Prevalence and risk factors for cerebral infarction and carotid artery stenosis in peripheral arterial disease.

Abstract

The purpose of the study was to examine the prevalence and risk factors for cerebral infarction (CI) and carotid artery stenosis (CAS) in patients with peripheral arterial disease (PAD) compared with normal controls.
A cross-sectional analysis was performed in 857 subjects (PAD: 543, controls: 314). CI and lacunar infarction (LI) were evaluated using brain computed tomography. Intima-media thickening (IMT) and CAS were measured with ultrasound.
The prevalences of CI and LI were higher in patients with PAD than in controls (15.0% vs. 9.8%, 41.0% vs. 13.4%, respectively, p < 0.05). In multiple logistic analysis, CI was associated with diabetes mellitus, low HDL cholesterol and CAS ≥ 70% (p < 0.05). LI was associated with age, PAD, diabetes mellitus, and estimated glomerular filtration rate (p < 0.05). The prevalences of CAS ≥ 70% and CAS ≥ 50% were higher in patients with PAD than in controls (5.2% vs. 0.6%, 17.6% vs. 3.8%, respectively, p < 0.01). Mean and max IMT differed significantly between the two groups (PAD vs. controls: 1.01 ± 0.45 vs. 0.90 ± 0.28, 2.67 ± 2.00 vs. 1.73 ± 1.05 mm, respectively, p < 0.001). CAS ≥ 70% correlated with high LDL cholesterol, and CAS ≥ 50% with age and PAD. IMT was positively correlated with PAD, high LDL cholesterol, age, and hypertension (p < 0.05).
Prevalences of CI and CAS were markedly higher in patients with PAD than in controls, indicating that PAD is a meaningful risk factor for CI, LI, and CAS. This suggests that screening for CI and CAS is important for managements in PAD, as with screening for PAD in patients with stroke.

Full text

Page 1

Prevalence and risk factors for cerebral infarction and carotid artery stenosis
in peripheral arterial disease
Yoshihiro Arakia, Hisao Kumakuraa,*, Hiroyoshi Kanaia, Shu Kasamaa, Hiroyuki Suminoa,
Akiko Ichikawaa, Toshio Itoa, Toshiya Iwasakia, Yoshiaki Takayamaa, Shuichi Ichikawaa,
Kishu Fujitab, Kuniki Nakashimab, Kazutomo Minamib, Masahiko Kurabayashic
aDepartment of Internal Medicine, Cardiovascular Hospital of Central Japan (Kitakanto Cardiovascular Hospital), Shimohakoda 740 Hokkitu-machi,
Shibukawa, Gunma, Japan
bDepartment of Cardiovascular Surgery, Cardiovascular Hospital of Central Japan (Kitakanto Cardiovascular Hospital), Shibukawa, Gunma Prefecture 377-0061, Japan
cDepartment of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
a r t i c l e i n f o
Article history:
Received 2 April 2012
Received in revised form
9 May 2012
Accepted 15 May 2012
Available online 4 June 2012
Keywords:
Cerebral infarction
Carotid artery stenosis
Intima-media thickening
Peripheral arterial disease
Stroke
a b s t r a c t
Objective: The purpose of the study was to examine the prevalence and risk factors for cerebral infarction
(CI) and carotid artery stenosis (CAS) in patients with peripheral arterial disease (PAD) compared with
normal controls.
Method: A cross-sectional analysis was performed in 857 subjects (PAD: 543, controls: 314). CI and
lacunar infarction (LI) were evaluated using brain computed tomography. Intima-media thickening (IMT)
and CAS were measured with ultrasound.
Results: The prevalences of CI and LI were higher in patients with PAD than in controls (15.0% vs. 9.8%,
41.0% vs. 13.4%, respectively, p < 0.05). In multiple logistic analysis, CI was associated with diabetes
mellitus, low HDL cholesterol and CAS ? 70% (p < 0.05). LI was associated with age, PAD, diabetes
mellitus, and estimated glomerular filtration rate (p < 0.05). The prevalences of CAS ? 70% and
CAS ? 50% were higher in patients with PAD than in controls (5.2% vs. 0.6%, 17.6% vs. 3.8%, respectively,
p < 0.01). Mean and max IMT differed significantly between the two groups (PAD vs. controls: 1.01 ? 0.45
vs. 0.90 ? 0.28, 2.67 ? 2.00 vs. 1.73 ? 1.05 mm, respectively, p < 0.001). CAS ? 70% correlated with high
LDL cholesterol, and CAS ? 50% with age and PAD. IMT was positively correlated with PAD, high LDL
cholesterol, age, and hypertension (p < 0.05).
Conclusions: Prevalences of CI and CAS were markedly higher in patients with PAD than in controls,
indicating that PAD is a meaningful risk factor for CI, LI, and CAS. This suggests that screening for CI and
CAS is important for managements in PAD, as with screening for PAD in patients with stroke.
? 2012 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Cerebral infarction (CI) and coronary heart disease (CHD) are
closely associated with peripheral arterial disease (PAD), and are
majorcauses of death inpatients with PAD [1e4]. Patients with PAD
also complicate with diabetes mellitus or hyperlipidemia and may
have extensive and severe systemic atherosclerosis that is
responsible for the mortality due to CI and CHD [1,3]. In patients
with stroke or transient ischemic attack (TIA), symptomatic or
asymptomatic PAD is independently associated with recurrent
vascular events and stroke [5,6], and atherosclerotic carotid artery
stenosis (CAS) is an important cause of ischemic stroke [7]. We have
reported that stroke is an independent risk factor for progress of
Fontaine stages in PAD [8]. Asymptomatic CI is also a precursor of
symptomatic stroke or insidious brain damage [9], which indicates
theimportance of screening for thepresence of CI or CAS inpatients
with PAD. Furthermore, CI or CAS is considerable for treatment and
rehabilitation of patients with PAD [1,2].
However, the prevalence and risk factors for CI and CAS are not
fully understood in patients with PAD, and the prevalences of these
diseases compared with age-matched normal controls are unclear.
* Corresponding author. Tel.: þ81 27 232 7111; fax: þ81 27 233 9092.
E-mail address: kumakura@sannet.ne.jp (H. Kumakura).
Contents lists available at SciVerse ScienceDirect
Atherosclerosis
journal homepage: www.elsevier.com/locate/atherosclerosis
0021-9150/$ e see front matter ? 2012 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.atherosclerosis.2012.05.019
Atherosclerosis 223 (2012) 473e477

Page 2

The purpose of the present study was to examine these issues in
a population of patients with PAD and in healthy controls.
2. Patients and methods
2.1. Patients and control subjects
The study included patients with PAD and healthy controls who
were referred to the Cardiovascular Hospital of Central Japan
(Kitakanto Cardiovascular Hospital) between January 1st, 2005 and
December 31st, 2010. The subjects with PAD were 543 consecutive
patients with ABI < 0.90 at their first visit. The final diagnosis of
PAD was based on clinical symptoms and iliac or femoropopliteal
artery stenosis ? 70% on angiography or ultrasound. Clinical stages
of PAD were classified using the criteria of the Inter-Society
Consensus for the Management of Peripheral Arterial Disease [1].
ABI was determined in all subjects using ABI-form (Colin, Tokyo,
Japan), which simultaneously measures bilateral arm and ankle
blood pressure by an oscillometric method. In the patients with
PAD, blood was collected during fasting in the morning for deter-
mination of total cholesterol, low density lipoprotein (LDL)
cholesterol, high density lipoprotein (HDL) cholesterol, triglyceride,
glucose, glycosylated hemoglobin A1c, and uric acid.
Diabetes mellitus, hypertension, stroke, and CHD were studied as
risk factors for arteriosclerosis. Diabetes was defined as a fasting
plasma glucose level >126 mg/dL for at least two measurements or
a requirement for antidiabetic therapy [10]. Hypertension was
defined as blood pressure ?140/90 mmHg recorded at least twice or
intakeofantihypertensiveagents.Theestimatedglomerularfiltration
rate (eGFR) was estimated using the Modification of Diet in
Renal Disease (MDRD) equation for creatinine, as modified by the
Japanese Society ofNephrology:
1.73 m2) ¼ 194 ? (Scr)?1.094? (Age)?0.287(?0.739 if female) [11]. An
electrocardiogram was recorded and echocardiography was per-
formedforeachpatient.CHD wasconsideredto bepresentwhenthe
patienthadahistoryofthisdiseaseorshowedapositivesigninstress/
rest myocardial perfusion scintigraphy or coronary angiography.
The 560 age-matched control subjects were recruited at the time
of their annual medical check-up at our hospital. This check-up
included a physical examination, measurement of ABI, chest X-ray,
stress electrocardiogram, and echocardiography. Blood wascollected
during fasting in the morning for determination of total cholesterol,
LDL cholesterol, HDL cholesterol, triglyceride, glucose, glycosylated
hemoglobin A1c, and uric acid. Subjects with physician-diagnosed
PAD based on ABI < 1.00, physical symptoms, or ABI ? 1.40 were
excluded. Subjects were also excluded if they had physician-
diagnosed diabetes mellitus, hypertension, hyperlipidemia, CHD, or
a history of stroke or TIA. Diabetes mellitus and hypertension were
diagnosedasnotedabove.Lipidabnormalities were diagnosedbased
on intake of lipid-lowering agents or LDL cholesterol ? 140 mg/dL
[12], HDL cholesterol < 40 mg/dL [1,12], or triglyceride ? 150 mg/dL
[12,13]. Recruitment was tailored to yield approximately an age- and
gender-matchedcontrolgroup,and 314 healthysubjects were finally
recruited as controls. A brain computed tomography (CT) scan and
carotidultrasoundwereperformedinsubjectswithoutriskfactorsfor
these procedures.
Prior to the start of the study, the patients and control subjects
received a full explanation of the examination methods, and gave
written informed consent. The study protocol was approved by the
CardiovascularHospitalofCentralJapanMedicalEthicalCommittee.
eGFR(mL/min/
2.2. Assessment of CI and CAS
A brain CT scan (Aquillion 64, Toshiba, Tokyo, Japan) was
performed in 5- or 10-mm thick sections without use of
a contrast agent. The scans were evaluated by two radiologists
whowereblindedtothe characteristics
Infarcts > 1.5 cm in diameter on brain CT are considered to be
CI of potential large-artery atherosclerotic origin. A low density
lesion with a diameter of ?1.5 cm on CT was categorized as
a lacunar infarction (LI).
The wall thickness of the bilateral carotid arteries was measured
by ultrasound (Aplio SSA-770A; Toshiba, Tokyo, Japan) using a 7.5-
MHz linear type B-mode probe. The measurements were made
after the subject had rested forat least 10 min in the supine position
with the neck in slight hyperextension for optimal visualization of
the common carotid arteries, carotid bulb, and extracranial internal
and external carotid arteries on both sides. The imaging protocol
involved obtaining 3 longitudinal views (anterior-oblique, lateral,
and posterior-oblique) of the distal 10 mm of the right and left
common carotid arteries and internal carotid arteries. The internal
carotid artery was defined as including the carotid bulb and the
extracranial segment of the internal carotid artery distal to the tip
of the flow divider that separates the internal and external carotid
arteries. The end-diastolic intima-media thickness (IMT) of the far
wall of the common carotid artery was measured bilaterally from
the 3 scan views 10 mm proximal to the bulb, and averaged to
obtain the mean IMT. The max IMT was defined as the single
thickest wall in the same way from the 3 scan views on the internal
and common carotid arteries. The presence of a plaque was defined
as a thickening of the IMT > 1.1 mm. CAS was evaluated using the
North American Symptomatic
Collaborators (NASCET) method [14]. All scans were evaluated by
an ultrasonographic physician who was blinded to the clinical
characteristics of the subjects.
ofthesubjects.
CarotidEndarterectomy Trial
2.3. Statistical analysis
Data are expressed as mean values ? standard deviation. The
two groups were compared using a t-test and proportions were
compared by Chi-square analysis. Relationships between athero-
sclerotic lesions and risk factors were studied using multiple
regression analysis and multiple logistic analysis. SPSS v.17.0 (SPSS
Inc, Chicago, IL) was used for all calculations. A p-value <0.05 was
considered to indicate a significant difference.
Table 1
Baseline clinical characteristics and risk factors in patients with peripheral arterial
disease (PAD) and age-matched normal controls.
Risk factorPAD n ¼ 543
71.3 ? 9.4
80.8%
22.1 ? 3.4
0.62 ? 0.26
329 (61.2%)
186 (34.5%)
104 (19.3%)
189 (35.3%)
408 (75.7%)
53 (9.8%)
190 ? 40.2
116 ? 35.7
48.7 ? 21.7
150 ? 33.1
1.42 ? 1.66
5.9 ? 1.74
6.0 ? 1.21
Controls n ¼ 314
71.1 ? 6.7
79.8%
22.5 ? 4.1
1.12 ? 0.21
0 (0%)
0 (0%)
0 (0%)
0 (0%)
246 (58.6%)
0 (0%)
166 ? 26.1
96 ? 21.0
58.3 ? 15.5
103 ? 18.9
0.76 ? 0.20
5.3 ? 1.47
5.3 ? 0.20
p-value
Age (year)
Gender (male)
BMI (kg/m2)
ABI
Hypertension
Diabetes mellitus
Stroke or TIA
Coronary heart disease
Smoker
Atrial fibrillation
Total-C (mg/dL)
LDL-C (mg/dL)
HDL-C (mg/dL)
Triglyceride (mg/dL)
Creatinine
Uric acid (mg/dL)
HbA1c (%)
0.796
0.823
0.111
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
BMI: body mass index, ABI: ankle brachial pressure index, TIA: transient ischemic
attack, Total-C: total cholesterol, LDL-C: low density lipoprotein cholesterol, HDL-C:
high density lipoprotein cholesterol, HbA1c: glycosylated hemoglobin A1c.
Y. Araki et al. / Atherosclerosis 223 (2012) 473e477
474

Page 3

3. Results
3.1. Patient characteristics
The subjects were 543 patients with PAD and 314 age-matched
healthy controls. The characteristics of the subjects, including
complications and risk factors, are shown in Table 1. There were no
significant differences in age, gender and body mass index. The
prevalences of hypertension, diabetes mellitus, CHD, smoking, and
atrial fibrillation were higher in the patients with PAD, and 19.3% of
the patients had a history of stroke or TIA. Serum levels of total
cholesterol, LDL cholesterol, triglycerides, creatinine, uric acid and
glycosylated hemoglobin A1c were higher, and HDL cholesterol was
lower, in patients with PAD compared with controls.
3.2. Prevalence of CI and CAS
The prevalence of CI on CT was higher in patients with PAD than
in controls (p ¼ 0.032, Fig. 1) and the complication rate of LI was
also higher in the patients (p < 0.001). The total prevalence of CI or
LI was higher in patients with PAD compared to controls
(p < 0.001). The prevalences of CAS ? 70% (p ¼ 0.004) and ?50%
(p < 0.001) were also higher in patients with PAD. The mean and
max IMT were 1.01 ? 0.45 and 2.67 ? 2.00 mm, respectively, in
patients with PAD, and 0.90 ? 0.28 and 1.73 ? 1.05 mm, respec-
tively, in controls, with each differing significantly between the
groups (both p < 0.001). The prevalence of carotid plaque was also
higher in patients with PAD (p ¼ 0.002, Fig. 1). The variability in
ultrasonography was assessed by performing 5 measurements over
a period of 1 month in 12 volunteers. The intra-observer coefficient
of variation for the IMT measurements was 5.5 ? 0.8%.
3.3. Risk factors for CI and CAS
Multiple logistic analysis showed that CI was associated with
diabetes mellitus, low HDL cholesterol and CAS ? 70%, and had
a tendency to be associated with male gender, PAD, and high LDL
cholesterol (Fig. 2a). LI was associated with PAD, age, eGFR, and
diabetes mellitus (Fig. 2b). The odds ratio of LI was 2.8 times higher
in patients with PAD. LI also showed a tendency to be associated
with hypertension and high LDL cholesterol. No carotid ultrasound
parameters showed a relationship with LI, and atrial fibrillationwas
notcorrelated with CI or LI. CAS ? 70%was correlated with high LDL
cholesterol (Fig. 3a) and CAS ? 50% showed significant correlations
with age and PAD (Fig. 3b). The odds ratio of CAS ? 50% was 3.2
times higher in patients with PAD. Stepwise forward multiple
regression analysis indicated that IMT was positively correlated
with PAD, high LDL cholesterol, age, and hypertension (Table 2,
p ¼ 0.046).
4. Discussion
4.1. Prevalence for CI and LI
This is the first report of the prevalence and risk factors for CI or
LI detected by CT in patients with PAD, compared with age-
matched controls. In this study, the history of stroke or TIA was
19.3%, but the prevalence of CI or LI by brain CT was 56.0% in
patients with PAD, which was significantly higher than the rate of
23.2% in controls. Baseline data in the REduction of Athero-
thrombosis for Continued Health (REACH) registry indicate that
16.58% and 15.23% of PAD patients have a history of stroke and TIA,
respectively, worldwide [15]. In the Japanese population, 20.66% of
PAD patients have a history of stroke or TIA [16]. Our data suggest
a high prevalence of asymptomatic CI or LI that remained hidden in
the patients with PAD, whose mean age was 71 years old. Asymp-
tomatic CI is a precursor of symptomatic stroke or insidious brain
damage [9], which indicates the importance of screening for the
presence of CI or LI in patients with PAD.
Fig. 1. Prevalence of cerebral infarction (CI), lacunar infarction (LI), CI or LI, carotid
artery stenosis (CAS) ? 70%, CAS ? 50%, and carotid artery plaque. *p < 0.05, **p < 0.01.
124 100.5
Age (years) 1.031 (0.983-1.043)0.406
Gender (male) 2.113(0.982-4.549)0.056
PAD2.125 (0.962-5.239) 0.079
Hypertension 1.924 0.787-4.703) 0.151
Diabetes mellitus 1.825 (1.019-3.270) 0.043*
Smoking 0.655 (0.334-1.286) 0.219
CHD 1.069 (0.591-1.932) 0.826
eGFR1.010 (0.999-1.021) 0.088
High LDL-C 1.715 (0.972-3.027)0.063
Low HDL-C 1.969 (1.147-3.381) 0.014 *
High TG0.788 (0.450-1.381) 0.406
CAS 70%3.324(1.025-10.781)0.045 *
Odds ratio (95%CI) p-value
124 100.5
Age (years) 1.028 (1.006-1.051) 0.011 *
Gender (male) 0.998(0.567-1.755) 0.993
PAD 2.763 (1.373-5.561) 0.004 *
Hypertension 1.488 (0.994-2.229) 0.054
Diabetes mellitus 1.582 (1.029-2.439) 0.037 *
Smoking 1.428 (0.842-2.421) 0.186
CHD 1.016 (0.664-1.555)0.742
eGFR 0.990 (0.981-0.998) 0.015 *
High LDL-C 1.433 (0.967-2.125) 0.075
Low HDL-C 1.050 (0.699-1.577) 0.815
High TG1.301 (0.876-1.933)0.192
CAS 70% 0.806(0.295-2.206)0.675
Odds ratio (95%CI) p-value
a
b
Fig. 2. Relationships of (a) cerebral infarction and (b) lacunar infarction with risk
factors in multiple logistic analysis. *p < 0.05, PAD: peripheral arterial disease, CHD:
coronary heart disease, eGFR: estimated glomerular filtration rate, LDL-C: low density
lipoprotein cholesterol, HDL-C: high density lipoprotein cholesterol, TG: triglyceride,
CAS: carotid artery stenosis.
Y. Araki et al. / Atherosclerosis 223 (2012) 473e477
475

Page 4

4.2. Risk factors for CI and LI
In our study, CI was associated with diabetes mellitus, low HDL
cholesterol and CAS ? 70%, and showed a tendency to be associated
with male gender, PAD, and high LDL cholesterol. Diabetes mellitus,
low HDL cholesterol, and high LDL cholesterol are important risk
factorsfordevelopmentoflarge-arteryatheroscleroticstroke[17].In
contrast, LI results from occlusion of a single perforating artery [18],
and in this study LI was associated with age, PAD, and low eGFR. No
carotid ultrasound parameters showed a relationship with LI. The
odds ratio of LI was 2.8 times higher inpatients with PAD compared
with controls after adjustment for other risk factors. Age and eGFR
are important risk factors for systemic atherosclerosis [19,20], and
our study also showed that asymptomatic microvascular cerebral
disease progressed silently in patients with PAD.
4.3. Correlation between PAD and CI
Despite the high risks of stroke in patients with PAD [21] and of
PAD in patients with stroke [5], consideration of PAD is omitted
from guidelines for treatment, rehabilitation, and prevention of
stroke [2,17,22]. We have reported that stroke is an independent
risk factor for progress of Fontaine stages in PAD, along with age,
diabetes, and female gender [8]. Decreased physical capability,
sensory disturbance for wounds, and systemic atherosclerosis may
be contributors to these findings [1,8]. Based on a large epidemio-
logic study [23], the 2011 ACCF/AHA guidelines modified the agefor
consideration of ABI diagnostic testing to ?65 years old or ?50
years old with a history of smoking or diabetes [24]. It was also
suggested that antiplatelet therapy can be useful to reduce the risk
ofcardiovascular events inasymptomatic
ABI ? 0.90 [24]. In patients with CI, symptomatic or asymptomatic
PAD is independently associated with recurrent stroke or TIA [5,6].
Our results also suggest that screening for PAD in patients with
stroke or TIA is as important as screening for CI or CAS in patients
with PAD.
individuals with
4.4. Prevalence for CAS
Atherosclerotic CAS is an important cause of ischemic stroke [7].
Our study showed that 17.6% of patients with PAD had CAS ? 50%
and 5.2% had CAS ? 70%. Mostaza et al. found a 14.3% prevalence of
CAS ? 50% in patients with PAD (mean age: 66.7 years old),
compared to 4.7% in a control group with normal ABI and matched
for age, gender and diabetes [25]. Our results showed a prevalence
of CAS ? 50% that was slightly higher than those in previous
studies, which may be due to the higher mean age of our patients.
Among the controls in the current study, 3.8% had CAS ? 50% and
0.6% had CAS ? 70%. In population-based studies the rates of CAS
have varied from 2% to 11% [26,27]. The slightly lower rate of CAS in
our controls may have arisen because we excluded subjects with
diabetes mellitus. Thus, the results of our study are in accordance
with previous studies.
4.5. Risk factors for CAS
The presence of intermittent claudication or asymptomatic PAD
has been reported to be significantly associated with increased IMT
[28]. In our subjects, multiple regression analysis showed that IMT
was positively correlated with PAD, high LDL cholesterol, age, and
hypertension. Analysis of the relationship between CAS ? 70% and
potential risk factors revealed a correlation with high LDL choles-
terol. The odds ratio of CAS ? 50% was 3.2 times higher in patients
with PAD. Carotid and femoral IMT have been positively correlated
with LDL cholesterol [29] and Rockman et al. found relationships of
occult CAS with CHD, smoking, and hypertension in patients with
these risk factors, without data for PAD [27]. Our study highlighted
PAD and high LDL cholesterol as risk factors for CAS, with CI asso-
ciated with CAS ? 70%, along with low HDL cholesterol and dia-
betes mellitus.
4.6. Study limitations
The limitations of this study include the relatively small sample
size and the performance of the studyat a single facility. We did not
exclude smokers from the controls because the prevalence of
former or current smokers was too high to ignore. We also did not
use population-based data. Therefore, further studies are needed to
determine the exact prevalence and risk factors for CI, LI, and CAS in
patients with PAD.
124100.5
Age (years) 1.011 (0.958-1.065)0.684
Gender (male) 1.841(0.331-9.229) 0.485
PAD 1.851 (0.146-23.543) 0.635
Hypertension 0.940 (0.346-2.369) 0.840
Diabetes mellitus 1.603 (0.600-4.278) 0.347
Smoking 3.038 (0.478-19.294) 0.239
CHD 0.482 (0.166-1.407) 0.184
eGFR 0.999 (0.978-1.20) 0.899
High LDL-C 2.729 (1.066-6.989)0.036 *
Low HDL-C 1.640 (0.638-4.219)0.305
High TG1.137 (0.441-2.932) 0.790
Odds ratio (95%CI) p-value
124 100.5
Age (years)1.036 (1.005-1.067)0.024 *
Gender (male)1.258(0.551-2.876)0.586
PAD 3.213 (1.036-9.962) 0.043 *
Hypertension 0.786 (0.458-1.350) 0.383
Diabetes mellitus 1.157 (0.652-2.054) 0.619
Smoking 1.450 (0.656-3.203) 0.359
CHD 1.234 (0.715-2.133)0.450
eGFR0.995 (0.983-1.007)0.431
High LDL-C 1.502 (0.888-2.541)0.125
Low HDL-C 1.344 (0.781-2.311)0.287
High TG 1.077 (0.627-1.849)0.788
Odds ratio (95%CI) p-value
a
b
Fig. 3. Relationships of (a) carotid artery stenosis ? 70% and (b) carotid artery
stenosis ? 50% with risk factors in multiple logistic analysis. *p < 0.05, PAD: peripheral
arterial disease, CHD: coronary heart disease, eGFR: estimated glomerular filtration
rate, LDL-C: low density lipoprotein cholesterol, HDL-C: high density lipoprotein
cholesterol, TG: triglyceride.
Table 2
Correlationbetweenintima-media thickness(IMT) and otherrisk factors in stepwise
forward multiple regressions analysis.
Risk factor
b
95% C.I.
p-value
PAD
High LDL-C
Age
Hypertension
0.124
0.117
0.106
0.101
0.026e0.244
0.029e0.194
0.001e0.010
0.002e0.180
0.015
0.008
0.014
0.046
R2¼ 0.057, F for change in R2¼ 3.991, p ¼ 0.046.
PAD: peripheral arterial disease, LDL-C: low density lipoprotein cholesterol.
Y. Araki et al. / Atherosclerosis 223 (2012) 473e477
476

Page 5

5. Conclusion
The prevalences of cerebral and carotid artery lesions were
markedly higher in patients with PAD compared to healthy
controls, and dyslipidemia and diabetes mellitus were critical risk
factors for CI and LI. These results showing a high risk of cerebral
and carotid artery lesions in patients with PAD suggest that
screening for CI and CAS is important for treatment, rehabilitation
and prevention in these patients, as with screening for PAD in
patients with stroke.
References
[1] Norgren L, Hiatt WR, Dormandy JA, et al. Inter-society consensus for the
management of peripheral arterial disease (TASC II). J Vasc Surg 2007;45-
(Suppl. S):S5e67.
[2] Banerjee A, Fowkes FG, Rothwell PM. Associations between peripheral artery
disease and ischemic stroke: implications for primary and secondary
prevention. Stroke 2010;41:2102e7.
[3] Kumakura H, Kanai H, Aizaki M, et al. The influence of the obesity paradox and
chronic kidney disease on long-term survival in a Japanese cohort with
peripheral arterial disease. J Vasc Surg 2010;52:110e7.
[4] Murphy TP, Dhangana R, Pencina MJ, et al. Ankle-brachial index and cardio-
vascular risk prediction: an analysis of 11,594 individuals with 10-year
follow-up. Atherosclerosis 2012;220:160e7.
[5] Sen S, Lynch Jr DR, Kaltsas E, et al. Association of asymptomatic peripheral
arterial disease with vascular events in patients with stroke or transient
ischemic attack. Stroke 2009;40:3472e7.
[6] Tsivgoulis G, Bogiatzi C, Heliopoulos I, et al. Low ankle-brachial index predicts
early risk of recurrent stroke in patients with acute cerebral ischemia.
Atherosclerosis 2012;220:407e12.
[7] Tejada J, Diez-Tejedor E, Hernandez-Echebarria L, et al. Does a relationship
exist between carotid stenosis and lacunar infarction? Stroke 2003;34:
1404e9.
[8] Kumakura H, Kanai H, Araki Y, et al. Sex-related differences in Japanese
patients with peripheral arterial disease. Atherosclerosis 2011;219:846e50.
[9] Shinkawa A, Ueda K, Kiyohara Y, et al. Silent cerebral infarction in a commu-
nity-based autopsy series in Japan. The Hisayama study. Stroke 1995;26:
380e5.
[10] Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.
Report of the expert committee on the diagnosis and classification of diabetes
mellitus. Diabetes Care 2003;26(Suppl. 1):S5e20.
[11] Matsuo S, Imai E, Horio M, et al. Revised equations for estimated GFR from
serum creatinine in Japan. Am J Kidney Dis 2009;53:982e92.
[12] Teramoto T, Sasaki J, Ueshima H, et al. Executive summary of Japan athero-
sclerosis society (JAS) guideline for diagnosis and prevention of atherosclerotic
cardiovascular diseases for Japanese. J Atheroscler Thromb 2007;14:45e50.
[13] Castelli WP. Lipids, risk factors and ischaemic heart disease. Atherosclerosis
1996;124(Suppl.):S1e9.
[14] North American Symptomatic Carotid Endarterectomy Trial Collaborators.
Beneficial effect of carotid endarterectomy in symptomatic patients with
high-grade carotid stenosis. N Engl J Med 1991;325:445e53.
[15] Cacoub PP, Abola MT, Baumgartner I, et al. Cardiovascular risk factor control
and outcomes in peripheral artery disease patients in the reduction of athe-
rothrombosis for continued health (REACH) registry. Atherosclerosis 2009;
204:e86e92.
[16] Yamazaki T, Goto S, Shigematsu H, et al. Prevalence, awareness and treatment
of cardiovascular risk factors in patients at high risk of atherothrombosis in
Japan. Circ J 2007;71:995e1003.
[17] Furie KL, Kasner SE, Adams RJ, et al. Guidelines for the prevention of stroke in
patients with stroke or transient ischemic attack: a guideline for healthcare
professionals from the American heart association/American stroke associa-
tion. Stroke 2011;42:227e76.
[18] Bejot Y, Catteau A, Caillier M, et al. Trends in incidence, risk factors, and
survival in symptomatic lacunar stroke in Dijon, France, from 1989 to 2006:
a population-based study. Stroke 2008;39:1945e51.
[19] Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for
development of cardiovascular disease: a statement from the American heart
association councils on kidney in cardiovascular disease, high blood pressure
research, clinical cardiology, and epidemiology and prevention. Circulation
2003;108:2154e69.
[20] Endo M, Kumakura H, Kanai H, et al. Prevalence and risk factors for renal
artery stenosis and chronic kidney disease in Japanese patients with periph-
eral arterial disease. Hypertens Res 2010;33:911e5.
[21] Leng GC, Lee AJ, Fowkes FG, et al. Incidence, natural history and cardiovascular
events in symptomatic and asymptomatic peripheral arterial disease in the
general population. Int J Epidemiol 1996;25:1172e81.
[22] Adams Jr HP, del Zoppo G, Alberts MJ, et al. Guidelines for the early
management of adults with ischemic stroke: a guideline from the American
heart association/American stroke association stroke council, clinical cardi-
ology council, cardiovascular radiology and intervention council, and the
atherosclerotic peripheral vascular disease and quality of care outcomes in
research interdisciplinary working groups: the American academy of
neurology affirms the value of this guideline as an educational tool for
neurologists. Stroke 2007;38:1655e711.
[23] Diehm C, Allenberg JR, Pittrow D, et al. Mortality and vascular morbidity in
older adults with asymptomatic versus symptomatic peripheral artery
disease. Circulation 2009;120:2053e61.
[24] 2011 ACCF/AHA focused update of the guideline for the management of
patients with peripheral artery disease (updating the 2005 guideline):
a report of the American college of cardiology foundation/American heart
association task force on practice guidelines. Circulation 2011;124:2020e45.
[25] Mostaza JM, Gonzalez-Juanatey JR, Castillo J, et al. Prevalence of carotid
stenosis and silent myocardial ischemia in asymptomatic subjects with a low
ankle-brachial index. J Vasc Surg 2009;49:104e8.
[26] O’Leary DH, Polak JF, Kronmal RA, et al. Distribution and correlates of sono-
graphically detected carotid artery disease in the cardiovascular health study.
The CHS collaborative research group. Stroke 1992;23:1752e60.
[27] Rockman CB, Jacobowitz GR, Gagne PJ, et al. Focused screening for occult
carotid artery disease: patients with known heart disease are at high risk.
J Vasc Surg 2004;39:44e51.
[28] Allan PL, Mowbray PI, Lee AJ, et al. Relationship between carotid intima-media
thickness and symptomatic and asymptomatic peripheral arterial disease. The
Edinburgh artery study. Stroke 1997;28:348e53.
[29] Gariepy J, Simon A, Massonneau M, et al. Wall thickening of carotid and
femoral arteries in male subjects with isolated hypercholesterolemia.
PCVMETRA group. Prevention Cardio-Vasculaire en Medecine du Travail.
Atherosclerosis 1995;113:141e51.
Y. Araki et al. / Atherosclerosis 223 (2012) 473e477
477