Restenosis: Remodeling Versus Intimal Hyperplasia

Saturday, March 2, 1996 atherosclerosis throughout the arterial tree. Arterioscler Thromb 1994; 14:133-140. 7. Faggiotto A, Ross R. Studies of hypercholesterolemia in the nonhuman primate. II. Fatty streak conversion to fibrous plaque. Arteriosclerosis 1984; 4:341356. 8. Masuda J, Ross R. Atherogenesis during low-level hypercholesterolemia in the nonhuman primate. II. Fatty streak conversion to fibrous plaque. Arteriosclerosis 1990; 10:178-187. 9. Skinner MP, Yuan C, Mitsumori L, Hayes CE, Raines EW, Nelson JA, Ross R. Serial magnetic resonance imaging of experimental atherosclerosis detects lesion fine structure, progression, and complications in vivo. Nature Med 1995; 1: 69-73. 3:20 pm Cellular and Molecular Basis of Restenosis Alexander W Clowes, MD Representative Papers 1. Geary RL, Koyama N, Wang TW, VergeI S, Clowes AW. Failure of heparin to inhibit intimal hyperplasia in injured baboon arteries: the role of heparin-sensitive and -insensitive pathways in the stimulation of smooth muscle cell migration and proliferation. Circulation 1995; 91:2972-2981.

2. Koyama N, Hart CE, Clowes AW. Different functions of the platelet-derived growth factor-alpha and -beta receptors for the migration and proliferation of cultured baboon smooth muscle cells. Circ Res 1994; 75:682691. 3. Bendeck MP, Zempo N, Clowes AW, Galardy RE, Reidy MA. Smooth muscle cell migration and matrix metalloproteinase expression after arterial injury in the rat. Circ Res 1994; 75:539-545. 4. Nikkari ST, Clowes AW. Restenosis after vascular reconstruction. Ann Med 1994; 26:95100. 5. Clowes AW. Control of intimal hyperplasia by heparin. J Heart Lung Transplant 1992; 11(3 Pt 2):S21. 6. Clowes AW, Reidy MA. Prevention of stenosis after vascular reconstruction: pharmaco-

logical control of intimal hyperplasiareview. J Vasc Surg 1991; 13:885-891.

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3:40 pm Restenosis: Remodeling Versus Intimal Hyperplasia Gary H. Gibbons, MD Cell Growth and Cell Death in Vascular Remodeling: Therapeutic Implications for Restenosis

(This paper also supports a 4:50 pm presentation on "Prevention of Restenosis: Gene and Other Biologic Strategies.") Learning objectives: (1) To focus on the cause of restenosis. (2) To describe therapy for vascular disease that may improve the clinical effectiveness of interventional procedures.

Restenosis after interventional angioplasty is one of the most vexing problems in cardiovascular medicine. It is refractory to many conventional medical therapies. Recent studies show that lasers, atherectomy devices, and stents are all plagued by restenosis. Given the lack of success when using various empirical pharmacotherapies and advanced devices, more effective therapeutic strategies must be based on an understanding of the underlying pathobiologic mechanisms that cause restenosis. Lack of understanding is due, in part, because rio animal model truly reflects the process of restenosis in humans with vascular disease. Ideally, insights into the process must be based on serial, longitudinal examinations. Quantitative angiographs have shown that most patients maintain much of the acute gain in lumen dimensions induced by angioplasty; only a few experience a net loss in lumen dimensions. Those who study the problem of restenosis focus on why balloon angioplasty fails. Maybe we should focus on why it may work. Over the past 30 years, animal model studies have shown that balloon injury to the vessel wall elicits vascular lesion formation. The response-to-injury hypothesis proposed by Ross has emphasized that vessel injury induces the activation of growth factors that promote a reparative response characterized by vascular cell proliferation, migration, and matrix production. This promotes intimal lesion formation and, eventually, a clinically significant vessel stenosis. Over the past 20 years, much evidence has

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Saturday, March 2, 1996 Successful Angioplasty: Vascular Enlargement Remodeling

Restenosis: Intimal hyperplasia

Restenosis: Vascular Shrinkage Remodeling Responses to balloon angioplasty been amassed, based on animal model studies, that documents the role of growth factors and cell proliferation in the expansion of the intima in response to injury. Consequently, vascular biologists would not have suggested that balloon angioplasty is clearly clinically efficacious. Paradoxically, a balloon injury presumed to cause lesion formation can be used for the treatment of vascular disease. Usually, balloon angioplasty has long-term efficacy. Nevertheless, the obvious empiric efficacy of balloon angioplasty has forced students of vascular biology to reexamine current conventional thinking. How can balloon angioplasty injury halt the progression of clinical vascular disease?

mote an increase in vessel dimensions versus processes that promote the progression of vascular disease and lesion stenosis. This would predict the success or failure of balloon angioplasty depending on the relative balance of these opposing forces that determine vessel structure (Figure). The vasculature has an adaptive capacity to remodel itself. The paradox that results from understanding restenosis within the narrow perspective of the response-to-injury hypothesis is, thus, reconciled. Concept of Vascular Remodeling The process of vascular remodeling involves the intrinsic capacity of the vasculature to alter its geometry as a response to its microenvironment. Generally, this involves changes in overall vessel dimensions, lumen dimensions, wall thickness to lumen ratios, or the intima-media ratios. Four fundamental cellular processes may be involved in vascular remodeling: cell growth, cell death, cell migration, and extracellular matrix modification.

A critically important observation of serial quantitative angiography studies of the vascular response to angioplasty in patients with vascular disease is that restenosis is not a dichotomous process. Restenosis, defined as the late loss of the acute gain in lumen dimension induced by angioplasty, follows a continuum from minimum loss to complete occlusion. Vascular Disorders Most patients maintain much of the gain inPulmonary Aneurysm duced by the angioplasty procedure. In conhypertension Restenosis after Angiogenesis trast to many animal models in which balloon angioplasty injury induces a net loss in lumen area, only a Systemic arterial Arteriovenous fistula few patients exhibit a worsening of vascular hypertension disease compared with the pre-angioplasty base- Atherosclerosis Transplant arteriopathy line status. This suggests that the vasculature Vein graft stenosis Patent ductus arteriosus has the countervailing capacity to limit the narrowing of lumen induced by vessel injury or progressive vascular disease. Although vascular remodeling occurs in a wide spectrum of vascular disorders (Table), it is not Given this limitation, an alternative model can be based on the notion of vascular remodeling. necessarily pathologic. It is a critical compoThe response to balloon angioplasty involves a nent of an organism's normal development. An balance between cellular processes that prounderstanding of the normal capacity of the

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Saturday, March 2, 1996 vasculature to remodel itself under physiologic conditions is important in understanding the process under pathologic circumstances such as restenosis. The vascular tree undergoes a continual process of growth, arborization, and regression. These changes are determined in large part by hemodynamic forces and the metabolic demands of tissues. This plasticity of the vasculature is not only apparent during development but is retained throughout adulthood. A chronic increase in blood flow created by placement of an arteriovenous shunt induces a structural increase in vessel dimensions. Conversely, Langille and his colleagues have shown that an artery shrinks in response to a chronic decrease in flow. Moreover, these investigators showed the endothelial cell dependence of the remodeling response by preventing the flow-induced change through denudation of the intimal surface. Thus, the capacity of the vasculature to enlarge or shrink is related to the capacity of the endothelium to serve as a mechanotransducer of hemodynamic stimuli. This suggests that the endothelium serves as a mechanotransducer surface that senses change in hemodynamic forces and is capable of inducing cell growth or cell death in response to the microenvironment. Given that shearing stress (the tractive force exerted by blood flow) is directly proportional to flow velocity and inversely proportional to the vessel radius cubed, the shrinkage or enlargement remodeling phenomenon is in accordance with the maintenance of a constant level of shearing stress throughout the circulation. Recent studies have documented that the endothelium has specialized flow-sensitive ion channels coupled to the activation of transcription factors that regulate genetic programs responsive to hemodynamic stimuli. Based on in vitro models, the endothelium modulates the expression of autocrineparacrine vasoactive factors, growth factors, matrix proteins, and adhesion molecules in response to changes in shearing stress. One of the best examples of the process of vascular remodeling involves the dramatic changes in vessel architecture that occur during normal development. For example, the abdominal aorta undergoes dramatic remodeling responses because of the changes in the circulation that accompany parturition. The abdominal aorta must enlarge to provide blood flow to the

placental circulation along the umbilical artery and to the caudal half of the body. Because of this, the abdominal aorta has a higher growth rate and dimension than the thoracic aorta in utero. Yet, once the placenta no longer requires substantial blood flows, the umbilical circulation regresses and the abdominal aorta remodels itself according to the reduced flow demands.

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The significance of vascular remodeling under pathologic circumstances was most clearly suggested by Glagov's work with atherosclerotic vessels. In careful studies of autopsy specimens, he observed a striking relationship between atherosclerotic intimal lesion dimensions and the overall dimension of the internal elastic membrane. He described an apparent "compensatory enlargement" in which the overall vessel size appeared to increase so that lumen dimensions could be maintained despite the encroachment of the enlarging intimal lesion. Moreover, he noted an apparent critical threshold at which the capacity to enlarge reached a limit and expansion of the intimal lesion produced a significant stenosis of the lumen. Although the mechanism of this response is not clear, it may be related to the capacity of the endothelium to sense changes in hemodynamic stimuli and modulate overall vessel dimensions. The expansion of the intimal lesion initially reduces the vessel radius, which effectively increases the shearing stress sensed by the endothelium. In response to this, the vessel undergoes a remodeling response to increase overall vessel dimensions; consequently, shearing stress is returned to the previous level. Thus, the process of compensatory enlargement in pathologic vessels is similar to the enlargement remodeling that occurs in response to chronic increases in flow in normal vessels. This shows that the vasculature has the intrinsic capacity to arrest the progression of vascular lesions. Possibly, angioplasty works by activating this intrinsic remodeling capacity of the vasculature. These observations emphasize that the process of vascular remodeling can either shrink or enlarge the vessel. Moreover, this intrinsic capacity of the vasculature to change its architecture occurs under normal physiologic and pathologic conditions. A critical feature of the vascular remodeling process is that changes in lumen dimensions fail to assess adequately the full extent of the phenomenon. Thus, the conventional techniques of quantitative angiography fail to give us a clear insight into the

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Saturday, March 2, 1996

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that promote the success of angioplasty or the processes that result in restenosis. Recently, studies with intravascular US have begun to provide further insight into the process of vascular remodeling in vascular disease. These in situ patient studies have confirmed observations from autopsy surveys. Unfortunately, controlled, longitudinal studies that involve serial assessment of the vasculature by this technique are few. This is an important limitation because cross-sectional studies must arbitrarily designate a certain vessel segment as the "reference" point. Nevertheless, if vascular remodeling is a local response to a disease process or its local microenvironment, defining a "reference segment" that is either without disease, is not influenced by diseased segments within a given arterial segment, or has not undergone vascular remodeling is difficult. Interpretation of these cross-sectional studies of vascular remodeling must, therefore, be done with great caution.

shrinkage remodeling, causing little net gain in lumen dimensions. Preliminary cross-sectional studies by Leon et aI, with the use of intravascular US, appear to confirm these observations in the coronary vasculature. Increasing evidence supports the idea of vascular remodeling as an alternative model for defining the mechanisms of restenosis after angioplasty. Future clinical studies involving serial assessments of vessel architecture beyond the lumen will document that vascular remodeling is an important determinant of the therapeutic success or failure of balloon angioplasty. The most effective therapies to prevent restenosis may involve interventions at processes that influence intimal lesion dimensions and the process of vascular remodeling.

Mechanisms of Restenosis: Cell Growth and Cell Death An important component of the response to injury involves changes in the state of cell differentiation. Unlike cardiac or skeletal muscle, Yet, one recent study used B-mode US to evalvascular smooth-muscle cells maintain the plasuate patients undergoing superficial femoral articity necessary to "de-differentiate" in response tery angioplasty and has documented vascular to environmental stimuli. Vascular smooth-musremodeling in peripheral vessels after angiocle cells within the nondiseased vessel exhibit a plasty. This study showed that a structural in"contractile" phenotype characterized by the crease in overall vessel dimensions related to expression of contractile proteins consistent vessel stretch and dissection results in an acute with a specialized form of smooth-muscle cell. gain in lumen dimensions. Similar observations Additionally, this "contractile" phenotype is ashave been obtained by using intravascular US. sociated with the quiescent, growth-arrested Moreover, this study documented that many state of cells in a normal vessel. At the other patients successfully respond to angioplasty by end of the spectrum, vascular smooth-muscle maintaining this overall increase in vessel dicells exhibit a "synthetic" phenotype typified mension without experiencing a significant reby cell proliferation, increased production of active increase in the size of the intimal lesion. extracellular matrix proteins, and decreased exThese patients undergo an enlargement remodpression of specialized contractile proteins. eling process that maintains much of the acute These "activated," "synthetic" cells also exhibit gain of angioplasty. Another interesting set of increased expression of autocrine-paracrine patients were those that had restenosis after angrowth factors, cytokines and chemokines. This gioplasty; a subset of patients appeared to fit phenotypic modulation thereby promotes the the response-to-injury model because they cell proliferation, cell migration, and matrix manifested an increase in intimal lesion mass production that results in lesion formation. If as a predominant mechanism of the late loss in smooth-muscle cells are obtained from human lumen dimension after angioplasty. Yet, in anatherectomy specimens, which are taken from other subset of patients with restenosis, a depatients that have restenotic lesions as comcrease in overall lumen dimensions without a pared with a primary atherosclerotic lesion, the significant expansion of the intimal lesion mass cells from the restenotic lesions exhibit this was observed. According to the vascular re"synthetic" phenotype and enhanced growth modeling example, this apparent paradox may characteristics. Thus, changes in a cell phenoreflect either a failure to undergo enlargement type are an important determinant of the reremodeling to maintain the acute gain or a sponse to injury and vascular remodeling. time-dependent process of enlargement remodeling followed by a subsequent phase of

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Saturday, March 2, 1996 The conventional response-to-injury model suggests that restenosis is a vasoproliferative disorder in which cell proliferation and migration is stimulated by the induction of growth-factor expression by balloon injury. Evidence from several groups of investigators shows that human restenotic lesions obtained at autopsy or by atherectomy exhibit an apparent accumulation of intimal cells, and these cells appear to have increased expression of various growth factors. Researchers are unsure whether these restenotic intimal lesions are characterized by an actual increase in cell replication compared with primary atherosclerotic plaques. Clearly, the techniques employed to assess the question suffer from potential sampling problems (eg, time after angioplasty and the limited sampling obtained by atherectomy).

Cells have a built-in genetic program for cellular suicide, called "apoptosis." It is a common mechanism of cell deletion in many contexts in which tissue remodeling occurs. The tadpole loses its tail and we lose the webbing between our fingers in utero because of programmed cell death. This is distinct from necrosis (death by murder) because it is genetically programmed, characterized by nuclear chromatin and cellular shrinkage rather than the cell swelling of necrotic death, and is often an insidious form of cell deletion without evidence of tissue inflammation. Cells that undergo apoptosis are often phagocytosed by neighboring cells without spillage of inflammatory intracellular contents. The role of apoptosis in the process of vascular remodeling and restenosis after angioplasty remains to be defined.

Although increasing evidence shows that intimal hyperplasia is not the cause of all forms of restenosis, it still may be a significant contributor in many cases. Much of the late loss in lumen dimensions observed after stent placement is related to intimal hyperplasia. Stent placement in a stenotic lesion appears to prevent elastic recoil and promotes enlargement remodeling. Yet, it is also dearly associated with an exuberant neointimallesion response to both the acute distension injury and the continued presence of the foreign body. Therefore, the therapeutic strategies directed against cell proliferation may be particularly useful adjunctive treatments for further optimizing maintenance of the increased acute gain induced by stents as compared with balloon angioplasty.

Recently, Cho et al have reported that the shrinkage remodeling response induced by a chronic decrease in blood flow is associated with the induction of apoptosis. Their seminal study suggests that activation of programmed cell death is a mechanism for altering vessel structure in response to its microenvironment.Similarly, several groups of investigators have reported that balloon injury is associated with the induction of cell death during the later stages of neointimal lesion formation. Moreover, Isner et al have provided evidence that cell death is readily detected within human atheroma and restenotic lesions. Although the technique used in these clinical specimens is not specific for apoptotic death, and the actual rate of apoptotic cell death may be inflated in these studies, the findings are consistent with the notion that cell death may playas important a role as cell growth in determining vessel structure.

Within the context of the response-to-injury model, most therapeutic approaches have focused on modulating the cell-growth response to injury. Some therapeutic strategies have considered the restenotic lesion a tumor growth. Yet, recent advances in cancer biology have led to the recognition that many tumors increase in size due to a defect in the regulation of cell death rather than aberrant uncontrolled cell growth (eg, follicular lymphoma). Obviously.. the overall cell population within a tumor or the intima space must reflect a balance of the birth rate versus the death rate. Thus, factors that regulate the death rate are likely to be as important as factors that regulate the growth rate.

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Although these recent reports have described cell death in days to weeks after balloon injury, cell death by apoptosis is an acute response to balloon injury that occurs within hours after vessel distension. In preliminary studies in a variety of vessels including rabbit carotid and iliofemoral vessels and the pig carotid and coronary vessels, we have found that balloon angioplasty injury induces an acute activation of programmed cell death in medial cells within 2 hours of injury. Findings suggest that the vascular remodeling process may begin quickly after balloon injury. The overall dimensions of the media may be determined by the relative degree of cell loss by apoptosis versus the de-

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Saturday, March 2, 1996 of cell proliferation induced by the injury. The remodeling may begin with a destructive process of cell deletion followed by a phase of reconstruction in which the cellularity and dimensions of the vessel are determined by a balance of cell growth and cell death. Perhaps, cell death is necessary to maintain the acute gain after the procedure. Besides the acute induction of apoptosis in response to balloon angioplasty injury, the cell phenotype may modulate the propensity to undergo cell death. In particular, vessels that had a preexistent neointima containing phenotypically modified cells exhibited little evidence of apoptosis in contrast to the substantial induction of apoptosis in normal medial cells exposed to the same stimulus. Findings suggest that phenotypic modulation affects the susceptibility to cell death and the propensity for cell growth. Taken together, these observations suggest that the phenotypic mix of cells within the lesion undergoing angioplasty may determine how much apoptosis is induced by balloon injury and influence the vascular remodeling response that follows. Based on these findings, the apparent paradox that balloon angioplasty relieves vascular disease rather than worsens it as predicted by the response-to-injury hypothesis should be reconsidered. If balloon angioplasty involves the induction of cell death by apoptosis, the deletion of cells within the diseased vessel is beneficial to the overall process of promoting a larger lumen. Vessels may have the capacity to maintain the acute gain of angioplasty because of a process of cell death and vascular remodeling. New therapeutic options may involve modulating the process of programmed cell death for modifying the vascular remodeling response to balloon injury. Future investigation will determine the role of apoptosis in the pathogenesis of restenosis after angioplasty. Novel Therapies for Restenosis According to the response-to-injury hypothesis, neointima formation is associated with increased expression of a variety of mitogens and cell proliferation. In devising therapeutic strategies to prevent restenosis, given the multiplicity of growth factors expressed in the response to injury, a strategy to block any single factor is unlikely to be effective. A more efficacious approach would involve blocking the final common pathway used by all mitogens in the acti-

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vation of cell proliferation. Accordingly, a genetic engineering strategy may be followed that prevents the expression of cell-cycle regulatory genes to inhibit cell proliferation and, therefore, neointima formation. The in vivo genetic engineering strategy uses two antigenes: antisense oligonucleotides (ODN) and transcription factor decoys. This antigene plan is based on the central notion that DNA is transcribed to RNA, RNA is translated into proteins, and the synthesis of certain proteins is essential for the cell to orchestrate cellcycle progression and undergo mitosis. Antisense ODN are small DNA molecules that bind specifically to certain mRNA and target that RNA for intracellular destruction. Thus, antisense ODN targeted against certain cell-cycle regulatory genes can render a cell incapable of cell-cycle progression and proliferation. Based on our understanding of the genetic program that coordinates cell-cycle progression, several genes (proliferating cell nuclear antigen [PCNAl, cdc2, cdk2, and cyclin Bl) were targeted to prevent neointima formation. Unfortunately, poor cellular uptake limits the use of ODN as drugs. Accordingly, the use of a virus proteincoated liposome system, the HVJ liposome method, was developed as a highly efficient molecular delivery system for achieving high intracellular concentrations of ODN without nonspecific toxicity. Similar success has been achieved by using a microporous balloon delivery system with antisense ODN directed against c-myc in the porcine coronary balloon-injury model. By using the HVJ liposome molecular delivery system in the rat carotid balloon-injury model, a single intraluminal administration of antisense ODN directed against cell-cycle regulatory genes prevented lesion formation for up to 8 weeks. A blockade of more than one target was more effective than using antisense ODN against a single cell-cycle regulatory gene. Therefore, an anti-gene strategy that results in a coordinated inhibition of several cell-cycle regulatory genes would be particularly efficacious. Cell-cycle progression is a highly orchestrated event involving a tightly coordinated, sequential activation of cell-cycle regulatory genes. A critical locus of regulation involves the transcription factor E2F, which is the essential activator of several critical cell-cycle regulatory genes, including c-myb, c-myc, PCNA, cdc2, and thymidine kinase. Cells are maintained in a

Saturday, March 2, 1996 quiescent state by the Rb protein that binds and sequesters E2F in the cytoplasm. The phosphorylation of Rb, the release of E2F from Rb, and the binding of E2F to specific cis elements within the promoter regions of cell cycle genes result in DNA synthesis and mitosis. Cis element decoys could be synthesized that would bind to E2F within the cytoplasm and thereby mimic the growth-arresting action of Rb by restricting the capacity of E2F to bind to the actual cis elements of the endogenous cellcycle regulatory genes. Studies at our institution have confirmed that E2F transcription factor decoys can be delivered into cells to inhibit selectively the transcription of genes activated by E2F and thereby abrogate the cell proliferation response to mitogens. Intralumenal delivery of E2F transcription factor decoy ODN resulted in a sustained blockade of neointima formation in the rat carotid injury model. Thus, inhibition of cell cycle progression by these antigene approaches prevents lesion formation after balloon injury. Long-term inhibition was achieved although oligonucleotides fail to maintain functionality beyond 2 weeks in vivo. Possibly, cell-cycle arrest induced by this antigene strategy has effects beyond simply blocking cell proliferation. In fact, several studies suggest that blockade of cell-cycle regulatory gene expression also inhibits cell migration and matrix production. Moreover, in preliminary studies, we observed differential expression of growth factors and matrix proteins in injured vessels treated with active antisense ODN versus control ODN that fail to inhibit growth. These findings suggest that blockade of cell-cycle regulatory gene expression has a longer-term influence on cell phenotype that may also modulate the process of lesion formation and vascular remodeling. Also, the cell-cycle arrest of vascular smoothmuscle cells stimulated by mitogens can begin programmed cell death. Thus, strategies targeted against a blockade of cell proliferation can also influence other processes involved in restenosis, such as cell migration, matrix production, and apoptosis. Given that vein graft failure is also related to neointima formation, we tested the hypothesis that this genetic engineering strategy can be used to prevent graft occlusion. Vein grafts with antisense ODN directed against PCNA and cdc2 ex vivo were transfected and implanted in the arterial circulation, following the rabbit ca-

rotid interpositional graft model. The grafts treated with antisense ODN failed to exhibit the cell proliferation and neointima formation observed in the control-treated ODN. Intriguingly, the antisense-treated vein grafts retained the capacity to undergo vascular remodeling so that the vein graft media would thicken to achieve a structure similar to an artery. Essentially, the genetically modified vein graft remodeled itself according to the hemodynamic stresses of the arterial circulation. When the rabbits were hyperlipidemic, accelerated atherosclerosis in the control vein grafts was observed as previously described. In contrast, accelerated atherosclerosis failed to develop in the genetically modified vein grafts in hyperlipidemic animals for up to 3 months. Clearly, the functionality of the antisense ODN is not apparent after 3 months; however, the effect of antisense ODN-induced cell-cycle arrest treatment clearly persists. In preliminary studies, the cells within the antisense-treated grafts are phenotypically modified so that they fail to express the molecules necessary to promote accelerated atherosclerosis (eg, adhesion molecules such as VCAM-l). This long-term change in cell phenotype is likely to confer the long-term efficacy of the antisense ODN treatment strategy.

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Future Directions Given the vascular remodeling model outlined here, the most effective therapeutic strategies to prevent restenosis may involve a multi-pronged attack on the various mechanisms of angioplasty failure. Initially, we must prevent the acute causes of failure, such as thrombosis and elastic recoil. Consequently, new generation anti-platelet and anti-thrombotic agents, the increased use and development of stents, and improvements in device deployment will effectively solve these problems. Ideally, a longterm therapeutic strategy should achieve the maximum acute gain after intervention. Currently, the approach to maximizing the acute gain is limited by the concern that it induces greater injury and therefore greater intimal hyperplasia as a response to injury. Yet, if we couple therapeutic strategies that prevent intimal hyperplasia to strategies that promote the greatest acute gain, we will succeed in preventing restenosis. A combination of stents and antisense ODN or transcription-factor ODN may be an optimal synergistic treatment strategy. Finally, we must begin to develop strategies to enhance vascular enlargement remodeling and

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Saturday, March 2, 1996 reduce the likelihood of shrinkage remodeling. This will require further elucidation of the mechanisms governing these remodeling processes. Strategies devised against cell proliferation may also have favorable consequences in promoting enlargement remodeling. Certain antiproliferative strategies that have concomitant effects on cell phenotype, matrix production, and the regulation of apoptosis may promote enlargement remodeling, as well as inhibit intimal hyperplasia. A treatment strategy targeted against both intimal hyperplasia and shrinkage remodeling has the greatest potential for longterm efficacy. The development of such a treatment strategy is the next great challenge in interventional cardiovascular medicine.

Morishita R, Gibbons GH, Ellison KE, et al. Single intraluminal delivery of antisense cdc2 kinase and PCNA oligonucleotides results in chronic inhibition of neointimal hyperplasia. Proc Nat! Acad Sci USA 1993; 90:8474-8478. Schwartz SM, Bennett MR. Death by any other name. Am) Pathol 1995; 147:229-234. Von der Leyen H, Gibbons GH, Morishita R, et al. Gene therapy inhibiting neointimal vascular lesion: in vivo transfer of endothelial cell nitric oxide synthase gene. Proc Nat! Acad Sci USA 1995; 92:11371141.

Diagnosis

Selected Bibliography Finkel T, Epstein SE. Gene therapy for vascular disease. FASEB) 1995; 9:843-851. Gibbons GH, Dzau V). Emerging concept of vascular remodeling. New Eng!) Medicine 1994; 330:1431-1438. Glagov S, Zarins C, Giddens DP, Ku DN. Hemodynamics and atherosclerosis: insights and perspectives gained from studies of human arteries. Arch Pathol Lab Med 1988: 112:1018-1031. Henderson), Chambers], )eddy TA, Chamberlain), Whittingham TA. Serial investigation of balloon angioplasty induced change in the superficial femoral artery using colour duplex ultrasound. Br) Radiol 1994; 67:546-551. Isner ]M, Kearney M, Bortman S, Passeri). Apoptosis in human atherosclerosis and restenosis. Circulation 1995; 91:2703-2711. Langille BL. Remodeling of developing and mature arteries: endothelium, smooth muscle and matrix. ) Cardiovasc Pharmacol 1993; 21(suppl I):Sl1-S17. Mann M), Gibbons GH, Kernoff RS, et al. Genetic engineering of vein grafts resistant to atherosclerosis. Proc Nat! Acad Sci USA 1995; 92:4502-4506. Morishita R, Gibbons GH, Ellison KE, et al. Intimal hyperplasia after vascular injury is inhibited by antisense cdk 2 kinase oligonucleotides.) Clin Invest 1994; 93: 1458-1464. Morishita R, Gibbons GH, Ellison KE, et al. Novel molecular strategy using cis element "decoy" of E2F binding site inhibits smooth muscle proliferation in vivo. Proc Nat! Acad Sci USA 1995; 92:5855-5859.

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4:00 pm Intravascular US Characterizations of Angioplasty Mechanisms and Restenosis Rodney A. White, MD (See earlier article on "Intravascular US Evaluation of Atherosclerosis")

Treatment 4:10 pm Mechanical Approaches to Restenosis Barry T. Katzen, MD Learning objective: To describe mechanical devices used to improve both initial and longterm results of percutaneous intervention, including "debulking" to remove plaque, stents, and derivatives of stent technology.

Restenosis remains the principal cause of failure of percutaneous transluminal angioplasty (PTA) despite the specific anatomic site being addressed. Results of angioplasty vary from site to site, but, overall, long-term results are better in larger vessels (aorta, iliac arteries) and worse in small to medium-sized vessels (renal, coronary, and superficial femoral arteries). In an attempt to increase patency rates, a variety of new devices have been developed to both extend percutaneous revascularization to more patients and to prolong time to restenosis, making intervention more cost-effective. Atherectomy Atherectomy was first described by Simpson when a new device was developed to remove plaque to produce lumenal widening. The method can be used for both coronary and pe-