Analysis of the Sex-Specific Risk Factors for Arterial Stiffness

Abstract

Background:

To explore the sex-specific risk factors of associated with arterial stiffness.

Methods:

A total of 28,291 participants from the Kailuan study cohort were enrolled in this study. A multivariate linear regression analysis and a multivariate logistic regression model were used to analyze the influencing factors of arteriosclerosis (indexed using the brachial–ankle pulse wave velocity, baPWV) between different sexes.

Results:

The incidence of arteriosclerosis (baPWV greater than or equal to 1400 cm/s) was 54.70%. The incidence of arteriosclerosis in males (62.13%) was higher than in females (37.41%) (p < 0.01). According to age stratification (5 years difference for each group), the baPWV values of males in all age groups <70 years were higher than in females (p < 0.01). The increase in baPWV values was higher in females over 45 years than in males and correlated with males in the 70–75 age group. The multivariate linear regression model showed that for every 5-year increase in age, the baPWV increased by 62.55 cm/s in males and 71.86 cm/s in females. Furthermore, for every 10 mmHg increase in systolic blood pressure (SBP), the baPWV increased by 61.01 cm/s in males and 51.86 cm/s in females. Regular physical exercise reduced the baPWV in males, but there was no statistical correlation in females. The waist-to-hip ratio (WHR) increased the baPWV in females yet was not statistically significant in males. Multivariate logistic regression analysis showed that after adjusting for confounding factors (age, WHR, SBP, heart rate, triglyceride, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), high-sensitivity C-reactive protein (hs-CRP), estimated glomerular filtration rate (eGFR), diabetes, higher education, higher income, smoking, drinking, and physical exercise), males were 1.89 times more likely than females to develop arteriosclerosis (p < 0.05). A stratified analysis of males and females showed that the risk of arteriosclerosis was higher in females than in males in the 45–60 and over 60 age groups compared with those in the under 44 age group (p < 0.01). Diabetes, LDL-C, and hs-CRP were more likely to be correlated with arteriosclerosis in females than in males (odds ratio (OR): 2.32, 1.26, 1.08 vs. 1.83, 1.17, 1.02, respectively, p < 0.05). Higher education levels reduced the risk of arteriosclerosis in males and females, with OR values of 0.64 and 0.84, respectively (p < 0.05).

Conclusions:

The arteriosclerosis detection rate in males was higher than in females. Conversely, the increase in baPWV in females older than 45 years was higher than in males. Meanwhile, WHR, diabetes, LDL-C, and hs-CRP were more likely to be correlated with arteriosclerosis in females.

Clinical Trial Registration:

Chinese Clinical Trail Registry, URL: https://www.chictr.org.cn/showproj.html?proj=8050. Unique identifier: ChiCTR-TNRC-11001489 .

Graphical abstract

Keywords

sex-specific / arteriosclerosis / baPWV / risk factors

1. Introduction

Arteriosclerosis is a process whereby the arterial wall thickens, resulting in decreased wall compliance, loss of elasticity, and narrowing of the lumen [1]. Increased arterial stiffness increases the risk of hypertension [2], coronary heart disease [3], stroke [4], renal dysfunction [5], cognitive dysfunction [6], and peripheral vascular disease [7]. Therefore, early prevention of increased arterial stiffness significantly reduces the risk of cardiovascular and cerebrovascular diseases. However, the compliance of the aorta decreases, and the stiffness increases with age [8]. The Framingham study found that females, hypertension, increased body mass index, and diabetes were also risk factors for arteriosclerosis [9]. Other studies found that uric acid excretion fraction and estimated glomerular filtration rate were inversely proportional to the brachial–ankle pulse wave velocity (baPWV) [10, 11]. However, regular aerobic exercise can reduce the degree of arteriosclerosis [12].

Carotid–femoral pulse wave velocity (cfPWV) is the gold standard for predicting arteriosclerosis [7, 13], yet measuring the cfPWV is relatively complex. Notably, the baPWV and cfPWV exhibit a good correlation. The baPWV method is simple and reproducible and is a sensitive index to evaluate arteriosclerosis [14]. The guidelines and consensus of China on the Prevention and Treatment of Cardiovascular Disease published in 2008 consider a baPWV \ge1400 cm/s to be consistent with arteriosclerosis [15].

The baPWV differs among different sex groups. Wang X et al. [16] found that in patients under 50 years, the baPWV was higher in males than in females, and when the age was over 50, there was no statistical difference between baPWV in males vs. females. Benetos et al. [17] found the same phenomenon in patients \le80 years old and >80 years old. Some studies have suggested the possibility that these differences are due to age [16, 17, 18], height [19], blood pressure [20], and sex hormones [21]. However, no studies exist on the differences in the factors affecting arterial stiffness among different sexes in China. Therefore, we analyzed those factors responsible for arterial stiffness in Chinese males and females.

2. Materials and Methods

2.1 Study Participants

Data were derived from the Kailuan study. Briefly, the Kailuan study is a prospective, community-based cohort study that aimed to investigate the epidemiology of cardiovascular diseases in Chinese adults. All participants underwent assessments via questionnaires, clinical examinations, and laboratory tests upon enrollment and were followed up every two years. Details regarding data collection were described previously [22, 23, 24, 25, 26].

The study enrolled participants older than 18 years who underwent baPWV measurements from 2010 to 2017. Exclusion criteria included a history of myocardial infarction, stroke, cancer, or peripheral vascular disease before the baPWV measurement. The ethics committees at Kailuan General Hospital approved the study, following the guidelines outlined by the Helsinki Declaration. Written informed consent was obtained from all participants. Baseline data on demographics and cardiovascular risk factors were collected when the baPWV measurements were performed.

2.2 Measurements for baPWV

We collected baPWV values using a BP-203 RPE III networked arteriosclerosis detection device produced by Omron Health Medical (Liaoning, China) Co., Ltd. Participants underwent baPWV measurements after at least 5 minutes of rest in the supine position. Cuffs were wrapped on both arms and ankles. The lower edge of the arm cuff was positioned 2–3 cm above the cubital fossa transverse striation, while the lower edge of the ankle cuff was positioned 1–2 cm above the medial malleolus. The heartbeat monitor was placed on the left edge of the sternum, and electrocardiogram electrodes were placed on both wrists. The resulting baPWV value could be directly read using the network connection. The methodology for the baPWV measurement remained constant for all participants.

2.3 Definition of Arteriosclerosis

The definition for arteriosclerosis was derived from the American Heart Association Medical/Scientific Report (1993) criteria: baPWV 1400 cm/s for normal arterial stiffness, baPWV \ge1400 cm/s for arteriosclerosis. Likewise, the guideline and Consensus 2008 for Cardiovascular Disease Prevention and Treatment defines a baPWV \ge1400 cm/s as arteriosclerosis [15].

2.4 Statistical Analysis

We presented continuous variables as the mean \pm standard deviation (SD) or median with interquartile range and categorical variables as percentages. The baseline characteristics of participants were compared between females and males using t- or Wilcoxon tests for continuous variables and \chi² test for categorical variables.

We examined cross-sectional correlates of arteriosclerosis (baPWV \ge1400 cm/s) using multiple linear regression analysis and multivariable backward logistic regression in males and females, retaining covariates with a p-value 0.05, including age, sex, body mass index (BMI), alcohol consumption, physical exercise, history of diabetes, history of hyperlipidemia, education level, fasting blood glucose (FBG), total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-sensitivity C-reactive protein (hs-CRP), and use of antidiabetic and lipid-lowering drugs.

Two-sided p-values 0.05 were considered statistically significant. All analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA).

3. Results

3.1 Study Participants

From January 1, 2010, to December 31, 2017, 30,148 participants in the Kailuan study underwent baPWV measurements. After excluding participants with a history of myocardial infarction, stroke, cancer, or peripheral vascular disease, 28,291 participants were included in the current analysis (Fig. 1).

3.2 Comparison of Baseline Characteristics

The average age among the 28,291 participants was 48.12 \pm 12.53 years, and 19,783 were males (69.93%). Compared with females, males had a higher baPWV, mean age, BMI, blood pressure (systolic blood pressure (SBP), diastolic blood pressure (DBP)), heart rate, estimated glomerular filtration rate (eGFR), hypertension, diabetes, hyperlipidemia, smoking, and alcohol consumption (p 0.01). Females administered more lipid-lowering drugs and had higher education levels than males (p 0.01) (Table 1).

3.3 Prevalence of Arterial Stiffness

The detection rate of arteriosclerosis in males (62.13%) was higher than in females (37.41%) (p 0.01). The changes in baPWV were described by age stratification (over 30 years old according to an increase in age of 5 years). The baPWV increased with age in the different sex groups (p 0.05) (Table 2). The baPWV in males was higher than in females in all age groups 70 years old (p 0.01). However, from age 45 years and older, the baPWV increased faster in females than in males (Fig. 2).

3.4 Determinants of Arterial Stiffness in Different Sex Groups

Using baPWV as the dependent variable, the statistically significant correlated factors (Table 3) were entered into the multiple linear regression model; eight statistically significant factors were identified in the male and female populations. For every increase of 5 years in age, the baPWV in males increased by 62.55 cm/s and 71.86 cm/s in females. For every 10 mmHg increase in the SBP, the baPWV increased in males and females by 61.01 cm/s and 51.86 cm/s. Physical exercise significantly reduced the baPWV in males but was not statistically significant in females. Females with a higher WHR demonstrated a greater, although not significantly different, baPWV than males (Table 4).

Using a multivariable logistic regression analysis, we found that the risk of arteriosclerosis in males was 1.89 times higher than in females (p 0.01) (Table 5). The stratified analysis of males and females showed that the risk of arteriosclerosis was higher in females aged 45–60 years and older than those under 44 years and was higher than in males (p 0.01). The correlation between diabetes and arteriosclerosis in females was stronger than in males (odds ratio (OR): 2.32 vs. 1.82, p 0.01). Higher education levels reduced the risk of arteriosclerosis in males and females (OR: 0.64, 95% confidence interval (CI): 0.51–0.79; OR: 0.83, 95% CI: 0.74–0.95, respectively) (Table 6).

4. Discussion

Our study found that the prevalence of arteriosclerosis in males was higher than in females and that the baPWV in both males and females showed a trend of increasing with age. In all age groups 65 years old, the baPWV values in males were higher than in females. However, starting at 45 years, the baPWV values for females increased with age and were higher than for males over 71. Vermeersch et al. [27] found that in individuals over 45 years, the baPWV increased more rapidly in females than in males. Benetos et al. [17] found that the baPWV values in males were higher than in females before age 60. This indicates that arteriosclerosis exists in the process of physiological senescence, and the incidence of arteriosclerosis in females correlates more with aging. A possible explanation for the acceleration in baPWV increase in women over 45 years is that estrogen levels decrease, and arterial stiffness increases significantly in menopausal women [28]. Studies have also reported that androgen increased arterial stiffness by altering the arterial structures [21, 29], which may also be responsible for the baPWV values in males and females before age 65.

In addition to age factors, this study found that SBP, heart rate, uric acid, diabetes mellitus, triglyceride, and LDL-C levels were positively correlated with the baPWV in males and females, and for every 10 mmHg increase in SBP, the baPWV in males and females increased by 61.01 cm/s and 51.86 cm/s, respectively. The BLSA study found that elevated SBP was significantly associated with elevated baPWV and exhibited a stronger correlation in the male population [20]. Physical exercise reduced baPWV values in males, which was not statistically different from females, while high-density lipoprotein cholesterol (HDL-C) was the opposite. Heart rate and diabetes promoted similar changes in male and female baPWV values.

After adjusting for confounding factors, the risk of arteriosclerosis in males was 1.89 times higher than in females (95% CI: 1.73–2.06). Moreover, the risk of arteriosclerosis increased by 9.63 times in the group aged over 60 years. The risk of arteriosclerosis increases by 0.74 times for every 10 mmHg increase in SBP. The risk of arteriosclerosis in the diabetic population is 2.26 times greater than in the non-diabetic population. In addition, heart rate, triglyceride, and LDL-C are also risk factors for arteriosclerosis. This shows that being male is an independent risk factor for arteriosclerosis, and age is the most significant factor in increased arterial stiffness. Blood pressure, diabetes, heart rate, and blood lipid levels also increase arterial stiffness to varying degrees. Conversely, having a higher education was a protective factor against arteriosclerosis (OR: 0.74, 95% CI: 0.68–0.80).

By analyzing the influencing factors of arterial stiffness by sex, it was found that age, SBP, heart rate, LDL-C, hs-CRP, and diabetes are the risk factors for increased baPWV values in males and females.Compared with people aged \le44, the risk of arteriosclerosis in females aged 45–59 and \ge60 is 3.49 times and 24.19 times, that in males aged 1.80 times and 10.81 times, indicating that the correlation between age and female arterial stiffness is higher than in male. Compared with the non-diabetic population, the risk of arteriosclerosis in female diabetic patients is higher than that in male (OR: 2.32–1.82). Higher education levels reduced the risk of arteriosclerosis in males and females (OR: 0.83, 95% CI: 0.74–0.95 vs. OR: 0.64, 95% CI: 0.51–0.79, respectively). Comparatively, individuals with higher education levels may have a healthier lifestyle; thus, a variable lifestyle is the main factor influencing the increase in arteriosclerosis, which may correlate to why a higher education level reduces the risk of arteriosclerosis. The proportion of females with higher education (50.46%) is higher than that of males (32.73%), which may be why the OR value for females is lower than for males. HDL-C reduces the risk of arteriosclerosis in females (OR: 0.73, 95% CI: 0.58–0.93), and there is no statistical difference between HDL-C and males. Lebrun et al. [30] also found that increased HDL-C reduced arterial stiffness. SBP, heart rate, LDL-C, and hs-CRP have little difference in increasing the risk of arteriosclerosis in males and females, and the OR values are 1.63, 1.03, 1.16, 1.02 and 1.66, 1.03, 1.27, and 1.08, respectively.

Our study found significant differences in arterial stiffness between different sexes. Age, blood pressure, diabetes, LDL-C, heart rate, and hs-CRP are arteriosclerosis risk factors. Age and diabetes are more related to arterial stiffness in females than males, and blood pressure pertains more to arterial stiffness in males than females. Similarly, aging and blood pressure also increase the risk of arteriosclerosis in males and females, respectively. Therefore, actively monitoring and controlling blood pressure, blood sugar, and blood lipids to maintain them at relatively normal and stable levels can reduce the occurrence and development of subclinical arteriosclerosis.

Although our study found that the influencing factors of arterial stiffness are different between sexes, this study has some limitations: (1) cfPWV, the gold standard of predicting arteriosclerosis, was not used as the detection method. However, baPWV not only presents a good correlation with cfPWV but was also included in the recommended standard of arteriosclerosis evaluation by the American Heart Association [7]. (2) There is a lack of data on whether the female subjects were or were not menopausal, and the reasons for the accelerated growth of baPWV after age 45 are uncertain. (3) Furthermore, this study did not exclude the influence of patients taking antihypertensive, hypoglycemic, and lipid-lowering drugs from the results, meaning that it cannot be ruled out that such people were not included in the sensitivity analysis. (4) When analyzing the differences in influencing factors of arterial stiffness between different sexes, although possible confounding factors were corrected for as much as possible, other confounding factors exist, such as environmental changes and heritage factors, which were not corrected.

5. Conclusions

The detection rate of arteriosclerosis in males was higher than in females. The baPWV value in males under 70 years was higher than in females. However, after 45 years, the increase in the baPWV rate in females according to age was higher than in males. The WHR, SBP, diabetes, LDL-C, and hs-CRP measurements correlated more with female arteriosclerosis. Higher education and physical exercise levels reduced the risk of arteriosclerosis in males and females.

Availability of Data and Materials

The data are obtainable on request from the corresponding author in this study. They are not publicly available due to privacy issues.

References

[1] Ge J, Xu Y. Chapter 4: Atherosclerosis and coronary atherosclerotic heart disease. Internal Medicine (220). 8th edn. People’s Health Publishing House: Beijing. 2013.

[2] Milan A, Tosello F, Fabbri A, Vairo A, Leone D, Chiarlo M, et al. Arterial stiffness: from physiology to clinical implications. High Blood Pressure & Cardiovascular Prevention. 2011; 18: 1–12.

[3] Willum-Hansen T, Staessen JA, Torp-Pedersen C, Rasmussen S, Thijs L, Ibsen H, et al. Prognostic value of aortic pulse wave velocity as index of arterial stiffness in the general population. Circulation. 2006; 113: 664–670.

[4] Saji N, Kimura K, Yagita Y, Kawarai T, Shimizu H, Kita Y. Comparison of arteriosclerotic indicators in patients with ischemic stroke: ankle-brachial index, brachial-ankle pulse wave velocity and cardio-ankle vascular index. Hypertension Research. 2015; 38: 323–328.

[5] Ouchi M, Oba K, Saigusa T, Watanabe K, Ohara M, Matsumura N, et al. Association between pulse wave velocity and a marker of renal tubular damage (N-acetyl-β-D-glucosaminidase) in patients without diabetes. Journal of Clinical Hypertension. 2015; 17: 290–297.

[6] Böhm M, Schumacher H, Leong D, Mancia G, Unger T, Schmieder R, et al. Systolic blood pressure variation and mean heart rate is associated with cognitive dysfunction in patients with high cardiovascular risk. Hypertension. 2015; 65: 651–661.

[7] Townsend RR, Wilkinson IB, Schiffrin EL, Avolio AP, Chirinos JA, Cockcroft JR, et al. Recommendations for Improving and Standardizing Vascular Research on Arterial Stiffness: A Scientific Statement From the American Heart Association. Hypertension. 2015; 66: 698–722.

[8] Ushigome E, Fukui M, Hamaguchi M, Tanaka T, Atsuta H, Mogami SI, et al. Maximum home systolic blood pressure is a useful indicator of arterial stiffness in patients with type 2 diabetes mellitus: post hoc analysis of a cross-sectional multicenter study. Diabetes Research and Clinical Practice. 2014; 105: 344–351.

[9] Niiranen TJ, Lyass A, Larson MG, Hamburg NM, Benjamin EJ, Mitchell GF, et al. Prevalence, Correlates, and Prognosis of Healthy Vascular Aging in a Western Community-Dwelling Cohort: The Framingham Heart Study. Hypertension. 2017; 70: 267–274.

[10] Miyatake N, Shikata K, Makino H, Numata T. Relation between the estimated glomerular filtration rate and pulse wave velocity in Japanese. Internal Medicine. 2010; 49: 1315–1320.

[11] Hu JW, Wang Y, Chu C, Yan Y, Wang K, Zheng W, et al. The Relationships of the Fractional Excretion of Uric Acid with Brachial-Ankle Pulse Wave Velocity and Ankle Brachial Index in Chinese Young Adults. Kidney & Blood Pressure Research. 2018; 43: 234–245.

[12] Andersson C, Lyass A, Larson MG, Spartano NL, Vita JA, Benjamin EJ, et al. Physical activity measured by accelerometry and its associations with cardiac structure and vascular function in young and middle-aged adults. Journal of the American Heart Association. 2015; 4: e001528.

[13] Van Bortel LM, Laurent S, Boutouyrie P, Chowienczyk P, Cruickshank JK, De Backer T, et al. Expert consensus document on the measurement of aortic stiffness in daily practice using carotid-femoral pulse wave velocity. Journal of Hypertension. 2012; 30: 445–448.

[14] Tanaka H, Munakata M, Kawano Y, Ohishi M, Shoji T, Sugawara J, et al. Comparison between carotid-femoral and brachial-ankle pulse wave velocity as measures of arterial stiffness. Journal of Hypertension. 2009; 27: 2022–2027.

[15] Dayi Hu. Chapter 5: Clinical Significance Evaluation of Non invasive Arterial Function Testing ChineseExpert Consensus. Guidelines and Consensus for the Prevention and Treatment of CardiovascularDiseases (pp. 37–43). 2008 edn. People’s Health Publishing House: Beijing. 2008.

[16] Wang X, Xie J, Zhang LJ, Hu DY, Luo YL, Wang JW. Reference values of brachial-ankle pulse wave velocity for Northern Chinese. Chinese Medical Journal. 2009; 122: 2103–2106.

[17] Benetos A, Watfa G, Hanon O, Salvi P, Fantin F, Toulza O, et al. Pulse wave velocity is associated with 1-year cognitive decline in the elderly older than 80 years: the PARTAGE study. Journal of the American Medical Directors Association. 2012; 13: 239–243.

[18] Mattace-Raso FUS, van der Cammen TJM, Hofman A, van Popele NM, Bos ML, Schalekamp MADH, et al. Arterial stiffness and risk of coronary heart disease and stroke: the Rotterdam Study. Circulation. 2006; 113: 657–663.

[19] Smulyan H, Marchais SJ, Pannier B, Guerin AP, Safar ME, London GM. Influence of body height on pulsatile arterial hemodynamic data. Journal of the American College of Cardiology. 1998; 31: 1103–1109.

[20] Canepa M, Viazzi F, Strait JB, Ameri P, Pontremoli R, Brunelli C, et al. Longitudinal Association Between Serum Uric Acid and Arterial Stiffness: Results From the Baltimore Longitudinal Study of Aging. Hypertension. 2017; 69: 228–235.

[21] Fantin F, Mattocks A, Bulpitt CJ, Banya W, Rajkumar C. Is augmentation index a good measure of vascular stiffness in the elderly? Age and Ageing. 2007; 36: 43–48.

[22] Wu S, Huang Z, Yang X, Zhou Y, Wang A, Chen L, et al. Prevalence of ideal cardiovascular health and its relationship with the 4-year cardiovascular events in a northern Chinese industrial city. Circulation. Cardiovascular Quality and Outcomes. 2012; 5: 487–493.

[23] Wu S, Li Y, Jin C, Yang P, Li D, Li H, et al. Intra-individual variability of high-sensitivity C-reactive protein in Chinese general population. International Journal of Cardiology. 2012; 157: 75–79.

[24] Zhang Q, Zhou Y, Gao X, Wang C, Zhang S, Wang A, et al. Ideal cardiovascular health metrics and the risks of ischemic and intracerebral hemorrhagic stroke. Stroke. 2013; 44: 2451–2456.

[25] Zheng X, Zhang R, Liu X, Zhao H, Liu H, Gao J, et al. Association between cumulative exposure to ideal cardiovascular health and arterial stiffness. Atherosclerosis. 2017; 260: 56–62.

[26] Chen S, Li W, Jin C, Vaidya A, Gao J, Yang H, et al. Resting Heart Rate Trajectory Pattern Predicts Arterial Stiffness in a Community-Based Chinese Cohort. Arteriosclerosis, Thrombosis, and Vascular Biology. 2017; 37: 359–364.

[27] Vermeersch SJ, Rietzschel ER, De Buyzere ML, De Bacquer D, De Backer G, Van Bortel LM, et al. Age and gender related patterns in carotid-femoral PWV and carotid and femoral stiffness in a large healthy, middle-aged population. Journal of Hypertension. 2008; 26: 1411–1419.

[28] Natoli AK, Medley TL, Ahimastos AA, Drew BG, Thearle DJ, Dilley RJ, et al. Sex steroids modulate human aortic smooth muscle cell matrix protein deposition and matrix metalloproteinase expression. Hypertension. 2005; 46: 1129–1134.

[29] Ahimastos AA, Formosa M, Dart AM, Kingwell BA. Gender differences in large artery stiffness pre- and post puberty. The Journal of Clinical Endocrinology and Metabolism. 2003; 88: 5375–5380.

[30] Lebrun CEI, van der Schouw YT, Bak AAA, de Jong FH, Pols HAP, Grobbee DE, et al. Arterial stiffness in postmenopausal women: determinants of pulse wave velocity. Journal of Hypertension. 2002; 20: 2165–2172.