Open Journal of Respiratory Diseases, 2013, 3, 25-30 Published Online February 2013 (
Leg Atherosclerosis in Japanese COPD Patients:
Prevalence of Undiagnosed Peripheral Artery Disease
and Association between Leg Atherosclerosis and
Clinical Indices
Hirofumi Matsuoka, Yusuke Matsumoto, Kengo Kimura, Midori Koyama,
Towa Uzu, Yasuko Koma, Kensuke Fukumitsu, Yoshitaka Kasai,
Nariyasu Nakashima, Daiki Masuya, Harukazu Yoshimatsu, Yujiro Suzuki
Department of Respiratory Medicine, Shinko Hospital, Kobe, Japan
Received September 25, 2012; revised October 28, 2012; accepted November 7, 2012
Introduction: Several studies have suggested that decreased FEV1 is associated with cardiovascular risk in COPD pa-
tients. Objective: To identify the prevalence of undiagnosed peripheral artery disease (PAD) and the relationship be-
tween leg atherosclerosis and clinical indices, which predict COPD mortality in Japanese COPD patients. Methods: We
performed a cross-sectional study in 51 COPD patients and 51 age-matched, healthy control smokers. We measured
ankle-brachial index (ABI) as a marker of atherosclerosis of the legs, pulmonary function, body mass index, modified
Medical Research Council (MMRC) dyspnea scale, and smoking pack-years. We also calculated the ADO index (Age,
Dyspnea, and Obstruction), an established predictor of mortality in COPD patients. Co-morbidities including diabetes
mellitus, hypertension, and hypercholesterolemia were identified from blood laboratory tests and medical records. Re-
sults: Five subjects (9.8%) had an ABI < 0.9. ABI was significantly lower in the COPD patients than in the healthy
control smokers (p < 0.05). The prevalence of PAD was marginally higher in COPD patients than in control smokers (p
= 0.09), with the prevalence of ABI < 1.0 being significantly higher in COPD patients than in control smokers (p =
0.04). In the COPD patients, ABI showed significant correlations with age (p = 0.006), FEV1 (p = 0.004), smoking
pack-years (p = 0.047), MMRC dyspnea scale (p = 0.0005), SaO2 (p = 0.001), and ADO index (p < 0.001). Multiple
linear regression modeling showed the factors associated independently with ABI were age, FEV1, smoking pack-years,
MMRC dyspnea scale, and SaO2. Conclusion: The risk of leg atherosclerosis in Japanese COPD patients is higher than
in smokers without COPD. Leg atherosclerosis in COPD patients is associated with clinical indices that predict COPD
Keywords: COPD; Peripheral Artery Disease; Leg Atherosclerosis; Ankle-Brachial Index
1. Introduction
Tobacco smoking is the most important risk factor for
both the development and progression of COPD. Chronic
obstructive pulmonary disease (COPD) is the fourth lead-
ing cause of death worldwide [1]. Recently, COPD has
been recognized as a systemic disease [2,3], and in par-
ticular, is associated with a markedly increased risk of
cardiovascular disease [4], which accounts for approxi-
mately 25% to 40% of mortality in COPD patients [5,6].
OPD is characterized by chronic airflow limitation re-
sulting from an excessive inflammatory response of the
lungs to cigarette smoking [7], an established risk factor
for cardiovascular disease. However, recent studies have
also shown that COPD is associated with cardiovascular
risk independent of classical risk factors [8-10]. Further-
more, several studies have demonstrated that atheroscle-
rosis is associated with FEV1 [11-14]. These findings in-
dicate that the severity of COPD is associated with athe-
Peripheral arterial disease (PAD) is a manifestation of
systemic atherosclerosis, and is a common disorder asso-
ciated with a very high risk of myocardial infarction, is-
chemic stroke, and death [15]. The prognosis of patients
with lower extremity PAD is characterized by an increa-
sed risk for cardiovascular ischemic events due to con-
comitant coronary artery disease and cerebrovascular
disease [16,17]. There is evidence that these cardiovas-
cular ischemic events are more frequent than ischemic
limb events in cohorts of patients with lower extremity
opyright © 2013 SciRes. OJRD
PAD [18]. Lower extremity PAD should therefore be con-
sidered as a sign of potentially diffuse and significant ar-
terial disease [15].
Several studies have reported that the rate of cardio-
vascular death in the smoking population in Japan is
lower than in other developed countries [19,20]. How-
ever, there are no data comparing the prevalence of PAD
in COPD patients and healthy smokers in the Japanese
population, and only limited data on the relationship be-
tween leg atherosclerosis and clinical indices in COPD
2. Method
2.1. Subjects Studied
Subjects with COPD with a smoking history and age-
matched control smokers were recruited from an outpa-
tient clinic at Shinko Hospital. The control smokers with-
out COPD were recruited from individuals treated at our
hospital for chronic bronchitis without lung function ab-
normalities, or for health status check-ups. Control smok-
ers were ex-smokers or current smokers without lung func-
tion abnormalities. An age-matched (within 1 year) con-
trol smoker was selected randomly for each subject with
COPD. Subjects with a history of respiratory infection
within the previous 4 weeks, asthma, or active malignan-
cy were not included in the study. Cardiovascular comor-
bidity was recorded carefully. Patients already diagnosed
with PAD were excluded from the study.
Body mass index (BMI) was calculated as weight (in
kilograms) divided by height squared (in meters). Hyper-
tension was defined as either a systolic blood pressure
140 mmHg, diastolic blood pressure 90 mmHg, or
self-reported use of antihypertensive medication. Diabe-
tes mellitus was defined as either a fasting glucose level
126 mg/dl, a non-fasting glucose level 200 mg/dl,
a self-reported physician diagnosis, or pharmacologic hy-
poglycemic treatment. Subjects with a low-density lipo-
protein (LDL)-cholesterol level 140 mg/dl or using li-
pid-lowering drugs were considered to have hypercholes-
terolemia. The subjects also completed a medical history
that included questions about their current smoking status
and history.
Spirometry was performed on all subjects using a com-
puted spirometer (CHESTAC-8800, CHEST M. I., Inc.,
Tokyo, Japan). The protocol for the lung function mea-
surements conformed to the recommendations of the Ame-
rican Thoracic Society [21]. This study was approved by
the Ethics Committee of Shinko Hospital, and informed
consent was obtained from all subjects prior to enroll-
2.2. Ankle-Brachial Index
The ABI is calculated as the ratio of ankle to arm systolic
blood pressure and is used commonly in clinical practice
to assess lower extremity PAD [15]. In all cases, the sub-
jects rested in the supine position for 5 min before meas-
urement of ABI. Using appropriately sized blood pres-
sure cuffs, systolic blood pressure was measured in both
brachial arteries and both leg arteries using an automated
device. All measurements were performed by staff in a
blinded manner. We used the measurement from the leg
with the lower ABI in the analyses.
2.3. Clinical Evaluation
Patients completed the modified Medical Research Coun-
cil dyspnea scale (MMRC) questionnaire [22]. The ADO
index is calculated using age, MMRC, and FEV1, and is a
better predictor of mortality from COPD than the tradi-
tional BODE index [23]. The ADO score ranges from 0
to 10 points, with higher scores indicating higher morta-
2.4. Statistical Analysis
JMP software (SAS Institute Inc., Cary, NC, USA) was
used for the analyses. The results are presented as mean
(SEM) or number (percentage). Differences between the
COPD patients and control smokers were compared us-
ing unpaired Student’s t-tests for continuous variables
and χ2-tests for categorical data. Spearman’s rank test
was used to examine correlations between the variables.
Multivariate linear regression was performed using each
parameter as a dependent variable in order to determine
the independent predictors of ABI. Due to the strong as-
sociation between age and SaO2, these variables were in-
cluded in separate models as candidate variables. P-va-
lues < 0.05 were considered statistically significant.
3. Results
3.1. Subject Characteristics
The characteristics of the subjects are shown in Table 1.
The mean age of the COPD subjects was 72.4 years. The
prevalence of ABI < 0.9 was marginally higher in the
COPD group than in the control group (9.8% vs 2.0%, p
= 0.092). The prevalence of ABI < 1.0 was significantly
higher in the COPD group than in the control group
(19.6% vs 5.9%, p = 0.037). FEV1, BMI, and ABI were
significantly lower in the COPD subjects compared to
the control smokers (all p < 0.05). Age, gender, smoking
status and pack-year histories, and prevalence of comor-
bidities were similar between the two groups.
The association of ABI with cardiovascular risk factors
and clinical indices
In the COPD patients, ABI correlated significantly
with age (r = 0.37, p = 0.006), FEV1 (r = 0.28, p =
0.004), smoking pack-years (r = 0.28, p = 0.047),
Copyright © 2013 SciRes. OJRD
Table 1. Characteristics of the subjects.
Control smoker
(n = 51) COPD (n = 51)P-value
Age (yr) 72.1 (7.4) 72.4 (6.8) 0.76
Male gender, n (%) 45 (88.2) 44 (84.6) 0.56
Current smokers, n (%) 15 (30.0) 8 (15.7) 0.084
Pack-years 55.9 (31.6) 60.0(34.5) 0.66
FEV1 (%) 95.4 (19.1) 47.2 (20.4) <0.001
BMI (kg/m2) 23.8 (3.4) 21.8 (3.5) 0.0042
ABI 1.13 (0.1) 1.07 (0.1) 0.0054
ABI < 0.9
ABI < 1.1
1 (2.0)
3 (5.9)
5 (9.8)
10 (19.6)
Comorbidity, n (%)
Hypertension 14 (27.5) 19 (37.3) 0.29
Diabetes mellitus 8 (15.7) 4 (7.8) 0.22
Hypercholesterolemia 13 (25.5) 7 (13.7) 0.075
Ischemic heart disease 7 (13.7) 3 (5.9) 0.19
Values are expressed as mean (SD) unless stated otherwise.
MMRC dyspnea scale (r = 0.47, p = 0.0005), resting
SaO2 (r = 0.45, p = 0.001) (Table 2), and ADO index (r =
0.51, p < 0.001) (Figure 1). There were no associations
between ABI and BMI, smoking status, prevalence of
comorbidities, or history of ischemic heart disease (Table
Multiple linear regression modeling, after adjustment
for age, FEV1, smoking pack-years, and MMRC dyspnea
scale, showed that age (p = 0.0046), FEV1 (p = 0.027),
smoking pack-years (p = 0.0018), and MMRC dyspnea
scale (p = 0.023) were independent factors associated
significantly with ABI (Table 4 (a)). Adjustment for SaO2,
FEV1, smoking pack-years, and MMRC dyspnea scale,
showed that SaO2 (p = 0.037), smoking pack-years (p =
0.037), and MMRC dyspnea scale (p = 0.013) were sig-
nificant independent determinants of ABI (Table 4 (b)).
4. Discussion
In this study we showed that the prevalence of undiag-
nosed PAD was approximately 10% in Japanese COPD
patients, a rate marginally higher than that of age-ma-
tched healthy control smokers. ABI in COPD patients
was lower than in healthy smokers. Age, MMRC, FEV1,
smoking pack-years, and SaO2 were associated with ABI
in COPD patients. There was also a negative correlation
between ABI and the ADO index, which predicts COPD
mortality. To our knowledge, this is the first report on the
prevalence of undiagnosed PAD in Japanese COPD pa-
tients and also the relationship between ABI and clinical-
Table 2. Association between continuous variables and ABI
analyzed by spearman’s rank test.
r p
Age 0.37 0.006
FEV1 0.28 0.004
BMI 0.079 0.58
Pack-years 0.28 0.047
MMRC 0.47 0.0005
SaO2 0.45 0.001
Table 3. Mean difference in ABI between the dichotomous
Current smoking 0.053 0.18
Hypertension 0.0077 0.30
Hyperlipidemia 0.046 0.79
Diabetes mellitus 0.0027 0.96
Ischemic heart disease 0.074 0.25
Table 4. Multiple linear regression of ABI. (a) Adjusted for
age, FEV1, pack-years, and MMRC; (b) Adjusted for SaO2,
FEV1, pack-years, and MMRC.
OR 95% CI p
Age 0.999 0.991 - 0.998 0.0046
FEV1 1.001 1.000 - 1.003 0.027
Pack-years 0.998 0.998 - 0.999 0.0018
MMRC 0.977 0.958 - 0.996 0.023
OR 95% CI p
SaO2 1.016 1.001 - 1.031 0.037
FEV1 1.000 0.999 - 1.072 0.34
Pack-years 0.999 0.998 - 0.999 0.037
MMRC 0.973 0.953 - 0.993 0.013
indices associated with COPD mortality.
Approximately 10% of COPD patients in this study
had an ABI < 0.9. There are only limited published data
on the prevalence of lower extremity PAD in COPD pa-
tients. A high prevalence of lower extremity PAD in
COPD patients was reported in a study from France, that
showed 123 of 151 (81.4%) of patients with moderate-
to-severe COPD had pathological ABI values (ABI < 0.9)
[24]. On the basis of the findings of the present study it
appears that the prevalence of lower extremity PAD in
COPD patients in Japan may be lower than that in pa-
tients in Europe. One reason for this result may be that
we excluded subjects who had already been diagnosed
with PAD. Another reason may be that the prevalence of
Copyright © 2013 SciRes. OJRD
Figure 1. Association between ABI and ADO index. ABI
showed a significant and negative correlation with ADO in-
dex (r = 0.51, p = 0.0001).
PAD is low in both COPD patients and the general popu-
lation in Japan compared with other developed countries.
Several studies have also reported that the rate of car-
diovascular death in the smoking population and PAD
patients is lower in Japan than in other developed coun-
tries [19,20,25,26]. However, in this study, the preva-
lence of PAD in COPD patients tended to be high, with
the proportion of subjects with an ABI < 1.1 being sig-
nificantly greater than in control subjects. Fowkes et al.
demonstrated that subjects with an ABI 0.91 to 1.10 had
higher mortality and cardiovascular event rates than those
with a normal ABI [27]. Therefore, as in other countries,
attention should be paid to the risk of cardiovascular dis-
eases in Japanese COPD patients.
Recent studies have demonstrated that atherosclerosis
is associated with FEV1 [11-14]. In the Atherosclerosis
Risk in Communities (ARIC) Study, decreased FEV1 was
associated with decreased ABI in smoking subjects even
after adjustment for cardiovascular risk factors [12]. Iwa-
moto et al. [14], measured the carotid intima-media thick-
ness and focal atheromatous plaque as indicators of sub-
clinical atherosclerosis in patients with airflow limitation
and control smokers. They showed that mean carotid in-
tima-media thickness was greater in patients with an air-
flow limitation than in the controls. Furthermore, their
data showed significant associations between thickened
intima-media thickness and decreased FEV1. Although
the mechanism for these associations was unclear, it is
possible hypoxia occurring in the later stages of COPD
may have induced an abnormal inflammatory response,
reflected by increased CRP [28] and oxidative stress [29].
In our study, resting SaO2 showed a significant and posi-
tive correlation with ABI, and was an independent deter-
minant of ABI. This finding indicates that hypoxia may
contribute to atherosclerosis in COPD patients. Further
studies are required to conclusively determine the mecha-
nisms of these interactions.
We also showed that MMRC was associated with ABI.
The severity of dyspnea has been shown to be a better
predictor of mortality in COPD than airway obstruction
[20]. COPD patients with the most severe dyspnea were
shown to be more likely to die than those with only mild
dyspnea [20]. A low ABI is a predictor of systemic athe-
rosclerosis and risk of cardiovascular events [27]. Eng-
strom et al. reported that reduced FEV1 was associated
with an increased incidence of hospitalizations due to
heart failure [30]. Therefore, not only poor lung function,
but also impaired cardiac function may contribute to dys-
pnea in patients with a low ABI.
In this study, the presence of cardiac risk factors (hy-
pertension, diabetes mellitus, and hypercholesterolemia)
was not associated with ABI. One reason for this result
may be that the prevalence of these diseases was low in
COPD subjects in this study.
In the present study the ADO index correlated better
with ABI than either age, FEV1, or MMRC. The ADO in-
dex is a multidimensional index developed by Puhan et
al. [23] that incorporates age, dyspnea, and airflow ob-
struction. The index predicts 3-year mortality from COPD
more accurately than the BODE index, which is currently
used to estimate a patient’s risk of death from COPD.
There is evidence that both these multidimensional indi-
ces predict survival better than FEV1 alone [31]. Several
studies have shown that airflow limitation is an inde-
pendent risk factor for cardiovascular disease. However,
there is no established threshold for the relationship be-
tween cardiovascular risk and FEV1. In this study all
patients with an ABI < 0.9 had an ADO index score of 5
points or greater. This result suggests that the ADO index
has the ability to predict cardiovascular risk in COPD
patients. A study in a large number of subjects is required
to determine the cut-off point of the ADO index for
screening cardiovascular disease in COPD patients.
Coronary and cerebrovascular diseases frequently co-
exist in PAD patients [15]. There is an approximately 2-
to 4-fold excess of cardiovascular disease in patients with
lower extremity PAD [16,17]. The prognosis of patients
with lower extremity PAD is characterized by an in-
creased risk for cardiovascular ischemic events due to
concomitant coronary artery disease and cerebrovascular
disease [16,17]. These cardiovascular ischemic events are
more frequent than ischemic limb events in any cohort of
patients with lower extremity PAD [18]. Lower extremity
arterial disease should therefore also be viewed as a sign
of potentially diffuse and significant arterial disease [15].
Measurement of ABI may be useful for identifying pa-
tients at high risk who may benefit from aggressive the-
rapeutic intervention [32-35]. The guidelines of the Ame-
Copyright © 2013 SciRes. OJRD
rican College of Cardiology (ACC) and American Heart
Association (AHA) for the management of patients with
PAD recommends that ABI should be considered as a
routine test for all patients who are 49 years of age and
younger with a history of diabetes and 1 other risk factor,
those 50 to 69 years of age with a history of smoking or
diabetes, and those aged 70 years or older [15]. In accor-
dance with these guidelines the majority of COPD pa-
tients should have ABI measured.
There were some limitations in this study. The number
of subjects was small and therefore a study on a larger
number of subjects is needed to conclusively establish
the prevalence of PAD in COPD subjects. Although some
studies have reported an association between atheroscle-
rosis and nocturnal hypoxia [36], the current study did not
evaluate this relationship.
5. Conclusion
In this study we showed that the rate of atherosclerosis in
COPD patients in Japan was lower than in similar pa-
tients in other developed countries. However, we showed
the rate of atherosclerosis in COPD patients was higher
than in healthy smokers, with this finding being consis-
tent to data of other countries. Leg atherosclerosis was
also shown to be associated with clinical indices related
to COPD mortality. It is therefore important that more
attention is paid to leg atherosclerosis in Japanese COPD
6. Acknowledgements
We thank Masahiro Motoki, Takanori Matsutani, Taka-
hiko Ando, Kaori Tai, Megumi Sakano, Nanae Kiyokawa,
and Kanako Ichimaru of the clinical laboratory of Shinko
Hospital for carrying out the pulmonary function tests
and measuring ABI.
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COPD: Chronic Obstructive Pulmonary Disease
FEV1: Forced Expiratory Volume in one second
PAD: Peripheral Artery Disease
BI: Ankle-Brachial Index
BMI: Body Mass Index
MMRC: Modified Medical Research Council
SaO2: Arterial Oxygen Saturation
Ease of Use (Heading 2)