925

Original Article

Relationship between Brachial-Ankle Pulse Wave

Velocity and Heart Rate Variability in
Young Japanese Men
Mutsuhiro NAKAO,, Kyoko NOMURA,, Kanae KARITA,
Mariko NISHIKITANI, and Eiji YANO

This study examined the relationship between arterial stiffness and autonomic nervous function in a young
population. A cross-sectional study was conducted on 382 Japanese males, aged 24 to 39 years, who worked
at the same information service company. Brachial-ankle pulse wave velocity (baPWV) was measured using
an automatic waveform analyzer, and the spectral power of heart rate variability in the low frequency (LF:
0.04 0.15 Hz) and the high frequency (HF: 0.15 0.40 Hz) band was evaluated by the maximum entropy
method. LF/HF and HF were used as the indicators of sympathetic and parasympathetic nervous activity, re-
spectively. Psycho-hormonal responses were examined by the Profile of Mood State (tension-anxiety and
anger-hostility scales) and Hamiltons Depression Scale with serum cortisol and catecholamine levels. In a
univariate analysis, baPWV was positively associated with the following variables (all p0.05): LF/HF, age,
body mass index, systolic and diastolic blood pressures, heart rate, serum total cholesterol and triglycerides,
blood glucose, and plasma cortisol and noradrenaline. Multiple regression analysis indicated that LF/HF was
an independent predictor of baPWV (p0.05), after controlling for significant effects of age, systolic blood
pressure, and plasma noradrenaline levels. There was no significant effect of HF on baPWV in this multivari-
ate analysis. Neither mood state nor health-related lifestyle factors such as smoking were significant. It was
suggested that baPWV is closely associated with sympathetic nervous activity in young men.
(Hypertens Res 2004; 27: 925 931)

Key Words: arterial stiffness, brachial-ankle pulse wave velocity, heart rate variability, mood state, stress

Introduction
Increased arterial stiffness is one of the pathological states of
vascular diseases, and is closely associated with atheroscle-
rotic cardiovascular diseases (CVD). Pulse wave velocity
(PWV) is known to be an indicator of this arterial stiffness,
and the measurement of brachial-ankle PWV (baPWV) has
recently been applied as a simple and reliable marker to
screen the general population for intensive prevention of
CVD (16).
It has been reported that major contributing factors to ba-
PWV were age, blood pressure (BP), and gender in a Japanese
population (3). A more recent study revealed that baPWV it-
self was an independent risk factor for the presence of CVD,
after adjusting for the significant effects of diabetes and hy-
perlipidemia in male Japanese patients (6). However, there
have been few studies focusing on the specific relationship
between baPWV and autonomic nervous function. If hyper-
activity of sympathetic nervous function were to be clearly

From the Department of Hygiene and Public Health, Teikyo University School of Medicine, Tokyo, Japan, and Division of Psychosomatic
Medicine, Teikyo University Hospital, Tokyo, Japan.
This work was supported partly by a grant from the Occupational Health Promotion Foundation (2003), Tokyo, Japan.
Address for Reprints: Mutsuhiro Nakao, M.D., M.P.H., Ph.D., Department of Hygiene and Public Health, Teikyo University School of Medicine, 2111
Kaga, Itabashi-ku, Tokyo, Japan. E-mail: mnakao@med.teikyo-u.ac.jp
Received June 3, 2004; Accepted in revised form August 18, 2004.
926 Hypertens Res Vol. 27, No. 12 (2004)
Fig. 1. Determination method of the front point of the
pulse-wave. The amplitude of the pulse wave (A) is defined
as the height from the bottom point to the peak point. To
draw a straight line (l), the x-intercept was set by going back
a definite amount of time (B) from the bottom point, and the
slope () was based on the value of A. The front point of
pulse-wave (F) was then determined as the most distant
point from the straight line (L), which is scanned between
the bottom point and inflexion point.
linked to the increase of baPWV, then preventive interven-
tions, such as relaxation training for lowering BP (710) and
for general stress management (11, 12), would be effective
for those with high CVD risks in the early stages. Moreover,
the 7th report of the Joint National Committee on the Pre-
vention, Detection, Evaluation, and Treatment of High
Blood Pressure (JNC 7) stated that those with 120139
mmHg systolic BP (SBP) or 8089 mmHg diastolic BP
(DBP) are to be regarded as prehypertensive and should
adopt lifestyle modifications while they are young (13, 14).
We therefore considered that it would be meaningful to clari-
fy the specific role of autonomic nervous function on ba-
PWV in a young population, and to take the effects of BP
and other CVD risk factors into account.
Analysis of heart rate (HR) variability has proven to be a
powerful tool in the investigation of autonomic control of the
heart and now is the most common method used to provide
non-invasive indicators of the autonomic nervous system
(15). The purpose of the present study was to examine the
relationship between baPWV and HR variability, utilizing
the routine health checkups in a cohort of workers.
Methods
Study Setting and Subjects
The investigation was carried out at 8:3011:30 AM be-
tween June and July, 2003 in the course of a periodic health
check-up in a Japanese information service company. The
company is located in the central area of Tokyo, and offers
Information-Technology (IT) consultation, system integra-
tion solutions, and data management. Because subjects did
not include blue-collar workers who were required to under-
go special examinations relating to their jobs, the examina-
tions were performed along with the regular employer-spon-
sored screening programs mandated by the Japanese Indus-
trial Safety and Health Law (16), which were done under
contract by the clinical staff of a medical company.
Among the approximately 1,000 employees, the 526 who
were younger than 40 years received annual check-ups in the
health center of the company. Those aged 40 years or older
were referred to an independent health examination center
outside the company. The check-ups were mandatory and
therefore the attendance rate was 100%. Female workers
were excluded from analysis because of the small sample
size (n89) and the hormonal effects of the menstrual cycle
on HR variance and other variables. Among the 437 male
subjects, those with arrhythmia in electrocardiograph (n
26) and those under treatment for coronary heart disease
(n5), hypertension (n2), diabetes mellitus (n2), or hy-
percholesterolemia (n1) were also excluded from the
analysis. In addition, 19 subjects with an ankle-brachial pres-
sure index (ABI) of less than 0.9 were excluded because
their low ABI range indicated that they would probably have
arteriosclerosis obliterans, which would result in a loss of
PWV (4, 17). Therefore, the final study group consisted of
382 male workers with a mean age of 30 years.
The study design was approved by the Committee of La-
bor and Safety in the company, and all participants provided
their written informed consent to participate.
baPWV
All the subjects were instructed to refrain from breakfast,
coffee, and smoking on the morning of the checkups in order
to obtain the most accurate data possible. baPWV, BP, and
ankle-brachial pressure index were simultaneously measured
using an automatic waveform analyzer (VaSera VS-1000;
Fukuda, Tokyo, Japan). Measurements were taken with sub-
jects lying in a supine position after resting for at least 5 min.
Occlusion and monitoring cuffs were placed around both
sites of the upper and lower extremities of subjects.
The pulse-wave sampling rate of the analyzer was 1 kHz.
By identifying both the peak and bottom points in the pulse-
wave cycle, the amplitude (peakbottom) was calculated,
and an inflection point (i.e., d2/dt2 wave-height0) was
mathematically determined between the bottom point and
peak point (Fig. 1). Between the bottom point and inflection
point of the pulse-wave, a front point was defined as the
most distant point from a straight line whose x-intercept was
set back from the bottom point by constant time and whose
slope was based on the value of the pulse-wave amplitude
(Fig. 1). This means of determining the wave front point is
an original method associated with the VaSera VS-1000 Sys-
tem, and has been submitted for a patent.
The time interval between the wave front of the brachial

waveform and that of the ankle waveform was defined as the
time interval between the brachium and ankle (Tba). The
path length from the heart to the brachium is referred to as
Lb, and that from the heart to the ankle is designated La.
(LaLb) was estimated automatically according to the body
height of the subject, using the following equation: LaLb
0.59body height (cm)14.2. baPWV was then calculated
as follows: baPWV(LaLb)/Tba. The mean of the right-
and left-sided baPWV at the second measurement was used
for analysis in the present study.
HR Variability
A regular screening for heart disease was then performed by
electrocardiography, and the RR interval data over a period
of 5 min were stored on a personal computer. To obtain sta-
ble data, only the RR intervals over the last 1 min were
used for analysis.
Spectral analysis using the maximum entropy method (18)
was applied to the time-series data of HR variability.
Although fast Fourier transform and the autoregressive
method have been widely used for spectral analysis, these
methods have some weaknesses, such as poor resolution due
to the effect of the window functions and the small lag time.
The maximum entropy method was developed to overcome
these disadvantages and was considered to have a high de-
gree of resolution despite the limited duration of data gather-
ing (19). Two frequency bands of interest were considered: a
low frequency (LF: 0.040.15 Hz) and a high frequency (HF:
0.150.40 Hz) band. LF/HF was considered to reflect sympa-
thetic nervous activity, and HF to reflect parasympathetic
nervous activity (7, 8, 20).
CVD Risk Factors
Based on the previous baPWV studies (3, 21, 22), the fol-
lowing physiological risk factors of CVD were assessed:
age, body mass index (BMI), BP, HR, serum total-choles-
terol (T-cho), serum triglyceride (TG), and fasting blood
sugar (FBS). In addition to these traditional CVD risk fac-
tors, plasma catecholamine (adrenaline, noradrenaline, and
dopamine) and cortisol levels were assessed. Because the
study was conducted in the setting of a routine health exami-
nation, a blood catheter was not used for measurement of
plasma catecholamine and cortisol levels. Instead, blood was
directly taken through the cubital vein after 15 min of supine
rest. T-cho, TG, and FBS were measured by standard labora-
tory techniques. After centrifugation by 1,500g for 10 min
at 4 C, the supernatant volume was stored at 40 C until
the assay. Plasma catecholamine was measured by routine
high-performance liquid chromatography (23), and plasma
cortisol was measured by radioimmunoassays (24).
Health-related lifestyle factors (alcohol consumption,
smoking, and lack of exercise) were also examined in this in-
terview. The three variables were dichotomized, with regular
Nakao et al: Pulse Wave Velocity and Heart Rate Variability 927
drinking once a week or more frequently, current smoking,
and irregular exercise of less than once a week defined as
positive (16).
Psychological Conditions
Considering the possible effects of mood states on autonom-
ic nervous function, two questionnaires, the Profile of Mood
States (POMS) and 21-item Hamilton Depression Scale
(HAM-D) were administered to each subject during the ex-
amination. The reliability and validity of the Japanese ver-
sion of the POMS have been examined (25, 26), and the
POMS tension-anxiety and anger-hostility scales were ana-
lyzed in this study. The HAM-D questionnaire assesses the
degree of depression, and has frequently been used in a clini-
cal setting, such as in trials of the pharmacological effects of
new antidepressants (27).
Statistical Methods
Data analyses were conducted using the SAS statistical
package (SAS Institute Inc., Cary, USA) (28). All the tests
were two-sided, and values of p<0.05 were considered to in-
dicate statistical significance.
First, Spearmans correlational analysis was conducted to
assess the association of baPWV with HR variability (LF/HF
and HF), cardiac risk factors, and psychological conditions,
because the distribution of baPWV was not found to be nor-
mal by Shapiro-Wilk test (p>0.05). Then, the values of HR
variability were transformed into four ordinal categories
(i.e., lowest, lower, higher, and highest) using the cut-off
points of three quartiles (25%, median, and 75%), and one-
way analysis of variance (Bonferroni method) was used to
analyze the differences in baPWV among the four groups.
This analysis was specifically intended to confirm the trend
of baPWV corresponding to the relative ranks of LF/HF and
HF, because it has often been pointed out that the absolute
values tend to vary greatly among subjects.
Finally, a multiple regression analysis was used to exam-
ine whether baPWV was independently predicted by LF/HF
or HF, after controlling for the significant effects of other
cardiovascular risk factors. Candidate predictors selected in
this multivariate model were the variables significantly cor-
related to baPWV by a simple correlational analysis.
Results
MeansSD of baPWV were 11.11.3 m/s, and ranged
from 8.2 to 16.5. baPWV was significantly and positively as-
sociated with LF/HF, age, BMI, SBP and DBP, HR, T-cho,
TG, FBS, and plasma cortisol and noradrenaline levels
(Table 1). In contrast, it was significantly and negatively as-
sociated with HF. Plasma adrenalin and dopamine levels,
POMS tension-anxiety and anger-hostility scores, HAM-D
scores, and health-related lifestyle factors of alcohol con-
928 Hypertens Res Vol. 27, No. 12 (2004)

Table 1. Associations of Brachial-Ankle Pulse-Wave Velocity (baPWV) with Heart Rate Variability and Physical, Psychologi-
cal and Behavioral Variables in 382 Young Men

Correlation to baPWVa
Variables MeansSD [range]
Coefficient p value
Continuous variables
Heart rate variability
Ratio of low to high frequency (LF/HF) 2.52.5 [0.115.8] 0.185 <0.0005
HF (ms2) 480.5588.0 [20.54,582] 0.20800 <0.0001
Physiological variables
Age 30.45.00 [2439] 0.380 <0.0001
Body mass index (kg/m2) 22.63.00 [16.234.3] 0.107 <0.0500
Systolic blood pressure (mmHg) 119.311.70 [92160] 0.390 <0.0001
Diastolic blood pressure (mmHg) 72.19.20 [50108] 0.367 <0.0001
Heart rate (beats/min) 64.310.1 [44102] 0.266 <0.0001
Serum total cholesterol (mg/dl) 183.535.90 [93311] 0.221 <0.0001
Serum triglyceride (mg/dl) 109.583.50 [28814] 0.188 <0.0005
Fasting blood sugar (mg/dl) 89.711.2 [72250] 0.136 <0.0100
Plasma cortisol (pg/ml) 14.65.10 [0.635.4] 0.140 <0.0100
Plasma catecholamine (pg/ml)
Adrenaline 0.050.04 [0.010.65] 0.078 NSb
Noradrenaline 0.380.14 [0.111.30] 0.128 <0.0500
Dopamine 0.010.01 [0.010.06] 0.070 NS
Psychological variables, scores
POMS tension-anxiety 9.86.2 [035] 0.013 NS
POMS anger-hostility 6.06.7 [036] 0.064 NS
Hamilton depression scale 6.84.8 [027] 0.001 NS
Dichotomized variables (n (%))
Alcohol (1: >1 per week / 0: <1 per week) 288 (75%) / 94 (25%) 0.055 NS
Smoking (1: current / 0: past or never) 163 (43%) / 219 (57%) 0.001 NS
Lack of exercise (1: never / 0: >1 per week) 258 (68%) / 124 (32%) 0.001 NS

Spearmans correlation coefficient. NS, not significant (p>0.05).

sumption, smoking, and lack of exercise were not significant
(Table 1).
LF/HF was significantly associated with the following
CVD risk factors (Spearmans correlational coefficient): age
(0.149, p<0.005), BMI (0.129, p<0.01), SBP (0.177,
p<0.0005), HR (0.199, p<0.0001), T-cho (0.150, p<0.005),
TG (0.131, p<0.01), plasma adrenaline (0.132, p<0.01), and
plasma noradrenaline (0.111, p<0.05). As for HF, it was sig-
nificantly associated with age (0.404, p<0.0001), BMI
(0.189, p<0.0001), SBP (0.216, p<0.0001), DBP
(0.208, p<0.0001), HR (0.492, p<0.0001), T-cho
( 0.197, p<0.0001), TG ( 0.253, p<0.0001), FBS
(0.171, p<0.001), plasma cortisol (0.171, p<0.0005),
and lack of exercise (0.168, p<0.0005).
When LF/HF values were divided into four groups, the
mean values of baPWV were found to differ significantly
among the four groups by ANOVA. baPWV was significant-
ly increased with the increase of LF/HF by trend test (Fig.
2). When HF values were divided into four groups, the mean
values of baPWV were found to differ significantly among
the four groups by ANOVA. However, the trend was in-
significant (p>0.05) among the HF groups by trend test
(Fig. 2).
The multiple regression analysis indicated that LF/HF sig-
nificantly predicted baPWV after controlling for the effects
of cardiac risk factors (model 1 in Table 2), but failed to find
such significant associations between HF and baPWV (mod-
el 2 in Table 2). The effects of age, SBP, and plasma nora-
drenaline levels were significant in both models (Table 2).
Discussion
In the present study, baPWV was positively associated with
LF/HF, and negatively associated with HF by correlational
analysis. The trend was statistically confirmed between ba-
PWV and LF/HF, after dividing the values of LF/HF into four
ordinal categories. Furthermore, LF/HF significantly predict-
ed baPWV in the multivariate analysis, after adjusting for
age, SBP, and plasma noradrenaline levels. As far as we
know, this was the first human study to show a clear, quanti-
tative relationship between baPWV and sympathetic nervous
tone, after taking the effects of important variables such as
 Nakao et al: Pulse Wave Velocity and Heart Rate Variability 929

BP, HR, BMI, T-cho, and FBS into consideration. In support
of the present findings, recent studies have linked sympathet-
ic nervous system hyperresponsivity to accelerated develop-
ment of carotid atherosclerosis in human subjects and mon-
keys (2931). However, PWV is considered to assess func-
tioning of both muscular and elastic arteries, and the results
of the present studies did not permit any conclusions as to
whether hyperactivity of the sympathetic nervous system
Fig. 2. Effects of the ratio of low to high frequency (LF/HF)
and high frequency (HF) of heart rate variability on
brachial-ankle pulse-wave velocity (baPWV). LF/HF was di-
vided into four groups according to the 25, 50, and 75 per-
centiles: a lowest group (n99, LF/HF<0.9), lower group
(n90, 0.9LF/HF<1.7), higher group (n92, 1.7LF/HF
<3.1), and highest group (n101, LF/HF3.1). HF was di-
vided into four groups according to the 25, 50, and 75 per-
centiles (ms2): a lowest group (n96, HF<134), lower
group (n 94, 134HF<301), higher group (n 93,
301HF<612), and highest group (n99, HF612). There
were significant main effects of LF/HF groups (F11.69,
p<0.0001) and HF groups (F14.63, p<0.0001) on baPWV
by one-way analysis of variance. LF/HF was also found to
have a significant effect through the trend test (p<0.05).
was associated with the stiffness of elastic arteries or
whether it was simply a reflection of the tension of muscular
arteries. Further studies will be needed to clarify the exact
mechanism mediating LF/HF and baPWV.
Contrary to the clear associations of baPWV with HR
variability and physiological variables, no psychological or
health-related lifestyle variables were significantly associat-
ed with baPWV in the present study. These results were un-
expected, since type A behavior patterns or specific mood
states like anger and hostility have been known to predict ar-
teriosclerosis (32, 33), and because we have speculated that
an accumulation of negative feelings and unhealthy lifestyle
factors causes arterial stiffness through hyperactivity of sym-
pathetic nervous function (34, 35).
A possible explanation for our findings was that hyperac-
tivity of the sympathetic nervous function might be mainly
affected by physiological conditions rather than by the psy-
cho-behavioral variables examined in the present study. This
interpretation might be supported by the results that both
LF/HF and HF were significantly associated only with physi-
cal CVD risk factors such as BMI, SBP, HR, T-cho, and TG
in the present study. The second possible explanation is that
the method used to monitor psychological and behavioral
conditions in the present study may have been inadequate to
detect a significant association between such stressed condi-
tions and autonomic nervous function. The monitoring of
more objective stressors, including excessive working hours
or workload, might be used to examine this possibility in a
future study (36).
Third, the significant associations between baPWV and
physiological variables without the contribution of psycho-
behavioral variables might be a phenomenon specific to
young subjects. Although many previous studies have shown
that psychological stress induces the elevation of BP and

Table 2. Predictors of Brachial-Ankle Pulse-Wave Velocity (n382): Results of Multiple Regression Analysis
Model 1a Model 2b
Independent variables c
Slope p value Slope p value
Heart rate variability (LF/HF or HF) 000.112 <0.0500 0.022 NSd
Age (years old) 000.242 <0.0001 000.248 <0.0001
Body mass index (kg/m2) 0.086 NS 0.092 NS
Systolic blood pressuree (mmHg) 000.378 <0.0001 000.343 <0.0001
Heart rate (beats/min) 000.060 NS 000.079 NS
Serum total cholesterolf (mg/dl) 000.058 NS 000.063 NS
Fasting blood sugar (mg/dl) 000.039 NS 000.048 NS
Plasma cortisol (pg/ml) 000.004 NS 000.011 NS
Plasma noradrenaline (pg/ml) 000.100 <0.0500 000.111 <0.0500
a
Ratio of low to high frequency (LF/HF) was adopted as an independent variable of heart rate variability in model 1 (r 20.314).
b
High frequency (HF) was adopted as an independent variable of heart rate variability in model 2 (r 20.300). c Slope: standardized
regression coefficient. d NS, not significant (p>0.05). e Concerning systolic and diastolic blood pressures, only systolic blood pressure
was adopted as an independent variable of blood pressure, considering colliniarity effects between both blood pressures. f Concerning
serum total cholesterol and triglyceride levels, only serum total cholesterol level was adopted as an independent variable of serum cho-
lesterol level, considering colliniarity effects between the two cholesterol levels.
930 Hypertens Res Vol. 27, No. 12 (2004)
other variables related to coronary artery disease (CAD) risk
factors in young adults, most of the studies used acute and
intermediate stress parameters such as an experimental stress
test and preparation for examination (3739). There is thus
an urgent need to determine the duration of chronic stress
needed to cause cardiovascular changes in the future. If such
changes require a long period of time, regular physical ex-
aminations would be sufficient to screen young adults with a
high risk of CAD.
Finally, the validity of measurement for baPWV should be
mentioned in the present study. In various large populations,
baPWV has been reported to be a valid, non-invasive
method of monitoring arterial stiffness (16, 40). However,
most of these studies were conducted using a plethysmo-
graphic apparatus (PWV/ABI; Colin Co., Ltd., Tokyo,
Japan) rather than using the system employed here; accord-
ingly, the validity of the present system should be studied in
the near future.
Through a thorough assessment of baPWV in a screening
examination, the monitoring of HR variability might be im-
portant for detecting individuals with high CAD risks at the
early stage.
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