From the Department of Pathology, Osaka City University Medical School
(R.K., M.U.); the Department of Cardiology, Osaka City General Hospital
(T.N.); the Department of Food and Nutrition, Faculty of Human Life Science,
Osaka City University (A.K.), Osaka, Japan; and the Department of
Cardiovascular Pathology, Academic Medical Center, University of Amsterdam,
the Netherlands (A.E.B.).
Correspondence to Dr Makiko Ueda, Department of Pathology, Osaka City University Medical School, 1–4-54 Asahi-machi, Abeno-ku, Osaka, 545, Japan.
Methods and Results—We investigated 11 stented coronary
arteries (9 Palmaz-Schatz stents, 1 Wiktor stent, and 1 ACS Multi-Link
stent) obtained from 11 patients who had died 2 days to 21 months after
stenting. We focused on gross, histological, and
immunohistochemical aspects of the repair processes. Two patients
developed symptoms of restenosis. Serial sections were stained
with antibodies against smooth muscle cells (SMCs),
macrophages, and endothelial cells. At 9 and 12
days after stenting, the stent sites showed thrombus formation with
early formation of neointima composed of abundant
macrophages and
Conclusions—These observations strongly support the concept that
neointimal proliferation in humans is a process of staged
redifferentiation of SMCs, which may cause in-stent stenosis.
Moreover, the exuberant neointimal proliferation with
accumulation of macrophages and extensive neovascularization at
sites of stent restenosis suggests a role for organization of
mural thrombus.
We are not aware of any systematic studies in humans focusing on gross,
histological, and immunohistochemical aspects of the
repair processes involved. The present study addresses this
need.
A Palmaz-Schatz stent (Johnson & Johnson Interventional System) was
inserted into 9 sites. One coronary artery received a Wiktor
stent (Medtronic Inc); the remaining artery contained an ACS Multi-Link
stent (Advanced Cardiovascular Systems).
All patients with coronary stents were treated initially with
heparin and then maintained on different drug regimens: heparin only
(patients 1, 2, 3, and 5); aspirin only (patient 11); aspirin and
ticlopidine (patients 4 and 8); aspirin, warfarin, and
dipyridamole (patient 9); and warfarin only (patients
6, 7, and 10). High-pressure stent dilatation, which recently became
standard, was performed in 6 patients (patients 3, 6, 7, 8, 10, and
11).
Two patients (patients 7 and 8) developed recurrent angina pectoris,
which was electrocardiographically related to the stented
coronary artery. The signs and symptoms were considered
indications of restenosis; angiography, however, could not be
done in any of these patients.
Histological Investigations
After fixation, the stent fragments on the cut surface of each of the
5-mm segments were removed under a dissection microscope. Each 5-mm
segment was then routinely processed and embedded in paraffin. From
each segment, sections were cut at 8- or 10-µm thickness. Each time a
portion was encountered that still contained residual stent fragments,
these fragments were removed carefully, again by cutting the fragments
and pulling them out of the paraffin-embedding block; thereafter, the
sectioning continued. From each segment,
In the remaining 2 patients (patients 5 and 9), only paraffin blocks
from the sites of coronary stenting were available for the
study; microscopic sections were made by use of the same method as
described above. Of these sections, every 20th and 21st sections were
stained with hematoxylin-eosin and Weigert's elastic van Gieson's
stain, respectively. The other sections were used for
immunohistochemical staining.
Immunohistochemical Investigations
Double Staining
At 30 days after stenting (patient 5), the areas around the struts
still contained remnants of thrombus, but there was distinct
proliferation of
From 64 days on (patients 6, 8, 9, 10, and 11), all sites with stenting
showed a distinct layer of neointimal tissue, albeit to
varying degrees. In 4 lesions without clinical evidence of
restenosis (patients 6, 9, 10, and 11; 64 days and 12, 15, and
21 months after stenting, respectively), the thickening of the
neointimal tissue was distinctly less than in
restenotic lesions (Figures 3 through 5
The site with clinical restenosis after stenting (patient 8; 5
months after stenting) presented exuberant
neointimal formation, resulting in almost total occlusion
(Figure 6
Wiktor Stent (Patient 1, 1 Site)
ACS Multi-Link Stent (Patient 7, 1 Site)
Subacute Thrombosis
Late Stent Stenosis
In 1987 in their study of coronary arteries of dogs, Schatz and
coworkers16 considered intimal hyperplasia a
consequence of intense fibroblast proliferation at 8 weeks after
stenting. The present study in humans, using immunocytochemical
markers, clearly shows that cellular components invading the thrombotic
aggregates at the sites of laceration at the earliest stages are
spindle-shaped cells negative for actin markers such as HHF-35 and 1A4.
However, at 30 days, a neointima is clearly identifiable,
and the spindle-shaped cells present within this layer appear to be
positive with both actin markers. This sequence strongly suggests that
during the evolution of the neointima, the
Despite similarities between experimental animal models and humans, the
present study also shows important differences in the healing
phenomena after stenting. First, a restenotic lesion, which
occurred 85 days after implantation of the ACS Multi-Link stent
(patient 7) and 5 months after implantation of a Palmaz-Schatz stent
(patient 8), showed excessive neointimal proliferation
composed of numerous macrophages; SMCs; and abundant, newly
formed microvessels, which led to almost total occlusion of the lumen
(Figures 6
Another difference with the earlier experiments by Schatz and
coworkers16 performed on normal coronary
arteries in dogs is that in their series, the maximal
neointimal thickness occurred at 8 weeks after stent
implantation; this was followed by sclerotic changes with less
cellularity and marked regression of the neointima by 32
weeks.16 However, in our series of human
coronary arteries, each containing atherosclerotic disease, we
observed lesions with intervals between stent implantation and death
ranging from 12 to 21 months, and each showed distinct cellularity
composed predominantly of
In the experimental dog model used by Schatz and
coworkers,16 reendothelialization
after stenting, using the scanning electron microscope, appeared
incomplete at 1 week. At 3 weeks, a mosaic type of
endothelial cell lining was found, and full
endothelial covering with mature and elongated cells
was seen at 32 weeks.16 Thus far, 1 autopsied
case, 8 weeks after a Palmaz-Schatz stent implantation, also reports a
neointima covered by endothelial cells
overlying the area of the stent.1 However, there
is no immunohistochemical identification of these
endothelial cells. In the present study, with
regard to immunostaining characteristics with anti-vWF
antibody, nonrestenotic lesions after stenting revealed partial
endothelial cell regeneration at 64 days and complete
restoration of the endothelial cell lining in lesions
at 12, 15, and 21 months after stenting. Further studies with more
cases are needed to clarify a more detailed time course of
reendothelialization at the site of coronary
stenting in humans. Nevertheless, the present study, for the first
time, provides immunohistochemical data regarding
reendothelialization after stenting in human
coronary arteries.
Restenosis Versus Nonrestenosis
Study Limitations
Received January 6, 1998;
revision received March 2, 1998;
accepted March 17, 1998.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Neointimal Tissue Response at Sites of Coronary Stenting in Humans
Macroscopic, Histological, and Immunohistochemical Analyses
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Experimental animal
studies have shown that coronary stenting induces
neointimal proliferation. However, the histopathological
events after coronary stenting in humans have not been
studied systematically. 
-actin–negative spindle cells. From 64 days
on, all sites with stenting showed a distinct layer of
neointima, albeit to varying degrees. In
nonrestenotic lesions, neointimal thickening was
markedly less than in restenotic lesions but without
qualitative differences; the neointima contained
macrophages but was composed predominantly of
-actin-positive SMCs.
Key Words: stents • restenosis • coronary disease • immunohistochemistry
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Coronary
stenting is the only procedure that has been proven to reduce the
incidence of late restenosis after
PTCA.1 2 3 However, thus far only sparse data are
available in humans regarding the healing processes involved after
stent implantation. Indeed, an enormous gap exists between animal
experiments on one hand and insights obtained from observations in
humans on the other. In fact, to the best of our knowledge, only 4
autopsy case reports exist of patients who had died 12 hours, 15 days,
3 weeks, and 8 weeks, respectively, after implantation of a
coronary stent,1 4 5 and in 2 instances,
atherectomy specimens, retrieved from restenotic lesions after
coronary stenting with a Palmaz-Schatz device, have been
reported.6 Obviously, there is a need for more
detailed information in humans.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Patients
This study is based on 11 coronary arteries obtained at
autopsy from 11 patients who had undergone elective or emergency
coronary stenting. The relevant clinical data are summarized in
the Table
. The mean age of the patients (9 men and 2
women) was 76±6.4 years (range, 66 to 83 years). In 3 patients with
acute myocardial infarction (patients 2, 3, and 4), stent implantation
was performed to treat coronary dissection after emergency
PTCA. One patient (patient 1) with stable angina underwent stenting to
treat coronary dissection after PTCA. All 4 patients (patients
1, 2, 3, and 4) showed immediate post-PTCA angiographic evidence of
dissection before stent implantation. Two patients (patients 7 and 11)
with stable angina underwent primary stenting of a stenotic
lesion in the left circumflex coronary artery and in the LAD,
respectively. In 1 patient (patient 5) with unstable angina and 90%
stenosis of the left main trunk, intracoronary stent
implantation was performed because the patient refused to undergo
coronary artery bypass grafting. In the 4 remaining patients
(patients 6, 8, 9, and 10), stent implantation was performed for
restenosis after PTCA. In these 11 patients, the interval
between coronary stenting and death ranged from 2 days to
21 months.
View this table:
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Table 1. Clinical Data Relevant to This Study of 11 Patients Who
Underwent Coronary Artery Stenting
In 9 of the 11 patients, the whole heart was available for
study. The site of stenting was identified by comparing the clinical
angiograms with the heart specimens. The coronary arteries were
removed from the epicardial surface, and the site containing the stent
was cut with scissors into 5-mm segments. Care was taken to have the
articulation of the Palmaz-Schatz stent within 1 of these segments. In
the present study, designed to investigate the cellular components
at the stenting site with specific immunohistochemical techniques, we
did not select an embedding method in methyl methacrylate recommended
for obtaining intact cross sections.7 In 4
hearts, the coronary artery segments were fixed in buffered
formalin; in the remaining 5 hearts, the segments were fixed in
methanol-Carnoy's fixative. 
100 to 300 sections were
cut. This procedure thus allowed us to obtain an adequate overview of
all the stented arterial segments.
Single Staining
The cellular components were analyzed by use of
monoclonal antibodies against actin (1A4, HHF-35, and CGA-7), vimentin,
macrophages (HAM-56 and PGM-1), and endothelial
cell vWF. The 3 actin markers were used to study the state of
differentiated SMCs. 1A4 and HHF-35 are markers that are the first to
become positive when SMCs differentiate toward the contractile
phenotype; once fully differentiated as such, CGA-7 also
becomes positive.8 9 10 Sections were incubated
with the primary antibody for 1 hour at room temperature. The sections
were then subjected to a three-step staining procedure with the use of
streptavidin-biotin complex with horseradish peroxidase for color
detection. Buffered saline was used for washing between the subsequent
incubation steps. Horseradish peroxidase activity was visualized with
3-amino-9-ethylcarbazole, and the sections were counterstained faintly
with hematoxylin.
For the simultaneous identification of SMCs and
macrophages, the following subsequent incubation steps were
performed: normal goat serum (15 minutes), blotting, no washing,
cocktail of 2 primary monoclonal antibodies (anti-SMC -actin, 1A4
[IgG2a] and anti-macrophage, HAM-56 [IgM] for 60 minutes),
cocktail of 2 secondary antibodies consisting of biotinylated goat
anti-mouse IgG2a and alkaline phosphatase–conjugated goat anti-mouse
IgM (30 minutes), and ß-galactosidase–labeled streptavidin (30
minutes). The enzymatic activity of ß-galactosidase for 1A4 (IgG2a)
was visualized in turquoise (BioGenex Kit, San Ramon), and that of
alkaline phosphatase for HAM-56 (IgM) was visualized in red (New
Fuchsin Kit, Dako).11
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Palmaz-Schatz Stent (Nine Sites)
Three patients who had undergone emergency Palmaz-Schatz
stenting after failed PTCA clinically developed subacute thrombosis
6 to 12 days after stenting. Gross investigation confirmed occlusive
thrombus formation at the site of the stent (Figure 1). Light microscopical study showed that
all sites contained a preexisting eccentric plaque and revealed that
the struts of the stent had lacerated the arterial wall and
caused a local response. At 6 days after stenting (patient 2), the site
of the struts showed thrombus formation and an accumulation of
macrophages around the struts. At 9 and 12 days after stenting
(patients 3 and 4), the stent sites at the site of the thrombus
revealed only minimal cellular reaction around the struts, whereas the
stent sites proximal or distal to the thrombus showed a more prominent
cellular reaction mixed with mural thrombus (Figure 2). In the latter, the cellular reaction
was characterized by an early proliferation of neointimal
tissue composed of abundant macrophages and actin-negative
spindle-shaped cells, which stained positive for vimentin but negative
with actin markers 1A4, HHF-35, and CGA-7 (Figure 2B through 2D). No
positivity with the antibody against vWF was found at the luminal
surface of the neointimal tissue (Figure 2E). Moreover, in
these 3 patients, PTCA-related medial dissection at the border area
between the plaque wall and plaque-free wall of a stented eccentric
plaque was observed. The neointima alongside the dissection
was also composed of macrophages and spindle-shaped cells, most
of which were negative for the actin markers.
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Figure 1. Segment of the LAD 9 days after PTCA and stenting
with complete thrombotic occlusion (patient 3 in the Table 
). A, Gross
aspect of a cross section that reveals total occlusion of the lumen by
thrombus. There is an eccentric atherosclerotic plaque. B,
Histological section from the cut surface shown in A.
The lumen contains an occlusive thrombus (T), which relates to the site
of stenting (stent struts indicated by arrowheads). At the site of the
stent struts, there is no cellular reaction, whereas the site of the
PTCA-related medial dissection (arrow) shows distinct
neointimal proliferation (asterisk). AS indicates
preexisting atherosclerotic plaque. Elastic tissue stain. Magnification
B, x55.
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Figure 2. Segment of the LAD of the same
patient shown in Figure 1 , 9 days after PTCA and stenting, which is
taken more proximally and shows partial thrombotic adherence. A through
E are serial sections. A, Hematoxylin-eosin stain. There is a distinct
neointima (asterisks) with adherent mural thrombus at the
site of a stent strut (arrowhead). B, Staining for vimentin reveals
that the cells of the neointima are positive for vimentin.
C, Anti–HHF-35. The spindle-shaped cells within the
neointima do not stain with the -actin marker at this
stage (compare with B). D, Anti–HAM-56. The neointima
contains HAM-56–positive macrophages. E, Anti-vWF. There are
no positive-staining endothelial cells at the luminal
surface of the neointima. There is positive staining of
endothelial cells of the vasa vasorum (arrow), shown at
higher magnification in the inset. Magnification A through D, x110; E,
x72; inset E, x217.-actin–positive SMCs, with only occasional
macrophages. No vWF-positive cells, covering the
neointima, were observed at this site. ; compare with Figure 6). In these nonrestenotic lesions, the neointima
was composed predominantly of -actin–positive SMCs, with some
macrophages and foreign body giant cells located adjacent to
the struts. The lesion at 64 days, moreover, showed fibrin, considered
a remnant of a previous thrombus, within the neointima
close to the luminal surface (Figure 3);
no remnants of thrombus were found within the neointima at
12, 15, and 21 months after stenting (Figures 4 and 5).
In the lesion at 64 days, positive staining with the anti-vWF antibody
was observed partially at the luminal surface of the
neointima. However, in lesions at 12, 15, and 21 months, a
complete lining of vWF-positive endothelial cells was
found at the luminal surface (Figure 5).
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Figure 3. Segment of the LAD 64 days after stenting (patient
6 in the Table ). A, Gross aspect of a cross section showing an
eccentric atherosclerotic plaque (AS) and neointima
surrounding stent struts. B, Elastic tissue stain of the same cut
surface shown in A. There is a distinct, eccentric atherosclerotic
plaque. The site of a stent strut (arrowhead) is covered by
neointima (asterisks). C, Higher magnification of the area
containing the arrowhead shown in B. The site of the strut is distinct
(arrowhead), and the area around the strut contains
neointima with fibrin as remnants of previous thrombosis
(T) close to the luminal surface. Hematoxylin-eosin stain. D,
Immunodouble staining with 1A4 (turquoise) and HAM-56 (red) from the
same site shown in C. The neointima around the strut
(arrowhead) is composed mainly of SMCs with occasional
macrophages. Magnification B, x21; C and D, x92.
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Figure 4. Segment of the LAD 15 months after stenting
(patient 10 in the Table ). A, Gross aspect of a cross section shows an
eccentric atherosclerotic plaque (AS) and distinct
neointimal proliferation around the struts of the stent. B,
Immunodouble stain of the same cross section shown in A, with 1A4
(turquoise) and HAM-56 (red). The neointima (asterisks)
consists mainly of SMCs. The sites of the stent struts are indicated by
arrowheads. Magnification B, x18.
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Figure 5. Segment of the LAD 21 months after stenting
(patient 11 in the Table ). A, Gross aspect of a cross section shows an
eccentric atherosclerotic plaque (AS) and extensive
neointimal formation with considerable luminal narrowing.
The stent struts are clearly visible within the neointima.
B, Elastic tissue stain of the section shown in A. There is extensive
neointimal tissue (asterisks) around the stent struts
(arrowheads). C, Same section as shown in B immunostained
with 1A4. The neointima around the stent struts
(arrowheads) is composed almost totally of SMCs. D, Staining for vWF.
The luminal surface of the neointima is lined by
vWF-positive cells, considered regenerated endothelial
cells. Magnification B and C, x33; D, x368.
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Figure 6. Segment of the right
coronary artery 5 months after stenting, with
restenosis (patient 8 in the Table ). A, Gross aspect of a cross
section shows almost total occlusion caused by excessive
neointimal proliferation. B, Histology of the cross section
shown in A. There is exuberant neointimal formation related
to the stent procedure ("stent"). The sites of stent struts are
indicated by arrowheads. The previous PTCA procedure had caused
distinct laceration of the preexistent wall, which has resulted in
post-PTCA neointima ("PTCA") with a much more compact
structure with a much higher density of collagen. The post-PTCA
neointima is markedly compressed by the implanted stent.
Elastic tissue stain. C, Hematoxylin-eosin stain. The
neointima formed around the stent struts (arrowheads)
contains distinct microvessels. D, Immunodouble stain with 1A4
(turquoise) and HAM-56 (red) shows an extensive accumulation of SMCs
around the stent struts (arrowheads) with scattered macrophages
and numerous microvessels in the deeper layers of the
neointima. E, Staining for vWF. Around the stent struts
(arrowheads), abundant microvessels are seen that stain positive with
anti-vWF. AS indicates preexisting atherosclerotic plaque.
Magnification B, x18; C, x62; D and E, x132.). The neointima
contained newly formed microvessels and scattered macrophages,
particularly in the deep layers with extensive accumulation of SMCs.
This patient had PTCA-related restenosis and thus had undergone
stenting. The neointima formed after PTCA before stenting
was clearly identified adjacent to the stent struts and distinct from
the neointima induced by stenting. In fact, because of
stent implantation, the post-PTCA neointima was markedly
compressed, partially disrupted, and covered by a second
neointima, which accounted for the post stent neointima
(Figure 6).
The site 2 days after stenting showed occlusive intravascular
thrombosis. Microscopically, PTCA-related medial dissection was
present, and the stent struts had caused additional local
laceration of the arterial wall.
The patient developed clinical signs and symptoms of
restenosis and died 85 days after stenting. Gross and
microscopic evaluations showed excessive neointimal
formation, causing almost total occlusion (Figure 7). At the site of restenosis,
the deep layers of the neointima contained abundant
macrophages and newly formed capillaries, whereas the
superficial layers consisted almost entirely of SMCs (Figure 7).
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Figure 7. Segment of the left circumflex artery 85 days
after stenting with restenosis (patient 7 in the Table ). A,
Gross aspect of a cross section shows almost total occlusion at the
site of stenting caused by exuberant neointimal
proliferation. B, Elastic tissue stain of the cut surface shown in A.
The excessive neointimal proliferation (asterisks) is
distinct and is seen to cause restenosis. The site of the stent
struts is indicated by arrowheads. C, Immunodouble staining with 1A4
(turquoise) and HAM-56 (red) shows that the superficial layer of the
neointimal proliferation is composed almost entirely of
SMCs, whereas the deep layers, close to the stent struts (arrowheads),
contain numerous macrophages (see E). D, Staining for vWF shows
that the neointima contains an almost concentric layer of
neovascularization in the deep parts. The stent struts are indicated by
arrowheads. The luminal surface also contains vWF-positive cells,
considered regenerated endothelial cells. E,
Immunodouble staining with 1A4 (turquoise) and HAM-56 (red) shows, at
higher magnification, the area indicated between arrows in C. The site
of the stent strut is indicated by an arrowhead. Note the accumulation
of macrophages (red) and the more superficial dominance of SMCs
(turquoise). F, Staining for vWF. The area indicated between arrows in
D is shown at higher magnification. An arrowhead indicates the site of
the stent strut. Note the vWF-positive microvessels present in the
deep layers. AS indicates preexisting atherosclerotic plaque.
Magnification B, x18; C and D, x62; E and F, x147.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
To the best of our knowledge, the present study, based
on 11 stented sites in 11 patients and with an interval between stent
implantation and death ranging from 2 days to 21 months, is the first
systematic investigation into the pathobiology of stent
stenosis in humans. Several aspects need further consideration.
To this end, we will consider all 11 stents together, because the vast
majority (9 of 11) were Palmaz-Schatz stents.
Our series contains 4 patients (patients 1, 2, 3, and 4) in
whom (sub)acute thrombosis after stenting had
occurred. It is interesting that each of these 4 patients received
stents because of a failure of a PTCA procedure that in each patient
had led to a dissection extending into the media. Indeed, in patients
in whom stenting is performed as a bailout procedure after PTCA
failure, the reported incidence of thrombosis is relatively high and
varies between 6.9%12 and
16%.13 The question remains what
mechanisms underlie the relationship between the initial PTCA-related
medial dissection and the occurrence of subacute thrombosis after
stenting.
This study of human coronary arteries suggests that the
sequence of events leading to a neointima formation after
implantation of stents is basically similar to that encountered in
animal models14 15 16 and is very similar to that
observed in post-PTCA repair processes.8 9 10 17
In general terms, the initial event is that of local thrombus
formation, adjacent to the stent struts, gradually invaded by cellular
components such as macrophages and -actin–negative
spindle-shaped cells accompanied by the deposition of extracellular
matrix components. This eventually differentiates into a much more
fibrocellular lesion containing -actin–positive SMCs. These
observations strongly suggest that mural thrombosis with
macrophage infiltration at the earliest stage after stenting
may be crucial in recruiting SMCs from the arterial wall.
Indeed, platelet adherence and aggregation promote the subsequent
healing process through the release of growth
factors.18 19 20 Macrophages also secrete a
variety of cytokines and growth factors that have been shown in
vitro to cause SMC proliferation and
migration.21 22 Experimental animal studies have
suggested that PDGF, secreted not only from activated
platelets but also from macrophages and other vascular
cells, is 1 of the major growth factors involved in the process of
neointimal formation after balloon
injury.23 24 25 Furthermore, our own in situ
hybridization and immunohistochemical studies of human coronary
arteries after PTCA using frozen sections have shown that PDGF-A and -B
mRNAs, PDGF-B protein, and PDGF-ß receptor protein are expressed in
neointimal lesions containing macrophages and
actin- negative spindle-shaped cells.10 26
Whether similar phenomena occur in the process of
neointimal formation in human coronary arteries
after stenting is unknown, but the possibility is intriguing, and
future studies using frozen sections obtained from stenting sites
should look into these aspects. -actin–negative spindle-shaped cells most likely represent
dedifferentiated SMCs, which in time gradually redifferentiate into
-actin–positive SMCs. This concept of staged redifferentiation of
neointimal SMCs is endorsed by experimental
studies27 28 29 and is relevant because we
previously demonstrated almost identical shifts in the cytoskeletal
phenotype of spindle-shaped cells during the development of the
neointima after angioplasty injury in human
coronary arteries.8 9 It could be argued
that the -actin–negative spindle-shaped cells observed early in the
neointima might represent not only dedifferentiated
SMCs but also other cell types such as infiltrating macrophages
that have lost their specific antigen or fibroblasts—a point of view
that at this stage, cannot be elucidated. and 7). It is the quantity of these features that
makes them exceptional; neovascularization and macrophages with
occasional giant cells are common findings, particularly adjacent to
stent wires, in both experimental animal models14
and this study in human coronary arteries. These observations
are of interest because both sites of restenosis after stent
implantation show large numbers of macrophages and extensive
neovascularization, features not observed to this extent at
"nonrestenotic" stent sites. In this context, it is
important that Moreno and associates30 recently
showed that the amount of macrophages in preexistent
atherosclerotic lesions is a predictor for restenosis after
PTCA. Previously, Strauss et al6 compared
coronary atherectomy material obtained from patients with
restenosis after stenting with that obtained from patients with
restenosis after angioplasty or atherectomy. They concluded
that SMC proliferation was the predominant feature in
restenotic tissue regardless of the initiating procedure and
without any unique features attributable to stenting in general or to a
particular type of stent. This apparent controversy is of considerable
interest. We have indicated previously that once the post-PTCA
laceration, particularly in concentric lesions, is limited to the
atheroma, the repair process is often accompanied by
neovascularization and accumulation of macrophages in the
deeper parts of the
neointima.10 17 26 Hence, the
formation of a concentric layer of neovascularization and
macrophage accumulation in the deep parts of the
neointima may result from organization processes of
thrombosis, which initially was formed around the stent wires at the
sites of initial laceration. Accumulation of SMCs at the luminal side
follows at a later stage. -actin–positive SMCs without obvious
sclerotic changes. These observations clearly indicate that
fibrosclerosis as seen in normal dog arteries certainly cannot be
considered the rule in human atherosclerotic coronary arteries,
at least not within the limits of our study, which is 2 years after
stenting. It remains to be settled in future studies with more cases
whether the differences between our observations and those obtained in
dogs relate merely to species differences or to the fact that normal
arteries in dogs cannot be considered to represent the basic
mechanisms that underlie poststenting neointimal formation
in atherosclerotic lesions in humans.
Previous studies have suggested that chronic stent recoil may
contribute significantly to stent
restenosis.31 32 However, recent serial
intravascular ultrasound studies have demonstrated that chronic stent
recoil is minimal and that late luminal loss and in-stent
restenosis are the result of neointimal tissue
proliferation.33 34 35 In the present
study, neointimal proliferation was present from 9 days
after stenting on. The salient histological features
were basically the same whether restenosis had developed or
not. Indeed, from this small series, it appears that the differences
between restenosis and "nonrestenosis" are
quantitative rather than qualitative. Be that as it may, the
observations presented here strongly support the concept that
stent stenosis is caused by neointimal
proliferation.
This study represents only a limited number of autopsied
cases obtained from patients after implantation of a coronary
artery stent, most of which were Palmaz-Schatz stents. We
presented only 1 case with a Wiktor stent and 1 with an ACS
Multi-Link stent. The question arises, therefore, whether the findings
obtained at the site of stenting with the Palmaz-Schatz stent apply to
other stents; the observations suggest that this is so, but the limited
number of cases does not allow a firm statement to this end.
Selected Abbreviations and Acronyms
LAD
=
left anterior descending coronary artery
PDGF
=
platelet-derived growth factor
SMC
=
smooth muscle cell
vWF
=
von Willebrand factor
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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