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10 0000@Www Jstage JST Go jp@Article@Jat@23@11@2335436@Article
10 0000@Www Jstage JST Go jp@Article@Jat@23@11@2335436@Article
10 0000@Www Jstage JST Go jp@Article@Jat@23@11@2335436@Article
doi: 10.5551/jat.35436
Original Article
1
Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima,
Japan
2
Global Career Design Center, Hiroshima University, Hiroshima, Japan
3
Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima
University, Hiroshima, Japan
4
Department of Gastroenterology and Metabolism, Institute of Biomedical and Health Sciences, Graduate School of Biomedical and
Health Sciences, Hiroshima University Hiroshima, Japan
5
Hiroshima International University, Hiroshima, Japan
6
Division of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital,
Hiroshima, Japan
Aim: Both vascular function and structure are independent predictors of cardiovascular events. The
purpose of this study was to evaluate vascular function and structure of a leg artery in patients with
peripheral artery disease (PAD).
Methods: We measured flow-mediated vasodilatation (FMD) and nitroglycerine-induced vasodilation
(NID) as indices of vascular function and intima-media thickness (IMT) as an index of vascular
structure of the popliteal artery in 100 subjects, including 20 patients with Buerger disease and 30
patients with atherosclerotic PAD, 20 age- and sex-matched subjects without Buerger disease (control
group) and 30 age- and sex-matched patients without atherosclerotic PAD (control group).
Results: IMT was significantly larger in the Buerger group than in the control group (Buerger, 0.63
0.20 mm; control, 0.500.07 mm; P = 0.01), whereas there were no significant differences in FMD
and NID between the two groups. IMT was significantly larger in the atherosclerotic PAD group
than in the control group (atherosclerotic PAD, 0.800.22 mm; control, 0.650.14 mm; P 0.01),
and FMD and NID were significantly smaller in the atherosclerotic PAD group than in the control
group (FMD: atherosclerotic PAD, 3.9%1.1%; control, 5.0%1.8%; P 0.01; and NID: athero-
sclerotic PAD, 6.1%2.0%; control, 8.4%2.1%; P 0.01).
Conclusion: These findings suggest that vascular function is preserved in patients with Buerger dis-
ease and that both vascular function and vascular structure are impaired in patients with atheroscle-
rotic PAD.
Key words: Peripheral artery disease, Buerger disease, Flow-mediated vasodilatation, Nitroglycerine-
induced vasodilation, Intima-media thickness
Copyright2016 Japan Atherosclerosis Society
This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.
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Iwamoto et al .
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Vascular Function and Structure in PAD
22C 25C) throughout the study. A 23-gauge poly- changes over the cardiac cycle was displayed in real
ethylene catheter was inserted into the left deep ante- time using the FMD mode of the tracking system.
cubital vein to obtain blood samples. Thirty minutes This allowed the ultrasound images to be optimized at
after maintaining the prone position, basal popliteal the start of the scan and the transducer position to be
artery diameter and IMT were measured. Then, FMD adjusted immediately for optimal tracking perfor-
was measured in the popliteal artery. After comple- mance throughout the scan. Pulsed Doppler flow was
tion, we next measured NID with confirmation that assessed at baseline and during peak hyperemic flow,
the popliteal artery diameter had recovered to the which was confirmed to occur within 15 s after cuff
baseline value. The observers were blind to the proto- deflation. Blood flow velocity was calculated from the
col of this study. color Doppler data and was displayed as a waveform
in real time. The baseline longitudinal image of the
Measurement of Popliteal Artery IMT artery was acquired for 30 s and then the blood pres-
The ultrasound unit Aloka-7 (Aloka Co, Tokyo, sure cuff was inflated to 50 mm Hg above systolic
Japan) equipped with a linear, phased-array high-fre- pressure for 5 min. The longitudinal image of the
quency (13-MHz) transducer was used for scanning artery was recorded continuously until 5 min after
the popliteal artery. Ultrasound longitudinal images of cuff deflation. Pulsed Doppler velocity signals were
the popliteal artery were acquired at the end of the obtained for 20 s at baseline and for 10 s immediately
diastole (defined as the R wave of an electrocardio- after cuff deflation. Changes in brachial artery diame-
gram), in which the far wall intima-media interface ter were immediately expressed as per cent change rel-
was clearly defined. The leading edge of the intima ative to the vessel diameter before cuff inflation. FMD
and the media-adventitia interface were traced as con- was calculated as the per cent change in peak vessel
tinuous lines. A total of 20 points over a 3-mm length diameter from the baseline value. %FMD [(peak
of IMT in the 10-mm longitudinal image depicted in diameter baseline diameter)/baseline diameter] was
the analysis display were measured and the mean value used for analysis. Blood flow volume was calculated by
per image was automatically calculated. IMT was multiplying the Doppler flow velocity (corrected for
measured at the same point in each different image. the angle) by heart rate and vessel cross-sectional area
The average of mean values obtained from 10 cardiac (-r 2). Reactive hyperemia was calculated as the maxi-
cycles was defined as IMT of the popliteal artery. All mum percentage increase in flow after cuff deflation
of the duplex ultrasonography scans were performed compared with baseline flow. After a 10-min period to
by ultrasonograhic specialists. allow baseline conditions of the artery to be reestab-
The coefficient of variation for IMT was 4.9% in lished, another baseline scan was performed.
our laboratory. The response to nitroglycerine was used for assess-
ment of endothelium-independent vasodilation. NID
Measurement of Vascular Function was measured as described previously 28). Briefly, after
A high-resolution linear artery transducer was acquiring baseline rest images for 30 s, a sublingual
coupled to computer-assisted analysis software tablet (75 g nitroglycerine) was given, and images of
(Aloka-7, ALOKA Co., Tokyo, Japan) that used an the artery were recorded continuously until the dila-
automated edge detection system for measurement of tion reached a plateau after administration of nitro-
artery diameter. A blood pressure cuff was placed glycerine. Subjects who had received nitrate treatment
around the thigh. The target artery was scanned longi- and subjects in whom the sublingually administered
tudinally. When the clearest B-mode image of the inti- nitroglycerine tablet did not dissolved during the mea-
mal interfaces between the lumen and vessel wall was surement, were excluded from this study. NID was
obtained, the transducer was held at the same point automatically calculated as a per cent change in peak
throughout the scan by a special probe holder (MP- vessel diameter from the baseline value. Percentage of
PH0001, ALOKA Co.) to ensure consistency of the NID [(peak diameter baseline diameter)/baseline
image. A baseline image was acquired and blood flow diameter] was used for analysis.
was estimated by time averaging the pulsed Doppler The coefficient of variation for the baseline diam-
velocity signal obtained from a sample volume. Then eter was 2.9% in our laboratory.
the blood pressure cuff was inflated to 50 mm Hg
above systolic pressure for 5 min. Depth and gain set- Analytical Methods
ting were set to optimize the images of the arterial Samples of venous blood were placed in tubes
lumen wall interface. When the tracking gate was containing sodium ethylenediamine tetraacetic acid (1
placed on the intima, the artery diameter was auto- mg/mL) and in polystyrene tubes. The ethylenedi-
matically tracked and the waveform of diameter amine tetraacetic acid-containing tubes were chilled
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Iwamoto et al .
promptly in an ice bath. Plasma was immediately sep- routine chemical methods.
arated by centrifugation at 3100 g for 10 min at 4C,
and serum was separated by centrifugation at 1000 g Statistical Analysis
for 10 min at room temperature. Samples were stored Results are presented as the meansstandard
at 80C until the time of assay. Serum concentra- deviation (SD) for continuous variables and as per-
tions of total cholesterol, triglycerides, high-density centages for categorical variables. Statistical signifi-
lipoprotein cholesterol, low-density lipoprotein cho- cance was set at a level of P 0.05. Comparisons
lesterol, glucose, and electrolytes were determined by between groups were carried out using P for trend
1264
Vascular Function and Structure in PAD
P=0.40 P=0.19
10 15
10
0 0
Buerger disease Buerger disease Buerger disease Buerger disease
No Yes No Yes
Fig. 1. Bar graphs show flow-mediated vasodilation and nitroglycerine-induced vasodilation in patients with and
without Buerger disease.
Results 0.8
Baseline Clinical Characteristics
The baseline clinical characteristics are summa-
rized in Table 1. Of the 20 patients with Buerger dis-
ease, 18 (90.0%) were men and two (10.0%) were
women; three (15.0%) had hypertension, four 0.4
(20.0%) had dyslipidemia, one (5.0%) had diabetes
mellitus, four (20.0%) were current smokers and none
had previous coronary heart disease. Serum concentra-
tion of high-density lipoprotein cholesterol and ABI
were significantly lower in the Buerger group than in 0
the control group. There were no significant differ- Buerger disease Buerger disease
ences in other parameters between the two groups. No Yes
Of the 30 subjects with atherosclerotic PAD, 22
(73.3%) were men and eight (26.7%) were women; Fig. 2. Bar graph shows the brachial intima-media thickness
in patients with and without Buerger disease.
28 (93.3%) had hypertension, 11 (36.7%) had dyslip-
idemia, 20 (66.7%) had diabetes mellitus, four
(13.3%) were current smokers, and 15 (50.0%) had
previous coronary heart disease. Heart rate, serum than in the atherosclerotic PAD control group. There
concentration of glucose, and ratio of previous coro- were no significant differences in other parameters
nary heart disease were significantly higher in the ath- between the two groups.
erosclerotic PAD group than in the atherosclerotic
PAD control group. Body mass index and ABI were
significantly lower in the atherosclerotic PAD group
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Iwamoto et al .
P<0.01 P<0.01
10 15
10
0 0
Arterosclerotic Arterosclerotic Arterosclerotic Arterosclerotic
PAD PAD PAD PAD
No Yes No Yes
Fig. 3. Bar graphs show flow-mediated vasodilation and nitroglycerine-induced vasodilation in patients with and
without atherosclerotic peripheral arterial disease.
Vascular Function and Structure in Patients with with Buerger disease. These findings suggest that vas-
Buerger Disease and Patients with Atherosclerotic cular function of a leg artery is preserved in patients
PAD with Buerger disease and that both vascular function
There were no significant differences in FMD and vascular structure of a leg artery are impaired in
and NID between the Buerger group and control group patients with atherosclerotic PAD.
(FMD: Buerger group, 5.7%1.8%; control group, It is well known that patients with PAD, particu-
6.1%0.9%; P = 0.40; and NID: Buerger group, larly atherosclerotic PAD, have a high prevalence of
8.6%3.6%; control group, 9.8%1.7%; P = 0.19, cardiovascular morbidity and mortality 1, 2). Atheroscle-
Fig. 1). IMT was significantly larger in the Buerger rosis progressively develops with aging in patients with
group than in the control group (Buerger group, atherosclerotic PAD. Endothelial dysfunction is the
0.630.20 mm; control group, 0.500.07 mm; P = initial step in the pathogenesis of atherosclerosis,
0.01, Fig. 2). resulting in cardiovascular complications 12, 13). Recently,
FMD and NID were significantly smaller in the we reported that both FMD and NID were impaired
atherosclerotic PAD group than in the control group in patients with PAD 19). In addition, brachial IMT
(FMD: atherosclerotic PAD group, 3.9%1.1%; con- was correlated with NID, suggesting that vascular
trol group, 5.0%1.8%; P 0.01 and NID: athero- smooth muscle function is also impaired in relation to
sclerotic PAD group, 6.1%2.0%; control group, increased brachial IMT 11). In the present study, in the
8.4%2.1%; P 0.01, Fig. 3). IMT was significantly popliteal artery also, IMT was increased and FMD
larger in the atherosclerotic PAD group than in the and NID were impaired in patients with atheroscle-
control group (atherosclerotic PAD group, 0.800.22 rotic PAD, suggesting that atherosclerotic PAD has an
mm; control group, 0.650.14 mm; P 0.01, Fig. 4). advanced vascular failure. Severe vascular failure may
contribute to the high cardiovascular morbidity and
mortality rates in atherosclerotic PAD.
Discussion On the other hand, it has been reported that
In the present study, we demonstrated that IMT there is no significant difference in the rate of mortal-
of the popliteal artery was increased both in patients ity between patients with Buerger disease and normal
with Buerger disease and patients with atherosclerotic populations 4, 5). Some investigators have reported that
PAD compared with those in control groups. FMD the survival rate of patients with Buerger disease is sig-
and NID of the popliteal artery were impaired in nificantly lower than that in the general population 4, 36).
patients with atherosclerotic PAD but not in patients Cumulative survival rate was significantly higher in
1266
Vascular Function and Structure in PAD
PAD.
0.8 Acknowledgments
We thank Megumi Wakisaka, Ki-ichiro Kawano
and Satoko Michiyama for their excellent secretarial
assistance.
0.4
Sources of Founding
This study was supported in part by a Grant-in-
Aid for Scientific Research from the Ministry of Edu-
cation, Science and Culture of Japan (1859081500
0 and 21590898) and a Grant in Aid of Japanese Arte-
Arterosclerotic Arterosclerotic riosclerosis Prevention Fund.
PAD PAD
No Yes
Disclosures
Fig. 4. Bar graph shows the brachial intima-media thickness
in patients with and without atherosclerotic peripheral
None.
arterial disease.
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