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© 1995 American Heart Association, Inc.
Articles |
Restenosis After Experimental Angioplasty
Intimal, Medial, and Adventitial Changes Associated With Constrictive Remodeling
From the Departments of Cell Biology (A.L., G.M.C.), Cardiology (A.L., L.G., P.L.W.), Biostatistics (M.G.), and Biomedical Engineering (A.L., J.F.C.), Research Institute, Cleveland (Ohio) Clinic Foundation.
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Abstract |
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Abstract Predicting and preventing arterial restenosis after angioplasty has failed despite considerable research into mechanisms and techniques. We examined the roles of chronic constriction, neointimal-medial growth, and adventitial changes in restenosis in atherosclerotic rabbits. Angioplasty was performed on femoral artery lesions 4 weeks after lesion induction by air drying and cholesterol-supplemented diet. Angiographic and histological evaluation was conducted 3 to 4 weeks after angioplasty. The angiographic minimum luminal diameter (MLD) increased from 1.31±0.21 to 1.73±0.41 mm after angioplasty. Loss in MLD by 3 to 4 weeks was 0.95±0.64 mm. Initial gain and late loss correlated (P=.008). Late residual stenosis, defined histologically as the difference between the luminal areas of a proximal reference site and lesion site normalized by the luminal area of the reference site, was 52±32%. Histological indices of chronic constriction, neointimal-medial growth, and adventitial growth were defined on the basis of the areas of these arterial wall layers at the lesion site relative to the reference site. Another parameter defined as the ratio of adventitial area to the area of intima+media at the lesion site allowed evaluation of the relative importance of these layers. Surprisingly, late residual stenosis correlated with chronic constriction (P=.0003) but not with neointimal-medial growth or adventitial growth. The ratio of adventitial area to the area of intima+media at the lesion site also correlated with chronic constriction (P=.01). These findings suggest that factors related to arterial remodeling rather than neointimal-medial growth may dominate the response to angioplasty.
Key Words: atherosclerosis • chronic constriction • neointimal-medial growth • vascular remodeling
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Many approaches to reduce postangioplasty restenosis have focused on retarding smooth muscle cell growth, but other strategies have been used as well, such as cholesterol lowering1 and administration of antithrombotic agents.2 There is a paradox between early smooth muscle cell proliferation occurring <15 days after angioplasty and the delayed clinical expression of restenosis at 3 to 6 months.3 4 5 6 7 8 9 10 11 Encouraging results from experimental studies have led to human trials; however, there generally appears to be a lack of success in clinical studies. Limitations in animal models have been considered to be largely responsible for the discrepancy.12 13 14 However, it is possible that this lack of success is a consequence of the fact that the target has often been hyperplasia resulting from smooth muscle cell proliferation, which may not be the primary mechanism by which restenosis occurs. Autopsy studies in humans do not uniformly support the notion that smooth muscle cell proliferation is the primary determinant of restenosis.3 8 9 12 15 16 17 18 19 20 21 22 Recently, it has been reported that restenosis in humans was present at autopsy without smooth muscle cell proliferation in a significant proportion of patients.3 Moreover, it has been clearly shown in humans by Glagov et al23 that the coronary atherosclerotic plaque can initially develop around the lumen without luminal narrowing, a phenomenon called compensatory enlargement. Instead of hyperplasia, a rearrangement of the tissue after angioplasty could be analogous to that proposed to explain the reduction of the arterial lumen in chronic hypertension24 25 and, more generally, the changes in arterial diameter subsequent to altered flow.26
Atherectomy may not improve restenosis rates over traditional balloon angioplasty12 27 ; however, retrospective and prospective clinical studies have shown that stenting may decrease the rate of restenosis independent of the acutely larger mean luminal diameters obtained by stenting during percutaneous transluminal coronary angioplasty.28 29 30 This raises the question of whether chronic constriction of the arterial lesion site may be one of the processes contributing to restenosis. Limited observations related to this issue in animal as well as in human restenosis have recently been reported.3 31 32 33 34 35 36 To document this possibility quantitatively in an experimental study would be valuable, and to demonstrate that this occurs in an animal model would afford opportunities for further study. The purpose of the present study was to evaluate the relative roles of chronic constriction and arterial neointimal-medial growth in postangioplasty restenosis in a rabbit model of atherosclerosis and angioplasty.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Animal Model
Induction of Focal Atherosclerosis in Rabbit Femoral Arteries
Cholesterol feeding after femoral artery air desiccation has been used previously to induce atherosclerosis and to study restenosis after subsequent angioplasty in rabbits. The features of this model have been well documented, and its advantages and disadvantages have been thoroughly discussed.37 38 39 Male New Zealand White rabbits were used in the present study after approval by the Animal Research Committee of the Cleveland Clinic Foundation.
Rabbits were anesthetized by intramuscular injection of xylazine (5 mg/kg) and ketamine (35 mg/kg). Proximal and distal ligatures were used to isolate a segment of 1-cm length of the femoral arteries that was cannulated. Vascular injury was induced in the isolated segments by air infusion. The isolated segments were then demarcated by metal clips in the surrounding tissue, and the ligatures were removed. The animals were allowed to recover and then placed on a 2% cholesterol and 6% peanut oil diet for 4 weeks.37 38 39 40 Acetaminophen (10 mg/kg) was given orally for 3 days for postoperative pain relief. Ampicillin (50 mg/kg) was given intramuscularly immediately after the surgical procedure.
An additional group of 6 rabbits underwent the same induction of focal atherosclerosis, followed by control angiograms (see below) at 4 and 8 weeks, after which the arteries were removed for histological evaluation. They did not have angioplasty; they served as a control group to evaluate whether constriction occurred as part of the healing response to the initial air-drying injury or the surgical procedure itself.
Femoral Angioplasty
Four weeks after induction of focal femoral lesions, balloon
angioplasty was performed as described.37 38 After carotid
artery isolation, a 5F sheath (Cordis) was advanced into the descending
thoracic aorta. A bolus of 120 U/kg heparin was injected
intra-arterially. A baseline iliofemoral angiogram was performed by
manual injection of 3 to 5 mL angiographic Renografin 60 (Squibb
Diagnostics) via a 4F angiographic catheter positioned proximal to the
iliac bifurcation. Angiography was performed after an intra-arterial
injection of 10 mg lidocaine, which was administered to minimize
possible spasm.38 Angiograms were recorded on both a
videotape system and 35-mm film on a Phillips 6-in image intensifier
(Phillips Medical Systems). A 5-mm marker was placed at the level of
the spine for calculation of magnification. The angiographic catheter
was exchanged for a 0.014-in angiography guide wire (Advanced
Cardiovascular Systems), and a 2.5±0.5-mm angioplasty balloon catheter
(Advanced Cardiovascular Systems) was selected visually to conform to
the size of the artery (the ratio of the balloon diameter to the
arterial diameter was estimated to be 1.0 to 1.2). The balloon was
advanced under fluoroscopic guidance and positioned across the stenosis
by using the previously placed metal clips as a marker under the
superficial femoral artery, which delimited the reference site.
Angioplasty consisted of three inflations, each with a 30-second ramp
time to 6 atm and then 6 atm for 60 seconds.
Angiography was performed 10 minutes after the last balloon inflation and immediately after an intra-arterial injection of 10 mg of lidocaine to minimize postangioplasty spasm.38 The angiographic catheter was then removed, and the right carotid artery was ligated. The subcutaneous tissue was sutured with catgut, and the skin was sutured with silk. After angioplasty, the high cholesterol diet was replaced by normal rabbit chow.
Angiography was repeated 3 to 4 weeks (25.4±2.5 days) after angioplasty by using the above technique, and the rabbits were subsequently killed with 200 mg IV sodium pentobarbital immediately before pressure-perfusion fixation. The distal arterial tree was flushed with 10 mL saline followed by in situ fixation using 100 mL of a 10% buffered formaldehyde solution infused at 100 mm Hg. Three- to 5-cm segments of femoral artery were excised, and the tissue was stored in 10% buffered formaldehyde for light microscopy and morphometry.
Histology
Arterial specimens were embedded in paraffin and cut in serial
sections, at sites 1.5 to 2.5 mm apart, from the proximal to the distal
end. Duplicate slides were stained with trichrome. Morphometric
analysis was performed by using the Bioquant System IV Image
Analysis System (R&M Biometrics) to measure the cross-sectional areas
indicated.
Data Analysis and Interpretation
Angiography
Minimum luminal diameter (MLD) was measured by two physicians
using electronic calipers, and final results were obtained by averaging
the two separate measurements. Accuracy of this method is within 0.08
mm.41 Initial gain was defined as the difference between
MLD before and immediately after angioplasty. Angioplasty was
considered successful if the relative gain in luminal diameter was
>20%. Late loss was defined by the difference between MLD immediately
and 3 to 4 weeks after angioplasty. Angiographic restenosis at
termination was evaluated by late loss of the initial gain.
Histology
Each artery was analyzed morphometrically at two sites: the
lesion site, defined by the cross section with the smallest luminal
area of five to seven lesion sites sampled, and the uninjured reference
site, defined by a nearby site upstream from the focal lesion (just
above the superficial femoral artery) with no disruption of the
internal elastic lamina and no hyperplasia of the intima. Parameters
were calculated from reference and lesion site measurements of luminal
area, area of intima+media, and the areas circumscribed by the external
elastic lamina and the outer border of the arterial wall.
The area of the intima+media, delimited by the external elastic lamina, was used to evaluate neointimal-medial growth, rather than intima and media separately, because of frequently incomplete repair of the disruption of the internal elastic lamina following angioplasty. Neointimal-medial growth was defined as the difference between the area of intima+media of the proximal reference site and the lesion site normalized by the area of intima+media of the reference site. Adventitial growth was defined as the difference between the area of adventitia of the proximal reference site and the lesion site normalized by the area of adventitia of the reference site. An index of chronic constriction was defined by the ratio of the area circumscribed by the external elastic lamina of the lesion site to the area circumscribed by the external elastic lamina of the reference site. A histological measure of late residual stenosis was defined by the difference between the luminal areas of the reference and lesion sites normalized by the luminal area of the reference site. An additional parameter defined as the ratio of adventitial area to the area of intima+media at the lesion site was used to explore at the site of angioplasty the relative contributions of these two layers to the altered arterial wall. The latter parameter was not indexed to a feature of the reference site.
Statistical Considerations
Student's paired t test was used to compare
angiographic data at different steps of the protocol. Since no
correlation was found between the two femoral arteries from a given
rabbit, these lesions were treated as independent observations in the
analyses presented. Correlations between pairs of factors were
evaluated with Spearman's rank correlation. To test for independence
of chronic constriction, neointimal-medial growth, and late
residual stenosis, multiple linear regression models were run
separately against each factor testing the other two. The results for
the population of arteries are expressed as mean±SD.
Of 38 animals (76 femoral vessels) entering the study, one died during the angioplasty procedure, and four additional animals died of pneumonia during the study period. Lesions in which occlusions precluded angioplasty or in which the described angioplasty protocol was not performed were excluded from the study. (An alternate procedure, performed for another purpose and involving progressive inflation, was carried out in 13 contralateral lesions that were excluded from the present study because the protocol was not identical. Interestingly, the correlations reported in the present study also held if these lesions were included in the analysis.) The pool of analyzed vessels was 46, including the 10 nonballooned control vessels, from 33 animals.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Influence of Angioplasty on the Atherosclerotic Lesion
Angiography
The MLD at the lesion site before angioplasty averaged 1.31±0.21 mm (see Table 1
). Immediately after
angioplasty, the MLD increased significantly to 1.73±0.41 mm
(P=.0001, Fig 1). Angiographic success (see
"Materials and Methods") was obtained in 84% of the vessels. The
average initial gain of the MLD was 0.42±0.44 mm. Final MLD at the
lesion site 3 to 4 weeks after angioplasty was significantly reduced to
0.78±0.46 mm (P=.0001, Fig 1). The late loss in luminal
diameter (0.95±0.64 mm) was significantly different from the initial
gain (P=.0001). Analogous to human quantitative angiographic
analysis,28 the initial gain and the late loss of the
MLD obtained by angiography exhibited a positive correlation (Fig 2, P=.008, r=.49; excludes
outlier: -1.6, -1.1). There was a correlation between angiographic
restenosis (late loss) and late residual (histological) stenosis
(P=.003, r=.50).
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indicates MLD
before angioplasty; 
, immediately after angioplasty; and 
,
3 to 4 weeks after angioplasty.
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Reference diameters for each animal before, immediately after, and 3 to 4 weeks after angioplasty were divided by the reference diameter immediately before angioplasty to allow comparisons among animals. Immediately after angioplasty, the normalized reference diameter was 0.99±0.07 (mean±SD) (n=36). At 3 to 4 weeks after angioplasty, the normalized reference diameter was 0.96±0.17 (n=36). Thus, there was no statistically significant difference between the normalized reference diameter at either time and the diameter before angioplasty (P=.55 and P=.15, respectively); ie, the reference site appeared unaffected by the constriction and neointimal-medial growth that governed the restenotic response at the lesion site.
In a control group that did not receive angioplasty, the MLD at the lesion site 4 weeks after initial lesion induction averaged 1.24±0.25 mm. Final MLD at the lesion site 3 to 4 weeks after this first angiogram averaged 1.17±0.26 mm. Thus, there was no statistically significant difference in MLDs at the lesion site between these times or in the MLDs of the arteries before angioplasty (P=.29).
Histology
Averages of the areas of arterial wall layers are displayed in
Table 2. Histologically defined late residual stenosis
(see "Materials and Methods") averaged 52±32% at termination
(ie, an average loss of 52% in the luminal area compared with the
reference site), indicating a general restenotic response in the
population of lesions.
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Influence of Chronic Constriction, Neointimal-Medial Growth, and
Adventitial Growth on Restenosis
The relation between the histological parameters and the
degree of restenosis was examined. Surprisingly,
neointimal-medial growth appeared to be independent of, and
a poor predictor for, the severity of the late residual stenosis (Fig 3, P=.63, r=.08). Nor did
adventitial growth correlate with either late residual stenosis (Fig 4, P=.36, r=.15) or chronic
constriction (P=.31, r=.17). In contrast, late
residual stenosis clearly correlated with chronic constriction (Fig 5, P=.0001, r=-.67); ie, the
greater the constriction (the lower the constriction index), the more
severe the late residual stenosis. The degree of constriction among the
lesions was observed to be more a continuum than a bimodal
distribution, with some arteries exhibiting constriction (constriction
index <1) and others exhibiting compensatory enlargement (constriction
index >1). Adventitial growth and neointimal-medial growth
exhibited a positive correlation (P=.0006,
r=.58). Neointimal-medial growth and chronic constriction
exhibited an inverse correlation. That is, the more severe the
constriction (the lower the constriction index), the less the
neointimal-medial growth (Fig 6,
P=.01, r=.41).
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Remodeling of the Adventitia and the Intima+Media at the Lesion
Site: Relation to Chronic Constriction
We evaluated the relation among the adventitia, the intima+media,
and chronic constriction at the site of angioplasty. The ratio of the
adventitial area to the area of the intima+media at the lesion site
correlated with chronic constriction (ie, inversely correlated with the
constriction index; see Fig 7; P=.01;
r=-.41).
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Vascular Remodeling in Nonballooned Atherosclerotic Arteries
In the control group that did not receive angioplasty, the
index of neointimal-medial growth averaged 0.40±0.11 at
the end of 7 to 8 weeks after the initial air-drying lesion. The index
of chronic constriction averaged 1.41±0.47. There was no constriction
but, rather, an enlargement of these arteries. There was a significant
difference in constriction indexes between ballooned and nonballooned
arteries at termination (P<.01). Moreover, there was an
inverse correlation between neointimal-medial growth and
late residual stenosis (P=.045, r=.59). That is,
this control group appeared to exhibit compensatory enlargement. There
was no correlation between late residual stenosis and the index of
constriction (P=.20, r=.27). Thus, nonballooned
arteries did not exhibit constriction in response to the initial
injury, and constriction observed in ballooned animals, therefore,
could not be attributed to the initial lesion induction.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Vascular Remodeling and Stenotic Lesions After Experimental and Human Vascular Injury
Restenosis after angioplasty is often attributed to hyperplasia induced by smooth muscle cell proliferation.7 8 9 15 The rationale for using an animal model in the present study was to analyze simultaneously the variations of the lumen, the fibrocellular response of the arterial wall, and the constriction exhibited by the wall at the angioplasty site compared with a proximal reference site of the same artery. Our results demonstrate that a chronic constriction occurs and is an important correlate of restenosis 3 to 4 weeks after balloon dilation in the injured rabbit femoral artery. This finding has important basic and clinical implications, since it suggests that restenosis is not solely related to neointimal-medial growth. To minimize animal-to-animal variations, we normalized each dilated atherosclerotic site to an upstream uninjured site that did not undergo either air desiccation or angioplasty and was clearly anatomically identifiable (see "Materials and Methods"). This allowed us to examine the outcomes of the restenosis process, both neointimal-medial growth and chronic constriction, for each injury site. We analyzed the response to angioplasty more as a continuum (from no effect on the luminal area to complete occlusion) than as a dichotomous "restenosed" or "nonrestenosed" categorization. We thus identified stenotic arteries with increased intimal+medial area, arteries that exhibited generalized constriction without marked increases in neointimal-medial growth, and arteries with a mixed response with varying degrees of neointimal-medial growth and either constriction or dilation (Fig 3
). The diversity of
this response is in general agreement with human data that suggest
heterogeneity in the histological restenotic
response.3 7 8 9 15 16 17 18 19 20 21 22 Although there are methodological
differences among various studies, our data are in agreement with
recent studies evaluating the same remodeling
concept.33 34 35 Kakuta et al34 took a different
approach: they compared outcomes at the dilated sites immediately and 4
weeks after angioplasty between two groups and therefore used unpaired
Student's t test in a similar atherosclerotic rabbit model.
Using a dichotomous definition of restenosis, they defined restenotic
and nonrestenotic arteries from the chronic animals. Despite these
methodological differences and invoking the concept of compensatory
enlargement defined by Glagov et al23 rather than a
chronic constrictive process, they drew conclusions that were similar
to ours. That is, differences in compensatory enlargement, not
neointimal formation, accounted for restenosis. Post et
al35 used a methodology similar to that of Kakuta et al,
three different experimental populations (normal rabbits and normal and
atherosclerotic Yucatan pigs), and two angioplasty procedures (standard
balloon and thermal angioplasty). They also found that remodeling, not
intimal hyperplasia, correlated with restenosis.35 Our
data indicate that there was not only a lack of enlargement but also a
constrictive process that influenced the outcome. In apparent contrast,
in a recent study that also used a rabbit model of angioplasty, Gertz
et al42 concluded that geometric remodeling was not the
principal determinant of restenosis after balloon angioplasty. They
found a correlation between the balloon-treated sites that were the
most narrowed by plaque and the ones with the smallest luminal areas.
Comparisons are difficult between this and other studies because of the
lack of quantitative plaque parameters.
Our results indicate a need to monitor and quantify the extent of
chronic constriction in response to angioplasty, and the results
suggest a need for new parameters to describe restenosis. Prevention of
chronic constriction may prove to be more critical than prevention of
neointimal-medial growth in the control of restenosis after
angioplasty. There is a strong inverse correlation between
neointimal-medial growth and chronic constriction (see Fig 6). Of interest, it was recently reported that a similar inverse
correlation between neointimal hyperplasia and chronic
constriction was observed in intravascular ultrasound data from a study
of restenotic human coronary arteries.36 The
interpretation of such a correlation remains obscure, as does the
question of which, if either, of these might be the dependent variable.
It is possible that a lack of neointimal growth results
from chronic constriction, but it is also possible that compensatory
enlargement follows neointimal growth.
It is interesting to note that our data are also in general agreement with certain human data.3 7 8 9 15 16 17 18 19 20 21 22 The absence of intimal proliferation in 40% of humans late after coronary angioplasty has been described in a limited autopsy study of 20 patients with restenosis, suggesting the concept of late recoil.3 Recently, intracoronary ultrasound imaging was used to evaluate angioplasty in preliminary studies in humans. Decreased hyperplasia and a contracted perimeter of the external elastic lamina were noted in restenotic lesions compared with nonrestenotic lesions, casting doubt on a dominant role of smooth muscle cell proliferation in restenosis.31 32 36 In atherectomy specimens of human restenotic lesions, others have found that smooth muscle cell proliferation occurred inconsistently and at low levels, as shown by cell cycle–specific labeling.43 Moreover, it has been shown that similar levels of smooth muscle cell proliferation occurred in both restenotic and nonrestenotic lesions evaluated at autopsy.22 Thus, hyperplasia alone does not appear to be sufficient to account for restenosis in humans.
Potential Mechanisms of Chronic Constriction
Several mechanisms to explain chronic constriction can be
proposed. Acute recoil has been proposed as a potential mechanism
contributing to restenosis.44 In the present study,
angiograms taken 10 minutes after angioplasty exhibited an improvement
of >20% in 84% of the lesions; acute elastic recoil (ie, loss of the
gain obtained during balloon inflation) was apparent in only 9% of the
lesions (data not shown). In contrast, if we define angiographic
restenosis in our data by using an analogy to criteria used after human
angioplasty (ie, as a loss of >50% of the initial gain), our data
show that restenosis occurred in 65% of the lesions. This suggests
that acute recoil did not determine the subsequent outcome. Moreover,
in other experimental models of restenosis after angioplasty, no recoil
was observed immediately and 3 days after
angioplasty.34 45
Interestingly, it has been shown that patients presenting with a higher probability for spasm, both at the time of angioplasty and at a 6-month angiographic measurement, developed restenosis in 81% of cases.46 In another study, spasm detected 6 months after angioplasty was present in 50% of the restenotic lesions versus 7% in lesions without restenosis.47 In addition, it was reported that patients with spasm at the time of angioplasty, but not 6 months after angioplasty, exhibited a 19% restenosis rate, whereas patients with spasm at the time of angioplasty and 6 months after angioplasty had a 55% restenosis rate.48 These clinical observations invite speculation as to whether arterial spasm may be linked to chronic constriction.
The constrictive response we have quantified in these experiments and a part of the multiple influences that affect restenosis may be determined by the same forces that govern arterial remodeling. The phenomenon of vascular remodeling has been described as changes in luminal and external diameters in response to hypertensive vascular changes,24 25 49 and it has also been characterized as a flow-dependent phenomenon.26 50 51 52 Although the mechanisms are uncertain, data support the concept that a vessel wall remodels in response to chronic changes in flow and pressure by the induction of various constricting or dilating pathways.26 An increase in wall shear stress can lead to luminal enlargement until normalization of the shear stress; an increase in the tension on the artery wall may induce a proliferative response.51 52 53 54 Angioplasty-related healing may involve an analogous series of changes that may lead in some instances to the chronic constriction we observe. What is perceived as a variable constrictive response may result instead from a variable absence of relaxing influences. Oxidized lipoproteins and their constituent lipids have been shown to decrease endothelium-dependent relaxation. The degree of endothelial injury and regrowth may thereby influence vascular tone in the repairing vessel wall. Thus, the formation of lipoprotein oxidation products, perhaps mediated by an increased influx into the balloon injury site of plasma lipoproteins and free radical–producing inflammatory cells,55 may influence the rapidity of the repair process,56 neointimal growth,57 58 the extent of injury,59 and the level of vasorelaxation.60
Unlike other studies examining the relative impacts of remodeling and hyperplasia on restenosis,33 34 35 our approach included an evaluation of remodeling of the adventitial layer after balloon dilation. We found no correlation between adventitial growth alone and chronic constriction; however, the ratio of the adventitial area to the area of the intima+media at the lesion site correlated with chronic constriction. Our data suggest that constriction at the site of angioplasty may be affected by multiple structural changes, including rearrangement of not only the intima and media but also the adventitia. Changes in the adventitia are unlikely related to procedures used to form the initial lesion, since control lesions treated identically but without angioplasty did not exhibit constriction or such adventitial changes.
We hypothesize that the postangioplasty healing may lead to changes that include an altered balance between the relative sizes of the adventitia and the intima+media in favor of the adventitia. This relative dominance of the adventitia may effectively impair compensatory enlargement and result in an apparent chronic constriction. Further studies are needed to evaluate this hypothesis and to quantify the process further.
Since our data were obtained in an animal model of restenosis, any
extrapolation of these observations to humans obviously requires
caution. The mediators of the constrictive response are unknown, and
the response we observe could be model specific. However, we know from
our control data that the constriction is independent of the induction
of the lesion. It is interesting to note, with all due caution, that
prominent features of this restenotic model coincide with features
observed in humans. As in humans, in this model a sizable fraction but
not all of the arteries restenose to a level that would be expected to
jeopardize tissue perfusion. The concept derived from angiographic data
in humans (that greater gain correlates with greater
loss61 62 ) was shown for this model in the present
study (Fig 2), and the occurrence of nonproliferative restenosis has
already been suggested in humans.3 30 Nevertheless,
confirmation of our results should be sought from other experimental
models.63
Summary
In the present study, we evaluated the syndrome of restenosis
in a rabbit experimental model by analyzing the lesion morphometrically
compared with an uninjured site of the same artery. A chronic
constriction, perceived at the level of the external elastic lamina,
correlated more closely with luminal narrowing 3 to 4 weeks after
angioplasty than did neointimal-medial growth. Moreover, a
change in the relative contributions of intima, media, and adventitia
at the lesion site in favor of the adventitia suggested a possible
mechanism for constriction. Studies to explore further the cause of the
constriction may be facilitated by an animal model such as that used in
the present study.
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Acknowledgments |
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This study was partially funded by a grant from the National Institutes of Health (HL-47852). Dr Lafont was the recipient of a Fellowship from the American Heart Association, Northeast Ohio Affiliate, Inc. We thank Dr Paul Vanhoutte for helpful discussions, Dr Ian Sarembock for teaching us the animal model, Manny Ferrer for help during the experiments, Ed Herderick for performing the morphometry, Charlie Kaul, Bob Lewis, Ron Porter, and Ray Terrell for their technical assistance, and Kathryn Brock for editorial assistance.
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Footnotes |
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Reprint requests to Guy M. Chisolm, PhD, Department of Cell Biology/NC10, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195.
Received April 21, 1994; accepted March 10, 1995.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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S. Assadnia, J. P. Rapp, A. L. Nestor, T. Pringle, G. J. Cerilli, W. T. Gunning III, T. H. Webb, M. Kligman, and D. C. Allison Strain Differences in Neointimal Hyperplasia in the Rat Circ. Res., June 11, 1999; 84(11): 1252 - 1257. [Abstract] [Full Text] [PDF]
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D. Meerkin, J.-C. Tardif, I. R. Crocker, A. Arsenault, M. Joyal, G. Lucier, S. B. King III, D. O. Williams, P. W. Serruys, and R. Bonan Effects of Intracoronary ß-Radiation Therapy After Coronary Angioplasty : An Intravascular Ultrasound Study Circulation, April 6, 1999; 99(13): 1660 - 1665. [Abstract] [Full Text] [PDF]
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T. Le Tourneau, E. Van Belle, D. Corseaux, B. Vallet, G. Lebuffe, B. Dupuis, J.-M. Lablanche, E. McFadden, C. Bauters, and M. E. Bertrand Role of nitric oxide in restenosis after experimental balloon angioplasty in the hypercholesterolemic rabbit: effects on neointimal hyperplasia and vascular remodeling J. Am. Coll. Cardiol., March 1, 1999; 33(3): 876 - 882. [Abstract] [Full Text] [PDF]
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J. M. Bosmans, C. J. Vrints, M. M. Kockx, H. Bult, K. M. C. Cromheeke, and A. G. Herman Continuous Perivascular L-Arginine Delivery Increases Total Vessel Area and Reduces Neointimal Thickening After Experimental Balloon Dilatation Arterioscler Thromb Vasc Biol, March 1, 1999; 19(3): 767 - 776. [Abstract] [Full Text] [PDF]
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I. J. Kullo, R. D. Simari, and R. S. Schwartz Vascular Gene Transfer : From Bench to Bedside Arterioscler Thromb Vasc Biol, February 1, 1999; 19(2): 196 - 207. [Full Text] [PDF]
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M. R Bennett Apoptosis of vascular smooth muscle cells in vascular remodelling and atherosclerotic plaque rupture Cardiovasc Res, February 1, 1999; 41(2): 361 - 368. [Abstract] [Full Text] [PDF]
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G. Cote, J.-C. Tardif, J. Lesperance, J. Lambert, M. Bourassa, R. Bonan, G. Gosselin, M. Joyal, J.-F. Tanguay, S. Nattel, et al. Effects of Probucol on Vascular Remodeling After Coronary Angioplasty Circulation, January 12, 1999; 99(1): 30 - 35. [Abstract] [Full Text] [PDF]
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M. Labinaz, K. Pels, C. Hoffert, S. Aggarwal, and E. R O'Brien Time course and importance of neoadventitial formation in arterial remodeling following balloon angioplasty of porcine coronary arteries Cardiovasc Res, January 1, 1999; 41(1): 255 - 266. [Abstract] [Full Text] [PDF]
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E. A. de Vrey, G. S. Mintz, C. von Birgelen, T. Kimura, M. Noboyoshi, J. J. Popma, P. W. Serruys, and M. B. Leon Serial volumetric (three-dimensional) intravascular ultrasound analysis of restenosis after directional coronary atherectomy J. Am. Coll. Cardiol., December 1, 1998; 32(7): 1874 - 1880. [Abstract] [Full Text] [PDF]
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P. Zandberg, J. L. M. Peters, P. N. M. Demacker, M. J. Smit, E. G. de Reeder, and D. G. Meuleman Tibolone Prevents Atherosclerotic Lesion Formation in Cholesterol-Fed, Ovariectomized Rabbits Arterioscler Thromb Vasc Biol, December 1, 1998; 18(12): 1844 - 1854. [Abstract] [Full Text] [PDF]
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O. Varenne, S. Pislaru, H. Gillijns, N. Van Pelt, R. D. Gerard, P. Zoldhelyi, F. Van de Werf, D. Collen, and S. P. Janssens Local Adenovirus-Mediated Transfer of Human Endothelial Nitric Oxide Synthase Reduces Luminal Narrowing After Coronary Angioplasty in Pigs Circulation, September 1, 1998; 98(9): 919 - 926. [Abstract] [Full Text] [PDF]
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A. J. Lansky, G. S. Mintz, J. J. Popma, A. D. Pichard, K. M. Kent, L. F. Satler, D. S. Baim, R. E. Kuntz, C. Simonton, R. M. Bersin, et al. Remodeling after directional coronary atherectomy (with and without adjunct percutaneous transluminal coronary angioplasty): a serial angiographic and intravascular ultrasound analysis from the optimal atherectomy restenosis study J. Am. Coll. Cardiol., August 1, 1998; 32(2): 329 - 337. [Abstract] [Full Text] [PDF]
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A. Lafont and D. Faxon Why do animal models of post-angioplasty restenosis sometimes poorly predict the outcome of clinical trials? Cardiovasc Res, July 1, 1998; 39(1): 50 - 59. [Full Text] [PDF]
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B.J.G.L de Smet, J van der Zande, Y.J.M van der Helm, R.E Kuntz, C Borst, and M.J Post The atherosclerotic Yucatan animal model to study the arterial response after balloon angioplasty: the natural history of remodeling Cardiovasc Res, July 1, 1998; 39(1): 224 - 232. [Abstract] [Full Text] [PDF]
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B. J. G. L. de Smet, G. Pasterkamp, Y. J. van der Helm, C. Borst, and M. J. Post The Relation Between De Novo Atherosclerosis Remodeling and Angioplasty-Induced Remodeling in an Atherosclerotic Yucatan Micropig Model Arterioscler Thromb Vasc Biol, May 1, 1998; 18(5): 702 - 707. [Abstract] [Full Text] [PDF]
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E. Van Belle, C. Bauters, T. Asahara, and J. M. Isner Endothelial regrowth after arterial injury: from vascular repair to therapeutics Cardiovasc Res, April 1, 1998; 38(1): 54 - 68. [Full Text] [PDF]
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P. Libby Gene Therapy of Restenosis : Promise and Perils Circ. Res., February 23, 1998; 82(3): 404 - 406. [Full Text] [PDF]
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M. Challah, E. Villard, M. Philippe, A. Ribadeau-Dumas, B. Giraudeau, P. Janiak, J.-P. Vilaine, F. Soubrier, and J.-B. Michel Angiotensin I-Converting Enzyme Genotype Influences Arterial Response to Injury in Normotensive Rats Arterioscler Thromb Vasc Biol, February 1, 1998; 18(2): 235 - 243. [Abstract] [Full Text] [PDF]
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C. I. Seye, A.-P. Gadeau, D. Daret, F. Dupuch, P. Alzieu, L. Capron, and C. Desgranges Overexpression of the P2Y2 Purinoceptor in Intimal Lesions of the Rat Aorta Arterioscler Thromb Vasc Biol, December 1, 1997; 17(12): 3602 - 3610. [Abstract] [Full Text]
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S.D. Gertz, W. L Barry, L. W Gimple, Shmuel Banai, L. S Perez, C. A McNamara, E. R Powers, M. Ragosta, G. K Owens, W. C Roberts, et al. Predictors of luminal narrowing by neointima after angioplasty in atherosclerotic rabbits Cardiovasc Res, December 1, 1997; 36(3): 396 - 407. [Abstract] [Full Text] [PDF]
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M. C.J Persoons, M. J.A.P Daemen, E. M van Kleef, G. E.L.M Grauls, E. Wijers, and C. A Bruggeman Neointimal smooth muscle cell phenotype is important in its susceptibility to cytomegalovirus (CMV) infection: a study in rat Cardiovasc Res, November 1, 1997; 36(2): 282 - 288. [Abstract] [Full Text] [PDF]
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E. Van Belle, C. Bauters, E. Hubert, J.-C. Bodart, K. Abolmaali, T. Meurice, E. P. McFadden, J.-M. Lablanche, and M. E. Bertrand Restenosis Rates in Diabetic Patients : A Comparison of Coronary Stenting and Balloon Angioplasty in Native Coronary Vessels Circulation, September 2, 1997; 96(5): 1454 - 1460. [Abstract] [Full Text]
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L. J Feldman and G. Steg Optimal techniques for arterial gene transfer Cardiovasc Res, September 1, 1997; 35(3): 391 - 404. [Abstract] [Full Text] [PDF]
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A. H Baker, D. Mehta, S. J George, and G. D Angelini Prevention of vein graft failure: potential applications for gene therapy Cardiovasc Res, September 1, 1997; 35(3): 442 - 450. [Abstract] [Full Text] [PDF]
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T. Kimura, S. Kaburagi, T. Tamura, H. Yokoi, Y. Nakagawa, H. Yokoi, N. Hamasaki, H. Nosaka, M. Nobuyoshi, G. S. Mintz, et al. Remodeling of Human Coronary Arteries Undergoing Coronary Angioplasty or Atherectomy Circulation, July 15, 1997; 96(2): 475 - 483. [Abstract] [Full Text]
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C. Amant, C. Bauters, J.-C. Bodart, J.-M. Lablanche, G. Grollier, N. Danchin, M. Hamon, F. Richard, N. Helbecque, E. P. McFadden, et al. D Allele of the Angiotensin I–Converting Enzyme Is a Major Risk Factor for Restenosis After Coronary Stenting Circulation, July 1, 1997; 96(1): 56 - 60. [Abstract] [Full Text]
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W. D. Coats, P. Whittaker, D. T. Cheung, J. W. Currier, B. Han, and D. P. Faxon Collagen Content Is Significantly Lower in Restenotic Versus Nonrestenotic Vessels After Balloon Angioplasty in the Atherosclerotic Rabbit Model Circulation, March 4, 1997; 95(5): 1293 - 1300. [Abstract] [Full Text]
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T. T. Lim, D. H. Liang, J. Botas, J. S. Schroeder, S. N. Oesterle, and A. C. Yeung Role of Compensatory Enlargement and Shrinkage in Transplant Coronary Artery Disease: Serial Intravascular Ultrasound Study Circulation, February 18, 1997; 95(4): 855 - 859. [Abstract] [Full Text]
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Y. Shi, J. E. O'Brien, L. Ala-Kokko, W. Chung, J. D. Mannion, and A. Zalewski Origin of Extracellular Matrix Synthesis During Coronary Repair Circulation, February 18, 1997; 95(4): 997 - 1006. [Abstract] [Full Text]
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E. Van Belle, F. O. Tio, T. Couffinhal, L. Maillard, J. Passeri, and J. M. Isner Stent Endothelialization: Time Course, Impact of Local Catheter Delivery, Feasibility of Recombinant Protein Administration, and Response to Cytokine Expedition Circulation, January 21, 1997; 95(2): 438 - 448. [Abstract] [Full Text]
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H. Luo, T. Nishioka, N. L. Eigler, J. S. Forrester, M. C. Fishbein, H. Berglund, and R. J. Siegel Coronary Artery Restenosis After Balloon Angioplasty in Humans Is Associated With Circumferential Coronary Constriction Arterioscler Thromb Vasc Biol, November 1, 1996; 16(11): 1393 - 1398. [Abstract] [Full Text]
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Y. Shi, J. E. O'Brien, A. Fard, and A. Zalewski Transforming Growth Factor-ß1 Expression and Myofibroblast Formation During Arterial Repair Arterioscler Thromb Vasc Biol, October 1, 1996; 16(10): 1298 - 1305. [Abstract] [Full Text]
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C. Gerdes, V. Faber-Steinfeld, O. Yalkinoglu, and S. Wohlfeil Comparison of the Effects of the Thrombin Inhibitor r-Hirudin in Four Animal Models of Neointima Formation After Arterial Injury Arterioscler Thromb Vasc Biol, October 1, 1996; 16(10): 1306 - 1311. [Abstract] [Full Text]
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Y. Shi, J. E. O'Brien, A. Fard, J. D. Mannion, D. Wang, and A. Zalewski Adventitial Myofibroblasts Contribute to Neointimal Formation in Injured Porcine Coronary Arteries Circulation, October 1, 1996; 94(7): 1655 - 1664. [Abstract] [Full Text]
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L. A. Guzman, V. Labhasetwar, C. Song, Y. Jang, A. M. Lincoff, R. Levy, and E. J. Topol Local Intraluminal Infusion of Biodegradable Polymeric Nanoparticles: A Novel Approach for Prolonged Drug Delivery After Balloon Angioplasty Circulation, September 15, 1996; 94(6): 1441 - 1448. [Abstract] [Full Text]
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G. S. Mintz, J. J. Popma, A. D. Pichard, K. M. Kent, L. F. Satler, S. Chiu Wong, M. K. Hong, J. A. Kovach, and M. B. Leon Arterial Remodeling After Coronary Angioplasty : A Serial Intravascular Ultrasound Study Circulation, July 1, 1996; 94(1): 35 - 43. [Abstract] [Full Text]
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H. Rud Andersen, M. Mæng, M. Thorwest, and E. Falk Remodeling Rather Than Neointimal Formation Explains Luminal Narrowing After Deep Vessel Wall Injury : Insights From a Porcine Coronary (Re)stenosis Model Circulation, May 1, 1996; 93(9): 1716 - 1724. [Abstract] [Full Text]
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R. Riessen, T. N. Wight, C. Pastore, C. Henley, and J. M. Isner Distribution of Hyaluronan During Extracellular Matrix Remodeling in Human Restenotic Arteries and Balloon-Injured Rat Carotid Arteries Circulation, March 15, 1996; 93(6): 1141 - 1147. [Abstract] [Full Text]
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L. A. Guzman, M. J. Mick, A. M. Arnold, F. Forudi, and P. L. Whitlow Role of Intimal Hyperplasia and Arterial Remodeling After Balloon Angioplasty : An Experimental Study in the Atherosclerotic Rabbit Model Arterioscler Thromb Vasc Biol, March 1, 1996; 16(3): 479 - 487. [Abstract] [Full Text]
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Y. Shi, M. Pieniek, A. Fard, J. O'Brien, J. D. Mannion, and A. Zalewski Adventitial Remodeling After Coronary Arterial Injury Circulation, January 15, 1996; 93(2): 340 - 348. [Abstract] [Full Text]
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P. G. Steg, M. Ziol, O. Tahlil, C. Robert, P. Masson, D. Pruneau, P. Bruneval, and P. Belichard Reduction of Intimal Hyperplasia by Naroparcil, a 4-Methylumbelliferyl ß-D-Xyloside Analogue, After Arterial Injury in the Hypercholesterolemic Rabbit Circ. Res., November 1, 1995; 77(5): 919 - 926. [Abstract] [Full Text]
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