Atherosclerosis 238 (2015) 147e152

Contents lists available at ScienceDirect

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

Age-related progression of arterial stiffness and its elevated positive

association with blood pressure in healthy people
Wen Wen a, 1, Rong Luo b, 1, Xiaojing Tang a, Lan Tang b, Hunter X. Huang a, Xiaoyan Wen a,
Shan Hu a, Bin Peng a, *
a
Department of Medical Statistics, School of Public Health, Chongqing Medical University, Chongqing 400016, China
b
Department of Physical Examination, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China

a r t i c l e i n f o a b s t r a c t

Article history: Objective: Arterial stiffness occurs as a consequence of age and arteriosclerosis, but the mechanics of the
Received 17 July 2014 progression of arterial stiffness along with age is not fully explored. We aim to investigate the age-related
Received in revised form progression of arterial stiffness through the examination of 4659 healthy subjects aged from 20 to 75.
15 October 2014
Methods: The cardio-ankle vascular index (CAVI) was used as a marker of arterial stiffness. Piecewise
Accepted 20 October 2014
Available online 29 November 2014
linear regression model was utilized to analyze the association between different stages of age and
arterial stiffness. The mean CAVI values of age groups were calculated to fit the linear regression and
curvilinear regression models. We also constructed multiple regression models to examine the in-
Keywords:
Arterial stiffness
teractions of blood pressure and age on CAVI. Result: The regression coefficients (b) of piecewise linear
Age regression of each age group (<35, 35e44, 45e59, >59) were 0.07062, 0.03133, 0.03840 and 0.07272 for
Blood pressure men, and 0.03342, 0.02025, 0.04826 and 0.10604 for women, respectively. The highest R square came
Growth curve from curvilinear regression for men (R2 ¼ 0.9220), and piecewise linear regression for women
Cardio-ankle vascular index (CAVI) (R2 ¼ 0.9454). The interactions between each type of blood pressure and age were significant (all
P < 0.001). Conclusion: There were various increased trends between different stages of age. Age-related
progression of arterial stiffness could be better explained by a growth curve, rather than a straight line. In
addition, blood pressure has an increasingly positive association with CAVI values as age increases.
© 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction measuring time, CAVI is independent of BP, which makes it more

Arterial stiffness is the reduced capability of an artery to expand
and contract in response to pressure changes [1]. The main cause
for age-related stiffness is due to the loss of elasticity of the arterial
walls from mechanical stress [2]. Numerous data have indicated a
linear relationship between arterial stiffness and age [3e5]. Others
have also found accelerated stiffening between 50 and 60 years of
age [6]. The recent research by Su-Yeon Choi et al. [7] reported an
age-stratified increase of arterial stiffness in healthy Koreans adults
in 2013. These researches suggest that the issue of age-related
progression of arterial stiffness have not been fully explored.
Cardio-ankle vascular index (CAVI) is a non-invasive method of
measuring arterial stiffness that developed in 2004 [8,9]. However,
while pulse wave velocity (PWV) is influenced by BP at the
* Corresponding author.
E-mail address: pengbin@cqmu.edu.com (B. Peng).
1
Wen Wen and Rong Luo contributed equally to this work.
stable and precise than other PWV methods [10]. Thus, CAVI has
better reproducibility for clinical practice [8,11,12].
In this study, we aim to investigate the relationship between
arterial stiffness with the progression of age in a large number of
healthy Chinese subjects. We focused on two aspects of age-related
progression of arterial stiffness: 1) the variation and trend of
arterial stiffness among young adults, middle aged adults and the
elderly, 2) the optimal fitting growth curve of arterial stiffness along
with aging.
2. Subjects and methods
Data from a total of 16,340 subjects who finished the exami-
nation of arterial stiffness using CAVI were collected from the
Medical Examination Center of the Chongqing Medical University.
Subjects who had known or were treated for hypertension, diabetes
mellitus, dyslipidemia, hyperuricemia, renal dysfunction, abnormal
white blood cell, heart disease, stroke or gout were excluded from

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148 W. Wen et al. / Atherosclerosis 238 (2015) 147e152

this total population. We also excluded subjects who were not in
previous cases but satisfied the flowing criteria: systolic blood
pressure (SBP) 140 mmHg, diastolic blood pressure 90 mmHg,
fasting blood glucose (FPG) >7.0 mmol/L, total cholesterol (TC)
6.22 mmol/L, high-density lipoprotein cholesterol (HDL-C)
1.04 mmol/L, low-density lipoprotein cholesterol (LDL-C)
4.14 mmol/L, triglyceride (TG) 2.26 mmol/L, urine creatinine
(UCr) 130 mg/dL or uric acid (UA) 420umol/L. Furthermore, we
excluded subjects with a low ankle-brachial index (ABI <0.9)
because their case may lead to inaccurate CAVI values [8]. At last,
4659 of remaining subjects were regarded as healthy population
with less risk factors for cardiovascular diseases and included in
this study.
2.4. Statistical analysis
The piecewise linear regression model was used to analyze the
increments of b regression coefficients (Db) between different
stages of age for CAVI in men and women. To investigate the growth
curve of arterial stiffness, the mean CAVI value of each age was
calculated; linear regression model and curvilinear regression
model were used to fit the data of mean CAVI values by each age. To
examine the interactions between age and SBP, DBP and PP on the
dependent variable CAVI, multiple regression models were used on
the three blood pressure indices and the relevant variables were
centered around their means values to reduce errors caused by
different scales. Data were analyzed using SAS 9.1.

2.1. Medical examination 3. Results

The medical examination was conducted by the Medical Ex- We included 28.5% of all examined subjects in this study who
amination Center of Chongqing Medical University, which had were less at-risk with cardiovascular disease and were regarded as
obtained ISO 15189 certification since 2006. The routine medical the healthy population. The characteristics of the healthy popula-
examination includes a physical examination, a fasting blood tion were summarized in Table 1. Their average age was
sample, and ultrasonography. 45.24 ± 10.76 for men (ranging from 20 to 75 years old) and
Height, body weight, and waist circumference (WC) were 44.90 ± 9.79 for women (ranging from 21 to 74 years old). 17.57% of
measured in the physical examination. Blood pressure was also men and 15.50% of women were less than 35 years old, 30.89% of
measured in the left arm using a standard mercury sphygmoma- men and 32.57% of women were from 35 to 44 years old, and 41.82%
nometer after subjects sits quietly for at least 5 min. Fasting blood and 45.46% were from 45 to 59 years old, and 9.73% of men and
sampling was obtained from the antecubital vein in the morning, 6.47% of women were more than 59 years of age. The mean CAVI
and the serum was separated and centrifuged after blood coagu- was 7.29 ± 0.84 for men and 6.96 ± 0.81 for women. All variables,
lation. Blood cells, hemoglobin, platelet, FPG, TG, TC, HDL-C, LDL-C, except age and TC, show a significant difference between men and
UCr, UA, and more were measured with standard laboratory pro- women (all P < 0.05). Supplemental Table 1 provided the CAVI
cedures using automatic biochemical analyzer. Abdominal ultra- means and percentile values according to quintiles of age by
sonography was performed by experienced technicians on HD7 gender.
ultrasound system. We performed piecewise linear regression analysis to assess the
variation and trend of arterial stiffness among Early Young-Adult,
2.2. Measurement of cardio-ankle vascular index Late Young-Adult, Middle-aged Adult and the Elderly. The piece-
wise linear function were specified by four slopes, one for each age
CAVI was measured by a Vasera VS-1000 vascular screening group (<35, 35e44, 45e59, >59); and three breakpoints, with the
system with subjects resting in a supine position. Electrodes for
electrocardiography were placed on both wrists, and a microphone Table 1
was placed on the sternum for phonocardiography. Both ankles and General information of subjects.
brachium were secured with cuffs. The subjects then rested for
Variables Total (4659) Men (n ¼ 2169) Women (2490) P value
5e10 min before the examinations were performed. PWV, SBP, and
DBP were automatically measured to calculate the values for right Age (year) 45.06 (10.25) 45.24 (10.76) 44.90 (9.79) 0.3459
<35 (%) 16.46 (767) 17.57 (381) 15.50 (386) e
and left CAVI, as follows: CAVI ¼ a[{2r  1/(SBP  DBP)}  {ln(SBP/
35e44 (%) 31.79 (1481) 30.89 (670) 32.57 (811) e
DBP)  PWV2}] þ b, where a and b are constant and r is blood 45e59 (%) 43.76 (2039) 41.82 (907) 45.46 (1132) e
density. The left and right CAVI values were then used to calculate >59 (%) 7.98 (372) 9.73 (211) 6.47 (161) e
the average CAVI values, which were used to analyze. Height (cm) 162.03 (8.02) 168.05 (6.04) 156.78 (5,42) <0.0001
The ankle-brachial index (ABI) was also calculated at the same Weight (kg) 59.42 (9.34) 65.27 (8.58) 54.33 (6.59) <0.0001
BMI (kg/m2) 22.56 (2.53) 23.08 (2.55) 22.10 (2.42) <0.0001
time by dividing the value of the upper arm BP by the value of the WC (cm) 77.09 (7.91) 81.47 (7.13) 73.27 (6.45) <0.0001
lower arm BP. ABI reflects the possibility of peripheral artery SBP (mmHg) 114.84 (11.85) 117.26 (11.07) 112.74 (12.10) <0.0001
occlusive disease (PAOD) in subjects [13], ABI value of less than 0.9 DBP (mmHg) 71.89 (8.51) 73.96 (8.13) 70.09 (8.43) <0.0001
indicates the possibility of PAOD due to decreased blood flow [14]. PP (mmHg) 42.95 (8.90) 43.31 (8.37) 42.64 (9.33) 0.0001
WBC (/L) 5.80 (1.22) 6.00 (1.21) 5.63 (1.20) <0.0001
TC (mmol/L) 4.65 (0.67) 4.65 (0.65) 4.65 (0.68) 0.6852
2.3. Definition TG (mmol/L) 1.07 (0.39) 1.16 (0.39) 1.00 (0.38) <0.0001
HDL-C (mmol/L) 1.59 (0.35) 1.48 (0.30) 1.70 (0.35) <0.0001
LDL-C (mmol/L) 2.65 (0.59) 2.75 (0.57) 2.57 (0.59) <0.0001
The subjects in this study were ranged from 20 to 75 years old. FPG (mmol/L) 5.05 (0.41) 5.06 (0.43) 5.03 (0.40) 0.0040
According to World Health Organization, people age 18 to 44 are UCr (mg/dL) 66.54 (14.38) 78.29 (10.37) 56.30 (8.27) <0.0001
defined as young, 45e59 as middle age, and over 60 years old as UA (umol/L) 303.30 (65.24) 343.79 (51.93) 268.02 (54.26) <0.0001
elderly. However, the National Bureau of Statistics of China has a CAVI (m/s) 7.11 (0.84) 7.29 (0.84) 6.96 (0.81) <0.0001
different system of dividing age, which defined the young as aged Continuous variables are given as the mean (standard deviation) or median (quartile
15e34. We combined the two systems and came up with four range); Categorical variables are given as a percentage (number). BMI: body mass
distinct age groups. Subjects with ages <35, 35e44, 45e59, and index. WC: waist circumference. SBP: systolic blood pressure. DBP: diastolic blood
pressure. PP: pulse blood pressure, was calculated as SBP - DBP. TC: total cholesterol.
>59 were organized into the Early Young-Adult group, the Late TG: triglyceride. FPG: fasting blood glucose. HDL-C: high-density lipoprotein
Young-Adult group, the Middle-Aged Adult group, and the Elderly cholesterol. LDL-C: low-density lipoprotein cholesterol. UCr: urine creatinine. UA:
group, respectively. uric acid. CAVI: cardio-ankle vascular index.

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 W. Wen et al. / Atherosclerosis 238 (2015) 147e152
significant change of slope being determined by comparing the
difference in value of the next age group. The analysis results were
exhibited in Table 2. For men, the increment of regression coeffi-
cient between age group of 35 to 44 and 45 to 59 was 0.00707, but it
was a non-significant change (P ¼ 0.3990). While for women, the
increment of regression coefficient between the age group of less
than 35 and 35 to 44 was not significant (Db ¼ 0.01317,
P ¼ 0.3024). We therefore regarded the variation of CAVI between
these groups of men and women to be constant.
The increased trends of arterial stiffness at each age group were
summarized by gender. For men, the CAVI showed an acute incre-
ment before 35 years old; but the increment slowed down at age
groups of 35 to 44 and 45 to 59; and once again, when over 59 years
old, the increment of CAVI elevated to the highest. For women, the
CAVI kept a low increment at age groups of less than 35 and 35 to
44; it then increased to a higher increment at age group of 45e59;
and finally increased to the highest increment of over 59 years old.
Previous results have demonstrated the variation and trend
between different stages of age. We further infer that the rela-
tionship between age and arterial stiffness could also be repre-
sented by a growth curve. Next, to test this hypothesis, we
calculated the average CAVI of each age, and constructed curvi-
linear regressions to fit the data. General linear regression and
piecewise linear regression were also constructed and their fitted
results were used to make a comparison with that of curvilinear
linear regression. The classification of piecewise linear regression
was based on the previous demonstrated stratification. We illus-
trated the results in Fig. 1, all models had remarkable statistical
significance (all p < 0.0001). The R-Square (R2) of curvilinear
regression (men: 0.9220, women: 0.9440) and piecewise regres-
sion (men: 0.9209, women: 0.9454) were very similar, and both
higher than that of general linear regression (men: 0.8994, women:
0.8569).
Finally, to further exemplify the varying effect of age on arterial
stiffness, we examined the age-related relationship between blood
pressure and arterial stiffness in the healthy population. We per-
formed the stepwise multiple linear regression analysis which in-
cludes an interaction term between age and each blood pressure
index (SBP, DBP and PP). These results are summarized in Table 3.
Age, sex, height, weight, WC, TC, FPG, UCr and blood pressure
indices were entered in the models. There also was a significant
interaction between each blood pressure index and age. Fig. 2 il-
lustrates the nature of these interactions. In Early Young-Adult (age
<35), increased PP is associated with a lower CAVI value whereas in
the Elderly (age >59), increased PP is associated with a higher CAVI
value. For SBP and DBP, the figure also demonstrated that blood
pressure indices have an increasingly positive association with CAVI
values as age increases.
4. Discussion
In this study, we found various increased trends with different
stages of age in healthy adults. Age-related progression of arterial
Table 2
Coefficient increments (Db) of piecewise linear regressions of CAVI on the stages of
age.
Stages of age Men Women
(yrs)
Db b P value Db b P
coefficients coefficients coefficients coefficients value
<35 0.07062 0.07062 <0.0001 0.03342 0.03342
35e44 0.03929 0.03133 0.0037 0.01317 0.02025
45e59 0.00707 0.03840 0.3990 0.02801 0.04826
>59 0.03432 0.07272 0.0008 0.05778 0.10604
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149
stiffness could be better explained by a growth curve, rather than a
straight line. In addition, blood pressure indices have an increas-
ingly positive association with CAVI values as age increases, which
further demonstrated the changed progression of arterial stiffness
along with aging.
Arterial aging is caused by various mechanisms. The principal
structural change is medial degeneration, which leads to the pro-
gressive stiffening of the large elastic arteries [2]. Longstanding
arterial pulsation in the central artery has a direct effect on the
structural matrix proteins, collagen and elastin in the arterial wall,
which disrupts muscular attachments and causes elastin fibers to
fatigue and fracture [7]. Accumulation of advanced glycation end-
products on the proteins also alters their physical properties and
causes stiffness of the fibers [15]. Another major change in the
arterial wall that comes with age is the calcium deposition, which
might contribute to the loss of arterial distensibility [16]. Endo-
thelial dysfunction is a characteristic of arterial aging, triggered by a
decrease in antioxidative capacity and an increase in oxidative
stress [17,18]. Increased stiffness of vascular smooth muscle cells
have also been reported to mediate aging-related vascular stiffness
by increasing adhesion molecule expression [19,20]. All of these
changes in the arterial structure will appear normally as subject
age; however, having cardiovascular risk factors will increase the
age-related progression of arterial stiffness [21e23].
Middle-aged Adult and the Elderly in women have higher CAVI
increment than that of their male counterparts of the same age
group. This phenomenon may be connected to studies done on
women who experience higher risk of cardiovascular disease after
menopause [24,25], a process that begins around age 50. Re-
searchers connected this pattern to decreasing levels of the female
hormone estrogen during menopause [26,27]. Estrogen has been
shown to prevent paradoxic vasoconstriction [28], and protect
phospholipids residing in the plasma membrane of vascular
smooth muscle cells from peroxidation and peroxidation-induced
cell growth and migration [29]. In addition, its beneficial effects
on the lipid profile, with significant elevations in high density li-
poprotein cholesterol and reductions in low density lipoprotein
cholesterol have also been reported [30,31]. However, further
studies are needed to establish the connection of female rapid CAVI
increments with menopause and to clarify its mechanics.
We also observed a steep gradient of increasing CAVI values in
the Early Young-Adults group of men. However, we failed to show a
clear mechanism linking this stage of age with rapid increment of
arterial stiffness in a healthy population, although several possi-
bilities unrelated with clinical factors have been proposed. A study
[32], performed by researchers at the School of Public Health in
Berkeley, U.S.A., found that the stress from a very demanding job for
a subject who is highly reactive to stress resulted in the thickening
of the internal walls of the carotid arteries and formation of
atherosclerotic plaques, which progressively obstructed blood flow.
Both factors are markers of the progression of atherosclerosis.
Cigarette smoking can also result in a several-fold increase in the
risk of peripheral arterial disease [33,34] and at least a two-fold
increase in the risk of coronary artery disease [35]. These two
major forms of cardiovascular disease associated with smoking are
the sequelae of atherothrombosis [36]. Further research is needed
to determine in which physiological factors or social environmental
factors are the cause for male youths to have an acute increment for
arterial stiffness.
A growth curve is an empirical model of the evolution of a
quantity over time and was widely used in various anthropometric
0.0001 parameters among children to describe their properties as they
0.3024 aged [37,38]. However, most age-related associations with clinical
0.0004 indices could not be shown by a growth curve, especially in adults,
0.0003
because they do not show significant increases with time. Arterial
150 W. Wen et al. / Atherosclerosis 238 (2015) 147e152

Fig. 1. Linear, piecewise linear and curvilinear regressions of cardio-ankle vascular index (CAVI) on age for men and women, with the solid lines as fitted regression lines.

Table 3
Multiple linear regression analysis showing the interaction between age and BP indices with CAVI as independent variables.

Variables Model1 Model2 Model3

Standardized b coefficients P value Standardized b coefficients P value Standardized b coefficients P value

Age 0.53464 <0.0001 0.53964 <0.0001 0.52119 <0.0001

Sex 0.05344 0.0143 0.04661 0.0338 0.05907 0.0068
height 0.27080 <0.0001 0.27115 <0.0001 0.26980 <0.0001
Weight 0.32824 <0.0001 0.33909 <0.0001 0.32133 <0.0001
WC 0.09602 0.0001 0.10120 <0.0001 0.09625 0.0001
TG 0.03945 0.0017 0.03698 0.0035 0.04007 0.0015
FPG 0.02527 0.0374 0.02705 0.0265 0.02613 0.0313
UCr 0.10908 <0.0001 0.10982 <0.0001 0.10714 <0.0001
SBP 0.20432 <0.0001 e e e e
Age  SBP 0.25313 <0.0001 e e e e
DBP e e 0.07999 0.0264 e e
Age  DBP e e 0.12098 0.0006 e e
PP e e e e 0.20449 <0.0001
Age  PP e e e e 0.23407 <0.0001

Each of the three models only includes one of blood pressures (SBP, DBP and PP) and its interaction term with age.
WC: waist circumference. SBP: systolic blood pressure. DBP: diastolic blood pressure. PP: pulse pressure, was calculated as SBP - DBP. TG: triglyceride. FPG: fasting blood
glucose.
UCr: urine creatinine.

stiffness is strongly associated with age. Our findings indicated that
the function fitting effects of the curvilinear regression and the
piecewise linear regression were similar and both were above 0.9,
which suggested that the two models could represent reality well.
In our study, we opted to use the conventional classification of age;
with young adults, middle-aged adults and the elderly in piecewise
regression function. However, due to the method limitation, if a
different classification between stages of age was used, then a
different trend between arterial stiffness and stages of age would be
displayed. We considered that the growth curve of curvilinear
regression to closely represent the nature of the growth progres-
sion of arterial stiffness.
The relative importance of the various components of blood
pressure in predicting cardiovascular disease risk has undergone
several changes. Initially, DBP was regarded to be the best measure
of risks [39,40]. However, SBP was later thought to be a more
powerful predictor of cardiovascular disease risk than DBP due to
the advantage of SBP having a closer correlation to age [41,42]. PP
has generally attributed to arterial stiffening. Since Bramwell and
Hill [43] first drew attention to the association of PP and arterial

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 W. Wen et al. / Atherosclerosis 238 (2015) 147e152
Fig. 2. Interactions between the four stages of age and blood pressure on CAVI, with the slope of each regression line representing the relationship between blood pressure and CAVI
at each stage of age. Line denoted with an asterisk (*) are lines with a slope is significant at 0.05. Each blood pressure values was centered around its mean.
stiffness, large epidemiological studies have confirmed a positive
correlation between PP and PWV along with their detailed mech-
anisms [44,45].
Arterial stiffness is greater in high SBP, high DBP, and high PP
individuals [46,47]. However, the effect of normal blood pressure
on arterial stiffness is not clear. For normal adults, age-related in-
creases in blood pressure are mainly attributable to an increase in
SBP while maintaining or having a slight decrease in DBP, which
also leads to a widening in PP [48]. Research has shown that a low
DBP may be an early marker of increased SV and/or arterial stiffness
in young adults [49]. However, Su-Yeon Choi et al. [7] have found
age-associated arterial stiffness would increase without any blood
pressure changes in the healthy population. In our study, we found
that SBP, DBP and PP have an increasingly positive association with
CAVI values as subjects age, and that elevated PP might be associ-
ated with reduced CAVI in young adults. This suggests that the
cardiovascular system of young adults may be capable of adapting
to the normal increase of blood pressure; and as people age, the
structural change of the vessel wall, such as compliant elastin fibers
degeneration and deposition of stiffer collagen, will possibly in-
crease the association between blood pressure and arterial
stiffness.
The analysis was based on a medical examination data, where
most of the subjects enrolled in the research have already entered
the workplace. Therefore, there were only 115 adults who were less
than 26 years old, rendering the sample size small for subjects aged
from 20 to 25. In addition, many elderly subjects did not meet the
requirements for being healthy, and thus were also excluded from
our study, leaving the sample size for subjects aged 65 to 75 also
small. Due to these reasons, the trends among the ends of regres-
sion line may contain a larger margin of error due to the lacking of
sufficient representativeness in subjects within those ages.
Furthermore, owing to the deficient of information on the life style
our subjects choose to live, we did not assess the effect of smoking,
work stress, and other life style related factors on arterial stiffness,
and so we do not know whether our results are applicable to all
healthy population. Finally, because we were unable to collect the
prospective data, the age-related progression of arterial stiffness
reported in our study may contain limitations caused by the design
of the cross-sectional study.
Conflicts of interest
None.
Acknowledgments
The authors would like to thank the Medical Examination
Center in the Chongqing Medical University for the data collection,
and also of the help from teachers and students of the Medical
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151
Statistics department in the School of Public Health of Chongqing
Medical University.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.atherosclerosis.2014.10.089.
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