Cardiovascular Research 1998 39(1):50-59; doi:10.1016/S0008-6363(98)00109-6
© 1998 by European Society of Cardiology
Copyright © 1998, European Society of Cardiology
Why do animal models of post-angioplasty restenosis sometimes poorly predict the outcome of clinical trials?
Antoine Lafonta,* and
David Faxonb
aDepartment of Cardiology, University René Descartes, Boucicaut Hospital, 78 rue de la Convention, 75015 Paris, France
bDivision of Cardiology, University of South California, Los Angeles, California, USA
* Corresponding author. Tel.: 33609664209; E-mail: antoine.lafont@bcc.ap-hop-paris.fr
Received 10 February 1998; accepted 13 March 1998
The 20th anniversary of percutaneous transluminal coronary angioplasty (PTCA), first introduced by Andreas Gruentzig MD, was recently celebrated. Since its introduction, millions of people have been successfully treated by PTCA. Despite its overwhelming success, 30 to 50% of patients develop restenosis, a rate that has changed little since the introduction of the technique. After 20 years of dramatic technical refinement and intensive research, we still do not know why a dilated artery will maintain patency and not develop restenosis or will develop restenosis. The lack of understanding about restenosis has often been attributed to inappropriate experimental models, incomplete or incorrect analysis of the models that has led to a focus on the wrong pathophysiologic target [1–4]. In the review, we will describe the various animal models used to study restenosis, and clarify the limitations and advantages of each in order to better delineate the ideal model of experimental angioplasty and restenosis. While outstanding reviews have already been written on this subject within the last five years [5–8], this review will be different from the former ones because it will take into account the following major changes: Stent-related restenosis, which is different from balloon-related restenosis, and arterial remodeling [9–12]. Arterial remodeling has transformed our understanding of restenosis and is of great clinical relevance, as shown by the good concordance between experimental data and human data obtained by intravascular ultrasound [13–19].
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1 Experimental models
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Before angioplasty started, balloon abrasion with endothelial
denudation represented the gold standard for studying the response
to vascular injury and smooth muscle cell proliferation and
migration
[20–25]. The idea of balloon angioplasty seemed
to be a questionable method, and the occurrence of restenosis
was not a surprise. Thus, experimental models of restenosis
preexisted the clinical recognition of restenosis after angioplasty.
All experimental models of restenosis require a living animal in which an artery has been injured by a balloon catheter or some other means. The differences between each model concern mainly the animal species, the size of the artery lumen, the presence or absence of atherosclerosis, the extent of thrombogenicity of the model and the degree of the balloon injury. The most commonly used animal models include the rat, rabbit and swine.
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2 The rat model
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This is the first model used since it was developed to study
the response to injury and atherosclerosis and, therefore, preceded
the development of angioplasty. The lesion is created by abrasion
of the internal carotid artery by a Fogarty balloon being surgically
introduced via the external carotid artery
[22, 26]. The resulting
lesion is usually evaluated by histology two weeks after angioplasty
and is characterized by a pure neointimal hyperplasia with smooth
muscle proliferation and matrix deposition (
Fig. 1). A lighter
injury, limited to the endothelium, by a nylon filament results
in a mild proliferative response
[20, 27]. The rat model represents
the easiest model to use, because it is very cheap, lesions
develop rapidly, and it requires minimal equipment and does
not require a catheterization laboratory. It was used initially
as an atherosclerotic model to study smooth muscle cell proliferation
and migration and extensive literature exists concerning these
events
[21, 23, 28–35]. In the setting of angioplasty,
the model was used to test the efficacy of strategies targeting
smooth muscle cell proliferation
[35–41]. The disadvantages
of this model are the following: It utilizes a normal artery,
and the balloon injury does not reflect the angioplasty procedure,
since the latex Fogarty balloon significantly overstretches
a normal artery at low pressure, whereas the PVC balloon angioplasty
catheter maintains a balloon-to-artery ratio of 1.2:1. The histology
of the lesion is unlike human atherosclerosis as it lacks several
features of the human atherosclerotic lesion, such as calcification
and calcium deposits, and it is unlike human restenosis since
it occurs in a normal artery.
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3 The rabbit model
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This model, unlike the rat model, is usually a double injury
model. The first injury serves to develop an atherosclerotic
lesion that will undergo a second injury i.e., the angioplasty.
The first lesion often, but not always, is developed by use
of a high cholesterol diet (classically 6% peanut oil and 2%
cholesterol). The initial injury is usually developed in two
possible ways, either balloon abrasion or air-desiccation
[42–45].
The advantage of air-desiccation is that it clearly provides
a well defined focal lesion site
[13, 42]. Three to six weeks
after lesion induction, an angioplasty is performed under angiographic
control. Four weeks after angioplasty, an angiogram is performed
immediately before sacrifice and histologic evaluation. The
features of the lesion are characterized by smooth muscle proliferation,
extracellular matrix accumulation and inflammation with an abundant
presence of foam cells (
Fig. 2). The acute histological findings
after angioplasty are characterized by dissection of the artery
as well as the presence of thrombus. Thus, the rabbit model
mimics relatively well the angioplasty process occurring in
humans, and it can be used to study new experimental procedure-,
device- or drugs-related strategies
[43, 46–68]. It also
can be used to evaluate mechanisms of restenosis, extracellular
matrix formation and inflammation occurring after angioplasty
[13–19, 69–73]. While the model is closer to the
human situation, caution must be taken because of significant
differences from human restenosis. The major criticism has been
the abundant presence of foam cells, although they are also
present to a lesser degree in humans. Finally, a less frequently
used rabbit model is the ear artery injury model: This model
offers the main advantage of being very easy to perform
[74].
Ear artery has been used for arterial gene transfer
[75]. Typically,
it consists of a lesion induced either by air-desiccation or
crushing the artery, which is performed without any surgical
or x-ray means (
Fig. 3). The lesion is mainly based on neointimal
hyperplasia
[74]. The artery is of easy access. However, the
size of the artery lumen (1 mm) renders the model less accessible
for angioplasty.
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Fig. 3 Photomicrograph of an atherosclerotic ear artery from a rabbit. Adenovirus-mediated lacZ gene transfer β-galactosidase expression is seen in endothelial cells (blue color), but not in the neointima (N), performed four weeks after lesion induction.
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4 The pig model
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Unlike the rabbit model, this model usually is a single injury
model
[8]. The injury is performed either in the carotid artery
or in the coronary artery
[76, 77]. Most commonly, the lesion
is induced by overstretching the artery via a balloon catheter,
which is sometimes pulled back to increase the injury. The balloon
artery ratio classically is greater than 1.4. This degree of
stretch injury is necessary in order to fracture the external
elastic lamina in order to induce a sufficient degree of neointimal
hyperplasia (
Fig. 4). The degree of tearing of the external
elastic membrane correlates with the degree of intimal hyperplasia
[78]. An injury score has been proposed, which correlates with
neointimal hyperplasia and allows for more reliable comparisons
between animal groups
[78]. It is important to note that the
degree of stretch injury that is used in these models does not
reflect what is used in angioplasty procedures in humans
[79].
In some cases, the lesion is induced by stent placement in the
carotid or the coronary artery. The stent is also overexpanded,
which results in a severe stenosis during follow-up. In contrast
with rabbits, the pigs are usually not placed on a high cholesterol
diet, due to cost and the time required to induce lesion formation
[80]. Although the model has been described
[82–85], the
lesion that forms following the overstretch coronary balloon
angioplasty is mainly a neointima with smooth muscle cell proliferation
without foam cells
[77–86]. There is usually partial or
occlusive thrombus formation. The pig model is characterized
by a higher thrombogenicity than the other models
[87–89].
This can be explained by a lower circulating plasminogen level
[89]. Like the rat and the rabbit models, the pig has been mainly
used for evaluation of strategies that inhibit smooth muscle
proliferation
[8, 76, 89–100]. Unlike all other models,
the pig model utilizes the coronary vessels, thus allowing optimal
evaluation of the angioplasty procedure and the evaluation of
new coronary devices
[97–100].
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Fig. 4 Photomicrograph of a pig coronary artery. The lesion was induced by the use of balloon thermal injury (80°C for 30 s). Reproduced by courtesy of Dr Gregoire et al. from "Arterial remodeling a critical factor for restenosis". Lafont and Topol, editors, Dordrecht: Kluwer, 1997, p 172.
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5 The dog model
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As carnivores, dogs do not easily develop atherosclerotic lesions.
The reaction to acute injury (angioplasty) or chronic injury
(stent) does result in a mild neointimal reaction. However,
plasminogen levels are higher than in humans
[89]. This model
has been used mainly to test interventional cardiology devices,
such as lasers and stents, because coronary artery anatomy is
similar to human coronary anatomy
[101–103]. Another dog
model involves the placement of a ligature around the LAD, to
induce cyclic flow variations, followed by balloon injury distal
to the ligature
[104]. Restenotic-like lesions have been shown
to develop. However, given the difficulty in creating lesions,
this model is infrequently used.
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6 The nonhuman primate model
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The nonhuman primates (chimpanzee, baboon, rhesus macacus, cynomologus
monkey) most closely mimic the human given their close relationship
to the human species. In order to induce atherosclerosis, animals
are usually placed on a high cholesterol diet
[25]. Lesion development
can be assessed by noninvasive techniques such as MRI or IVUS.
Lesion development usually takes many months or years
[105, 106].
The histology of the lesions is the closest to human atherosclerotic
lesions (
Fig. 5)
[107]. However, the cost, the long period of
lesion induction, and the difficulty in handling these species
makes this model unrealistic for standard use in the evaluation
of mechanisms or preventive strategies of restenosis.
6.1 Interpretation of experimental studies
Restenosis after angioplasty has been classically attributed
to neointimal formation due to smooth muscle cell proliferation
and matrix secretion
[4, 5, 7, 108]. Experimental models were
designed to produce neointimal hyperplasia in order to test
treatments against smooth muscle proliferation
[3, 42, 77].
However, there has been a major discrepancy between the overall
success of many interventions in these models and their failure
in clinical trials
[109–124]. Animal models have been
considered responsible for this failure. We will analyze the
causes of the apparent failure of these models to lead to a
treatment for the prevention of restenosis in humans.
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7 Are the models wrong?
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It is important to question the validity of the animal models.
Are these models not appropriate? Differences in species represent
an issue that must not be underestimated. The rat model is not
considered to be representative of the angioplasty procedure,
and rat and human species are very different. On the other hand,
the nonhuman primate appears to be nearly ideal, although it
does not involve the coronary vessels. The size of the vessel
is also an important issue. The normal rat carotid artery is
much smaller in size and is structurally different from the
human coronary artery. As Muller et al.
[5]pointed out, the
response to injury will be different in a muscular or elastic
artery. With regard to the size and structure, the rabbit iliac
artery comes closer to the human coronary artery. There has
also been a misunderstanding between the severe stretching injury
induced by angioplasty on the artery wall, and the mild denudation
injury necessary for lesion induction to obtain an atherosclerotic
lesion. The lack of an atherosclerotic lesion prior to angioplasty
is also an important issue with respect to the similarity to
man, in which normal arteries are usually not subjected to angioplasty.
While it is important to recognize these limitations and differences
between the animal models and the human situation, the models
can appropriately provide answers to specific questions. For
instance, if it is important to determine the mechanism of a
drug on smooth muscle cell proliferation, then a number of animal
models will be capable of answering this question
[51, 77, 86, 125].
The results however should not be interpreted to mean that the
drug is also able to inhibit restenosis in man. The extrapolation
of animal studies directly to man is unreasonable given the
vast differences between animal models and man and the complexity
of the restenotic process.
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8 Were the analysis or the endpoints wrong?
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The methods used in analyzing data from the restenotic models
is critical in order to evaluate first the appropriateness of
the model and, second, the validity of the data. In order to
determine if restenosis has occurred, it is customary to compare
the lumen of the dilated area to a reference lumen. While this
is the clinical method for defining restenosis, it is surprising
to see (in numerous studies) that it is often not reported.
The second parameter that is used to define the degree of restenosis
is the area of the neointima. While this is frequently reported
instead of changes in lumen diameter, it is not a good reflection
of restenosis. The explanation for this is the importance given
to neointimal hyperplasia as the major mechanism for restenosis.
Neointimal thickness is frequently measured to evaluate neointimal
hyperplasia, although it represents both cellular content and
matrix deposition. It also can be affected by tissue fixation.
The third parameter that is measured to assess restenosis is
the area circumscribed by the external elastic lamina. This
parameter evaluates the ability of the artery to undergo positive
or negative remodeling. Since the importance of remodeling was
not appreciated prior to 1993, much of the experimental data
evaluating various treatments to prevent restenosis failed to
take remodeling into account.
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9 Discrepancy between animal studies and clinical trials
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The discrepancy between positive results in experimental models
and overall failure to reproduce these results in humans has
been partly explained by the following points: Inadequate dose
of drugs, inadequate statistical power, poorly defined endpoints
and a focus on less important therapeutic targets.
Currier and Faxon [1]have pointed out the worrisome discrepancy between the drug dosages used in animals and in humans, with the ratio between animal and human studies being two- to 40 times greater. The time when the drug was delivered is also of importance, having a substantially greater effect if pretreatment is given.
Too small a number of patients have been included in most of the clinical trials; this might also be the reason for the lack of statistical significance. This methodological issue was already raised by Muller et al. [5]five years ago and continues to be a significant problem.
Another methodological issue is the difference of endpoints: In animal models, endpoints are mainly the neointimal hyperplasia and lumen areas, whereas angiographic lumen loss or target vessel revascularization have been the clinical endpoints. Recently, with the emergence of intracoronary ultrasound, changes in neointimal thickness and remodeling are now measurable in man as well [18].
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10 Misunderstanding of the targets
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On the basis of animal studies and human pathological studies,
the main hypothesis for the mechanism of restenosis was attributed
to intimal hyperplasia. Smooth muscle proliferation was considered
to play a major role in restenosis because it was established
to occur in experimental models as well as in humans. A link
was made between restenosis and neointimal growth, despite the
lack of a proven correlation between the degree of neointimal
thickening and restenosis. Neointimal development was considered
to be a tumor reducing the lumen because the artery was considered
to be a "rigid tube" that could not expand or shrink, independently
of the arterial growth. It is clear that neointimal growth occurring
in a "rigid tube" will irrevocably turn into lumen narrowing.
Waller et al.
[126]detected the absence of intimal hyperplasia
in a number of patients who developed restenosis clinically,
from a small series of twenty patients who came to necropsy.
The lack of evaluation of the area circumscribed by the external
elastic lamina, a measure of remodeling, led to a focus on intimal
hyperplasia and smooth muscle proliferation, the wrong target,
and helps to explain why experimental models were apparently
unable to predict the ability of drugs to inhibit restenosis.
10.1 Arterial remodeling after balloon angioplasty
When it became apparent that arteries could undergo remodeling, measurement of the histomorphometric parameters of the external or internal elastic lamina were used. In all of the models except the rat model, restenosis was found not to be primarily related to neointimal hyperplasia, but to constrictive remodeling and/or a lack of enlargement [12–17, 107]. The greatest advance in our understanding of restenosis has been the understanding of the role of remodeling and the potential new targets to prevent this problem. Conversely, the rigid tube model applies perfectly to in-stent restenosis [127]. The irony has been to focus on neointimal hyperplasia during the era of balloon angioplasty and to discover the role of the remodeling in restenosis at the time of the stent era, since stenting reduces restenosis by inhibiting constrictive remodeling, as shown by the STRESS/BENESTENT trials [10, 11]. While stenting can prevent unfavorable remodeling, it leads to excessive intimal hyperplasia, as shown in the porcine model. The stented vessel in which neointimal hyperplasia occurs inside the stent will behave as a rigid tube, as originally conceived. There is no possibility of enlargement. In a sense, this simplifies restenosis by limiting the process only to intimal hyperplasia and thrombosis. An important consequence of in-stent restenosis is the need for applicable models for this new cause of restenosis, distinct from balloon-related restenosis. The swine stent model proposed by Schwartz et al. [77]five years ago is currently the best model for studying stent restenosis; however, it is probably not ideal. The atherosclerotic rabbit model could offer an interesting complement.
10.2 Perspectives
We have learned a lot from our experimental models about restenosis. We have identified two major forms of restenosis that appear to be independent; balloon related- and in-stent restenosis. Balloon-related restenosis is largely due to unfavorable arterial remodeling. In the future, we need to define new targets to prevent constrictive remodeling and promote positive remodeling. Preliminary work has already been done. Antioxidants have been shown to reduce restenosis in various models, such as the atherosclerotic rabbit and the porcine models [52, 62, 96]. Experimental data suggest that their prevention of restenosis is due to an effect on remodeling. This finding led to the success in reducing restenosis in humans by probucol. In the Multivitamin Probucol Trial, late loss was reduced by 50% and this favorable action was demonstrated to be related to favorable remodeling and to be independent of neointimal hyperplasia, via intracoronary ultrasound [128, 129]. These results should encourage further research into new targets with the help of experimental models. Stent-related restenosis is paradoxically well characterized, but solutions to prevent or reduce it are not yet established. The current focus is more towards local drug delivery than the new treatment options. Development of gene therapy, local irradiation or coated stents might help to overcome the double problem of a healing process and a foreign body [33, 34, 130–134]. Bauters et al.[135]have shown that the human homozygote phenotype DD was clearly related to a higher risk of in-stent restenosis. Further work with transgenic models might also help to detect populations at risk of an intense reaction of smooth muscle cell proliferation [125, 136].
Time for primary review 22 days.
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References
|
|---|
- Currier J.W, Faxon D.P. Restenosis after percutaneous transluminal coronary angioplasty: have we been aiming at the wrong target? J Am Coll Cardiol (1995) 25:516–520.[Abstract]
- Lafont A, Guérot C, Lemarchand P. Which gene for which restenosis? Lancet (1995) 346:1442–1443.[CrossRef][ISI][Medline]
- Ferrell M, Fuster V, Gold H.K, Chesebro J.H. A dilemma for the 1990s. Choosing appropriate experimental animal model for the prevention of restenosis. Circulation (1992) 85:1630–1631.[Free Full Text]
- Liu M.W, Roubin G.S, King S.B. Restenosis after coronary angioplasty: potential biologic determinants and role of intimal hyperplasia. Circulation (1989) 79:1374–1387.[Abstract/Free Full Text]
- Muller D, Ellis S, Topol E. Experimental models of coronary artery restenosis. J Am Coll Cardiol (1992) 19:418–432.[Abstract]
- Bauters C, Meurice T, Hamon M, et al. Mechanisms and prevention of restenosis: from experimental models to clinical practice. Cardiovasc Res (1996) 31:835–846.[Free Full Text]
- Schwartz R. Animal models of human coronary restenosis. In Topol E, editor. Coronary and peripheral angioplasty. Saunders: 1994:365–381.
- Schwartz R, Huber K, Murphy J, et al. Restenosis and the proportional neointimal response to coronary artery injury: Results in a porcine model. J Am Coll Cardiol (1992) 19:267–274.[Abstract]
- Santoian E.C, King S.B 3rd. Intravascular stents, intimal proliferation and restenosis. J Am Coll Cardiol (1992) 19:877–879.[ISI][Medline]
- Serruys P.W, Macaya C, De Jaegere P, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med (1994) 331:489–495.[Abstract/Free Full Text]
- Fischman D.L, Leon M.B, Baim D.S, et al. A randomized comparison of coronary stent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med (1994) 331:496–501.[Abstract/Free Full Text]
- Post M.J, de Smet B.J, van der Helm Y, Borst C, Kuntz R.E. Arterial remodeling after balloon angioplasty or stenting in an atherosclerotic experimental model. Circulation (1997) 96:996–1003.[Abstract/Free Full Text]
- Lafont A, Guzman L.A, Whitlow P.L, et al. Restenosis after experimental angioplasty. Intimal, medial, and adventitial changes associated with constrictive remodeling. Circ Res (1995) 76:996–1002.[Abstract/Free Full Text]
- Kakuta T, Currier J.W, Haudenschild C.C, Ryan T.J, Faxon D.P. Differences in compensatory vessel enlargement, not intimal formation, account for restenosis after angioplasty in the hypercholesterolemic rabbit model. Circulation (1994) 89:2809–2815.[Abstract/Free Full Text]
- Post M.J, Borst C, Pasterkamp G, Haudenschild C.C. Arterial remodeling in atherosclerosis and restenosis: a vague concept of a distinct phenomenon. Atherosclerosis (1995) 118:S115–S123.[ISI][Medline]
- Guzman LA, Mick MJ, Arnold AM, Forudi F, Whitlow PL. Role of intimal hyperplasia and arterial remodeling after balloon angioplasty: an experimental study in the atherosclerotic rabbit model. Arterioscler Thromb Vasc Biol 1996;16:479–487.
- Andersen H.G, Maeng M, Thorwest M, Falk E. Remodeling rather than neointimal formation explains luminal narrowing after deep vessel wall injury. Insights from a porcine coronary (re)stenosis model. Circulation (1996) 93:1716–1724.[Abstract/Free Full Text]
- Mintz G.S, Popma J.J, Pichard A.D, et al. Arterial remodeling after coronary angioplasty. A serial intravascular ultrasound study. Circulation (1996) 94:35–43.[Abstract/Free Full Text]
- Mintz G.S, Popma J.J, Hong M.K, et al. Intravascular ultrasound to discern device-specific effects and mechanisms of restenosis. Am J Cardiol (1996) 78:18–22.[CrossRef][ISI][Medline]
- Fishman J.A, Ryan G.B, Karnovsky M.J. Endothelial regeneration in the rat carotid artery and the significance of endothelial denudation in the pathogenesis of myointimal thickening. Lab Invest (1975) 32:339–351.[ISI][Medline]
- Clowes A.W, Karnovsky M.J. Failure of certain antiplatelet drugs to affect myointimal thickening following arterial endothelial injury in the rat. Lab Invest (1977) 36:452–464.[ISI][Medline]
- Clowes A.W, Karnovsky M.J. Suppression by heparin of smooth muscle cell proliferation in injured arteries. Nature (1977) 265:625–626.[CrossRef][Medline]
- Clowes A.W, Reidy M.A, Clowes M.M. Kinetics of cellular proliferation after arterial injury. I. Smooth muscle cell growth in the absence of endothelium. Lab Invest (1983) 49:327–333.[ISI][Medline]
- Nam S.C, Lee W.M, Jarmolych J, Lee K.T, Thomas W.A. Rapid production of advanced atherosclerosis in swine by a combination of endothelial injury and cholesterol feeding. Exp Mol Pathol (1973) 18:369–379.[CrossRef][ISI][Medline]
- Blaton V, Peeters H. The nonhuman primates as models for studying human atherosclerosis: Studies on the chimpanzee, the baboon and the rhesus macacus. Adv Exp Med Biol (1976) 67:33–64.[Medline]
- Fingerle J, Au Y.P.T, Clowes A.W, Reidy M.A. Intimal lesion formation in rat carotid arteries after endothelial denudation in absence of medial injury. Arteriosclerosis (1990) 10:1082–1087.[Abstract/Free Full Text]
- Clowes A.W, Reidy M.A, Clowes M.M. Mechanisms of stenosis after arterial injury. Lab Invest (1983) 49:208–215.[ISI][Medline]
- Clowes A.W, Schwartz S.M. Significance of quiescent smooth muscle migration in the injured rat carotid artery. Circ Res (1985) 56:139–145.[Abstract/Free Full Text]
- Clowes A.W, Clowes M.M, Reidy M.A. Kinetics of cellular proliferation after arterial injury. III. Endothelial and smooth muscle cell growth in chronically denuded vessels. Lab Invest (1986) 54:295–303.[ISI][Medline]
- Ye L, Mora R, Akhayani N, Haudenschild C.C, Liau G. Growth factor and cytokine-regulated hyaluronan-binding protein TSG-6 is localized to the injury-induced rat neointima and confers enhanced growth in vascular smooth muscle cells. Circ Res (1997) 81:289–296.[Abstract/Free Full Text]
- Chen D, Krasinski K, Sylvester A, et al. Downregulation of cyclin-dependent kinase 2 activity and cyclin A promoter activity in vascular smooth muscle cells by p27 (KIP1), an inhibitor of neointima formation in the rat carotid artery. J Clin Invest (1997) 99:2334–2341.[ISI][Medline]
- Mills C.J, Northrup J.L, Hullinger T.G, et al. Temporal expression of c-fos mRNA following balloon injury in the rat common carotid artery. Cardiovasc Res (1996) 32:954–961.[Abstract/Free Full Text]
- Chang M.W, Ohno T, Gordon D, et al. Adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene inhibits vascular smooth muscle cell proliferation and neointima formation following balloon angioplasty of the rat carotid artery. Mol Med (1995) 1:172–181.[ISI][Medline]
- Chang M.W, Barr E, Lu M.M, Barton K, Leiden J.M. Adenovirus-mediated over-expression of the cyclin/cyclin-dependent kinase inhibitor, p21 inhibits vascular smooth muscle cell proliferation and neointima formation in the rat carotid artery model of balloon angioplasty. J Clin Invest (1995) 96:2260–2268.[ISI][Medline]
- Majesky M.W, Schwartz S.M, Clowes M.M, Clowes A.W. Heparin regulates smooth muscle cell S phase entry in the injured rat carotid artery. Circ Res (1987) 61:296–300.[Abstract/Free Full Text]
- Ferns G.A, Raines E.W, Sprugel K.H, et al. Inhibition of neointimal smooth muscle accumulation after angioplasty by an antibody to PDGF. Science (1991) 253:1129–1132.[Abstract/Free Full Text]
- Reidy M.A, Silver M. Endothelial regeneration. VII. Lack of intimal proliferation after defined injury to rat aorta. Am J Pathol (1985) 118:173–177.[Abstract]
- Powell J, Clozel J, Muller R, et al. Inhibitors of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury. Science (1989) 245:186–188.[Abstract/Free Full Text]
- Wengrovitz M, Selassie L.G, Gifford R.R.M, Thiele B.L. Cyclosporin inhibits the development of medial thickening after experimental arterial thickening. J Vasc Surg (1990) 12:1–7.[CrossRef][ISI][Medline]
- Tiell M.L, Sussman I.I, Gordon P.B, Sanders R.N. Suppression of fibroblast proliferation in vitro and of neointimal hyperplasia in vivo by the triazolopyrimidine, trapidil. Artery (1983) 12:33–50.[ISI][Medline]
- Lundergan C, Foegh M.L, Vargas R, et al. Inhibition of myointimal proliferation of the rat carotid artery by the peptides, angiopeptin and BIM 23034. Atherosclerosis (1989) 80:49–55.[CrossRef][ISI][Medline]
- Sarembock I.J, LaVeau P.J, Sigal S.L, et al. Influence of inflation pressure and balloon size on the development of intimal hyperplasia after balloon angioplasty: a study in the atherosclerotic rabbit. Circulation (1989) 80:1029–1040.[Abstract/Free Full Text]
- Wilensky R.L, March K.L, Gradus-Pizlo I, et al. Vascular injury, repair, and restenosis after percutaneous transluminal angioplasty in the atherosclerotic rabbit. Circulation (1995) 92:2995–3005.[Abstract/Free Full Text]
- Faxon D.P, Weber V.J, Haudenschild C, et al. Acute effects of transluminal angioplasty in three models of atherosclerosis. Arteriosclerosis (1982) 2:125–133.[Abstract/Free Full Text]
- Faxon D.P, Sanborn T.A, Weber V.J, et al. Restenosis following transluminal angioplasty in experimental atherosclerosis. Arteriosclerosis (1984) 4:189–195.[Abstract/Free Full Text]
- Sarembock I.J, Gertz S.D, Thome L.M, et al. Effectiveness of hirulog in reducing restenosis after balloon angioplasty of atherosclerotic femoral arteries in rabbits. J Vasc Res (1996) 33:308–314.[ISI][Medline]
- Ragosta M, Gimple L.W, Gertz S.D, et al. Specific factor Xa inhibition reduces restenosis after balloon angioplasty of atherosclerotic femoral arteries in rabbits. Circulation (1994) 89:1262–1271.[Abstract/Free Full Text]
- Lichtenstein A.H, Chobanian A.V. Effect of fish oil on atherogenesis in Watanabe heritable hyperlipidemic rabbit. Arteriosclerosis (1990) 10:597–606.[Abstract/Free Full Text]
- Ragosta M, Barry W.L, Gimple L.W, et al. Effect of thrombin inhibition with desulfatohirudin on early kinetics of cellular proliferation after balloon angioplasty in atherosclerotic rabbits. Circulation (1996) 93:1194–1200.[Abstract/Free Full Text]
- Fukuyama J, Ichikawa K, Hamano S, Shibata N. Tranilast suppresses the vascular intimal hyperplasia after balloon injury in rabbits fed on a high-cholesterol diet. Eur J Pharmacol (1996) 318:327–332.[CrossRef][ISI][Medline]
- Hanke H, Strohschneider T, Oberhoff M, Betz E, Karsch K.R. Time course of smooth muscle cell proliferation in the intima and media of arteries following experimental angioplasty. Circ Res (1990) 67:651–659.[Abstract/Free Full Text]
- Schneider J.E, Berk B.C, Gravanis M.B, et al. Probucol decreases neointimal formation in a swine model of coronary artery balloon injury. A possible role for antioxidants in restenosis. Circulation (1993) 88:628–637.[Abstract/Free Full Text]
- Steg P.G, Tahlil O, Aubailly N, et al. Reduction of restenosis after angioplasty in an atheromatous rabbit model by suicide gene therapy. Circulation (1997) 96:408–411.[Abstract/Free Full Text]
- Gellman J, Ezekowitz M.D, Sarembock I.J, et al. Effect of lovastatin on intimal hyperplasia after balloon angioplasty: A study in an atherosclerotic hypercholesterolemic rabbit. J Am Coll Cardiol (1991) 17:251–259.[Abstract]
- Gimple L.W, Gertz S.D, Haber H.L, et al. Effect of chronic subcutaneous or intramural administration of heparin on femoral artery restenosis after balloon angioplasty in hypercholesterolemic rabbits. A quantitative angiographic and histopathological study. Circulation (1992) 86:1536–1546.[Abstract/Free Full Text]
- Lyle E.M, Fujita T, Conner M.W, et al. Effect of inhibitors of factor Xa or platelet adhesion, heparin, and aspirin on platelet deposition in an atherosclerotic rabbit model of angioplasty injury. J Pharmacol Toxicol Methods (1995) 33:53–61.[CrossRef][ISI][Medline]
- Bilazarian S.D, Currier J.W, Haudenschild C.C, et al. Angiotensin converting enzyme inhibition reduces restenosis in experimental angioplasty (abstract). J Am Coll Cardiol (1991) 17:268A.
- McKenney P, Currier J, Haudenschild C, Heyman D, Faxon D. Cyclosporin A does not inhibit restenosis in experimental angioplasty (abstract). Circulation (1991) 84(suppl_II):II–70.
- Liu M.W, Roubin G.S, Robinson K.A, et al. Trapidil in preventing restenosis after balloon angioplasty in the atherosclerotic rabbit. Circulation (1990) 81:1089–1093.[Abstract/Free Full Text]
- Hong M.K, Bhatti T, Matthews B.J, et al. The effect of porous infusion balloon-delivered angiopeptin on myointimal hyperplasia after balloon injury in the rabbit. Circulation (1993) 88:638–648.[Abstract/Free Full Text]
- Faxon D.P, Sanborn T.A, Haudenschild C.C, Ryan T.J. Effect of antiplatelet therapy on restenosis after experimental angioplasty. Am J Cardiol (1984) 53:72C–76C.[CrossRef][Medline]
- Lafont A.M, Chai Y.C, Cornhill J.F, et al. Effect of alpha-tocopherol on restenosis after angioplasty in a model of experimental atherosclerosis. J Clin Invest (1995) 95:1018–1025.[ISI][Medline]
- Gellman J, Healey G, Chen Q, et al. The effect of very low dose irradiation on restenosis following balloon angioplasty. A study in the atherosclerotic rabbit (abstract). Circulation 1991;84(suppl II):II-331.
- Robinson K.A, Roubin G.S, Siegel R.J, et al. Intra-arterial stenting in the atherosclerotic rabbit. Circulation (1988) 78:646–653.[Abstract/Free Full Text]
- Merritt R, Guruge B.L, Miller D.D, Chaitman B.R, Bora P.S. Moderate alcohol feeding attenuates postinjury vascular cell proliferation in rabbit angioplasty model. J Cardiovasc Pharmacol (1997) 30:19–25.[CrossRef][ISI][Medline]
- Anderson H.V, Zaatari G.S, Roubin G.S, Leimgruber P.P, Gruentzig A.R. Steerable fiberoptic catheter delivery of laser energy in atherosclerotic rabbits. Am Heart J (1986) 111:1065–1072.[CrossRef][ISI][Medline]
- Rosenfeldt F.L, Chi L, Black A.J, et al. Excimer laser angioplasty in the atherosclerotic rabbit: comparison with balloon angioplasty. Am Heart J (1992) 124:349–355.[CrossRef][ISI][Medline]
- Jang Y, Guzman L.A, Lincoff A.M, et al. Influence of blockade at specific levels of the coagulation cascade on restenosis in a rabbit atherosclerotic femoral artery injury model. Circulation (1995) 92:3041–3050.[Abstract/Free Full Text]
- Coats W.D Jr., Cheung D.T, Han B, Currier J.W, Faxon D.P. Balloon angioplasty significantly increases collagen content but does not alter collagen subtype I/III ratios in the atherosclerotic rabbit iliac model. J Mol Cell Cardiol (1996) 28:441–446.[CrossRef][ISI][Medline]
- Coats W.D Jr., Whittaker P, Cheung D.T, et al. Collagen content is significantly lower in restenotic versus nonrestenotic vessels after balloon angioplasty in the atherosclerotic rabbit model. Circulation (1997) 95:1293–1300.[Abstract/Free Full Text]
- Strauss B.H, Chisholm R.J, Keeley F.W, et al. Extracellular matrix remodeling after balloon angioplasty injury in a rabbit model of restenosis. Circ Res (1994) 75:650–658.[Abstract/Free Full Text]
- Strauss B.H, Roubin R, Batchelor W.B, et al. In vivo collagen turnover following experimental balloon angioplasty injury and the role of matrix metalloproteinases. Circ Res (1996) 79:541–550.[Abstract/Free Full Text]
- Gertz S.D, Gimple L.W, Banai S, et al. Geometric remodeling is not the principal pathogenetic process in restenosis after balloon angioplasty. Evidence from correlative angiographic–histomorphometric studies of atherosclerotic arteries in rabbits. Circulation (1994) 90:3001–3008.[Abstract/Free Full Text]
- Banai S, Shou M, Correa R, et al. Rabbit ear model of injury-induced arterial smooth muscle cell proliferation: Kinetics, reproducibility, and implications. Circ Res (1991) 69:748–756.[Abstract/Free Full Text]
- Losordo D.W, Pickering J.G, Takeshita S, et al. Use of the rabbit ear artery to serially assess foreign protein secretion after site-specific arterial gene transfer in vivo. Circulation (1994) 89:785–792.[Abstract/Free Full Text]
- Steele P.M, Chesebro J.H, Stanson A.W, et al. Balloon angioplasty: natural history of the pathophysiological response to injury in a pig model. Circ Res (1985) 57:105–112.[Abstract/Free Full Text]
- Schwartz R.S, Murphy J.G, Edwards W.D, et al. Restenosis after balloon angioplasty: Practical proliferation model in porcine coronary arteries. Circulation (1990) 82:2190–2200.[Abstract/Free Full Text]
- Weiner B.H, Ockene I.S, Jarmolych J, Fritz K.E, Daoud A.S. Comparison of pathologic and angiographic findings in a porcine preparation of coronary atherosclerosis. Circulation (1985) 72:1081–1086.[Abstract/Free Full Text]
- Schwartz R, Koval T, Edwards W, et al. Effect of external beam irradiation on neointimal hyperplasia after experimental coronary artery injury. J Am Coll Cardiol (1992) 19:1106–1113.[Abstract]
- Reitman J.S, Mahley R.W, Fry D.L. Yucatan miniature swine as a model for diet-induced atherosclerosis. Atherosclerosis (1982) 43:119–132.[CrossRef][ISI][Medline]
- Santoian E.D, Schneider J.E, Gravanis M.B, et al. Angiopeptin inhibits intimal hyperplasia after angioplasty in porcine coronary arteries. Circulation (1993) 88:11–14.[Abstract/Free Full Text]
- Rodgers G.P, Minor S.T, Robinson K, et al. Adjuvant therapy for intracoronary stents: investigations in atherosclerotic swine. Circulation (1990) 82:560–569.[Abstract/Free Full Text]
- Gal D, Rondione A.J, Slovekai G.A, et al. Atherosclerotic Yucatan microswine: an animal model with high-grade, fibrocalcific, nonfatty lesions suitable for testing catheter-based interventions. Am Heart J (1990) 119:291–300.[CrossRef][ISI][Medline]
- Fuster V, Lie T.J, Badimon L, et al. Spontaneous and diet-induced coronary atherosclerosis in normal swine and swine with von Willebrand disease. Arteriosclerosis (1985) 5:67–73.[Abstract/Free Full Text]
- Griggs T.R, Reddick R.L, Sultzer D, Brinkhous K.M. Susceptibility to atherosclerosis in aortas and coronary arteries of swine with von Willebrand's disease. Am J Pathol (1981) 102:137–145.[Abstract]
- Martinez-Gonzalez J, Badimon L. Human and porcine smooth muscle cells share similar proliferation dependence on the mevalonate pathway: implication for in vivo interventions in the porcine model. Eur J Clin Invest (1996) 26:1023–1032.[CrossRef][ISI][Medline]
- Chesebro J.A, Lam J.Y.T, Badimon L, Fuster V. Restenosis after arterial angioplasty: A hemorheologic response to injury. Am J Cardiol (1987) 60:10B–16B.[Medline]
- Ip J.H, Fuster V, Israel D, et al. The role of platelets, thrombin and hyperplasia in restenosis after coronary angioplasty. J Am Coll Cardiol (1991) 17:77B–88B.[Medline]
- Mason R, Read M. Some species differences in fibrinolysis and blood coagulation. J Biomed Mater Res (1971) 5:121–128.[CrossRef][Medline]
- Murphy JG, Schwartz RS, Edwards WD, et al. Methotrexate and azathioprine fail to inhibit porcine coronary restenosis. Circulation 1990;82:III-429.
- Groves P.H, Banning A.P, Penny W.J, et al. Kinetics of smooth muscle cell proliferation and intimal thickening in a pig carotid model of balloon injury. Atherosclerosis (1995) 117:83–96.[CrossRef][ISI][Medline]
- Huckle W.R, Drag M.D, Acker W.R, et al. Effects of subtype-selective and balanced angiotensin II receptor antagonists in a porcine coronary artery model of vascular restenosis. Circulation (1996) 93:1009–1019.[Abstract/Free Full Text]
- Huber K.C, Schwartz R.S, Edwards W.D, et al. Effects of angiotensin converting enzyme inhibition on neointimal proliferation in a porcine coronary injury model. Am Heart J (1993) 125:695–701.[CrossRef][ISI][Medline]
- Burke S.E, Lubbers N.L, Gagne G.D, et al. Selective antagonism of the ET(A) receptor reduces neointimal hyperplasia after balloon-induced vascular injury in pigs. J Cardiovasc Pharmacol (1997) 30:33–41.[CrossRef][ISI][Medline]
- Veinot J.P, Edwards W.D, Camrud A.R, et al. The effects of lovastatin on neointimal hyperplasia following injury in a porcine coronary artery model. Can J Cardiol (1996) 12:65–70.[ISI][Medline]
- Nunes G.L, Sgoutas D.S, Redden R.A, et al. Combination of vitamins C and E alters the response to coronary balloon injury in the pig. Arterioscler Thromb Vasc Biol (1995) 15:156–165.[Abstract/Free Full Text]
- Van Der Giessen W.J, Serruys P.W, Van Beusekom H.M.M, et al. Coronary stenting with a new, radioopaque, balloon-expandable endoprosthesis in pigs. Circulation (1991) 83:1788–1798.[Abstract/Free Full Text]
- Carter A.J, Laird J.R. Experimental results with endovascular irradiation via a radioactive stent. Int J Radiat Oncol Biol Phys (1996) 36:797–803.[CrossRef][ISI][Medline]
- Hata H, Ohara Y, Kuga T, et al. Vasoreactivity and restenosis after coronary angioplasty in the atherosclerotic pig model. Coron Artery Dis (1995) 6:503–511.[ISI][Medline]
- Weinberger J, Amols H, Ennis R.D, et al. Intracoronary irradiation: dose–response for the prevention of restenosis in swine. Int J Radiat Oncol Biol Phys (1996) 36:767–775.[CrossRef][ISI][Medline]
- Filippo C, Abela G.S, Fenech A, et al. Transluminal laser irradiation of coronary arteries in live dogs: an angiographic and morphologic study of acute effects. Am J Cardiol (1985) 57:171–174.[ISI]
- Roubin G.S, Robinson K.A, King S.B, et al. Early and late results of intracoronary arterial stenting after coronary angioplasty in dogs. Circulation (1987) 76:891–897.[Abstract/Free Full Text]
- Schatz R.A, Palmaz J.C, Tio F.O, et al. Balloon expandable intracoronary stents in the adult dog. Circulation (1987) 76:450–456.[Abstract/Free Full Text]
- Willerson J.T, Yao S.K, McNatt J, et al. Liposome-bound prostaglandin E1 often prevents cyclic flow variations in stenosed and endothelium-injured canine coronary arteries. Circulation (1994) 89:1786–1791.[Abstract/Free Full Text]
- Mondy J.S, Williams J.K, Adams M.R, Dean R.H, Geary R.L. Structural determinants of lumen narrowing after angioplasty in atherosclerotic nonhuman primates. J Vasc Surg (1997) 26:875–883.[CrossRef][ISI][Medline]
- Rudel L.L. Genetic factors influence the atherogenic response of lipoproteins to dietary fat and cholesterol in nonhuman primates. J Am Coll Nutr (1997) 16:306–312.[Abstract]
- Geary R.L, Williams J.K, Golden D, et al. Time course of cellular proliferation, intimal hyperplasia, and remodeling following angioplasty in monkeys with established atherosclerosis. A nonhuman primate model of restenosis. Arterioscler Thromb Vasc Biol (1996) 16:34–43.[Abstract/Free Full Text]
- Bauters C, Hamon M, Van Belle E, et al. Restenosis after coronary angioplasty. Contribution of experimental models. Arch Mal Coeur Vaiss (1993) 86:47–56.[ISI][Medline]
- Karsch K.R, Preisack M.B, Baildon R, et al. Low molecular weight heparin (reviparin) in percutaneous transluminal coronary angioplasty. Results of a randomized, double-blind, unfractionated heparin and placebo-controlled, multicenter trial (REDUCE trial). Reduction of restenosis after PTCA, early administration of reviparin in a double-blind unfractionated heparin and placebo-controlled evaluation. J Am Coll Cardiol (1996) 28:1437–1443.[Abstract]
- Cairns J.A, Gill J, Morton B, et al. Fish oils and low-molecular-weight heparin for the reduction of restenosis after percutaneous transluminal coronary angioplasty. The EMPAR Study. Circulation (1996) 94:1553–1560.[Abstract/Free Full Text]
- Berger P.B, Holmes D.R Jr., Ohman E.M, et al. Restenosis, reocclusion and adverse cardiovascular events after successful balloon angioplasty of occluded versus nonoccluded coronary arteries. Results from the Multicenter American Research Trial with cilazapril after angioplasty to prevent transluminal coronary obstruction and restenosis. J Am Coll Cardiol (1996) 27:1–7.[Abstract]
- Savage M.P, Goldberg S, Bove A.A, et al. Effect of thromboxane A2 blockade on clinical outcome and restenosis after successful coronary angioplasty. Multi-Hospital Eastern Atlantic Restenosis Trial. Circulation (1995) 92:3194–3200.[Abstract/Free Full Text]
- Ellis S.G, Roubin G.S, Wilentz J, Douglas J.S, King S.B. Effect of 18–24 hour heparin administration for prevention of restenosis after uncomplicated coronary angioplasty. Am Heart J (1989) 117:777–782.[CrossRef][ISI][Medline]
- Brack M.J, Ray S, Chauban A, et al. The subcutaneous Heparin and Angioplasty Restenosis Prevention (SHARP) trial. Results of a multicenter randomized trial investigating the effects of high dose unfractionated heparin on angiographic restenosis and clinical outcome. J Am Coll Cardiol (1995) 26:947–954.[Abstract]
- Serruys P.W, Herrman J.P, Simon R, et al. A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty. Helvetica investigators. N Engl J Med (1995) 333:757&
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1 Experimental models
2 The rat model
