© 1996 American Heart Association, Inc.
Articles |
Time Course of Cellular Proliferation, Intimal Hyperplasia, and Remodeling Following Angioplasty in Monkeys With Established Atherosclerosis
A Nonhuman Primate Model of Restenosis
From the Departments of Surgery (R.L.G., D.G.B., M.E.B.) and Comparative Medicine (J.K.W., D.G., M.R.A.), The Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC.
Correspondence to Randolph L. Geary, MD, Division of Surgical Sciences, Bowman Gray School of Medicine, Wake Forest University, Medical Center Blvd, Winston-Salem, NC 27157-1095. E-mail rgeary@isnet.is.wfu.edu.
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Abstract |
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Abstract Animal models of arterial injury have failed to predict effective therapy to prevent restenosis in humans. While this may relate to species differences in the control of smooth muscle cell growth, many studies have used nonatherosclerotic animals, thereby failing to consider the importance of atherosclerosis in the response to injury. In an attempt to model human restenosis more accurately, we characterized the response to angioplasty in atherosclerotic monkeys. Twenty-one cynomolgus monkeys were fed an atherogenic diet for 36 months (plasma cholesterol, 12±1 mmol/L [470±23 mg/dL]). Angioplasty was then performed in the left iliac artery. After 4, 7, 14, or 28 days, bromodeoxyuridine was given to label proliferating cells, and iliac arteries were fixed in situ at physiological pressure (5 or 6 animals at each time point). Comparisons were made between injured and uninjured iliac arteries within each animal. Angioplasty often fractured the intimal plaque and media, transiently increasing lumen caliber (4 days: lumen area, 232.5±80.3% of control) and artery size as reflected by external elastic lamina area (EEL). EEL and lumen caliber returned to baseline by 7 days. Proliferation was increased throughout the artery wall at 4 and 7 days and later declined to control rates (4 days, injured versus uninjured: adventitia, 45.0±6.2% versus 16.3±7.2%; media, 8.6±2.6% versus 0.6±0.1%; intima, 16.0±5.6% versus 7.8±3.1%). The intima thickened markedly from 14 to 28 days, but an increase in EEL generally prevented further loss of the short-term gain in lumen caliber (28 days, percent of control: intimal area, 342.8±88.9%; EEL area, 150.2±28.9%; lumen area, 119.3±21.3%). The response to angioplasty in atherosclerotic monkeys appears to closely resemble that in humans. Plaque fracture, delayed recoil, intimal hyperplasia, and remodeling may each be important in determining late lumen caliber. This primate model should prove valuable in defining cellular and biochemical mediators of human restenosis.
Key Words: angioplasty • remodeling • restenosis • cellular proliferation • Macaca fascicularis
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Atherosclerosis and its complications remain a major cause of death and disability in Western societies. Symptomatic end-organ ischemia frequently leads to the need for arterial reconstruction. Regardless of the method used (angioplasty, atherectomy, bypass grafting, endarterectomy, or stenting), all forms of arterial reconstruction unavoidably injure the underlying artery wall. Arterial injury sets into motion a complex series of biochemical and cellular events that frequently culminate in a recurrent stenosis. Thirty percent to 60% of coronary arteries develop restenosis at the site of angioplasty within 1 year of the procedure.1 2
To develop useful strategies to prevent restenosis, the appropriate cellular and molecular targets for intervention must be defined. This requires improved insight into the structural and cellular responses to angioplasty. Although small-animal models have contributed greatly to our understanding of intimal hyperplasia after arterial injury, a multitude of drugs shown to be effective in these models3 4 have been ineffective in preventing restenosis in humans.5 6 7 8 There are several possible explanations. There may be species differences in the control of SMC migration or proliferation.9 Furthermore, it has been suggested that the importance of intimal hyperplasia as a major determinant of restenosis may be overestimated.10 11 12 Finally, previous studies have often used nonatherosclerotic animals and thereby failed to consider the probable importance of the underlying atherosclerosis in defining the response to injury in human beings.3 4 9 13 These issues underscore the need for animal models that more closely mimic the human situation in which restenosis occurs in response to injury of arteries with preexisting advanced atherosclerosis.
The animal model that most closely mimics the progression of atherosclerosis in humans is diet-induced atherosclerosis in the macaque.14 15 16 This model has been well-characterized in long-term studies of primary atherosclerosis and atherosclerosis regression.16 17 18 19 The response to angioplasty in this unique model of atherosclerosis has not been previously characterized in detail. We describe here the time course of structural and cellular responses to angioplasty in atherosclerotic cynomolgus macaques. The results suggest that this model may prove invaluable in determining cellular and biochemical mediators of the response to angioplasty.
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Methods |
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Animal Model
Twenty-one ovariectomized female cynomolgus monkeys (Macaca fascicularis) were fed an atherogenic diet for 3 years to establish complex atherosclerotic lesions. The diet contained 0.28 mg cholesterol per calorie and was composed of 17% protein, 38% carbohydrate, and 45% lipid (46% saturated, 43% monounsaturated, and 11% polyunsaturated fatty acids). Each monkey then underwent balloon angioplasty of the left common iliac artery; the right common iliac artery served as an uninjured intra-animal control vessel. Animals were anesthetized with ketamine hydrochloride (10 mg/kg IM) and butorphanol (0.05 mg/kg IM). The depth of anesthesia was closely monitored, and animals were given more drug as necessary. The left femoral artery was exposed, heparin was administered (100 U/kg, Elkins-Sinn, Inc), and under fluoroscopic guidance a 3F balloon catheter (V. Mueller Inc) was passed proximally into the distal aorta. The balloon was then inflated and retrieved under tension three times. The catheter was removed, the arterial puncture repaired with 7-0 polypropylene suture (Davis and Geck), and blood flow restored. For uniformity, the same individual performed all balloon injuries. Wounds were closed in layers, antibiotic was administered (Cefazolin sodium, 25 mg/kg IM), and the animals were returned to single-animal cages until recovery from surgery.
Animals were euthanatized 4, 7, 14, or 28 days after angioplasty (5 animals at 4, 7, and 14 days and 6 animals at 28 days). BrdU was given (45 mg/kg IM, Boehringer Mannheim) 18 hours and 6 hours before death to label proliferating cells. Animals were sedated with ketamine (15 mg/kg IM) and butorphanol (0.05 mg/kg IM) and heparinized (300 U/kg IV). Deep anesthesia was achieved with pentobarbital (100 mg/kg IV), and the distal abdominal aorta was cannulated. Iliac arteries were perfused in situ at physiological pressure with lactated Ringer's solution until rinsed clear and then with 10% neutral buffered formalin for 1 hour. The distal aorta and iliac and femoral arteries were then removed en bloc and placed into fresh formalin for 36 hours before paraffin embedding.
All animal care and procedures were performed at the Comparative Medicine Clinical Research Center of The Bowman Gray School of Medicine in accordance with state and federal laws. Animal protocols were approved by the Bowman Gray Animal Care and Use Committee and conformed to guidelines set forth by the American Association for Accreditation of Laboratory Animal Care and by National Institutes of Health publication 86-23, Guide for the Care and Use of Laboratory Animals.
Histology and Morphometry
Fixed common iliac arteries were
cut into five sequential rings
for paraffin embedding. Sections 5 µm thick were cut from each block
and stained with Verhoeff–van Gieson's stain for morphometric
analysis. Cross sections were projected onto a computerized
digitizing pad with a camera lucida; the luminal, IEL, and EEL
perimeters were measured; and the luminal, intimal, and medial areas
were calculated for each ring. Mean values for each iliac artery
(injured and uninjured) were determined by averaging
cross-sectional measurements from each of the five adjacent rings.
Perimeter measurements were converted to circumference for comparisons
of overall artery size (EEL area), IEL area, and luminal caliber.
Iliac Artery Atherosclerosis in Cynomolgus
Monkeys
The similarity of diet-induced
atherosclerosis between left and right common iliac
arteries was compared in individual monkeys previously involved in
long-term atherosclerosis research. A review of the
Cardiovascular Pathology Archives Database of the
Department of Comparative Medicine of Wake Forest University provided
data on iliac artery plaque areas from 159 male and 171 female
cynomolgus monkeys. Arteries had been perfusion fixed at
physiological pressures and divided into three
rings for paraffin embedding. Cross sections from each ring were
digitized by computer-assisted morphometry, and a mean intimal area
for each vessel was determined by averaging values from the three
rings. Comparisons were made within individual animals between right
and left iliac arteries, and correlation coefficients were
determined.
Immunohistochemistry
To determine the cellular composition
and degree of
proliferation (see below) in the intima, media, and adventitia,
sections from iliac arteries were deparaffinized in xylene, rehydrated
in graded alcohols, and immunostained. For cell-type
identification, antibodies specific to SMC 
-actin
(Boehringer), endothelial cell vWF (Dako), and
macrophage CD68 antigen (Dako) were applied. Primary antibodies
were localized with appropriate biotinylated secondary antibodies and
tertiary avidin-biotin complex staining (Vector Laboratories).
Control slides were stained with the appropriate nonimmune IgG in place
of the primary antibody. Sections were counterstained with hematoxylin
and examined by light microscopy.
Cellular Proliferation After Angioplasty
BrdU (45 mg/kg IM,
Boehringer) was given 18 hours and 6
hours before death to label cells entering the S phase during the 24
hours before necropsy.9 This strategy should label two
separate groups of dividing cells, since the S phase is estimated to be
6 hours for vascular SMCs. Deparaffinized sections from all iliac
rings were stained with a monoclonal antibody against BrdU
(Boehringer Mannheim). Sections were treated for 30 minutes
with Protease-24 (0.1 µg/mL, Dako) and then for 10 minutes with 0.1N
HCl, both at 37°C. The primary antibody (Dako) was then applied at a
dilution of 1:20 and incubated overnight at 4°C. A biotinylated
secondary antibody was applied and localized with the avidin-biotin
complex reaction (Vector), and sections were counterstained with
hematoxylin and examined with a x60 objective. Proliferating intimal,
medial, and adventitial cells were identified by dark brown nuclear
staining and counted for each cross section. Total intimal and medial
cell numbers were estimated in the same sections by multiplying the
intimal or medial cross-sectional areas (see above) by the number
of nuclei per square millimeter (estimated by counting nuclei in eight
representative high-power fields of defined area by
use of an eyepiece reticule).9 A BrdU labeling index
(percent) was calculated for the intima and media by dividing labeled
nuclei by the total number of nuclei and multiplying by 100.
Adventitial labeling was estimated by counting labeled and unlabeled
nuclei in eight regions around each cross section (at least 100 nuclei
per cross section), expressing labeled nuclei as a fraction of total
nuclei counted. A mean labeling index for each vessel compartment of
each artery was determined by averaging values from sections adjacent
to those five sections used for morphometry in each artery (see
above).
Statistical Analysis
Paired comparisons were made between
injured and uninjured
arteries within individual animals at each specific time point by
paired, two-tailed Student's t test. Variables
compared include luminal, intimal, medial, and EEL areas and intimal,
medial, and adventitial BrdU labeling indexes after injury. Results are
expressed as the mean of means±SEM, and n=5 unless otherwise
stated.
Statistical significance was assumed for P<.05. Statistics
were performed with STATVIEW software for the Macintosh
(Abacus Concepts, Inc).
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Results |
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Iliac Artery Atherosclerosis in Cynomolgus Monkeys
The common iliac artery was selected for angioplasty because of its predilection for atherosclerosis with right to left uniformity within animals. A retrospective review of iliac lesion morphometry in 109 male and 203 female atherosclerotic cynomolgus monkeys showed right to left correlations in lesion size of r=.98 and r=.97, respectively. Similar correlations were found for lumen areas in the same animals with r=.90 and r=.87 for males and females, respectively. This relationship held true in the present study, in which a comparison of intimal area in right and left iliac arteries from animals 4 and 7 days after unilateral iliac angioplasty (before neointimal ingrowth) demonstrated a correlation of r=.98 (n=9). This symmetry in iliac artery caliber and lesion size allowed for paired comparisons within individual monkeys.
Plasma Lipids and Primary
Atherosclerosis
The atherogenic diet resulted in a mean total plasma
cholesterol of 12±1 mmol/L (470.03±22.58 mg/dL) and a
mean plasma lipoprotein(a) of 31.12±3.80 mg/dL (range, 0.50 to 55.25
mg/dL). Atherosclerosis in uninjured right iliac
arteries (n=20) resulted in an average intimal area of 0.62±0.12
mm2. Plaque occupied a mean of 19.8±3.2% of IEL area,
with a mean ratio of intimal to medial area of 113.4±22.9%. Uninjured
plaques were composed primarily of SMCs, macrophages, and
extracellular matrix beneath an endothelial cell
monolayer (Fig 1
). Plaques were frequently complicated
by regions of calcification and necrosis and by microvascular ingrowth
of "plaque vasa" (Fig 1).
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Short-term Structural Changes After Angioplasty
After
angioplasty one animal died of cardiac complications, and
one injured iliac artery thrombosed and was excluded from paired
analysis (Fig 2A). Mural thrombus was minimal in
patent injured arteries 4 and 7 days after angioplasty and absent at
later times. Acute plaque fracture and dissection were common, and the
IEL and underlying media were often fractured as well (Fig 2).
The EEL
remained intact in nearly all sections. These injuries transiently
increased lumen and EEL areas at 4 days compared with contralateral
uninjured control iliac arteries, but artery size (EEL area) and lumen
area returned to baseline by 7 days (Fig 3). This loss
of the short-term gain in lumen caliber suggests that delayed
contraction of the artery wall occurred between 4 and 7 days, since
neointimal ingrowth was not measurable until 14 days after
angioplasty (Fig 3). At 14 days, fractures and dissections had
begun to
heal and fill in with a new layer of intimal tissue (Fig 2C).
New
intimal growth was typical in appearance for neointima,
composed mostly of SMCs and extracellular matrix beneath a regenerating
endothelium. The neointima thickened
markedly between 14 and 28 days, increasing total intimal area by
3.5 times that of uninjured controls (Figs 2D and
3).
Neointima was histologically distinct from
the underlying preexisting atherosclerosis, with few
macrophages or vasa, no calcification, and a more
homogeneous extracellular matrix than the underlying plaque
(Fig 2D). Matrix in the neointima stained pale with
Verhoeff–van Gieson's stain, suggesting a proteoglycan-rich
composition with little collagen in comparison with the media and
adventitia.
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.05).
Mean artery size (EEL area) increased moderately by 28 days
after
angioplasty (150.2±28.9% of control). This increase in artery size
accompanied a large relative increase in neointimal area,
and the net result was a maintenance of the average lumen area
(119.3±21.3% of control, Fig 3
). At 28 days one half of
injured
arteries maintained lumen areas greater than uninjured controls, and
one half had smaller lumen areas. Interestingly, the apparent
compensatory enlargement or remodeling was often greatest in arteries
with the greatest accumulation of neointima (Fig 4).
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Cell Proliferation After Angioplasty
Intimal thickening was
preceded by a distinct wave of cellular
proliferation throughout the artery wall at 4 and 7 days after
angioplasty (Fig 5). BrdU labeling increased in the
adventitia, media, and atherosclerotic plaque at 4 days after
angioplasty. Labeling decreased slightly by 7 days and returned to
control levels at 14 and 28 days after angioplasty (Fig 5).
Surprisingly, proliferation in the new intimal tissue at 14 and 28 days
was minimal and largely confined to the luminal
endothelium and immediately subjacent SMCs.
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Immunohistochemistry
combining the anti-BrdU antibody with cell
type–specific antibodies identified the majority of proliferating
cells in the injured media as -actin–positive SMCs (Fig
6). Uninjured atherosclerotic plaques had fairly high
rates of BrdU labeling, largely colocalized to CD68-positive
macrophages (Fig 1). At 4 and 7 days after angioplasty, roughly
half of the identifiable BrdU-labeled intimal plaque cells (those also
staining with -actin, CD68, or vWF antibodies) were CD68
positive. Excluding microvessels, more than one half of the
BrdU-labeled cells in the adventitia were negative for the three
cell-specific antibodies. A number of BrdU-labeled cells in the
adventitia were identified as macrophages or microvascular
endothelial cells but rarely as SMCs. -Actin
staining was occasionally seen in the adventitia at 7 and 14 days
after injury, usually overlying regions of medial fracture, and these
cells were occasionally BrdU positive. This was not a
consistent finding and appeared to be transient, since the
adventitia at 28 days was largely -actin negative.
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Although the
majority of cells in the media and in
neointima were -actin positive, many cells in the
preexisting atherosclerotic plaque and adventitia did not stain with
the three cell type–specific antibodies. Also, after injury,
plaque or luminal endothelial cells could not be
reliably localized with an antibody to vWF because of the vWF in the
mural thrombus and artery wall after angioplasty (data not shown). The
likely presence of other cell types, such as fibroblasts and
lymphocytes, and difficulty optimizing staining conditions for the cell
type–specific antibodies combined with the anti-BrdU antibody in
formalin-fixed tissues (anti-CD68, anti-vWF, and anti-BrdU
antibodies each require different protease digestions for antigen
retrieval) precluded accurate quantification of double-labeled cell
populations.
Baseline proliferation was relatively high in the
adventitia and
intimal macrophages of uninjured control iliac arteries (Figs 1
and 5). To determine whether this was related to the proximity
of the
uninjured to injured iliac artery, we stained coronary artery
cross sections from 5 animals in the 28-day group to determine baseline
proliferation rates. Coronary arteries also demonstrated high
rates of BrdU labeling in the atheroma (5.20±2.38%) and
adventitia (8.60±3.67%). In the atheroma, BrdU labeling
largely colocalized with macrophages staining for the CD68
antibody.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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Animal models of arterial injury, and particularly nonatherosclerotic models, have recently come under scrutiny because of their failure to predict effective strategies for prevention of restenosis in human beings.3 4 An increasing number of clinical trials using drugs effective in animals have produced negative results.5 8 20 The reasons for the discrepancies between clinical and experimental results are unclear. There may be significant species differences in the regulation of cellular proliferation and migration after arterial injury. Also, the failure to study the response of atherosclerotic vessels may produce differing results. Furthermore, the extent of intimal hyperplasia induced by arterial injury, the end point measured in most experimental models, may actually be only one of a number of determinants of restenosis in human beings.10 11 21 These issues indicate the potential value of an animal model that more closely mimics the injury response of atherosclerotic human arteries.
The data presented here represent the first description of the early time course of structural and proliferative events in response to arterial balloon catheter injury in a relevant primate model of atherosclerosis. This model of the injury response appears to share many morphological characteristics with the response observed in human patients.22 23 24 25 These include an acute stretching of the artery wall, plaque fracture, dissection, and occasionally medial fracture or delamination. A thin mural thrombus often formed on the injured luminal surface, but acute thrombotic occlusion was uncommon. Subsequent changes included a loss of the short-term gain in lumen caliber, probably due to artery wall contraction, and later neointimal hyperplasia. In some cases, the short-term gain in lumen caliber persisted. This appeared to be the result of a concomitant increase in arterial diameter that suggested a remodeling process.
In addition, the data contribute new information regarding cellular proliferation as it relates to the sequence of structural changes in the artery wall after injury. For example, the artery and lumen increased in size immediately after injury. This response was transitory and no longer evident at day 7. This loss of the short-term gain in lumen caliber occurred at a time when cellular proliferation was maximal but before any increase in intimal area. Thus, it appears that there was a delayed constriction of the artery wall that may indicate a return of contractile function to the media and intima after angioplasty. The timing of this contraction is consistent with a report by Jamal et al,26 who showed that contractile function in the injured rabbit carotid artery returned between 2 and 7 days after balloon denudation. This could also represent an endothelial cell–mediated response to a decrease in shear stress caused by the increased lumen caliber after angioplasty. This seems unlikely, however, given our observation of mural thrombus at 7 days after angioplasty, suggesting a lack of complete reendothelialization.
Our data also indicate that, although cellular proliferation had largely subsided by day 14, the bulk of new lesion growth occurred later, between 14 and 28 days. This suggests that migration and extracellular matrix deposition were key factors in the neointimal formation between 14 and 28 days after injury. We have begun to characterize extracellular matrix expression in the neointima using immunohistochemistry and in situ hybridization and found increased hyaluronan, chondroitin-6-sulfate, and type I procollagen in the forming neointima at 14 and 28 days after angioplasty (R.L.G., unpublished results, 1995). Furthermore, we identified a surprisingly high rate of proliferation in the uninjured atherosclerotic plaque and adventitia. Of particular interest was the finding that the increase in intimal mitotic activity was primarily due to plaque macrophages. It is intriguing to speculate on whether macrophages were labeled while proliferating in the plaque or whether these cells were trafficking into the lesion after being labeled in the reticuloendothelial system.
While SMC proliferation may be an initial step in the arterial response to injury, the importance of this process to the continued loss of the short-term gain in lumen caliber remains unclear. Differences among species in the control of SMC proliferation and migration has recently been suggested by work in nonhuman primates. Low-molecular-weight heparin and the angiotensin-converting enzyme inhibitor cilazapril both decreased proliferation and inhibited lesion formation in the well-characterized rat carotid balloon injury model.3 4 Conversely, both were ineffective at inhibiting intimal hyperplasia in nonatherosclerotic baboons9 27 and preventing restenosis in human clinical trials.5 6 7 8 20 These data suggest, at least in rats and baboons, that growth-regulatory programs after arterial injury may vary among species and that nonhuman primate models may better predict human responses.
Other studies have recently challenged the role of SMC proliferation in restenosis. O'Brien et al10 reported very low rates of proliferation in human coronary restenosis specimens retrieved between 1 and 390 days after angioplasty or atherectomy, as measured by immunohistochemical labeling of PCNA. At first glance, this report appears to be at odds with our findings of high proliferative indexes during the first week after angioplasty in atherosclerotic monkeys. At later times, however, our data are very similar in that the wave of proliferation subsides in the monkey model after day 7. It may be that in the O'Brien et al study, too few specimens were retrieved within the first week after angioplasty to accurately detect a brief but significant wave of proliferation. Of the four specimens retrieved within 6 days of an angioplasty, three had PCNA-labeled nuclei. Another consideration is that lesions requiring reintervention for "restenosis" at such an early interval after the initial procedure probably differ from those that develop restenosis after a successful angioplasty.
The issue of proliferation is further complicated by the study of Pickering et al,28 who reported rates of proliferation between 15% and 20% using PCNA analysis in restenosis specimens retrieved by atherectomy from peripheral and coronary arteries. These patients were all beyond the first month of their procedure, at a time when our data and those of O'Brien et al10 suggest that proliferation would be low. The use of PCNA may account for some of the variability between these studies, because it is less cell-cycle specific than BrdU, and thresholding for positive cells can vary. Further analysis of the rare human lesions removed within the first few days of a successful angioplasty may help to settle these discrepancies.
Intimal hyperplasia is seen after virtually all forms of arterial injury. This observation has led to the view that the degree of intimal thickening determines the degree of lumen encroachment. It should also be considered that intimal thickening is probably only one of many determinants of restenosis. In atherosclerosis and perhaps restenosis, when lesions grow in size there is a compensatory enlargement or "remodeling" of the artery that also results, at least initially, in increased lumen diameter.16 29 30 It seems possible, if not likely, that interrelationships between lesion growth and artery remodeling may determine the ultimate response to injury and that this process is very different in atherosclerotic and nonatherosclerotic vessels. Furthermore, the balance between neointimal growth and arterial remodeling may be tipped in either direction by inherent genetic characteristics of the individual,31 32 characteristics of the underlying atherosclerotic lesion,24 33 34 local hemodynamic forces,30 or some combination of these and other factors to ultimately determine whether restenosis occurs.
Although this model appears to depict many aspects of the human response to angioplasty, there are important differences and some limitations. Stenosis due to atherosclerosis is unpredictable in the monkey model, and the number of animals required to screen for stenosis is unfeasible for studies of this size.16 Therefore, we are studying loss of the short-term gain in lumen caliber after angioplasty, which is the mechanism of restenosis in human beings, but we are not truly studying restenosis per se. It is encouraging, however, that just as one half of human patients develop restenosis after coronary angioplasty, only one half of the animals in the present study maintained the short-term gain in lumen caliber after 28 days (ie, a successful angioplasty). Another potential limitation of this model relates to the use of a Fogarty balloon catheter rather than a Gruentzig-type angioplasty catheter. In a pilot study, the degree of injury caused by the Gruentzig catheter was unpredictable in the atherosclerotic cynomolgus carotid artery. This may relate to difficulty in determining an optimal target diameter that will reproducibly injure plaques that vary in complexity and extent. Our goal was to develop a model of a significant and reproducible injury, and this was achieved with the three-pass Fogarty technique. Similarities between our morphological observations and human lesion morphology immediately after angioplasty25 and at later times35 indicate the potential relevance of the type of injury and its extent in a subset of patients or lesions after percutaneous transluminal coronary angioplasty in humans. The longitudinal traction induced by the balloon withdrawal does differ from the stationary Gruentzig injury, but how this difference may alter the injury response, if at all, is not known.
Although the critical pathophysiological events remain to be identified, the data presented here indicate a remarkable similarity between human and nonhuman primate responses to arterial injury and additionally the potential usefulness of this model of atherosclerosis in the study of the restenosis process.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported in part by grant PO1-HL-45666 from the National Institutes of Health. The authors would like to thank Karla Essick for assistance in preparing the manuscript and Davis and Geck for the generous gift of the vascular suture.
Received June 19, 1995; accepted October 24, 1995.
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TopAbstractIntroductionMethods Results Discussion References |
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