Japanese Journal of Applied Physics
Vol. 44, No. 8, 2005, pp. 6297–6301#2005 The Japan Society of Applied Physics

Change in Elasticity Caused by Flow-Mediated Dilation Measured
Only for Intima–Media Region of Brachial Artery
Masataka S UGIMOTO, Hideyuki H ASEGAWA and Hiroshi K ANAI
Graduate School of Engineering, Tohoku University, Sendai 980-8579, Japan(Received November 12, 2004; accepted May 12, 2005; published August 5, 2005)

Endothelial dysfunction is considered to be an initial step of arteriosclerosis [R. Ross: N. Engl. J. Med. 340 (2004) 115]. For
the assessment of the endothelium function, brachial artery ﬂow-mediated dilation (FMD) caused by increased blood ﬂow has
been evaluated with ultrasonic diagnostic equipment. In the case of conventional methods, the change in artery diameter
caused by FMD is measured [M. Hashimoto et al.: Circulation 92 (1995) 3431]. Although the arterial wall has a layered
structure (intima, media, and adventitia), such a structure is not taken into account in conventional methods because thechange in diameter depends on the characteristic of the entire wall. However, smooth muscle present only in the media
contributes to FMD, whereas the collagen-rich hard adventitia does not contribute. In this study, we measure the change inelasticity of only the intima–media region including smooth muscle using the phased tracking method [H. Kanai et al.: IEEE
Trans. Ultrason. Ferroelectr. Freq. Control 43 (1996) 791]. From the change in elasticity, FMD measured only for the intima–
media region by our proposed method was found to be more sensitive than that measured for the entire wall by theconventional method. [DOI: 10.1143/JJAP.44.6297]
KEYWORDS: flow-mediated dilation (FMD), endothelium function, nitric oxide (NO), atherosclerosis

1.

Introduction

Endothelial damage is a possible trigger of the development of atherosclerosis.1) Therefore, it is very important todiagnose endothelial damage at an early stage. In the case of
conventional methods, blood ﬂow in the brachial artery is
stopped using a cuﬀ at a pressure of 250 mmHg for 5 min.2)
After recirculation, the increase in the diameter of thebrachial artery due to ﬂow-mediated dilation (FMD) ismeasured to evaluate the endothelium function.2) Smoothmuscle only in the media is relaxed by nitric oxide (NO) thatis generated in the endothelium in response to increased
blood ﬂow, whereas the collagen-rich hard adventitia does
not respond to NO. However, the change in diameter, which
is used in conventional methods, is dependent on themechanical properties of the entire wall including theadventitia. Therefore, the sensitivity in FMD detection
deteriorates because the layered structure (intima, media
and adventitia) is not taken into account in conventional
methods. In this study, the change in elasticity of the intima–
media region was measured with a high accuracy and a good
reproducibility using the phased tracking method3,4) toimprove the sensitivity of FMD detection.
2.

Principles

2.1 Elasticity estimation of arterial wall
For the measurement of a small change in wall thickness,the phase shift of the echo caused by the displacement of an
object is estimated from two consecutive echoes. For thispurpose, quadrature demodulation is applied to the received
ultrasonic waves reﬂected by the object, and then thein-phase and the quadrature signals are A/D-converted.
From the demodulated signal zðt; d þ xðtÞÞ reﬂected at
depth d þ xðtÞ at time t, where d and xðtÞ are the initial
depth set at t ¼ 0 and the displacement of the object along
the direction of depth, respectively, the phase shift ðtÞ
during a pulse repetition interval, T, is obtained from thecomplex cross correlation function between zðt; d þ xðtÞÞ andE-mail address: hkanai@ecei.tohoku.ac.jp

zðt þ T; d þ xðtÞÞ.3,4)
From the estimated phase shift ^ðtÞ, the velocity vðtÞ ofthe object is obtained as follows:v^ðtÞ ¼ 

c0 ^ðtÞ;
2!0 Tð2:1Þ

where !0 and c0 are the center angular frequency of theultrasonic pulse and the speed of sound, respectively.
In the velocity estimation, the object position is tracked byintegrating the velocity vðtÞ during the pulse repetitioninterval T as follows:x^ðt þ TÞ ¼ x^ðtÞ þ v^ðtÞ  T
c0
¼ x^ðtÞ ^ðtÞ:2!0

ð2:2Þ

From the displacements xA ðtÞ and xB ðtÞ of two points (Aand B), which are set in the arterial wall along an ultrasonicbeam, the small change in thickness hðtÞ between thesetwo points is obtained as follows:h^ðtÞ ¼ x^A ðtÞ  x^B ðtÞZt¼ fv^A ðtÞ  v^B ðtÞg dt:
ð2:3Þ
0

The change in thickness hðtÞ corresponds to the straincaused by the change in blood pressure pðtÞ. Therefore, fromthe maximum change in wall thickness hmax ¼ maxt jhðtÞj
and the maximum change in blood pressure pmax (diﬀerence between systolic pressure and diastolic pressure), theapproximate circumferential elastic modulus Eh is obtained
as follows:5,6)


1 r0
pmax
Eh 
þ1
;
ð2:4Þ
hmax
2 h0
h0
where r0 and h0 are the inner radius and wall thickness at theend diastole, respectively.
2.2 Procedure for in vivo measurement
Blood ﬂow in the brachial artery is blocked by surrounding the forearm with a cuﬀ at a pressure of 250 mmHg for

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M. S UGIMOTO et al.

5 min. After the release of the cuﬀ, nitric oxide, which is
generated in the endothelium in response to shear stresscaused by increased blood ﬂow, relaxes the smooth muscle
in the media. We measured the change in the elasticity of theintima–media region of the artery due to FMD with a
10 MHz linear-type ultrasonic probe (Aloka, SSD6500) 11
times at an interval of about 10 s. The change in thickness
was measured for two consecutive heartbeats in eachmeasurement.
2.3

Determination of optimum layer for measuring change
in thickness
The change in wall thickness needs to be measured withgood reproducibility to detect the change in elasticity.
However, it is diﬃcult to measure the change in the wall
thickness of the brachial artery in comparison with the
carotid artery because the wall of the brachial artery isthinner than that of the carotid artery and the change inthickness is small. Therefore, the optimum layer formeasuring the change in thickness is determined as follows:
As shown by the data (Fig. 1) measured from a 24-year-old
male, when we examine echoes from the lumen to theoutside of the posterior wall of the artery along an ultrasonicbeam indicated by a vertical arrow with dashed line in
Fig. 1(b), ﬁrstly, a clear echo, which is reﬂected from thelumen–intima interface, can be found. Then, the amplitudeof the echo slightly decreases in the media region, and thatof the echo increases again around the media–adventitia
interface.7) To obtain the change in thickness due to theheartbeat of the intima–media region, two points were
designated as the lumen–intima interface and the media–
adventitia interface along an ultrasonic beam.
As shown in Fig. 1(c), the echo from the lumen–intima
interface can be easily recognized. Therefore, the lumen–
intima interface din is manually set as shown in Fig. 1(b),and the displacement xin ðtÞ at this point din is estimated by
the phased tracking method.3,4) A slight diﬀerence in the
manually assigned depth din does not have serious inﬂuenceson the estimation of the artery wall elasticity.
To obtain the change in thickness, another point must be
set along the same ultrasonic beam to determine the layer tobe analyzed. However, as shown in Fig. 1(c), the beginning

2 mmof the echo from the media–adventitia interface is not veryclear in comparison with that from the lumen–intima
interface because there are weak echoes from the inside of
the wall. Therefore, the optimum layer for the measurementof the change in thickness is determined as follows.
Although it is diﬃcult to clearly diﬀerentiate the echo fromthe media–adventitia interface from echoes from scatterers
in the media, the amplitude of the echo from the media–
adventitia interface is larger than those of other echoes.
Therefore, with respect to measured RF data showing atypical pattern of echoes from the lumen–intima and media–
adventitia interfaces (as shown in Fig. 1), the beginning of
the echo from the media–adventitia interface is approximately assigned manually as the ﬁrst candidate point d1 .
Then, multiple candidate points din (k ¼ 1; 2; . . . ; 9) are
assigned along the ultrasonic beam at a pitch of 19.25 mm.
The distance from d1 to dk is set at 154 mm in considerationof the half-value width of an employed ultrasonic pulse of
122 mm. Then, the displacement xk ðtÞ (k ¼ 1; 2; . . . ; 9) ofeach point, dk , is estimated, and the change in thicknesshk ðtÞ between two points, din and dk , is obtained byhk ðtÞ ¼ xk ðtÞ  xin ðtÞ ðk ¼ 1; 2; . . . ; 9Þ:

ð2:5Þ

The change in thickness hk ðtÞ is measured for each of
two consecutive heartbeats in one measurement, and the
maximum Hk;1 and Hk;2 of the measured change inthickness hk ðtÞ are determined for both heartbeats. From
Hk;1 and Hk;2 , the reproducibility between two heartbeatsis evaluated by the normalized standard deviation k (k ¼1; 2; . . . ; 9) of the maximum change in thickness deﬁned bysﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃ
N1X
jHk;i  H j2
N i¼1
k ¼
ðk ¼ 1; 2; . . . ; 9Þ: ð2:6Þ
H
H ¼

N
1X
Hk;i ;
N i¼1

ð2:7Þ

where N is the number of heartbeats (in this study, N ¼ 2).
The distance from din to d1 is set to be larger than pulse
width.
In Fig. 2, k obtained for RF data showing a typical
pattern of echoes (the same data shown in Fig. 1) is plotted
as a function of distance, dk  din . From the point dmin which
gives the minimum of k , the thickness of the layer to be(a)
0.5 mm
(b)

α
(c)
0.4
...

d9

...

lumen

...

anterior
wall

d in
d1

0.5 mm0.6

2 mm

posterior
wall

0.2

α min
0
327

Fig. 1. (a) B-mode image of brachial artery of 24-year-old male alongplane perpendicular to axis of artery. (b) Enlarged view of region
surrounded by white line in (a). (c) Received RF signal along ultrasonicbeam indicated by vertical arrow with dashed line in (b).

366

404

443
481
thickness of layer [µµm]Fig. 2. Determination of optimum layer corresponding to intima–media
region from normalized standard deviation, min , of maximum change inthickness.

Jpn. J. Appl. Phys., Vol. 44, No. 8 (2005)

M. SUGIMOTO et al.

3000

depth

(a)

6299

(a)

first beatsecond beatx in (t)x min (t)1.0elasticity [kPa]

5.0 mm

2500
2000
1500

(b)

1000

(c)

500

(d)

0

mm/s 0–1.0
1.0mm/s 0

(b)

0.30

–1.0
20

(e)

α

µm 0

0.20

–20
0

1

2

Fig. 3. (a) M-mode image of brachial artery (24-year-old male). (b)Electrocardiogram. (c) Velocity at point designated as lumen–intima
interface. (d) Velocity at point designated as media–adventitia interface.
(e) Change in thickness.

analyzed is determined to be dmin  din . din and dmin are set
at echoes from the lumen–intima and media–adventitia
interfaces, respectively. Therefore, the change in the thickness of the intima–media region can be obtained.

0
avascularization

20

40

60
time [s]10080

release of cuff

Fig. 4. (a) Changes in elasticity for intima–media region after recirculation (24-year-old male). (b) Change in  obtained with respect tooptimum layer, dmin  din .

3000

(a)

first beatsecond beat2500

In Vivo Experimental Results

2000
elasticity [kPa]

Figure 3(a) shows an M-mode image of the brachial arteryof the same subject shown in Fig. 1 immediately after
release of the cuﬀ (t ¼ 0). By determining the optimum
layer as described in §2.3, the change in the thickness of thelayer corresponding to the intima–media region is obtained
as shown in Fig. 3(e) by measuring velocities at two points,
din and dmin , as shown in Figs. 3(c) and 3(d). Changes in the
thickness and elasticity of the intima–media region were
determined for other successive measurements.
Figure 4 shows the change in elasticity of the intima–
media region. Around 30 s after the release of the cuﬀ, thediscriminate decrease was found in the measured elasticity.
From the mean elasticity between two heartbeats, thenormalized maximum decrease in the elastic modulus
compared with the elastic modulus at t ¼ 0 was determined
to be 65.1%.
Figure 5(a) shows the change in elasticity of the brachialartery of the same subject shown in Fig. 4 obtained by
setting din to be deeper by one point than that in Fig. 4. From
the results shown in Fig. 5, a slight diﬀerence in setting dindoes not have serious inﬂuences.
Figures 6 and 7 show changes in elasticity measured fora 25-year-old male and a 31-year-old male, respectively.
The maximum decreases in the elastic modulus comparedwith the elastic modulus at t ¼ 0 were 42.7 and 52.5%,
respectively.
These FMD% values evaluated from elasticity werecompared with those obtained by the conventional arterydiameter measurements. Figures 8(a), 9(a), and 10(a) show
RF echoes obtained at R-waves (ﬁrst beat) of the electrocardiogram during successive measurements. From Figs.
8(a), 9(a), and 10(a), artery diameter at each measurement
was measured as shown in Figs. 8(b), 9(b), and 10(b).

0

1500
1000
500
0
(b)

0.3
0.2
α

3.

0.10

time [s]0.1
0avascularization

0

20

40

60

80

100

time [s]release of cuff

Fig. 5. Changes in (a) elasticity and (b)  for intima–media region afterrecirculation (24-year-old male). Intima–media interface, din , shifted in
the depth direction by one point in comparison with that shown in Fig. 4.

FMD% values obtained from artery diameter were 6.7, 1.4,
and 11.0% for the 24-year-old male, the 25-year-old male,and the 31-year-old male, respectively. These values werecomparable to those reported in literature,2) and it was foundthat FMD% obtained by the proposed method is much larger
than that obtained by the conventional diameter measurement. These results can be well explained by the ﬁnding thatnitric oxide generated in the endothelium speciﬁcally relaxes
smooth muscle in the media. From these results, for theevaluation of endothelium function, the measurement of thedecrease in the elasticity of the intima–media region isconsidered to be more eﬀective than the measurement of theincrease in diameter by conventional methods.

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M. S UGIMOTO et al.

1000

1000

(a)

elasticity [kPa]800

elasticity [kPa]

600

600

400

400

200

200

0

0
0.12

(b)

α

0.10

α

800

0.12

(b)

0.10

0.08

0.08

0.06

0.06

0.04

0.04

0.02

0.02

0
avascularization(a)first beatsecond beatfirst beatsecond beat

0
0

20

40

60
time [s]

80

100

0

avascularization

20

40

60

80

100

time [s]release of cuff

release of cuff

Fig. 6. Changes in (a) elasticity and (b)  for intima–media region afterrecirculation (25-year-old male).

Fig. 7. Changes in (a) elasticity and (b)  for intima–media region afterrecirculation (31-year-old male).

diameter

5.0 mmanterior wall

lumen−intima
interfaceposterior wall

(a)
5.0

diameter [mm]

4.5
4.19
4.0

3.91

3.5

3.0
avascularization

(b)
0

10

20

30

40

50
time [s]

60

70

80

90

release of cuff

Fig. 8. (a) RF signal obtained at each measurement after release of cuﬀ (24-year-old male). (b) Change in inner diameter obtained fromdistance between lumen–intima interfaces of anterior and posterior walls indicated by dashed lines in (a).

4.

Conclusions

We measured the change in elasticity only in the intima–
media region. The layer, in which elasticity was obtained,
was determined on the basis of the reproducibility of thechange in thickness measured for two heartbeats. The
normalized change in elasticity measured by the proposed
method was much larger than the normalized change indiameter measured by conventional methods because theconventional methods evaluate the mechanical property ofthe entire wall. From these results, the proposed method has
a potential for improving the sensitivity of noninvasive
evaluation of the endothelium function by measuring thechange in elasticity due to FMD only for the intima–media
region including smooth muscle.

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M. SUGIMOTO et al.

6301

diameter

5.0 mmanterior wall

lumen−intima
interfaceposeterior wall(a)4.6

diameter [mm]

4.5

4.49
4.43

4.4

4.3

4.2

(b)
0

avascularization

20

40

60
time [s]80100

release of cuff

Fig. 9. (a) RF signal obtained at each measurement after release of cuﬀ (25-year-old male). (b) Change in inner diameter obtained fromdistance between lumen–intima interfaces of anterior and posterior walls indicated by dashed lines in (a).

diameter

5.0 mmanterior wall

lumen−intima
interfaceposterior wall
(a)
5.0
4.83

diameter [mm]

4.5
4.35

4.0

3.5

3.0
avascularization

(b)
0

20

40

60
time [s]80100

release of cuff

Fig. 10. (a) RF signal obtained at each measurement after release of cuﬀ (31-year-old male). (b) Change in inner diameter obtained
from distance between lumen–intima interfaces of anterior and posterior walls indicated by dashed lines in (a).

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