Journal of Atherosclerosis and Thrombosis Vol. 20, No. 8

678

Original Article

Arterial Wall Elasticity Measured Using the Phased Tracking
Method and Atherosclerotic Risk Factors in Patients withType 2 Diabetes
Michiaki Miyamoto 1, Kazuhiko Kotani 1, Kenta Okada 2, Akihiko Ando 2, Hideyuki Hasegawa 3, 4,
Hiroshi Kanai 4, 3, Shun Ishibashi 2, Toshiyuki Yamada 1, Nobuyuki Taniguchi 1
1

Department of Clinical Laboratory Medicine, Jichi Medical University, Tochigi, Japan
Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Tochigi, Japan
3
Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan
4
Graduate School of Engineering, Tohoku University, Sendai, Japan
2

Aim: The aim of this study was to investigate the relationship between atherosclerotic manifestations
and brachial and radial arterial wall elasticity (AWE) measured using the phased tracking method inpatients with type 2 diabetes mellitus (T2DM).
Methods: This study included T2DM patients (n = 220, mean age 59 years) without a history ofstroke or coronary artery disease. The brachial AWE, radial AWE, carotid mean intima-media thickness (IMT), max-IMT and flow-mediated vasodilation (FMD) were measured. The patients wereclassified according to the number of atherosclerotic risk factors, including obesity, dyslipidemia andhypertension. Group 1 included T2DM patients only, group 2 included patients with two risk factors, group 3 included patients with three risk factors and group 4 included patients with four risk
factors. The patients were also divided into two groups according to microangiopathic complications, including retinopathy and nephropathy. The between-group differences were analyzed.
Results: The brachial AWE (548, 697, 755 and 771 kPa for groups 1, 2, 3 and 4, respectively) andradial AWE (532, 637, 717 and 782 kPa for groups 1, 2, 3 and 4, respectively) significantly increased
in association with an increasing number of risk factors. The brachial AWE and radial AWE were significantly higher in the patients with microangiopathic complications than in those without microangiopathic complications (brachial AWE 797 and 694 kPa and radial AWE 780 and 660 kPa, respectively). Receiver operating characteristic curve analyses revealed that, for brachial AWE and radial
AWE, the area under the curve was equal to the max-IMT and higher than the mean-IMT and FMD.
Conclusions: Upper limb AWE measurement can reflect the degree of atherosclerosis risk overload
and may be useful for evaluating vascular complications in T2DM patients.
J Atheroscler Thromb, 2013; 20:678-687.
Key words: Ultrasonography, Carotid intima-media thickness, Flow-mediated vasodilation

Introduction
Type 2 diabetes mellitus (T2DM) is associatedwith atherosclerosis, which leads to various vascularcomplications, including macroangiopathies, such as
Address for correspondence: Kazuhiko Kotani, Department ofClinical Laboratory Medicine, Jichi Medical University,
3311-1 Yakushiji, Shimotsuke-City, Tochigi 329-0498, Japan
E-mail: kazukotani@jichi.ac.jp
Received: October 18, 2012
Accepted for publication: March 10, 2013

coronary artery disease and strokes, and microangiopathies, such as retinopathy and nephropathy 1-5). The
addition of obesity, dyslipidemia and hypertension to
T2DM accelerates the progression of atherosclerosis
and increases the risk of cardiovascular disease 3, 6-8).
Managing these atherosclerotic risk factors can prevent
atherosclerotic progression 9); therefore, it is importantto evaluate a patient’s atherosclerotic risk overload
prior to the occurrence of cardiovascular events 10, 11).
Several atherosclerotic markers, such as the carotid
intima-media thickness (IMT) and flow-mediatedArterial Wall Elasticity in Type 2 Diabetes

vasodilation (FMD), are useful for assessing atherosclerotic risks, although they do not always predictcardiovascular risks among T2DM patients 12, 13).
Recently, a noninvasive, transcutaneous, ultrasonic technique using the phased tracking method wasdeveloped to evaluate arterial wall elasticity (AWE).
This method is believed to be able to detect atherosclerotic changes in association with regional tissue
composition 14-16). During a single heartbeat, the displacement of each point of the arterial wall from theluminal surface to the adventitia is tracked along an
ultrasonic beam, and minute changes in the thicknessof different layers can be detected, allowing the elastic
modulus to provide information on regional tissue
composition 14-16). The AWE is expressed as the meanelastic modulus of the entire arterial wall of a regional
artery. Because it is an easy-to-use and noninvasive
method, measuring the AWE using the phased tracking
method is suitable as an atherosclerotic screening test.
The phased tracking method has been used todemonstrate that soft tissue, such as soft plaques witha lipid core within the arteries have a low AWE, whilea high AWE is seen in stiff tissue, such as lesions where
calcification and proliferation of vascular smoothmuscle and collagen exist 14). The carotid AWE has
been reported to be significantly associated with atherosclerotic markers, such as the carotid max-IMT andpulse wave velocity, in T2DM patients 15), whereas theradial AWE is significantly associated with the serum
C-reactive protein level, a chronic inflammatory
index, in healthy subjects 16, 17). Therefore, measuring
the AWE may be useful for evaluating the degree ofatherosclerotic overload. However, currently, only afew studies have evaluated the AWE measured according to the phased tracking method in different arteries
or different populations 15, 16); therefore, further clinicaldata are required to establish the clinical utility of
AWE measurement using this method. For this purpose, we investigated the relationship between the
degree of atherosclerotic risk overload and the AWE in
addition to the differences in AWE between patientswith and without microangiopathic complications inorder to determine whether upper limb AWE measurement can be used as new approach for evaluating
atherosclerosis.
Aim
The brachial AWE, radial AWE and other ultrasonic atherosclerosis-related markers, including the
carotid IMT and FMD, and conventional atherosclerotic risk factors were measured in T2DM patients
without a history of stroke or coronary artery disease.

679This study investigated whether brachial and radial
AWE values are correlated with the number of atherosclerotic risk factors in T2DM patients. Furthermore,
we investigated the brachial and radial AWE inpatients with microangiopathic complications because
patients with diabetic microangiopathic complications, particularly those in the advanced stage, constitute a special population with a high risk for cardiovascular events 18-20).
Methods
Subjects
A total of 220 patients with T2DM (men, 57%;
mean±standard deviation [SD] age, 59±11 years)
were sequentially included in this cross-sectional hospital-based study. The Ethics Committee at Jichi
Medical University approved the study, and eachpatient gave their informed consent. Patients with ahistory of stroke or coronary artery disease were
excluded. All of the study patients were stable andreceiving antidiabetic treatments, such as diet therapy,
oral medications and insulin. T2DM was diagnosed
based on the World Health Organization (WHO) andAmerican Diabetes Association (ADA) criteria: a fasting plasma glucose level of ≥ 126 mg/dL and/or a
2-hour plasma glucose level after a 75-g oral glucose
tolerance test of ≥ 200 mg/dL 21, 22).
The diagnosis of retinopathy was determined bya trained ophthalmologist using indirect ophthalmoscopic examinations based on the presence of clinicalfeatures in the fundus in both eyes 23). Advanced-stage
retinopathy was defined as proliferative retinopathy,
severe nonproliferative retinopathy, post vitreous surgery retinopathy or post panretinal photocoagulation 23). The renal function was assessed using the estimated glomerular filtration rate (eGFR), which was
calculated according to the glomerular filtration rateequation for Japanese subjects 24). Patients with an
eGFR of ≤ 30 mL/min/1.73 m2 and/or macroalbuminuria (a urinary albumin-to-creatinine ratio [ACR]of ≥ 300 mg/g creatinine [Cr]) were classified as having advanced stage disease 25-27). Nephropathy wasdefined as an eGFR of ≤ 60 mL/min/1.73 m2 and/or
microalbuminuria (ACR ≥ 30 mg/g Cr) 26, 27).
The patients were divided into four groups basedon the number of atherosclerotic risk factors, including obesity, dyslipidemia and hypertension 3, 6). Group
1 included patients with T2DM only, group 2 included
patients with two risk factors, group 3 included
patients with three risk factors and group 4 included
patients with all four risk factors. The patients were
further classified into two groups: those with and680

Miyamoto et al .

without microangiopathic complications, including
advanced-stage retinopathy or nephropathy.
Physical Examinations
Smoking habits were determined in interviews
conducted by doctors, and smokers were defined as
current smokers. The body mass index (BMI) was calculated as the weight divided by the square of the
body height while wearing light clothes. Obesity wasdefined as a BMI of ≥ 25.0 kg/m2 based on the Japan
Society for the Study of Obesity criteria 28). Bloodpressure was measured twice in the supine position
with a minimum of five minutes between measurements, and the mean value was recorded. Hypertension was defined as a systolic blood pressure of ≥ 140
mmHg and/or a diastolic blood pressure of ≥ 90 mmHg
and/or the current use of antihypertensive agents 29).
Laboratory Measurements
Blood samples were drawn in the morning after a
12-hour fast. The level of hemoglobin A1c (HbA1c)
was measured using high-performance liquid chromatography. The present study used the value of HbA1c(%) estimated as a National Glycohemoglobin Standardization Program (NGSP) equivalent value (%)(HbA1c [Japan Diabetes Society: JDS]＋0.4%) 30). The
levels of blood glucose, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol(HDL-C), triglycerides and Cr were determined enzymatically. Dyslipidemia was defined as an LDL-C
level of ≥ 140 mg/dL, an HDL-C level of ＜ 40 mg/dL,
a triglyceride level of ≥ 150 mg/dL and/or the current
use of statins or fibrates 31). The ACR in spot urine wasalso assessed, and values of albuminuria surpassing thesensitivity of the ACR measurement were recorded as
300 mg/g Cr.
Using B-mode ultrasound imaging with a 5- to
10-MHz linear transducer (ALOKA, SSD-α10, Tokyo,
Japan), the mean-IMT and max-IMT were evaluatedbilaterally at the common carotid artery, bifurcationand internal carotid arteries 32, 33). The mean-IMT was
measured in the bilateral common carotid arteries(excluding the bulbus), and the levels at two or moremeasurement points were averaged 32, 33). The maxIMT was measured at the greatest IMT in the bilateralcommon carotid arteries, the bulbus and the internal
carotid arteries 32).
For the FMD measurements, the patients fasted
and did not use tobacco for at least eight hours before
measurement 34, 35). The FMD was assessed in thepatient’s right brachial artery above the antecubital
fossa in the supine position in a quiet, temperaturecontrolled room. The diameter of the brachial arterywas measured continuously using B-mode ultrasound.
A cuff was placed on the forearm and, after measuring
the baseline diameter, arterial occlusion was induced by
cuff inflation to a pressure of 200 mmHg or 50 mmHg
above the systolic blood pressure for five minutes.
When the cuff was released, the FMD was calculated
as the maximum percent increase in the diameter during hyperemia compared with the baseline diameter.
Measurement of Arterial Wall Elasticity Using thePhased Tracking Method
The brachial AWE and radial AWE were evaluated using the phased tracking method 14-16). The brachial and radial arteries were assessed above the antecubital fossa and approximately 5 cm proximal to thewrist with the palm turned upward, respectively, inthe supine position in a quiet, temperature-controlled
room. The arteries were scanned in the longitudinalplane using B-mode ultrasound imaging with an 8- to
16-MHz linear array transducer (DIASUS, Dynamic
Imaging Ltd., Livingston, UK). Ultrasound was used
to record changes in the thickness of the artery during
a single heartbeat. The arterial wall was divided intolayered blocks with a depth of 312 μm and a width of
200 μm for the entire wall, and the elastic modulus ofeach layer (Eθ [Pascal: Pa]) was calculated using theequation Eθ = (1/2)×(r 0/h 0＋1)×(ΔPmax/εr), where εr =Δhmax/h 0, Δhmax is the maximum decrease in the thickness of the 312-μm layer during one heartbeat, ΔPmax
is the pulse pressure and h 0 and r 0 are the initial thicknesses of the layer and radius of the vessel at end-diastole, respectively. The elastic modulus was determinedfor each 312-μm layer, and the AWE was expressed as
the mean level of all layers. The AWE was determinedin the bilateral brachial and radial arteries, and thebilateral averages of each artery were used for all analyses. All examinations were performed by the same
trained physician. The intraobserver coefficients ofvariation for the brachial AWE and radial AWE values
were 9.3% and 10.9%, respectively.
Statistical Analyses
The data are presented as the mean±SD, median(interquartile range) or number (%). The betweengroup differences of each parameter were comparedusing a one-way analysis of variance (ANOVA) with amultiple comparison test or the chi-square test.
ANOVA adjusted for confounding factors, such asage, sex, the smoking status, the Cr level and ACR,
was performed to determine the between-group differences in atherosclerotic parameters, such as the brachial AWE, radial AWE, mean-IMT, max-IMT and
FMD. The between-group differences in atherosclero-Arterial Wall Elasticity in Type 2 Diabetes

681

Table 1. Patient profiles for each group based on the number of atherosclerotic risk factors
Parameter
Male (%)
Age (years)
Body mass index (kg/m2)
Smoking (%)
SBP (mmHg)
DBP (mmHg)
Anti-HT agents (%)
RAS inhibitors (%)
CCB (%)
β blockers (%)
Diuretics (%)
Glucose (mg/dL)
Hemoglobin A1c (%)
Antidiabetic agents (%)
OHA (%)
Insulin treatment (%)
Retinopathy (%)
Non-advanced stage (%)
Advanced stage (%)
LDL-cholesterol (mg/dL)
HDL-cholesterol (mg/dL)
Triglycerides (mg/dL)
Anti-HL agents (%)
Statins (%)
Fibrates (%)
Cr (mg/dL)
eGFR (mL/min/1.73 m2)
ACR (mg/g Cr)
Nephropathy (%)
Non-advanced stage (%)
Advanced stage (%)
Mean-IMT (mm)Max-IMT (mm)FMD (%)
Brachial AWE (kPa)
Radial AWE (kPa)All(n = 220)

Group 1(n = 22)

Group 2(n = 65)

126 (57%)
59±11
25±6
47 (21%)128±1577±9112 (51%)
104 (47%)
69 (31%)
11 (5%)
28 (13%)135±427.9±2.0
158 (72%)109 (50%)49 (22%)80 (36%)42 (19%)38 (17%)109±3257±19108 (81-160)
87 (40%)79 (36%)8 (4%)
0.68 (0.59-0.80)
83±24
16 (8-86)
100 (45%)
70 (32%)30 (14%)0.72±0.12
1.60±0.84
2.4±1.9721±217692±222

13 (59%)57±1420±2
6 (27%)
117±1372±80 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
127±547.9±2.3
13 (59%)7 (32%)
6 (27%)
2 (9%)
1 (5%)
1 (5%)
106±2278±25
58 (50-84)
0 (0%)
0 (0%)
0 (0%)
0.66 (0.53-0.80)
88±25
10 (7-23)
5 (23%)
4 (18%)
2 (9%)
0.70±0.13
1.31±0.74
3.4±2.9548±141532±149

40 (62%)61±923±3＊
14 (22%)
125±1576±915 (23%)
13 (20%)8 (12%)
1 (2%)
4 (6%)
134±437.9±2.3
41 (63%)29 (45%)12 (18%)20 (31%)
12 (18%)8 (12%)
109±3157±18＊
104 (65-126)＊
17 (26%)15 (23%)2 (3%)
0.70 (0.59-0.79)
84±23
17 (10-87)
27 (42%)17 (26%)10 (15%)0.70±0.09
1.53±0.70
2.4±1.5697±200＊637±207

Group 3(n = 76)

Group 4(n = 57)

33 (58%)40 (53%)
58±10
60±11
26±6＊, §30±4＊, §, †18 (24%)9 (16%)
129±15＊134±14＊, §77±980±9＊, §＊, §52 (91%)＊, §, †45 (59%)＊, §42 (55%)49 (86%)＊, §, †＊, §27 (36%)34 (60%)＊, §, †
7 (9%)
3 (5%)
11 (14%)＊, §13 (23%)＊, §, †136±42139±388.0±2.0
7.7±1.6
57 (75%)47 (82%)43 (57%)30 (53%)14 (18%)17 (30%)30 (39%)＊28 (49%)＊, §13 (17%)16 (21%)
17 (22%)12 (21%)
114±33104±3356±16＊
52±18＊＊
110 (83-171)
153 (100-194)＊, §＊, §34 (45%)36 (63%)＊, §, †＊, §33 (43%)31 (54%)＊, §1 (1%)
5 (9%)
0.69 (0.59-0.84) 0.66 (0.57-0.79)
80±26
84±21
17 (9-84)
21 (9-143)
39 (51%)29 (51%)29 (38%)20 (35%)10 (13%)9 (16%)
0.74±0.14
0.74±0.11
1.68±0.92
1.70±0.89
2.4±1.92.1±1.6755±222＊771±221＊717±206＊782±238＊, §p-value
0.76
0.32＜ 0.010.62＜ 0.01＜ 0.01＜ 0.01＜ 0.01＜ 0.01
0.13
0.01
0.67
0.87
0.05
0.16
0.34
0.01
0.10
0.14
0.37
＜ 0.01＜ 0.01＜ 0.01＜ 0.01
0.10
0.71
0.45
0.08
0.08
0.21
0.58
0.15
0.21
0.05
＜ 0.01＜ 0.01

SBP: systolic blood pressure; DBP: diastolic blood pressure; Anti-HT: antihypertensive; RAS: renin-angiotensin system; CCB: calcium channel
blockers; OHA: oral antihyperglycemic agents; LDL: low-density lipoprotein; HDL: high-density lipoprotein; Anti-HL: antihyperlipidemic; Cr:creatinine; eGFR: estimated glomerular filtration rate; ACR: urinary albumin-to-Cr ratio; IMT: intima-media thickness; FMD: flow-mediatedvasodilation; AWE: arterial wall elasticity; Pa: Pascal. The patients were divided into four groups based on the number of the following atherosclerotic risk factors: diabetes mellitus, obesity, dyslipidemia and hypertension. Group 1 included patients with diabetes mellitus only, group 2 included
patients with two risk factors, group 3 included patients with three risk factors and group 4 included patients with all four risk factors. The data arepresented as the mean±standard deviation, median (interquartile range) or number (%). The levels of triglycerides and Cr and the ACR values
were log-transformed due to their skewed distributions. The p-values were determined using a one-way analysis of variance with multiple compari＊§†son tests or the chi-square test with residual tests. Significance level: p ＜ 0.05 vs. group 1; p ＜ 0.05 vs. group 2; p ＜ 0.05 vs. group 3.

sis parameters adjusted for antidiabetic medications,antihypertensive medications, antihyperlipidemic medications, retinopathy and nephropathy, in addition toage, sex, the smoking status and the ACR, were also
analyzed. Additionally, the groups with and without
microangiopathic complications were compared usingMiyamoto et al .

682

0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

1200
1100
1000
900
800
700
600
500
400
300
200
100
0

Max-IMT (mm)Group 1 Group 2 Group 3 Group 4

*

7.0
6.0
5.0
4.0
3.0
2.0
1.0
0

Group 1 Group 2 Group 3 Group 4

Radial AWE (kPa)Group 1 Group 2 Group 3 Group 4**

FMD (%)

Brachial AWE (kPa)

Mean-IMT (mm)0.9Group 1 Group 2 Group 3 Group 4

*

1200
1100
1000
900
800
700
600
500
400
300
200
100
0

㫝

*

Group 1 Group 2 Group 3 Group 4

Fig. 1. Differences between the groups classified by the number of atherosclerotic risk factors. Group 1 included
patients with diabetes mellitus only, group 2 included patient with two risk factors, group 3 included
patients with three risk factors and group 4 included patients with all four risk factors. IMT: intima-media
thickness; AWE: arterial wall elasticity; Pa: Pascal; FMD: flow-mediated vasodilation. Significance level: ＊p ＜0.05 vs. group 1; §p ＜ 0.05 vs. group 2; †p ＜ 0.05 vs. group 3.

Student’s t -test and the chi-square test. Receiver-operating characteristic (ROC) curve analyses of the meanIMT, max-IMT, brachial AWE, radial AWE and FMD
in the patients with microangiopathic complications
were performed, and the areas under the curve (AUCs)
were compared 36).
In all analyses, the log-transformed values of thelevels of triglycerides and Cr and the ACR were used
due to their skewed distributions. A value of p ＜ 0.05
was considered to be significant. All statistical analyses, except for the comparisons of the AUC, were performed using the Dr. SPSS II version 11 software program (SPSS Inc., Tokyo, Japan). The AUC comparisons were made using the StatFlex version 6 software
package (Artech, Co., Ltd., Osaka, Japan).
Results
The patient characteristics of each group basedon the number of atherosclerotic risk factors areshown in Table 1 and Fig. 1. As the number of atherosclerotic risk factors increased, the number ofpatients with retinopathy and nephropathy tended toincrease. In addition, the mean-IMT and max-IMT
values showed a tendency to increase from groups 1 to4. The FMD tended to decrease from groups 1 to 4.
The brachial AWE and radial AWE values significantly increased from groups 1 to 4. The brachial
AWE value was significantly higher in groups 2, 3 and4 than in group 1. The radial AWE value was significantly higher in group 4 than in groups 1 and 2, andthe radial AWE value was significantly higher in group
3 than in group 1.
After adjusting for age, sex, the smoking status,
the Cr level and the ACR, significant between-groupdifferences were found in brachial AWE (p ＜ 0.01) andradial AWE (p ＜ 0.01), and a marginally significant
between-group difference was found in FMD (p =Arterial Wall Elasticity in Type 2 Diabetes

683

Table 2. Patient profiles for the groups with and without microangiopathic complications
Parameter
Male (%)
Age (years)
Body mass index (kg/m2)
Smoking (%)
SBP (mmHg)
DBP (mmHg)
Anti-HT agents (%)
RAS inhibitors (%)
CCB (%)
β blockers (%)
Diuretics (%)
Glucose (mg/dL)
Hemoglobin A1c (%)
Antidiabetic agents (%)
OHA (%)
Insulin treatment (%)
Retinopathy (%)
Non-advanced stage (%)
Advanced stage (%)
LDL-cholesterol (mg/dL)
HDL-cholesterol (mg/dL)
Triglycerides (mg/dL)
Anti-HL agents (%)
Statins (%)
Fibrates (%)
Cr (mg/dL)
eGFR (mL/min/1.73 m2)
ACR (mg/g Cr)
Nephropathy (%)
Non-advanced stage (%)
Advanced stage (%)
Mean-IMT (mm)Max-IMT (mm)FMD (%)
Brachial AWE (kPa)
Radial AWE (kPa)All(n = 220)

Without complications(n = 162)

With complications(n = 58)

p-value

126 (57%)
59±11
25±6
47 (21%)128±1577±9112 (51%)
104 (47%)
69 (31%)
11 (5%)
28 (13%)135±427.9±2.0
158 (72%)109 (50%)49 (22%)80 (36%)42 (19%)38 (17%)109±3257±19108 (81-160)
87 (40%)79 (36%)8 (4%)
0.68 (0.59-0.80)
83±24
16 (8-86)
100 (45%)
70 (32%)30 (14%)0.72±0.12
1.60±0.84
2.4±1.9721±217692±22292 (57%)60±1125±634 (21%)127±1576±1073 (45%)67 (41%)47 (29%)8 (5%)
17 (10%)133±41
7.6±1.9109 (67%)
85 (52%)24 (15%)33 (20%)33 (20%)0 (0%)
110±3160±20102 (70-146)
63 (39%)57 (35%)6 (4%)
0.68 (0.57-0.80)
84±22
13 (8-34)
55 (34%)55 (34%)0 (0%)
0.72±0.12
1.48±0.65
2.5±1.9694±213660±20734 (59%)58±1026±5
13 (22%)131±1479±939 (67%)37 (64%)22 (38%)3 (5%)
11 (19%)142±458.5±2.2
49 (84%)24 (41%)25 (43%)47 (81%)9 (16%)
38 (66%)106±3451±14120 (86-175)
24 (41%)22 (38%)2 (3%)
0.70 (0.61-0.86)80±28239 (28-300)
45 (78%)15 (26%)30 (52%)0.73±0.12
1.96±1.15
2.1±1.6797±212780±243

0.81
0.17
0.70
0.82
0.04
0.04
＜ 0.01＜ 0.01
0.21
0.94
0.10
0.19
＜ 0.010.01
0.15＜ 0.01＜ 0.010.42＜ 0.010.47＜ 0.01
0.01
0.74
0.71
0.93
0.19
0.57
＜ 0.01＜ 0.010.26＜ 0.010.59＜ 0.010.17＜ 0.01＜ 0.01

SBP: systolic blood pressure; DBP: diastolic blood pressure; Anti-HT: antihypertensive; RAS: renin-angiotensin system; CCB: calcium channel
blockers; OHA: oral antihyperglycemic agents; LDL: low-density lipoprotein; HDL: high-density lipoprotein; Anti-HL: antihyperlipidemic; Cr:creatinine; eGFR: estimated glomerular filtration rate; ACR: urinary albumin-to-Cr ratio; IMT: intima-media thickness; FMD: flow-mediatedvasodilation; AWE: arterial wall elasticity; Pa: Pascal. Microangiopathic complications included advanced-stage retinopathy and nephropathy. The
patients were divided into groups with and without microangiopathic complications. The data are presented as the mean±standard deviation,
median (interquartile range) or number (%). The levels of triglycerides and Cr and the ACR values were log-transformed due to their skewed distributions. The p-values were determined using Student’s t -test or the chi-square test. Significance level: p ＜ 0.05.

0.05). Furthermore, there were significant betweengroup differences in brachial AWE (p ＜ 0.01) andradial AWE (p ＜ 0.01), but not in the FMD values(p = 0.65), after adjusting for antidiabetic medications,antihypertensive medications, antihyperlipidemic

medications, retinopathy and nephropathy, in addition to age, sex, the smoking status and the ACR.
The patients’ characteristics in the groups withand without microangiopathic complications areshown in Table 2. The max-IMT, brachial AWE andMiyamoto et al .

50
25

100

AUC = 0.52
p = 0.70

Max-IMT5000

AUC = 0.62
p = 0.01

50

AUC = 0.66
p < 0.01

25100

25 50 75 100
1 – Specificity (%)

Brachial AWE

75

0
0

25 50 75 100
1 – Specificity (%)

75

25

100
Sensitivity (%)

75

0
0

Sensitivity (%)

Mean-IMT

Sensitivity (%)

Sensitivity (%)

100

25 50 75 100
1 – Specificity (%)
Radial AWE

75

50
25
0
0

FMD

100
Sensitivity (%)

684

AUC = 0.65
p < 0.01
25 50 75 100
1 – Specificity (%)

75
50

AUC = 0.56
p = 0.1725
0
025 50 75 100
1 – Specificity (%)

Mean-IMTvs. Max-IMT
vs. Brachial AWE
vs. Radial AWE
vs. FMD
Max-IMTvs. Brachial AWE
vs. Radial AWE
vs. FMD
Brachial AWE
vs. Radial AWE
vs. FMD
Radial AWE
vs. FMD

P for difference
0.11
0.02
0.03
0.47
0.52
0.62
0.39
0.89
0.12
0.07

Fig. 2. ROC curve analyses of the mean-IMT, max-IMT, brachial AWE, radial AWE and FMD for microangiopathic
complications were performed, and the AUCs were measured. ROC: receiver operating characteristic; IMT:
intima-media thickness; AWE: arterial wall elasticity; FMD: flow-mediated vasodilation; AUC: area under thereceiver operating characteristic curve. Significance level: p ＜ 0.05.

radial AWE values were significantly higher in thegroup with microangiopathic complications than in
the group without microangiopathic complications.
The ROC curves of the mean-IMT, max-IMT, brachial AWE, radial AWE and FMD regarding microangiopathic complications are shown in Fig. 2. The
AUCs of the mean-IMT, max-IMT, brachial AWE,
radial AWE and FMD were 0.52 (95% confidence
interval [CI] 0.43-0.60, p = 0.70), 0.62 (95% CI 0.530.71, p = 0.01), 0.66 (95% CI 0.58-0.74, p ＜ 0.01),
0.65 (95% CI 0.57-0.73, p ＜ 0.01) and 0.56 (95% CI
0.47-0.65, p = 0.17), respectively. When comparing
the AUCs of the mean-IMT, max-IMT, brachial
AWE, radial AWE and FMD, no differences were
found among the max-IMT, brachial AWE, radial
AWE or FMD. The AUCs of the brachial and radial
AWE were significantly higher than that of the meanIMT (Fig. 2).

Discussion
As the number of atherosclerotic risk factors
increased, the brachial AWE and radial AWE values
increased in the T2DM patients without a history ofstroke or coronary artery disease. Although the meanIMT and max-IMT tended to increase while the
FMD decreased, the brachial and radial AWE produced more clear findings of atherosclerotic risk, tosome extent, than the other ultrasonic atherosclerosisrelated markers. When comparing the groups withand without microangiopathic complications, themax-IMT, brachial AWE and radial AWE values werehigher in the group with microangiopathic complications than in the group without microangiopathic
complications. Although the AUCs of the brachial
and radial AWE did not exhibit a high accuracy, theAUCs of the brachial and radial AWE were approximately equal to that of the max-IMT and higher than

Arterial Wall Elasticity in Type 2 Diabetes

those of the mean-IMT and FMD. Considering thatultrasonic markers for atherosclerosis are not always
established 5, 13, 37-40) and the clinical relevance of maxIMT for atherosclerosis has been indicated 41) in
T2DM patients, it appears meaningful to note thatthe brachial and radial AWE may reflect atherosclerotic risks, similar to the max-IMT and superior to themean-IMT and FMD, in this population.
As atherosclerotic disease progresses, endothelial
dysfunction leads to secretory disorders of physiologically active substances, such as nitric oxide derived fromthe endothelium, inhibition of vascular smooth muscle relaxation and reductions in vascular tone 17, 42, 43).
This can partly induce the proliferation of vascularsmooth muscle cells and reduce the vascular smoothmuscle function 17, 42, 43). Histopathological data obtainedusing the phased tracking method indicate high AWE
values in tissue with proliferation of vascular smoothmuscle cells 14). Another study showed that the radial
AWE is significantly and positively correlated with theserum C-reactive protein level, an inflammatory index 16).
Inflammation induced by endothelial dysfunction is
the primary pathological basis for atherosclerosis 17).
Therefore, AWE measurement can be used to assessthe degree of atherosclerotic overload and vascularcomplications.
FMD is the preferred method for evaluating theendothelial function 34, 35, 44), and the measurements of
AWE and FMD are thought to partially overlap. In
this study, the FMD tended to decrease in association
with an increased number of atherosclerotic risk factors; however, the degree was not large compared withthat of brachial and radial AWE. This may be because
the patients in our study had poor glycemic control
and multiple atherosclerotic risk factors, and the mean
FMD value was decreased, even in group 1 (normal
range 5-10% 45, 46)).
The carotid artery is a common site of atherosclerosis, and atherosclerotic changes in the carotid
artery often reflect systemic atherosclerosis 37, 47, 48). A
large number of studies have demonstrated that the
carotid IMT is higher in patients with atheroscleroticrisk factors than in healthy subjects 33, 49), while otherstudies have showed that the carotid IMT is weakly
correlated with cardiovascular disease in T2DM
patients 13, 38). Previous studies of the association
between the IMT and microangiopathic complications have reported that the mean-IMT is weakly correlated with microangiopathic complications, while
the max-IMT is positively correlated with microangiopathic complications 37, 41). In our study, the carotid
IMT did not clearly increase in association withincreased atherosclerotic risk factors, and the max-

685

IMT was increased significantly in the patients withmicroangiopathic complications. Our results support
the findings of previous studies 13, 37-39), and we thinkthat the weak correlation observed between the carotid
mean-IMT and atherosclerotic risks may be partly due
to our study population containing T2DM patients.
The present study is associated with several limitations. The study design was cross-sectional, and cardiovascular event outcomes were not evaluated. Prospective evaluations are needed to confirm the resultsof our study.
Conclusions
As the number of atherosclerotic risk factors
increased, the brachial and radial AWE values increasedin T2DM patients without a history of stroke or coronary artery disease. The brachial and radial AWE used
to detect microangiopathic complications wereapproximately equal to the max-IMT. These results
indicate that the brachial and radial AWE can reflect
the degree of atherosclerotic overload and may be useful for detecting vascular complications. Measuring
the upper limb AWE would be useful for assessing thedegree of subclinical atherosclerosis and lead to new
approaches for evaluating atherosclerosis.
Acknowledgments
This study was supported in part by Jichi Medical University.
Conflict of Interest Statement
The authors declare that there are no financial orother conflicts of interest.
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