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Atherosclerosis 166 (2003) 303 /309

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Influences of age and gender on results of noninvasive brachial ankle /

pulse wave velocity measurement* a survey of 12 517 subjects /

Hirofumi Tomiyama a, Akira Yamashina a,*, Tomio Arai a, Kenichi Hirose a,


Yutaka Koji a, Taishiro Chikamori a, Saburoh Hori b, Yoshio Yamamoto c,
Nobutaka Doba d, Shigeaki Hinohara d
a
The Second Department of Internal Medicine, Tokyo Medical University, 6-7-1, Nishi-shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
b
The Preventive Medical Center, St. Luke’s International Hospital, Tokyo, Japan
c
The Health Care Center, Kajima Corporation, Tokyo, Japan
d
The Life Planning Center, Tokyo, Japan

Received 7 February 2002; received in revised form 26 March 2002; accepted 29 August 2002

Abstract

The present study was conducted to evaluate the influences of age and gender on the results of noninvasive brachial /ankle pulse
wave velocity (baPWV). In 12 517 subjects who had no medication and no history of cardiovascular diseases, multiple regression
analysis demonstrated that age, blood pressure, body mass index, triglycerides, blood glucose, and uric acid were significant
variables for baPWV in both genders. From this population, we extracted 7881 ‘healthy subjects’ (4488 males and 3393 females, 25 /
87 years) without any of the atherogenic risk factors, and the results of baPWV were analyzed chronologically in 5-year age
intervals. baPWV was lower in females than in males until age 60, and became similar in both genders over age 60. Multiple
regression analysis demonstrated that not only the value of R2 but also the coefficient of the effect of age on baPWV are larger in
females than in males. In the estimation of the regression curve, the relationship between age and baPWV demonstrated a quadratic
curve in both genders. Thus, aging influences baPWV, and its effect is more prominent in female. Menopause seems to be the crucial
phenomenon to explain the augmented increase in arterial stiffness with aging in females.
# 2002 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Pulse wave velocity; Age; Gender; Pulse pressure

1. Introduction Contrary to carotid-femoral PWV, baPWV includes


peripheral components of the arterial tree. Because the
Increasing arterial stiffness is one of pathological influence of age differs in different parts of the arterial
states of vascular damages, and is closely associated tree [8], a proper evaluation of the influence of age and
with atherosclerotic cardiovascular diseases [1]. Pulse gender on baPWV is mandatory. This information is
wave velocity (PWV) is known to be an indicator of indispensable to establish the application of baPWV as a
arterial stiffness [2,3] and a marker of vascular damages surrogate marker in the diagnosis and management of
[4,5]. While carotid-femoral PWV is an established atherosclerotic cardiovascular diseases.
method for measuring PWV [4,5], a simpler method of The present study was conducted to evaluate the
measuring brachial/ankle PWV (baPWV) is recently influences of age and gender on baPWV. However,
available [6,7]. We have demonstrated the validity and previous studies have demonstrated that conventional
reproducibility of baPWV and its potential use for atherosclerotic risk factors such as hypertension [9],
screening vascular damage in a large population [7]. diabetes mellitus [10], dyslipidemia [11], obesity [12], and
smoking [13] influence PWV. In this study, we first
verified the significance of these atherosclerotic risk
* Corresponding author. Tel.: /81-3-3342-6111; fax: /81-3-3342-
4820 factors on baPWV in over 12 000 subjects. Then, to
E-mail address: akyam@tokyo-med.ac.jp (A. Yamashina). eliminate these confounding factors, we extracted a
0021-9150/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 0 2 1 - 9 1 5 0 ( 0 2 ) 0 0 3 3 2 - 5
304 H. Tomiyama et al. / Atherosclerosis 166 (2003) 303 /309

population of ‘healthy subjects’ who had no athero- was 2.4% and intraobserver CV (n /17) was 5.8%. In
sclerostic risk factors, and analyzed the baPWV by patients with coronary heart diseases, interobserver CV
gender and by 5-year age intervals (from age 25 to over (n /18) was 8.4% and intraobserver CV (n /41) was
70). 13.3%. CV in reproducibility of heart-brachial PWV
measured in the same subjects as for baPWV were as
follows. In healthy subjects, the interobserver (n /15)
2. Methods and intraobserver (n/17) CV were 3.1 and 9.1%,
respectively. In patients with coronary heart diseases,
2.1. Instruments the interobserver (n /18) and intraobserver CV (n /41)
were 10.7 and 11.7%, respectively.
Brachial /ankle PWV was measured using a volume- In all the studies, baPWV and heart-brachial PWV
plethymographic apparatus (form PWV/ABI, Colin Co. were obtained after at least 5 min rest.
Ltd, Komaki, Japan). This instrument records PWV,
blood pressure, electrocardiogram, and heart sounds 2.2. Subjects
simultaneously [6,7]. The subject was examined in
supine position. Electrodes of electrocardiogram were First, a total of 12 517 subjects (age range: 25/87
placed on both wrists, a microphone for detecting heart years) were recruited from those who underwent annual
sounds was placed on the left edge of sternum, and cuffs health screening examinations (including the measure-
were wrapped on both brachia and ankles. The cuffs ment of baPWV) at Tokyo Medical University Hospital
were connected to a plethymographic sensor that or its affiliated institutes. Informed consent was ob-
determines volume pulse form and an oscillometric tained from all subjects. The medical history and
pressure sensor that measures blood pressure. The pulse symptoms of each subject were confirmed by the
volume waveforms were recorded using a semiconductor consulting doctor. All the subjects were not on medica-
pressure sensor (the sample acquisition frequency for tion; had no medical history of atherogenic diseases,
PWV was set at 1200 Hz). cardiovascular diseases, renal insufficiency (serum crea-
Volume waveforms for the brachium and ankle were tinine ‘/1.5 mg/dl), or other diseases requiring medical
stored for a sampling time of 10 s with automatic gain treatment; and had a normal ankle/brachial pressure
analysis and quality adjustment. Sufficient waveform index determined form PWV/ABI ( /0.9). Among these
data were obtained in this stored sample. McDonald subjects, 7881 ‘healthy subjects’ with no atherosclerotic
reported that the mean value of the phase velocity above risk factors were extracted for further analysis of
2 /2.5 Hz was very close to the wave front velocity [14]. baPWV by gender and by age. A ‘healthy subject’ was
The characteristic points of waveforms were determined defined by the following criteria: blood pressure B/140/
automatically according to this phase velocity theory. 90 mmHg, fasting blood glucose B/110 mg/dl, total
The components over 5 Hz were stored using pass-filter cholesterol B/240 mg/dl, triglycerides B/150 mg/dl, uric
and the wave front was determined. The time interval acid B/7.5 mg/dl, body mass index B/25, and no history
between the wave front of brachial waveform and that of smoking.
of ankle waveform was defined as the time interval
between brachium and ankle (DTba). The distance
between sampling points of baPWV was calculated 2.3. Laboratory measurements
automatically according to the height of the subject.
The path length from the heart to the brachium (Lb) Plasma total cholesterol, high-density lipoprotein
was obtained from superficial measurements and was cholesterol, triglycerides, uric acid, and blood sugar
expressed using the following equation: Lb /0.2195 / levels were measured enzymatically. All blood samples
height of the patient (cm)/2.0734. The path length were obtained in a fasting state in the morning.
from the heart to ankle (La) was expressed using the
following equation: La /(0.8129 /height of the patient 2.4. Statistics
(cm)/12.328). Finally, baPWV was calculated from the
following equation: baPWV /(La/Lb)/DTba. Data are expressed as mean9/SD. Statistical analysis
The time interval between the foot of second heart was performed using the SPSS software package (SPSS,
sound and the dicrotic notch of brachial waveform was Chicago, IL). Difference between two groups were
defined as the time interval between heart and brachium evaluated by Wilcoxon’s test. Linear regression analysis
(DThb). Heart-brachial PWV was obtained using the was performed to evaluate the association between
following equation: heart-brachial PWV /Lb/DThb. baPWV and other clinical variables. Then, step-wise
As previously mentioned [7], the coefficients of multiple regression analysis was performed to determine
variation (CV) in reproducibility of baPWV were as the correlation and independent variables for baPWV. A
follows. In healthy subjects, interobserver CV (n/15) value of P B/0.05 was considered statistically significant.
H. Tomiyama et al. / Atherosclerosis 166 (2003) 303 /309 305

Table 1 Table 3
Anthoropometrics in all participants (n 12 517) Results of step-wise multiple regression analysis to assess the correla-
tion of baPWV with other variables in all subjects (n 12 517)
Gender Male Female P -value
Covariate Beta t -value P -value R2
Number 8227 4290
Age 45911 45912 ns In male 0.56
SBP (mmHg) 126915 117916 P B 0.01 Age 0.32 34.13 0.01
DBP (mmHg) 80910 72910 P B 0.01 SBP 0.35 16.45 0.01
MBP (mmHg) 96912 89913 P B 0.01 DBP
PP (mmHg) 4698 4599 P B 0.01 MBP 0.22 9.82 0.01
baPWV (cm/s) 12909249 11669244 P B 0.01 PP Ns
BMI (kg/m2) 2494 2193 P B 0.01 BMI 0.08 9.85 0.01
TC (mg/dl) 195930 200934 P B 0.01 TC Ns
HDL (mg/dl) 57913 73915 P B 0.01 HDL Ns
TG (mg/dl) 113977 71938 P B 0.01 T/HR Ns
T/HR 3.691.0 2.990.7 P B 0.01 TG 0.04 5.20 0.01
FBS (mg/dl) 95917 91910 P B 0.01 FBS 0.43 5.20 0.01
UA (mg/dl) 6.091.2 4.490.9 P B 0.01 UA 0.36 4.22 0.01
Smoke 3097 515 P B 0.01 Smoke Ns
In female 0.70
Abbreviations: SBP, systolic blood pressure; DBP, diastolic blood
Age 0.37 34.79 0.01
pressure; MBP, mean blood pressure; PP, pulse pressure; baPWV,
SBP 0.39 15.08 0.01
brachial /ankle pulse wave velocity; BMI, body mass index; TC,
DBP Ns
plasma level of total cholesterol; HDL, plasma level of high-density
MBP 0.19 7.17 0.01
cholesterol; T/HR, total cholesterol and high-density cholesterol ratio;
PP Ns
TG, plasma levels of triglycerides; FBS, fasting blood glucose; UA,
BMI 0.09 9.09 0.01
plasma level of uric acid; Smoke, number of subjects having history of
TC Ns
smoking.
HDL 0.02 2.44 0.01
T/HR Ns
3. Results TG 0.03 3.12 0.01
FBS 0.04 4.02 0.01
Table 1 depicts the anthropometrics of all 12 517 UA 0.04 4.45 0.01
Smoke Ns
participants.
Table 2 depicts the coefficients of correaltion in linear Abbreviations: SBP, systolic blood pressure; DBP, diastolic blood
regression analysis between baPWV and other clinical pressure; MBP, mean blood pressure; PP, pulse pressure; BMI, body
variables in all participants. This analysis showed that mass index; TC, plasma level of total cholesterol; HDL, plasma level of
high-density cholesterol; T/HR, total cholesterol and high-density
hemodynamic variables and parameters reflecting either cholesterol ratio; TG, plasma levels of triglycerides; FBS, fasting
blood glucose; UA, plasma level of uric acid; Smoke, subjects having
history of smoking.
Table 2
Coefficients of correlation from linear regression analysis between
baPWV and other clinical variables in all subjects (n 12 517) atherosclerotic risk factors or metabolic disorders cor-
related with baPWV in both genders. Table 3 depicts the
Correlates Male Female
results of step-wise multiple regression analysis between
Age 0.50a 0.68a baPWV and other clinical variables in both genders. Age
SBP 0.61a 0.75a and blood pressure variables were potent significant
DBP 0.61a 0.68a variables for baPWV, and body mass index, triglycer-
MBP 0.64a 0.75a
PP 0.34a 0.60a ides, uric acid, and fasting blood sugar were significant
BMI 0.04a 0.26a but weak variables for baPWV in both genders.
TC 0.15a 0.34a To study the effect of gender and age on baPWV,
HDL 0.03a 0.05a confounding factors were eliminated by extracting a
T/HR 0.07a 0.30a
TG 0.12a 0.33a group of healthy subjects (n /7881) free of the athero-
FBS 0.18a 0.33a sclerotic factors. Table 4 depicts the anthropometrics of
UA 0.12a 0.27a 7881 healthy subjects (4488 males and 3393 females; age:
Abbreviations: SBP, systolic blood pressure; DBP, diastolic blood
439/11 years, range: 25/87 years) by chronological
pressure; MBP, mean blood pressure; PP, pulse pressure; BMI, body classification. While systolic and diastolic blood pres-
mass index; TC, plasma level of total cholesterol; HDL, plasma level of sures were lower in females than in males aged B/60
high-density cholesterol; T/HR, total cholesterol and high-density years, systolic blood pressure was similar in both
cholesterol ratio; TG, plasma levels of triglycerides; FBS, fasting
blood glucose; UA, plasma level of uric acid.
genders from age 60. Females were shorter than males
a
P B 0.01. in all age groups.
306 H. Tomiyama et al. / Atherosclerosis 166 (2003) 303 /309

Table 4
Anthropometrics in healthy subjects (n 7881) in chronological classification

Age (yr) 25 /29 30 /34 35 /39 40 /44 45 /49 50 /54 55 /59 60 /64 65 /69 70 /

Numb
m 158 1037 875 574 504 590 415 194 79 62
f 168 781 722 531 383 368 239 101 50 50
Height (cm)
m 17296 17396 17296 17295 17096 17096 16896 16895 16695 16496
f 16095a 16095a 16095a 15995a 15895a 15795a 15695a 15595a 15495a 15296a
BMI (kg/m2)
m 2292 2292 2292 2392 2392 2392 2392 2392 2392 2292
f 1992a 2092a 2092a 2092a 2192a 2192a 2192a 2192a 2192a 2092b
SBP (mmHg)
m 11999 11999 11999 11999 12099 12199 122910 12299 12399 124911
f 10899a 10899a 10999a 11299a 114911a 116910a 119911b 120911 122911 124911
DBP (mmHg)
m 7197 7396 7496 7597 7797 7896 7896 7996 7996 7797
f 6596a 6696a 6897a 7097a 7198a 7298a 7497a 7498a 7598a 7496a
HR (bpm)
m 63910 6299 64910 6499 6499 6499 6399 6399 64911 64911
f 64910 6499a 67910a 6699a 66910a 6599b 66910a 6598b 68910b 71910a
TC (mg/dl)
m 176924 180923 183923 190923 191924 193923 195922 194922 197923 196922
f 178926 177923b 186924b 187924b 196925a 204923a 207922a 209919a 201923 209920a
HDL (mg/dl)
m 59910 58910 58912 59913 61913 59912 60913 62914 62914 63916
f 72913a 72913a 74914a 73915a 73915a 75915a 74915a 74915a 70913a 71915a
T/HR
m 3.190.6 3.290.7 3.290.7 3.490.8 3.390.8 3.490.7 3.490.7 3.390.7 3.490.7 3.290.7
f 2.590.6a 2.590.5a 2.690.5a 2.690.6a 2.890.6a 2.890.6a 2.990.6a 2.990.6a 2.990.5a 3.090.7
TG (mg/dl)
m 77928 78929 83929 85929 85929 87930 87927 84924 81931 81928
f 54918a 54923a 57921a 61925a 68927a 68925a 73929a 73925a 76925 86928
FBS (mg/dl)
m 8996 8997 9298 9298 9398 9599 9599 98910 9799 9698
f 8696a 8696a 8996a 9097a 9198a 9297a 9399a 96910 9497b 9599
UA (mg/dl)
m 5.790.9 5.790.9 5.790.9 5.890.9 5.891.0 5.791.0 5.691.0 5.791.0 5.990.9 5.690.9
f 4.190.8a 4.190.8a 4.190.8a 4.290.8a 4.290.8a 4.490.9a 4.590.9a 4.590.8a 4.690.8a 5.091.0b

Abbreviations: Numb, number of subjects; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rates;
TC, plasma level of total cholesterol; HDL, plasma level of high-density cholesterol; T/HR, total cholesterol and high-density cholesterol ratio; TG,
plasma levels of triglycerides; FBS, fasting blood glucose; UA, plasma level of uric acid; m, male; f, female.
a
P B 0.01 vs. male.
b
P B 0.05 vs. male.

Fig. 1 depicts the chronological changes in pulse Table 5 depicts the results of step-wise multiple
pressure, mean blood pressure, heart-brachial PWV, regression analysis between baPWV and other clinical
and baPWV. While pulse pressure was lower in fe- variables in both genders. Age is an independent
males than in males until age 45, it was higher in females variable for baPWV. Blood pressure, but not pulse
than in males from age 55. On the other hand, baPWV pressure, was a significant variable for baPWV in both
was lower in female than in male until age 60, and genders. In addition, not only the value of R2 in the
was similar in both genders from age 60. Heart-brach- regression analysis, but also the coefficient of the effect
ial PWV was higher in male than in female in all of age on baPWV is larger in female than that in male.
ages. In estimation of the regression curve, the relationship
H. Tomiyama et al. / Atherosclerosis 166 (2003) 303 /309 307

Fig. 1. Chronological changes in baPWV, heart-brachial PWV, mean blood pressure, and pulse pressure in both genders. Abbreviation: Open circle
represents female and closed circle represents male. hbPWV, heart-brachial pulse wave velocity, baPWV, brachial /ankle pulse wave velocity, MBP,
mean blood pressure, PP, pulse pressure. *P B/0.05 between male and female, **P B/0.01 between male and female.

between age and baPWV demonstrates a quadratic chronological analysis of the influence of age on PWV.
curve in both genders as follows: Therefore, an impeccable conclusion about the influence
of age on PWV could not be arrived from these studies.
Male: baPWV /0.20 /age2/12.13 /age/1341.34 On the other hand, aging increases the incidence of
(R2 /0.16, P B/0.01) atherogenic metabolic disorders [19]. These disorders
Female: baPWV /0.16 /age2/4.40 /age/977.52 influence baPWV [9 /12]. In the present study, a multi-
(R2 /0.37, P B/0.01) ple regression analysis demonstrates that these influ-
ences on baPWV are weak, but significant.
Consequently, to evaluate the influence of age on
4. Discussion baPWV, we extracted a population of apparently
healthy subjects who had no atherogenic and metabolic
It is well noted that menopause aggravates the disorders.
progression of atherosclerotic cardiovascular diseases Our series consisted of more than 7000 healthy adult
[15]. Arterial stiffness plays important roles in the subjects and allowed a rather fine chronological classi-
development of atherosclerosis [1]. While it is logically fication at 5-year age intervals, spanning age 25 to over
possible that the progression of arterial stiffness with 70 years. The chronological evaluation of baPWV in
age differs in males and females, several studies reported males and females clearly demonstrated that age influ-
that aging increases arterial stiffness similarly in both ences baPWV differently in both genders, and the
genders [16 /18]. However, these studies included pa- augmentation of arterial stiffness with aging is more
tients with hypertension. Elevated blood pressure is an prominent in female.
important determinant of PWV [9]. The numbers of Aging induces structural and functional abnormalities
subjects in the previous studies were also too small for such as arterial wall hypertrophy and degeneration or
308 H. Tomiyama et al. / Atherosclerosis 166 (2003) 303 /309

Table 5 contain more muscular component and central sites


Results of step-wise multiple regression analysis to assess the correla- contain more elastic component [15,23]. Not only
tion of baPWV with other variables in healthy subjects (n 7881)
estrogen receptor, but androgen receptor also has been
Covariate Beta t -value P -value R2 demonstrated in vascular smooth muscle cell [24,25].
Accordingly, it is possible that the influence of age on
In male 0.29 peripheral sites and central sites in the arterial tree is
Age 0.10 3.00 0.01
SBP ns
different in males and females. In the present study, the
DBP 0.20 3.12 0.01 heart-brachial PWV assessed peripheral sites in the
MBP 0.33 5.32 0.01 upper limb and baPWV assessed peripheral sites in the
PP ns lower limb and central site. While the chronological
BMI 0.09 3.00 0.01 change of baPWV was more marked in female, heart-
TC ns
HDL ns
brachial PWC was higher in males than in females at all
T/HR ns ages. Thus, the augmentation of arterial stiffness with
TG ns aging might be prominent in central sites (aorta) and/or
FBS ns peripheral sites in lower extremities in females. Using
UA ns phase-contrast magnetic resonance imaging, Rogers et
Smoke ns
al [26] demonstrated that age-associated increase in
In female 0.42 aortic PWV primarily affecting the proximal sites.
Age 0.25 5.81 0.01
SBP 0.30 3.79 0.01
Recently, pulse pressure has been focused as an
DBP ns independent risk for cardiovascular diseases [27]. Left
MBP 0.22 2.62 0.01 ventricular ejection and vascular component determine
PP ns the pulse pressure [28]. In this vascular component,
BMI ns arterial stiffness and arterial wave reflection are pre-
TC ns
HDL ns
dominant factors [17,28]. In this study, baPWV reflect-
T/HR ns ing arterial stiffness was lower in female than in male
TG ns until age 60, and became similar in both genders after
FBS ns age 60. On the other hand, while pulse pressure was
UA ns lower in female than in male until age 50, it was higher
Smoke ns
in female than in male over age 50. Thus, the increase of
Abbreviations: SBP, systolic blood pressure; DBP, diastolic blood pulse pressure with age does not parallel the increase of
pressure; MBP, mean blood pressure; PP, pulse pressure; BMI, body baPWV. This phenomenon was similar to the report of
mass index; TC, plasma level of total cholesterol; HDL, plasma level of Smulyan et al. [17]. They demonstrated that smaller
high-density cholesterol; T/HR, total cholesterol and high-density
cholesterol ratio; TG, plasma levels of triglycerides; FBS, fasting
physical characteristics are important determinants for
blood glucose; UA, plasma level of uric acid; Smoke, subjects having the increase of pulsality with age in female and was
history of smoking. independent of increasing arterial stiffness with age. In
our multivariate analysis, mean blood pressure, but not
disorganization of the medial layer [20,21]. These pulse pressure, was significantly associated with
changes increase PWV because of increased arterial baPWV. While PWV is an important factor for deter-
stiffness. In the present study, multivariate analysis mining pulse pressure, Meaume et al. [29] demonstrated
demonstrated that age is a more important determinant that carotid-femoral PWV is a predictor of cardiovas-
of baPWV in females than in males independent of cular death independent of pulse pressure. Thus,
blood pressure variables. Furthermore, baPWV is baPWV and pulse pressure seem to reflect different
increased in a quadratic manner around age 50 to 60s pathophysiological states in cardiovascular diseases.
in females. While we could not confirm the menopause
status in each individual, these results suggest that 4.1. Clinical implication and limitations
menopause is an important factor influencing arterial
Carotid-femoral PWV has been shown to be related
stiffness in healthy female subjects. Some studies de-
to atherosclerotic changes in carotid artery [4], and is a
monstrated that estrogen has beneficial effects on
useful marker for predicting prognosis in patients with
arterial stiffness [22]. The present study suggests that
either hypertension or renal insufficiency [30,31]. Thus,
the exhaustion of estrogen augments the age-related several studies have demonstrated that the assessment of
arterial stiffing. PWV is useful for the diagnosis and management of
In the arterial tree, atherosclerotic changes progress atherosclerotic cardiovascular diseases. While accumu-
independently in peripheral sites and central sites [23]. lated data tend to indicate that baPWV determination
Arterial stiffness reflects the changes of arterial wall may be a similar marker as carotid-femoral PWV [6,7],
degeneration [2,3]. In the arterial tree, peripheral sites the present study demonstrated significant influences of
H. Tomiyama et al. / Atherosclerosis 166 (2003) 303 /309 309

age and gender on baPWV. Further studies are needed [12] Toto-Moukouo JJ, Achimastos A, Asmar RG, Hugues CJ, Safar
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