J Med Ultrasonics (2006) 33:203–210
DOI 10.1007/s10396-006-0111-1© The Japan Society of Ultrasonics in Medicine 2006

ORIGINAL ARTICLE
Toshio YAMAGISHI · Makoto KATO · Yoshiro KOIWA
Hideyuki HASEGAWA · Hiroshi KANAI

Usefulness of measurement of carotid arterial wall elasticity distribution in
detection of early-stage atherosclerotic lesions caused by cigarette smoking

Received: December 27, 2005 / Accepted: April 28, 2006

Abstract
Purpose. The aim of this study was to evaluate early-stage
changes in the arterial wall caused by smoking.
Methods. A newly developed real-time ultrasonic measurement system was used to measure the elasticity distributionof the carotid arterial intima-media complex in 53 healthy
male volunteers (mean age: 37.6 years), including 27
smokers. Simultaneous measurement of the elasticity distribution and intima-media thickness (IMT) was performed at
six locations in the bilateral carotid arteries.
Results. The mean elastic modulus in the radial direction(Er) of the carotid arterial area where the IMT was less than
1.1 mm in smokers was larger than that in age-matched nonsmokers. There were no significant correlations between
IMT and Er at the same location. However, a significant
positive correlation was observed between the maximum
IMT (maxIMT) and that of Er (maxEr) in six locations. In
smokers, maxEr had a better correlation with the smoking
index, and areas of IMT less than 1.1 mm containing harderlesions of Er ≥ 160 kPa were significantly more frequent
than in nonsmokers.
Conclusion. Measurement of carotid arterial wall elasticity
is useful for detecting distortion in the intramural elasticity
distribution that occurs prior to IMT thickening caused bysmoking as an early-stage atherosclerotic sign.

T. Yamagishi (*)
Department of Internal Medicine, Tohoku Kosai Hospital, 2-3-11
Kokubun, Aoba, Sendai 980-0803, Japan
Tel. +81-22-227-2211; Fax +81-22-227-2228
e-mail: tyamagishi@tohokukosai.com
M. KatoHealthcare Business Company, Matsushita Electric Industrial Co.,
Yokohama, JapanY. Koiwa
Department of Medical Sciences, Graduate School of Medicine,
Tohoku University, Sendai, Japan
H. Hasegawa, H. Kanai
Department of Electronic Engineering, Graduate School ofEngineering, Tohoku University, Sendai, Japan

Keywords elasticity distribution · carotid arteries · intimamedia thickness · atherosclerosis

Introduction
Smoking is known to be a major risk factor for atherosclerosis, which can induce stroke and/or myocardial infarction,and cause endothelial dysfunction and arterial plaque inthe early stages of atherosclerosis. Carotid arterial intimamedia thickness (IMT) is one of the established indices ofchronic changes in atherosclerosis. For example, an IMTthat is valued equal to or thicker than an absolute threshold (such as 1.1 mm) or a predicted IMT based on age andother potential covariates is considered to be atherosclerotic.1–4 Measurement of increases or decreases in IMT
provides information about the speed of atherosclerotic
progression and the efficacy of drugs for improving atherosclerotic lesions. However, the IMT does not directly indicate the stiffness of the arterial wall.
Recently, a new ultrasonic system that can measure theregional elasticity of an arterial wall by using the phasedtracking method was developed.5–11 The modulus of elasticity has also been successfully derived from measurement of
the change in arterial wall thickness, as an index of “stiffness/softness.” This technology has been successfully combined with a system for displaying the modulus of elasticity
in color on two-dimensional ultrasound images of arteries,
enabling evaluation of the characteristics of the arterial wallin real time.
The aim of the present study was to determine whether
early-stage atherosclerotic changes can be detected by using
an ultrasonic-based tissue characterization system for arterial walls. We found that measurement of the carotid arterial wall elasticity distribution was useful for detecting
early-stage atherosclerotic lesions caused by cigarettesmoking.

204
Table 1. Characteristics of the study populationnSmoking index (cigarettes × years)
Age (years)
BMI (kg/m2)
Systolic BP (mmHg)
Diastolic BP (mmHg)
Pulse pressure (mmHg)
Heart rate (bpm)

Nonsmokers

SmokersP

26–
37.9 ± 6.6
23.4 ± 3.1
114.1 ± 9.3
72.5 ± 7.5
41.6 ± 10.4
68.2 ± 9.4

27343.5 ± 172.0
38.7 ± 7.2
23.5 ± 3.4
117.9 ± 10.7
73.7 ± 10.1
44.2 ± 7.5
70.0 ± 7.2

0.67
0.87
0.18
0.64
0.31
0.46

Values are expressed as mean ± SD
BMI, body mass index; BP, blood pressure

Materials and methods
Subjects
The study group comprised 53 healthy male volunteers aged
20 to 49 years (mean age 37.6 ± 7.2 years). None of the participants had systemic hypertension (blood pressure<140/90 mmHg), diabetes mellitus (fasting glucose <110mg/dl, HbA1c <5.8%), hypercholesterolemia (fasting totalcholesterol <220 mg/dL), or cardiac disease, and none wastaking any medication. Chronic smokers (n = 27) werematched for age, height, and weight with nonsmokers (n =26). Table 1 shows the characteristics of the study population. There was no significant difference between smokers
and nonsmokers with respect to any parameter. Smoking
status was categorically evaluated on the basis of selfreports. The smokers smoked an average of 19.2 ± 5.3 cigarettes per day for 17.3 ± 6.6 years. The smoking index was
defined as the product of the number of cigarettes smoked
per day and smoking years. The average smoking index was
343.5 ± 172.0 (cigarettes × years). The nonsmoking group
was composed of only men who had never smoked; it did
not include past smokers or passive smokers in the office
and/or at home.

Carotid IMT and elasticity measurements
The subjects were studied after having abstained from caffeine, alcohol, and smoking during the previous 12 h. The
subjects rested in a supine position for 15 min in a quiet
room before the baseline hemodynamic measurements
were obtained. Brachial blood pressure and heart rate(mean of three readings) were measured in the right arm
with an automated digital oscillometric sphygmomanometer (EW-3110; Matsushita Electric Works, Osaka, Japan).
The subjects provided informed consent, and the study wasapproved by the institutional ethics committee of Tohoku
Kosai Hospital and Matsushita Electrical Industrial Co.,Ltd.
An imaging study of the bilateral common carotid arteries was performed using a high-resolution ultrasonic measurement system (Panasonic, prototype) with a center
frequency of 7.5 MHz. One well-trained sonographer who

regularly participates in quality control measurement sessions performed all ultrasound scans.
IMT can only be determined accurately in the far wall
position, because only the far wall IMT is defined by leadingedges, which enables correct ultrasonographic representation.Therefore, the far walls of the following sites were measured: (1) the distal 3 cm of the straight part of bothcommon carotid arteries; (2) the distal 1 cm of both carotid
bulbs; and (3) the right and left carotid bulbs (from 1 cm
proximal to the level of the flow divider).
This system measures the radial strain of the arterial walland calculates the elasticity from the radial strain and theblood pressure. The distribution of the elasticity is displayed
as a 2D cross-sectional color image on a B-mode image, andthe image is updated at every heartbeat. For measurementof minute changes in thickness, this system uses the phased
tracking method.5–10 Elasticity was estimated at intervals of
80 µm in the depth direction and 400 µm in the axial direction. From the maximum change in thickness during one
heartbeat, the radial strain of each assigned layer in theartery wall (εr) was calculated as follows:
εr = (hmax − hmin)/hmax,(1)where hmax and hmin are the maximum and the minimum
thickness of an assigned layer in the wall, respectively.
Elastic modulus in the radial direction (Er) and elastic
modulus in the circumferential direction (Eθ) were calculated as follows:
Er = pulse pressure/εrEθ = 1/2 × (r0/h0 + 1) × Er

(2)
(3)

where pulse pressure is the difference between the systolicand diastolic brachial blood pressure (the carotid bloodpressure would be more accurate but is not easy tomeasure), h0 is the initial thickness of the wall, and r0 is theinitial radius of the vessel. The measurement reproducibility for this system has been reported previously.11 The sonographer trained to obtain an Er measurement deviation ofless than 10% in the same subject.
Pulse Wave Velocity (PWV) measurements
Brachial-ankle PWV (baPWV) was measured using a
volume-plethysmographic apparatus (Form/ABI; Colin,

205

Aichi, Japan) from simultaneous blood pressure andwaveform measurements from all four limbs along withelectrocardiogram and phonogram tracings. PWV was automatically calculated by time-phasic analysis using the following formula: distance between two sites divided by pulse
wave transit time. baPWV was measured from the ascending point of the right brachial pulse volume recorder to theascending point of each ankle pulse volume recorder. The
distance between the right brachium and ankle was estimated as described previously.12
Statistical analysis
Data are expressed as the mean ± SD. Statistical analysis was
performed using the SPSS software package (SPSS, Chicago,
IL, USA), and a value of P < 0.05 was considered significant.
The differences between smokers and nonsmokers wereanalyzed by one-way analysis of variance (ANOVA). Linear
regression analysis was performed to evaluate the association between IMT, elasticity, or baPWV and other clinicalvariables. Multiple linear regression analysis was applied toevaluate whether the relationship between the two parameters was independent of other related factors.

Results
Figure 1 shows a typical image of the right carotid arterial
wall of a 44-year-old male smoker. In this image, themaximum IMT was 0.8 mm, and the average values of Er
and Eθ in the colored area were 82 kPa and 473 kPa, respectively. The pattern of distribution of the elasticity modulus
was scattered and heterogeneous (Figs. 1B, 4A).
The relationships between the maximum IMT and theaverage Er at the right carotid artery in all cases are shownin Fig. 2A. In this area, the maximum IMT was less than 1.1mm, and there was no significant relationship between the
maximum IMT and Er. The average Er but not average Eθ
in smokers was significantly higher than that in nonsmokers (Er, 39.2 ± 13.7 kPa vs 29.3 ± 7.3 kPa, P = 0.0020, Fig. 2C;Eθ, 147 ± 50.1 kPa vs 127.6 ± 37.4 kPa, P = 0.10), although
there was no difference in the maximum IMT values
between the two groups (0.63 ± 0.12 mm vs 0.61 ± 0.13 mm,
P = 0.52, Fig. 2B). Calcified plaque on B-mode imaging was
found in two smokers in their 40s (data not shown).
By examining six locations on the bilateral carotid arteries, we defined the maximum IMT value as maxIMT, themaximum value of average Er as maxEr, and the maximun

Er
500
250
anterior walllumen

0 (kPa)inner radius
intima-media complex

posterior wall

thickness of wall
adventitiaaFig. 1A,B. Typical imaging of the right carotid arterial wall with the
IMT and elasticity recorded simultaneously, shown here for a 44-yearold male smoker. a B-mode image. In the intima-media complex area,
the solid red line shows the position of the maximum IMT (0.8 mm)
and the solid white line shows that of the minimum (0.6 mm). b Distri-b
bution of the elastic modulus in the radial direction (Er). The coloredarea in the white box shows the distribution of Er at intervals of 80 µm
in the depth direction and 400 µm in the axial direction according to
the color scale at the upper right. The averages of Er and Eθ are 82 kPa
and 473 kPa, respectively

206

SmokerNon-smoker

8070

r=0.11 p=0.43

60
50

the maximum valueof IMT (mm)

1.0

0.8

0.6

0.4

b

Non-smoker

Smoker60

40

50
the averageof Er (kPa)

the average of Er (kPa)

Fig. 2. a Plots of maximum IMT
and average Er at the central
side of the right carotid artery.
No significant correlation
between the two was seen.
b Average maximum IMT values
in smokers and nonsmokers
were not significantly different(0.63 ± 0.12 mm vs 0.61 ±0.13 mm, P = 0.52). c The
average Er in smokers was
significantly higher than that innonsmokers (39.2 ± 13.7 kPa vs29.3 ± 7.3 kPa, P = 0.0020)

30
20

*

40
30
20

10
0.4 0.5 0.6 0.7 0.8
a

c

10

Non-smoker

Smokerthe maximum value of
IMT (mm)Table 2. Comparison of atherosclerotic parameters

maxIMT (mm)maxEr (kPa)maxEθ (kPa)baPWV (cm/s)
Number of cells with Er ≥ 160 kPaa

Nonsmokers(n = 26)

Smokers(n = 27)P

0.86 ± 0.14
37.3 ± 10.3
171.0 ± 59.0
1211.2 ± 132.4
2.6 ± 4.5

0.99 ± 0.26
44.5 ± 14.2
190.0 ± 52.0
1220.8 ± 139.0
10.2 ± 13.1

0.02840.03940.23
0.80
0.0078

Values are expressed as mean ± SD
IMT, intima-media thickness; baPWV, brachial-ankle pulse wave velocity; maxIMT, maxEr, andmaxEθ, maximum values of IMT, Er, and Eθ for six locations, respectivelya
Details are shown in Fig. 4

value of average Eθ as maxEθ. As shown in Table 2, there
were significant increases in maxIMT and maxEr insmokers compared with nonsmokers. MaxEθ showed only
a statistically nonsignificant tendency to increase insmokers. There was no difference in baPWV between thetwo groups (Table 2).
Figure 3 shows that in smokers, maxEr had a better
correlation with the smoking index (r = 0.59, P = 0.0013,
Fig. 3C) than with age (r = 0.48, P = 0.0109, Fig. 3A), andmaxIMT had a better correlation with age (r = 0.66, P =0.0001, Fig. 3B) than with the smoking index (r = 0.46, P =0.0161, Fig. 3D). As shown in Table 3, maxEθ had similarcorrelations with age (r = 0.35, P = 0.08) and smoking index(r = 0.50, P = 0.0080). We compared the relationship of eachof maxIMT, maxEr, maxEθ, and baPWV with age andsmoking index, as shown in Table 3. In nonsmokers, baPWV
had the highest correlation with age, and the rank of thecorrelation coefficients with age was baPWV > maxIMT >elastic modulus (maxEθ > maxEr). In smokers, maxIMT
had the highest correlation with age, and the rank of thecorrelation coefficients with age was maxIMT > baPWV >elastic modulus (maxEr > maxEθ). In contrast, the rank of
the correlation coefficients with smoking index was elastic
modulus (maxEr > maxEθ) > maxIMT > baPWV.Therefore,
maxEr reflected the effects of smoking better than maxIMT
and baPWV.
In smokers, areas of intima-media complex less than 1.1
mm in thickness were observed to contain harder lesions of
160 kPa or higher (Er ≥ 160 kPa) more frequently than in
nonsmokers, and the number of cells with Er ≥ 160 kPa
counted from the histogram of Er was compared between
the two groups. For example, in the case shown in Fig. 1, thenumber of cells with Er ≥ 160 kPa was 19 (8%, Fig. 4A).
Figure 4B shows that the number of cells with Er ≥ 160 kPa

207
r=0.48, p=0.0109

70

70

60

60

50
40

50
40

30

30

20

20

20

30

40

50

0

Age (years)ar=0.59, p=0.0013

80

maxEr (kPa)maxEr (kPa)80cr=0.66, p=0.0001

600

800

r=0.46, p=0.0161
1.6

1.4

1.4

maxIMT (mm)maxIMT (mm)400

Smoking index (cigarettes x years)

1.6

1.2
1.0
0.8
0.6
20

200

1.2
1.0
0.8
0.6

30

b

40

0

50

d

Age (years)

200

400

600

800

Smoking index (cigarettes x years)

Fig. 3. Correlation of age with maxEr (a) and maxIMT (b), and correlation of smoking index with maxEr (c) and maxIMT (d) in smokers

Table 3. Correlation coefficients for parameters in nonsmokers andsmokersNonsmokers
maxIMT vs maxEr
maxIMT vs maxEθAge vs maxIMT
Age vs maxEr
Age vs maxEθAge vs baPWV
Smokers
maxIMT vs maxEr
maxIMT vs maxEθAge vs maxIMT
Age vs maxEr
Age vs maxEθAge vs baPWV
Smoking index vs maxIMT
Smoking index vs maxEr
Smoking index vs maxEθ
Smoking index vs baPWV

r

P

0.06
0.10
0.42
0.24
0.36
0.47

0.78
0.63
0.03250.24
0.08
0.0183

0.39
0.33
0.66
0.48
0.35
0.57
0.46
0.59
0.50
0.26

0.04560.09
0.00010.01090.08
0.00210.01610.00130.00800.20

IMT, intima-media thickness; baPWV, brachial-ankle pulse wave velocity; maxIMT, maxEr, and maxEθ, maximum values of IMT, Er, and Eθ
for six locations, respectively

was significantly and positively associated with age forsmokers but not for nonsmokers. Some younger smokers intheir 20s had harder carotid lesions. As shown in Table 2,
there were significant increases in the number of cells with
Er ≥ 160 kPa in smokers compared with nonsmokers, whichaccording to age were 1.3 in nonsmokers in their 20s (n =3), 9.0 in smokers in their 20s (n = 4), 1.2 in nonsmokers intheir 30s (n = 10), 6.9 in smokers in their 30s (n = 9), 4.0 in
nonsmokers in their 40s (n = 13), and 12.6 in smokers
in their 40s (n = 14, Fig. 4C). In multiple regression analysis, the number of cells with Er ≥ 160 kPa showed a significant correlation with age and smoking (r = 0.49, F = 7.7496,
P = 0.0012).

Discussion
Cigarette smoking is a risk factor for atherosclerosis, andtherefore myocardial infarction and stroke later in life. The
aim of the present study was to show a direct relationshipbetween chronic smoking and carotid arterial stiffness in a
population without additional cardiovascular risk factors.

35 Er<160kPa

Frequency

30

211 cells (92%)

Number of cells with Er⭌160(kPa)

208
Er⭌160kPa
19 cells (8%)

25
20
15
10
5
0

0

Number of cells with Er⭌160 (kPa)

a

b

50

100

200 300
Er (kPa)

Smokerr=0.38196
Non-smoker r=0.36912

400

500

15

10

5

40s
30s

c

Smoker20s

Non-smoker

p=0.0493
p=0.0635

40
30
20
10
0
20

30
40
Age (years)

50

We found that there was heterogeneity and increased
elasticity of the carotid arterial wall in smokers, which could
be a good marker of early-stage atherosclerosis caused bychronic smoking. We focused only on relatively young men
because in women it is sometimes difficult to rule out theeffects of female hormones, and subjects older than 50 years
would be more affected by aging.
Measurement of IMT allows the detection of atherosclerotic lesions with morphological changes and remodeling such as thickening and calcification, which would
happen perhaps later in the time course. IMT is also correlated with age, and it increases in older subjects. However,it cannot be used to assess acute or early changes in the arterial wall caused by cigarette smoking. In the present study,
we demonstrated that IMT in smokers in their 40s was significantly increased and that some smokers showed calcified
plaque, which was previously thought not to occur at suchan early age, while some younger subjects in their 20s
without thickening of the intima-media complex alreadyshowed harder carotid lesions, at least in terms of elasticity(Fig. 4B).
PWV and the augmentation index (AIx) are establishedmarkers of atherosclerosis,13 but they cannot reveal regional
atherosclerotic changes, even though they are related toultrasonographically detected atherosclerotic changes inFig. 4. a Histogram of the carotid arterial elasticity (Er) of the same
44-year-old smoker as in Fig. 1. b Plots of age versus number of cellswith Er ≥ 160 kPa for men in their 20s, 30s, and 40s. Significant correlations were seen for smokers (solid line) but not for nonsmokers(dotted line). Correlation coefficients and P values are shown in thepanel. c Average number of cells with Er ≥ 160 kPa in age-matchedsmokers and nonsmokers

the carotid artery. Several studies14,15 have indicated that
acute cigarette smoking increases the arterial stiffness measured by PWV and/or AIx. However, the chronic effects ofsmoking are controversial. Wollersheim et al.16 described
increased arterial stiffness of the popliteal artery and a tendency toward stiffening of the common femoral and carotid
arteries in 13 habitual smokers measured ultrasonographically by using the pressure–strain elastic modulus. Mahmud
et al.15 observed a much higher AIx in smokers comparedwith nonsmokers in a young homogenous group of healthy
adults who were matched for age, height, weight, and hemodynamic status, although there was no statistically significant difference in PWV. However, others have found nodifference in the regional arterial compliance between
smokers and nonsmokers.17,18 Liang et al.19 reported thatsmoking does not influence the lumen-to-wall ratio but hasa significant effect on wall stiffness. Munakata et al.12
reported that age, systolic blood pressure, and the stage ofhypertensive organ damage are major determinants ofbaPWV. Such discrepant results for chronic smoking effects
on increases in arterial wall stiffness might be caused, atleast partly, by differences in experimental methodologies.
Therefore, in order to focus on the chronic effects ofsmoking, elasticity was measured in the present study. All
measurements were carried out after the subjects had not209

smoked during the previous 12 h to rule out the acute effectsof smoking. Although PWV was not different between
smokers and nonsmokers, the carotid arterial elasticity insmokers was significantly higher than that in age-matchednonsmokers (Table 2). A positive significant correlation wasobserved between maxIMT and maxEr in the measurements at the six locations. Although maxEr_ and maxIMT
were significantly correlated with age and the smoking
index, maxEr reflected the effects of smoking better thanmaxIMT and baPWV (Table 3). In addition, the harderareas (Er ≥ 160 kPa) were found to be more highly reproducible and were seen more frequently in smokers than in
nonsmokers. Thus, it seems that distortion in the intramuralelasticity distribution occurs prior to IMT thickening causedby smoking.
However, there are limitations to our study that should
be considered. First, in this noninvasive study, the actual
structure cannot be determined, and we can only speculate
as to what the underlying changes may be. Different
cardiovascular risk factors, such as high blood pressure,changes in lipid and sugar profiles, endothelial factors, andchanges in arterial wall structure and function, appeared toinfluence the relationships among arterial geometry, wallstress, and stiffness in different ways. Our results, however,are consistent with those showing that smoking initiallycauses increased stiffness. Endothelium-dependent functional changes are also likely to contribute to the increased
stiffness, given the adverse effects of smoking on endothelial function. It has been previously demonstrated that there
is a good relationship between elasticity obtained using thecurrent method and the tissue characteristics obtained fromisolated iliac arteries with plaques.7 The cross-sectional elasticity distribution could be classified into three categories:
lipids, a mixture of smooth muscle and collagen fibers, andothers. Lee et al.20 reported that the stiffness of fibrous caps
from human atherosclerotic plaques is related to the underlying histological structure. It is possible that the harderlesions (Er ≥ 160 kPa) represent changes due to chronic
spasms caused by endothelial dysfunction or a remodeled
region that contains more collagen fibers or minor calcification. Inagaki et al.21 reported that there is a relationshipbetween collagen content and elasticity. Based on thisreport, we estimated that Er = 160 kPa, still a provisional
figure, could be the elasticity associated with 10% collagen,and used this as a borderline value for early changes inatherosclerosis.
Second, Eθ may be an ideal marker to indicate the elasticity of the arterial wall itself because Er (an apparent elasticity) is influenced not only by an increase in elasticity but
also by the thickness of the arterial wall at the same location, especially in the thicker areas. However, a limitationof the measurement of Eθ with the current technique is thatechoic demonstration of the borders of the anterior walland the adventitia of the posterior wall of the carotid arteryis fuzzy and imprecise, especially on curved boundaries suchas the bulb and severely atherosclerotic regions. Without an
accurate measurement of h0/r0 as described in the materials
and methods section, Eθ cannot represent the real elasticity. In fact, the statistical values for Eθ were not as good as

those for Er and IMT in the present study. As shown in Fig.
2, within the range of IMT values of our subjects, theincrease in Er was not related to the increase in IMT at thesame location. Therefore, we believe that increases in Er insmokers are increases in stiffness associated mainly withsmoking. However, we cannot distinguish chronic spasms
caused by smoking from early atherosclerotic remodeling at
this stage.
Further studies will be needed to determine the actual
meaning of the changes in the elastic modulus in smokers
and to refine the technique for measuring such changes.

Conclusion
Measurement of carotid arterial wall elasticity distribution
to detect early-stage atherosclerotic lesions caused bysmoking may be more useful than conventional IMT
measurement.

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