Atherosclerosis 208 (2010) 167170

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

Diabetic state as a crucial factor for impaired arterial elastic properties in patients
with peripheral arterial disease
Shinji Makita , Hiroki Matsui, Yujirou Naganuma, Akihiko Abiko, Makiko Tamada, Motoyuki Nakamura
Division of Cardiology, Department of Internal Medicine, Memorial Heart Center, Iwate Medical University, 19-1 Uchimaru, Morioka 020-8505, Japan

a r t i c l e

i n f o

Article history:
Received 25 January 2009
Received in revised form 16 April 2009
Accepted 29 June 2009
Available online 8 July 2009
Keywords:
Peripheral arterial disease
Ultrasonography
Carotid artery
Stiffness
Diabetes mellitus

a b s t r a c t
Background: Increased arterial stiffness is associated with greater risk of cardiovascular events and mortality. However, in patients with peripheral arterial disease (PAD) who have severe atherosclerotic disorder
or risk clustering, the major determinants of increased stiffness have been not claried.
Methods: This study investigated the associations between elastic properties of the carotid artery as measured by ultrasonography and atherosclerotic risk factors, with particular focus on diabetes mellitus (DM),
in PAD patients (n = 481; mean age, 69.6 years). DM was dened as hemoglobin A1c 6.5%, administration
of anti-diabetic agents, or DM pattern on 75-g oral glucose tolerance test. Stiffness index was calculated
from luminal diameter changes measured by the M-mode method using a linear array imaging probe.
Results: Stiffness parameter was signicantly increased in diabetic patients compared with non-diabetic
patients (9.56 0.35 vs. 8.31 0.32; p = 0.009) in an age- and gender-adjusted model. This signicant
difference was maintained in a multivariate-adjusted model including age, gender, hypertension, hyperlipidemia, obesity and smoking history (9.43 0.36 vs. 8.39 0.33; p = 0.037). No signicant differences in
mean intima-media complex thickness or plaque score of the carotid artery were seen between diabetic
and non-diabetic patients.
Conclusion: Diabetic condition impairs the elastic properties of arteries, independent of other known
atherosclerotic risk factors or excessive intimal diseases in PAD patients. This may support the notion
that diabetic condition can worsen prognosis for PAD patients.
2009 Elsevier Ireland Ltd. All rights reserved.

1. Introduction
Increased arterial stiffness is associated with greater risk of
cardiovascular events and mortality, as well as conventional
atherosclerotic risk factors [16]. This increased stiffness is generally the result of a damaging effect on arterial walls over time from
conventional cardiovascular risk factors, notably age and hypertension [7]. Several studies among preclinical atherosclerotic subjects
have shown that arterial stiffness is increased in patients with diabetes mellitus (DM) [813].
Patients with peripheral arterial disease (PAD) are known to display many atherosclerotic risk factors, and usually show advanced
systemic atherosclerosis. Under such conditions, impaired elastic
properties are expected to represent a crucial additional factor that
deteriorates prognosis and morbidity. However, in subjects with
severe atherosclerotic disorder or displaying risk clustering, the
details of major determinants of increased stiffness have not been
claried, and the effects of diabetic state on arterial stiffness are
unknown.

Corresponding author. Tel.: +81 19 651 5111x2324; fax: +81 19 651 7072.
E-mail address: makitas@seagreen.ocn.ne.jp (S. Makita).
0021-9150/$ see front matter 2009 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.atherosclerosis.2009.06.033

Although measurement of pulse wave velocity is widely used to

estimate arterial or aortic elastic properties, this method is limited
by arterial occlusive or dilated lesion and changes in blood pressure. We investigated the impact of diabetic state on carotid arterial
elastic properties in patients with PAD using an ultrasonographic
method.
2. Methods
2.1. Subjects
Subjects comprised 500 consecutive patients with evident PAD
who underwent carotid ultrasonography in our university hospital
from January 1998 to March 2008. Of these, 481 patients whose data
sets were complete for the present analysis (mean age, 69.6 8.3
years; range 4086 years; 436 men; 45 women) were enrolled in
this study. The majority of these patients had visited our hospital
with symptoms of leg ischemia and had received a rst evaluation for PAD condition or a therapeutic plan. Some patients were
diagnosed with PAD during the evaluation of other cardiovascular
diseases. PAD was diagnosed by digital subtraction angiography,
contrast-enhanced multi-detector row computed tomography (CT)
angiography or Doppler ultrasonography of the lower extremities,

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S. Makita et al. / Atherosclerosis 208 (2010) 167170

and ankle-brachial pressure index (ABI) <0.90. All patients were

displayed 1 occlusive lesion with a reduction in diameter >50%
as evaluated by angiographic modalities. The majority of enrolled
patients were receiving a variety of oral medications for risk factors
and PAD.
2.2. Ultrasonographic evaluations
All patients underwent ultrasonographic carotid examination
using a SSA-380A (Toshiba Medical Systems, Tochigi, Japan),
SONOS-5500 (Philips, MA, USA) or LOGIQ 700 (GE Yokogawa Medical Systems, Tokyo, Japan) scanner equipped with a 7.510 MHz
linear array imaging probe. After the subject had rested for 5 min in
a supine position, ultrasonographic examinations were performed
between 09:00 and 17:00. Room temperature was kept at around
24 C. Smoking was prohibited for at least 3 h before the examination, and neither speaking nor sleeping was permitted during
measurements.
The common carotid artery (CCA), carotid bulb, and internal
and external carotid arteries on both sides were carefully scanned
under B-mode imaging from multiple directions. In the CCA at 1.0,
2.0 and 3.0 cm proximal to the beginning of the carotid bulb, IMT
of the far wall was measured on the maximally zoomed image.
IMT was dened as the distance between the leading edge of the
lumenintima and the leading edge of the mediaadventitia echo.
Mean value of the 3 points was calculated for each side, and the
largest value was used for analysis. Plaque was dened as a regional
intimal thickening, >1.4 mm in height or double the adjacent IMT
height. Plaque score was dened as the sum of the maximum height
of each plaque located in the whole extracranial portion of both
carotid arteries [14].
End-diastolic luminal diameter (Dd ) and peak systolic luminal
diameter (Ds ) were carefully measured under M-mode imaging
with longitudinal B-mode guidance at a site 1.0 cm proximal to
the beginning of the carotid bulb [15]. If a plaque lay at the site
of diameter measurement, a site at a more proximal point was chosen to avoid the plaque. Carotid elastic properties were calculated
according to the following standard formula [16]:
stiffness parameter = ln

P  
s

Pd

Dd
Ds Dd

where Ps and Pd indicate systolic and diastolic brachial blood

pressure, respectively, as measured by the auscultatory method
with a mercury sphygmomanometer or automatic digital sphygmomanometer just after scanning. To reduce pressure-dependency
on elastic behavior, stiffness parameter was chosen for the
assessment of arterial elastic properties, rather than luminal distensibility. Mean values for both sides were used for analysis. Regarding
the reproducibility of the stiffness parameter index, the coefcient of dispersion was 5.3% and the coefcient of variation (CV)
was 7.1% (n = 22, by 2 measurements) in subjects from our previous
report [15]. Body surface area (BSA)-adjusted luminal diameter was
calculated as Dd divided by the square of BSA.
2.3. Denition of risk factors
DM was dened as a random blood glucose level 200 mg/dL,
hemoglobin A1c level 6.5%, or current anti-diabetic therapy. All
patients who did not meet this criterion underwent a 75-g oral glucose tolerance test (OGTT). Patients who showed a blood glucose
level 200 mg/dL at 2 h after the OGTT were also diagnosed with
DM, in accordance with World Health Organization criteria. Hypertension was assumed to be present in patients with a history of
hypertension who were taking anti-hypertensive drugs. Hyperlipidemia was diagnosed in patients with serum total cholesterol level
>220 mg/dL, low-density lipoprotein cholesterol level >140 mg/dL,

Table 1
Clinical characteristics in diabetic and non-diabetic patients with peripheral arterial
disease.
Non-diabetic
(n = 272)

Diabetic
(n = 209)

Age (years)
Height (cm)
Body weight (kg)
Body mass index (kg/m2 )
Systolic BP (mmHg)
Diastolic BP (mmHg)

69.6 9.2
160.7 7.9
56.1 9.0
21.7 3.0
140 22
75 12

69.7 8.2
161.3 6.8
58.8 9.5
22.6 3.1
142 22
75 12

Creatinine (mg/dL)
Total cholesterol (mg/dL)
Triglyceride (mg/dL)
HDL-cholesterol (mg/dL)
Fasting blood glucose (mg/dL)
Hemoglobin A1c (%)

1.17 1.09
190 36
126 78
49 16
101 39
5.1 0.7

1.17 1.14
184 38
138 102
45 14
115 34
6.3 1.3

Hypertension (%)
Hyperlipidemia (%)
Smoking history (%)
Obesity (%)

73.4
13.1
85.6
11.7

82.9
23.9
85.2
21.1

0.018
0.003
0.91
0.009

ABI (lower side)

Fontain classication I/II/III/IV (%)

0.55 0.17
13.3/75.8/3.3/7.5

0.52 0.18
12.8/75.2/3.5/8.5

0.27
0.87

0.96
0.42
0.002
0.003
0.28
0.99
0.96
0.25
0.35
0.053
0.032
<0.001

BP, blood pressure; HDL, high-density lipoprotein; ABI, ankle-brachial pressure

index.

or current lipid-lowering therapy. In addition, a history of smoking

and presence of obesity (body mass index (BMI) >25 kg/m2 ) were
used as other traditional cardiovascular risk factors.
2.4. Statistical analysis
Comparisons between groups with or without DM were performed using the unpaired t-test. Inter-group differences in
prevalence were compared by 2 test. Analysis of covariance
(ANCOVA) was used to assess the effects of DM on the stiffness parameter index in models adjusted by atherosclerotic
risk factors (Model 1, adjusted by age and male gender; Model 2,
adjusted by age, male gender, presence of hypertension, hyperlipidemia, smoking and obesity). To conrm the signicant impact
of DM on increased stiffness index, forward stepwise regression
analysis was also performed in the model including the same
risk factors. The nal model was determined using Pin < 0.05 and
Pout > 0.10. To examine the association of stiffness index and the
severity of diabetic state, Pearsons correlation analysis was applied
between fasting glucose level or hemoglobin A1c and natural logtransformed stiffness parameter . All analyses were performed
using SPSS version 11.0 statistical software (Chicago, IL, USA). Values in tables are expressed as mean standard deviation. Estimated
values of stiffness parameter in the multivariate-adjusted model
are expressed as mean standard error of the mean (SEM).
3. Results
Among the enrolled PAD patients, 209 patients (43.4%) were
diagnosed with the presence of diabetic state. Demographic data
for PAD patients with and without DM are shown in Table 1.
Body weight, BMI, hemoglobin A1c level, fasting blood glucose
level, prevalence of hypertension, hyperlipidemia and obesity were
higher in diabetic patients than in non-diabetic patients. Age, blood
pressure, other laboratory data, and severity of leg ischemia did not
differ signicantly between groups. Administration rates for antidiabetic, anti-hypertensive or other vasoactive medications in the
2 groups are shown in Table 2. Anti-hypertensive agents, particularly calcium channel blockers, were signicantly more frequently
used among diabetic patients. Angiotensin (AT1) receptor blockers tended to be frequently used by diabetic patients (p = 0.07). No

S. Makita et al. / Atherosclerosis 208 (2010) 167170

Table 4
Risk factors associated with stiffness index in the stepwise regression model.

Table 2
Percentage of patients taking vasoactive and anti-diabetic agents.

Anti-hypertensives
Calcium channel blockers
ACE inhibitors
Angiotensin receptor blockers
Beta blockers
Others
Anti-diabetic agents
Sulphonyl urea
Other oral
Insulin injection
Anti-platelets
Prostaglandin analogues
Eicosapentaenoic acid
Statins

Non-diabetic
(n = 272)

Diabetic (n = 209)

70.6
46.7
16.5
15.1
5.1
6.2

80.8
56.9
18.1
21.5
5.3
5.3

0.031
0.026
0.63
0.07
0.95
0.65

30.1
17.7
12.0
7.6

91.5
81.3
11.4
14.0

90.0
81.4
13.4
16.2

0.55
0.71
0.54
0.48

Anti-platelets include cilostazol, sarpogrelate and asprin.

signicant differences were found in other medications between

groups.
Comparisons of carotid ultrasonographic indices between diabetic and non-diabetic patients are shown in Table 3. No signicant
differences were seen in mean IMT or plaque score of the CCA
between patients with and without DM. Likewise, BSA-adjusted
luminal diameter of the CCA did not differ signicantly between
diabetic and non-diabetic patients. Conversely, stiffness parameter
was signicantly greater in diabetic patients than in non-diabetic
patients (crude data: 9.56 5.35 vs. 8.31 4.94, respectively;
p = 0.010). This signicant difference was also found when adjusted
by age and gender (Model 1; p = 0.009). Furthermore, the significant difference in stiffness parameter was maintained even in
the multivariate-adjusted model including age, gender, presence of
hypertension, hyperlipidemia, obesity and smoking history (Model
2, estimated mean value SEM: 9.43 0.36 vs. 8.39 0.33, respectively; p = 0.037).
In Model 2, presence of hypertension also showed a signicant association with increased stiffness parameter in
PAD patients (p = 0.010). Estimated mean values in hypertensive
and non-hypertensive patients were 9.20 0.27 and 7.65 0.52,
respectively. A signicant difference in plaque score was apparent between hypertensive and non-hypertensive patients in the
same multivariate-adjusted model (estimated mean value SEM:
5.83 0.25 vs. 4.22 0.47, respectively; p = 0.003) (table not
shown).
In stepwise multiple regression analysis, presence of diabetic
state was signicantly correlated with increased stiffness paramTable 3
Comparisons of carotid ultrasonographic indices between diabetic and non-diabetic
patients.

Average IMT (mm)

Plaque score
BSA-adjusted luminal
diameter (mm)
Stiffness parameter
Crude data
Adjusted model 1a
Adjusted model 2b

169

Non-diabetic (n = 272)

Diabetic (n = 209)

0.91 0.18
5.49 4.71
5.33 0.74

0.92 0.18
5.23 4.55
5.43 0.68

0.45
0.54
0.16

8.31 4.94
8.31 0.32
8.39 0.33

9.56 5.35
9.56 0.35
9.43 0.36

0.010
0.009
0.037

IMT, intima-media complex thickness; BSA, body surface area.

Analysis of covariance was applied to Model 1 and Model 2.
Values of stiffness index in Model 1 and Model 2 are expressed as estimated
mean SEM.
a
Model 1: adjusted by age and gender.
b
Model 2: adjusted by age, gender, hypertension, hyperlipidemia, obesity and
smoking.

Forward stepwise regression analysis (n = 481)

Age (10-year increase)

Diabetic state (+)
Hypertension (+)
Body mass index >25.0 kg/m2
Hyperlipidemia (+)
Smoking history (+)
Male gender

Standardized
coefcient ()

Results in nal model

0.192
0.131
0.115
0.062
0.038
0.023
0.067

<0.001
0.004
0.012
0.19
0.42
0.63
0.15

Included
Included
Included
Excluded
Excluded
Excluded
Excluded

eter (standardized coefcient = 0.131; p = 0.004), as was 10-year

increase in age and presence of hypertension. These 3 clinical factors were included in the nal model for stepwise analysis (Table 4).
While fasting glucose level did not correlate with logtransformed stiffness parameter , a signicant association was
identied between hemoglobin A1c and log-transformed stiffness
parameter (r = 0.176; p = 0.017).
4. Discussion
In PAD patients, little attention has been given to the role of
DM in determining the arterial elastic properties in the literature
to date. The present study revealed that diabetic state contributed
to impaired arterial elastic properties as dened by the stiffness
parameter of the carotid artery in patients with PAD. This impact
of diabetic state was independent of other risk factors. Interestingly,
impairment of elastic properties in patients with diabetic state was
found independent of intimal diseases such as increased IMT and
plaque formation.
In a community-based population from the Atherosclerotic Risk
Community study, persons with non-insulin-dependent diabetes
or borderline glucose intolerance reportedly showed stiffer carotid
arteries than their counterparts with normal glucose tolerance,
and decreased elasticity was independent of artery wall thickness
[17]. The Hoorn study showed that, in a population-based cohort,
both impaired glucose tolerance and DM were associated with
increased arterial stiffness, but that an important part of these
changes occurred before the onset of DM [18]. In animal models of
diabetes, aortic stiffness has been shown to be increased by deposition of advanced glycation end-products to the aortic wall matrix
[1921]. Not only constructive changes in arterial wall matrix, but
also vasoactive substances produced from vascular endothelial cells
can alter vascular tone, an important determinant of arterial stiffness. In diabetic patients, impaired nitric oxide production in the
vascular wall has been considered one cause of increased arterial
stiffness [22,23].
Increased arterial stiffness in hypertensive patients has been
attributed to the fatiguing effects of high blood pressure and
long-term cyclic stress on elastic bers, resulting in degenerative
alterations of the medial layer [24,25]. In our study, hypertensive
patients showed a signicant association with increased stiffness
index in the multivariate model. However, plaque score was more
severe in hypertensive patients than in non-hypertensive patients.
Increased arterial stiffness in hypertensive patients thus seemed
dependent on simultaneous increases in wall thickness or intimal
diseases. On the other hand, against a background of numerous
clustered atherosclerotic risk factors, diabetic state increased arterial stiffness without excessive intimal morphological changes. This
suggests that diabetic state has a larger effect on arterial sclerosis
than atherosis, and may be worthy of special mention.
Arterial stiffness is thought to increase the risk of cardiovascular disease through several mechanisms [26]. Laurent et al. reported
that, in a study on hypertensive patients, pulse wave velocity was

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S. Makita et al. / Atherosclerosis 208 (2010) 167170

signicantly associated with all-cause and cardiovascular mortality,

independent of previous cardiovascular diseases, age, and diabetes
[2]. In end-stage renal disease patients with diabetes, increased
aortic stiffness has been shown to contribute to higher all-cause
and cardiovascular mortality rates [27]. These data may indicate
reduced elasticity of the aortic or arterial walls as an important
determinant of life expectancy in patients with hypertension or DM.
In fact, insulin-dependent type II DM is reportedly associated with
increased risk of mortality in PAD patients with increased serum
lipoprotein levels [28]. The present results are compatible with the
concept that prognosis of PAD patients may be markedly affected by
the presence of diabetic state. Diabetic patients with PAD should be
managed with strict exploration or control of coexisting cardiovascular risk factors or other atherosclerotic diseases. Moreover, since
impairment of arterial elastic properties was already found in the
group showing mild DM (mean hemoglobin A1c, 6.3%; mean fasting glucose level, 115 mg/dL; anti-diabetic drug use, 30.1%) in the
present study, early identication of diabetic condition might aid
in reducing cardiovascular complications and improving prognosis
for PAD patients.
Some study limitations should be noted. Although brachial arterial blood pressures were used for calculating stiffness index in this
study, evaluation using conventional tonometric devices would be
recommended for estimating central or carotid pulse pressure [29].
Our study protocol concerning the examination for measurement
of stiffness did not completely meet the recommendations for standardization of subject conditions [30]. The majority of patients in
this study were receiving oral vasoactive medications such as antihypertensive drugs, which were not matched between diabetic and
non-diabetic patients. Arterial wall behavior has been recognized
to be altered by anti-hypertensive agents such as calcium antagonists and angiotensin-converting enzyme inhibitors [31,32]. The
inuences of these agents on our results were therefore not quantied. Finally, multivariate analysis was concisely performed using
the evidence of risk factors, but not using continuous variables of
clinical parameters, so this study could not rule out any effects of
anti-diabetic, anti-hypertensive or lipid-lowering agents on arterial
wall behaviors.
In conclusion, diabetic condition specically impaired arterial
elastic properties in PAD patients, independent of other known
atherosclerotic risk factors or morphological changes in the arterial wall. This result may support the notion that diabetic condition
can worsen the prognosis of PAD patients.
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