J Cardiol 2005 Apr; 45（4）: 139 – 147

Thiazolidinedione
Treatment
Attenuates Diffuse NeointimalHyperplasia in Restenotic Lesions
After Coronary Stent Implantationin Type 2 Diabetic Patients : An
Intravascular Ultrasound Study
Tsutomu

TAKAGI, MD, FJCC

Atsushi YAMAMURO, MD＊
Koichi TAMITA, MD＊
Minako KATAYAMA, MD＊
Shigefumi

MORIOKA, MD, FJCC＊

Abstract ─────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────
Objectives. Thiazolidinedione treatment reduces neointimal tissue proliferation after coronary stentimplantation in diabetic patients. However, in-stent restenosis still persists in patients treated with thiazolidinedione. The effect of thiazolidinedione treatment on the pattern of in-stent restenosis remains unclear.
This study investigated whether thiazolidinedione treatment attenuates diffuse neointimal hyperplasia in
restenotic lesions after coronary stent implantation in diabetic patients.
Methods. Volumetric intravascular ultrasound was performed at 6 months after coronary stent implantation in 76 patients with restenotic lesions who received either conventional anti-diabetic treatment（controlgroup, n ＝ 56）or thiazolidinedione treatment（thiazolidinedione group, n ＝ 20）.
Results. There were no significant differences between the two groups in stent volume（99 ± 32 vs 90 ±or in minimal lumen area in the stent（1.4 ± 0.6 vs 1.6 ± 0.5 mm2, respec20 mm3, respectively, p ＝ 0.26）
tively, p ＝ 0.11）. However, there were significant reductions in neointimal volume（56 ± 25 vs 36 ±（56 ± 11% vs 41 ± 8%, respectively, p ＜ 0.01）in the
11 mm3, respectively, p ＜ 0.01）and neointimal index
thiazolidinedione group. Coefficient of variation of neointimal tissue accumulation was greater in the thiazolidinedione group（45.5%）than in the control group（25.2%）.
Conclusions. Intravascular ultrasound study demonstrated that together with reduction of overall neointimal tissue proliferation, thiazolidinedione treatment caused greater point-to-point heterogeneity in the
neointimal tissue accumulation in restenotic lesions after coronary stent implantation. This finding strongly
suggests that thiazolidinedione treatment attenuates diffuse in-stent restenosis in diabetic patients.
─────────────────────────────────────────────────────────────────────────────────────────────────────────────────────J Cardiol 2005 Apr ; 45
（4）
: 139−147

Key Words
Diabetes mellitus thiazolidinedione
Stent

INTRODUCTION
Diabetes mellitus is a powerful determinant of
in-stent neointimal hyperplasia and diffuse in-stentrestenosis（ISR）
after coronary stent implantation1−4）.

Restenosis

Intravascular ultrasoundRecent intravascular ultrasound（ IVUS）studies
have demonstrated that troglitazone and pioglitazone, anti-diabetic thiazolidinedione agents, reduce
neointimal hyperplasia after coronary stent implantation in patients with type 2 diabetes mellitus5−7）.

──────────────────────────────────────────────
高木循環器科診療所 : 〒 604−8811 京都市中京区壬生賀陽御所町 3−3 ; ＊神戸市立中央市民病院 循環器内科，神戸Takagi Cardiology Clinic, Kyoto ; ＊ Division of Cardiology, Kobe General Hospital, Kobe
Address for correspondence : TAKAGI T, MD, FJCC, Takagi Cardiology Clinic, Mibu Kayogosho-cho 3−3, Nakagyo-ku, Kyoto
604−8811 ; E-mail : tcardiol@qb4.so-net.ne.jp
Manuscript received September 27, 2004 ; revised January 14 and 31, 2005 ; accepted January 31, 2005

139

140

Takagi, Yamamuro, Tamita et al

However, angiographic ISR still persisted in 19%
to 23% of the stented lesions in patients treatedwith thiazolidinedione6,7）. The pattern of ISR may
convey prognostic information about subsequent
target vessel revascularization. Previous studies
showed a high recurrence rate after treating diffuse
ISR1,8−10）.
The present study investigated whether thiazolidinedione treatment attenuates diffuse neointimal
hyperplasia in restenotic lesions after coronary
stent implantation in diabetic patients.
SUBJECTS AND METHODS
Study patients and protocol
This prospective, randomized trial in Kobe
General Hospital evaluated the effects of troglitazone and pioglitazone on neointimal tissue proliferation after coronary stent implantation in patientswith type 2 diabetes mellitus5,7）. Quantitative angiographic assessments were done at baseline, poststenting and at 6-month follow-up using CMS（Medis Medical Imaging Systems）. Measurementsfrom multiple projections were performed and theleast favorable findings were recorded. ISR was
defined as ＞
− 50% diameter stenosis within the stent
at follow-up. The Kobe General Hospital IVUSdiabetes mellitus registry containes 184 stented
lesions, of which 76 lesions with angiographic ISR
at a 6-month follow-up were selected for the current analysis. There were 20 lesions in the thiazolidinedione group and 56 lesions in the control
group. All patients gave written informed consent
before randomization as previously reported5−7）.
The study protocol was approved by the institutional ethic committee.
Intravascular ultrasound imaging and analysis
IVUS was performed at a 6-month follow-up.
Images were acquired using commercially available
imaging systems with 30 MHz mechanical transducers（CVIS/Boston Scientific Corporation）withautomated transducer pullback（0.5 mm/sec）afteradministration of intracoronary isosorbide dinitrate（1 to 2 mg）. IVUS at 6-month follow-up was
obtained before repeat coronary intervention for the
ISR.
Quantitative analysis was performed with validated, commercially available planimetry software（Tapemeasure, IndecSystem, Inc.）. Cross-sectional
measurements of stent and lumen area were performed manually every 1 mm throughout the stent.

Simpson s method was used to calculate stent,
lumen, and neointimal（＝ stent − lumen）volumes.
Neointimal volume index was calculated as neointimal volume divided by stent volume. Neointimalarea index was calculated as neointimal area divided by stent area at the image slice with minimal
lumen area. The axial variability of neointimal
accumulation was assessed by calculating the coefficient of variation（CV）of the increase in neointimal proliferation by dividing the standard deviation（SD）of the neointimal area by the mean neointimal
11）
area .
Statistical analysis
Continuous data are presented as mean ± SD,
and categorical data are presented as frequencies.
Continuous variables were compared using theMann-Whitney U-test. Categorical variables werecompared using the Fisher exact probability test.
Results of IVUS measurements, clinical, angiographic and procedural characteristics were determined using lesion-based assessments. A two-sidevalue of p ＜ 0.05 was considered significant.
RESULTSAs shown in Table 1, there were no significant
differences in patient characteristics between thetwo groups. Glucose levels at baseline and at 6month follow-up were equivalent in both groups.
As shown in Table 2, there were no significant differences between the two groups in medical treatment except the use of alpha-glucosidase inhibitors
was more frequent in the control group. Table 3
summarizes angiographic and procedural characteristics. There were no significant differences inangiographic and procedural characteristics
between the two groups. Fig. 1 shows the results ofquantitative coronary angiographic analysis. There
were no significant differences between the twogroups in minimal lumen diameter at baseline,
post-stenting, or 6-month follow-up.
As shown in Fig. 2, volumetric IVUS analysis
demonstrated that there was no significant difference in stent volume between the two groups（99 ±32 vs 90 ± 20 mm2, p ＝ 0.26）. However, lumen
volume in the thiazolidinedione group was significantly greater than in the control group. Neointimal
volume and index in the thiazolidinedione groupwere significantly smaller than in the control group（56 ± 25 vs 36 ± 11 mm2, p ＜ 0.01 ; 56 ± 11% vs
41 ± 8%, p ＜ 0.01）. As shown in Fig. 3, IVUS
J Cardiol 2005 Apr; 45（4）: 139 – 147

Thiazolidinedione Attenuates Diffuse In-Stent Restenosis

141

Table 1 Patient characteristics
Thiazolidinedione（n＝20）

Control（n＝56）

p value

Age（yr）

66±10

64±9

0.21

Sex
（male/female）

13/7

40/16

0.58

BMI-baseline（kg/m ）24.8±2.1

25.7±2.8

0.13

Systolic BP（mmHg）

136±15131±180.28

Diastolic BP（mmHg）

72±10

71±10

0.94

FBS-baseline（mg/dl）

134±25138±380.46

FBS-follow-up（mg/dl）

122±30125±260.53

HbA1c-baseline（%）

6.8±1.0

6.8±1.4

0.61（%）
HbA1c-follow-up

6.4±0.96.4±1.3

0.41

2

Continuous values are mean±SD.
BMI＝body mass index ; BP＝blood pressure ; FBS＝fasting blood sugar ; HbA1c＝hemoglobin A1c.

Table 2 Medical treatments
Thiazolidinedione（n＝20）

Control（n＝56）

p value15（ 75）44（ 79）

0.76

0

0

NA

Calcium channel blocker2（ 10）

8（ 14）＞0.99

Beta-blocker

14（ 70）38（ 68）＞0.99

Statins12（ 60）34（ 61）＞0.99

ACE inhibitor
AngiotensinⅡreceptor blocker

Probucol

0

2（ 4）

＞0.99

Aspirin20（100）56（100）NA

Ticlopidine20（100）56（100）NA

Cilostazol2（ 10）

4（ 7）

0.65

Alpha-glucosidase inhibitors3（ 15）

35（ 63）＜0.01

Sulfonylurea9（ 45）

23（ 41）0.80

Insulin4（ 20）

7（ 13）

0.47（ ）: %.
ACE＝angiotensin converting enzyme ; NA＝no account.

measurement of the image slice with minimal
lumen area showed no significant difference instent area, lumen area
（1.4 ± 0.6 vs 1.6 ± 0.5 mm2,
p ＝ 0.11）, neointimal area, or neointimal areaindex between the two groups. We assessed theaxial variability in neointimal proliferation in thetwo groups by calculating the CV of the neointimal
area（CV ＝ SD of neointimal area/mean neointimalarea）. The CV of neointimal area was significantly
greater in the thiazolidinedione group than in thecontrol group（45.5% vs 25.2%, p ＜ 0.01 ; Fig. 4）.
Fig. 5 shows representative cases of the twogroups, to demonstrate the axial distribution of the
neointimal area standardized by the mean neointimal area. Greater point-to-point variability of
J Cardiol 2005 Apr; 45（4）: 139 – 147

neointimal area was seen in the thiazolidinedionegroup.
DISCUSSION
The present IVUS study demonstrated thattogether with the reduction of overall neointimal
hyperplasia, thiazolidinedione treatment caused
greater point-to-point heterogeneity in neointimal
accumulation in restenotic lesions after coronary
stent implantation.
The mechanism of ISR is the result of neointimal
hyperplasia12,13）. Histological studies in humans
have demonstrated that early thrombus formation
and acute inflammation are followed by neointimal
tissue proliferation in the chronic stage after coro-

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Takagi, Yamamuro, Tamita et al

Table 3 Angiographic characteristics

LAD/LCX/RCA

Thiazolidinedione（n＝20）

Control（n＝56）

p value

13/3/4

37/6/130.69

Lesion classification
A/B/C

2/14/4

4/41/80.65

Reference diameter（mm）

2.7±0.2

2.8±0.4

0.27

MLD-baseline（mm）

0.8±0.3

0.8±0.3

0.74

Lesion length（mm）11.9±3.2

12.3±3.7

0.81

Stent
MultiLink/NIR/Terumo

12/8/042/13/1

0.16

Stent length（mm）

15.9±3.3

16.8±4.4

0.38

Balloon diameter（mm）

2.8±0.3

2.9±0.4

0.15

Balloon pressure（atm）

11.5±1.7

11.8±2.1

0.62

Continuous values are mean±SD.
LAD＝left anterior descending artery ; LCX＝left circumflex artery ; RCA＝right coronary artery ; MLD＝minimal lumen diameter.

％
100
80

ControlPre
Post
Follow−up
Thiazolidinedione
Pre
Post
Follow−up

60
40
20
0
0

1

2

3

4

Intravascular ultrasound measurement（volume）

Minimal lumen diameter（mm）

mm3

Fig. 1 Quantitative coronary angiographic
analysis demonstrating no significant
differences between the two groups inminimal lumen diameter at baseline,
post-stent, or 6-month follow-up

p＝0.2610080

p＝0.01 p＜0.01

60

p＜0.01

％
60

40

40

20

20
0

0
Stent
volumeLumen Neointimal Neointimal
volume volume
index

Thiazolidinedione

Control

Fig. 2 Volumetric intravascular ultrasoundanalysis demonstrating no significant difference between the twogroups in stent volume
Lumen volume in the thiazolidinedionegroup was significantly greater than in thecontrol group, and neointimal volume andindex in the thiazolidinedione group weresignificantly smaller than in the control
group.

J Cardiol 2005 Apr; 45（4）: 139 – 147

Intravascular ultrasound measurement（image slice at minimal lumen area）

Thiazolidinedione Attenuates Diffuse In-Stent Restenosis

143

mm2
p＝0.06 ％8
7
p＝0.4660
6p＝0.125440
3p＝0.1120
2
100
Stent area Lumen Neointimal Neointimal
index
area
area
Thiazolidinedione

Control

Coefficient of variation

％
60
40

20
0
Thiazolidinedione

Control

Fig. 4 Heterogeneity in neointimal accumulation
The coefficient of variance of the neointimal area wassignificantly greater in the thiazolidinedione group thanin the control group.

Fig. 3 Intravascular ultrasound measurement at image
slice with minimal lumen area showing no significant differences in stent area, lumen area,
neointimal area, or neointimal area index
between the two groups

Thiazolidinedione

Control

CV＝47％
Mean NA＝3.4mm2
Mean SA＝8.1mm2
Neointimal index＝42％
Max NA＝6.1mm2

CV＝13％
Mean NA＝5.1mm2
Mean SA＝8.2mm2
Neointimal index＝62％
Max NA＝6.1mm2
1.52NA/mean NA

NA/mean NA

p＜0.01

1

0.5

1.5
1
0.5

0

0
1 2 3 4 5 6 7 8 91011 121314 15

1 2 3 4 5 6 7 8 91011 121314 15

Axial distance（mm）

Axial distance（mm）

Fig. 5 Representative cases demonstrating the axial distribution of neointimal tissue accumulation
Both panels demonstrate axial distribution of neointimal area standardized by mean neointimal area. There
were no significant differences between the two cases in stent length, mean stent area or maximal neointimal area. The right panel shows greater point-to-point variability of neointimal area in the thiazolidinedione treated case.
CV ＝ coefficient of variation ; NA ＝ neointimal area ; SA ＝ stent area ; Max NA ＝ maximal neointimal
area.

nary stent implantation14,15）. Analysis of directional
atherectomy specimens of early ISR tissue showed
predominantly smooth muscle cells. The lesion cellularity decreases with time over weeks or months,
and extra-cellular matrix（proteoglycans and collagen）becomes the predominant component ofrestenotic lesions16）. ISR is predominantly affected
J Cardiol 2005 Apr; 45（4）: 139 – 147

by local conditions at the site of coronary stenting,such as vessel size, stent type, and stent length17）.
Several IVUS studies have reported that greater
pre- or post-interventional plaque burden is associated with greater neointimal tissue proliferation
after stent implantation18−20）. Postmortem histologic
analysis of ISR demonstrated that neointimal thick-144

Takagi, Yamamuro, Tamita et alness at stent strut sites was greatest at sites of medial injury15）. These local conditions may contributeto the focal ISR or point-to-point heterogeneity of
neointimal tissue accumulation even in diabetic
patients with thiazolidinedione treated. The presence of diabetes mellitus accelerates the process of
neointimal tissue proliferation and promotes thedevelopment of diffuse ISR. Diabetes mellitus
results in increased inflammation, increased plateletactivation, impaired fibrinolysis, and abnormal
coagulation. Patients with type 2 diabetes mellitus
have increased inflammation as indicated byincreased generation of reactive oxygen species bymononuclear cells21）. Patients with diabetes mellitus also have elevated levels of interleukin-6, tumor
necrosis factor-alpha, and C-reactive protein22,23）.
Type 2 diabetes mellitus enhances the synthesis ofplasminogen activator inhibitor type 1（PAI-1）24）.
PAI-1 inhibits endogenous intravascular fibrinolysis, and increased PAI-1 levels lead to impaired fibrinolysis and thus the prothrombotic state25）. PAI-1
is also implicated in the inhibition of proteolysis,
which allows for increased deposition of extra-cellular matrix, an important component of restenostic
lesions in diabetic patients26）. Increased smoothmuscle cell proliferation with exaggerated neointimal hyperplasia has also been demonstrated in diabetic animal models26,27）.
The thiazolidinedione agents are a family of peroxisome proliferator activated receptor-gamma ligands, and form a new class of pharmacologicalagents for the treatment of type 2 diabetes
mellitus28−30）. Thiazolidinedione has potential protective effects on cardiovascular function. These
drugs inhibit growth factor-induced proliferation ofvascular smooth muscle cells, inhibit smooth muscle cell migration, and attenuate the development of
neointimal hyperplasia after balloon-induced vascular injury in animal models31−36）. Recent studies
have demonstrated that pioglitazone enhances
apoptosis in balloon-induced vascular injury, andreduces coronary vascular inflammation in an animal model37,38）. Thiazolidinedione reduces PAI-1
and C-reactive protein concentration in diabetic
patients39−42）. Rosiglitazone reduces ISR after coronary stent implantation in diabetic patients.
Rosiglitazone also reduces high-sensitivity C-reactive protein concentration in diabetic patients43）.
These studies suggest that thiazolidinedione treatment attenuates the accelerated process of neointimal hyperplasia and causes greater point-to-point

heterogeneity in neointimal accumulation in ISR
via several mechanisms : anti-inflammatory effects,
down-regulation of PAI-1 expression, inhibition ofcellular tissue growth, and enhancing regression ofdeveloped neointimal tissue after coronary stentimplantation. Further study is required to evaluate
whether the effect of thiazolidinedione on high-sensitivity C-reactive protein levels or PAI-1 expression is associated with reduction of neointimal tissue proliferation after coronary stent implantationin diabetic patients.
Clinical implications
The present study suggests that thiazolidinedione
treatment attenuates diffuse ISR in diabetic
patients. The pattern of ISR gives prognostic information about subsequent target vessel revascularization. Diffuse ISR is associated with high recurrence rate after repeat coronary intervention 1−4）.
Therefore, thiazolidinedione treatment may provide
subsequent benefits for diabetic patients who
undergo repeat coronary intervention. Further studies are warranted to determine whether thiazolidinedione treatment reduces subsequent restenosis
after repeat coronary intervention for the ISR.
Study limitations
The present study had some intrinsic limitations.
This study was a single center, non-placebo-controlled study with a small number of patients, raising the possibility of selection bias and low statistical power. IVUS cannot be used to measure lumen
dimensions smaller than the imaging catheter.
When the tissue encompassed the IVUS catheter,
the lumen was assumed to be the physical size of
the IVUS catheter. Therefore, 1.0 mm was thesmallest minimal lumen diameter, and 0.8 mm2 was
the smallest cross-sectional lumen area that could
be measured before re-intervention. This limitation
may underestimate the late lumen loss or neointimal tissue proliferation in severely restenotic
lesions. In addition, because of the finite resolutionof IVUS, very thin neointimal proliferation on thestent struts could not be differentiated by quantitative IVUS analysis. A previous angiographic study
classified diffuse ISR into three classes, diffuse
intra-stent ISR, diffuse proliferative ISR, and diffuse ISR with total occlusion2）. The rate of subsequent revascularization after repeat interventional
treatment in diffuse proliferative ISR and diffuse
ISR with total occlusion was greater than in diffuse
J Cardiol 2005 Apr; 45（4）: 139 – 147

Thiazolidinedione Attenuates Diffuse In-Stent Restenosis

intra-stent ISR2）. Because totally occluded diffuse
ISR was difficult to cross with the IVUS catheter
before repeat intervention, diffuse ISR with total
occlusion was not included in the current IVUS
analysis. In addition, because IVUS images wereobtained within the stent, quantitative IVUS analysis might underestimate diffuse proliferative ISR.

要

145

CONCLUSIONS
Together with the reduction of overall neointimal
hyperplasia, thiazolidinedione treatment causes
greater point-to-point heterogeneity in neointimal
accumulation. This finding strongly suggests thatthiazolidinedione treatment attenuates diffuse ISR
after coronary stent implantation in diabetic
patients.
約2 型糖尿病患者において Thiazolidinedione 治療はステント内再狭窄病変におけるび漫性新生内膜増殖を抑制する: 血管内エコー法を用いた検討
高 木
背

力

山 室

淳

民田

浩一

片山美奈子

盛岡

茂文

景 : 2 型糖尿病患者においてチアゾリジン誘導体（thiazolidinedione）が冠動脈ステント留置後のステント内新生内膜増殖を抑制することが報告されている．しかしながら，thiazolidinedione 治療を行った患者においてもステント再狭窄が残存する．
目

的 : 本研究の目的は，そのようなステント再狭窄例において，thiazolidinedione がび漫性ステ

ント内新生内膜増殖を抑制するか否かを検討することである．
方法 : 対象は神戸市立中央市民病院で血管内エコー検査（IVUS）−糖尿病レジストリーに登録された 186 病変中，慢性期の冠動脈造影でステント再狭窄を認めた 76 病変である．対象を thiazolidinedione 治療群 20 病変，対照群（通常治療群）56 病変を 2 群に分け，全例について，再冠動脈形成術実施前の IVUS 画像について定量的 IVUS 解析を実施した．
結果 : 対照群と thiazolidinedione 治療群の定量的 IVUS 解析の結果では，ステント容積（99 ± 32

vs 90 ± 20 mm3，p ＝ 0.26）やステント内最小血管面積（1.4 ± 0.6 vs 1.6 ± 0.5 mm2，p ＝ 0.11）について両群間に有意差を認めなかった．しかし，ステント内新生内膜容積（56 ± 25 vs 36 ± 11 mm3，p ＜0.01）や新生内膜インデックス（56 ± 11% vs 41 ± 8%，p ＜ 0.01）については対照群と比較して thiazolidinedione 治療群で有意に小さかった．ステント内新生内膜増殖の不均一性を検討するため新生内膜増殖の coefficient of variation について両群間で比較検討した．Coefficient of variation は対照群
（25.2%）と比較して thiazolidinedione 治療群（45.5%）で有意に大きく，thiazolidinedione 治療群においてより不均一な新生内膜増殖を認めた．
結論 : ステント再狭窄病変の定量的 IVUS 解析により，対照群ではステント全体に均一な新生内膜増殖を認めるのに対して，thiazolidinedione 治療群ではより不均一なステント内新生内膜増殖を認めることが判明した．このことから，thiazolidinedione 治療が 2 型糖尿病患者におけるび漫性ス
テント再狭窄を予防する可能性が示唆された．

J Cardiol 2005 Apr; 45（4）: 139−147

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