From the Cardiovascular Division, Osaka Police Hospital (M.A., A.H.,
T.A., K.K.); the Division of Cardiology, The First Department of Medicine,
Osaka University School of Medicine (Y.U., M.K., M.H.); and the Cardiovascular
Division, Kansai Rosai Hospital, Amagasaki (S.N.), Japan.
Correspondence to Masanori Asakura, Cardiovascular Division, Osaka Police Hospital, 10–31 Kitayama-cho, Tennoji-ku, Osaka, 543 Japan.
Methods and Results—In 12 patients who received a Wiktor
coronary stent, serial angiographic and angioscopic
examinations were performed immediately, 2 to 4 weeks, 3 months, 6
months, and 3 years after the stenting without repetition of
angioplasty. Neointimal thickness was determined by
angiography as the difference between stent and luminal diameters. The
angioscopic appearance of neointima over the stent was
classified as transparent or nontransparent according to the visibility
of the majority of the stent. Neointimal thickness
increased significantly at 3 months (0.75±0.32 mm) without
further changes at 6 months (0.74±0.32 mm). Thereafter, however,
it decreased significantly over 3 years (0.51±0.26 mm). The
angioscopic appearance was classified as transparent in 8 patients
(100%) immediately after stenting, 6 patients (100%) at 2 to 4 weeks,
2 patients (17%) at 3 months, 2 patients (20%) at 6 months, and 7
patients (58%) at 3 years.
Conclusions—The neointima became thick and
nontransparent until 6 months and then became thin and transparent by 3
years. We conclude that neointimal remodeling exists after
stenting and plays a major role in the alteration of coronary
luminal diameter after stenting.
Study Protocol
Angiographic and Angioscopic Evaluations
Statistical Analysis
Angiographic and Angioscopic Follow-up
Angioscopic images of a representative case are shown
in Figure 2
Gradual luminal narrowing after stenting has been thought to be due to
intimal hyperplasia in the animal
experiments.8 9 10 11 Schatz et
al8 reported in a dog model that the in-stent
neointima became thick and nontransparent in the early
phase, with cellular proliferation and matrix production, but
became thinner and sclerotic in the later phase, with cell number
decrease. The neointimal remodeling defined as the phasic
process of hyperplasia (thickening) and cell number decrease (thinning)
is detected in animal models of coronary artery injury and is a
common observation in the healing process after injury.
The present study revealed that the neointima
first became nontransparent with thickening and then became thinner and
transparent over 3 years. Thrombus was observed more often in the
earlier follow-ups and disappeared completely at 3 years. The finding
of thrombus over the neointima in the early follow-up may
reflect incomplete anticoagulant activity of the neointima.
Thus, the disappearance of thrombus over the neointima may
be an indicator of functional neointimal maturation. The
neointimal maturation8 12 appeared to
occur after 3 to 6 months in human coronary arteries. The
present results revealed that neointimal remodeling
also exists in human coronary arteries after stent
implantation. The mechanism of neointimal thinning may be
associated with the decrease in cellular components. Isner et
al13 reported that apoptosis is a feature
of human vascular pathology in restenotic lesions and suggested
that apoptosis may modulate the cellularity of lesions with
extensive proliferative activity. Apoptosis in
neointima may be involved in the mechanisms of cell number
decrease and of neointimal thinning. Although the
transparency of neointima may be determined in part by its
thickness, it may reflect the histological composition
of the neointima.
Our results may support the concept that the amount of luminal
narrowing detected at 6 months is not always the final outcome of
angioplasty with stents and that it can improve thereafter. Although we
often observe lesions with restenosis at 6 months, we may be
able to follow them up without reintervention if they do not cause
severe myocardial ischemia. Although our findings were based on
observations in a relatively small number of patients, it does occur
that the neointima regresses naturally, at least in a
selected group of patients. Further investigations are necessary to
determine in which group of patients this phenomenon commonly occurs.
These findings may stimulate research to determine the mechanisms
involved in this intimal thinning, with a possible value in limiting
stent restenosis.
Received November 4, 1997;
revision received March 16, 1998;
accepted March 23, 1998.
2.
Serruys PW, de Jaegere P, Kimeneij F, Macaya C,
Rutsch W, Heyndrickx G, Emanuelsson H, Marco J, Legrand V,
Materne P, Berardi J, Sigwart U, Colombo A, Goy JJ, Heuvel P, Delcan J,
Morel M, for the Benestent Study Group. A comparison of balloon
expandable stent placement with balloon angioplasty in patients with
coronary artery disease. N Engl J Med. 1994;331:489–495.
3.
Kimura T, Yokoi N, Nakagawa Y, Tamura T, Kaburagai S,
Sawada Y, Sato Y, Yokoi H, Hamasaki N, Nosaka H, Hamasaki N, Mosaka H,
Nobuyoshi M. Three-year follow-up after implantation of metallic
coronary-artery stents. N Engl J Med. 1996;334:561–566.
4.
Ueda Y, Nanto S, Komamura K, Kodama K.
Neointimal coverage of stents in human coronary
arteries observed by angioscopy. J Am Coll Cardiol. 1994;23:341–346.[Abstract]
5.
Ueda Y, Asakura M, Hirayama A, Komamura K, Hori M,
Kodama K. Intracoronary morphology of culprit lesion after
reperfusion in acute myocardial infarction. J Am Coll
Cardiol. 1996;27:606–610.[Abstract]
6.
Ueda Y, Nanto S, Komamura K, Kodama K. Elastic recoil
and intimal thickening after coronary stenting. J
Intervent Cardiol. 1995;8:137–141.[Medline]
[Order article via Infotrieve]
7.
Haude M, Erbel R, Issa H, Meyer J. Quantitative
analysis of elastic recoil after balloon angioplasty and after
intracoronary implantation of balloon-expandable Palmaz-Schatz
stents. J Am Coll Cardiol. 1993;21:26–34.[Abstract]
8.
Schatz RA, Palmaz JC, Tio FO, Garcia F, Garcia O,
Reuter SR. Balloon-expandable intracoronary stents in the adult
dog. Circulation. 1987;76:450–457.
9.
Karas SP, Gravanis MB, Santoian EC, Robinson KA,
Anderberg KA, King SB. Coronary intimal proliferation after
balloon injury and stenting in swine: an animal model of
restenosis. J Am Coll Cardiol. 1992;20:467–474.[Abstract]
10.
Giessen WJ, Serruys OW, Beusekom HMM, Woerkens LJ, Loon
H, Soei LK, Strauss BH, Beatt KJ, Verdouw PD. Coronary stenting
with a new radiopaque, balloon-expandable endoprosthesis in
pigs. Circulation. 1991;83:1788–1798.
11.
Robinson KA, Roubin G, King S, Sigel R, Rodgers G,
Apkarian RP. Correlated microscopic observations of
arterial response to intravascular stenting. Scanning
Microsc. 1989;3:665–679.[Medline]
[Order article via Infotrieve]
12.
White CJ, Ramee SR, Banks AK, Mesa JE, Chokshi S, Isner
JM. A new balloon-expandable tantalum coil stent: angiographic patency
and histologic findings in an atherogenic swine model. J Am
Coll Cardiol. 1992;19:870–876.[Abstract]
13.
Isner JM, Kearney M, Bortman S, Passeri J.
Apoptosis in human atherosclerosis and
restenosis. Circulation. 1995;91:2703–2711.
© 1998 American Heart Association, Inc.
Brief Rapid Communications
Remodeling of In-Stent Neointima, Which Became Thinner and Transparent Over 3 Years
Serial Angiographic and Angioscopic Follow-up
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Recently, it has been
reported that the luminal diameter shows phasic changes after stenting:
the progression of luminal narrowing followed by its regression. To
elucidate the mechanisms involved in the phasic changes in luminal
diameter after stenting, we examined the changes in
neointimal thickness and the appearance of
neointima by a series of angiographic and angioscopic
observations for 3 years after stent implantation.
Key Words: stents • angiography • remodeling • restenosis • imaging
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Two randomized
trials1 2 revealed that coronary stenting
reduces the incidence of restenosis after angioplasty. A recent
study3 on the 3-year follow-up after stent
implantation reported an increase in luminal diameter in the later
phase, although the mechanisms involved in this phenomenon were not
clarified. We hypothesized that a thinning of in-stent
neointima occurs and increases the luminal diameter in the
long-term follow-ups. In the present study, to elucidate the
process of neointimal maturation and the mechanism of
luminal diameter increase in the long-term follow-up, we observed the
neointimal thickness and the appearance of
neointima using a series of angiographic and angioscopic
examinations for 3 years after the implantation of coronary
stents.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Study Patients
Between April 1992 and June 1993, Wiktor stents (Medtronic) were
implanted prospectively and consecutively in 30 patients, 40 to 80
years old (mean, 61 years), 27 male and 3 female, with effort angina.
We previously reported the results of 3-month follow-up of 21 of these
patients.4 The inclusion criteria were (1)
coronary artery disease with >75% stenosis, (2)
angiographic demonstration of severe elastic recoil or coronary
dissection immediately after angioplasty that was thought to cause
acute or subacute closure or restenosis after previous
angioplasty, and (3) informed consent given for the use of the device
and follow-up examinations. The exclusion criteria were (1) left main
coronary artery disease, (2) lesions of coronary artery
bypass grafts, (3) contraindications to aggressive anticoagulant or
antiplatelet therapy, (4) a long coronary dissection that
required >2 stents, (5) chronic total occlusion, (6) acute myocardial
infarction, and (7) poor cardiac function as defined by left
ventricular global ejection fraction <30%. The patients
who died or underwent repeated angioplasty before the 3-year follow-up
were excluded from analysis in the present study. This
study protocol was approved by the Osaka Police Hospital Ethical
Committee.
Serial angiographic and angioscopic examinations were scheduled
immediately, 2 to 4 weeks, 3 months, 6 months, and 3 years after stent
implantation. The angioscopic observations4 5
were made while the blood was cleared away from view by the injection
of 3% dextran-40. The images from the angioscope (VFS-1300 or MC-800E,
Nihon Kohden) were recorded by an S-VHS videotape. We used
conventional anticoagulant and antiplatelet therapy throughout the
study. Intravenous heparin (200 U/kg body wt), oral aspirin
(300 to 330 mg/d), dipyridamole (75 mg/d), and warfarin
were administered.
The minimal luminal diameter of the lesion and the stent
diameter were measured by hand calipers on pictures in the same view
for each patient by 2 cardiologists. Because, with the radiopacity of
the Wiktor stent, its diameter and luminal diameter can be measured
simultaneously on an angiogram, the neointimal
thickness was calculated as the difference between
them.6 7 The angioscopic images were reviewed by
two specialists. The neointima over the stent was judged to
be transparent or nontransparent according to the visibility of the
majority of stent. Both transparent neointima and uncovered
stent were classified as transparent in this study. The existence of
thrombus over the neointima was also evaluated. The two
observers independently evaluated 100 pictures, and 10 days later, they
reevaluated the same 100 pictures to check the intraobserver and
interobserver variabilities. The intraobserver variability was 2% and
3% for each specialist, respectively, and interobserver variability
was 5%.
The data from the angiographic measurements are shown as
mean±SD. The changes and the differences of these data were
analyzed with a one-way ANOVA and Scheffé's multiple
comparison test. A value of P<0.05 was regarded as
statistically significant.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Patient Characteristics
Thirty patients were enrolled in this study, but 1 patient died, 2
received angioplasty for acute stent occlusion on the day of stenting,
and 6 received angioplasty for the in-stent restenosis within 6
months. No patient required angioplasty after 6 months. In 1 patient,
angioscopic examination could not be performed because of the
significant stenosis in the left main coronary artery
at 3-year follow-up. The catheterization was not
performed at 3 years in 8 patients: 2 because of noncardiac diseases
and 6 because they refused the examination. The remaining 12 patients
(mean age, 59 years; 11 male and 1 female) were analyzed in
this study.
Angiographic data (Figure 1
)
revealed phasic changes in minimal luminal diameter and in
neointimal thickness. Minimal luminal diameter decreased at
3 to 6 months but increased at 3 years after the stenting: This time
course is associated with the changes in neointimal
thickness. No significant change in stent diameter was observed,
suggesting that the stent prevented recoil for 3 years.
View larger version (17K):
[in a new window]
Figure 1. Serial changes in minimal luminal diameter, stent
diameter, and neointimal thickness. Data are mean±SD.
*P<0.05 vs immediately after stenting.
P<0.05 vs 6 months after stenting.. The neointima
(Table) was classified as transparent in 8 patients
(100%) immediately after stenting, in 6 (100%) at 2 to 4 weeks, 2
(17%) at 3 months, 2 (20%) at 6 months, and 7 (58%) at 3 years. In 2
patients, the neointima was consistently classified
as transparent at 3 months, 6 months, and 3 years. In 5 patients,
although the neointima was classified as nontransparent at
3 or 6 months, it became transparent at 3 years. Even in 4 patients who
were classified as nontransparent at 3 years, the neointima
became partially transparent compared with that at 3 or 6 months. The
thrombus (Table) was occasionally observed on the stent or
neointima in the earlier period after stenting, but no
thrombus was observed over the neointima at 3 years in any
patient.
View larger version (39K):
[in a new window]
Figure 2. Representative case of
neointimal maturation observed by angioscopy in a
58-year-old man with effort angina. In this case, stent was implanted
because a large dissection was recognized after balloon angioplasty in
right coronary artery. (a) Proximal end of stent wire
immediately after implantation. Uncovered stent wire was observed. This
image was classified as transparent. (b) Proximal end of stent wire 2
weeks after implantation. Uncovered stent wire was observed. This image
was classified as transparent. (c) Proximal end of stent wire 3 months
after implantation. Stent wire, covered by white neointima,
was not visible. This image was classified as nontransparent. (d)
Proximal end of stent wire 6 months after implantation. Although stent
was partially visible, this image was classified as nontransparent. (e)
Proximal end of stent wire 3 years after implantation. Stent wire
covered by transparent neointima became visible again. This
image was classified as transparent.
View this table:
[in a new window]
Table 1. Angioscopic
Data
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
The minimal luminal diameter decreased significantly at 3 to 6
months and then increased significantly at 3 years. The decrease in
in-stent luminal diameter by 6 months is due to neointimal
thickening, as we have previously reported,6
although the vascular constriction (vascular remodeling) is thought to
be a major mechanism of restenosis after balloon angioplasty
without stenting. The main mechanisms of in-stent restenosis
and in-stent lumen diameter increase may be attributable to the
thickening and subsequent thinning of neointima,
respectively. The present study is the first to reveal that the
increase in the luminal diameter at 3 years is attributable to the
thinning of the neointima.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
1.
Fischman DL, Leon MB, Baim DS, Schatz RA, Savage
MP, Penn I, Detre K, Veltri L, Ricci D, Nobuyoshi M, Cleman M, Heusere
R, Almond D, Teirstein PS, Fish RD, Colombo A, Brinker J, Moses J,
Shaknovich A, Hirshfield J, Bailey S, Ellis S, Rake R, Goldberg S, for
the Stent Restenosis Study Investigators. A randomized
comparison of coronary stent placement and balloon angioplasty
in the treatment of coronary artery disease. N Engl
J Med. 1994;331:496–511.
This article has been cited by other articles:
 |
|
 |
|
  R. D. Kenagy, S.-K. Min, A. W. Clowes, and J. D. Sandy Cell Death-associated ADAMTS4 and Versican Degradation in Vascular Tissue J. Histochem. Cytochem., September 1, 2009; 57(9): 889 - 897. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D.F. Kallmes, Y.H. Ding, D. Dai, R. Kadirvel, D.A. Lewis, and H.J. Cloft A Second-Generation, Endoluminal, Flow-Disrupting Device for Treatment of Saccular Aneurysms AJNR Am. J. Neuroradiol., June 1, 2009; 30(6): 1153 - 1158. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Yokoyama, M. Takano, M. Yamamoto, S. Inami, S. Sakai, K. Okamatsu, S. Okuni, K. Seimiya, D. Murakami, T. Ohba, et al. Extended Follow-Up by Serial Angioscopic Observation for Bare-Metal Stents in Native Coronary Arteries: From Healing Response to Atherosclerotic Transformation of Neointima Circ Cardiovasc Interv, June 1, 2009; 2(3): 205 - 212. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Higo, Y. Ueda, J. Oyabu, K. Okada, M. Nishio, A. Hirata, K. Kashiwase, N. Ogasawara, S. Hirotani, and K. Kodama Atherosclerotic and thrombogenic neointima formed over sirolimus drug-eluting stent an angioscopic study. J. Am. Coll. Cardiol. Img., May 1, 2009; 2(5): 616 - 624. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Awata, J.-i. Kotani, M. Uematsu, T. Morozumi, T. Watanabe, T. Onishi, O. Iida, F. Sera, S. Nanto, M. Hori, et al. Serial Angioscopic Evidence of Incomplete Neointimal Coverage After Sirolimus-Eluting Stent Implantation: Comparison With Bare-Metal Stents Circulation, August 21, 2007; 116(8): 910 - 916. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Takano, T. Ohba, S. Inami, K. Seimiya, S. Sakai, and K. Mizuno Angioscopic differences in neointimal coverage and in persistence of thrombus between sirolimus-eluting stents and bare metal stents after a 6-month implantation Eur. Heart J., September 2, 2006; 27(18): 2189 - 2195. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-i. Kotani, M. Awata, S. Nanto, M. Uematsu, F. Oshima, H. Minamiguchi, G. S. Mintz, and S. Nagata Incomplete Neointimal Coverage of Sirolimus-Eluting Stents: Angioscopic Findings J. Am. Coll. Cardiol., May 16, 2006; 47(10): 2108 - 2111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. D. Kenagy, J. W. Fischer, S. Lara, J. D. Sandy, A. W. Clowes, and T. N. Wight Accumulation and Loss of Extracellular Matrix During Shear Stress-mediated Intimal Growth and Regression in Baboon Vascular Grafts J. Histochem. Cytochem., January 1, 2005; 53(1): 131 - 140. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Farb, F. D. Kolodgie, J.-Y. Hwang, A. P. Burke, K. Tefera, D. K. Weber, T. N. Wight, and R. Virmani Extracellular Matrix Changes in Stented Human Coronary Arteries Circulation, August 24, 2004; 110(8): 940 - 947. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T Hayashi, A Kimura, and K Ishikawa Acute myocardial infarction caused by thrombotic occlusion at a stent site two years after conventional stent implantation Heart, May 1, 2004; 90(5): e26 - e26. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Bax and P. V. Oemrawsingh Can Molecular Imaging Predict In-Stent Restenosis? J. Nucl. Med., February 1, 2004; 45(2): 300 - 301. [Full Text] [PDF]
|
|
|
|
|
|
T. Kimura, K. Abe, S. Shizuta, K. Odashiro, Y. Yoshida, K. Sakai, K. Kaitani, K. Inoue, Y. Nakagawa, H. Yokoi, et al. Long-Term Clinical and Angiographic Follow-Up After Coronary Stent Placement in Native Coronary Arteries Circulation, June 25, 2002; 105(25): 2986 - 2991. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. N. Ruygrok, M. W.I. Webster, V. de Valk, G.-A. van Es, J. A. Ormiston, M.-A. M. Morel, and P. W. Serruys Clinical and Angiographic Factors Associated With Asymptomatic Restenosis After Percutaneous Coronary Intervention Circulation, November 6, 2001; 104(19): 2289 - 2294. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H J G H Mulder, M J Schalij, B Kauer, R F Visser, P R M van Dijkman, J W Jukema, A H Zwinderman, and A V G Bruschke Pravastatin and endothelium dependent vasomotion after coronary angioplasty: the PREFACE trial Heart, November 1, 2001; 86(5): 533 - 539. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-J. Park, M.-K. Hong, C. W. Lee, J.-J. Kim, J.-K. Song, D.-H. Kang, S.-W. Park, and G. S. Mintz Elective stenting of unprotected left main coronary artery stenosis: Effect of debulking before stenting and intravascular ultrasound guidance J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1054 - 1060. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. SCHIELE The "angioplastically correct" follow up strategy after stent implantation Heart, April 1, 2001; 85(4): 363 - 364. [Full Text]
|
|
|
|
|
|
P K Haager, E R Schwarz, J v. Dahl, H G Klues, T Reffelmann, and P Hanrath Long term angiographic and clinical follow up in patients with stent implantation for symptomatic myocardial bridging Heart, October 1, 2000; 84(4): 403 - 408. [Abstract] [Full Text]
|
|
|
|
|
|
P. N. Ruygrok, R. Melkert, M.-A. M. Morel, J. A. Ormiston, F. W. Bar, F. Fernandez-Aviles, H. Suryapranata, K. D. Dawkins, C. Hanet, P. W. Serruys, et al. Does angiography six months after coronary intervention influence management and outcome? J. Am. Coll. Cardiol., November 1, 1999; 34(5): 1507 - 1511. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||