Atherosclerosis 196 (2008) 391–397

A novel method for evaluating human carotid artery elasticity: Possible
detection of early stage atherosclerosis in subjects with type 2 diabetes
Hisashi Okimoto a,1 , Yasushi Ishigaki a,1 , Yoshihiro Koiwa b , Yoshinori Hinokio a ,Takehide Ogihara c , Susumu Suzuki a , Hideki Katagiri c,f , Takayoshi Ohkubo d,f ,Hideyuki Hasegawa e , Hiroshi Kanai e , Yoshitomo Oka a,g,∗
a Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Japanb Division of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Japanc Division of Advanced Therapeutics for Metabolic Diseases, Tohoku University Graduate School of Medicine, Japand Department of Planning for Drug Development and Clinical Evaluation, Tohoku University Graduate Schoolof Pharmaceutical Science and Medicine, Japane Department of Electrical Engineering, Tohoku University Graduate School of Engineering, Japanf The 21st Century COE Programs, Comprehensive Research and Education Center for Planningof Drug Development and Clinical Evaluation, Japang The 21st Century COE Programs, Center for Innovative Therapeutic Development towards the Conquestof Signal Transduction Diseases, Tohoku University, Sendai, Japan
Received 29 March 2006; received in revised form 5 September 2006; accepted 12 November 2006
Available online 18 December 2006

Abstract
We recently developed a novel method for evaluating the elasticity of arterial walls, the phased tracking method. Herein, we evaluatedatherosclerosis of the carotid artery with this method in 242 individuals with type 2 diabetes. In multiple regression analysis of subject
status, age, systolic blood pressure and hyperlipidemia were found to be independently associated with carotid artery elasticity values. We
also measured currently established values for atherosclerosis, carotid artery IMT and baPWV, in these subjects. Carotid artery elasticity
correlated with max IMT (r = 0.291, p < 0.01), plaque score (PS) (r = 0.220, p < 0.01) and baPWV (r = 0.345, p < 0.01). Elasticity, max IMT
and plaque score, all correlated with the number of risk factors for atherosclerosis, i.e. hypertension, hyperlipidemia and smoking, in addition
to diabetes, consistent with the view that these values reflect atherosclerosis. Importantly, however, in subjects with IMT <1.1 mm, who areclassified as not having atherosclerosis as defined by IMT criteria, only carotid artery elasticity correlated with the number of risk factors(p < 0.05). These results suggest that (1) the measured carotid artery elasticity values reflect atherosclerosis and (2) our novel method has
potential for detecting atherosclerosis in its early stage.
© 2006 Elsevier Ireland Ltd. All rights reserved.
Keywords: Human carotid artery elasticity; Atherosclerosis; Diabetes

1. Introduction∗ Corresponding author at: Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi,
Aoba-ku, Sendai 980-8575, Japan. Tel.: +81 22 717 7611;
fax: +81 22 717 7611.
E-mail address: oka-y@mail.tains.tohoku.ac.jp (Y. Oka).
1 These authors contributed equally to this work.

0021-9150/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.atherosclerosis.2006.11.020

Individuals with type 2 diabetes are at very high risk foratherosclerosis [1]. Although many methods have been developed for detecting atherosclerosis, those currently available
are mainly for detecting established atherosclerosis. Therefore, the disease process is well-advanced at the time ofdiagnosis. To reduce future cardiovascular complications insubjects with atherogenic disorders such as type 2 diabetes

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H. Okimoto et al. / Atherosclerosis 196 (2008) 391–397

mellitus, detection of early stage atherosclerosis is urgently
needed.
Carotid intima-media thickness (IMT) is a wellestablished surrogate marker for cardiovascular risk [2].
Measuring IMT with ultrasonography is non-invasive andrelatively simple [3,4], and IMT is now commonly employed
as an endpoint marker in clinical trials. Carotid IMT correlates with cardiovascular risk factors and indeed predicts
macrovascular events such as myocardial infarction [5] andstroke [6]. Carotid IMT is greater in subjects with diabetes,
both type 1 [7] and type 2 [8,9], than in non-diabetic subjectsof the same age. When analyzed in diabetic patients, IMT
correlates with glycemic control and the duration of diabetes.
Interventions, such as blood glucose lowering [10], lipid lowering [11], ACE inhibition [12] and anti-platelet treatment[13], have been demonstrated to suppress IMT progression.
However, it has also been reported that IMT is not affectedby either therapeutic interventions [14] or glycemic control[15]. These conflicting results might be attributable to a verysmall change in IMT, a 0.1 mm increase per decade in normal
subjects. Such a small change may mask actual change due
to inter-assay variations in IMT measurement. Most importantly, it is not possible to make a diagnosis of atherosclerosis
until the appearance of arterial wall thickening.
We recently developed a novel non-invasive method forevaluating the movement of multiple sites in cardiac andarterial walls (3.616 measurement sites/9.0 mm × 6.4 mm)
during a single heartbeat [16,17]. This innovative phased
tracking method enables us to evaluate regional characteristics; the softer the site, the more easily it deforms during
one heartbeat. This reflects regional elasticity. This method
has already been applied to the in vivo detection of regionalchanges in cardiac and arterial walls [18–20], and the interventricular septum [21]. Evaluation of plaque vulnerability
has also been attempted [16]. It is theoretically possible todetect qualitative changes in the carotid arterial wall withthis method. We therefore tested the possibility of being able
to detect atherosclerosis in the early stage.
Herein, we show that carotid artery elasticity, as measured
in Japanese subjects with type 2 diabetes, correlates wellwith results obtained with currently established methods forevaluating atherosclerosis. Most importantly, elasticity correlates with the number of risk factors for atherosclerosisin those with IMT <1.1 mm, who are classified as not having atherosclerosis as defined by IMT criteria [22,23]. These
results strongly suggest that it is possible to detect early stage
atherosclerosis with this novel method.

2. Methods
2.1. Study subjects
The study subjects were recruited from among patients
followed at the diabetes clinic at Tohoku University Hospital. Patients with type 1 diabetes, renal failure (serum

Table 1
Subject characteristics
NumberAge (years)
Male (%)
Body weight (kg)BMI (kg/m2 )Duration of diabetes (years)
Fasting blood glucose (mg/dl)
HbA1c (%)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Total cholesterol (mg/dl)
HDL cholesterol (mg/dl)
LDL cholesterol (mg/dl)
Triglyceride (mg/dl)
Uric acid (mg/dl)
High-sensitive CRP (mg/dl)
Diabetic retinopathy (%)
Microalbumiuria or proteinuria (%)
Diabetic neuropathy (%)
Diet:OHA:insulin (%)
Hyperlipidemia (%)
Hypertension (%)
Current smoker (%)
BMI >25 (%)

242
62.1 ± 12.4
54.1
62.2 ± 13.6
24.2 ± 4.2
12.0 ± 9.70
141 ± 32.1
7.08 ± 1.33
130 ± 18.3
75.8 ± 11.1
191 ± 38.4
51.2 ± 14.6
115 ± 31.9
127 ± 94.1
5.09 ± 1.37
0.18 ± 0.23
30.2
38.8
46.4
20.0:37.8:42.2
37.2
39.3
30.6
38.0

Data are presented as means ± S.D.

creatinine >2.0 mg/dl), severe heart failure (NYHA functional class 2–4), atrial fibrillation and peripheral arterial
disease were excluded from the study. All participants analyzed were Japanese type 2 diabetes patients (n = 242) who
met the WHO criteria for diabetes mellitus. The study protocol was approved by the Tohoku University Institutional
Review Board. Informed consent was obtained from eachpatient. Subjects characteristics are shown in Table 1.
We used the following criteria for atherogenic risk
factors. Hyperlipidemia was defined as total cholesterol≥5.7 mmol/dl (220 mg/dl) and/or triglyceride ≥1.7 mmol/l(150 mg/dl), based on the definition proposed by the Japan
Atherosclerosis Society in 2002, or taking antihyperlipidemic drugs. The subjects whose systolic BP ≥140 mmHg
and/or diastolic BP ≥90 mmHg (The Japanese Society ofHypertension guidelines in 2004) or who were taking antihypertensive drugs were defined as having hypertension. The
subjects who currently smoked were classified as current
smokers.
2.2. Measurement of ABI and baPWV
Ankle brachial pressure index (ABI) and brachial ankle
pulse wave velocity (baPWV) were measured using an automatic waveform analyzer (BP-203RPE; Colin Co., Komaki,
Japan) after a 5 min rest. This device was designed to simultaneously measure blood pressure levels in both arms (brachialarteries) and ankles (posterior tibial arteries), and to then calculate the ankle systolic BP/brachial systolic BP. Pulse waves
were recorded on the right brachial artery and both posterior
tibial arteries. The average baPWV was calculated by divid-

H. Okimoto et al. / Atherosclerosis 196 (2008) 391–397

ing the arm–ankle distance by the pulse wave transmission
time between these points.
2.3. Measurement of carotid artery intima-media
thickness
Intima-media thickness of the carotid arteries was measured using ultrasound diagnostic equipment (EUB-450,
Hitachi Medico, Tokyo, Japan) with an electrical linear transducer (mid-frequency of 7.5 MHz). The common carotid
artery (CCA), carotid bulb and portions of the internal andexternal carotid arteries on both sides were scanned with thesubject in the supine position. The scan encompasses theregion between 30 mm proximal to the beginning of the dilation of the bifurcation bulb and 15 mm distal to the CCA flow
divider. We defined the max IMT as the thickest IMT in thescanned regions [24] and a max IMT <1.1 mm was considered normal. We defined a plaque, a focal IMT thickening, as
an area with IMT ≥1.1 mm and calculated the plaque score(PS) by totaling the maximal thickness values of all plaques inthe scanned area [25]. The scans were performed by a trained
sonographer and the scanning period averaged 20 min in eachpatient.
2.4. Measurement of arterial wall elasticity
Real-time measurement of regional elasticity in the carotid
artery wall was achieved based on a previously describedmethod [20] with ultrasound diagnostic equipment (prototype system by Panasonic). With this system, an ultrasoundbeam is used for sequential scanning at 32 positions with a linear type 7.5 MHz probe. Multiple points were preset from theluminal surface to the adventitia along each beam with constant intervals of 320 ␮m, and multiple layers were defined as
being between two neighboring points. Then, the displace-393

ment of each point preset along each beam was obtainedby applying the phased tracking method to the received
echo. Minute changes in the thickness of each layer were
determined by subtracting displacements of two neighboring points. The elasticity of each layer was obtained fromthe thickness change and the blood pressure measured at theupper arm. Since the reflected ultrasound was resampled at
an interval of 107 ns (=80 ␮m along the depth direction) after
quadrature demodulation, we further divided each layer witha thickness of 320 ␮m into four points, shifted the initial depthof each layer by one-fourth of 320 ␮m, and applied the above
procedure to each depth. Thus, the elasticity was obtained atintervals of 80 ␮m in the depth direction and 200 ␮m in theaxial direction of the artery. A cross-sectional image and theprocess of elasticity measurement are schematically depicted
in Fig. 1.
2.5. Statistical analysis
Variables were compared using Pearson’s regression analysis and Student’s t-test as appropriate. Then, a multiple
linear regression analysis was performed to evaluate the independent parameters that were significantly related to arterial
elasticity. The relationships between number of risk factors
and the values of atherosclerosis markers were examined byanalysis of covariance (ANCOVA), adjusted with age as acovariate. A p value less than 0.05 was accepted as indicating statistical significance. All statistical analyses were
performed using the Statistical Package for the Social Sciences Version 13.0 (SPSS Japan Inc., Tokyo, Japan).

3. Results
We assessed the associations of carotid artery elasticity
with subject characteristics (Table 2). Elasticity correlated

Fig. 1. The intima–media complex was visualized by conventional B-mode scanning (A), and minute thickness changes in the layers at each depth (113
depths × 32 beams per 9 mm × 6.4 mm scanned area) during one heart beat were then recorded by the phased tracking method (B). Thickness changes in eachlayer represent deformity, a reflection of elasticity. This elasticity is displayed as a 2D cross-sectional color image on B-mode scanning, and the image isupdated at every heartbeat (C). The elasticity distribution is shown as a histogram (D). Representative results obtained from a normal subject, case A (male,age 40), are shown. Case B (male, age 45), in marked contrast, suffered from type 2 diabetes, hyperlipidemia and an old cerebral infarction, but had an IMT of
only 0.5 mm, the same thickness as that of case A. The elasticity (E) was, however, extremely different from that of case A, as shown in the histogram (F).

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H. Okimoto et al. / Atherosclerosis 196 (2008) 391–397
Table 4Multivariate adjustment for parameters related to arterial elasticity

Table 2
Associations between arterial elasticity and subject characteristics
Variablesr-Valuep-Value

Variables

Coefficient (β)

95% CI

p-Value

Age
Duration of diabetes
Fasting blood glucose
HbA1c
Total cholesterol
HDL cholesterol
LDL cholesterol
Triglyceride
Systolic blood pressure
Diastolic blood pressure
Uric acid
High-sensitive CRP

0.34
0.136
−0.012−0.003
0.103
0.066
0.089
−0.064
0.443
0.147
−0.03
0.037

<0.01
<0.05
0.86
0.97
0.10
0.31
0.17
0.32
<0.01
<0.05
0.65
0.56

Age (years)
Duration of diabetes(years)Systolic blood pressure(mmHg)
Hyperlipidemia

0.28
−0.02

0.18–0.43−0.18–0.14

<0.01
0.77

0.39

0.21–0.38

<0.01

0.11

0.08–6.24<0.05

Table 3
Mean arterial elasticity values in the presence and absence of cardiovascularrisk factors
Variables

Elasticity (kPa)MaleHyperlipidemia
Hypertension
Current smoker
BMI >25
Diabetic retinopathy
Diabetic nephropathy
Diabetic neuropathy

p

−

+

51.6 ± 12.6
49.8 ± 12.3
49.6 ± 13.3
51.6 ± 13.3
51.6 ± 13.7
52.3 ± 13.7
50.5 ± 13.6
50.8 ± 12.9

51.0 ± 14.5
54.7 ± 13.7
54.8 ± 13.6
51.8 ± 14.5
51.6 ± 13.5
50.9 ± 14.1
53.9 ± 13.6
51.4 ± 14.4

Data are presented as means ± S.D.

0.99
<0.01
<0.01
0.88
0.99
0.67
0.06
0.65

with age (r = 0.340, p < 0.01), duration of diabetes (r = 0.136,
p < 0.05) and blood pressure, both systolic (r = 0.430,
p < 0.01) and diastolic (r = 0.147, p < 0.05).
We then examined whether or not cardiovascular risk factors affect arterial elasticity values (Table 3). Hyperlipidemic
subjects had significantly higher arterial elasticity values thanthose with normal lipid profiles. Similarly, subjects withhypertension had higher values. However, arterial elasticity values did not depend on other risk factors, such as sex,
obesity, smoking and diabetic complications.
To elucidate the independent variables affecting arterial
elasticity, we performed multiple linear regression analysis with parameters related to elasticity. We employed four
clinical parameters, age, duration of diabetes, systolic bloodpressure and hyperlipidemia, based on the results shown in
Tables 2 and 3. We found age, systolic blood pressure andhyperlipidemia to be independently associated with elasticity
values (Table 4).

Fig. 2. Correlations between arterial elasticity values and max IMT (A), plaque score (B), baPWV (C) and ABI (D).

H. Okimoto et al. / Atherosclerosis 196 (2008) 391–397

To assess the clinical relevance of carotid artery elasticity, we compared our elasticity values to those obtained withcurrently established methods for evaluating atherosclerosis:
max IMT, plaque score, baPWV and ABI. Carotid artery elasticity showed significant positive correlations with max IMT(r = 0.291, p < 0.01) (Fig. 2A), the plaque score (r = 0.220,
p < 0.01, n = 160) (Fig. 2B) and baPWV (r = 0.345, p < 0.01)(Fig. 2C) in subjects with type 2 diabetes. It should be kept inmind that the plaque score can be obtained only in subjects
with IMT ≥1.1 mm (n = 160), such that the correlation wasstudied only in those having definite atherosclerosis based on

395

IMT criteria [22,23]. Arterial elasticity showed no correlation with the ABI value (r = −0.087, p = 0.176) (Fig. 2D).
However, when we performed multiple linear regression
analysis adjusted with independent parameters, age, systolicblood pressure and hyperlipidemia (Table 4), the correlations
between elasticity and atherosclerosis markers (max IMT,
plaque score and baPWV) were no longer present.
In a subject with more than one risk factor, the atherosclerotic process would be accelerated and thus affect the valuesof atherosclerosis markers. Four modifiable risk factors, diabetes, hypertension, hyperlipidemia and current smoking,Fig. 3. Correlations of values reflecting atherosclerosis with the number of risk factors in all study subjects (A–E, n = 242) and subjects with max IMT <1.1 mm(F–I, n = 82). Data are presented as means ± S.E. * p < 0.05, ** p < 0.01.

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H. Okimoto et al. / Atherosclerosis 196 (2008) 391–397

were taken into account in this study. All subjects had atleast one risk factor, diabetes. When all the subjects wereanalyzed by ANCOVA, adjusted with age as a covariate, thehigher the number of risk factors, the greater the attenuation of arterial elasticity values, max IMT and the plaquescore (Fig. 3A, B, E). However, very interestingly, whensubjects with max IMT <1.1 mm, who are regarded as nothaving atherosclerosis based on IMT criteria, were analyzed(n = 82), only age-adjusted carotid artery elasticity correlatedwith an increasing number of risk factors (Fig. 3F). Other
age-adjusted parameters for evaluating atherosclerosis, max
IMT, baPWV and ABI, showed no significant correlations
with a greater number of risk factors in subjects with max
IMT <1.1 mm (Fig. 3G–I).

4. Discussions
Our most important finding is that in subjects with max
IMT <1.1 mm, who are regarded as being free of atherosclerosis based on IMT criteria [22,23], only carotid artery
elasticity as measured with our novel non-invasive method
correlated with an increasing number of risk factors. No
other values obtained with the currently available methods
showed correlations with the number of risk factors in these“non-atherosclerotic” subjects. Thus, our novel method of
measuring arterial wall elasticity raises the possibility ofdetecting atherosclerosis in its early stage.
Carotid artery elasticity correlates well with results
obtained with currently established methods for evaluating
atherosclerosis in subjects with type 2 diabetes. These results
strongly suggest that elasticity as measured with our current
method reflects the severity of atherosclerosis. The measurement procedures are relatively simple, essentially the same as
those of B-mode ultrasonography. In addition, arterial wall
elasticity is shown as a color coded cross-sectional image
with a side by side B-mode ultrasonogram, which is verypractical in the clinical setting.
This novel ultrasonic method accurately tracks the movement of the arterial wall based on both the phase and themagnitude of demodulated signals, allowing instantaneous
determination of the position of an object. With this method,
it is possible to accurately detect small-amplitude velocity
signals, less than a few micrometers, that are superimposedon arterial wall motion due to the heartbeat. This methodthus allows the elasticity, a qualitative feature, of the arterial
wall to be evaluated. In addition to detecting the early stage
atherosclerosis, this method may enable us to evaluate progression or regression of atherosclerosis in a much shortertime than currently available methods. This possibility isextremely interesting because a means of evaluating whether
or not a treatment is effective for preventing atherosclerosis
is urgently needed. It usually takes years to detect the progression or regression of atherosclerosis, while it may takeonly months with our present method of qualitative arterial
wall measurement. For example, it may be possible to detect

an improvement in response to statin treatment within a few
months. Similarly, we will be able to assess the effects onatherosclerosis of altering risk factors within months. Thesepossibilities clearly merits further study.
A variety of methods are widely used for evaluating
atherosclerosis. Measuring carotid IMT with ultrasound is
one of the most well-established methods because it is safe,
non-invasive, reproducible and easy to perform. IMT provides quantitative information, i.e. vessel-wall thickness.
Depicting changes in IMT is thus generally thought to takea long time. baPWV is also a non-invasive method, whichassesses atherosclerosis, as a reflection of arterial stiffness,and the usefulness of baPWV has been reported in clinicalstudies [26–28]. However, the pulse wave velocity depends
on the ratio of the inner radius of the artery to wall thickness,
which is not related to regional elasticity. It also reportedly
depends on heart rate [29].
While the elasticity average of the intima and media of
the carotid artery wall was calculated and used for evaluation of atherosclerosis in this study, another interesting aspectof elasticity is its distribution. The elasticity distribution,
which is depicted in a histogram, might provide additional
information regarding qualitative changes in atherosclerosis, and should be comprehensively studied in the future.
In conclusion, our novel method for evaluating carotid
artery wall elasticity holds promise for early detection ofatherosclerosis.

Acknowledgments
This work was supported by a Grant-in-Aid for Scientific Research (17790599) to Y. Ishigaki and the 21stCentury COE Programs “Innovative Therapeutic Development towards the Conquest of Signal Transduction Diseases”
to Y. Oka from the Ministry of Education, Science, Sports
and Culture of Japan. This work was also supported by aGrant-in-Aid for Research on Human Genome, Tissue Engineering (H17-genome-003) to Y. Oka. We thank Healthcare
Business Company, Matsushita Electric Industrial Co., Ltd.
(Panasonic), Yokohama, Japan for supplying the prototype
elasticity measurement system for this study.

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