Normative and mean carotid intima-media thickness values according to metabolic syndrome in Koreans: The Namwon Study

Atherosclerosis 234 (2014) 230e236

Contents lists available at ScienceDirect

Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis

Normative and mean carotid intima-media thickness values according to metabolic syndrome in Koreans: The Namwon Study Young-Hoon Lee a, b, Min-Ho Shin c, Sun-Seog Kweon c, d, Hae-Sung Nam e, Kyeong-Soo Park f, Jin-Su Choi c, Seong-Woo Choi g, Hye-Yeon Kim f, Gyung-Jae Oh a, b, Hye-Ran Ahn c, Hyun-Suk Oh c, Seul-Ki Jeong h, * a

Department of Preventive Medicine & Institute of Wonkwang Medical Science, Wonkwang University College of Medicine, Iksan, South Korea Regional Cardiocerebrovascular Center, Wonkwang University Hospital, Iksan, South Korea Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, South Korea d Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, South Korea e Department of Preventive Medicine, Chungnam National University College of Medicine, Daejeon, South Korea f Department of Preventive Medicine, Seonam University College of Medicine, Namwon, South Korea g Department of Preventive Medicine, Chosun University Medical School, Gwangju, South Korea h Department of Neurology & Research Institute of Clinical Medicine, Chonbuk National University, Jeonju, South Korea b c

a r t i c l e i n f o

a b s t r a c t

Article history: Received 23 August 2013 Received in revised form 5 February 2014 Accepted 25 February 2014 Available online 18 March 2014

Objectives: We determined the gender- and age-specific normative values of carotid intima-media thickness (IMT) in a healthy Korean population. We also present the mean age-specific carotid IMT values according to the presence of metabolic syndrome (MetS) and the number of MetS components. Methods: A total of 9374 subjects from the Namwon Study aged 45e74 years were included in the analysis. Subjects without hypertension, diabetes, dyslipidemia, obesity, and current smoking were classified as the healthy reference population (n ¼ 2595). MetS was identified by the presence of three or more of the following five components: abdominal obesity, high triglycerides, low high-density lipoprotein cholesterol, high blood pressure, and high fasting blood glucose. Common carotid artery IMT (CCA-IMT) and carotid bulb IMT values were determined in a region free of plaque by B-mode carotid ultrasonography. Results: The mean normative CCA-IMT values of 45e49, 50e54, 55e59, 60e64, 65e69, and 70e74 year old males were 0.614, 0.671, 0.711, 0.759, 0.783, and 0.787 mm and 0.613, 0.653, 0.689, 0.718, 0.753, and 0.778 mm for females, respectively. An increase in CCA-IMT of 0.007 mm/year was estimated in both genders. The mean CCA-IMT values of subjects with 0, 1, 2, 3, 4, and 5 MetS components were 0.744, 0.753, 0.765, 0.766, 0.771, and 0.798 mm for males and 0.688, 0.705, 0.724, 0.734, 0.757, and 0.762 mm for females, respectively. Conclusion: The gender-specific normative carotid IMT values were determined in a large healthy Korean population. An increasing trend in the CCA-IMT values was observed with an increasing number of MetS components in both genders. Ó 2014 Elsevier Ireland Ltd. All rights reserved.

Keywords: Atherosclerosis Carotid intima-media thickness Metabolic syndrome Reference values

1. Introduction Carotid intima-media thickness (IMT) measured by highresolution B-mode ultrasonography is a surrogate marker of

* Corresponding author. Department of Neurology & Research Institute of Clinical Medicine, Chonbuk National University e Biomedical Research Institute of Chonbuk National University Hospital, San 2-20, Geumam-dong, Deokjin-gu, Jeonju, Jeonbuk 561-180, South Korea. Tel.: þ82 63 250 1590; fax: þ82 63 251 9363. E-mail address: [email protected] (S.-K. Jeong). http://dx.doi.org/10.1016/j.atherosclerosis.2014.02.023 0021-9150/Ó 2014 Elsevier Ireland Ltd. All rights reserved.

systemic subclinical atherosclerosis. Numerous epidemiological studies have demonstrated a relationship between carotid IMT and incident cardiovascular disease (CVD) events [1e3]. Carotid ultrasonography is being increasingly used as an endpoint in epidemiological and interventional studies due to noninvasiveness, low cost, safety, and simplicity. Early screening of intermediate to high risk population and individuals for future CVD is important because the detection of subclinical atherosclerosis allows the physician to implement CVD prevention efforts [4].

Y.-H. Lee et al. / Atherosclerosis 234 (2014) 230e236

In epidemiology and clinical practice, the carotid IMT measured from each subject should be interpreted based on gender-, age-, and race-specific normative data [5]. In particular, carotid IMT data for some ethnic groups cannot be directly applied to others. While several studies have presented the normative carotid IMT values for the Caucasian population, limited information is available on carotid IMT values for healthy Asian populations. Although a few studies have reported normative data on carotid IMT in Koreans [6e9], the small sample size, loose criteria for healthy population, or non-community population are considered potential weak points. To date, epidemiological studies have shown that metabolic syndrome (MetS), which is a constellation of metabolic risk factors, is a strong indicator for future CVD events and death [10,11]. Previous studies show a relationship between MetS and carotid atherosclerosis as assessed by ultrasonography [12e14]. Significant differences are observed in carotid IMT between subjects with MetS and subjects without, and an increase in carotid IMT with a corresponding increase in the number of MetS components was observed in several studies [9e17]. However, few studies have reported mean gender- and age-specific IMT values according to the number of MetS components in a large general population. The objective of our study was to determine the gender- and age-specific normative carotid IMT values in a healthy Korean population. In addition, the mean age-specific carotid IMT values according to the presence of MetS and the number of MetS components were assessed in males and females to present the reference values for a Korean population. 2. Methods 2.1. Study population The Namwon Study is an ongoing population-based prospective cohort study designed to examine the prevalence, incidence, and risk factors for chronic disease including CVD, osteoporosis, and dementia in community-dwelling adults aged 45e74 years [18]. The 2005 census reported 33,068 residents (14,960 men and 18,108 women) aged 45e74 years in Namwon city. A total of 10,667 participants who live in Namwon city, a representative rural area in Jeonbuk province in Korea, were enrolled in the baseline survey between January 2004 and February 2007 (participation rate ¼ 32.3%, 28.1% for men and 35.7% for women). We excluded 455 subjects with missing information or poor carotid ultrasonography images and 761 subjects who had a history of coronary heart disease or cerebrovascular disease during the baseline survey. A total of 9374 subjects were included in the final analysis after further exclusion of 77 subjects with missing information on MetS components. All subjects were fully informed of the study content and gave informed consent for use of their data. This study protocol was approved by the Institutional Review Boards of Chonnam National University Hospital and Chonbuk National University Hospital independently. 2.2. Interview and physical, and laboratory examinations Information on each subject’s demographics, smoking, alcohol intake, medical history, and medications was obtained using a standardized questionnaire administered by trained interviewers. Data on alcohol intake and smoking habits were collected using a standardized questionnaire administered by a well-trained member of our research staff. Current drinkers were defined as those who drank alcoholic beverage during the 12 months prior to the interview. In terms of smoking status, participants were classified

231

as never-smokers, former smokers, and current smokers. Current smokers were participants who smoked at the time of the interview among those who had smoked at least 100 cigarettes during their lifetime. All participants underwent a physical examination using a standardized protocol performed by trained staff. Height and weight were measured in light clothing without shoes. Body mass index (BMI) was calculated as weight divided by height squared (kg/m2). Waist circumference (WC) was measured at the midpoint between the lowest rib margin and the iliac crest during expiration. Blood pressure was measured using a standard mercury sphygmomanometer in the sitting position on the right upper arm after a 5-min rest. Three consecutive blood pressure measurements were performed at 1-min intervals, and systolic blood pressure (SBP) and diastolic blood pressure (DBP) were recorded to the nearest 2 mmHg. The average of the three measurements was used for analysis. After a 12-h overnight fast, blood samples were collected from an antecubital vein in the morning. Fasting blood glucose (FBG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), gamma-glutamyltransferase (GGT), and uric acid (UA) levels were measured using an enzymatic method and an automatic analyzer (Hitachi 7600, Hitachi Ltd., Tokyo, Japan). High-sensitive C-reactive protein (hs-CRP) was measured by latex-enhanced nephelometry using a high-sensitivity assay analyzer (Behring Nephelometer II; Dade-Behring Diagnostics, Marburg, Germany). Urinary albumin and creatinine concentrations were determined by immunoturbidimetry and the modified Jaffe method (model 7600 chemical analyzer; Hitachi, Tokyo, Japan), respectively. The urinary albumin-to-creatinine ratio (UACR) was calculated based on urinary albumin and creatinine levels. According to the National Cholesterol Education Program, Adult Treatment Panel III [19], the American Diabetes Association [20], and the Korean Society for the Study of Obesity [21], MetS was identified by the presence of three or more of the following five components: 1) abdominal obesity (WC  90 cm for males and 85 cm for females); 2) high TG (150 mg/dL); 3) low HDL-C (<40 mg/dL for males and <50 mg/dL for females); 4) high blood pressure (SBP  130 mmHg and/or DBP  85 mmHg and/or current use of anti-hypertensive medication); 5) high FBG (100 mg/dL and/or current use of anti-diabetic medication). 2.3. Carotid ultrasonography A high-resolution B-mode ultrasound (SONOACE 9900; Medison, Seoul, Korea) equipped with a 7.5 MHz linear array transducer was used for carotid ultrasonography. In the longitudinal view, IMT was determined as the distance from the mediae adventitia interface to the intimaelumen interface on the far wall in a region free of plaque [22]. The examiner assessed the presence of carotid plaques, which were defined as focal structures that encroached into the lumen by at least 100% of the surrounding IMT value. Common carotid artery IMT (CCA-IMT) was measured between the origin of the carotid bulb and a point 10 mm proximal to the CCA, and the carotid bulb IMT (CB-IMT) was measured in the carotid bulb region. CCA-IMT and CB-IMT values were determined as the average of the maximum IMT of the left and right CCA and CB. Two sonographers conducted repeated ultrasound examinations to ensure reproducibility (n ¼ 189). Correlation coefficients for inter- and intra-sonographer variability were 0.86 and 0.90 for CCA-IMT. Kappa coefficients for carotid plaques were 0.76 for intersonographer agreement and 0.85 for intra-sonographer agreement. A single trained reader analyzed the still images using Sigma Scan

232

Y.-H. Lee et al. / Atherosclerosis 234 (2014) 230e236

Pro 5.0 (SPSS Inc., Chicago, IL, USA). Intra-reader reliabilities were evaluated in 139 cases. The correlation coefficient for intra-reader variability was 0.94 for CCA-IMT. The kappa coefficient for carotid plaques was 0.91 for intra-reader agreement. 2.4. Statistical analysis Baseline characteristics of the study population are presented as frequencies (percentage) or means (standard deviation; SD) or median [interquartile range] for skewed distributions. Differences between males and females were compared using Student’s t-test or the ManneWhitney U-test for continuous variables and the chisquare test for categorical variables. Subjects without any of the following conditions were classified as the healthy reference population (n ¼ 2595): hypertension (SBP  140 mmHg or DBP  90 mmHg or anti-hypertensive medication); diabetes (FBG  126 mg/dL or anti-diabetic medication); dyslipidemia (TC  230 mg/dL or TG  200 mg/dL or HDL-C < 40 mg/dL or antidyslipidemic medication) [23]; obesity (BMI  30.0 kg/m2); current smoking. First, CCA-IMT and CB-IMT values by 5-year age groups and gender among the healthy reference population, are presented as mean (SD), 95% confidence interval (CI), range, 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles. Linear trends in mean CCA-IMT and CB-IMT according to 5-year age groups were analyzed. Second, among the total study population, CCA-IMT values according to the presence of MetS and the number of MetS components are presented as mean and SD by 5-year age groups in males and females. The differences in CCA-IMT between subjects with MetS and those without were compared using Student’s t-test. Linear trends in the mean CCA-IMT according to 5-year age groups were analyzed using a general linear model. Third, linear regression analyses were performed to estimate the increase in the CCA-IMT and CB-IMT per year in the healthy reference population. The increase in the CCAIMT with MetS than without and the increase per number of MetS components in both genders before and after adjusting for age were also estimated by linear regression analysis. 3. Results 3.1. Characteristics of the study population and the healthy reference population Significant differences between males and females were observed for age, BMI, WC, SBP, DBP, FGS, TC, HDL-C, TG, GGT, UACR, hs-CRP, and the prevalence of current drinking, current smoking, anti-hypertensive medication, and anti-diabetic medication (Table 1). Gender differences among the healthy reference population (n ¼ 2595) who were free of hypertension, diabetes, dyslipidemia, obesity, and current smoking are shown in Table 2. Males were significantly older than females. Significant differences between the genders were observed for BMI, SBP, DBP, FGS, TC, GGT, UACR, hs-CRP, and the proportion of current drinking in the healthy population. 3.2. Normative CCA-IMT and CB-IMT values in the healthy reference population The CCA-IMT and CB-IMT values in the healthy population according to 5 year age groups are shown in Tables 3 and 4, respectively. The normative mean CCA-IMT values were 0.740  0.136 mm (95% CI, 0.730e0.750 mm) for males and 0.697  0.123 mm (95% CI, 0.691e0.702 mm) for females (P-difference <0.001). The normative mean CCA-IMT values increased with age in both genders. An

Table 1 Characteristics of the entire study population (n ¼ 9374). Males (n ¼ 3659) Females (n ¼ 5715) Age, years Body mass index, kg/m2 Waist circumference, cm Systolic blood pressure, mmHg Diastolic blood pressure, mmHg Fasting blood glucose, mg/dL Total cholesterol, mg/dL HDL cholesterol, mg/dL Triglycerides, mg/dLb GGT, U/Lb UACR, mg/gb hs-CRP, mg/mL

b

Current drinking, n (%) Current smoking, n (%) Anti-hypertensive medication, n (%) Anti-diabetic medication, n (%) Anti-dyslipidemic medication, n (%)

Pa

P

62.1 23.9 85.3 126.6

(7.7) (2.9) (7.9) (17.1)

61.0 24.6 86.4 125.0

(7.9) (3.2) (8.7) (18.9)

<0.001 e <0.001 <0.001 <0.001 <0.001 <0.001 0.004

81.0

(9.9)

80.0

(10.3)

<0.001 <0.001

108.0

(25.7)

102.1

(22.1)

<0.001 <0.001

(37.0) (11.8) [88.0 e185.0] [12.0 e23.0] [9.2 e31.8] [0.03 e0.13] (36.4) (3.7) (20.4)

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

182.4 46.6 134.0

(36.0) 194.4 (12.3) 48.4 [89.0 127.0 e206.0] 32.0 [20.0 16.0 e60.0] 13.0 [7.8 16.2 e25.8] 0.08 [0.03 0.06 e0.17] 2436 (66.6) 2081 1233 (33.7) 214 684 (18.7) 1167

<0.001 <0.001 <0.001

0.236

<0.001

0.159

<0.001 <0.001 <0.001 <0.001 0.041 0.005

294

(8.0)

343

(6.0)

<0.001

0.001

156

(4.3)

266

(4.7)

0.373

0.598

Data are means (standard deviation) or median [interquartile range] or frequency (percentage). HDL-C, high-density lipoprotein cholesterol; GGT, gamma-glutamyltransferase; UACR, urinary albumin-to-creatinine ratio; hs-CRP, high-sensitive C-reactive protein. a P-value adjusted for age. b ManneWhitney U-test.

increase in the CCA-IMT of 0.007 mm/year was estimated in both genders (Table 3). The normative mean CB-IMT values were 0.883  0.142 mm (95% CI, 0.872e0.893 mm) for males and 0.806  0.144 mm (95% CI, 0.799e0.812 mm) for females (P-difference <0.001). The normative mean CB-IMT values increased with age in both genders. An increase in CB-IMT of 0.007 and 0.006 mm/year was estimated in males and females, respectively (Table 4). The CB-IMT was significantly higher compared to CCA-IMT in all gender-specific 5-year age groups (data not shown). 3.3. CCA-IMT according to MetS and the number of MetS components Among the entire study population, MetS was present in 39.2% of males and 49.1% of females (P-difference <0.001). The agespecific prevalence of MetS was highest for males (44.6%) and for females (49.1%) in the age group of 55e59 years (Supplemental Table 1). Table 5 shows the differences in the CCA-IMT values between subjects with MetS and those without, according to the 5year age groups in males and females. The CCA-IMT value in males with MetS was significantly greater than those without MetS (0.771 vs. 0.756 mm; P ¼ 0.003) and also in females (0.746 vs. 0.712 mm; P < 0.001). An increase in the CCA-IMT of 0.014 mm and 0.034 mm with MetS and without MetS was estimated in both males and females, and an increase in the CCA-IMT of 0.022 mm and 0.022 mm with MetS and without MetS was estimated in both males and females, after adjusting for age, respectively. The mean CCA-IMT values increased with the number of MetS components in both males and females, respectively. Significant

Y.-H. Lee et al. / Atherosclerosis 234 (2014) 230e236

4. Discussion

Table 2 Characteristics of the healthy reference populationa (n ¼ 2595). Males (n ¼ 713) Age, years 62.8 Body mass index, kg/m2 23.2 Waist circumference, cm 83.0 Systolic blood pressure, 118.0 mmHg Diastolic blood pressure, 76.7 mmHg Fasting blood glucose, 99.7 mg/dL Total cholesterol, mg/dL 178.5 HDL cholesterol, mg/dL 53.2 94.0 Triglycerides, mg/dLc GGT, U/Lc UACR, mg/gc hs-CRP, mg/mL

c

Current drinking, n(%)

Pb

Females (n ¼ 1882)

P

(7.9) (2.5) (7.1) (11.2)

59.3 23.5 83.5 114.6

(8.2) (2.8) (8.2) (11.7)

<0.001 e 0.016 0.717 0.110 0.488 <0.001 <0.001

(7.0)

75.2

(7.3)

<0.001 <0.001

(10.0)

95.7

(9.2)

<0.001 <0.001

(25.8) (10.6) [71.0 e130.0] 24.0 [16.0 e43.0] 10.6 [6.7 e18.2] 0.05 [0.03 e0.13] 456 (64.0)

182.4 53.4 97.0

(25.6) (10.4) [70.0 e129.0] 14.0 [11.0 e19.0] 13.0 [7.7 e21.8] 0.04 [0.02 e0.09] 731 (38.8)

233

<0.001 <0.001 0.694 0.821 0.845 0.233 <0.001 <0.001 <0.001

0.157

<0.001

0.016

<0.001 <0.001

Data are means (standard deviation) or median [interquartile range] or frequency (percentage). HDL-C, high-density lipoprotein cholesterol; GGT, gamma-glutamyltransferase; UACR, urinary albumin-to-creatinine ratio; hs-CRP, high-sensitive C-reactive protein. a Subjects without any of the following conditions: 1) hypertension (systolic blood pressure  140 mmHg or diastolic blood pressure  90 mmHg or antihypertensive medication); 2) diabetes (fasting blood glucose  126 mg/dL or antidiabetic medication); 3) dyslipidemia (total cholesterol  230 mg/dL or triglycerides  200 mg/dL or HDL < 40 mg/dL or anti-dyslipidemic medication); 4) obesity (body mass index  30.0 kg/m2); 5) current smoking. b P-value adjusted for age. c Mann-Whitney U-test.

trends in the CCA-IMT values according to the number of MetS components were observed in both males and females (Ps < 0.001). An increase in CCA-IMT of 0.008 and 0.016 mm per number of MetS components was estimated in both males and females and an increase in CCA-IMT of 0.011 and 0.010 mm per number of MetS components was estimated in both males and females, after adjusting for age, respectively (Supplemental Table 2).

We identified the gender- and age-specific normative CCA-IMT and CB-IMT values in a large healthy population-based sample aged 45e74 years. The arterial age of the Korean subjects could be estimated by comparing individual carotid IMT measurements with the percentile distributions of carotid IMT presented in our study. Moreover, the mean gender- and age-specific CCA-IMT values according to the presence of MetS and the number of MetS components were presented by 5-year age groups. An increasing trend in the CCA-IMT values was observed with an increasing number of MetS components in both genders. Measurement of carotid IMT by B-mode ultrasonography is a non-invasive, inexpensive, and reproducible technique for early detection of subclinical atherosclerosis [24]. The relationship between carotid IMT and CVD is well established, as the greater the carotid IMT value, the higher the risk for incident CVD events [1e 3,25]. To prevent CVD at the individual and population levels, it is important to identify and quantify carotid atherosclerosis in the intermediate to high-risk population. Our population-specific normative data will allow a comparison with measured carotid IMT in each subject. Moreover, gender-, age, and ethnic-specific normative carotid IMT data are needed because carotid IMT data of some groups cannot be directly applied to other groups, particularly other ethnic groups. In general, carotid IMT values 75th percentile for the subjects age, gender, and ethnicity are regarded as abnormal atherosclerosis and an increased risk for CVD, and an active intervention is needed [5]. Several large epidemiological studies from North America and Europe have reported carotid IMT values in percentiles by gender, age, and ethnicity [5]. The Atherosclerosis Risk in Communities (ARIC) Study [26] and the Multi-Ethnic Study of Atherosclerosis (MESA) Study [3] show similar CCA-IMT values in Caucasians and African Americans of both genders. The Cardiovascular Health Study (CHS) [27] presented relatively higher CCA-IMT values than those of the ARIC and MESA studies. The mean CCA-IMT values of the CHS were 0.1 mm higher than the present study, whereas data in the CHS included prevalent CVD subjects. European studies such as the Carotid Atherosclerosis Progression Study (CAPS) [28] and the Malmo Diet and Cancer Study (MDCS) [29] reported CCA-IMT values, mostly of white populations, as relatively thicker than

Table 3 Mean CCA-IMT (mm) values according to age group among the healthy reference population.a No.

Mean (SD)

95% CI

Range

Percentile 5

10

25

50

75

90

95

b

Males 45e49 years 50e54 years 55e59 years 60e64 years 65e69 years 70e74 years Sub-total

61 75 126 129 157 165 713

0.614 0.671 0.711 0.759 0.783 0.787 0.740

(0.093) (0.107) (0.135) (0.118) (0.141) (0.123) (0.136)

0.590e0.637 0.650e0.695 0.687e0.735 0.738e0.779 0.761e0.805 0.768e0.806 0.730e0.750

0.455e0.917 0.500e0.984 0.460e1.462 0.545e1.281 0.477e1.286 0.522e1.341 0.455e1.462

0.468 0.509 0.549 0.596 0.594 0.585 0.549

0.506 0.546 0.571 0.636 0.604 0.643 0.590

0.545 0.591 0.603 0.682 0.688 0.708 0.643

0.598 0.653 0.688 0.733 0.776 0.778 0.730

0.687 0.733 0.778 0.821 0.868 0.865 0.821

0.733 0.823 0.867 0.911 0.933 0.959 0.914

0.754 0.877 0.924 1.005 1.056 1.002 0.964

Femalesb 45e49 years 50e54 years 55e59 years 60e64 years 65e69 years 70e74 years Sub-total

329 324 299 356 375 199 1882

0.613 0.653 0.689 0.718 0.753 0.778 0.697

(0.101) (0.116) (0.107) (0.103) (0.114) (0.122) (0.123)

0.602e0.624 0.640e0.665 0.676e0.701 0.707e0.728 0.741e0.765 0.761e0.795 0.691e0.702

0.415e1.244 0.434e1.371 0.460e1.100 0.480e1.096 0.460e1.196 0.505e1.344 0.415e1.371

0.464 0.505 0.509 0.553 0.594 0.595 0.509

0.504 0.509 0.550 0.595 0.617 0.640 0.549

0.549 0.575 0.598 0.643 0.685 0.688 0.598

0.598 0.640 0.685 0.698 0.733 0.775 0.688

0.662 0.699 0.734 0.778 0.823 0.832 0.778

0.733 0.782 0.823 0.863 0.914 0.957 0.864

0.803 0.867 0.869 0.912 0.959 1.004 0.914

CCA-IMT, common carotid artery intima-media thickness; SD, standard deviation; CI, confidence interval. a Subjects without any of the following conditions: 1) hypertension (systolic blood pressure 140 mmHg or diastolic blood pressure 90 mmHg or anti-hypertensive medication); 2) diabetes (fasting blood glucose 126 mg/dL or anti-diabetic medication); 3) dyslipidemia (total cholesterol 230 mg/dL or triglycerides 200 mg/dL or HDL < 40 mg/dL or anti-dyslipidemic medication); 4) obesity (body mass index 30.0 kg/m2); 5) current smoking. b þ0.007 mm and þ0.007 mm per year in males and females, respectively.

234

Y.-H. Lee et al. / Atherosclerosis 234 (2014) 230e236

Table 4 Mean CB-IMT (mm) values according to age group among the healthy reference population.a No

Mean (SD)

95% CI

Range

Percentile 5

10

25

50

75

90

95

b

Males 45e49 years 50e54 years 55e59 years 60e64 years 65e69 years 70e74 years Sub-total

61 75 126 129 157 165 713

0.782 0.800 0.854 0.901 0.910 0.939 0.883

(0.125) (0.131) (0.135) (0.146) (0.126) (0.128) (0.142)

0.750e0.814 0.770e0.830 0.830e0.877 0.876e0.927 0.890e0.930 0.919e0.958 0.872e0.893

0.460e1.016 0.477e1.152 0.554e1.331 0.564e1.286 0.593e1.232 0.685e1.436 0.460e1.436

0.594 0.593 0.646 0.627 0.654 0.746 0.648

0.606 0.643 0.688 0.727 0.750 0.791 0.697

0.725 0.698 0.778 0.786 0.830 0.839 0.786

0.778 0.786 0.866 0.910 0.912 0.914 0.870

0.861 0.912 0.921 1.007 1.002 1.017 0.965

0.965 0.968 1.005 1.100 1.093 1.100 1.061

1.004 1.014 1.103 1.126 1.106 1.144 1.105

Femalesb 45e49 years 50e54 years 55e59 years 60e64 years 65e69 years 70e74 years Sub-total

329 324 299 356 375 199 1882

0.724 0.761 0.798 0.835 0.857 0.877 0.806

(0.123) (0.130) (0.132) (0.138) (0.134) (0.154) (0.144)

0.711e0.738 0.747e0.776 0.783e0.813 0.820e0.849 0.843e0.870 0.856e0.899 0.799e0.812

0.470e1.146 0.477e1.196 0.460e1.242 0.460e1.416 0.464e1.395 0.509e1.610 0.460e1.610

0.554 0.567 0.598 0.637 0.654 0.645 0.598

0.598 0.598 0.640 0.685 0.695 0.707 0.639

0.641 0.662 0.696 0.739 0.768 0.778 0.697

0.697 0.741 0.785 0.823 0.832 0.867 0.786

0.785 0.837 0.876 0.921 0.921 0.966 0.909

0.871 0.944 0.964 1.010 1.052 1.050 1.004

0.963 1.006 1.048 1.055 1.105 1.147 1.055

CB-IMT, carotid bulb intima-media thickness; SD, standard deviation; CI, confidence interval. a Subjects without any of the following conditions: 1) hypertension (systolic blood pressure  140 mmHg or diastolic blood pressure  90 mmHg or anti-hypertensive medication); 2) diabetes (fasting blood glucose  126 mg/dL or anti-diabetic medication); 3) dyslipidemia (total cholesterol  230 mg/dL or triglycerides  200 mg/dL or HDL < 40 mg/dL or anti-dyslipidemic medication); 4) obesity (body mass index  30.0 kg/m2); 5) current smoking. b þ0.007 mm and þ0.006 mm per year in males and females, respectively.

those in the ARIC and MESA studies. The CCA-IMT values of the CAPS and MDCS were slightly greater than the data in our study. Normative carotid IMT data have been reported for Koreans by previous studies. Bae et al. [8] reported left/right CCA-IMT as 0.65/ 0.65 mm for males and 0.64/0.62 mm for females, respectively, among healthy subjects visiting the hospital aged 35e64 years (n ¼ 227). Cho et al. [7] reported that the mean carotid IMT values of subjects aged 40e49, 50e59, 60e69, and 70e79 years were 0.61, 0.72, 0.77, and 0.88 mm for males and 0.60, 0.67, 0.71, and 0.76 mm for females, respectively (n ¼ 757). The carotid IMT values of these studies were similar or slightly thicker compared with our findings. However, two Korean studies examined a convenient sample that visited the hospital rather than a population-based sample and applied relatively loose criteria to gather their healthy reference sample [7,8]. A study on a rural Korean middle-aged population, named the ARIRANG Study, presented the normative CCA-IMT values of a healthy reference sample of 40e49-, 50e59-, and 60e 70-year-old males as 0.55, 0.59, and 0.66 mm and 0.48, 0.55, and 0.63 mm for females respectively [6]. The mean CCA-IMT in our study was thicker by w0.1 mm compared to that in the ARIRANG Study, but the ARIRANG Study examined a relatively small healthy sample (n ¼ 433), measured the carotid IMT on either side, and did not assess the presence of carotid plaque [6]. Because limited data on normative carotid IMT have been reported for the Asian population, we indirectly compared our normative carotid IMT values with the results for the general Asian population. The mean CCA-IMTs of subjects in Japan without a history of coronary heart disease or cerebrovascular disease aged 50e59, 60e69, and 70e79 years were 0.85, 0.93, and 1.02 mm for males and 0.84, 0.90, and 0.99 mm for females, respectively [30]. The mean CCA-IMT of Japanese males aged 40e74 years (mean age 61.8 years) was 0.81 mm [31]. Among subjects aged 18e85 years (mean age 49 years) without symptomatic vascular diseases, such as stroke, transient ischemia, coronary heart disease, congestive heart failure, or intermittent claudication, the mean CCA-IMTs observed were 0.68 for Taiwanese males and 0.66 mm for Taiwanese females [32]. The mean CCA-IMT of Chinese males aged 50e85 years (mean age 62.1 years) who had never smoked was 0.75 mm [33]. The carotid IMT values of these studies reflected greater thickness compared with our findings for similar gender-specific

age groups. Differences in geographic and ethnic characteristics, criteria for healthy populations, sample sizes, measurement sites and techniques, and definitions of carotid IMT may partially explain the differences in gender- and age-specific carotid IMTs between our study and previous research. Numerous epidemiological studies have demonstrated the relationship between MetS and carotid atherosclerosis [12e17]. In line with previous findings, the CCA-IMT value of subjects with MetS was significantly greater than those without MetS for males (0.771 vs. 0.756 mm) and females (0.746 vs. 0.712 mm) in our study. Although some studies have presented increasing carotid IMT values according to the number of MetS components [9,15,16], few studies have reported mean gender- and age-specific IMT values according to the number of MetS components in a large general population. Our study presented reference data on age-specific carotid IMT values by the number of MetS components in a large general population. Because MetS and carotid IMT are significant risk factors for CVD events, carotid measurements should be compared with reference data based on gender, age, and ethnicity. Several limitations to this study should be discussed. First, a single trained reader analyzed the carotid ultrasonography still images using manual rather than semi-automatic image-analysis software, which tends to shorten reading time and improve reproducibility [34,35]. However, correlation coefficients for intrareader variability were 0.94 for CCA-IMT in our analysis, suggesting high reproducibility. Second, although this study did not use carotid plaque as an outcome variable, the definition of plaque is important because carotid IMT was measured in a plaque-free region. Our definition of carotid plaque, which was defined as focal structures that encroached into the lumen by at least 100% of the surrounding IMT value, was somewhat different compared with the Mannheim consensus [22]. The definition of carotid plaque in our study may have influenced the carotid IMT values. Third, our present result is difficult to represent an Asian population because no data on other Asian population were suggested or compared. Nevertheless, our study had some strengths. First, it included a relatively large community-based population compared with that of previous studies. Second, carotid IMT values were presented according to 5-year rather than 10-year age groups because of the relatively large sample size within each 5-year age group.

Y.-H. Lee et al. / Atherosclerosis 234 (2014) 230e236 Table 5 Mean CCA-IMT (mm) values according to the presence of metabolic syndrome. Metabolic syndrome Absent Malesa,b 45e49 years 50e54 years 55e59 years 60e64 years 65e69 years 70e74 years Sub-total

Femalesa,b 45e49 years 50e54 years 55e59 years 60e64 years 65e69 years 70e74 years Sub-total

Total

P-difference

Present

0.635 0.697 0.726 0.762 0.794 0.816 0.756 <0.001

(0.101) (0.133) (0.119) (0.124) (0.137) (0.143) (0.140)

0.665 0.701 0.759 0.782 0.806 0.845 0.771 <0.001

(0.119) (0.123) (0.138) (0.139) (0.131) (0.126) (0.141)

0.647 0.699 0.741 0.770 0.798 0.825 0.762 <0.001

(0.109) (0.129) (0.129) (0.130) (0.135) (0.138) (0.141)

0.015 0.703 0.001 0.042 0.210 0.014 0.003

0.613 0.656 0.691 0.733 0.772 0.795 0.712 <0.001

(0.094) (0.110) (0.105) (0.112) (0.130) (0.130) (0.130)

0.660 0.679 0.723 0.753 0.783 0.804 0.746 <0.001

(0.125) (0.102) (0.115) (0.120) (0.133) (0.136) (0.131)

0.628 0.666 0.708 0.744 0.778 0.800 0.729 <0.001

(0.107) <0.001 (0.107) 0.002 (0.111) <0.001 (0.116) 0.002 (0.131) 0.146 (0.133) 0.329 (0.132) <0.001

Data are means (standard deviation). a þ0.014 mm and þ0.034 mm with MetS than without in males and females, respectively. b þ0.022 mm and þ0.022 mm with MetS than without in males and females after adjusting for age, respectively.

Information on age-specific carotid IMT values in a healthy reference sample will enable us to effectively interpret carotid atherosclerosis. Third, we measured not only CCA-IMT but also CB-IMT on both sides of the carotid artery to determine the reference values of the healthy Korean population. Fourth, use of more criteria, such as heavy drinking, peripheral arterial disease, and proteinuria, in the definition of the healthy reference sample may have decreased the normal carotid IMT values in our study. However, the more strictly criteria were applied, the smaller the healthy sample. In conclusion, gender-specific normative carotid IMT values were determined in a large healthy Korean population aged 45e74 years by 5-year age groups. Additionally, the mean gender- and age-specific carotid IMT values were presented according to MetS and the number of components in a community-dwelling population. Repeated measurements of carotid IMT in our study population and investigations from other study populations are needed to verify our results. Conflicts of interest None. Acknowledgments This study was supported (_501100002569) in 2013.

by

Wonkwang

University

Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.atherosclerosis.2014.02.023. References [1] Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 2007;115:459e67.

235

[2] Prati P, Tosetto A, Vanuzzo D, et al. Carotid intima media thickness and plaques can predict the occurrence of ischemic cerebrovascular events. Stroke 2008;39:2470e6. [3] O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson Jr SK. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 1999;340:14e22. [4] Greenland P, Alpert JS, Beller GA, et al. ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2010;56:e50e103. [5] Stein JH, Korcarz CE, Hurst RT, et al. Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force. Endorsed by the Society for Vascular Medicine. J Am Soc Echocardiogr 2008;21:93e111. [6] Youn YJ, Lee NS, Kim JY, et al. Normative values and correlates of mean common carotid intima-media thickness in the Korean rural middle-aged population: the Atherosclerosis RIsk of Rural Areas iN Korea General Population (ARIRANG) study. J Korean Med Sci 2011;26:365e71. [7] Cho YL, Kim DJ, Kim HD, et al. Reference values of carotid artery intima-media thickness and association with atherosclerotic risk factors in healthy subjects in Korea. Korean J Med 2003;64:275e83 [Korean]. [8] Bae JH, Seung KB, Jung HO, et al. Analysis of Korean carotid intima-media thickness in Korean healthy subjects and Patients with risk factors: Korea Multi-Center Epidemiological Study. Korean Circ J 2005;35:513e24 [Korean]. [9] Lee YH, Shin MH, Kweon SS, et al. Metabolic syndrome and carotid artery parameter in Koreans aged 50 years and older. Circ J 2010;74:560e6. [10] Galassi A, Reynolds K, He J. Metabolic syndrome and risk of cardiovascular disease: a meta-analysis. Am J Med 2006;119:812e9. [11] Gami AS, Witt BJ, Howard DE, et al. Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and metaanalysis of longitudinal studies. J Am Coll Cardiol 2007;49:403e14. [12] Bonora E, Kiechl S, Willeit J, et al. Bruneck study. Carotid atherosclerosis and coronary heart disease in the metabolic syndrome: prospective data from the Bruneck study. Diabetes Care 2003;26:1251e7. [13] Fan AZ. Metabolic syndrome and progression of atherosclerosis among middle-aged US adults. J Atheroscler Thromb 2006;13:46e54. [14] Iglseder B, Cip P, Malaimare L, Ladurner G, Paulweber B. The metabolic syndrome is a stronger risk factor for early carotid atherosclerosis in women than in men. Stroke 2005;36:1212e7. [15] Adolphe A, Cook LS, Huang X. A cross-sectional study of intima-media thickness, ethnicity, metabolic syndrome, and cardiovascular risk in 2268 study participants. Mayo Clin Proc 2009;84:221e8. [16] Pollex RL, Al-Shali KZ, House AA, et al. Relationship of the metabolic syndrome to carotid ultrasound traits. Cardiovasc Ultrasound 2006;4:28. [17] Empana JP, Zureik M, Gariepy J, et al. The metabolic syndrome and the carotid artery structure in noninstitutionalized elderly subjects: the three-city study. Stroke 2007;38:893e9. [18] Kweon SS, Shin MH, Jeong SK, et al. Cohort Profile: the Namwon Study and the Dong-gu Study. Int J Epidemiol; 2013. http://dx.doi.org/10.1093/ije/dys244 [Epub ahead of print]. [19] Grundy SM, Brewer Jr HB, Cleeman JI, Smith Jr SC, Lenfant C. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/ American Heart Association Conference on scientific issues related to definition. Circulation 2004;109:433e8. [20] Genuth S, Alberti KG, Bennett P, et al. Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 2003;26:3160e7. [21] Lee SY, Park HS, Kim DJ, et al. Appropriate waist circumference cutoff points for central obesity in Korean adults. Diabetes Res Clin Pract 2007;75:72e80. [22] Touboul PJ, Hennerici MG, Meairs S, et al. Mannheim carotid intima-media thickness and plaque consensus (2004e2006e2011). Cerebrovasc Dis 2012;34:290e6. [23] Committee for Establishing Treatment Instruction for Dyslipidemia of the Korean Society of Lipidology and Atherosclerosis. Guidelines for management of dyslipidemia. 2nd ed. Seoul: Korean Society of Lipidology and Atherosclerosis; 2009 [Korean]. [24] Cobble M, Bale B. Carotid intima-media thickness: knowledge and application to everyday practice. Postgrad Med 2010;122:10e8. [25] Chambless LE, Heiss G, Folsom AR, et al. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) Study, 1987e1993. Am J Epidemiol 1997;146:483e94. [26] Howard G, Sharrett AR, Heiss G, et al. Carotid artery intimal-medial thickness distribution in general populations as evaluated by B-mode ultrasound. ARIC Investigators. Stroke 1993;24:1297e304. [27] Fried LP, Borhani NO, Enright P, et al. The cardiovascular health study: design and rationale. Ann Epidemiol 1991;1:263e76. [28] Lorenz MW, von Kegler S, Steinmetz H, Markus HS, Sitzer M. Carotid intimamedia thickening indicates a higher vascular risk across a wide age range: prospective data from the Carotid Atherosclerosis Progression Study (CAPS). Stroke 2006;37:87e92. [29] Rosvall M, Janzon L, Berglund G, Engström G, Hedblad B. Incident coronary events and case fatality in relation to common carotid intima-media thickness. J Intern Med 2005;257:430e7.

236

Y.-H. Lee et al. / Atherosclerosis 234 (2014) 230e236

[30] Mannami T, Konishi M, Baba S, et al. Prevalence of asymptomatic carotid atherosclerotic lesions detected by high-resolution ultrasonography and its relation to cardiovascular risk factors in the general population of a Japanese city: the Suita study. Stroke 1997;28:518e25. [31] Kadota A, Miura K, Okamura T, et al. Carotid intima-media thickness and plaque in apparently healthy Japanese individuals with an estimated 10-year absolute risk of CAD death according to the Japan Atherosclerosis Society (JAS) guidelines 2012: the Shiga Epidemiological Study of Subclinical Atherosclerosis (SESSA). J Atheroscler Thromb 2013;20:755e66. [32] Sun Y, Lin CH, Lu CJ, Yip PK, Chen RC. Carotid atherosclerosis, intima media thickness and risk factors-an analysis of 1781 asymptomatic subjects in Taiwan. Atherosclerosis 2002;164:89e94.

[33] Jiang CQ, Xu L, Lam TH, et al. Smoking cessation and carotid atherosclerosis: the Guangzhou Biobank Cohort Study e CVD. J Epidemiol Community Health 2010;64:1004e9. [34] Gepner AD, Korcarz CE, Aeschlimann SE, et al. Validation of a carotid intimamedia thickness border detection program for use in an office setting. J Am Soc Echocardiogr 2006;19:223e8. [35] Stein JH, Korcarz CE, Mays ME, et al. A semiautomated ultrasound border detection program that facilitates clinical measurement of ultrasound carotid intima-media thickness. J Am Soc Echocardiogr 2005;18:244e51.