Factors associated with gender difference in the intima–media thickness of the common carotid artery

Clinical Radiology (2009) 64, 1097e1103

Factors associated with gender difference in the intimaemedia thickness of the common carotid artery T.-Y. Tana, C.-H. Lua, T.-K. Lina, C.-W. Lioua, Y.-C. Chuanga,*, U. Schminkeb Departments of aNeurology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, and bNeurology, Ernst Moritz Arndt University, Greifswald, Germany Received 9 February 2009; received in revised form 8 June 2009; accepted 10 June 2009

AIM: To investigate the gender differences associated with a thinner intimaemedia thickness (IMT) of the common carotid artery (CCA) in women. MATERIALS AND METHODS: In a sample of 218 consecutive healthy volunteers comprising 110 men and 108 women, the IMT of the CCA was measured using B-mode ultrasonography. Blood pressure, fasting blood sugar, body mass index (BMI), blood lipid profile, homocysteine, folic acid, uric acid, high sensitive C-reactive protein, and thiobarbituric acid reactive substances (TBARS) levels were measured and compared with each other in both genders. RESULTS: The IMT of the CCA was significantly thinner in women than in men (p ¼ 0.012). Blood pressure, fasting plasma glucose, BMI, low-density lipoprotein cholesterol, triglycerides, homocysteine, uric acid, and TBARS were significantly (p < 0.05) lower, folic acid and high-density lipoprotein cholesterol (HDL-C) were significantly (p < 0.0001) higher in women compared with men. Multivariable logistic regression analysis revealed that higher serum levels of homocysteine, uric acid, and TBARS, and lower serum levels of HDL-C were significantly (p < 0.05) associated with male sex. Multiple linear regression analysis further revealed that age, sex, and BMI were independently associated with CCA IMT. CONCLUSIONS: The IMT of the CCA was thinner in women than in men. Traditional vascular risk factors explain only a small amount of variance in multivariate regression models supporting the hypothesis that other behavioural, sex hormone-related or genetic factors, which have not been sufficiently explored so far, may play a role in the gender differences of IMT. ª 2009 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Introduction Gender differences exist in many diseases and medical conditions. In premenopausal women, the incidence and severity of hypertension, stroke, and other vascular diseases are lower than in men at similar ages or than in post-menopausal women.1 Gender differences further exist in * Guarantor and correspondent: Y.-C. Chuang, Department of Neurology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, 123, Ta-Pei Road, Niao-Sung Hsiang, Kaohsiung County 833, Taiwan. Tel.: þ886 7 7317123; fax: þ886 7 7318762. E-mail address: [email protected] (Y.-C. Chuang).

intermediate vascular risk factors, such as the intimaemedia thickness (IMT) of the common carotid artery (CCA), which is frequently used as a surrogate marker for subclinical atherosclerosis in multiple epidemiological and interventional studies.2e4 The pathophysiological mechanisms for these gender differences are still poorly understood, although emerging evidence suggests that sex hormone-dependent differences in vascular oxidative stress may play an important role.5e7 As gender is an unmodifiable risk factor for vascular diseases and the benefit of hormone-replacement therapy in women remain uncertain,8,9 investigating

0009-9260/$ - see front matter ª 2009 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.crad.2009.06.009

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for other factors than sex hormone-related differences may contribute to a greater understanding of the process of atherosclerosis. The aim of the present study was to explore the factors associated with a thinner IMT in women.

Subjects and methods Study design This was a single-centre, observational study. The study hospital was a medical centre and a main referral hospital serving an area with 3 million inhabitants. The institutional ethics committee approved the study protocol, and informed written consent was obtained from each of the participants.

Subjects From July 2006 to May 2007, a total of 218 consecutive volunteers (110 men and 108 women; age 18e65 years; mean age for men: 36.4 years; women: 37.7 years) who underwent an annual physical check-up were enrolled in this study. The exclusion criteria were based on a previous report.10 These criteria comprised stroke, ischaemic heart diseases, hypertension, diabetes mellitus (defined as a fasting blood glucose 6.93 mmol/l), and tobacco smoking. Additionally, participants with a clinical diagnosis of gout, arthritis, tophi or nephrolithiasis related to hyperuricaemia, and those who were treated with antihypertensive drugs, oral hypoglycaemic agents, vitamin supplements, or any kind of medication that could affect lipid or uric acid metabolism were excluded. All participants underwent a physical examination and were interviewed to assess their medical history. Blood pressure was measured in the sitting position and the body mass index (BMI) was calculated. The clinical records of the participants were reviewed for all possible exclusion criteria.

Assessment of atherosclerosis The IMT of the CCA was measured using ultrasonography. Longitudinal images of the CCA were recorded using a B-mode ultrasound system (Philips HDI 5000 System, ATL-Philips, Bothell, WA, USA) equipped with a 4e10 MHz linear array transducer. Participants were examined according to a standardized protocol by an experienced ultrasound technologist who was blinded to any clinical

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information. Both the left and right CCA were routinely scanned, defined as the 1 cm vascular wall segment of the CCA immediately proximal to the dilatation of the bifurcation plane. The images were optimized so that only the far wall was visualized in a single longitudinal view. These images were transferred to a workstation, and the IMT, defined as the distance between the interfaces between the lumeneintima and mediaeadventitia, were automatically measured using a computer software program (Q-LAB, ATL-Philips)11,12 (Fig. 1). These measurements were also performed in a single-blind fashion, and the mean IMT of the CCA was defined as the average of measurements obtained from the left and right CCA. The reproducibility of the automatic IMT measurement was assessed on 30 digitally stored longitudinal images of the CCA, in which the mean far wall CCA-IMT was measured independently by two different investigators. The between-reader coefficient of variation as calculated with a one-way random-effects analysis-of-variance (ANOVA) model was 1.2% and the corresponding intraclass correlation coefficient (reliability coefficient) was 99.6%.

Analysis of circulating biochemical markers Blood samples were taken between 8 and 10 a.m. after overnight fasting and analysed by the central laboratory of Chang Gung Memorial HospitalKaohsiung for serum levels of triglycerides, total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDLC), blood glucose, creatinine, uric acid, folic acid, homocysteine, and high sensitive C-reactive protein (hs-CRP).

Measurement of lipid peroxidation Lipid peroxidation as an indicator for oxidative damage was determined by measuring the plasma concentration of thiobarbituric acid reactive substances (TBARS) using the method of Ohkawa et al.13 A standard curve of TBARS was obtained by hydrolysis of 1,1,3,3-tetraethoxypropane.

Statistical analysis Three separate series of statistical analyses were performed using the SAS software package (version 9.1, SAS Statistical Institute, Cary, NC, USA). First, to compare demographic data between women and men, categorical variables were assessed using

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Figure 1 Longitudinal image plane of the distal portion of the common carotid artery with measurement of the intimaemedia thickness (IMT) of the far wall. The interfaces between lumen and intima and between media and adventitia were traced automatically using a computer software program (Q-LAB, ATL-Philips), which further provides multiple distance measurements between both interfaces. The mean IMT in this sample as computed as the average of multiple distance measurements is 0.63 mm.

Chi-square or Fisher’s exact test, and continuous variables were compared using Student’s t-test. Multivariable logistic regression analysis was performed for significant factors associated with gender. Continuous variables, which did not follow a normal distribution (bilateral CCA IMT, mean CCA IMT and hs-CRP), were transformed into square root (SQRT) to improve normality before comparison by Student’s t-test. Second, correlation analysis was used to evaluate the relationship between CCA IMT and variables that included age, blood pressure, BMI, fasting blood glucose, cholesterol profile, hs-CRP, homocysteine, folic acid, uric acid, and TBARS concentration. Third, two models of multiple linear regression analysis were performed to assess the impact of independent variables on the CCA IMT. Initially, all factors (excluding homocysteine and TBARS) that were significantly correlated with the mean CCA

IMT value were included into the multivariate linear regression model. In a second step, only those factors that were significantly associated with the IMT in the first model (age, sex, and BMI), were included in a second model.

Results CCA IMT is thinner in women Table 1 presents the baseline characteristics of the 218 participants. Univariate analysis revealed that the mean IMT of the left CCA and the mean CCA IMT of both sides were significantly thinner in women than in men. In both women and men the left CCA IMT was thicker than the right CCA IMT (mean  standard deviation; 0.556  0.10 mm versus 0.529  0.09 mm, p ¼ 0.004).

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Table 1

T.-Y. Tan et al.

Demographic data of 218 healthy adults

Age (years) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Fasting plasma glucose (mmol/l) Body mass index (kg/m2) Right CCA IMTa (mm) Left CCA IMTa (mm) Mean CCA IMTa (mm) Total cholesterol (mmol/l) HDL-C (mmol/l) LDL-C (mmol/l) Triglyceride (mmol/l) Homocysteine (mmol/l) Folic acid (nmol/l) Uric acid (mmol/l) hs-CRPa (mg/l) TBARS (mmol/l)

Men (n ¼ 110)

Women (n ¼ 108)

p-Value

36.4  11.1 123  10 78  9 5.06  0.5 24.3  3.6 0.540  0.098 0.576  0.120 0.558  0.102 5.05  0.88 1.35  0.31 3.11  0.75 1.36  0.76 11.1  2.8 22.02  11.12 363  66 1.3  1.9 0.94  0.49

37.7  11.9 117  13 73  8 4.9  0.4 21.9  3.3 0.517  0.085 0.536  0.079 0.527  0.078 4.92  0.98 1.66  0.39 2.82  0.83 0.99  0.95 8.1  2.1 27.69  11.58 280  54 1.0  1.4 0.64  0.36

0.41 0.002 <0.0001 0.009 <0.0001 0.069 0.004 0.012 0.29 <0.0001 0.014 0.002 <0.0001 <0.0001 <0.0001 0.23 <0.0001

Data are expressed in mean  SD. CCA IMT, intimaemedia thickness of the common carotid artery; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides; hs-CRP, high sensitive C-reactive protein; TBARS, thiobarbituric acid reactive substances. a Data transformed into square root before comparison.

Differences in demographic data and vascular risk factors between both genders Univariate analysis (Table 1) revealed that blood pressure, fasting blood sugar, BMI, LDL-C, triglycerides (TG), homocysteine, uric acid, and TBARS

Table 2 Multivariate logistic regression analysis with male gender as the outcome variable and several risk factors as predictor variables

Age (years) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Fasting plasma glucose (mmol/l) Body mass index (kg/m2) Total cholesterol (mmol/l) HDL-C (mmol/l) LDL-C (mmol/l) Triglyceride (mmol/l) Homocysteine (mmol/l) Folic acid (nmol/l) Uric acid (mmol/l) Hs-CRP (mg/l) TBARS (mmol/l)

Odds ratios (95% confidence interval)

p-Value

0.96(0.90e1.02) 1.01(0.94e1.08)

0.20 0.88

1.08(0.97e1.20)

0.18

1.07(0.99e1.15)

0.81

1.03(0.80e1.32) 1.21(0.95e1.55) 0.78(0.62e0.99) 0.82(0.64e1.05) 0.98(0.94e1.01) 1.86(1.33e2.61) 1.06(0.91e1.23) 2.62(1.44e4.78) 1.07(0.79e1.45) 7.8(1.50e40.68)

0.81 0.12 0.04 0.12 0.20 <0.0001 0.45 0.002 0.67 0.015

Values are expressed in mean  SD. CCA IMT, intimaemedia thickness of the common carotid artery; HDL-C, high-density lipoprotein cholesterol; LDL-C, lowdensity lipoprotein cholesterol; hs-CRP, high sensitive C-reactive protein; TBARS, thiobarbituric acid reactive substances.

were significantly lower, whereas folic acid and HDL-C were significant higher in women than in men. Multivariable logistic regression analysis (Table 2) showed that higher serum levels of homocysteine, uric acid, and TBARS, as well as lower serum levels of HDL-C were significantly associated with male gender.

Age, gender, and BMI were significantly associated with CCA IMT Based on correlation analysis, the first series revealed that age, sex, blood pressure, fasting blood glucose, BMI, blood lipid profile, folic acid, uric acid, and hs-CRP were significantly correlated with mean CCA IMT, whereas other variables were not (Table 3). TBARS and homocysteine showed insignificant correlation. Further multiple linear regression analyses were performed to assess the strength of the associations between potential predictor variables and mean IMT. Model 1 (Table 4) indicates that only age, gender, and BMI were significantly associated with the mean CCA IMT. Model 2 included only those three variables that were significantly associated with mean IMT in the fully adjusted model 1. According to model 2, the multiple linear regression formula was calculated as: SQRT IMT ðmeanÞ ¼ 0:528 þ 0:016  ðMale sexÞ þ 0:003  ðAgeÞ þ 0:003  ðBMIÞ

Factors associated with gender difference in the intima

Table 3 Correlation analysis of the effects of candidate factors on mean intimaemedia thickness of the common carotid artery in 218 healthy adults Variables

Correlation coefficient

p-Value

Age (years) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Fasting plasma glucose (mmol/l) Body mass index (kg/m2) Total cholesterol (mmol/l) HDL-C (mmol/l) LDL-C (mmol/l) Triglyceride (mmol/l) Homocysteine (mmol/l) Folic acid (nmol/l) Uric acid (mmol/l) hs-CRP (mg/l) TBARS (mmol/l)

0.673 0.374 0.341 0.342 0.417 0.268 0.167 0.287 0.20 0.108 0.157 0.156 0.295 0.03

<0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 0.017 <0.0001 0.003 0.11 0.021 0.022 <0.0001 0.677

CCA IMT, intimaemedia thickness of the common carotid artery; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; hs-CRP, high sensitive C-reactive protein; TBARS, thiobarbituric acid reactive substance.

Discussion In accordance with the findings from multiple, large-scale, epidemiological studies,2e4 the present study revealed a thinner CCA IMT in women than in men in a Taiwanese population. Although the majority of those well-established vascular risk factors, which were analysed in the present study, differ significantly between men and

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women, only serum levels of HDL-C, homocysteine, uric acid, and TBARS as an indicator of lipid peroxidation were significantly associated with female gender in a multiple logistic regression model. Furthermore, multivariate linear regression models, which included all major, well-established vascular risk factors, show that only sex, age, and BMI were independently associated with SQRT-transformed CCA IMT. In general, the amount of variance of CCA IMT explained by those wellestablished vascular risk factors is rather low. Behavioural risk factors, such as dietary habits, leisure time physical activity, moderate alcohol intake, and socio-demographic variables, which were not analysed in the present study, but which indicate a healthier lifestyle, may further contribute to the variance of CCA IMT.14 The unexplained variance raises the hypothesis that genetic factors or sex hormone-mediated processes may account for these gender specific differences in CCA IMT.2,5e7,15 The present study shows that an increase in SQRT CCA IMT was linearly related to the BMI at a rate of 0.003 per year, which demonstrates identical weight of age and BMI as a predictor of IMT. This relationship of CCA IMT with the aging process is in line with reports from Taiwan3 and Japan.16 Previous reports have outlined that carotid IMT is associated with obesity and an increase in BMI.17 A fundamental mechanism of atherogenesis in obese persons or in cases of increased BMI is lowgrade systemic inflammation.18 Women’s serum

Table 4 Multiple regression analysis of the association of the square root transformed intimaemedia thicknesses on candidate vascular risk factors Model 1

Constant Sex (male) Age Body mass index Systolic blood pressure Diastolic blood pressure Folic acid hs-CRPa Uric acid Fasting blood glucose Total cholesterol LDL-C HDL-C Triglyceride

Model 2

Regression coefficients

Standard error

p-Value

Regression coefficients

Standard error

p-Value

0.429 0.034 0.003 0.005 0.001 <0.001 <0.001 0.002 0.001 <0.001 0.001 0.001 0.001 <0.001

0.058 0.01 <0.001 0.002 <0.001 <0.001 0.001 0.002 0.003 <0.001 0.002 0.002 0.002 <0.001

<0.001 0.001 <0.001 0.003 0.067 0.922 0.927 0.307 0.714 0.464 0.625 0.584 0.551 0.428

0.528 0.016 0.003 0.003 e e e e e

0.018 0.006 <0.001 0.001 e e e e e

<0.001 <0.001 <0.001 <0.001 e e e e e

e

e

e

Dependent variable, square root transformed intimaemedia thicknesses (SQRT IMT) calculated using the formula, SQRT IMT (mean) ¼ 0.528 þ 0.016  (Male sex) þ 0.003  (Age) þ 0.003  (Body mass index). hs-CRP, high sensitive C-reactive protein; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. a Data transformed into square root before analysis.

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hs-CRP levels were higher than those observed in men, but the differences did not reach statistical significance. This may be explained by the fact that many of the BMI values were within the normal range in the present study, with the result that differences in hs-CRP difference were not large enough to reach significance. Until now, conflicting findings have been published concerning the impact of hs-CRP on early atherosclerosis. Some cross-sectional studies demonstrated that hs-CRP was associated with IMT,19,20 whereas others21,22 failed to demonstrate that hs-CRP can serve as an independent risk factor for early carotid atherosclerosis. In the present study, BMI contributed to the observed thickening of the CCA IMT in both sexes, but it remains unclear whether this effect was mediated via an inflammatory mechanism, as hs-CRP was the only inflammatory marker studied. Oxidative mechanisms were identified as a significant factor associated with thinner CCA IMTs in women. There is now a consensus that atherosclerosis represents a state of increased oxidative stress characterized by lipid and protein oxidation in the vascular wall.23 Chronic production of reactive oxygen species may exceed the capacity of cellular antioxidants, resulting in oxidative modification of LDL-C, promotion of proinflammatory responses, recruitment of macrophages, and the development of atherosclerotic lesions.23 The significant decrease TBARS levels detected in blood samples from women may indicate that women had reduced oxidative damage compared with men. Increasing evidence suggests that levels of vascular reactive oxygen species may be lower in women than men during health and disease.24 Also, gonadal sex hormones may play an important role in the regulation of vascular oxidative stress. For example, oestrogens, which are present in highest levels in premenopausal women, have been reported to lower vascular oxidative stress by modulating the expression and function of NADPH oxidases, as well as anti-oxidant enzymes.6,24 Further studies are required to clarify whether lower vascular oxidative stress in women, in fact, protects against the initiation and development of vascular disease and to further define the roles of gonadal sex hormones in such an effect. Elevated plasma homocysteine levels have been demonstrated as an independent risk factor for the progression of atherosclerosis.25,26 In the present study, men exhibited a significant increase in homocysteine levels and a decrease in folic acid concentration. LDL-C plays an important role in the atherosclerotic process by increasing endothelial permeability,

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retention of lipoproteins within the intima of blood vessels, recruitment of inflammatory cells and the formation of foam cells.23,27 Women had significantly lower LDL-C levels and higher HDL-C levels than men, which may have contributed to the CCA IMT differences between both genders. Serum uric acid levels were significantly associated with gender difference in CCA IMT. Possible explanations for this association may be related to hyperuricemia-induced endothelial dysfunction and facilitation of smooth muscle cell proliferation.28,29 Independent from other cardiovascular risk factors, uric acid levels are associated with carotid IMT30,31 and cardiovascular diseases.32,33 In conclusion, sex-related differences may become increasingly important for the understanding of pathomechanisms for atherosclerosis. Traditional vascular risk factors explain a small amount of variance in multivariate regression models supporting the hypothesis that other behavioural, sex hormone-related, or genetic factors, which have not been sufficiently explored so far, may play a role in gender differences of IMT.

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