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Journal of Atherosclerosis and Thrombosis  Vol. 22, No. 7

Original Article

Prevalence of High Arterial Stiffness and Gender-specific Differences in the Relationships with Classical Cardiovascular Risk Factors Wen Wen 1, Bin Peng 1, Xiaojing Tang 1, Hunter X. Huang 1, Xiaoyan Wen 1, Shan Hu 1 and Rong Luo 2 Wen Wen and Bin Peng contributed equally to this work. 1 2

Department of Medical Statistics, School of Public Health, Chongqing Medical University, Chongqing, China Department of Physical Examination, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China

Aim: To investigate the relationships between arterial stiffness and classic cardiovascular risk factors with respect to gender differences in addition to the prevalence of high arterial stiffness in Chongqing, China based on an examination of 18,336 subjects. Methods: The cardio-ankle vascular index was used as a marker of arterial stiffness. The relationships between arterial stiffness and body mass index (BMI) as well as metabolic syndrome (MetS) were estimated using logistic regression models. Results: The prevalence of high arterial stiffness was 12.74% in men and 9.91% in women. For age and BMI, compared with the reference group, men had higher adjusted odds ratios (ORs) in each group versus their female counterparts. For each individual index of MetS, the effects of waist circumference and systolic blood pressure (SBP) on high arterial stiffness exhibited remarkable gender differences, with women having higher ORs and adjusted ORs than men. As the sum of MetS traits increased, the ORs and adjusted ORs in the subjects also increased, with women having higher values than men in each group. Conclusions: Gender-specific differences exist in the prevalence of high arterial stiffness among subjects compared by age, BMI and MetS, with varying effects of influence for these factors between genders. J Atheroscler Thromb, 2015; 22: 706-717. Key words: Arterial stiffness, Gender difference, Body mass index, Metabolic syndrome, Prevalence

Introduction Arterial stiffness refers to the reduced capability of an artery to expand and contract in response to pressure changes 1). High arterial stiffness is reported to be an independent risk factor for various cardiovascular diseases 2-4), which are major causes of death in both China and Western countries 5, 6). Therefore, evaluating patients for high arterial stiffness may be an effecAddress for correspondence: Rong Luo, Department of Physical Examination, The First Affiliated Hospital of Chongqing Medical University, #1 Yixueyuan Road, Chongqing, 400016, China E-mail: [email protected] Received: June 23, 2014 Accepted for publication: November 11, 2014

tive tool for monitoring cardiovascular disease (CVD). The degree of arterial stiffness may be evaluated according to the cardio-ankle vascular index (CAVI), a non-invasive parameter developed in 2004 7, 8). While the pulse wave velocity (PWV) is influenced by blood pressure (BP) at the time of measurement, the CAVI is independent of BP, which makes it more stable and precise than other PWV methods 9). Therefore, the CAVI values exhibit better reproducibility for clinical practice 7, 10) and have been used extensively in many hospitals in China. The principles of CAVI measurement were previously described by Yamabe et al.11). Classical cardiovascular risk factors, including body mass index (BMI), and the cluster of risk factors comprising metabolic syndrome (MetS), are positively associated with arterial stiffness 12-14). However, there

Gender Differences of High Arterial Stiffness

are disputes among the scientific community regarding their associations, and opinions differ as to whether BMI is a risk or protective factor for arterial stiffness. Notably, inconsistent results are found across many studies, especially those in obese subjects 15-17). MetS is a significant risk factor for high arterial stiffness 18, 19), although it is unclear if all MetS traits are related to increased arterial stiffness. In addition, as many previous reports have shown, men often display a higher prevalence of arteriosclerosis than women 20, 21), as men more frequently suffer from higher rates of risk factors. For this reason, researchers often focus more on the prevalence of risk factors and thus neglect to notice differences in the actual effects of specific risk factors on high arterial stiffness between the genders. Therefore, we conducted a single-center study using medical examination data collected for subjects from many corners of society. Our goal was to analyze the relationships between arterial stiffness and BMI as well as MetS, especially in terms of gender differences. We also aimed to investigate the prevalence of high arterial stiffness in Chongqing, China. Methods Subjects Data for a total of 24,569 subjects who completed examinations for arterial stiffness based on CAVI measurements at the Medical Examination Center of the Chongqing Medical University First Affiliated Hospital during the period of 2010 to 2012 were collected. We excluded subjects currently being treated for arrhythmia, such as sinus bradycardia, premature atrial contractions and atrial fibrillation. Individuals with a low ankle-brachial index (ABI ＜ 0.9) were also excluded because such cases may involve inaccurate CAVI values 7). Furthermore, subjects missing information for age, height, weight, blood pressure, waist circumference, triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) and fasting blood glucose (FPG) were excluded for statistical reasons. Finally, a total of 18,837 subjects, including 12,087 men and 6,750 women, were eligible for this study. Medical Examinations The medical examinations were conducted by the Medical Examination Center at the Chongqing Medical University First Affiliated Hospital, which obtained ISO 15189 certification in 2006. The routine medical examination included a physical examination, collection of a fasting blood sample and ultrasonography. Height, body weight and waist circumference were measured during the physical examination.

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Blood pressure was also measured in the left arm using a standard mercury sphygmomanometer after the subject sat quietly for at least five minutes. Fasting blood sampling was performed from the antecubital vein in the morning, and the serum was separated and centrifuged after blood coagulation. The FPG, TG and HDL-C levels were measured according to standard laboratory procedures using an automatic biochemical analyzer. Measurement of the CAVI Values The CAVI values were measured using a Vasera VS-1000 vascular screening system with the subject resting in the supine position. Electrodes for electrocardiography were placed on both wrists, and a microphone was placed on the sternum for phonocardiography. Both ankles and the brachium were secured with cuffs. The subject then rested for five to 10 minutes before the examination was performed. The PWV, SBP and DBP levels were automatically measured to calculate the right and left CAVI values, as follows: CAVI = a[{2ρ/(SBP−DBP)}×{ln(SBP/DBP)×PWV2}] ＋b, where a and b are constants and ρ is the blood density. The left and right CAVI values were then used to calculate the average CAVI value. According to the manufacturer’s recommendations, a CAVI value less than 8 was considered to be normal, while that between 8 to 9 was considered borderline and that more than 9 was considered abnormal. Therefore, we defined subjects with an abnormal CAVI value (CAVI ＞ 9) as having high arterial stiffness. The ankle-brachial index (ABI) was also calculated at the same time by dividing the upper arm BP by the lower arm BP. Depending on its value, the ABI reflects possible peripheral artery occlusive disease (PAOD) 22), with an ABI of less than 0.9 indicating the possibility of PAOD due to a decreased blood flow 23). Definition The subjects in this study ranged from 20 to 94 years of age. According to the World Health Organization, individuals 18 to 44 years of age were defined as young adults, those 45 to 59 years of age were defined as middle-aged and those over 60 years of age were defined as elderly. Based on the Meta-Analysis Group of China Obesity Task Force guidelines 24), BMI ＜ 18.5 was defined as underweight, 18.5 ≤ BMI ＜ 24 was defined as normal, 24 ≤ BMI ＜ 28 was defined as overweight and BMI ≥ 28 was defined as obese. The waist-to-height ratio (WHtR) was calculated as waist circumference (m)/height (m). A WHtR of ≥ 0.5 or waist circumfer-

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Table 1. Clinical characteristics of the study subjects

Age (years) Waist circumference (cm) BMI (kg/m2) WHtR SBP (mmHg) DBP (mmHg) TG (mmol/L) HDL-C (mmol/L) FPG (mmol/L) CAVI (mmol/L) High BP (%) High FPG (%) High TG (%) High HDL-C (%) Central Obesity (%)

Men (n = 12087)

Women (n = 6750)

p

49.64±11.89 86.01±7.98 24.84±3.00 0.51±0.05 129.64±18.76 81.61±12.50 2.08±1.90 1.30±0.34 5.57±1.43 7.69±1.12 54.94 32.16 43.19 19.84 63.42

51.64±12.11 76.30±7.99 23.18±3.05 0.49±0.06 124.73±20.99 74.56±11.46 1.43±1.20 1.61±0.39 5.35±1.13 7.45±1.11 41.08 23.60 23.20 20.62 40.58

＜ 0.0001 ＜ 0.0001 ＜ 0.0001 ＜ 0.0001 ＜ 0.0001 ＜ 0.0001 ＜ 0.0001 ＜ 0.0001 ＜ 0.0001 ＜ 0.0001 ＜ 0.0001 ＜ 0.0001 ＜ 0.0001

0.1988 ＜ 0.0001

Continuous variables are presented as the mean±standard deviation; Categorical variables are given as percentages (%). BMI: body mass index. WHtR: waist-to-height ratio. SBP: systolic blood pressure. DBP: diastolic blood pressure. TG: triglycerides. FPG: fasting blood glucose. HDL-C: high-density lipoprotein cholesterol. CAVI: cardio-ankle vascular index. High BP: SBP ≥ 130 mmHg or DBP ≥ 85 mmHg. High FPG: FPG ≥ 5.6 mmol/L. High TG: serum TG ≥ 1.70 mmol/L. High HDL: HDL-C ＜ 1.03 mmol/L. Central obesity: WHtR ≥ 0.5 or WC ＞ 90 cm in men and WC ＞ 80 cm in women.

ence of ＞ 90 cm in men and waist circumference of cm in women was defined as central obesity. MetS was defined in accordance with the criteria revised by the International Diabetes Federation as the presence of three or more of the following traits: (i) central obesity; (ii) high BP, SBP ≥ 130 mmHg or DBP ≥ 85 mmHg; (iii) high FPG, FPG ≥ 5.6 mmol/L; (iv) high TG, serum TG ≥ 1.70 mmol/L; (v) high HDL-C, HDL-C ＜ 1.03 mmol/L. In addition, subjects who exhibited normal hematological index values but suffered from a history of hypertension, diabetes mellitus, dyslipidemia or other cardiovascular diseases, were also regarded as having MetS.

＞ 80

Statistical Analysis The clinical characteristics were compared between men and women. The significance of differences between the genders was determined using Student’s t -test for continuous data with a normal distribution, the Wilcoxon rank-sum test for data with a skewed distribution and the Chi-square test for dichotomous data. The Mantel-Haenszel Chi-Square test was used to identify associations between the prevalence of high arterial stiffness and age and/or the sum of MetS traits. Two logistic regression models were employed with the incidence of high arterial stiffness as the out-

come variable: (1) a logistic regression model that utilized age, BMI, waist circumference, SBP, DBP, FPG, TG and HDL as the independent variables, in which age and BMI were categorized as young adults, middle-aged and elderly and underweight, normal, overweight and obese, respectively, and waist circumference, SBP, DBP, FPG, TG and HDL categorized into four groups (Quartile 1, Quartile 2, Quartile 3 and Quartile 4) according to their quartile levels; (2) a logistic regression model using MetS as the independent variable, in which MetS was divided into six levels according to the sum of the MetS criteria met by each subject and age and BMI used to adjust the model. The SAS 9.13 software package was used for all analyses. Results The characteristics of the study subjects are summarized in Table 1. The mean age of all study subjects was 49.64±11.89 for men (ranging from 20 to 94 years) and 51.64±12.11 for women (ranging from 21 to 94 years). The mean CAVI value was 7.69±1.12 for men (ranging from 3.80 to 14.90) and 7.45±1.11 for women (ranging from 3.00 to 13.05). All items, except for high HDL, showed significant differences

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Table 2. Prevalence of high arterial stiffness by gender

Young adults Middle-aged The elderly Total

total

%

men

%

women

%

61/6094 598/8786 1550/3957 2209/18837

0.99 6.81 39.17 11.7

51/4188 458/5647 1031/2252 1540/12087

1.22 8.11 45.78 12.74

10/1906 140/3139 519/1705 669/6750

0.52 4.46 30.44 9.91

Young adults are defined as subjects 18 to 44 years of age. Middle-aged persons are defined as those 45 to 59 years of age. Elderly are defined as those 60 years of age or older.

Table 3. Logistic regression models for classical risk factors in both genders Men Variables

Groups

Prevalence (%)

OR (95%CI)

Adjusted OR (95%CI)

Age

Young adults Middle-aged The elderly

1.22 8.11 39.17

1.000 7.159 (5.345~9.589) 68.490 (51.336~91.376)

1.000 5.771 (4.290~7.762) 45.090 (35.454~60.773)

BMI

Obese Overweight Normal Underweight

10.40 11.99 14.19 22.60

1.000 1.174 (0.983~1.401) 1.425 (1.191~1.706) 2.498 (1.698~3.675)

1.000 1.368 (1.112~1.684) 2.590 (2.047~3.277) 11.557 (6.415~20.818)

Waist circumference

Quartile 1 Quartile 2 Quartile 3 Quartile 4

17.00 10.12 12.69 12.88

1.000 0.549 (0.368~0.819) 0.709 (0.495~1.015) 0.721 (0.515~1.011)

1.000 0.630 (0.371~1.068) 0.887 (0.534~1.471) 1.115 (0.675~1.842)

SBP

Quartile 1 Quartile 2 Quartile 3 Quartile 4

4.14 6.67 10.36 29.47

1.000 1.654 (1.311~2.087) 2.674 (2.164~3.305) 9.663 (7.948~11.748)

1.000 1.847 (1.416~2.410) 2.244 (1.721~2.926) 5.850 (4.439~7.710)

DBP

Quartile 1 Quartile 2 Quartile 3 Quartile 4

9.65 10.39 11.71 22.86

1.000 1.086 (0.916~1.287) 1.243 (1.052~1.468) 2.172 (1.864~2.531)

1.000 0.813 (0.655~1.010) 0.671 (0.533~0.844) 0.905 (0.711~1.152)

FPG

Quartile 1 Quartile 2 Quartile 3 Quartile 4

7.89 9.24 12.14 20.88

1.000 1.189 (0.991~1.427) 1.613 (1.349~1.929) 3.082 (2.621~3.624)

1.000 0.972 (0.786~1.202) 1.211 (0.980~1.497) 1.609 (1.322~1.959)

TG

Quartile 1 Quartile 2 Quartile 3 Quartile 4

13.91 12.91 12.63 11.53

1.000 0.917 (0.791~1.064) 0.894 (0.771~1.038) 0.806 (0.693~0.938)

1.000 1.129 (0.938~1.359) 1.281 (1.057~1.553) 1.389 (1.138~1.696)

HDL-C

Quartile 1 Quartile 2 Quartile 3 Quartile 4

14.30 12.03 12.35 12.31

1.000 0.820 (0.706~0.952) 0.845 (0.728~0.981) 0.842 (0.725~0.977)

1.000 0.876 (0.731~1.049) 0.745 (0.621~0.893) 0.756 (0.629~0.909)

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(Cont Table 3) Women Variables

Groups

Prevalence (%)

Age

Young adults Middle-aged The elderly

0.52 4.46 30.44

BMI

Obese Overweight Normal Underweight

11.72 14.34 7.87 5.62

1.000 1.262 (0.929~1.715) 0.644 (0.476~0.870) 0.447 (0.244~0.820)

1.000 2.582 (1.779~3.749) 3.104 (2.037~4.730) 3.314 (1.570~6.995)

Waist circumference

Quartile 1 Quartile 2 Quartile 3 Quartile 4

7.39 15.78 19.02 18.04

1.000 2.349 (1.899~2.906) 2.945 (2.323~3.734) 2.760 (2.043~3.730)

1.000 1.340 (1.026~1.750) 1.425 (1.037~1.959) 1.493 (1.029~2.410)

SBP

Quartile 1 Quartile 2 Quartile 3 Quartile 4

1.17 2.74 8.33 26.44

1.000 2.392 (1.393~4.108) 7.708 (4.754~12.496) 30.471 (19.146~48.494)

1.000 1.796 (1.023~3.153) 3.774 (2.231~6.387) 9.605 (5.641~16.353)

DBP

Quartile 1 Quartile 2 Quartile 3 Quartile 4

6.28 7.85 8.94 16.24

1.000 1.271 (0.972~1.661) 1.464 (1.123~1.910) 2.893 (2.271~3.685)

1.000 0.765 (0.556~1.051) 0.614 (0.445~0.848) 0.707 (0.515~0.971)

FPG

Quartile 1 Quartile 2 Quartile 3 Quartile 4

5.07 7.02 8.33 17.92

1.000 1.411 (1.059~1.880) 1.699 (1.276~2.262) 4.084 (3.189~5.231)

1.000 1.031 (0.748~1.422) 0.946 (0.686~1.304) 1.470 (1.106~1.953)

TG

Quartile 1 Quartile 2 Quartile 3 Quartile 4

3.55 7.91 11.68 16.26

1.000 2.331 (1.701~3.195) 3.589 (2.656~4.850) 5.268 (3.934~7.054)

1.000 1.441 (1.013~2.052) 1.562 (1.106~2.207) 1.622 (1.150~2.288)

HDL-C

Quartile 1 Quartile 2 Quartile 3 Quartile 4

6.17 8.10 10.99 14.33

1.000 1.399 (1.028~1.746) 1.877 (1.460~2.412) 2.543 (1.998~3.236)

1.000 0.860 (0.632~1.172) 0.856 (0.636~1.152) 0.785 (0.585~1.052)

＊

OR (95%CI) 1.000 8.851 (4.648~16.855) 82.970 (44.192~155.774)

Adjusted OR (95%CI) 1.000 4.850 (2.513~9.359) 26.708 (13.868~51.435)

＊

Prevalence stands for the prevalence of high arterial stiffness according to the group. BMI: body mass index. SBP: systolic blood pressure. DBP: diastolic blood pressure. TG: triglycerides. FPG: fasting blood glucose. HDL-C: high-density lipoprotein cholesterol. Young adults are defined as subjects 18 to 44 years of age. Middle-aged persons are defined as those 45 to 59 years of age. Elderly are defined as those 60 years of age or older. Underweight is defined as BMI ＜ 18.5, normal is defined as 18.5 ≤ BMI ＜ 24, overweight is defined as 24 ≤ BMI ＜ 28 and obese is defined as BMI ≥ 28.

between men and women (all p ＜ 0.001). The prevalence of high arterial stiffness was 11.73% in all study subjects, with a significant difference in the gender-specific prevalence, at 12.74% for men and 9.91% for women (χ2 = 2207.748, p ＜

0.0001). As shown in Table 2, the prevalence of high arterial stiffness increased as age increased (trend χ2 = 868.995, p ＜ 0.0001). Only 0.99% of the subjects with high arterial stiffness were young adults, while 6.81% of the middle-aged subjects were found to suf-

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Fig. 1. Trend of mean prevalence of high arterial stiffness in BMI and waist circumference levels between genders.

fer from high arterial stiffness. Meanwhile, high arterial stiffness was found in 39.17% of the subjects in the elderly group. The prevalence and odds ratios (ORs) of high arterial stiffness for each risk factor are presented in Table 3. As also shown in Table 2, men had a higher prevalence of high arterial stiffness than women in each age group; however, compared to young adults, the ORs for middle-aged and elderly women were higher than that for men (men: 7.159 and 68.490, women: 8.851 and 82.970), which suggests that women appear to be at greater risk of developing high arterial stiffness with age. However, when adjusted for other risk factors, the ORs for women in each age group were lower than those for men (men: 5.771 and 45.090, women: 4.850 and 26.708), which suggests that the effects of aging on high arterial stiffness remain greater in men than in women. As shown in Table 3, there were also noteworthy differences in BMI and waist circumference. For BMI, the underweight subjects demonstrated the highest prevalence and ORs of high arterial stiffness in men and the lowest prevalence and ORs in women (men:

22.60% and 2.498, women: 5.62% and 0.447). The overweight and obese subjects also showed a lower prevalence and ORs than the normal subjects in men and a higher prevalence and ORs in women. When adjusted for other risk factors, compared to the obese subjects, the overweight, normal and underweight groups displayed higher risks in both men and women, and with the effect of each BMI group being more significant in men than in women. For waist circumference, Quartile 1 group (＜ 81 cm), the reference group, demonstrated the highest prevalence and ORs in men and the lowest values in women (men: 17% and 1.000, women: 7.39% and 1.000). When adjusted for other risk factors, the effect of waist circumference was not significant in men, whereas a gradual increase was noted in women. The trends in the prevalence of high arterial stiffness according to BMI and waist circumference between the genders are shown in Fig. 1. Considering the significant effect of age on high arterial stiffness, the subjects were divided into young adult, middle-aged and elderly groups according to the BMI and waist circumference categories in order to calculate the mean

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Prevalence of high arterial stiffness (%)

40 35 30 25 20

men women

15 10 5 0 0

1

2

3

4

5

Numbers of MetS traits fulfilled Fig. 2. Prevalence of high arterial stiffness in the subjects exhibiting different numbers of metabolic syndrome traits.

prevalence of increased arterial stiffness. Consequently, different trends were observed between the genders as the BMI and waist circumference values increased. For BMI, there was a more obvious decreasing trend in men than in women. In contrast, for waist circumference, a greater increasing trend was noted in women than in men. Regarding the clinical indices of MetS (Table 3), the effect of SBP on high arterial stiffness exhibited a remarkable gender difference, in which larger ORs and adjusted ORs were found in women than in men. In contrast, the DBP and FPG indices did not show any significant differences between the genders, with the adjusted ORs of TG being slightly higher in women than in men and the adjusted ORs of HDL being significant in men but not in women. We further divided the subjects into six groups according to the sum of MetS criteria; the prevalence of high arterial stiffness in men and women in each of the six groups is presented in Fig. 2. As the number of MetS criteria fulfilled increased, the prevalence of high arterial stiffness in both genders increased (men: trend χ2 = 249.033, p ＜ 0.0001; women: trend χ2 = 525.387, p ＜ 0.0001). The subjects exhibiting at least one MetS trait had a significantly higher prevalence of high arterial stiffness than those with no traits, at approximately one to five times more than those without

Mets in men and four to 30 times in women; therefore, the prevalence of high arterial stiffness increased more rapidly in women. The differences of the effect of MetS on high arterial stiffness between men and women are shown in Table 4, with the ORs and adjusted ORs of both genders increasing as the number of MetS criteria fulfilled increased and higher ORs observed in women than their male counterparts in each group. Discussion The prevalence of high arterial stiffness has scarcely been reported in either China or Western countries. Hirasada K. et al.25) reported the prevalence of high arterial stiffness on the Amami islands and Kagoshima Mainland of Japan in 2010 and found geographical variation in the frequency of high arterial stiffness between the two islands. Compared to the results for these Japanese islands, we found that the prevalence of high arterial stiffness in Chongqing was slightly higher than that on the Amami islands and far lower than that on Kagoshima Mainland. The results of this comparison are shown in the Supplemental materials. In the above report, the total subject group ranged in age from only 40 to 70 years. Therefore, in order to accommodate their data, we removed the selection

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Table 4. Logistic regression models for the number of MetS traits between the genders # of MetS traits 0 1 2 3 4 5

Men ＊

Women ＊

Prevalence (%)

OR (95%CI)

Adjusted OR (95%CI)

Prevalence (%)

4.28 8.12 13.11 16.46 18.46 20.13

1.000 1.976 (1.489~2.621) 3.374 (2.589~4.397) 4.403 (3.387~5.724) 5.059 (3.853~6.643) 5.638 (4.048~7.837)

1.000 1.587 (1.143~2.204) 2.780 (2.021~3.824) 4.354 (3.138~6.041) 6.257 (4.417~8.863) 8.042 (5.280~12.250)

1.42 5.97 13.40 18.34 25.26 33.72

OR (95%CI)

Adjusted OR (95%CI)

1.000 1.000 4.415 (2.916~6.684) 2.576 (1.663~3.985) 10.757 (7.274~15.909) 4.025 (2.627~6.166) 15.608 (10.494~23.213) 5.310 (3.392~8.313) 23.485 (15.518~35.541) 7.773 (4.823~12.527) 35.360 (21.893~57.109) 11.755 (6.706~20.607)

Models are adjusted for age and BMI. Prevalence stands for the prevalence of high arterial stiffness according to the group.

＊

from our study subjects as well, with divisions of 40-49, 50-59 and 60-69 years of age. A Japanese report was the first to investigate the degree of geographical variation in high arterial stiffness as well as possible differences in lifestyle factors and clinical characteristics explaining this geographical variation. The results suggested that other environmental or genetic factors may improve the geographical variation in the levels of arterial stiffness between Chongqing and the above two Japanese islands. Arterial aging results in progressive stiffening of the arteries, and the mechanisms underlying this phenomenon have been reported in-depth pathophysiologically 26, 27). Although normal arterial stiffening occurs in individuals in association with age, some risk factors hasten this process 28, 29). Cardiovascular diseases (CVDs), such as hypertension and diabetes, are proven risk factors for arterial stiffness, while social and environmental factors, such as drinking, smoking and stress, accelerate the progression of arterial stiffness 30-32). In the present study, we found a higher effect of aging in men than in women, when adjusted for BMI, waist circumference, SBP, DBP, FPG, TG and HDL. However, we failed to exclude the influence of social and/ or environmental factors due to the lack of related data. The far greater risk of aging presented in men may involve aspects of social and environmental effects, and further research is thus needed to determine whether the primordial effects of aging are indeed larger in men than in women when social and environmental effects are eliminated. It is also noteworthy that, before adjusting for clinical risk factors, the middle-aged and elderly women appeared to have a higher risk of high arterial stiffness than men, when compared to that observed in the young adult group. Combined with the findings of a less effective protective effect of BMI and the higher

risk of waist circumference and MetS in women than in men, this difference in the ORs and adjusted ORs was the result of gender differences in the effects of risk factors. Obesity is regarded as a risk factor in the majority of cases of CVD 33). BMI, a conventional index of obesity, is widely used in research and risk analyses of CVD. We previously revealed that BMI is a protective factor for the incidence of high arterial stiffness. Although contradictory results have been reported by some researchers 15, 16), similar findings have been demonstrated in a large number of studies 34-37). In the current study, we found that the protective factor of BMI is more effective in men than in women and in fact appeared as a risk factor in women before adjusting for other risk factors. We speculate that the selection of the adjusted factors, especially gender, is one reason for this contradictory result. In addition, the complicated effects of body fat on cardiovascular factors are also important for determining the association between BMI and arterial stiffness. A growing body of literature has demonstrated that the distribution of body fat, not the absolute amount of adipose tissue, is associated with the increased risk of CVD observed in many overweight individuals 38). The intra-abdominal visceral pad has been pinpointed as the major culprit in the process. Waist circumference reflects the amount of intra-abdominal visceral adipose tissue to a certain degree. In the present study, we found waist circumference to also be a risk factor for arterial stiffness, with a higher risk effect in women than in men. These differences between men and women in the effect of BMI and waist circumference on high arterial stiffness may be due to physiological differences in body fat between men and women, such as differences in the distribution of body fat between the genders or the fact that women have roughly double the amount of

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body fat than men based on percentage 39). Hence, body fat is assumed to be a significant factor influencing the effects of BMI and waist circumference on arterial stiffness. However, the mechanisms underlying this relationship remains to be established. Intensive studies should therefore be conducted to clarify the specific influence and physiological mechanisms associated with the effects of body fat on arterial stiffening. The mechanisms linking symptoms of MetS with high arterial stiffness are not fully understood. However, one explanation has been proposed, in which differences in biology and physiology between the genders result in gender differences in the pathogeny, therapeutic effects and prognosis of CVD 40-43). During menopause, women are at higher risk of cardiovascular disease due to the loss of the vascular protective effects of estrogen, which helps to prevent myocardial and vascular diseases 44, 45). In addition, Madonna M. Roche reported that CVD affects women with diabetes more significantly than men, especially when the disease is diagnosed at a later stage 46). Our current findings indicate that high arterial stiffness is more prevalent in women than men exhibiting two or more MetS traits, and the cluster of Mets has a greater impact on women with high arterial stiffness than men, when adjusted for age and BMI. Subjects with an ABI of ＜0.9 may contain a high proportion of MetS sufferers, which possibly affects the outcomes of MetS. In the present study, we excluded 99 subjects with an ABI of ＜0.9, 91 of whom exhibited MetS (56 men and 35 women). Compared with the total number of MetS patients among both men and women (5,337 of men and 4,635 of women), the influence of the excluded subjects with MetS may be ignored. Nevertheless, there remain limitations associated with this study. First, the analysis was based on data for one center and the subjects enrolled in this research were most likely living in a certain area in Chongqing, which means that it is necessary to be cautious when extrapolating the conclusions to other regions. Furthermore, it is difficult to identify or analyze the degree of bias at this particular research institution. Lastly, we did not perform an analysis of the habits, behavior or drugs used by our patients, which may have negative effects with respect to the diagnostic criteria. Conclusion In conclusion, the prevalence of high arterial stiffness in this study was close to that observed on the Amami islands in Japan. We also found gender differences in the associations between high arterial stiffness

and several risk factors. For example, aging posed a far greater risk for high arterial stiffness in men than in women, and BMI was a protective factor against the emergence of high arterial stiffness in men versus women. Meanwhile, waist circumference, contrary to BMI, demonstrated a higher effect as a risk factor in women than in men. With respect to the individual clinical indices of MetS, only SBP showed a remarkable gender difference, with a higher risk in women than in men. However, as the sum of MetS traits increased, women were at greater risk of developing high arterial stiffness than men in each group. Acknowledgments The authors would like to thank the Medical Examination Center of Chongqing Medical University First Affiliated Hospital for performing the data collection and the teachers and students of the Medical Statistics Department of the School of Public Health of Chongqing Medical University for their assistance. Notice of Grant Support There was no financial support for this study. Conflicts of Interest None.

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Gender Differences of High Arterial Stiffness

Supplemental Table 1. Comparison of the prevalence of high arterial stiffness Age of Men (%)

Amami Island Kagoshima Mainland Chongqing

Age of Women (%)

40-49

50-59

60-69

40-49

50-59

60-69

5.6 13.3 3.47

15.4 37.2 11.21

37.9 76.1 30.87

1.0 13.8 1.16

7.6 28.4 6.29

23.0 63.2 21.28

men

a prevalenceofhigharterialstiffness(%)

80 70 60 50 ChongQing 40

Amamiisland

30

Kagoshimamainland

20 10 0 40Ͳ49

50Ͳ59

60Ͳ69

Supplemental Fig. 1a. Comparison of the prevalence of high arterial stiffness between Chongqing and the two Japanese islands in men by age.

women

b prevalenceofhigharterialstiffness(%)

70 60 50 40

ChongQing Amamiisland

30

Kagoshimamainland 20 10 0 40Ͳ49

50Ͳ59

60Ͳ69

Supplemental Fig. 1b. Comparison of the prevalence of high arterial stiffness between Chongqing and the two Japanese islands in women by age.