restenosis following implantation of bare metal coronary stents: pathophysiology and pathways...
TRANSCRIPT
-
ry stents:
ular
gender) may affect the incidence of restenosis seen after stent placement. A number of catheter-based interventions have been
e Multidisciplinary Drug
Advanced Drug Delivery Reviews 58 (2006) 358376
www.elsevier.com/locate/addrB This review is part of the Advanced Drug Delivery Reviews theused to treat in-stent restenosis. Although preliminary data suggest that the use of drug-eluting stents may be effective, only
intracoronary radiation has shown consistent efficacy in randomized trials.
D 2006 Elsevier B.V. All rights reserved.
Keywords: In-stent restenosis; Pathology; Bare metal stents; Vascular responses; Vascular injury
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359
2. Pathology of in-stent restenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360
3. Is the response to stenting similar to wound healing? Role of the extracellular matrix . . . . . . . . . . . . . . 361
4. Mechanism of restenosis after balloon angioplasty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361response to injuryB
Neal A. Scott *
Camino Cardiovascular Associates, 525 South Drive, Suite 107, Mountain View, CA 94040, USA
Received 17 February 2005; accepted 31 January 2006
Available online 6 March 2006
Abstract
This review summarizes the restenotic process that occurs after the implantation of bare metal coronary stents. The
pathology of in-stent restenosis is distinct from that seen after balloon angioplasty and is characterized by neointimal
proliferation and extracellular matrix deposition. The degree of neointimal proliferation is proportional to the amount of injury,
the intensity of the inflammatory infiltrate and the association of stent struts with lipid-filled plaque. In-stent restenosis also
appears to be associated with systemic markers of inflammation. Shear stress has an important influence on restenosis as does
the presence and adhesiveness of vascular progenitor cells. Clinical predictors (e.g., artery size, stent length, diabetes, andRestenosis following implantation of bare metal corona
Pathophysiology and pathways involved in the vasc0169-409X/$ - s
doi:10.1016/j.ad
Delivery Platfor
* Tel.: +1 650
E-mail addreme issue on bDrug-Eluting Stents: an InnovativmQ, Vol. 58/3, 2006.ee front matter D 2006 Elsevier B.V. All rights reserved.
dr.2006.01.015
961 7021; fax: +1 650 969 8679.
ss: [email protected].
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n in 1987 when
lacement of 24
y arteries of 19
ary-artery reste-
=4) after coro-
gioplasty. They
the group with
occlusion of a
sure, a second
uccessfully with
d after bypass
ound occlusion.
ithout evidence
he stented seg-
heir preliminary
may effectively
fter angioplasty,
be required to
eir preliminary
se of coronary
eliverThe catheter-based treatment of obstructive coro-
nary atherosclerosis was pioneered by Andreas
Gruentzig in the late 1970s when he and Senning
described the procedure they named percutaneous
transluminal coronary angioplasty. They reported that
6 of the 32 patients (19%) who had successful
angioplasty suffered restenosis, or re-narrowing of
the vessel, several months after the initial procedure
[1]. Subsequent registry studies of large numbers of
coronary angioplasty patients documented a restenosis
rate closer to 33% [2]. One of the first pathological
descriptions of restenosis after coronary angioplasty
was published by Essed et al. [3]., who described a
proliferative fibrocellular response that occluded the
coronary lumen. This report was later followed by
additional case reports confirming the fibrocellular
response to coronary angioplasty [4,5] that has
characterized restenosis. Since the early days of
coronary angioplasty, a myriad of devices (stents,
atherectomy, laser, rotablator, etc.) was developed
The era of coronary stenting bega
Sigwart et al. [9] described the p
self-expanding stents in the coronar
patients who presented with coron
noses (n =17) or abrupt closure (n
nary or coronary-bypass graft an
observed three complications in
coronary disease. One thrombotic
stent resulted in asymptomatic clo
acute thrombosis was managed s
thrombolysis, and one patient die
surgery for a suspected but unf
Follow-up continued for 9 months w
of any further restenoses within t
ments. The authors noted that t
experience suggested that stents
prevent occlusion and restenosis a
and that long-term follow-up would
validate the early success of th
results. The widespread elective u1. Introduction to show any significant reduction in coronary reste-
nosis is the stent [68].5. Mechanism of in-stent restenosis . . . . . . . . . . .
6. Inflammation . . . . . . . . . . . . . . . . . . . . .
6.1. Inflammatory mechanisms involved in the vasc
6.2. Circulating monocytes . . . . . . . . . . . . .
6.3. Mac-1 receptor. . . . . . . . . . . . . . . . .
6.4. Monocyte chemoattractant protein (MCP-1) . .
6.5. C-reactive protein . . . . . . . . . . . . . . .
7. Shear stress . . . . . . . . . . . . . . . . . . . . . .
8. Stent endothelialization . . . . . . . . . . . . . . . .
9. Progenitor cells . . . . . . . . . . . . . . . . . . . .
10. Clinical predictors of in-stent restenosis . . . . . . .
10.1. Procedural characteristics . . . . . . . . . . .
10.2. Diabetes . . . . . . . . . . . . . . . . . . .
10.3. Angiotensin converting enzyme . . . . . . .
10.4. Gender . . . . . . . . . . . . . . . . . . . .
11. Angiographic patterns of in-stent restenosis . . . . .
12. Treatment of in-stent restenosis . . . . . . . . . . . .
12.1. Radiation . . . . . . . . . . . . . . . . . . .
12.2. Rotational atherectomy . . . . . . . . . . . .
12.3. Cutting balloon . . . . . . . . . . . . . . . .
12.4. Laser angioplasty . . . . . . . . . . . . . . .
12.5. Drug-eluting stents . . . . . . . . . . . . . .
References. . . . . . . . . . . . . . . . . . . . . . . . . .
N.A. Scott / Advanced Drug Dwith the primary goal of decreasing the incidence of
restenosis after coronary angioplasty. The only device. . . . . . . . . . . . . . . . . . . . . . . . . . . 362
. . . . . . . . . . . . . . . . . . . . . . . . . . . 362
response to injury . . . . . . . . . . . . . . . . . . 362
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y Reviews 58 (2006) 358376 359stents occurred after they were shown to provide a
significant decrease in restenosis over elective
-
tion, morphological characteristics of the lesion, stent
design and method of analysis.
eliver2. Pathology of in-stent restenosis
Despite the very large number of coronary stents
used in patients over the past decade, there have been
relatively few pathologic studies of the course of these
devices after implantation. Komatsu et al. published
the first systematic examination of the neointimal
tissue response to stenting in 11 patients who died
between 2 days and 21 months after stenting. The four
patients who died within 12 days had occlusive
thrombus formation while the patients who died after
64 days had a distinct layer of neointima, albeit to
varying degrees. In non-restenotic lesions, neointimal
thickening was markedly less than in restenotic
lesions but without qualitative differences; the neo-
intima contained macrophages but was composed
predominantly of alpha-actin positive smooth muscle
cells [12].
In a more extensive study, Farb et al. [13] made
histological observations on 55 stents in 35 coronary
vessels (32 native arteries and 3 vein grafts) from 32balloon angioplasty in two randomized trials.
Restenosis occurred in 3242% of patients treated
with balloon angioplasty and 2232% of patients
treated with stents [7,8].
The major complications associated with coronary
stent placement are stent thrombosis and restenosis.
Stent thrombosis is a life-threatening condition that
involves the occlusion of the stent by thrombus. This
is rarely seen at the time of stent placement and more
commonly occurs within 130 days after the proce-
dure. This condition is usually associated with
myocardial infarction and commonly requires emer-
gent angioplasty or bypass surgery. The use of
improved stent delivery techniques involving high
deployment pressures to fully appose the stent to the
vessel wall, accompanied by the administration of
anti-platelet agents has decreased the incidence of this
complication to less than 1% [10,11]. Restenosis is the
most common complication associated with coronary
stent placement. The incidence of restenosis is
influenced by many factors including patient selec-
N.A. Scott / Advanced Drug D360patients. They examined plaquestent interaction,
thrombus formation, inflammation, and the presenceof a neointima. The mean duration of stent placement
was 39F82 days. Platelet-rich thrombi were acharacteristic of early lesions. Fibrin-rich thrombi
were commonly seen around stent struts, especially
early after stenting.
Acute inflammatory cells (neutrophils) associated
with stent struts were present more frequently in stents
implanted for V3 days and were related to theunderlying arterial wall morphology. There was more
of an inflammatory cellular response when the stent
struts were embedded in damaged media or a lipid
core when compared to fibrous plaque.
A neointima consisting of spindle-shaped mesen-
chymal cells (a-actin positive smooth muscle cells)within a proteoglycan matrix associated with stents
struts was not present in any of the 18 patients with
b11 days implant duration, however, this finding waspresent in 45% of patients who died at 1230 days
after stent placement and 100% of patients at N30days. In stents implanted for N30 days, neointimalthickness at stent strut sites was greater when medial
damage (medial laceration or rupture) was present
than when struts were in contact with plaque or intact
media. Based on their findings, the authors concluded
that the morphological changes following coronary
stenting involve early thrombus formation and an
acute inflammatory response followed by neointimal
growth. Medial injury and lipid core penetration by
struts resulted in an increased inflammatory response.
The relationship between inflammation and neo-
intimal formation was further examined by these
authors in a subsequent study [14]. Detailed histology
was performed on 116 stents implanted N90 days in87 coronary arteries from 56 patients. The mean
duration of stent implant was 10 months. In-stent
restenosis was defined as a stent area stenosis of
N75%. The inflammatory infiltrates associated withstenting were composed predominantly of macro-
phages with smaller numbers of T cells and rare B
cells. Neointimal inflammatory cell density correlated
with increased neointimal thickness, and the mean
number of inflammatory cells was 2.4-fold higher in
restenosis versus no restenosis cases. Peri-strut in-
flammatory cell density was increased in regions of
medial disruption compared with struts in contact with
fibrous plaque or an intact fibrous cap. The percent of
y Reviews 58 (2006) 358376the neointima occupied by macrophages was 3-fold
higher in restenosis versus no-restenosis cases. Lipid
-
a granulation tissue phase (macrophage infiltration,
myofibroblast in-growth and angiogenesis). The
reduced staining seen at later time points. Type I
collagen staining was weakest early after stent
eliverearly extracellular matrix consists of fibrin, fibro-
nectin, hyaluronan, and versican. Hyaluronan pro-
vides the matrix into which mesenchymal cells
migrate, promotes cell proliferation, and supplies
feedback regulation of growth factor synthesis.
Versican binds to hyaluronan and affords viscoelas-
ticity to healing tissues. Over time there is progres-
sive hyaluronan degradation, reabsorption of a
portion of the type III collagen, and synthesis of
type I collagen, decorin, and biglycan. These later
changes, along with the cross-linking of type I
collagen, are associated with wound contraction. In
uncomplicated dermal wounds, the healing is usually
complete by 2 weeks [16].
When postmortem human coronary arteries con-
taining stents underwent histological assessment of
neointimal proteoglycans, hyaluronan, collagen (typescore penetration was associated with an increased
neointimal thickness and increased numbers of
inflammatory cells compared with struts in contact
with fibrous plaque.
Similar findings were noted in an analysis of
saphenous vein bypass grafts [15]. Segments were
surgically retrieved from 10 patients (21 stents) at 3
days to 10 months after implantation of a self-
expanding Wallstent. Early observations revealed that
large amounts of platelets and leukocytes adhered to
the stent wires during the first few days. At 3 months,
the wires were embedded in a layered new intimal
thickening, consisting of smooth muscle cells and
collagenous matrix. In addition, foam cells were
abundant near the wires. Abnormal adherence of
leukocytes was noted as late as 10 months after
implantation.
3. Is the response to stenting similar to wound
healing? Role of the extracellular matrix
Similarities have been found between the cellular
and molecular mechanisms involved in stent reste-
nosis and wound healing. In wound healing, best
characterized by dermal injury responses, a throm-
botic and acute inflammatory reaction is followed by
N.A. Scott / Advanced Drug DI and III), smooth muscle cells, and CD44 (a cell
surface receptor for hyaluronan), neointimal versicanplacement, with progressively stronger staining with
time. Smooth muscle cell density and stent stenosis
were significantly reduced in stents implanted for over
18 months. CD44 staining co-localized with macro-
phages and was associated with increased neointimal
thickness. These findings suggested that the formation
of the extracellular matrix within human coronary
stents resembles that seen with wound healing. An
important finding of this study was that the response
to a coronary stent does not show complete healing
until 18 months after deployment [17].
In a study of atherectomy samples taken from
patients with in-stent restenosis, Chung et al. found
that the cellularity of the neointima decreased in time
after stenting. Early lesions (b3 months) were hyper-cellular, while late lesions (N3 months) were hypo-cellular. The cells seen were predominantly smooth
muscle cells, however, inflammatory cells were also
observed. Of the cell-depleted areas seen in the late
lesions, the extracellular matrix was composed of
either collagen-rich or collagen-poor areas. The
collagen-rich areas also stained for biglycan, while
the collagen-poor areas stained for versican and
hyaluronan [18]. These data suggest that enhanced
extracellular matrix rather than cellular proliferation
contribute to the later stages of in-stent restenosis.
4. Mechanism of restenosis after balloon
angioplasty
Three factors play a major role in restenosis after
balloon angioplasty: recoil, neointimal formation and
chronic remodeling. Recoil is defined as the elastic
response that occurs after overstretch of the vessel
and is usually seen immediately after balloonand hyaluronan staining was strongly positive, co-
localized with alpha-actin-positive smooth muscle
cells, and was greater in intensity in stents implanted
for less than 18 months when compared to stents
implanted for over 18 months. Conversely, decorin
staining was strongest in stents implanted for over 18
months. The neointima of stents implanted for less
than 18 months was rich in type III collagen, with
y Reviews 58 (2006) 358376 361deflation. Neointimal formation has a time course
that spans over several weeks to months. The
-
postulated. In animal models, chronic remodeling
appears to be the major component of restenosis
molecules that bind ligands on leukocytes. Selectins
mediate the initial attachment of platelets and the
eliverafter balloon angioplasty [20,21]. Serial ultrasound
studies performed in patients immediately after
angioplasty and 6 months later confirmed the
animals studies, showing that (1) a decrease in total
arterial cross-sectional area accounted for 70% to
75% of late lumen loss and (2) late lumen loss
correlated better with a decrease in the cross-
sectional area of the external elastic lamina than
with an increase in the plaque plus medial area
(neointimal proliferation) [22].
5. Mechanism of in-stent restenosis
A similar serial intravascular ultrasound study
performed on patients with stents found that in stented
segments, late lumen area loss correlated strongly
with tissue growth but only weakly with remodeling.
The authors concluded that since stents appear to
withstand the extrinsic compression of the artery from
arterial remodeling (the dominant mechanism of late
lumen loss in nonstented lesions) that in-stent
restenosis was the result of neointimal tissue forma-
tion (i.e., cellular proliferation and accumulation of
extracellular matrix) [23].
The existence of positive, peri-stent remodeling
was initially suggested by Hoffman et al. who
showed that stents induce proliferation both withinneointima is formed by cells and extracellular
matrix. It appears that the source of most of these
cells may be the adventitia, since intense prolifera-
tion occurs there 2 to 3 days after balloon injury in
porcine coronaries. When these cells are labeled,
they are found in the neointima several weeks later.
Seven days after injury, some proliferation is noted
in the medial layer [19]. The third component of
restenosis is chronic remodeling. Chronic remodeling
is due to extrinsic compression of the vessel, best
characterized by a decrease in the outer circumfer-
ence of the vessel, the external elastic lamina. The
cause of the chronic remodeling is likely fibrosis
although other causes such as changes in the
extracellular matrix composition and structure, and
chronic changes in vascular tone have also been
N.A. Scott / Advanced Drug D362the endoluminal surface of the stent and in the tissue
layers outside of the stent. They also showed thatrolling interaction of leukocytes with the luminal
endothelium. The integrin class of adhesion molecules
mediates the firm adhesion and transendothelial
migration. The beta-2 integrin molecule Mac-1
(CD11b/CD18) is present on neutrophils and mono-
cytes and appears to be of central importance in
leukocyte recruitment after vascular injury. In additionthe tissue increase outside of the stent was accom-
panied by positive remodeling (increased cross-
sectional area of the external elastic lamina) [24].
Nakamura et al. later found that the peri-stent
positive remodeling occurs to a variable extent and
is inversely correlated with the degree of neointimal
formation [25].
6. Inflammation
Several recent reviews have summarized the data
suggesting an important relationship between inflam-
mation and stent restenosis [26,27]. As noted above,
analyses of human restenotic tissue from autopsy
studies identified an inflammatory component in the
arterial response to stent placement [13,12] suggesting
a strong link between the extent of medial damage,
inflammation, and restenosis.
In animal models, a brisk early inflammatory
response was produced after balloon injury or stent
placement with abundant surface-adherent leukocytes
of monocyte and granulocyte lineage [28,29]. Days
and weeks later, macrophages invaded the forming
neointima and were observed clustering around the
struts, forming giant cells. Blockade of early mono-
cyte recruitment with anti-inflammatory agents
resulted in reduced late neointimal thickening
[30,31]. Rogers et al. have demonstrated a linear
relationship between tissue monocyte content and
neointimal area, suggesting a causal role for mono-
cytes in restenosis [29].
6.1. Inflammatory mechanisms involved in the
vascular response to injury
Upon injury, endothelial cells express adhesion
y Reviews 58 (2006) 358376to promoting the accumulation of leukocytes at sites
of vascular injury and the binding of platelets to
-
eliverneutrophils, Mac-1 amplifies the inflammatory re-
sponse by inducing neutrophil activation, upregulat-
ing cell adhesion molecule expression, and generating
signals that promote integrin activation and chemo-
kine synthesis. Proinflammatory cytokines provide a
chemotactic stimulus to the adherent leukocytes,
directing their migration into the intima. Recent
research has identified candidate chemoattractant
molecules responsible for this transmigration. For
example, monocyte chemoattractant protein-1 (MCP-
1) appears responsible for the direct migration of
monocytes into the intima at sites of lesion formation.
In addition to MCP-1, macrophage colony-stimu-
lating factor (M-CSF) contributes to the differentia-
tion of the blood monocyte into the macrophage foam
cell. Inflammatory mediators such as M-CSF augment
expression of macrophage scavenger receptors lead-
ing to the formation of lipid-laden macrophages. M-
CSF and other mediators can promote the replication
of macrophages within the intima as well. T lympho-
cytes also join macrophages in the intima during
lesion development. T cells encounter signals that
cause them to elaborate inflammatory cytokines such
as g-interferon and lymphotoxin (tumor necrosisfactor [TNF]-h) that in turn can stimulate macro-phages as well as vascular endothelial cells and
smooth muscle cells. These leukocytes, as well as
resident vascular wall cells, secrete cytokines and
growth factors (such as platelet-derived growth factor,
basic fibroblast growth factor and epidermal growth
factor) that can promote the migration and prolifera-
tion of smooth muscle cells. Medial smooth muscle
cells express specialized enzymes that can degrade
elastin and collagen in response to inflammatory
stimulation. This degradation of the arterial extracel-
lular matrix permits the penetration of the smooth
muscle cells through the elastic laminae and collag-
enous matrix of the injured artery.
6.2. Circulating monocytes
Fukuda et al. examined the circulating monocyte
count from peripheral blood samples taken immedi-
ately before stent implantation and daily for 7 days
after the intervention in 107 patients. All patients
underwent angiography and volumetric intravascular
N.A. Scott / Advanced Drug Dultrasound analysis 6 months later. They found that
the circulating monocyte count increased and reachedits peak 2 days after stent placement. The maximum
monocyte count after stent implantation showed a
significant positive correlation with neointimal stent
volume at 6-month follow-up. Angiographic resteno-
sis was observed in 22 patients and these patients had
a significantly higher maximum monocyte count than
patients without restenosis [32].
6.3. Mac-1 receptor
Leukocyte adhesion to injured arteries may occur
through a variety of selectin- and integrin-dependent
mechanisms involving platelets and extracellular
matrix proteins. In particular, leukocyte recruitment
to areas of extravascular inflammation is mediated by
the b2-integrin family of receptors. Of these receptors,
Mac-1 (CD11b/CD18/aLb2) is most commonly asso-
ciated with restenosis.
The multivalent binding properties of Mac-1 make
this receptor uniquely poised to regulate adhesive and
inflammatory processes after vascular injury. Mac-1 is
capable of binding fibrinogen, intercellular adhesion
molecule-1, and factor X, ligands that are abundant in
the injured wall. Mac-1 is, in fact, the primary
fibrinogen receptor on leukocytes, facilitating the
adhesion and transmigration of neutrophils and
monocytes at sites of fibrin and platelet deposition.
Recent clinical reports have implicated up-regulation
of Mac-1 with restenosis after coronary angioplasty
[3335].
When careful analysis of the transcardiac gradient
(coronary sinus blood minus the value of peripheral
blood) of CD11b (alpha-subunit of Mac-1) was
compared in patients who underwent coronary angio-
plasty or stenting, there were profound differences
between the two procedures. The gradient for neutro-
phil surface expression of CD11b increased 48 h after
coronary stenting, but this change showed less
significance 48 h after balloon angioplasty alone.
The gradient 48 h after the procedures for CD11b was
independently correlated with restenosis in both the
stent and angioplasty groups [36].
Inoue et al. examined the expression of CD11b and
binding of a monoclonal antibody against an activa-
tion-dependent neo-epitope of Mac-1 (8B2) on the
surface of polymorphonuclear leukocytes in 62
y Reviews 58 (2006) 358376 363patients undergoing coronary stenting. Transcardiac
CD11b expression increased significantly at 24 h and
-
elivermaximally at 48 h after stenting; 8B2 began to
increase at 10 min and was maximally increased at
48 h after stenting. These changes were more
prominent in patients with subsequent restenosis.
Multiple regression analysis showed that the late
lumen loss by quantitative coronary angiographic
analysis was independently correlated with the
CD11b increase and the 8B2 increase 48 h after the
procedure. Mac-1 activation, as assessed by 8B2
binding, was the most powerful predictor of late
lumen loss [37].
Rogers et al. [30] administered an antibody
directed against CD11b to rabbits immediately before,
and every 48 h after balloon or stent injury to the iliac
vessels. They found a marked decrease in neointimal
growth in the animals treated with the specific
antibody, suggesting that leukocyte recruitment and
infiltration is an important component of the neo-
intimal response to balloon and stent injury.
6.4. Monocyte chemoattractant protein (MCP-1)
Chemokines are a group of chemoattractant cyto-
kines produced by a number of somatic cells, including
endothelial cells, smooth muscle cells and leukocytes.
They include monocyte chemoattractant protein
(MCP-1), and interleukin (IL)-8, both of which recruit
leukocytes to areas of vascular injury. MCP-1 is the
prototype of the C-C chemokine-beta subfamily and
exhibits its most potent chemotactic activity toward
monocytes and T lymphocytes. In addition to promot-
ing the transmigration of circulating monocytes into
tissues, MCP-1 exerts various other effects on mono-
cytes, including superoxide anion induction, cytokine
production and adhesion molecule expression. MCP-1
expression is induced by inflammatory cytokines,
peptide growth factors, endothelial cells or vascular
smooth muscle cells. Since elevated levels of MCP-1
have been demonstrated in myocardial infarction, heart
failure and after angioplasty [38], this chemokine is
probably a key factor in the initiation of the inflam-
matory process and maintaining the proliferative
response to vascular injury.
After balloon angioplasty, plasma levels of MCP-1
increase and remain elevated in those patients who
develop restenosis [38]. Similarly, following stent
N.A. Scott / Advanced Drug D364placement, MCP-1 levels in plasma increase after
several days and are more likely to be elevated atfollow-up 6 months later in patients who have
restenosis [39]. When balloon overstretch injury and
stent placement are compared, stent implantation is
associated with a more intense acute and chronic, low-
grade inflammatory response [40]. In balloon-injured
arteries, leukocyte recruitment was confined to early
neutrophil infiltration. IL-8 and MCP-1 mRNA levels
peaked within hours and were undetectable at 14 days.
In contrast, in stented arteries, early neutrophil
recruitment was followed by prolonged macrophage
accumulation. IL-8 and MCP-1 mRNA levels peaked
within hours but were still detectable 14 days after
injury. In contrast to balloon injury, stent-induced
injury results in sustained chemokine expression and
leukocyte recruitment [41].
In animals, Horvath et al. used antibodies directed
against neutrophils or monocytes to determine the role
played by each cell type after either balloon angio-
plasty or stenting in a primate iliac model. They found
that monocyte-specific blockade achieved via block-
ade of the MCP-1 receptor was effective at reducing
neointimal hyperplasia after stenting. In contrast,
combined neutrophil and monocyte blockade
achieved by targeting the leukocyte beta (2)-integrin
beta-subunit CD18 was required to reduce neointimal
hyperplasia after balloon injury [42]. These studies
suggest that monocytes, and not polymorphonuclear
leukocytes, may play the more important role in stent
restenosis.
Ohtani et al. [43] recently devised a new strategy
for anti-MCP-1 gene therapy by transfecting an N-
terminal deletion mutant of the MCP-1 gene into
skeletal muscles. They used this strategy to investigate
the role of MCP-1 in experimental in-stent restenosis
in hypercholesterolemic rabbits and monkeys. Trans-
fection of the mutant MCP-1 gene suppressed
monocyte infiltration and activation in the stented
arterial wall and markedly reduced the development
of neointimal hyperplasia. This strategy also sup-
pressed local expression of MCP-1 and inflammatory
cytokines. They concluded that inhibition of MCP-1-
mediated inflammation is effective in reducing exper-
imental in-stent restenosis.
6.5. C-reactive protein
y Reviews 58 (2006) 358376Formerly considered solely as a biomarker for
inflammation, C-reactive protein (CRP) is now
-
Activation of various signaling cascades and
transcription factor systems, as well as the identifica-
eliverviewed as a prominent component of the vascular
inflammatory process. CRP is a protein that binds to
the C-polysaccharide of the pneumococcal cell wall. It
is part of the innate immunity that activates the
classical complement pathway after aggregation or
binding to ligands. CRP also binds to phospholipids
of damaged cells, with subsequent limited activation
of the complement system and enhanced uptake of
these cells by macrophages.
CRP also induces the secretion of interleukin-6 and
endothelin-1 and decreases the expression and bio-
availability of endothelial nitric oxide synthase in
human endothelial cells. In addition, CRP activates
macrophages to express cytokine and tissue factor and
enhances the uptake of LDL. CRP also amplifies the
proinflammatory effects of several other mediators,
including endotoxin.
Immunohistochemical staining for CRP on athe-
rectomy samples obtained from patients who under-
went directional coronary atherectomy or stenting as
their initial procedure demonstrated more staining for
CRP and macrophages in patients with in-stent
restenosis when compared to patients with restenosis
after atherectomy [44].
Although there have been a number of negative
and positive studies on the association between
plasma levels of CRP and restenosis, the study by
Versaci et al. strongly suggests a link between
elevated CRP levels and stent restenosis. The inves-
tigators enrolled 83 patients who underwent success-
ful stenting and had plasma CRP levels that were
elevated (N0.5 mg/dl) 72 h after the procedure. Thepatients were randomized to treatment with oral
prednisone or placebo for 45 days. Six-month
restenosis rates were lower in the prednisone group
(7% vs. 33%). The prednisone group also had a
better event free survival rate 1 year after the
procedure (93% vs. 65%) [45]. These data suggest
that there is a subpopulation of patients that can be
identified by systemic markers of inflammation and
that when these patients are treated with agents that
diminish the inflammatory process, restenosis can be
inhibited. Although other studies failed to demon-
strate a beneficial effect of corticosteroid adminis-
tration on restenosis, most of these studies were
performed on patients who underwent balloon
N.A. Scott / Advanced Drug Dangioplasty rather than stenting. In addition, either
a single corticosteroid dose or a much shorter coursetion of shear-stress-response elements in the promoters
of several genes relevant to both atherosclerotic and
restenotic processes (e.g., platelet-derived growth
factors A and B, macrophage chemoattractant pro-
tein-1, and vascular cell adhesion molecule-1 have
helped to provide insight into the cellular mechanismsof treatment was used. Also, no prior attempt was
made to target patients with high inflammatory
markers for treatment. A study by Walter et al.
[46] found that administration statins to patients with
elevated CRP levels could also decrease restenosis
rates.
7. Shear stress
Neointimal hyperplasia resulting in restenosis can
be observed within any discreet location of the stented
segment or can appear in a diffuse pattern. Although
certain systemic characteristics (e.g., the presence of
diabetes) or anatomical variables (small vessel diam-
eter, long lesion length) increase the probability of
restenosis, the presence or absence of these factors
does not explain the specific location of a site of
neointimal proliferation within a stent or its discrete or
diffuse pattern.
In a study that examined the role of blood flow in
the progression of atherosclerosis, Glagov et al.
determined that alterations in shear stress could cause
important compensatory changes in both luminal and
vessel diameter [47]. Biomechanical forces such as
fluid shear stresses stimulate the production in
endothelium of a large and diverse array of potent
biological mediators [48,49]. Some of these agents
involve gene regulation at the transcriptional level and
thus are analogous to endothelial activation by
humeral factors. The endothelial cell appears capable
of responding not only to the magnitude of the applied
forces but also to their temporal and spatial fluctua-
tions (e.g., steady versus pulsatile flow, uniform
laminar, disturbed laminar, or turbulent flow regions),
thus suggesting the existence of primary flow sensors
(receptors) that are coupled via distinct signaling
pathways to nuclear events [50,49].
y Reviews 58 (2006) 358376 365linking shear stress stimuli and genetic regulatory
events [51,49,48].
-
eliverCultured human endothelial cells exposed to two
well defined biomechanical stimulia steady laminar
shear stress and a turbulent shear stress of equivalent
spatial and temporal average intensity revealed
distinctive patterns of up- and down-regulation
associated with each type of stimulus in many of the
11,397 unique genes examined [51]. Different cyto-
skeletal morphologies were also observed in the cells
exposed to the two types of shear stress. Thus,
endothelial cells have the capacity to discriminate
among specific biomechanical forces and to translate
these input stimuli into distinctive phenotypes.
In vitro, endothelial cell proliferation increases
significantly when subjected to weak shear stress,
while strong shear stresses are associated with
increased nitric oxide production, and inhibition of
endothelial cell proliferation [52,53]. In addition,
exposure of endothelium to low and oscillating shear
stress is associated with atherosclerotic lesion devel-
opment [5457].
In vitro modeling studies [58] have demonstrated
focal areas within stents that have low shear stress
values and may provide a milieu for endothelial cell
activation and vascular proliferation. In vivo, coro-
nary stent implantation can change the three-
dimensional geometry and the shear stress distribu-
tion of the vessel. In addition to changes at the
entrance and exit zones of the stent [54], stagnation
zones around the stent struts have been demonstrat-
ed, along with a decrease of minimum wall shear
stress by 77% in stented compared to un-stented
vessels [59].
In an attempt to assess the effect of a device that,
when implanted within a stent, could increase wall
shear stress and thereby decrease restenosis, Carlier et
al. induced a local augmentation of wall shear stress
with a new device, the Anti-Restenotic Diffuser flow
divider. The investigators placed the flow divider
randomly in one of two identical stents placed in the
external iliac vessels of hypercholesterolemic rabbits.
The study was controlled for confounding factors
such as degree of hypercholesterolemia, blood
pressure and stent design. They demonstrated that
this device could locally increase wall shear stress
and induce a reduction in neointimal hyperplasia.
They also found a significant reduction in inflamma-
N.A. Scott / Advanced Drug D366tion that was associated with the increase in shear
stress [60].Although most studies that examined the effects
of shear stress on restenosis were performed in
animal models, the combination of intravascular
ultrasound, biplane angiography and computational
fluid dynamics has allowed investigators the unique
opportunity to acquire detailed measurements of
local wall geometry from a three-dimensional recon-
struction of a human coronary artery along with local
shear stresses. Since both biplane angiography and
intravascular ultrasound can be performed at the time
of stent placement and at follow-up, shear stress
values can be calculated, followed over time and
correlated to the observed changes in vascular
geometry.
Wentzel et al. [61] studied 14 patients 6 months
after implantation of a self-expanding coronary Wall-
stent. They performed three-dimensional reconstruc-
tion with a combined angiographic and intravascular
ultrasound technique. The bare stent reconstruction
was used to calculate in-stent shear stress at implan-
tation, by applying computational fluid dynamics.
They found that neointimal thickness measured 6
months after stent implantation was inversely related
to shear stress.
Thury et al. [62] calculated wall shear stress after
balloon angioplasty and determined its predictive
value for long-term outcome. Wall shear stress
values measured proximal to and in the dilated
lesion were higher in vessels that developed reste-
nosis. In-lesion wall shear stress was predictive of
angiographic restenosis and the proximal wall shear
stress value was an independent predictor of target
lesion revascularization.
Stone et al. [63] used also performed three-
dimensional coronary reconstruction with biplane
angiography and intravascular ultrasound to examine
changes in shear stress after coronary intervention.
They examined six stented arteries that underwent
intravascular profiling initially and at follow-up 6
months later. In these stented segments, there was
evidence of neointimal hyperplasia, with a decrease in
lumen radius and increase in endothelial shear stress
at all levels of baseline shear stress. Evidence of in-
stent restenosis appeared to occur to some degree in
each category of baseline endothelial shear stress in
this small group of patients. These exciting prelimi-
y Reviews 58 (2006) 358376nary studies suggest that the effect of endothelial
shear stress on the process of in-stent restenosis in
-
with other catheter-based interventions. Camori et al.
[70] studied patients who underwent a catheter-based
eliverintervention (stent placement, balloon angioplasty or
directional catheter atherectomy) on the left anterior
descending coronary artery. Several months after thehumans may be less clear than in animal studies and
will require more extensive investigation in larger
numbers of patients.
8. Stent endothelialization
An intact endothelial layer overlying the stent is
thought to be required for the inhibition of neointimal
growth. In addition to focal deep injury from struts
[6466] and overall arterial strain, stent deployment
also causes partial denudation of the endothelium in a
pattern unique to each stent configuration, suggesting
balloon-related injury. Rogers et al. used a finite
element analysis to determine that higher inflation
pressures, wider stent-strut openings, and more com-
pliant balloon materials cause larger surface-contact
areas and contact stresses between stent struts [67].
Regrowth of the endothelial layer after stent
placement occurs within 1 month in rabbit external
iliac vessels [68], however, this process may require
significantly more time in humans. Grewe et al. [69]
used scanning electron microscopy to examine
coronary artery segments from 18 patients who died
between 1 and 340 days after stent implantation.
They described three phases of stent integration. In
the acute phase (b6 weeks), the border between thevascular lumen and arterial wall was constituted by a
thin, multilayered thrombus. No endothelial cells
were found in the implantation zone, however,
smooth muscle cells and extracellular matrix were
detected. In the intermediate phase (612 weeks), the
neointima consisted of extracellular matrix and
increasing numbers of smooth muscle cells. Endo-
thelial cells were also found on the luminal surface
of the stent neointima. Complete re-endothelializa-
tion occurred in the chronic phase (3 months after
stent placement).
There is evidence to suggest that the response of
these regenerated endothelial cells to vasoactive
agents may differ significantly from the response seen
N.A. Scott / Advanced Drug Dintervention, endothelial reactivity was measured at a
segment distal to the treated lesion and quantified by9. Progenitor cells
In the past, the regeneration of injured endothelium
had been attributed to the migration and proliferation
of neighboring endothelial cells. Accumulating evi-
dence now indicates that bone marrow-derived cells
are involved in repair processes throughout the
cardiovascular system. These cells normally circulate
throughout the vascular system in very low levels.
However, following acute vascular injury, a rapid
increase in circulating levels of these endothelial
progenitor cells is seen [72]. Additionally, circulating
endothelial precursor cells can home to denuded parts
of the artery after balloon injury [73].
George et al. [74] examined 16 patients with
angiographically demonstrated in-stent restenosis
and compared them with eleven patients with
similar clinical presentation that exhibited patent
stents. The groups were similar with respect to the
use of drugs that could potentially influence
endothelial progenitor cell numbers. Circulating
endothelial progenitor cell numbers were determinedthe degree of angiographic spasm or dilation induced
by infused intracoronary acetylcholine, which acts
directly on the endothelium. There was persistent
endothelial dysfunction in the stented coronary artery.
More severe endothelium-dependent vasoconstriction
was observed in the left anterior descending of stented
patients than in the LAD of patients who had
undergone balloon angioplasty or atherectomy. The
stent group had more than twice as much distal spasm
as the other two groups (22% vs. 9%). Stenting was
the only variable associated with this marker of
endothelial dysfunction.
Vascular endothelial growth factor accelerates
endothelial repair by stimulating endothelial cell
migration and proliferation. Hedman et al. [71]
performed a randomized placebo-controlled, double
blind study to determine if VEGF gene transfer could
prevent in-stent restenosis. Although the gene transfer
procedure was tolerated well, there was no difference
in restenosis between the patients who received
vascular endothelial growth factor and the patients
who received placebo.
y Reviews 58 (2006) 358376 367by the colony-forming unit assay, and their pheno-
type was characterized by endothelial-cell markers.
-
origin of neointimal cells in in-stent restenosis,
atherectomy samples from patients with in-stent
eliverrestenosis were compared to samples from athero-
sclerotic primary lesions. Whereas alpha-smooth
muscle actin positive cells constituted the largest
intimal cell pool, immunohistochemical staining for
bone marrow- and neural crest-derived cells was
consistently present in in-stent restenosis. These data
suggest that in addition to endothelial progenitor
cells, other extravascular cells are recruited to the
neointima in the formation of human in-stent
restenosis [75].
10. Clinical predictors of in-stent restenosis
As with balloon angioplasty, clinical restenosis has
many definitions. Angiographic restenosis is usually
based on a dichotomous distinction of greater than
50% diameter stenosis at the site of stent placement.
Typically, the follow-up angiographic procedure is
performed at least 6 months after stent placement.
However, while angiographic parameters of restenosis
have added to the understanding of the mechanisms of
restenosis, clinical outcomes must be regarded as the
true measure of treatment success [76]. Clinical
definitions of success involve repeat procedures that
are usually based on symptoms or other signs of
myocardial ischemia. Target lesion revascularization
(TLR) is usually defined as any repeat percutaneousAdhesiveness of the endothelial progenitor cells
from both groups to extracellular matrix and to
endothelial cells was also assayed. Overall, patients
with in-stent restenosis and with patent stents
displayed a similar number of circulating endothelial
progenitor cells. Fibronectin-binding was compro-
mised in patients with in-stent restenosis as com-
pared with their controls exhibiting patent stents.
Patients with diffuse in-stent restenosis exhibited
reduced numbers of circulating endothelial progen-
itor cells in comparison with subjects with focal in-
stent lesions. These data suggest that reduced
numbers of circulating endothelial progenitor cells
and impaired adhesion of these cells to fibronectin
may contribute to diffuse in-stent restenosis.
In a study to assess the cellularity, cell type and
N.A. Scott / Advanced Drug D368revascularization or surgical bypass of the original
target lesion site that occurs 30 days after the indexprocedure. Target vessel revascularization (TVR)
usually describes a percutaneous revascularization or
bypass of the target lesion or any segment of the
epicardial coronary artery containing the target lesion
or more proximal vessels that may have been
traversed by the angioplasty guidewire. In a study of
over 6000 patients who underwent coronary stenting
and clinical and angiographic follow-up over a 12-
month period, Cutlip et al. [77] found that only one
half of patients with angiographic restenosis mani-
fested clinical restenosis. The likelihood of TLR
correlated with the severity of the angiographic
stenosis. An important observation was that the
duration of follow-up influenced the perceived rate
of clinical restenosis. They noted that the rate of TLR
was 7% at 6 months but increased to 12% at 1 year.
These findings suggest that the clinical response to
stenting may significantly differ from balloon angio-
plasty and require longer observation for clinical end-
points than the 6-month period usually used with
PTCA.
10.1. Procedural characteristics
Goldberg et al. [78] evaluated a consecutive series
of 456 coronary lesions with in-stent restenosis. They
defined diffuse restenosis as a follow-up lesion length
z10 mm and aggressive restenosis as either anincrease in lesion length from the original lesion or
a restenotic narrowing tighter than the original. They
found that diffuse restenosis was associated with a
smaller reference artery diameter, longer lesion length,
female gender, longer stent length and the use of coil
stents. Aggressive restenosis was more common in
women, with the use of Wallstents and with long stent
to lesion length ratios. Aggressive restenosis occurred
earlier and was more closely associated with symp-
toms and myocardial infarctions than non-aggressive
restenotic lesions. Several other studies have demon-
strated an association between restenosis and stent
length [7982], multiple stents [81,82], smaller final
minimal lumen diameter [79,80,82,83], and lack of
use of intravascular ultrasound [79].
10.2. Diabetes
y Reviews 58 (2006) 358376A number of large studies have suggested that
diabetics have a higher incidence of restenosis after
-
of co-morbid diseases, such as diabetes. In addition,
coronary diameter tends to be smaller in women.
eliverstent placement when compared to non-diabetics
[77,82,8486]. Gilbert et al. performed a multivariate
analysis on six studies including 1166 patients with
diabetes and 5070 without [87]. The average reste-
nosis rates among patients with and without diabetes
were 36.7% and 25.9%, respectively. Restenosis rates
were also shown to be higher among older patients
with and without diabetes. The authors found that the
diabetic patients were older and that the incidence of
restenosis after stenting is reduced by approximately
half after adjusting for age. They concluded that the
apparent effect of diabetes on restenosis is overstated.
A subsequent study retrospectively analyzed all
stented diabetic patients in 16 studies of percutaneous
coronary intervention. Within these studies, 418 of
3090 (14%) stented patients with 6-month angio-
graphic follow-up had diabetes. Restenosis occurred
in 21% of the non-diabetic and 31% of the diabetic
patients. There was no significant difference in age
between the two groups [88], suggesting that diabetes
is associated with an increased incidence of stent
restenosis. Another study suggested that an important
contributor to the increased incidence of revascular-
ization procedures seen in diabetics is not only
restenosis but also progression of coronary athero-
sclerotic disease [89]. At this time, it appears safe to
assume from the myriad of smaller studies conducted,
that diabetes does predispose to in-stent restenosis,
however, the amount of influence diabetes has on
restenosis is controversial.
10.3. Angiotensin converting enzyme
Since 1993, a number of studies have suggested a
correlation between angiotensin converting enzyme
genotype insertion or deletion polymorphism and
restenosis after coronary intervention. Elevated levels
of the DD genotype for angiotensin converting
enzyme (which is associated with high plasma
angiotensin converting enzyme levels) have been
associated with restenosis, however the data are
conflicting. Bonnici et al. [90] conducted a meta-
analysis of 16 studies involving 11 without stenting
(2535 patients) and 5 with stenting (4631 patients)
that examined the relationship between ACE genotype
and restenosis. There was no significant heterogeneity
N.A. Scott / Advanced Drug Dbetween studies of percutaneous intervention with
stenting and those without stenting. However, whenGiven these two predisposing factors, it is not
surprising that the incidence of in-stent restenosis
has been reported to be higher in women [78].
However, one study was unable to demonstrate an
increased risk of in-stent restenosis [91] and, in a
study comprising over 4000 patients (1025 women),
there was a lower risk of restenosis in women after
coronary stenting despite a preponderance of diabetes
and small vessel size [92]. Thus, there is controversy
as to whether gender in a significant influence on in-
stent restenosis. In an interesting study, Ferrero et al.
examined polymorphisms of the alpha-estrogen re-
ceptor gene in men and women and found that women
who were homozygous for the T-allele of the PvuII
polymorphism of the alpha-estrogen receptor gene
have a higher risk of in stent restenosis than men [93].
11. Angiographic patterns of in-stent restenosis
Mehran et al. [84] examined the angiographic
images of 288 in-stent restenosis lesions in 245
patients who were treated with tubular slotted stents
(primarily Palmaz-Schatz). All patients underwent
intravascular ultrasound in addition to angiography.
Class I Focal in-stent restenosis group. Lesions
are V10 mm in length and are positionedat the unscaffolded segment (i.e., articu-
lation or gap), the body of the stent, the
proximal or distal margin (but not both),the studies were grouped by size, the odds ratios
decreased with increasing study size. Also, blinding of
the laboratory staff also decreased the odds ratios. The
authors found weaker associations between the
angiotensin converting enzyme DD genotype and
restenosis in the larger and more rigorous studies and
suggested that much of this association may be
artifactual.
10.4. Gender
Women tend to develop coronary disease at a later
age then men, and as a result, have a higher incidence
y Reviews 58 (2006) 358376 369or a combination of these sites (multifocal
in-stent restenosis).
-
myocardial infarction. However, a significant increase
occurred in target lesion revascularization with
eliverincreasing levels of in-stent restenosis classification
(class I, 19%; class II, 35%; class III, 50%; and class
IV, 83%; P b0.0001). In a multivariate analysis, theonly parameters that predicted target lesion revascu-
larization after treatment of in-stent restenosis were
the pattern according to the angiographic classifica-
tion, the occurrence of previous in-stent restenosis and
the presence of diabetes mellitus.
12. Treatment of in-stent restenosis
Comprehensive reviews of the literature on the
treatment of in-stent restenosis have been published
[9496]. In an effort to identify the most effective
treatment modality for in-stent restenosis, Radke et
al. [97] reviewed all papers published between 1987
and March 2001 that reported clinical results of
treatment of in-stent restenosis with one of six
different treatment modalities: balloon angioplasty,
stentin-stent therapy, rotational atherectomy, direc-
tional atherectomy, excimer laser angioplasty, and
intracoronary radiation. They found 28 papers that
included a total of 3012 patients with a clinical
follow up of 9F64 months. They performed ameta-analysis and found that treatment of in-stent
restenosis was associated with a 30% rate of majorClass II bDiffuse intrastentQ in-stent restenosis.Lesions are N10 mm in length and areconfined to the stent(s), without extending
outside the margins of the stent(s).
Class III bDiffuse proliferativeQ in-stent restenosis.Lesions are N10 mm in length and extendbeyond the margin(s) of the stent(s).
Class IV In-stent restenosis with btotal occlusion.QLesions have a TIMI flow grade of 0.
Of the 288 lesions analyzed, 42% (n =121) were
focal (Class I), 21% (n =61) diffuse intrastent (Class
II), 30% (n =86) diffuse proliferative (Class III), and
7% (n =20) total occlusions.
The investigators found that the 1-year clinical
event rates were uniformly high, without significant
differences among the groups with respect to death or
N.A. Scott / Advanced Drug D370adverse cardiac events (death, myocardial infarction
or target lesion revascularization), regardless of thetype of device used. Repeat balloon angioplasty
was judged to be safe, associated with a high rate
of procedural success, cost-effective and had favor-
able long-term results in long lesions. After
adjustment of confounding factors (lesion length,
pre-procedural diameter stenosis, diabetes) the only
treatment modality felt to be superior to balloon
angioplasty was intracoronary radiation. Since 2001,
a number of multicenter studies have been pub-
lished that closely examine the efficacy of catheter-
based technologies in the treatment of in-stent
restenosis.
12.1. Radiation
Intravascular brachytherapy with both beta and
gamma sources has been proven in a number of
randomized trials to be an effective treatment for in-
stent restenosis [98]. The beneficial effect of radiation
is sustained, out to at least 5 years [99,100].
Restenosis rates after radiation were higher in longer
lesions, but still significantly less than controls
[98,101,102]. Diabetic patients, despite having longer
and more complex lesions, have been reported to have
no increase in target lesion revascularization when
compared to non-diabetic patients [103,104]. Al-
though some studies have shown a failure rate in
diabetics that was higher than non-diabetics, reste-
nosis rates were still lower than controls [105]. Sabate
et al. have demonstrated that the incidence of
neointimal proliferation after brachytherapy is similar
between diabetics and non-diabetics but the incidence
of late stent thrombosis and stenoses proximal or
distal to the stent were higher in diabetic patients and
were frequently the cause of the target lesion
revascularization [106].
Success after brachytherapy can be predicted by
the presenting angiographic pattern of the in-stent
restenosis. After treatment with gamma vascular
brachytherapy, the binary angiographic restenosis
rate increased with worsening in-stent restenosis
patterns; however, target lesion revascularization
and major adverse cardiac event rates increased for
focal, diffuse, and proliferative patterns of in-stent
restenosis but not for total occlusions [107]. In those
patients who develop restenosis after radiation for in-
y Reviews 58 (2006) 358376stent restenosis, the predominant angiographic pat-
tern of the lesions is focal restenosis, and these
-
eliverlesions respond well to conventional revasculariza-
tion methods [108].
12.2. Rotational atherectomy
A single-center randomized trial of rotational
atherectomy versus balloon angioplasty for diffuse
in-stent restenosis demonstrated a lower incidence of
target lesion revascularization in the rotational athe-
rectomy group [109]. However, a multicenter, ran-
domized, prospective trial comprising 298 patients
with in-stent restenosis showed no significant benefit
over balloon angioplasty [110].
12.3. Cutting balloon
The cutting balloon is a balloon catheter with three
or four microsurgical blades bonded longitudinally to
the balloon surface. When the balloon is expanded,
the blades incise and facilitate redistribution of the
lesion. In a randomized, prospective, multicenter trial
of cutting balloon angioplasty to conventional angio-
plasty, there was no difference in angiographic
restenosis rates or clinical events between the two
groups [111].
12.4. Laser angioplasty
In a multicenter registry that compared laser to
conventional balloon angioplasty in patients with in-
stent restenosis, there was no difference in the
incidence of major cardiac events or target lesion
revascularization [112]. However, the authors noted
that the lesions in the laser group were longer and
more complex.
12.5. Drug-eluting stents
The use of drug-eluting stents will be discussed
in detail in other chapters. However, several
relatively small trials have demonstrated that signif-
icant benefit may be obtained with implanting a
paclitaxel- [113] or rapamycin- [114116] eluting
stent as a treatment of for in-stent restenosis. The
benefit obtained may be similar to that seen with
intracoronary radiation [117]. In addition, high-dose
N.A. Scott / Advanced Drug Doral rapamycin has efficacy in prevention of in-stent
restenosis [118].References
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