaPWV, waist circumference, blood pressure (BP), fasting plasma glucose (FPG), lipid profile and serum uric acid (UA) were measured. The relationship between baPWV and MS/its components was analyzed. Results: BaPWV was significantly higher in the subjects with MS than in those without MS (P < 0.001 for both genders). By multivariate regression analysis, all the metabolic components were correlated to baPWV in the male and female subjects except low HDL-C and high UA in the male group. BP and FPG had the strongest correlation factors. The values of baPWV were positively correlated with the advanced age (P < 0.001) and the values of the MS components, and this correlation was stronger in the females than in the males (P < 0.001). Conclusion: Metabolic syndrome and its individual components were positively correlated with baPWV. Monitoring baPWV is helpful to identify early stage of arterial stiffness in those people with MS. © 2015 Elsevier Ireland Ltd. All rights reserved.

Keywords: Metabolic syndrome Brachial-ankle pulse wave velocity Arterial stiffness Cardiovascular diseases

1. Introduction Cardiovascular diseases (CVD) are the major causes of morbidity and mortality worldwide. In 2011, the World Health Organization (WHO) reported that approximately 17.3 million people died of CVD, representing 30% of all global deaths [1]. By 2030, it is estimated that there will be 23.6 million deaths from CVD. The situation is not optimistic also in China. The National Center of CVD in China has reported that about 1 in 5 Chinese adults has CVD, and the morbidity rate is on the rise in 2014 [2]. Furthermore, stroke can cause, in addition to death, various serious sequelae including disturbance of vision, aphasia, dysphagia, paralysis, urinary and fecal incontinence and so on. These consequences not only lower the patients' quality of life, but also increase the burden on the family even the whole society.

* Corresponding author. E-mail address: [email protected] (K. Ying). http://dx.doi.org/10.1016/j.atherosclerosis.2015.03.031 0021-9150/© 2015 Elsevier Ireland Ltd. All rights reserved.

Metabolic syndrome is a cluster of atherosclerosis and CVD risk factors such as central obesity, hypertension, dyslipidemia and glucose intolerance [3]. It often presents before the onset of CVD, and its components are usually related to the development and progression of CVD. Arterial stiffness is also related to atherosclerosis and CVD, and has been considered to be a strong independent predictor of coronary events and cardiovascular mortality in several patient groups. Arterial stiffness can be evaluated by the measurement of pulse wave velocity (PWV) along the arterial tree. PWV is an effective index of arterial stiffness of large arteries, and it is widely used for non-invasive assessment of atherosclerosis [4]. Some publications report that a PWV measurement can predict future cardiovascular events in hypertensive patients and elderly individuals, and is useful for evaluating carotid arteriosclerosis [5]. Researches have demonstrated good validity and reproducibility of brachial-ankle PWV (baPWV), as well as its strong association with central PWV [6,7]. The association of MS with arterial stiffness has been investigated in some studies [8e15]. Most of these studies have shown

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increased PWV in subjects with MS or with a larger number of MS components [8e12]. However, most of them were small sample researches or community-based researches [13]. Some studies were based on specific subjects, such as patients with systemic lupus erythematosus [14], and patients newly detected with suspected hypothyroidism [15]. Therefore, the results of these studies could not explain the association of MS with PWV very well. The aim of the present study was to evaluate the relationship between baPWV and MS and its individual components in a large sample size of 8599 subjects. 2. Material and methods 2.1. Study population This study included 8599 subjects (6659 men and 1940 women, age range from 18 to 75 years) who underwent physical examinations in Sir Run Run Shaw Hospital of the Zhejiang University School of Medicine from January 2011 to December 2013. All subjects were from Zhejiang Province, Jiangsu Province, Jiangxi Province and so on, which located in the southern part of China. Subjects with atherosclerotic cardiovascular disease, or stroke, or cardiomyopathy, or on medications for hypertension or diabetes were excluded. This study was approved by the Medical Ethics Committee of the Sir Run Run Shaw Hospital. Written informed consent was obtained from all the participants. 2.2. Measurement techniques Participants were asked to avoid a high fat and sugar diet for three days before the examination. Fasting blood samples were obtained from each subject, typically from 7 to 8 AM. The samples were immediately centrifuged and analyzed within 1 h. Fasting plasma glucose levels were measured by the hexokinase method (Abbott c16000, USA). Triglyceride levels were measured by the glycerol phosphate oxidase method (Abbott c16000, USA). HDL cholesterol levels were measured by the clearance assay method (Abbott c16000, USA). Waist circumference measurement was according to the WHO recommended method. It was measured midway between the lowest rib and the iliac crest by an anthropometric tape. Blood pressure was measured by the method recommended in China Hypertension Prevention Guidelines (2010 Edition) from the left arm of the patient on seated position. The mean of two blood pressure values obtained by two individual physicians was used for analysis. 2.3. Definition of the MS MS definition is based on the Joint Scientific Statement (A Joint Interim Statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity, Publish in Circulation, 2009) [3]. Obesity is defined by the WHO Asian Region. A person has metabolic syndrome if the waist circumference is increased (
85 cm for men and
80 cm for women) and at least two of the following factors are present: triglyceride (TG) level
1.7 mmol/L, systolic blood pressure (SBP)
130 mmHg or diastolic blood pressure (DBP)
85 mmHg, fasting plasma glucose (FPG)
5.6 mmol/L, and high-density lipoprotein (HDL) cholesterol <1.0 mmol/L in men or <1.30 mmol/L in women.

2.4. Measurements of brachial-ankle pulse wave velocity (baPWV) The baPWV was assessed by a non-invasive arterial atherosclerosis measuring system, VP-1000 (BP-203RPEII). Subjects took three deep breaths and rested in a supine position for at least 5 min before examination. The cuffs were wrapped on both sides of the brachium and ankle, which contained a plethysmographic sensor to determine the wave data. Blood pressure was measured by the oscillometric method. The baPWV was calculated as follows: baPWV ¼ (LaLb)/Tba (La: the path length from the heart to the ankle; Lb: the path length from the heart to the brachium; Tba: the time delay between the arrival of the pulse wave at the brachium and ankle). The mean of the right and left baPWV values was used for analysis. This method has been validated previously. 2.5. Quality control Data were collected by the coordinator who received strictly training. All the equipment was inspected. All the biochemical indices were assayed by the designated staff on fixed instruments. These indices were controlled using standard quality control serum. 2.6. Statistical analysis Input of the descriptive data was performed by a designated staff, and statistical analysis was carried out by SPSS version 19.0 (SPSS Inc., Chicago, IL, USA). The quantitative data were described as mean ± SD. A multiple linear regression model with step-wise selection and logistic regression analysis were used to estimate the correlation between MS/its components and baPWV in each group stratified by age. Standardized effect size (b value) was calculated to compare the relationship in each group. KruskaleWallis test was used for the comparisons among multiple groups. Variables with p values <0.05 were considered significant. 3. Results Complete data were obtained from 8599 subjects (6659 men and 1940 women), whose characteristics are summarized in Table 1. The ages of the male and female subjects were 46.2 ± 9.5 years and 46.2 ± 9.6 years, respectively (P ¼ 0.004). BaPWV and the other variables except for HDL were significantly higher in men than in women. The values of baPWV among different age groups were statistically significant in both the males and females. The changes of baPWV with age for the males and females are displayed in Fig. 1. The results showed that the values of baPWV were increased according to the advancing age in both gender (p < 0.001). And the effect of age on baPWV was greater in the females than that in the males. The correlation of MS and its components with baPWV values were analyzed in the males and females. The MS components were associated with increased baPWV in both the males and the females except for the low HDL-cholesterol level in the males as shown in Table 2. Elevated BP and FPG were the strongest factors affecting baPWV. The baPWV was significantly higher in both the male and female subjects with metabolic syndrome. A multiple logistic regression model was performed to examine the correlation between MS/its components and baPWV status in the males and females (Table 3). In this model, metabolic syndrome and its components were associated with increased baPWV in both the males and females except for the low HDL-cholesterol level in the males. High BP and high FPG are the most important factors for baPWV. The OR values were 4.5 for high BP, 2.2 for high FPG, 1.7 for

L. Chen et al. / Atherosclerosis 240 (2015) 345e350 Table 1 Demographic and clinical characteristic of study subjects stratified by Gender.a Variables

Male (n ¼ 6659)

Female (n ¼ 1940)

P value

46.2 ± 9.5 169.8 ± 5.7 72.7 ± 10.2 125.6 ± 15.4 78.2 ± 11.3 88.1 ± 8.5 5.30 ± 1.25 1.89 ± 1.49 1.16 ± 0.27

46.2 ± 9.6 158.1 ± 5.2 58.2 ± 8.2 117.9 ± 18.1 70.5 ± 11.3 77.6 ± 8.7 4.97 ± 0.91 1.27 ± 0.89 1.34 ± 0.37

0.063 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001

382.1 ± 80.4 1362 ± 225 n(%) 2974(44.7) 1382(20.8) 2220(33.3) 3091(46.4) 4516(67.8) 2095(31.5)

254.3 ± 60.1 1279 ± 263

<0.001 <0.001

566(29.2) 216(11.1) 875(45.1) 380(19.6) 726(37.4) 366(18.9)

<0.001 <0.001 <0.001 <0.001 <0.001 <0.001

Mean ± SD Age, year Height, cm Weight, cm Systolic blood pressure (SBP), mm Hg Diastolic blood pressure (DBP), mm Hg Waist circumference (WC), cm Fasting plasma glucose (FPG), mmol/L Triglyceride (TG), mmol/L High-density lipoprotein cholesterol (HDL-C), mmol/L Uric acid(UA), mmol/L BaPWV, cm/s Higher BP Higher FPG Lower HDL-C Higher TG Higher WC Metabolic syndrome (MS)

Large waist circumference denotes waist circumference
80 cm for females or
85 cm for males; higher blood pressure denotes systolic blood pressure
130 or diastolic blood pressure
85 mmHg or drug treatment; raised fasting plasma glucose (FPG) denotes FPG
5.6 mmol/L or drug treatment; raised triglyceride denotes triglyceride
1.70 mmol/L or drug treatment; lower high-density lipoprotein cholesterol (HDL-C)denotes HDL-C < 1.29 mmol/L for females or < 1.0 mmol/L for males or drug treatment. a Student-t test was used to analyze the gender difference of continuous variables; Gender differences of MS and its components were tested by chi square method.

high TG and 1.4 for high WC in the males, and 6.3 for high BP, 2.5 for high FPG, 1.9 for high TG, 1.6 for low HDL-cholesterol and 1.5 for high WC in the females, respectively. In both the males and females, the values of baPWV were significantly and positively correlated with the values of the components of MS (p < 0.001) (Fig. 2). 4. Discussion Pulse wave velocity (PWV) reflects arterial stiffness, and it is a marker of both the severity of vascular damage and the prognosis of cardiovascular diseases in certain patients, such as those with hypertension or with abnormal glucose metabolism [16]. MS and its

Fig. 1. Trend test of baPWV value with age in male and female, group1: age from 18 to 39 yrs, group2: age from 40 to 59 yrs, group3: age from 60 to 75 yrs.

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components have been associated with arterial stiffness and cardiovascular diseases. The research about the association of MS and its components with baPWV is a hot topic around the world. Several studies showed that baPWV was significantly higher in subjects with individual components of MS, and increased with the values of the components [17,18]. Since the components of MS are related to each another and frequently appear as cluster features, it is necessary to manage the components of MS together. Also, the different combinations of components of MS have different influences in PWV. It has been suggested that specific combinations of the components of MS may be more powerful predictors of mortality as compared with others. In a cross-countries study, Angelo Scuteri et al. showed that the clusters of MS components they identified as significant determinants of extremely stiff arteries (TBW, GBW, GTBW) may be useful to identify subjects from subgroups at higher CV risk [19] (W: abdominal obesity, T: high triglycerides, B: elevated blood pressure, H: low HDL cholesterol, G: elevated fasting glucose). In all, the association of MS with baPWV is not understood well. And questions such as which components are important factors, and which combination is more powerful in predicting higher baPWV are to be answered. Age has long been considered as an important factor affecting baPWV [20e23]. The values of baPWV are increased according to the advanced age in both genders. In a cross-section study of normal volunteers aged 3 days to 65 years, arterial stiffness reduced with age up to 8e10 years and then increased [24]. Other studies indicated that PWV increased 83% and 134% from birth to the age of 90 years in rural and urban Chinese subjects [22,23]. Aging induces structural and functional abnormalities such as arterial wall hypertrophy and degeneration or disorganization of the medial layer [24,25]. These changes increase PWV because of the increased arterial stiffness. In the present study, it was found that the values of baPWV were increased according to the age in both the males and females, and the augmentation of baPWV with aging is more significant in the females. Gender is another important factor affecting baPWV. Some studies indicated that women had lower baPWV than men in general [26]. There are two main reasons to explain this phenomenon. Firstly, estrogen plays an important role in it. Secondly, lifestyle is also one of the reasons. In China, smoking and drinking alcohol are more common in men than in women, which are the risk factors for arterial stiffness. Furthermore, in some studies, when stratified by age, women had lower baPWV than men only in the young and middle-aged populations. There was no significant difference in the elderly population, suggesting that differences in baPWV between men and women are age-related [20,26]. In the present study, the change of baPWV in the females was more obvious with age. And there was no statistically difference between the male and female in age 40 to 59, which is consistent with the findings of another study [20,26]. Since the levels of estrogens and androgens in both female and male fluctuate with age, it is possible that the influence of age on the arterial tree may contribute to this observation. Thus, menopause seems to be the crucial phenomenon to explain the increase of arterial stiffness with aging in female. In the present study, the correlations of baPWV with MS and its components were investigated. It was found that baPWV was significantly higher in the subjects with MS than in those without MS, and baPWV increased with the increase of the values of MS components. This result was consistent with those of other studies [17,18]. In the present study, BP and FPG were the strongest factors determining baPWV. The affect of the elevated BP on progressive baPWV may be due to its direct effect on the arterial walls. Elevated BP may accelerate arterial stiffening because it forces endothelial cells and arterial smooth muscle cells to be exposed to the increased arterial wall dispensability chronically, which reflects

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L. Chen et al. / Atherosclerosis 240 (2015) 345e350

Table 2 Associations of MS and Its Components with baPWV values in Males and Females.a MS and its components

High BP No Yes High FPG No Yes High TG No Yes Low HDL No Yes High WC No Yes High UA No Yes MS No Yes

Male (n ¼ 6659)

Female (n ¼ 1940)

baPWV, cm/s Mean ± SD

b(SE)

P value

baPWV, cm/s Mean(SD)

b(SE)

P value

1276 ± 160 1468 ± 248

Ref 161(5)

e <0.001

1183 ± 175 1513 ± 293

Ref 215(10)

e <0.001

1334 ± 209 1468 ± 253

Ref 92(6)

e <0.001

1252 ± 243 1497 ± 313

Ref 117(15)

e <0.001

1340 ± 228 1388 ± 219

Ref 53(5)

e <0.001

1250 ± 250 1400 ± 283

Ref 62(12)

e <0.001

1366 ± 234 1355 ± 207

Ref 14(5)

e 0.009

1256 ± 263 1307 ± 262

Ref 37(9)

e <0.001

1327 ± 218 1378 ± 226

Ref 51(6)

e <0.001

1216 ± 223 1384 ± 292

Ref 66(13)

e <0.001

1358 ± 224 1372 ± 225

14(6)

e 0.02

1269 ± 259 1419 ± 281

150(23)

e <0.001

1328 ± 212 1436 ± 234

Ref 108(6)

e <0.001

1233 ± 231 1478 ± 299

Ref 132(14)

e <0.001

a Multiple linear regression models were used to analyze the associations of MS and Its Components with baPWV values stratified by gender; Age, height, and weight were adjusted in the regression models.

Table 3 Multiple Logistic Regression Analysis of Associations between MS/Components and baPWV Status in Males and Females.a MS and its components

High BP No Yes High FPG No Yes High TG No Yes Low HDL No Yes High WC No Yes High UA No Yes MS No Yes

Male (n ¼ 6659)

Female (n ¼ 1940)

Subjects with high baPWV n(%)

OR(95%CI)

P value

Subjects with high baPWV n(%)

OR(95%CI)

P value

1228(33.3) 2103(70.7)

Ref 4.5(4.0e5.1)

e <0.001

481(35.0) 491(86.8)

Ref 6.3(4.7e8.4)

e <0.001

2373(45.0) 958(69.3)

Ref 2.2(1.9e2.5)

e <0.001

797(46.2) 175(81.0)

Ref 2.5(1.7e3.7)

e <0.001

1584(44.4) 1747(56.5)

Ref 1.7(1.5e1.9)

e <0.001

699(44.8) 273(71.8)

Ref 1.9(1.4e2.5)

e <0.001

2200(49.6) 1131(51.0)

Ref 1.0(0.9e1.1)

e 0.928

477(44.8) 495(56.6)

Ref 1.6(1.3e1.9)

e <0.001

942(46.3) 2451(54.5)

Ref 1.6(1.4e1.7)

e <0.001

471(38.8) 501(69.0)

Ref 1.5(1.1e2.0)

e 0.007

2294(49.0) 1099(55.2)

Ref 1.1(1.01.2)

e 0.102

890(49.1) 85(66.4)

Ref 2.9(2.0e4.1)

e <0.001

2007(43.8) 1386(66.2)

Ref 2.6(2.3e2.7)

e <0.001

670(42.6) 302(82.5)

Ref 3.0(2.1e4.3)

e <0.001

a Multiple logistic regression analysis was used to analyze the associations of MS and Its Components with baPWV values stratified by gender; Age, height, and weight were adjusted in the regression models.

arterial stiffening [27]. Hyperglycemia induces a large number of alterations at the cellular level of the vascular tissues, which potentially accelerates the atherosclerotic process. Animal and human studies have elucidated several major mechanisms that encompass most of the pathological alterations observed in the diabetic vasculature [28]. These include: (1) Nonenzymatic glycosylation of proteins and lipids, which can interfere with their normal function by disrupting molecular conformation, altering enzymatic activity, reducing degradative capacity, and interfering with receptor recognition. In addition, glycosylated proteins interact with a specific receptor present on all cells relevant to the atherosclerotic process, including monocyte-derived macrophages,

endothelial cells, and smooth muscle cells. The interaction of the glycosylated proteins with their receptor results in the induction of oxidative stress and proinflammatory responses. (2) Protein kinase C activation with subsequent alteration in growth factor expression. (3) Shunting of excess intracellular glucose into the hexosamine pathway, leading to O-linked glycosylation of various enzymes with perturbations in normal enzyme function. (4) Increase in oxidative stress by hyperglycemia through several pathways, the major mechanism of which appears to be the overproduction of the superoxide anion (O2) by the mitochondrial electron transport chain. (5) Promotion of inflammation by hyperglycemia through the induction of cytokine secretion by several types of cells

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cross-sectional study [49] also revealed that serum UA preferentially increased central elastic (carotid) over peripheral muscular (femoral and brachial) arteries stiffness, and positive association between serum UA levels and large artery stiffness existed only in females. On the contrary, a Korean cohort study [46] carried out in multi-rural communities demonstrated that serum UA was strongly associated with baPWV in male and weakly associated in female subjects. Lim [50] and Tomiyama [20] found that elevated UA level was not associated with heart-femoral PWV or baPWV in either males or females. The mechanisms that underline UA gender-specific effects were not clear but might involve gene discrepancies [51].In all, further research involving prospective and intervention studies should be required to identify the gender specific susceptibility to arterial stiffness with an elevated serum UA. Fig. 2. Trend test of baPWV value with the number of MS components in male and female and all subjects.

including monocytes and adipocytes. HDL-C is a protective factor for cardiovascular diseases. The results of the present study indicate that low HDL-C was correlated with high baPWV in the females but not in the males. There were some factors contributing to this observation. The compositional complexity and functional role of HDL-C were not taken into account in the present study. Khera et al. demonstrated that the influence of HDL-C on the inflammation, reverse cholesterol transport, oxidation, endothelial function, and gene transcription could not be assessed by the measurement of only the total HDL-C level [29]. Other studies indicated that drugs increasing HDL-C, such as fibrates, niacin, and inhibitors of cholesterol ester transfer protein had failed to consistently and significantly reduce the risk of major cardiovascular events, especially when combined with statins [30e34]. These evidences might explain why low HDL-C was correlated with high baPWV in the females of the present study. Furthermore, HDLs form a heterogeneous class of lipoproteins that differ in protein and lipid composition, shape, size, and density [35e39]. The association of HDL with cardiovascular diseases may depend on the size. Significant associations with risk of cardiovascular events or stroke were found for small-sized HDL in some studies [40,41], but not for medium-sized HDL [41,42], or largesized HDL in others [42e45]. However, in the present study, the various HDL subclasses were not analyzed, and the profile of the HDL subclasses in the males and females were unknown. It the future, it will be necessary to examine HDL subclasses, which may help to figure out the relationship between HDL and its subclasses with arterial stiffness and CVD. Although serum uric acid (UA) is not a component of MS, several epidemiological studies have addressed that serum UA level could be considered a risk indicator for CVD including MS, coronary artery disease, and carotid atherosclerosis [46]. It was found that baPWV in female subjects with hyperuricemia was significant higher than those without hyperuricemia, but not in the male group. It seems that elevated serum UA may be a risk factor for increased arterial stiffness. However, the exact mechanism of this association remains unclear. Several possible pathophysiological mechanisms linking UA and arterial stiffness have been proposed, including that UA may promote the proliferation of vascular smooth muscle cells, promote oxidation of LDL, upregulate the prothrombotic effects mediated by platelet activation, increase production of reactive oxygen species, impair nitric oxide generation, and stimulate the inflammatory pathways [47]. However, this gender-specific relationship is still controversial and not well elucidated. In the study of Ishizaka [48], Pearson's correlation coefficient between UA and baPWV is significant only in females. A

5. Conclusion In conclusion, MS and its individual components were positively correlation with baPWV. People with metabolic syndrome are associated with increased arterial stiffness and may be related to development and progression of CVD. Thus, we can investigate the arterial stiffness by baPWV which may guide to prevent or delay the development of CVD. 6. Limitation of the study There are some limitations in the present study. Firstly, specific clusters of MS components impact differently on arterial stiffness indexed as baPWV, but we did not explain the impact of different combinations of MS components on baPWV in this study. Secondly, estimated glomerular filtration rate (eGFR) is also an important component which potentially influencing arterial stiffness. Several studies across a broad spectrum of populations have shown that the risks of death and cardiovascular events are significantly increased in patients with lower eGFR [52]. Renal function data were not collected in the present study, which makes it impossible to evaluate the association between eGFR and baPWV. The comparison of different combinations of MS components on baPWV and eGFR should be investigated in the further studies. Funding programs Health Bureau of Zhejiang Province. (Grant No. 2010KYB058, 2012KYA108). Chinese Medicine Bureau of Zhejiang Province. (Grant No. 2012ZB099). Conflict of interest None. References [1] V.L. Roger, A.S. Go, D.M. Lloyd-Jones, et al., American heart association statistics committee and stroke statistics subcommittee. Heart disease and stroke statistics-2011 update: a report from the American heart association, Circulation 123 (2011) e18e209. [2] W. Chen, R. Gao, L. Lin, M. Zhu, W. Wang, et al., The report of Chinese CVD in 2013, Chin. Circulation J. 29 (2014) 487e491. [3] Alberti, et al., Harmonizing the metabolic syndrome, Circulation 120 (16) (2009) 1640e1645. €, Teemu Koivistoinen, Leena Moilanen, et al., Metabolic syndrome [4] Kalle Sipla and arterial stiffness:The health 2000 survey, Metabolism Clin. Exp. 56 (2007) 320e326. [5] Akilo Tsubakimoto, Isao Saito, Toshifumi Mannami, Yoshihiko Naito, et al., Impact of metabolic syndrome on brachial-ankle pulse wave velocity in Japanese, Hypertens. Res. 29 (2006) 29e37. 6 A. Yamashina, H. Tomiyama, K. Takeda, H. Tsuda, T. Arai, K. Hirose, Y. Koji,

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S. Hori, Y. Yamamoto, Validity, reproducibility, and clinical significance of noninvasive brachial-ankle pulse wave velocity measurement, Hypertens. Res. 25 (3) (2002) 359e364. [7] J.A. Im, J.W. Lee, J.Y. Shim, H.R. Lee, D.C. Lee, Association between brachialankle pulse wave velocity and cardiovascular risk factors in healthy adolescents, J. Pediatr. 150 (2007) 247e251. [8] N. Nakanishi, T. Shiraishi, M. Wada, Brachial-ankle pulse wave velocity and metabolic syndrome in a Japanese population: the minoh study, Hypertens. Res. 28 (2005) 125e131. [9] R.M. Henry, I. Ferreira, J.M. Dekker, et al., The metabolic syndrome in elderly individuals is associated with greater muscular, but not elastic arterial stiffness, independent of low-grade inflammation, endothelial dysfunction or insulin resistanceeThe hoorn study, J. Hum. Hypertens. 23 (2009) 718e727. [10] J.S. Nam, J.S. Park, M.H. Cho, et al., The association between pulse wave velocity and metabolic syndrome and adiponectin in patients with impaired fasting glucose: cardiovascular risks and adiponectin in IFG, Diabetes Res. Clin. Pract. 84 (2009) 145e151. [11] H. Satoh, R. Kishi, H. Tsutsui, Metabolic syndrome is a significant and independent risk factor for increased arterial stiffness in Japanese subjects, Hypertens. Res. 32 (2009) 1067e1071. [12] A. Hirashiki, T. Murohara, The impact of pulse wave velocity in a Japanese population with metabolic syndrome, Hypertens. Res. 32 (2009) 1045e1046. [13] Jin-Wen Wang, Zi-Qiang Zhou, Da-Yi Hu, Prevalence of arterial stiffness in North China, and associations with risk factors of cardiovascular disease:a community-based study, BMC Cardiovasc. Disord. 12 (2012) 119e127. [14] J.M. Sabio, J. Vargas-Hitos, M. Zamora-Pasadas, J.D. Mediavilla, N. Navarrete, A. Ramirez, C. Hidalgo-Tenorio, L. Jaimez, J. Martin, J. Jimenez-Alonso, Metabolic syndrome is associated with increased arterial stiffness and biomarkers of subclinical atherosclerosis in patients with systemic lupus erythematosus, J. Rheumatol. 36 (2009) 2204e2211. [15] T. Nagasaki, M. Inaba, S. Yamada, Y. Kumeda, Y. Hiura, Y. Nishizawa, Changes in brachial-ankle pulse wave velocity in subclinical hypothyroidism during normalization of thyroid function, Biomed. Pharmacother. 61 (2007) 482e487. [16] M.H. Lee, Sun K. Yoo, S.H. Jee, Jungchae Kim, The association between pulse wave velocity and metabolic syndrome in Korean, Disabil. Rehabilitation: Assistive Technol. 8 (2013) 140e144. [17] Young-Kwon Kim, Impact of the metabolic syndrome and its components on pulse wave velocity, Korean J. Intern. Med. 21 (2006) 109e115. [18] Chunyan Weng, Hong Yuan, Xiaohong Tang, Zhijun Huang, Kan Yang, Wei Chen, Pingting, Zhiheng Chen, Fangping Chen, Age- and gender dependent association between components of metabolic syndrome and subclinical arterial stiffness in a chinese population, Int. J. Med. Sci. 9 (2012) 730e737. [19] Angelo Scuteri, Pedro G. Cunha, E. Agabiti Rosei, et al., Arterial stiffness and influences of the metabolic syndrome: A cross-countries study, Atherosclerosis 233 (2014) 654e660. [20] H. Tomiyama, A. Yamashina, T. Arai, K. Hirose, Y. Koji, T. Chikamori, et al., Influences of age and gender on results of noninvasive brachial-ankle pulse wave velocity measurement: a survey of 12517 subjects, Atherosclerosis 166 (2003) 303e309. [21] A.A. Laogun, R.G. Gosling, In vivo arterial compliance in man, Clin. Phys. Physiol. Meas. 3 (1982) 201e212. [22] A.P. Avolio, S.G. Chen, R.P. Wang, et al., Effects of aging on changing arterial compliance and left ventricular load in a northern Chinese urban community, Circulation 68 (1) (1983) 50e58. [23] A.P. Avolio, D. Fa-Quan, L. Wei-Quiang, et al., Effects of aging on changing arterial distensibility in populations with high and low prevalence of hypertension: comparison between urban and rural communities in China, Circulation 71 (1985) 202e210. [24] H. Tanaka, F.A. Dinenno, K.D. Monahan, C.A. DeSouza, D.R. Seals, Carotid artery wall hypertrophy with age is related to local systolic blood pressure in healthy men, Arterioscler. Thromb. Vasc. Biol. 21 (2001) 82e87. [25] R.E. Tracy, Medial thickenings of coronary artery and the aging risk factor for atherosclerosis, Atherosclerosis 155 (2001) 337e346. [26] C. Weng, H. Yuan, K. Yang, X. Tang, et al., Gender-specific association between the metabolic syndrome and arterial stiffness in 8300 subjects, Am. J. Med. Sci. 346 (2013) 289e294. [27] D.A. Kass, Ventricular arterial stiffening:integrating the pathophysiology, Hypertension 46 (2005) 185e193. [28] Doron Aronson, Hyperglycemia and the pathobiology of diabetic complications, Facets. Adv. Cardiol. Basel. (2008) 1e16. Karger. [29] A.V. Khera, M. Cuchel, M. de la Llera-Moya, et al., Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis, N. Engl. J. Med. 364 (2011) 127e135. [30] G.G. Schwartz, A.G. Olsson, M. Abt, C.M. Ballantyne, P.J. Barter, J. Brumm, et al.,

[31]

[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

[40]

[41]

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51]

[52]

Effects of dalcetrapib in patients with a recent acute coronary syndrome, N. Engl. J. Med. 367 (2012) 2089e2099. P.J. Barter, M. Caulfield, M. Eriksson, S.M. Grundy, J.J. Kastelein, M. Komajda, et al., Effects of torcetrapib in patients at high risk for coronary events, N. Engl. J. Med. 357 (2007) 2109e2122. W.E. Boden, J.L. Probstfield, T. Anderson, B.R. Chaitman, P. Desvignes-Nickens, K. Koprowicz, et al., Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy, N. Engl. J. Med. 365 (2011) 2255e2267. H.N. Ginsberg, M.B. Elam, L.C. Lovato, J.R. Crouse 3rd, L.A. Leiter, P. Linz, et al., Effects of combination lipid therapy in type 2 diabetes mellitus, N. Engl. J. Med. 362 (2010) 1563e1574. A. Keech, R.J. Simes, P. Barter, J. Best, R. Scott, M.R. Taskinen, et al., Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial, Lancet 366 (2005) 1849e1861. A. Von Eckardstein, Implications of torcetrapib failure for the future of HDL therapy: is HDL-cholesterol the right target? Expert Rev. Cardiovasc Ther. 8 (2010) 345e358. R.S. Rosenson, H.B. Brewer Jr., W.S. Davidson, Z.A. Fayad, J. Fuster V,Goldstein, et al., Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport, Circulation 125 (2012) 1905e1919. R.S. Rosenson, H.B. Brewer Jr., M.J. Chapman, S. Fazio, M.M. Hussain, A. Kontush, et al., HDL measures, particle heterogeneity, proposed nomenclature, and relation to atherosclerotic cardiovascular events, Clin. Chem. 57 (2011) 392e410. K.A. Rye, P.J. Barter, Predictive value of different HDL particles for the protection against or risk of coronary heart disease, Biochim. Biophys. Acta 2012 (1821) 473e480. H.R. Superko, L. Pendyala, P.T. Williams, K.M. Momary, S.B. King 3rd, B.C. Garrett, High-density lipoprotein subclasses and their relationship to cardiovascular disease, J. Clin. Lipidol. 6 (2012) 496e523. J.D. Otvos, D. Collins, D.S. Freedman, I. Shalaurova, E.J. Schaefer, J.R. McNamara, et al., Low-density lipoprotein and high-density lipoprotein particle subclasses predict coronary events and are favorably changed by gemfibrozil therapy in the veterans affairs high-density lipoprotein intervention trial, Circulation 113 (2006) 1556e1563. C.L. Chei, K. Yamagishi, A. Kitamura, M. Kiyama, H. Imano, T. Ohira, et al., Highdensity lipoprotein subclasses and risk of stroke and its subtypes in Japanese population: the circulatory risk in communities study, Stroke 44 (2013) 327e333. P. Wurtz, J.R. Raiko, C.G. Magnussen, P. Soininen, A.J. Kangas, T. Tynkkynen, et al., High-throughput quantification of circulating metabolites improves prediction of subclinical atherosclerosis, Eur. Heart J. 33 (2012) 2307e2316. K. El Harchaoui, B.J. Arsenault, R. Franssen, J.P. Despres, G.K. Hovingh, E.S. Stroes, et al., High-density lipoprotein particle size and concentration and coronary risk, Ann. Intern Med. 150 (2009) 84e93. S. Mora, J.D. Otvos, N. Rifai, R.S. Rosenson, J.E. Buring, P.M. Ridker, Lipoprotein particle profiles by nuclear magnetic resonance compared with standard lipids and apolipoproteins in predicting incident cardiovascular disease in women, Circulation 119 (2009) 931e939. J.S. Berger, A.P. McGinn, B.V. Howard, L. Kuller, J.E. Manson, J. Otvos, et al., Lipid and lipoprotein biomarkers and the risk of ischemic stroke in postmenopausal women, Stroke 43 (2012) 958e966. J.S. Bae, D.H. Shin, P.S. Park, B.Y. Choi, M.K. Kim, et al., The impact of serum uric acid level on arterial stiffness and carotid atherosclerosis: the Korean multirural communities cohort study, Atherosclerosis 231 (2013) 145e151. J.I. Fang, J.S. Wu, Y.C. Yang, R.H. Wang, F.H. Lu, C.J. Chang, et al., High uric acid level associated with increased arterial stiffness in apparently healthy women, Atherosclerosis 236 (2014) 389e393. N. Ishi Zaka, Y. Ishizaka, E.I. Toda, H. Hashimoto, R. Nagai, M. Yamakado, Higher serum uric acid is associated with increased arterial stiffness in Japanese individuals, Atherosclerosis 192 (2007) 131e137. S. Bian, H. Guo, P. Ye, L. Luo, H. Wu, W. Xiao, et al., Serum uric acid level and diverse impacts on regional arterial stiffness and wave reflection, Iran. J. Publ. Health 41 (8) (2012) 33e41. J.H. Lim, Y.S. Kim, S.H. Na, M.Y. Rhee, M.M. Lee, Relationship between serum uric acid levels, metabolic syndrome,and arterial stiffness in Korean, Korean Circ. J. 40 (2010) 314e320. M. Kolz, T. Johnson, S. Sanna, A. Teumer, V. Vitart, M. Perola, M. Mangino, et al., Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations, PLoS Genet. 5 (6) (2009) e1000504. N. Nakagawa, F. Takahashi, J. Chinda, M. Kobayashi, Y. Hayashi, et al., A newly estimated glomerular filtration rate is independently associated with arterial stiffness in Japanese patients, Hypertens. Res. 31 (2) (2009) 193e201.