Carotid atherosclerosis and the risk factors in early postmenopausal Chinese women

Maturitas 63 (2009) 233–239

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Carotid atherosclerosis and the risk factors in early postmenopausal Chinese women Ruby H.Y. Yu a , Suzanne C. Ho a,∗ , Stella S.Y. Ho b , Sophie S.G. Chan a , Jean L.F. Woo c , A.T. Ahuja b a b c

Department of Community and Family Medicine, The Chinese University of Hong Kong, Hong Kong Department of Diagnostic Radiology & Organ Imaging, The Chinese University of Hong Kong, Hong Kong Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong

a r t i c l e

i n f o

Article history: Received 11 March 2008 Received in revised form 26 March 2009 Accepted 31 March 2009 Keywords: Atherosclerosis Carotid arteries Epidemiology and menopause

a b s t r a c t Objectives: To describe the distribution of intima-media thickness (IMT) and the prevalence of plaque by carotid segments, walls and sides, and to examine their associated risk factors in asymptomatic, early postmenopausal Chinese women in Hong Kong. Methods: Between 2002 and 2004, the study recruited 518 postmenopausal women aged 50–64 years. They were examined by B-mode ultrasound to measure the IMT and the prevalence of plaque at the near and far walls of common carotid (CCA), bifurcation (bulb), and internal carotid (ICA) of both the left and right carotid arteries. Blood pressures, obesity indices, lipids and glucose levels, sociodemographic, medical and lifestyle factors were also obtained. Results: The mean IMT was 0.76 ± 0.12 mm (range: 0.53–1.33 mm). IMT was significantly thicker on the far wall than on the near wall and differed among segments (being thickest at the bulb and the narrowest at the ICA). 21.8% had at least one plaque in the carotid artery with most of the plaque found at the bulb area. Systolic blood pressure had statistically significant relationship with IMT that were fairly homogeneous among different segments. Lipids were associated with the CCA and bulb IMT, but not the ICA IMT. Diabetes predicted only CCA IMT. Older age, higher waist–hip-ratio and low-density lipoprotein cholesterol were significant predictors of plaques at all sites combined. Conclusions: We described the distribution of IMT and the prevalence of plaque in asymptomatic, early postmenopausal Chinese women. Associations of risk factors with IMT of different arterial segments were also observed. © 2009 Elsevier Ireland Ltd. All rights reserved.

1. Background Cardiovascular disease (CVD) is considered an emerging epidemic in developing countries [1], and is also a major cause of serious illness and disability, particularly for women who, on average, live longer than men. The onset of menopause usually indicates a transition from a low to higher risk for CVD which has been attributed to unfavorable metabolic and hormonal changes. Therefore, the need to identify and treat the subclinical CVD among asymptomatic women soon after menopause is of public health importance to reduce the increased cardiovascular risk. B-mode ultrasonography of intima-media thickness (IMT) and plaque of the carotid artery offers a non-invasive way and is widely used to screen for the subclinical atherosclerosis [2], which progresses silently over a period of time before the clinical man-

∗ Corresponding author at: Department of Community and Family Medicine, The Chinese University of Hong Kong, 4th Floor, School of Public Health, Prince of Wales Hospital, Shatin, N.T., Hong Kong. Tel.: +852 2252 8775; fax: +852 2602 6986. E-mail address: [email protected] (S.C. Ho). 0378-5122/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2009.03.022

ifestations of CVD. Both IMT and plaque have been correlated to traditional vascular risk factors, to the extent of atherosclerotic lesions in the coronary, aortic and femoral circulations, and to future clinical cardiovascular events [3–9]. Therefore, early detection of increased IMT and plaques and their associated risk factors are of considerable clinical importance. However, there is no standardized protocol for the measurement of IMT. Definitions of the carotid segments, the walls and the sides to be investigated, and the use of mean or mean maximal IMT vary among studies, which makes comparisons among studies difficult. Moreover, established abnormal threshold for IMT does not currently exist. IMT ranges from 0.5 to 1.0 mm in adult populations, and values ≥1.0 mm are often regarded as abnormal [10,11]. A review paper has provided reference values for normal IMT measurements by sex and age groups [12], where most of these studies have involved Caucasians, who may differ significantly from Chinese in terms of lifestyle, diet and body physiology. Yet there has been little data on the distribution of IMT and the prevalence of plaque in early postmenopausal Chinese women. This study aimed to describe the distribution of IMT and the prevalence of plaque by carotid segments, walls, and sides, and to identify their associated risk factors in asymptomatic early

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postmenopausal Chinese women in Hong Kong. The different associations of risk factors on IMT of different arterial segments were also examined. The data obtained will strengthen the information base on cardiovascular risks in asymptomatic women soon after menopause, thereby establishing CVD prevention strategies for midlife women. 2. Methods 2.1. Study population From 2002 to 2004, 518 women aged 50–64 years and within 10 years since menopause (defined as 12 months since the cessation of the last menses) were recruited through random telephone dialing based on the most recent residential telephone directory. At least 6 attempts at different times of the day and at different days of the week were made for each number before it was considered a noncontact. If more than one postmenopausal woman in the household fell into the targeted age range of 50–64 years, the member with the most recent birthday was selected. A response rate of 62.5% was obtained. Women with surgical menopause, CVD, and severe disease conditions such as cancer and renal failure were excluded. Eligible subjects were invited for clinical assessment and carotid ultrasound measurements. All participants gave written informed consent, and the study was approved by the Ethics Committee of the Chinese University of Hong Kong. 2.2. Sample size estimation Sample size calculation was based on a conservative estimation of 15% plaque prevalence, based on results of previous populationbased studies. With ˛ = 0.05, p = 0.15, and d = 0.03, the sample size 2 required using the formula (z1−˛/2 p (1 − p)/d2 ) was estimated to be 545. However, a preliminary analysis among the initial 500 subjects revealed a plaque prevalence of around 20%, thus, a sample of 518 subjects was considered adequate for the study. 2.3. Clinical assessments The clinical assessments included blood sampling, blood pressure measurements, anthropometric measurements, and structured interviews. Twelve-hour fasting blood samples were collected and serum samples were stored at −86 ◦ C for biochemical measurements. Blood pressures were measured twice with a mercury sphygmomanometer on the right upper arm with the participant seated quietly for at least 5 min. Anthropometric measurements were made with the subjects wearing light clothing and no shoes. Body mass index (BMI), used as a measure of general obesity, was calculated as weight in kilograms divided by height in meters squared. Waist circumference (WC), an index of abdominal obesity, was measured over the abdomen at the smallest diameter between the costal margin and iliac crest. Hip circumference was measured at the level of the greater trochanters. Waist–hip-ratio (WHR) was calculated as the ratio of waist-to-hip circumferences. The structured interviewed included questions on sociodemographic characteristics, medical history, use of medication, and lifestyle variables such as smoking and alcohol drinking. Women were also asked to give information about the usual level of participation in occupational and leisure-time physical activity, sports and exercise, and household activity over the previous 12 months with the modified and locally translated Baecke questionnaire [13,14]. In addition, women who reported that she had frequently engaged in a given sporting activity/exercise was defined as physically active, or otherwise physically inactive. A validated food frequency questionnaire containing 60 food items was used to

assess dietary intake, and the results have been reported elsewhere [15]. 2.4. Biochemical measurements Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and fasting blood glucose (FBG) concentrations were determined by an enzymatic technique using an Alcyon 300 analyzer (Abbott Laboratories, Abbott Park, IL) with the use of commercial kits (Randox, Antrim, United Kingdom). The coefficient of variations (CVs) for the within-run precision (20 determinations within one run) for TC, HDL-C, LDL-C, TG, and FBG were 0.6%, 3.0%, 1.0%, 0.8%, and 0.9% respectively; and the CVs for the between-run precision (20 separate runs) for TC, HDL-C, LDL-C, TG, and FBG were 2.1% to 2.7%, 2.6% to 4.0%, 2.8% to 3.6%, 2.3% to 4.5%, and 3.3% respectively. Ranges for lipids were reported for 3 values of commercial quality control materials (lipids controls levels 1–3) and 1 value of human pool serum. 2.5. Definition of medical conditions Hypertension was defined as systolic blood pressure (SBP) of 140 mm Hg or greater and/or diastolic blood pressure (DBP) of 90 mm Hg or greater, or pharmacological treatment. General obesity were defined as a BMI of 25 kg/m2 or greater, whereas abdominal obesity was defined as a WC of 80 cm of greater for women, as recently proposed by the International Association for the Study of Obesity [16]. A WHR of 0.85 or greater is indicative of abdominal obesity, as proposed by the World Health Organization [17]. Hypercholesterolemia was defined as TC of 5.2 mmol/L or greater and/or pharmacological treatment. Diabetes was defined as FBG of 7.0 mmol/L or greater and/or self-reported physician diagnosis, or pharmacological treatment. 2.6. Carotid ultrasound measurements A 12.5-MHz linear probe of the HDI 5000 ultrasound scanner (Advanced Technology Laboratory, Bothell, WA) was used for measuring IMT at the near and far walls of three 10-mm segments: distal common carotid (CCA), bifurcation (bulb), and the proximal internal carotid (ICA) of both the left and right carotid arteries. For each of the 12 segments, sonographers measured the maximum IMT free of atherosclerotic plaque. The final IMT was defined as the average of maximal IMT at the 12 preselected sites. Previous studies have indicated that the inclusion of multiple sites within the carotid artery provides the most sensitive and statistically powerful assessment of atherosclerosis and that aggregating data across segments provides measures that are stable and less sensitive to measurement error [18,19]. The sonographers also identified atherosclerotic plaque along the defined artery segments (CCA, bulb, and ICA regardless of whether it was on the near or far wall) of both the left and right carotid arteries. Plaque was defined as a focal wall thickening of at least 1.5 mm. Based on earlier studies [20,21], the degree of plaque at the six segments was graded according to the following criteria: grade 0, no observable plaque; grade 1, one small plaque <30% of vessel diameter; grade 2, one medium plaque between 30% and 50% of the vessel diameter or multiple small plaques; and grade 3, one large plaque >50% vessel diameter or multiple plaques with at least one medium plaque. The grades were then totalled to form a plaque index representing the extent and severity of atherosclerosis. Because of the relatively small number of women with higher plaque index, they were also regrouped according to the absence or presence of plaque.

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Both scanning and reading were performed by certified sonographers blinded to the participants’ medical history and risk factors information collected from interviews. Reproducibility of the IMT measurement and the plaque index was assessed in 40 women who underwent 2 ultrasound examinations within 2 weeks. At each examination the scan was performed by 2 sonographers. The within-sonographer intraclass correlations were 0.83–0.88 for IMT, and 0.99 for plaque index, and between-sonographer correlations were 0.81–0.88 for IMT, and 0.88–0.99 for plaque index. 2.7. Statistical analysis Continuous variables are reported as mean and SD, and categorical variables were reported as percentages. Student’s t-test and ANOVA were used to compare groups for continuous variables and chi-square test for comparing proportions. Linear regression analyses were done using IMT as a dependent variable to identify the risk factors for increased IMT both overall and in different arterial segments. Binary logistic regression analyses were used to identify the risk factors associated with the presence of plaque. Because of the low prevalence of plaque at the CCA (2.5%) and ICA (5.0%), the associations of risk factors with plaque at individual segments were not analyzed. All analyses were carried out using the Window-based SPSS Statistical Package (version 13.0; SPSS Inc., Chicago, IL), and P values less than 0.05 were considered to be significant. 3. Results 3.1. Characteristics of study population A total of 518 early postmenopausal Chinese women were examined (mean age, 56 years; range, 50–64 years) (Table 1). The mean number of years since menopause was 5 years. 80.3% of the women were married and about half had secondary level of education. 23.9% had previous history of hypertension, of which 74.2% were receiving treatment for this condition. 18.0% gave a history of hypercholesterolemia, although among them only 21.5% reported taking lipid-lowering drugs in the three months prior to the study. 6.9% had a history of diabetes and most of them were receiving treatment (83.3%). The prevalence of smoking and regular alcohol drinking was low (less than 5%). Table 1 also presents the mean values of blood pressures, anthropometric, and biochemical measurements. 3.2. Distribution of IMT by segments, walls, sides, and age The IMT distribution was skewed to the right and the mean IMT in this study population was 0.76 ± 0.12 mm (Table 1), with a range from 0.53 to 1.33 mm (median, 0.74 mm). Less than 5% of the women had their mean IMT ≥ 1 mm (data not shown). Significant differences were observed among segments (P < 0.01) (greatest at the bulb, 0.96 ± 0.22 mm; followed by CCA, 0.74 ± 0.13 mm; and least at the ICA, 0.59 ± 0.13 mm) and between the near (0.75 ± 0.12 mm) and far walls (0.78 ± 0.15 mm) (P < 0.01). No statistically significant differences were observed between the left (0.77 ± 0.13 mm) and the right sides (0.76 ± 0.13 mm). IMT on both walls (near and far wall) and both sides (left and right artery) increased significantly with increasing age groups (P < 0.01) (Fig. 1). Among the three segments, IMT increased significantly with age at the CCA and bulb (P < 0.01), while a non-significant difference of ICA IMT was observed. 3.3. Association of IMT with cardiovascular risk factors Associations of cardiovascular risk factors with increased IMT in different arterial segments were presented (Table 2). Significant associations of SBP, and DBP with IMT at all 3 segments (CCA, bulb,

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Table 1 Characteristics of study population (N = 518). Variables

Values

Sociodemographic characteristics Age, year YSM, year Marital status, % married Educational attainment, % secondary or above Economic activity status, % housewife

56.35 ± 3.33 5.10 ± 2.76 80.3 55.4 70.3

Medical history Hypertension, % Hypercholesterolemia, % Diabetes, %

23.9 18.0 6.9

Use of medication Hormonal therapy, % Anti-hypertensive, % Lipid-lowering, % Anti-diabetic, %

5.0 17.8 3.9 5.8

Blood pressure measurements SBP, mm Hg DBP, mm Hg

127.46 ± 21.21 77.71 ± 10.36

Anthropometric measurements BMI, kg/m2 WC, cm WHR

23.58 ± 3.67 81.03 ± 9.54 0.83 ± 0.06

Biochemical measurements TC, mmol/L HDL-C, mmol/L LDL-C, mmol/L TG, mmol/L FBG, mmol/L

5.79 ± 1.06 1.82 ± 0.46 3.34 ± 0.87 1.33 ± 0.90 5.82 ± 1.70

Lifestyle variables Current smokers, % Regular drinkers, % Physical activity, total index Physically inactive, % Dietary total energy intake, kcal/day Dietary fat intake, g/day

1.5 3.5 8.86 ± 1.46 47.7 1379.49 ± 446.03 40.31 ± 20.82

Carotid ultrasound measurements IMT, mm Plaque index ≥ 1, % Plaque index ≥ 2, %

0.76 ± 0.12 21.8 11.0

Continuous variables are means ± SD. YSM: year since menopause, SBP: systolic blood pressure, DBP: diastolic blood pressure, BMI: body mass index, WC: waist circumference, WHR: waist–hip-ratio, TC: total cholesterol, HDL-C: high-density lipoprotein cholesterol, LDL-C: low-density lipoprotein cholesterol, TG: triglycerides, FBG: fasting blood glucose, physical activity (total index from the Baecke questionnaire), and IMT: intima-media thickness.

and ICA) were found. Higher BMI, higher WC and higher WHR were associated with increased CCA IMT. TC, HDL-C, LDL-C, and TG were also significantly associated with IMT at the CCA and the bulb. In multivariate regression analyses, age, SBP, HDL-C, and LDL-C were significantly associated with the mean CCA and bulb IMT. However, a significant association between diabetes and IMT was demonstrated only for the CCA IMT. SBP was the only significant predictor of an increased IMT at the ICA. When the models were repeated after exclusion of women who were using antihypertensive and lipid lowering medications, results were similar to those presented in the table (data not shown). 3.4. Prevalence of plaque by segments and age A total of 113 women (21.8%) had at least one atherosclerotic plaque (plaque index ≥1) in the carotid artery and 11.0% of the women had a plaque index ≥2 (Table 1). Most of the plaque occurred in the carotid bulb (19.1%), then the ICA (5.0%) and the CCA (2.5%) (P < 0.01) (Table 3). The prevalence of plaque increased with successive age groups, of 16.8%, 21.6%, and 34.1% for women in the younger age groups of 50–54 years, 55–59 years, and 60–64 years, respec-

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R.H.Y. Yu et al. / Maturitas 63 (2009) 233–239 Table 2 Linear regression analyses for the association between cardiovascular risk factors and carotid intima-media thickness. Predictors

Total R2

Mean IMT Age, years SBP, mm Hg HDL-C, mmol/L LDL-C, mmol/L

0.198

CCA IMT Age, years Diabetes SBP, mm Hg HDL-C, mmol/L LDL-C, mmol/L

0.289

Bulb IMT Age, years SBP, mm Hg HDL-C, mmol/L LDL-C, mmol/L

0.100

ICA IMT SBP, mm Hg

0.022

ˇ

SE of ˇ

P-value

0.007 0.001 −0.027 0.027

0.001 0.000 0.010 0.005

0.000 0.000 0.009 0.000

0.009 0.041 0.002 −0.024 0.027

0.001 0.015 0.000 0.011 0.006

0.000 0.008 0.000 0.029 0.000

0.009 0.001 −0.066 0.040

0.003 0.000 0.021 0.011

0.001 0.021 0.001 0.000

0.001

0.000

0.001

R2 indicates the coefficient of determination, represents the percentage of the variation in the dependent variable explained by the independent variables in the model, ˇ: regression coefficient, SE: standard error, IMT: intima-media thickness, SBP: systolic blood pressure, HDL-C: high-density lipoprotein cholesterol, and LDLC: low-density lipoprotein cholesterol. Stepwise multiple linear regression models adjusted for age, hormonal therapy (no vs. yes), SBP, body mass index, waist–hipratio, HDL-C, LDL-C, triglycerides, presence of diabetes (no vs. yes), smoking (never and ex-smokers vs. current smokers), alcohol drinking (never and non-regular drinkers vs. regular drinkers), physical activity (total index from the Baecke questionnaire), dietary total energy intakes per day (kcal), dietary total fat intakes per day (g), marital status (single, widowed, divorced, and separated vs. married), levels of education (below secondary and secondary vs. above secondary/below secondary vs. secondary and above secondary), and economic activity status (housewife vs. employed women).

Table 3 Proportion of women with at least one plaque by segments. Segments

n

%

P-value

Plaque index ≥ 1

CCA Bulb ICA

13 99 26

2.5 19.1 5.0

<0.001

Plaque index ≥ 2

CCA Bulb ICA

2 37 12

0.4 7.1 2.3

<0.001

CCA: common carotid artery, bulb: bifurcation, and ICA: internal carotid artery. P-values from chi-square tests for comparison of proportions.

Fig. 1. Distribution of IMT by segments, walls, sides and age. IMT: intima-media thickness, CCA: common carotid artery, Bulb: bifurcation, ICA: internal carotid artery, Near: near wall, Far: far wall, Left: left side, and Right: right side.

tively (P < 0.01). Moreover, a plaque index ≥2 was found in 6.4% of women aged 50–54 years and in 23.5% of women aged 60–64 years (P < 0.01) (data not shown). 3.5. Association of plaques with cardiovascular risk factors Age-adjusted odds ratio for atherosclerotic plaques in relation to categories of cardiovascular risk factors are reported in Table 4. SBP ≥ 140 mm Hg (odds ratio, 1.63; 95% CI, 1.04–2.57), WHR ≥ 0.85 (odds ratio, 1.72; 95% CI, 1.12–2.64), TC ≥ 5.2 mmol/L (odds ratio, 1.98; 95% CI, 1.18–3.30), and LDL-C ≥ 3.4 mmol/L (odds ratio, 2.37;

95% CI, 1.54–3.65) were associated with an increased risk of having carotid plaques. In multivariate regression analyses, age was independently associated with the presence of plaque, with an odds ratio of 1.08 (95% CI, 1.02–1.15). WHR ≥ 0.85 (odds ratio, 1.72; 95% CI, 1.11–2.66) and LDL-C ≥ 3.4 mmol/L (odds ratio, 2.36; 95% CI, 1.53–3.66) were both independently associated with the presence of plaque. However, SBP ≥ 140 mm Hg was no longer significantly associated with carotid plaques after adjustment for age. 4. Discussion The majority of population-based studies describing the distribution of IMT and the prevalence of plaque have been confined to Caucasians, with few studies in postmenopausal Chinese women. We described the distribution of IMT by carotid segments, walls, and sides, and their associated risk factors in a sample of asymptomatic Hong Kong Chinese women soon after menopause. The prevalence of plaque at different carotid segments and its associated risk factors was also examined.

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Table 4 Logistic regression analyses for the association between cardiovascular risk factors and carotid plaque. Plaque index ≥ 1, OR (95% CI) Variables

Age-adjusted modela

Multivariate-adjusted modelb

Age, year

–

1.08 (1.02–1.15)

Blood pressure measurements SBP ≥ 140 mm Hg DBP ≥ 90 mm Hg

1.63 (1.04–2.57) 1.33 (0.75–2.36)

NS –

Anthropometric measurements BMI ≥ 25 kg/m2 WC ≥ 80 cm WHR ≥ 0.85

1.54 (0.99–2.39) 1.46 (0.95–2.24) 1.72 (1.12–2.64)

NS – 1. 72 (1.11–2.66)

Biochemical measurements TC ≥ 5.2 mmol/L HDL < 1.2 mmol/L LDL ≥ 3.4 mmol/L TG ≥ 1.7 mmol/L FBG ≥ 7.0 mmol/L

1.98 (1.18–3.30) 1.16 (0.49–2.72) 2.37 (1.54–3.65) 1.37 (0.84–2.22) 1.22 (0.60–2.45)

– NS 2.36 (1.53–3.66) NS –

Presence of diabetes

1.75 (0.98–3.11)

NS

Lifestyle factors Current smokers Regular drinkers Physical activity, total index

1.17 (0.23–6.00) 1.06 (0.34–3.31) 0.98 (0.84–1.14)

NS NS NS

OR: odds ratio, CI: confidence interval, SBP: systolic blood pressure, DBP: diastolic blood pressure, BMI: body mass index, WC: waist circumference, WHR: waist–hip-ratio, TC: total cholesterol, HDL-C: high-density lipoprotein cholesterol, LDL-C: low-density lipoprotein cholesterol, TG: triglycerides, FBG: fasting blood glucose, and NS: non-significant. a Logistic regression model adjusted for age. b Forward stepwise logistic regression model adjusted for age, hormonal therapy (no vs. yes), SBP (<140 vs. ≥140 mm Hg), BMI (<25 vs. ≥25 kg/m2 ), WHR (<0.85 vs. ≥0.85), HDL-C (≥1.2 vs. <1.2 mmol/L), LDL-C (<3.4 vs. ≥3.4 mmol/L), TG (<1.7 vs. ≥1.7 mmol/L), presence of diabetes (no vs. yes), smoking (never and ex-smokers vs. current smokers), alcohol drinking (never and non-regular drinkers vs. regular drinkers), physical activity (total index from the Baecke questionnaire), dietary total energy intakes per day (kcal), dietary total fat intakes per day (g), marital status (single, widowed, divorced, and separated vs. married), levels of education (below secondary vs. secondary vs. above secondary), and economic activity status (housewife vs. employed women).

Our study revealed a mean IMT of 0.76 mm which was relatively higher than that found in another local population of 290 non-smoking Chinese women aged 42.0 ± 13.1 years (mean IMT: 0.56 ± 0.10 mm) [22]. The higher IMT in our study could be partly due to our study was conducted in older postmenopausal women. The onset of menopause favors metabolic and hormonal changes and an adverse cardiovascular risk factor profile [23]. Yeung et al. [24] also reported a lower IMT of 0.62 mm in 247 Hong Kong Chinese women aged 55.2 ± 0.13 years. However, only the CCA values were used in this study while our study used the mean IMT of values measured at the near and far walls of three segments including CCA, bulb, and ICA of both the left and right carotid arteries. Nevertheless, our finding was similar to that reported in some other studies. The Atherosclerosis Risk in Communities (ARIC) Study reported 0.75 ± 0.21 mm for the left CCA and 0.76 ± 0.22 mm for the right CCA for women aged 45–64 years, although menopausal status was not presented [25]. The Healthy Women Study reported a mean IMT value of 0.77 mm [20]. Consistent with some previous reports, we found statistically significant differences in the IMT values at the different carotid segments, where the bulb had generally larger IMT than the CCA and ICA [26–28]. The differential IMT in each segment is believed to be associated with the differential shear stress and residence time of blood experienced at the different parts of the segment wall. For example, the carotid bulb has the thickest IMT as it experiences the least oscillatory shear stress as a result of flow reversal at peak systole and a long residence time of blood due to stagnant blood during diastole [29]. Though the blood flow is laminar with a high shear stress, the CCA exhibits a moderately thick IMT because the prolonged interaction of blood with the vessel wall favors lipid infiltration. The ICA has the smallest IMT because oscillatory shear stress is expected to be highest in this relatively small segment [28,30].

We also found a higher IMT on the far wall than the near wall, but differences between the left and the right sides were statistically non-significant. The smaller near wall IMT may be partially explained by the measurement limitations in discerning the lumenintima surface using the B-mode ultrasound. Studies comparing ultrasound measurements of IMT with histology showed that ultrasonic far wall IMT truly and accurately represents IMT as measured by histology, but near wall measurement may be affected by the axial resolution and the gain setting of the ultrasound equipment, and may considerably underestimate the true IMT [31,32]. However, Furberg et al. [33] revealed that the CCA IMT progression rate was similar between the two walls and the inclusion of near wall measurements considerably reduced the variability of estimates of IMT progression. In addition, Bots et al. [34] demonstrated that the combined measurement of the near and far wall IMT of the CCA provides the strongest association with prevalent CVD and with the presence of atherosclerosis elsewhere in the arterial system. As expected, the mean IMT increased with increasing age, elevated SBP, and adverse lipid profiles. Risk factors for increased IMT may vary by arterial segments. Previous studies have indicated that certain risk factors had different associations with one or the other segment of the carotid artery [27,28]. Our findings revealed stronger associations of lipids with the IMT of the CCA and bulb than with the IMT of the ICA, and that could be related to a higher lipid infiltration because of the increased residence time of blood at those sites [35]. The bulb segment, which contains more macrophages than the CCA or the ICA segments [36], might also make the bulb more susceptible to lipid accumulation. Furthermore, an association was demonstrated between diabetes and CCA IMT but not the other arterial segments. The reasons for these differential associations are not clear. There is evidence that diabetes is associated with both decreased flow velocity and larger carotid diameter, which in turn may result in a reduced shear stress values, and consequently

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increase wall thickness and plaque localization [37]. However, SBP was similarly associated with IMT across segments. Our study showed that the prevalence of plaque was common (21.8%) and in agreement with previous reports, the bulb was the most common site of plaque formation [38,39]. A similar prevalence of plaque was observed in another local population (19.4%) [24]. In the ARIC study, the prevalences of plaque ranged from 18.0% to 41.6% among women aged 45–64 years [38]. The Healthy Women Study has reported a markedly higher prevalence of plaque (54%) [20] which might be related to the higher proportion of smokers in this population. However, different definitions of plaque used make the comparison of prevalence across studies difficult. We defined plaque as a focal wall thickening of at least 1.5 mm while Yeung et al. [24] defined plaque as IMT of 1.3 mm or greater or a focal protrusion into the lumen with a thickness of at least 50% more than the adjacent intima-media complex. Nevertheless, both definitions of plaque will allow classification of the vast majority of carotid lesions observed with ultrasound [40]. Some other studies, however, defined plaque as a focal wall thickening from 1.0 to 1.2 mm [26,41–44] while Bonithon-Kopp et al. [45] defined as a more advanced disease of focal wall thickening of at least 1.75 mm. The associated risk factors of the presence of plaque were also examined. As expected, carotid plaque was strongly related to age, and LDL-C was found to be the strongest predictor of the presence of plaque [46]. A high WHR (≥ 0.85) was independently associated with the presence of plaque, and the results have been reported previously [47]. However, because of the low prevalence, smoking was not an important risk factor in our study. There are several strengths and limitations in our study. This study was performed in a reasonably large sample of postmenopausal women and in whom cardiovascular risk factors were evaluated. This study was therefore large enough to allow detection of any segment-specific effect of cardiovascular risk factors on IMT. However, the small number of plaques at the CCA and ICA limited power to find an association between risk factors and plaques at those sites, and therefore we only analyzed the strength of the associations of risk factors and the presence of plaques at all sites combined. In addition, our data are cross-sectional and the temporal relationship between risk factors and IMT and the presence of plaque cannot be assessed. Finally, although we report results of multivariate adjustments for a number of potential confounders but we cannot exclude the possibility of residual confounding. Other atherosclerotic mechanisms and pathways, such as the effects of chronic inflammation should continue to be examined.

5. Conclusions Our population-based data revealed the distribution of IMT and the prevalence of plaque by carotid segments, walls, and sides in early postmenopausal Chinese women aged 50–64 years. The data will serve as reference values for mid-life Chinese women. A high prevalence of plaque among the study cohort was noted. Our data also demonstrated that the relationships between some risk factors and IMT are heterogeneous among arterial segments, and suggest that IMT measurements that include different segments are essential. The onset of menopause, the relatively unfavorable cardiovascular risk factor profiles and increasing risk with age indicated an early detection of subclinical atherosclerosis in midlife women would be valuable for the avoidance of morbidity and mortality associated with CVD. Further longitudinal studies are required to investigate the nature of the progression of IMT with age and to standardize measurement methods that would allow accurate comparisons across studies.

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