Factors Associated with Brachial-Ankle Pulse Wave Velocity in an Apparently Healthy Chinese Population

Purpose To investigate the factors influencing brachial-ankle pulse wave velocity (baPWV) in an apparently healthy Chinese population, especially the associations between baPWV and indices of blood pressure (BP). Methods A total of 1123 participants with no history of hypertension were enrolled in this study, and the baPWV and BP of all four limbs were measured along with other covariates. Correlation analyses and multivariate linear regression models were used to identify factors associated with baPWV. Results A total of 1123 participants (male 43.3%, mean age: 58.4 ± 13.9 years) were included. The average baPWV was 14.87 ± 3.21 m/s, and no difference was found between the sexes. Age was positively correlated with baPWV (r = 0.65, p < 0.01), especially in females (r = 0.71 versus 0.56 in males). The correlation coefficient between age and baPWV increased markedly after the age of 65 years. In addition, the resting heart rate (RHR), waist-hip ratio, glomerular filtration rate, and plasma glucose level were significantly correlated with baPWV (r = 0.25, 0.22, -0.43, and 0.25, respectively; p < 0.01). BP parameters were highly positively correlated with baPWV, especially systolic BP (SBP) and pulse pressure (PP). Multivariate regression revealed that age, BP parameters, and RHR were independently correlated with baPWV (p < 0.01) after adjusting for confounding factors. The standardized coefficients of SBP were greater than those of PP, followed by diastolic BP (DBP). Conclusion BaPWV increased with age, especially after 65 years. Age, BP, and RHR were independent factors associated with baPWV. The effect of SBP on baPWV was more prominent than that of PP.


Introduction
Arterial elasticity dysfunction is an important indicator of arteriosclerosis and is closely associated with cardiovascular diseases [1][2][3]. Increased arterial stiffness parallels structural changes in the medial layer of elastic arteries and is one of the pathological symptoms of vascular damage. Arterial stiffness is associated with future hypertension and cardiovascular events. Therefore, the prevention of arterial stiffness is of great importance [4].
Brachial-ankle pulse wave velocity (baPWV) is the most widely used measure of arterial stiffness in regular clinical and epidemiological settings due to its noninvasive and reproducible nature as well as the ease of follow-up and evaluation [5]. Higher baPWV was observed in patients with hypertension or other diseases, such as diabetes mellitus, dyslipidaemia, metabolic syndrome, chronic kidney disease, and ventricular hypertrophy [6][7][8][9]. baPWV was identified as an independent predictor of cardiovascular diseases, cardiovascular mortality, and all-cause mortality [1,10].
Most studies on baPWV-associated factors have focused on patients with hypertension and the other diseases mentioned above [11][12][13][14], but arterial stiffness is not confined to patients with hypertension. In nonhypertensive individuals, it is not clear whether blood pressure (BP) has an effect on baPWV. The factors influencing baPWV have been widely studied, but this relationship is less well defined. Taking the resting heart rate (RHR) as an example, studies have shown a positive association with baPWV, no association, or even an inverse association [15]. However, numerous studies have demonstrated robust associations between baPWV and RHR, ageing, higher body mass index (BMI), and reduced glomerular filtration rate (GFR) [16][17][18]. These associations are not well studied in Chinese adults without hypertension. Furthermore, whether the increase in arterial stiffness with advancing age results from the age-associated increase in BP is unknown.
The present study measured baPWV and BP, including bilateral ankle/brachial systolic BP, bilateral ankle/brachial diastolic BP, and bilateral ankle/brachial pulse pressure (PP), in a healthy northern Chinese population without hypertension or other atherosclerotic factors. We investigated the factors associated with baPWV and particularly studied whether BP was an independent factor influencing baPWV.

Subjects and Methods
A total of 1368 participants were recruited among the residents of urban Beijing in 2014. All participants received an explanation of the purpose of this investigation and voluntarily provided their consent to participate in this study. All protocols were approved by the Ethics Committee of the Chinese PLA General Hospital. The exclusion criteria were as follows: (1) pregnant women; (2) individuals taking medication; (3) subjects with a medical history of peripheral vascular diseases; (4) subjects with hypertension (BP ≥ 140/90 mmHg) or diagnosed with chronic kidney disease, diabetes mellitus, or dyslipidaemia (total cholesterol ≥ 5:9 mmol/L, triglycerides ≥ 1:70 mmol/L); (5) subjects with a medical history of cardiovascular diseases, such as stroke and myocardial infarction; and (6) BMI ≥ 28:0 kg/m 2 [17]. Data from 1123 participants were included in the final analysis ( Figure 1).
Participants underwent a comprehensive assessment with an Artery Stiffness Detector (OMRON VP-1000), including measurements of bilateral baPWV and BP in all four limbs and electrocardiography. The examination was conducted after the participants rested in the supine position for at least 5 min, and all examinations were performed by the same senior physician at the Chinese PLA General Hospital. The average values of the bilateral baPWV and BP were used for the analysis. The sum-PP was the sum of the PPs in the four limbs. Physical measurements, including body height, weight, waist circumference, and hip circumference, were also taken. BMI was calculated as the weight (kg) divided by the height squared (m 2 ). The waist-hip ratio (WHR) was calculated as the waist circumference divided by the hip circumference.
Subjects were required to fast for 8-12 h before blood sample collection. The plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein (TP), albumin, total bilirubin (TB), plasma glucose (PG), urea, urea acid, creatinine, total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and lowdensity lipoprotein cholesterol (LDL-C) levels were measured at the Biochemistry Laboratory of the Chinese PLA General Hospital. The GFR was calculated according to the Chronic Kidney Disease Epidemiology Collaboration creatinine (CKD-EPI) equation.
Data are presented as the means ± standard deviations for continuous variables and as the percentages (%) for categorical variables. The population characteristics stratified by baPWV quartiles were compared using ANOVA (continuous normally distributed parameters), Kruskal-Wallis tests (continuous nonnormally distributed variables), or  Correlation analyses were used to determine the relationships between baPWV and variables (BP parameters, age, height, weight, BMI, waist circumference, etc.). The Pearson correlation analysis was used to determine relationships between normally distributed variables, and the Spearman correlation analysis was used for nonnormally distributed variables. Multivariate linear regression was used to identify factors affecting baPWV with "stepwise" as the variable filtering method. To avoid multicollinearity, we included only one BP parameter at a time as an independent variable in the regression model, with age, WHR, PG, GFR, and RHR as covariates. Data analyses were performed using SPSS version 25.0 for Mac (SPSS, Chicago, IL, USA).

Results
In total, 1123 participants were eligible for inclusion in this study, including 486 males (43.3%) and 637 females (56.7%). The age ranges of the males and females were both 21 to 86 years, and the mean age of the population was 58:4 ± 13:9 years. The average baPWV was 14:87 ± 3:21 m/s, and there was no difference between the sexes (male: 15:02 ± 2:84 m/s, female: 14:75 ± 3:46 m/s; p = 0:170). According to baPWV quartiles, we stratified the study population into four groups: Q1 (baPWV There was a trend for gradually increasing age, GFR, RHR, and PG levels with increasing baPWV (p < 0:001) ( Table 1). The highest age, GFR, and RHR were observed in individuals with the highest quartiles of baPWV. The mean value of the sum-PP was 246:6 ± 47:1 mmHg. All indices of BP increased significantly as baPWV increased.
To analyse the relationships between baPWV and the BP indices, stepwise multivariate linear regression analysis was performed; the results are shown in Table 3. After adjusting for confounding factors (including WHR, PG, GFR, age, and RHR), the parameters of BP (sum-PP, SBP, DBP, and PP) were stable and significant determinants of baPWV. The standardized coefficient of SBP was greater than that of sum-PP in males, but the opposite was true in females, both followed by PP and DBP. In addition to the BP parameters, age and the RHR were also independent factors influencing baPWV.

Discussion
The present cross-sectional study of an apparently healthy northern Chinese population showed that baPWV increases with age and that the rate of increase accelerates after 65 years of age. People with higher RHRs or BP levels tend to have higher baPWV. The significantly positive correlation of BP with baPWV indicates that a higher BP is still a contributing factor to arterial stiffness, even when it is within the normal range. The effect of SBP on baPWV was more prominent than that of PP.
BaPWV is widely used to evaluate arterial stiffness, which reflects alterations in the structural and functional properties of the central and peripheral arteries. Carotidfemoral PWV (cfPWV) is the most validated technique and is regarded as the gold standard for PWV measurement [19]. However, because of its methodological difficulties and limited availability, cfPWV is not generally implemented in China. In contrast, the measurement of baPWV is easy and reproducible, as it simply involves using BP cuffs on the four extremities.
baPWV is elevated in patients with diabetes mellitus, hypertension, metabolic syndrome, chronic kidney disease, and sleep apnoea syndrome; and ageing, tachycardia, and the postmenopause period also result in increases in baPWV [19][20][21][22]. baPWV is an independent risk factor for cardiovascular events in patients with hypertension, but the optical cut-off values of baPWV for predicting cardiovascular disease are still controversial.  [24,25]. In the general Chinese population, Lu et al. reported that a baPWV of 16.7 m/s is the optimal threshold for cardiovascular risk stratification [26].
With the increasing use of baPWV to measure arterial stiffness and predict the risks of arteriosclerosis and cardiovascular death, the amount of research on the factors associated with baPWV in various populations has increased. Many studies have reported that baPWV increases substantially with increasing age [27][28][29], and our results are consistent with these well-established findings. A study including 3215 Japanese adolescents claimed that the effect of ageing was more prominent in males than in females [29]. However, the sex difference seems to be the opposite in adults, which has also been validated in our study (r = 0:56 in male versus r = 0:71 in female, p < 0:001) and other studies [17,28]. The level of plasma oestrogen or androgen during menopause may explain the augmented increase in baPWV with 3 BioMed Research International ageing in females [17,30]. Furthermore, our study illustrated a linear relationship between age and the value of baPWV, and a relatively closer correlation was observed in elderly people. A study reported that the age-related progression of arterial stiffness could be explained by a growth curve rather than a straight line [16].
Our study demonstrated that a higher BP is a contributing factor to arterial stiffness, even when it is within the  BioMed Research International normal range, and the effect of SBP on baPWV was more prominent than that of PP. The association between BP and arterial stiffness has been debated in various studies [11,13,26,27,31,32]. Longitudinal studies have shown that a large PP in childhood plays a role in the development of subclinical vascular damage in adulthood, and the early prevention of a large PP can reduce the future risk of cardiovascular disease [14]. Some BP-derived indicators, such as long-term BP variability and sum-PP [5,33], were also reported to be significantly associated with baPWV. This relationship between BP and arterial stiffness may be bidirectional because arterial stiffness contributes to the increase in BP, and arterial stiffening is accelerated in patients with hypertension [34]. They behave reciprocally as cause and effect, interacting in a vicious cycle [35]. However, a statement from the American Heart Association said that arterial stiffness represents a cause rather than a consequence of hypertension [15]. Monitoring BP may be useful for the identification of vascular impairment [36], and baPWV can be used to predict the progression of BP and incident hypertension and determine the individual response to antihypertensive treatment [37][38][39][40].
Whether baPWV could be a useful screening tool to identify apparently healthy subjects who should be targeted for inventions aimed at preventing incident hypertension requires further study. The effects of the RHR on PWV are still controversial, with conflicting results being observed. Some researchers in the Corinthia study suggested that the influence of the RHR on PWV is mediated by BP [41], and the product of the RHR times the BP was reported to be associated with baPWV [42]. However, approximately half of the existing epidemiological studies have reported a significant BP-independent association between the RHR and PWV [43]. Our study demonstrated that an increased RHR is independently associated with a higher baPWV, regardless of other confounders in apparently healthy individuals. Regarding the mechanism, an increased RHR can change the viscoelasticity of the arterial wall, thus increasing arterial stiffness [43]. A study including 912 females showed that the urea acid level and baPWV had a positive nonlinear correlation [44], but our study showed that the level of urea acid was significantly linearly correlated with baPWV in females but not in males. In the previous literature, total homocysteine levels, BMI, low creatinine clearance, proteinuria, urine albumin, and salt intake were also reported to be associated with baPWV [22,38,45].

BioMed Research International
The results of this study should be interpreted in light of potential limitations. Although the study participants included people without hypertension or other cardiovascular diseases, the BP measurements were only obtained on a single occasion and the medical history was not reliable enough. Our study is cross-sectional; therefore, we could not determine the temporality of the associated factors, and we could not identify a causal relationship between baPWV and BP. These problems should be addressed in future longitudinal studies with larger populations.

Conclusions
In summary, the subjects included in our study were apparently healthy and without cardiovascular risk factors, and we verified the factors affecting baPWV and the association between BP and baPWV. The results showed that in addition to age and the RHR, BP was independently associated with baPWV. The development of arterial stiffness accelerates in elderly people. The standardized coefficients of SBP were greater than those of PP, followed by DBP. These findings underscore the importance of early monitoring of higher SBP to protect vascular elasticity.

Data Availability
The data used to support the findings of this study are available from the corresponding author upon reasonable request.

Ethical Approval
All procedures in studies involving human participants were performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study was approved by the academic ethics and moral supervision committee of the Chinese PLA General Hospital (S2019-148-02).

Consent
All participants signed an informed consent form before participating in this study, and the purpose of the study was explained to the participants in advance.

Conflicts of Interest
The authors declare that they have no potential conflicts of interest to disclose.