This Article Extract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Costa, M. A. Articles by Simon, D. I. Search for Related Content PubMed PubMed Citation Articles by Costa, M. A. Articles by Simon, D. I. Related Collections Restenosis Smooth muscle proliferation and differentiation Catheter-based coronary interventions: stents

(Circulation. 2005;111:2257-2273.)
© 2005 American Heart Association, Inc.

Basic Science for Clinicians

Molecular Basis of Restenosis and Drug-Eluting Stents

Marco A. Costa, MD, PhD; Daniel I. Simon, MD

From the Division of Cardiology & Cardiovascular Imaging Core Laboratories, University of Florida, Shands-Jacksonville, Jacksonville, Fla (M.A.C.), and the Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (D.I.S.).

Correspondence to Daniel I. Simon, MD, Cardiovascular Division, 75 Francis St, Tower 3, Boston, MA 02115. E-mail dsimon{at}rics.bwh.harvard.edu

Key Words: stents • restenosis • inflammation • prevention • cells

	Introduction

Top Introduction Restenosis: Definitions and... An Integrated View of... Animal Model and Human... Molecular Mechanisms of... Antiinflammatory Approaches to... Human Evidence for the... Cell Cycle and Restenosis Local Drug Pharmacokinetics Clinical Aspects of Restenosis... Mechanism of Restenosis after... DES: Future Approaches Conclusion References

 

Resolution of restenosis probably requires both creation of the largest possible residual lumen and substantial inhibition of intimal hyperplasia.

— J.S. Forrester and coworkers¹

Dr Forrester’s prediction that resolution of restenosis would require the translational merging of molecular mechanisms of proliferation with local scaffolding and drug-delivery devices appears to have been remarkably prescient. The application of drug-eluting stent (DES) technology to improve clinical outcomes after percutaneous coronary intervention (PCI) represents one of the greatest success stories in cardiology. This review highlights the molecular basis of restenosis and DES for the clinical and interventional cardiologist and vascular biologist.

	Restenosis: Definitions and Mechanisms

Top Introduction Restenosis: Definitions and... An Integrated View of... Animal Model and Human... Molecular Mechanisms of... Antiinflammatory Approaches to... Human Evidence for the... Cell Cycle and Restenosis Local Drug Pharmacokinetics Clinical Aspects of Restenosis... Mechanism of Restenosis after... DES: Future Approaches Conclusion References

 
Restenosis is the arterial wall’s healing response to mechanical injury and comprises 2 main processes—neointimal hyperplasia (ie, smooth muscle migration/proliferation, extracellular matrix deposition) and vessel remodeling. Primarily on the basis of observations from animal studies, Forrester and coworkers¹ proposed a paradigm for neointimal hyperplasia as a general wound-healing response. Platelet aggregation, inflammatory cell infiltration, release of growth factors, medial smooth muscle cell (SMC) modulation and proliferation, proteoglycan deposition, and extracellular matrix remodeling were identified as the major milestones in the temporal sequence of this response. This view of the neointimal hyperplasia process was modified subsequently by Libby and colleagues² to reconcile certain important clinical features—namely, that thrombosis, often invoked as a cause of SMC proliferation, wanes before intimal thickening peaks and that antithrombotic therapy failed to eliminate restenosis. In this cascade model, a special case was made for the centrality of inflammation, and it was proposed that autocrine or paracrine mediators (eg, interleukin-1 [IL-1] and tumor necrosis factor), the expressions of which are triggered by vascular injury, contribute to deranged SMC behavior during restenosis.

The molecular mechanisms of the arterial remodeling are less well understood. The term remodeling has been applied largely to describe either vascular shrinkage or enlargement. The definition proposed by Schwartz et al,³ in which remodeling is characterized in a continuous spectrum by any change in vascular dimension, may better describe this compensatory phenomenon. Studies that used intravascular ultrasound provided the first evidence of the key role of negative remodeling (vessel shrinkage) on lumen deterioration in nonstented coronary arteries.^4,5 Adventitial myofibroblasts, which are capable of collagen synthesis and tissue contraction as seen in wound healing,^6,7 may play an important role in negative vessel remodeling observed in restenosis after balloon angioplasty. The association between enhanced inflammatory response and vessel enlargement, as observed in an experimental study, represents a potential protective effect against negative vessel remodeling.^7,8 Nevertheless, remodeling is virtually absent after stenting as observed by volumetric intravascular ultrasound (IVUS).^9,10 The superior outcomes of bare-metal stents compared with angioplasty result mainly from the scaffold property of these metallic prostheses, which prevents vessel shrinkage (elastic recoil and negative remodeling), despite inducing an enhanced neointimal hyperplasia response. The molecular basis of this enhanced proliferative response has been the focus of pharmacological prevention of restenosis and led to the ultimate development of DES.

	An Integrated View of the Pathophysiology of Restenosis

Top Introduction Restenosis: Definitions and... An Integrated View of... Animal Model and Human... Molecular Mechanisms of... Antiinflammatory Approaches to... Human Evidence for the... Cell Cycle and Restenosis Local Drug Pharmacokinetics Clinical Aspects of Restenosis... Mechanism of Restenosis after... DES: Future Approaches Conclusion References

 
An integrated view of the molecular and cellular events of in-stent restenosis has been proposed by Welt and Rogers (Figure 1).¹¹ A series of events are initiated immediately after balloon inflation or stent deployment. The initial consequences immediately after stent placement are deendothelialization, crush of the plaque (often with dissection into the tunica media and occasionally adventitia), and stretch of the entire artery. A layer of platelets and fibrin is then deposited at the injured site. Activated platelets on the surface expressing adhesion molecules such as P-selectin attach to circulating leukocytes via platelet receptors such as P-selectin glycoprotein (GP) ligand and begin a process of rolling along the injured surface. Leukocytes then bind tightly to the surface through the leukocyte integrin (ie, Mac-1) class of adhesion molecules via direct attachment to platelet receptors such as GP Ib and through cross-linking with fibrinogen to the GP IIb/IIIa receptor. Migration of leukocytes across the platelet-fibrin layer and diapedesis into the tissue is driven by chemical gradients of chemokines released from SMCs and resident macrophages.

View larger version (89K): [in this window] [in a new window]   Figure 1. Schematic of an integrated cascade of restenosis. A, Atherosclerotic vessel before intervention. B, Immediate result of stent placement with endothelial denudation and platelet/fibrinogen deposition. C and D, Leukocyte recruitment, infiltration, and SMC proliferation and migration in the days after injury. E, Neointimal thickening in the weeks after injury, with continued SMC proliferation and monocyte recruitment. F, Long-term (weeks to months) change from a predominantly cellular to a less cellular and more ECM-rich plaque. Reprinted with permission from Arterioscler Thromb Vasc Biol.11

Next is a granulation or cellular proliferation phase. Growth factors are subsequently released from platelets, leukocytes, and SMCs, which stimulate migration of SMCs from the media into the neointima. The resultant neointima consists of SMCs, extracellular matrix, and macrophages recruited over several weeks. Cellular division takes place in this phase, which appears to be essential for the subsequent development of restenosis.

Over longer time periods, the artery enters a phase of remodeling involving extracellular matrix (ECM) protein degradation and resynthesis. Accompanying this phase is a shift to fewer cellular elements and greater production of ECM. ECM is composed of various collagen subtypes and proteoglycans¹² and constitutes the major component of the mature restenotic plaque.¹³ In the balloon-angioplastied artery, reorganization of the ECM,¹⁴ replacing hydrated molecules by collagen, may lead to shrinkage of the entire artery and negative remodeling. In the stented artery, this phase has less impact because of minimal negative remodeling, although constituents of ECM such as hyaluronan, fibronectin, osteopontim and vitornectin also facilitate SMC migration.^15,16 In both balloon-angioplastied and stented arteries, reendothelialization of at least part of the injured vessel surface may occur.

	Animal Model and Human Evidence for the Role of Inflammation in Restenosis

Top Introduction Restenosis: Definitions and... An Integrated View of... Animal Model and Human... Molecular Mechanisms of... Antiinflammatory Approaches to... Human Evidence for the... Cell Cycle and Restenosis Local Drug Pharmacokinetics Clinical Aspects of Restenosis... Mechanism of Restenosis after... DES: Future Approaches Conclusion References

 
Experimental and clinical data indicate that leukocytes may be central to intimal growth after mechanical arterial injury. In animal models of vascular injury, leukocytes are recruited as a precursor to intimal thickening.^17,18 In animal models in which a stent is deployed to produce deep vessel wall trauma, a brisk early inflammatory response is induced with abundant surface-adherent neutrophils and monocytes.¹⁸ Days and weeks later, macrophages accumulate within the developing neointima and are observed clustering around stent struts. The number of vessel wall monocytes/macrophages is positively correlated with the neointimal area, suggesting a possible causal role for monocytes in restenosis. We and others have shown that blockade of early monocyte recruitment results in reduced late neointimal thickening.^19–21 Leukocytes likely modulate vascular repair through multiple mechanisms. Inflammatory cells may contribute to neointimal thickening because of their direct bulk within the intima,²² generation of injurious reactive oxygen intermediates,²³ elaboration of growth and chemotactic factors,²⁴ or production of enzymes (eg, matrix metalloproteinases, cathepsin S) capable of degrading extracellular constituents and thereby facilitating cell migration.^25,26

Quantitative immunohistochemical analysis of directional coronary atherectomy specimens from humans has shown that the number of macrophages present in the tissue at the time of angioplasty predicts future restenosis.²² Farb et al²⁷ reported findings from pathological studies of 116 stents from 56 patients after PCI. They found a strong link between the extent of medial damage, inflammation, and neointimal thickness. They reported a late occurrence of peri-strut neoangiogenesis, which was strongly correlated with inflammation. The causal relationship between new blood vessels and clinical restenosis could not be firmly established.

Systemic markers of inflammation also appear to be predictive of restenosis after balloon angioplasty. Stenting of patients with stable angina and low C-reactive protein levels at baseline is associated with a transient rise in C-reactive protein that returns to baseline within 48 to 72 hours.²⁸ Sustained elevations of C-reactive protein are associated with an increased risk of clinical and angiographic restenosis. Using flow cytometry, several groups have reported independently that balloon angioplasty and stenting are associated with upregulation of neutrophil CD11b that is positively correlated with clinical restenosis and late lumen loss,^29–31 and that cell activation occurred across the mechanically injured vessel.

	Molecular Mechanisms of Inflammation

Top Introduction Restenosis: Definitions and... An Integrated View of... Animal Model and Human... Molecular Mechanisms of... Antiinflammatory Approaches to... Human Evidence for the... Cell Cycle and Restenosis Local Drug Pharmacokinetics Clinical Aspects of Restenosis... Mechanism of Restenosis after... DES: Future Approaches Conclusion References

 
Adhesive interactions between vascular cells play important roles in orchestrating the inflammatory response. Recruitment of circulating leukocytes to vascular endothelium requires multistep adhesive and signaling events (including selectin-mediated attachment and rolling, leukocyte activation, and integrin-mediated firm adhesion and diapedesis) that result in the infiltration of inflammatory cells into the blood vessel wall.³² Firm attachment is mediated by members of the ß₂ integrin family, LFA-1 (_Lß₂, CD11a/CD18), Mac-1 (_Mß₂, CD11b/CD18), and p150,95 (_Mß₂, CD11c/CD18), which bind to endothelial counterligands (eg, intercellular adhesion molecule-1),³³ to endothelial-associated ECM proteins (eg, fibrinogen),³⁴ or to glycosaminoglycans.³⁵

Leukocyte recruitment and infiltration also occur at sites of vascular injury where the lining endothelial cells have been denuded and platelets and fibrin have been deposited. The initial tethering and rolling of leukocytes on platelet P-selectin³⁶ are followed by their firm adhesion and transplatelet migration, processes that are dependent on leukocyte Mac-1³⁷ and platelet GP Ib.³⁸ The precise cellular and molecular mechanisms of inflammation after arterial injury are highly dependent on the specific type of injury (ie, stent versus balloon and mechanical versus atherogenesis). For example, experimental stent deployment in animal arteries causes sustained elevation of monocyte chemoattractant protein-1 (MCP-1) after injury (14 days) compared with balloon-injured arteries (<24 hours).³⁹ Correspondingly, antibody-mediated blockade of CCR2, a primary leukocyte receptor for MCP-1, markedly diminished neointimal thickening after stent-induced but not balloon-induced injury in nonhuman primates.⁴⁰ In contrast to targeting Mac-1, which reduces neointimal thickening after experimental angioplasty^19,40,41 but does not attenuate atherogenesis,⁴² targeting MCP-1 also appears to benefit arteries affected by either mechanical injury or atherogenesis. Mice genetically deficient in MCP-1⁴³ or CCR2⁴⁴ demonstrated significant reductions in aortic lipid content, monocyte accumulation, and atherosclerotic lesion development, as well as neointimal thickening after experimental angioplasty.⁴⁵

Experimental observations support a causal relationship between inflammation and experimental restenosis. Antibody-mediated blockade¹⁹ or selective absence of Mac-1⁴¹ diminished leukocyte accumulation and limited neointimal thickening after experimental angioplasty or stent implantation. Targeting earlier, selectin-mediated interactions between platelets and leukocytes also markedly reduces leukocyte recruitment and neointimal thickening in a variety of animal models.⁴⁶ Blockade of the MCP-1 receptor CCR2 has been shown to reduce neointimal thickening within stented arterial segments. Interestingly, MCP-1 is upregulated after PCI in humans, and MCP-1 levels correlate with risk for restenosis.⁴⁷

	Antiinflammatory Approaches to Prevent Clinical Restenosis

Top Introduction Restenosis: Definitions and... An Integrated View of... Animal Model and Human... Molecular Mechanisms of... Antiinflammatory Approaches to... Human Evidence for the... Cell Cycle and Restenosis Local Drug Pharmacokinetics Clinical Aspects of Restenosis... Mechanism of Restenosis after... DES: Future Approaches Conclusion References

 
On the basis of overwhelming experimental and clinical evidence that inflammation drives restenosis, several investigators are pursuing clinical programs using systemic antiinflammatory therapies, including liposome-encapsulated bisphosphonates,⁴⁸ prednisone,⁴⁹ anti-CD18 or anti-CCR2 blockade,⁴⁰ and peroxisome proliferators-activated receptor- activator rosiglitazone.

Corticosteroids have long been shown to reduce the influx of mononuclear cells, to inhibit monocyte and macrophage function, and to influence SMC proliferation⁵⁰; however, clinical trials with systemic steroid therapy have shown mixed results.^49,51 Stents eluting steroid agents such as methylprednisolone (300 mg) were used in a porcine model and showed a reduction in neointimal proliferation as compared with a severe intimal hyperplasia promoted by the stent coated with polymer.⁵² The clinical correlate of this experiment was the STRIDE (Study of Anti-Restenosis with BiodivYsio Dexamethasone-Eluting Stent) study conducted in Europe. Restenosis (>50% diameter stenosis at follow-up) was 13.3% and late loss (the difference between the minimal luminal diameter [MLD] immediately after the procedure and the MLD at follow-up) was 0.45 mm (I. De Scheerder, MD, unpublished data, 2002). The inadequate release profile of the pharmacological agent, eluted almost completely in the first 24 hours after deployment, likely influenced the clinical effect of the drug. Tranilast, N-(3,4-dimethoxycinnamoyl) anthranilic acid, also has been shown to inhibit proliferation and migration of vascular SMCs in experimental models. A large multicenter trial failed to show antirestenosis effects of this agent administered systemically.⁵³ Initial experiments with the biodegradable Igaki-Tamai stent loaded with 184 µg of tranilast per stent have been initiated.

	Human Evidence for the Role of Cellular Proliferation in Restenosis

Top Introduction Restenosis: Definitions and... An Integrated View of... Animal Model and Human... Molecular Mechanisms of... Antiinflammatory Approaches to... Human Evidence for the... Cell Cycle and Restenosis Local Drug Pharmacokinetics Clinical Aspects of Restenosis... Mechanism of Restenosis after... DES: Future Approaches Conclusion References

 
Experimental studies have suggested that SMC proliferation is critical to neointimal formation after mechanical injury, including wire-, balloon-, and stent-induced injury. Using proliferation markers, such as proliferating nuclear cell antigen (PCNA) and incorporation of BrdU, these studies have observed peak proliferation rates of up to 10% to 20% of total medial cells 5 to 7 days after injury.^19,41,54 Human pathological data with regard to this issue are limited and controversial. Kearney and coworkers⁵⁵ retrieved in-stent restenotic tissue by directional atherectomy from 10 patients after percutaneous revascularization of peripheral artery disease. Cellular proliferation was evaluated via the use of antibodies to PCNA, cyclin E, and cdk2. Directional atherectomy tissue contained areas composed predominantly of SMCs. Evidence of ongoing SMC proliferative activity also was documented: 24.6±2.3% of SMCs were PCNA positive, 24.8±3.1% were cyclin E positive, and 22.5±2.2% were cdk2 positive. In contrast, O’Brien and colleagues estimated that the maximum percentage of cells that were replicating was <1.2%, as shown by the expression of H3 mRNA⁵⁶; however, high levels of focal replication also were observed, with up to 6.6% replicating cells. There is also evidence that cells of monocyte/macrophage lineage (HAM-56 positive) proliferate within human in-stent restenotic tissue.¹¹ The discrepancy between the levels of replication in animals and humans is likely secondary to the fact that animal studies examine proliferation at early time points (<1 week) when proliferation peaks, whereas human studies assess proliferation late (>3 months) when proliferation wanes. Nevertheless, the effectiveness of rapid-release sirolimus (>90% eluted in 30 days) in reducing late loss after clinical stenting⁵⁷ supports the biological relevance of early cellular proliferation even in humans. Taken together these observations support the notion that neointimal hyperplasia results from vascular cell (ie, SMC and monocyte/macrophage) proliferation and provide the basis for antirestenosis strategies targeting cell cycle division early after stent implantation.

	Cell Cycle and Restenosis

Top Introduction Restenosis: Definitions and... An Integrated View of... Animal Model and Human... Molecular Mechanisms of... Antiinflammatory Approaches to... Human Evidence for the... Cell Cycle and Restenosis Local Drug Pharmacokinetics Clinical Aspects of Restenosis... Mechanism of Restenosis after... DES: Future Approaches Conclusion References

 
Under normal conditions, SMCs are quiescent and exhibit low levels of proliferative activity. Mechanical injury or growth factors trigger the SMC progress through the G₁/S transition of the cell cycle^58,59 (Figure 2). The different phases of the cell cycle of eukaryotic cells are regulated by a series of protein complexes composed of cyclins (D, E, A, B), cyclin-dependent kinases (CDKs; CDK4, CDK2, p34^cdc2) and their cyclin-dependent inhibitors (CKIs; p27^Kip1, p70, p16^INK4).^60–62 The function of CKIs is regulated by changes in their concentration as well as in their localization in the cell. The concentration of p27^Kip1 is controlled predominantly by the ubiquitin-proteosome pathway.⁶³ The CKIs have distinct temporal and spatial patterns of expression in normal, injured, and diseased arteries (Figure 2).⁵⁸ p27^Kip1 is downregulated after arterial injury when cell proliferation increases. p21^Cip1 is not observed in normal arteries but is upregulated along with p27^Kip1 in later phases of arterial healing response and is associated with a significant decline in cell proliferation and an increase in procollagen and transforming growth factor-ß synthesis.⁵⁸ These findings suggest that p27^Kip1 and p21^Cip1 are endogenous regulators of G₁ transit in vascular SMCs and inhibit cell proliferation after arterial injury. p27^Kip1 and p21^Cip1 bind and alter the activities of cyclin D-, cyclin E-, and cyclin A-dependent kinases (CDK2) in quiescent cells, leading to the failure of G₁/S transition and cell cycle arrest.^64,65 Overexpression of p27^Kip1 results in cell cycle arrest in the G₁ phase.⁶⁶ Gene transfer of p27^Kip1 or p21^Cip1 into balloon-injured arteries produces a significant reduction in SMC proliferation and neointimal thickening.^58,67,68 Conversely, inhibition of p27^Kip1 increases the number of cells in S phase.⁶⁹ p27^Kip1-deficient mice develop hyperplasia in multiple organs, including endocrine tissues, thymus, and spleen.^70–72 Importantly, deficiency of p27^Kip1 has a prominent vascular phenotype with markedly increased neointimal thickening and inflammatory cell accumulation after mechanical arterial injury.⁵⁴

View larger version (23K): [in this window] [in a new window]   Figure 2. A, Regulation of the cell cycle. Progression through G1 phase of the cell cycle occurs by the assembly and phosphorylation of cyclin and CDKs. The CKIs act as brakes to halt the cyclin and arrest cycles. PCNA indicates proliferating cell nuclear antigen; Rb, retinoblastoma; P, phophorylated. Reprinted with permission from Circulation.74 B, Schematic representation of the temporal role of CKIs (p27Kip1, p21Cip1, and p16INK), transforming growth factor-ß, and collagen in SMC proliferation during arterial repair in porcine arteries.

The level of p27^Kip1 is also regulated by constituents of the ECM. Mature collagen (polymerized type 1 collagen) suppresses p70^S6k and has been shown to increase the levels of p27^Kip1, whereas monomeric collagen, which is present during degradation of ECM in the synthesis phase of restenosis, downregulates p27^Kip1. In addition, SMC migration appears to be regulated by the cell cycle.⁷³ SMCs in G₁ but not in later phases of the cell cycle have the ability to migrate on mitogenic stimulus, but the upregulation of p27^Kip1 inhibits cellular migration.^74,75

The cell cycle is a common hub of the different phases of the restenosis process. The unprecedented clinical successes of recent antirestenosis approaches targeting cellular division pathways illustrate its central role in the formation of neointimal hyperplasia. Currently available DES technologies deliver high concentrations of immunosuppressive or antitumor agents into the vessel wall. The specific molecular and cellular effects of these agents are discussed in the sections below. Clinical data on DES technologies were recently reviewed in this journal and are summarized in the Table.⁷⁶

View this table: [in this window] [in a new window]   Summary of Drug-Eluting Stent Clinical Data

Rapamycin
Rapamycin (sirolimus) is a natural macrocyclic lactone with potent immunosuppressive properties. The drug was isolated from Streptomyces hygroscopicus in the mid 1970s and approved by the Food and Drug Administration for the prophylaxis of renal transplant rejection in 1999 (Figure 3A). Other rapamycin analogs, such as everolimus, ABT-578, biolimus-A9, and temsirolimus, have been developed recently, and clinical investigations testing the safety and antirestenotic effects of these agents are under way.

View larger version (17K): [in this window] [in a new window]   Figure 3. A, Chemical structure of sirolimus showing the binding sites of FKBP, mTOR, and radical group that is replaced in other rapamycin analogs (everolimus: OCH2CH2OH; ABT-578: tetrazole; biolimus A9: OCH2CH2OR). Courtesy of Dr Robert Falotico, Cordis Johnson & Johnson, and used with permission. B, Structure of paclitaxel. Reprinted with permission from N Engl J Med.95 Copyright © 1995, Massachusetts Medical Society. All rights reserved.

Mechanism of Action
Rapamycin is actually a pro-drug that binds to specific cytosolic proteins. The mechanism of action of sirolimus is distinct from other immunosuppressive agents that act solely by inhibiting DNA synthesis. Sirolimus binds to the immunophilin FK506-binding protein 12 (FKBP12), which is upregulated in human neointimal SMCs.^77,78 FKBP12-independent effects of rapamycin remain unknown. The FKBP12/rapamycin complex binds to a specific cell cycle–regulatory protein, the mTOR (mammalian target of rapamycin), and inhibits its activation. TOR is a member of the P13K-related protein kinase (PIKK) family and is composed of up to 20 tandemly repeated motifs. PIKKs are involved with critical steps of the cell cycle, including checkpoints that govern DNA damage and repair.⁷⁹ The C-terminus of mTOR contains the FKBP12/rapamycin-binding domain. TOR binding to rapamycin is mediated by a 150-kDa peptide called raptor (regulatory-associated protein of mTOR).⁸⁰ Another protein named GbetaL has been shown to stabilize the interaction between raptor and mTOR. Recently, mTOR also has been shown to be part of a distinct complex independent of rapamycin.⁸¹

The precise downstream molecular effects of the inhibition of mTOR by rapamycin are not completely understood. mTOR is involved with a crucial event of the cell cycle, the transition between the G₁ and S phase, in which DNA replication occurs, thus leading to irreversible cellular commitment toward division (Figure 4). Thus, rapamycin has been shown to have a cytostatic effect and to induce cell-cycle arrest in late G₁ phase.^78,82 A known effect of rapamycin is the inhibition of serine/tyrosine kinase p70^S6k and upregulation of the p27^Kip1 (discussed above)⁸³ (Figure 4); however, at higher doses, rapamycin may inhibit cellular migration through a mechanism that is independent of p27^Kip175.

View larger version (33K): [in this window] [in a new window]   Figure 4. Upstream and downstream pathways of mTOR. Membrane receptors activated by various growth factors (ie, insulin, IL-2). G-protein couple receptors cause activation of phosphatidylinositol-3 kinase, which catalyzes the conversion of phosphatidylinositol4,5-biphosphate (PIP2) to phosphatidylinositol3,4,5-triphosphate (PIP3). PIP3 binds to a serine-threonine kinase, Akt, which affects the phosphorylation states of mTOR. Downstream, mTOR phosphorylates the phosphorylated heat-stable and acid-stable protein (Phas-1), which is a translational repressor that binds to eIF4E. This process releases the eukaryotic initiation factor eIF4F for initiation of protein translation. mTOR also stimulates the p70s6k mitogen-stimulated kinase. These processes are blocked by the FKBP12-sirolimus (SIR) complex.

Rapamycin has been shown to inhibit all phases of the restenosis cascade. Suzuki and colleagues tested sirolimus-eluting stents in porcine restenosis models.⁸⁴ Inflammation was markedly reduced in the treatment group, which paralleled the inhibition in neointimal hyperplasia formation.⁸⁴ Reendothelialization occurred at a similar degree in both DES and bare-metal stent groups. Reendothelialization after sirolimus-eluting stents also has been confirmed in human coronary arteries.⁸⁵ Rapamycin also has been shown to inhibit total protein and collagen synthesis involved in ECM formation. Furthermore, rapamycin inhibits SMC migration^75,86 and promotes a contractile rather than a proliferative phenotype.⁸⁷ As a result of these multiple mechanisms of action, sirolimus-eluting stents have been shown to reduce neointimal thickening as compared with both bare-metal and polymer-coated stents in various animal models and clinical trials.^{57,86,88–92}

The most sensitive cell lines respond to rapamycin at the nanomolar level (50% inhibitory concentration [IC50] <2 nmol/L). Rapamycin is effective over a range of doses (18 to 1200 µg/18-mm stent) in animal models. The current dose applied onto the stents is 140 µg/cm² (180 µg/18-mm stent), whereas 1200 µg of rapamycin per 18-mm stent did not reach toxic levels. This broad toxic-therapeutic window is critical because these devices are implanted in diseased human coronary arteries, which are highly heterogeneous in composition and asymmetric. Of note, the first series of patients treated with sirolimus-eluting stents have recently completed 5-year clinical and angiographic follow-up without evidence for adverse reactions associated with the device.

Taxanes
Paclitaxel (Taxol; Bristol-Myers Squibb) was isolated from the bark of the Western yew tree in 1971.⁹³ Paclitaxel is a diterpenoid compound that contains a complex 8-member taxane ring as its nucleus (Figure 3B). The side chain linked to the taxane ring at carbon 13 is essential for its antitumor activity. Modification of the side chain has led to identification of the more potent analog, docetaxel (Taxotere; Aventis Pharmaceuticals), which shares the same spectrum of clinical activity as paclitaxel but differs in its spectrum of toxicity. Originally purified as the parent molecule from yew bark, paclitaxel can now be obtained for commercial purposes by semisynthesis from 10-desacetylbaccatin, a precursor found in yew leaves. It also has been successfully synthesized⁹⁴ in a complex series of reactions. Paclitaxel has limited solubility and must be administered in a vehicle of 50% ethanol and 50% polyethoxylated castor, a formulation that is likely responsible for a high rate of hypersensitivity reactions.

Paclitaxel and docetaxel exhibit unique pharmacological action as inhibitors of mitosis, differing from the vinca alkaloids and colchicine derivatives in that they bind to a different site on ß-tubulin and promote rather than inhibit microtubule formation. The drugs play a central role in the therapy of ovarian, breast, lung, esophageal, bladder, and head and neck cancers.⁹⁵

Mechanism of Action
Interest in paclitaxel was stimulated by the finding that the drug possessed the unique ability to promote microtubule formation at cold temperatures and in the absence of guanosine 5'-triphosphate.^96,97 Microtubules form the mitotic spindle during cell division and are important in other cell functions, including maintenance of cell shape, motility, and intracellular transport.⁹⁵ Paclitaxel binds specifically to the ß-tubulin subunit of microtubules and appears to antagonize the disassembly of this key cytoskeletal protein, with the result that bundles of microtubules and aberrant structures derived from microtubules accumulate in the mitotic phase of the cell cycle. Arrest in mitosis (G₂/M phase) follows. Cell killing is dependent on both drug concentrations and duration of cell exposure. Paclitaxel enhances the cytotoxic effects of ionizing radiation in vitro, possibly by inducing arrest in the premitotic G₂ and mitotic phases of the cell cycle, which are the most radiosensitive phases.⁹⁵ Drugs that block the progression of cells through DNA synthesis (eg, sirolimus) and into mitosis may antagonize the toxic effects of taxanes. This may have significant implications for the clinical scenario of overlapping a sirolimus-eluting stent with a paclitaxel-eluting stent.

Paclitaxel also has distinct cell cycle–independent effects. Paclitaxel is capable of influencing cellular spreading and migration as a consequence of its effect on microtubule function.^98,99 The avidity of cell adhesion molecules, such as integrins, is regulated by cytoskeletal constraints, which keep integrin in an inactive state. Releasing these constraints results in increased lateral mobility and clustering of integrins, which effectively activate adhesion. Depolymerization of microtubules by colchicines or nocodazole and stabilization of microtubules by paclitaxel increase integrin mobility and activate adhesion.⁹⁹ In SMCs, these effects lead to a pronounced inhibition of SMC migration in vitro and in vivo.^98,100 A series of studies have shown that paclitaxel and lipopolysaccharide induce strikingly similar responses in murine macrophages.^101,102 Paclitaxel provides a second signal for murine macrophage tumoricidal activity via L-arginine–dependent nitric oxide (NO) synthesis^101,102 that appears to require paclitaxel binding to CD18¹⁰³ and protein kinase C.¹⁰² Paclitaxel also has immunomodulatory properties. Through its capacity to induce IL-12 production, paclitaxel may contribute to the correction of tumor-induced immune dysfunction.^104,105

Resistance
In cultured tumor cells, resistance to taxanes is associated in some lines with increased expression of the mdr-1 gene and its product, the P-glycoprotein; other resistant cells have ß-tubulin mutations, and these latter cells may display heightened sensitivity to vinca alkaloids.¹⁰⁶ Other cell lines display an increase in surviving, an antiapoptotic factor,¹⁰⁷ or aurora kinase, an enzyme that promotes the completion of mitosis.¹⁰⁸ The basis of clinical drug resistance is not known.

Therapeutic Uses
Paclitaxel and docetaxel have become central components of regimens for treating metastatic ovarian, breast, lung, and head and neck cancers.^109,110 Docetaxel has significant activity with estramustine for the treatment of hormone-refractory prostate cancer. Both drugs are used in either once-weekly or once-every-3-week regimens, with comparable response rates and somewhat different patterns of toxicity. The optimal schedule of taxane administration, alone or in combination with other drugs, is still under evaluation.

Unlike other antimitotic agents, paclitaxel shifts the cytoskeleton equilibrium toward assembly, leading to reduced vascular cell proliferation, migration, and signal transduction.⁹⁸ Stents eluting paclitaxel (200 µg per stent) reduced neointimal and medial cell proliferation at all time points (7, 28, 56, and 180 days) when placed in porcine coronary arteries¹¹¹; however, arteries treated with paclitaxel showed incomplete healing, late persistence of a large number of macrophages, and fibrin deposition. Similar findings were observed with a stent platform coated with cross-linked biodegradable polymer (chondroitin sulfate and gelatin) in rabbit iliac arteries.¹¹² These studies indicated the need for a tightly controlled drug release of paclitaxel because of its narrow toxic-therapeutic window and hydrophobic properties.

Early clinical studies of stents coated with 2 to 3 µg/mm² of paclitaxel without a polymer coating showed suboptimal antirestenosis effects.^113–115 On the other hand, stents coated with a poly(lactide-co--caprolactone) to control the release of the drug were effective in reducing late loss and restenosis in a series of clinical trials, the TAXUS studies.^116–118 Most of these studies tested stents coated with 85 µg of paclitaxel (1.0 µg/mm²) with an initial burst phase over the first 48 hours after implantation followed by a slow-release phase for 10 days (ie, slow-release formulation), but >80% of the drug remains unreleased from the polymer coating. The moderate-release Taxus stent (Boston Scientific) delivers an 8-fold higher dose of Taxol in the first 10 days.

	Local Drug Pharmacokinetics

Top Introduction Restenosis: Definitions and... An Integrated View of... Animal Model and Human... Molecular Mechanisms of... Antiinflammatory Approaches to... Human Evidence for the... Cell Cycle and Restenosis Local Drug Pharmacokinetics Clinical Aspects of Restenosis... Mechanism of Restenosis after... DES: Future Approaches Conclusion References

 
The biological effects of any pharmacological agent delivered locally are influenced by local transport forces, which are related to the properties of the target tissue.^119,120 The highly heterogeneous composition of the arterial wall¹²¹ and its asymmetric geometrical organization represents a challenge for most agents applied in DES technologies. The ideal compound for intramural delivery should contain hydrophobic elements to ensure high local concentrations as well as hydrophilic properties to allow homogeneous drug diffusion. Altered transport of these agents through the vessel wall may lead to both toxic levels in areas where the drug may accumulate (ie, surrounding the stent struts) and nontherapeutic levels in remote regions away from the drug reservoir (ie, adventitial tissue). In bovine internal carotid segments, tissue-loading profiles for rapamycin and paclitaxel were similar. Both drugs bind to the artery at 30 to 40 times bulk concentration; however, these drugs showed markedly different profiles of transmural distribution, with rapamycin distributing evenly through the artery, whereas paclitaxel remains primarily in the subintimal space.¹²²

	Clinical Aspects of Restenosis after DES

Top Introduction Restenosis: Definitions and... An Integrated View of... Animal Model and Human... Molecular Mechanisms of... Antiinflammatory Approaches to... Human Evidence for the... Cell Cycle and Restenosis Local Drug Pharmacokinetics Clinical Aspects of Restenosis... Mechanism of Restenosis after... DES: Future Approaches Conclusion References

 
Gruntzig and coworkers¹²³ observed that most clinical ischemic events related to vessel renarrowing occurred between 3 and 9 months after balloon angioplasty. This seminal observation illustrates the delay between the biological process and symptomatic presentation of restenosis, which results in a 70% increase in the incidence of target lesion revascularization between 6 and 12 months after the procedure.¹²⁴ The time frame to develop clinical signs of restenosis after DES may be further extended because antiproliferative agents may delay the biological response to injury. Indeed, intimal proliferation after brachytherapy seems to have a different time course¹²⁵ and pathological characteristics, as IVUS already elicited its echolucent appearance, dubbed "black hole."¹²⁶

In routine practice, noninvasive assessment of restenosis is an appropriate approach; however, objective criteria of restenosis are required in clinical trials testing the antiproliferative effects of a given therapy. The use of continuous angiographic criteria of lumen deterioration, namely late lumen loss, more closely reflects the magnitude of the intimal hyperplasia response after stenting.^127,128 Late loss represents an angiographic surrogate for neointimal proliferation within the stented segment because the remodeling component of restenosis is abolished. In adjacent nonstented segments (ie, in-segment and edge segments), the value of late loss to define vessel wall biological response to injury is limited by multiple confounding factors that influence luminal dimensions, such as elastic recoil, vessel spasm, and remodeling.

Late loss has been classically calculated as MLD immediately after the procedure minus MLD at follow-up without consideration of the location of the MLD. Angiographic measurements, however, are highly dependent on the site of the measurements and location of MLD. A mismatch between the location of the MLD between immediately after the procedure and follow-up, which occurs frequently,¹²⁹ affects the calculation of the true luminal deterioration, and consequently the proper assessment of the neointimal proliferation.

A customized angiographic methodology, which includes individual subsegmental (5 mm per segment) quantifications, has been proposed to calculate "true" late loss, which compares MLD between postprocedure and follow-up measurements at matched locations (M.A.C., unpublished data, 2004). This methodology allows the assessment of the vascular response (ie, late loss) at individual sites along the entire target segment. The variations in drug distribution, degree of injury, and tissue composition along the target vessel wall provide substrates for heterogeneous local vessel wall responses, which have been observed after balloon angioplasty.¹³⁰ Indeed, preliminary data from our core laboratory showed a mismatch between the sites of MLD in >50% of the assessments in patients with diabetes treated with either bare-metal or sirolimus-eluting stents. The relocation-of-MLD phenomenon resulted in a 0.26-mm difference between late loss measurements (unmatched versus matched MLD sites).

Although late loss represents the best angiographic surrogate of the biological arterial wall response in stented segments, its value as a clinically relevant end point has been questioned. The correlation between late loss and the need for repeat revascularization has been demonstrated recently.¹³¹

The classical binary definition of restenosis based on percentage diameter stenosis does not accurately depict the degree of deterioration of the vessel after angioplasty and does not convey a measure of the vessel’s response to injury. Angiographically detected lesions of 50% diameter stenosis at follow-up have been historically considered as representing "restenosis"; however, binary restenosis erroneously assumes that a patient with 51% diameter stenosis and another with 49% diameter stenosis have different intimal hyperplasia responses.

Other angiographic parameters that may have reasonable correlation with clinical restenosis are MLD at follow-up and percentage diameter stenosis. The parameter percentage diameter stenosis carries with it the assumption of normal-appearing reference segments, which is known from IVUS studies to be an erroneous assumption.¹³² Furthermore, the location of the MLD also interferes with the calculation of reference vessel size and consequently affects percentage diameter stenosis.

Finally, the clinical surrogates of restenosis, target lesion and target vessel revascularization should be regarded as the true measure of DES treatment success; however, clinical end points are subjective and do not determine the biological antiproliferative efficacy of DES.

	Mechanism of Restenosis after DES

Top Introduction Restenosis: Definitions and... An Integrated View of... Animal Model and Human... Molecular Mechanisms of... Antiinflammatory Approaches to... Human Evidence for the... Cell Cycle and Restenosis Local Drug Pharmacokinetics Clinical Aspects of Restenosis... Mechanism of Restenosis after... DES: Future Approaches Conclusion References

 
Our understanding of the mechanisms of DES failure is still limited. It appears that the causes of restenosis after implantation of bare-metal stents and DES are fundamentally the same. The relative contributions of individual factors to the development of clinical restenosis, however, appear to differ considerably between DES and bare-metal stents.

The magnitude of the biological response of DES on neointimal proliferation has likely unmasked the contribution of 2 other aspects of restenosis after bare stents: (1) mechanical-related failures, including stent underexpansion,¹³³ strut fracture, and plaque prolapse, and (2) technique-related factors, including barotrauma outside the stented segment or uncovered atherosclerotic plaques (ie, geographical miss).¹³⁴ The US Cypher Post-Marketing Surveillance study included 2067 patients (3245 lesions) treated with at least 1 sirolimus-eluting stent in 38 US hospitals. Procedural data from 31 patients with restenosis of the target segment was evaluated by an independent core laboratory. Geographical miss, a technique-related phenomenon, was depicted in all 11 segments with edge restenosis (M.A.C., unpublished data, 2004). Stent strut displacement, which represents a mechanical failure, was noted in 1 patient. The S.T.L.L.R. (Prospective Evaluation of the Impact of Stent Deployment Technique on Clinical Outcomes of Patients Treated With the Cypher Sirolimus-Eluting Stent) study is prospectively evaluating the impact of deployment techniques in the outcomes of 1500 patients treated with sirolimus-eluting stents in multiple centers around the United States. Preliminary results showed an incidence of longitudinal geographical miss in 45.8% of the procedures.

Although DES have drastically reduced angiographic and clinical restenosis across broad lesion and patient subsets, certain anatomic and clinical scenarios, such as patients with diabetes mellitus, restenotic lesions after brachytherapy (P. Teirstein, MD, unpublished data, 2004) or DES,¹³⁵ bypass graft disease, and bifurcations, continue to be problematic. In addition, the characteristics of intimal hyperplasia may be altered by potent medications that interfere with cell division. Echolucent intimal tissue, termed black hole (Figure 5), also has been depicted by IVUS in patients with restenosis after DES implantation, particularly those who have previously failed brachytherapy (M.A.C., unpublished data, 2004). The molecular mechanisms involved in the development of black hole are not understood but likely represent an altered cellular response to vascular injury. The hypocellularity of this intraluminal tissue and the homogeneous distribution of proteoglycans may explain the lack of ultrasound signal (echolucent). Regions of acelullar plasma-like collections were recently observed at 30 and 90 days after DES implantation in porcine coronary arteries.¹³⁶ Future studies combining IVUS and histology are required to reconcile clinical IVUS findings with histological observations in experimental models. Difficulty in visualizing this echolucent tissue by IVUS may puzzle operators who encounter patients with angiographic restenosis that is "undetectable" by IVUS. In addition, this phenomenon may affect the proper quantification of intimal proliferation in DES trials. Further investigations are required to elucidate this novel biological vessel wall response and its association with potent antiproliferative agents.

View larger version (62K): [in this window] [in a new window]   Figure 5. Cross-sectional IVUS image of black hole—with (left) and without (right) contours—after implantation of sirolimus-eluting stents in a restenotic lesion after brachytherapy.

The patterns of in-stent restenosis also have changed with DES and appear to be specific for each type of device. Restenosis after sirolimus-eluting stents are mostly (>90%) focal and usually located at the stent edges,^137,138 whereas diffuse intimal proliferation or total occlusion accounts for 50% of the restenosis cases after polymer-coated Taxol-eluting stent implantation (A. Colombo, MD, personal communication, 2004). A tentative association between the mechanisms and patterns of restenosis is illustrated in Figure 6.

View larger version (26K): [in this window] [in a new window]   Figure 6. Tentative association between the mechanisms and patterns (location) of restenosis. Strong associations are represented by thick lines, whereas weak relationships are represented by dashed lines. Complex anatomic or clinical scenarios are associated with both biological- and technique-related failures. In noncomplex cases, the biological response is almost completely blocked by the antiproliferative agent. Restenosis in noncomplex cases are mainly associated with technique-related failures and appears mostly at the stent edges or gaps between stents. On the other hand, biological as well as mechanical failures are mainly associated with in-stent restenosis. Bifurcation lesion represents an exception to this general rule because it is usually associated with technique-related failures (ie, inability to effectively treat the ostium of the side branch) but may affect the body of the main branch stent.

	DES: Future Approaches

Top Introduction Restenosis: Definitions and... An Integrated View of... Animal Model and Human... Molecular Mechanisms of... Antiinflammatory Approaches to... Human Evidence for the... Cell Cycle and Restenosis Local Drug Pharmacokinetics Clinical Aspects of Restenosis... Mechanism of Restenosis after... DES: Future Approaches Conclusion References

 
Endothelium and Restenosis
Endothelial integrity is essential for maintaining vascular homeostasis, and endothelial denudation results in neointimal thickening.^139,140 Endothelial cell products inhibit platelet function and thrombosis, control vessel wall permeability,¹⁴¹ and bind and inactivate mitogens, thereby inhibiting SMC growth.¹⁴² Endothelial dysfunction may persist for >3 months after vascular injury and is more pronounced after bare-metal stent implantation as compared with balloon angioplasty.¹⁴³ Whether the development of a functional endothelial layer is further delayed after DES implantation remains to be investigated. Experimental evidence from animal models suggests that the antiproliferative properties of paclitaxel may limit endothelial cell regrowth.¹¹¹ This may represent the basis for the recommended prolonged (6-month-long) dual antiplatelet therapy for patients treated with paclitaxel-eluting stents. Endothelial cell recoverage occurred to a similar extent (70%) in bare-metal stents and sirolimus-eluting stents implanted in dog coronary arteries.⁸⁴ Recent pathological analyses of human coronary arteries treated with sirolimus-eluting stents confirm almost complete reendothelialization of stents late after implantation.^85,144 These results are reassuring, but the functional status of endothelial cells covering DES was not assessed. Nevertheless, the incidence of stent thrombosis, which is one clinical consequence of abnormal healing and reendothelialization, remains low after DES implantation with recommended antiplatelet regimens.¹⁴⁵

Investigators have pursued diverse strategies, including pharmacological modulation, tissue engineering, gene and stem cell therapies, and even procedural modifications (ie, direct stenting) to limit endothelial injury, supplement endothelial cell products, accelerate endothelial cell regeneration, or all 3, to reduce neointimal thickening. Promoting rather than blocking the healing process by stimulating reendothelialization seems the most natural approach to prevent restenosis.

Rogers and coworkers¹⁴⁶ have explored whether stenting technique (ie, predilation versus direct stenting) and the degree of endothelial damage might determine later proliferative sequelae. En face staining of the luminal surfaces of stented iliac arteries of New Zealand White rabbits demonstrated endothelial cell loss immediately after stent expansion, which was restricted to interstices between stent struts. Remnant endothelium adjacent to struts provided the foundation for complete endothelial regeneration of the stented segment within 3 days. Vessel wall inflammation was reduced >80% in directly stented arteries, in concert with a 2-fold reduction in intimal thickening after 14 days, as compared with arteries completely denuded by balloon predilatation before stent expansion. These data indicate that the degree of endothelial injury, which is influenced by stent and balloon design and deployment technique, is an important determinant in the biological repair response to vascular injury.

Seminal experiments from the laboratory of Edelman and associates using tissue-engineered perivascular endothelial cell implants have identified the heparan sulfate proteoglycan perlecan as a potent inhibitor of neointimal hyperplasia after deep vascular injury, largely as a consequence of its ability to modulate thrombosis and inhibit basic fibroblast growth factor binding and activity.¹⁴⁷ In these experiments, endothelial cells were seeded onto 3-dimensional polymeric matrices and implanted adjacent to porcine carotid arteries subjected to deep injury. Thus, in this model, the endothelial cells are far from the lumen, allowing their biochemical regulatory properties to be dissociated from their boundary properties. Perivascular transplantation combined with the ability to genetically modify cultured endothelial cells provides a powerful tool to dissect the roles of various endothelial cell products in controlling the vascular response to injury. Although valuable from a proof-of-principle point of view, perivascular endothelial cell transplantation is obviously not practical clinically. Advances in tissue engineering may allow for endothelial cell seeding on stents.¹⁴⁸

Endothelial-derived NO also participates in the control of vascular healing by attenuating vascular inflammation and inhibiting SMC proliferation and migration.¹⁴⁹ With the highly efficient Sendai virus/liposome in vivo gene transfer technique, endothelial nitric oxide synthase (eNOS) gene transfection not only restored NO production of rat carotid arteries after endothelium denudation but also increased vascular reactivity of the injured vessels. Neointima formation at day 14 after balloon injury was inhibited by 70%. These observations provide further evidence that NO is an endogenous inhibitor of vascular lesion formation in vivo and suggest the possibility that strategies to increase eNOS or NO production are potential therapeutic approaches to treat neointimal hyperplasia.

Pharmacological strategies aiming at stimulating endothelial regeneration or NO production have been tested. Stents coated with oxygen free radical scavenger conjugated with polyesteramide coating were implanted in 45 patients in a multicenter study involving European and South American sites. The study failed to demonstrate the antirestenosis properties of NO donors. Estradiol has been shown to improve vascular healing, reduce SMC migration and proliferation, and promote local angiogenesis via NO-dependent and NO-independent mechanisms.¹⁵⁰ Stents eluting 17-ß estradiol were implanted in porcine coronary arteries and reduced neointimal hyperplasia by 40% as compared with control stents.¹⁵¹ Estradiol-eluting stents were subsequently implanted in human coronary arteries in a single-center feasibility study involving 30 patients with de novo coronary lesions. The average concentration was 2.54 µg/mm² of stent. There were no deaths or stent thromboses, and 1 patient underwent target lesion revascularization up to the 12-month follow-up, but a moderate in-stent luminal loss was observed.¹⁵² Stents were loaded on site by immersion in a solution of estradiol, which may have led to inadequate loading and elution of the drug.

Vascular endothelial growth factor (VEGF) has attracted attention for endothelial regeneration and angiogenesis.¹⁵³ VEGF is one of the most potent vascular permeability factors known and is thought to function as an endogenous regulator of endothelial integrity after injury, thereby protecting the artery from disease progression.¹⁵⁴ Previous animal studies have reported that local delivery of VEGF as naked DNA, adenovirus-mediated gene transfer, or recombinant protein after balloon- and stent-induced endothelial injury promotes endothelial regeneration, accelerates the recovery of endothelium-dependent relaxation, and reduces neointimal formation, suggesting the close correlation between accelerated endothelial integrity and reduced neointima after balloon and stent injury.^155–159 There is still considerable debate, however, over the vasculoprotective versus atherogenic effects of VEGF.¹⁶⁰ Increased expression of VEGF and its 2 receptors, VEGFR-1 (Flt-1) and VEFGR-2 (Flk-1), has been reported in atherosclerotic and restenotic lesions.^161,162 VEGF induces migration and activation of monocytes,¹⁶³ induces adhesion molecules¹⁶⁴ and MCP-1,¹⁶⁵ and enhances neointimal formation and atherogenesis by stimulating intraplaque angiogenesis in hypercholesterolemic animals without balloon injury^166,167 or by increasing monocyte infiltration into atherosclerotic lesions.¹⁶⁸ Therefore, it has remained somewhat unclear whether VEGF protects the artery from vascular disease or accelerates vascular disease. A soluble form of the VEGF receptor-1 (sFlt-1) is expressed endogenously by vascular endothelial cells and can inhibit VEGF activity by directly sequestering VEGF and by functioning as a dominant-negative inhibitor against VEGF.¹⁶⁹ Blockade of VEGF by sFlt-1 gene transfer attenuated neointimal formation after intraluminal injury in rabbits, rats, and mice.¹⁷⁰ sFlt-1 gene transfer markedly attenuated the early vascular inflammation and proliferation and later neointimal formation. sFlt-1 gene transfer also inhibited increased expression of inflammatory factors such as MCP-1 and VEGF. Thus, taken together, these observations suggest a far more complex story for VEGF in restenosis and indicate that increased expression and activity of endogenous VEGF are essential in the development of experimental restenosis after intraluminal injury by recruiting monocyte-lineage cells.

A phase II clinical study involving catheter-based local intracoronary gene transfer of VEGF (Kuopio Angiogenesis Trial) failed to reduce clinical and angiographic restenosis after balloon angioplasty and stenting.¹⁷¹ Recent exciting observations that VEGF-gene–eluting stents accelerate reendothelialization and reduce in-stent neointimal volume in animal models¹⁷² are likely to propel this approach to trials in humans, however.

The transplantation of endothelial progenitor cells (EPCs) represents a novel therapeutic approach to enhance endothelial cell regeneration, neovascularization, or both. EPCs are present in the systemic circulation and have been harvested from the peripheral circulation, expanded ex vivo, and administered to animals with limb or myocardial ischemia.^173,174 Iwaguro et al¹⁷⁵ recently investigated ex vivo phenotypic modulation as a method to enhance EPC function and to reduce the number of EPCs required for transplantation. The number of EPCs required to observe these effects was 30 times less than that required in previous animal studies to improve ischemic limb salvage. The combination of gene therapy with the techniques of cell transplantation represents a potential method for accelerating endothelial regeneration.

Bone Marrow–Derived Cells
Although the role of bone marrow–derived cells in vascular repair and regeneration has not been well defined in humans, accumulating evidence suggests that somatic stem cells in the bone marrow are capable of differentiating into vascular endothelial cells^176,177 and SMCs.^178,179 After vascular injury, it is hypothesized that progenitor cells from bone marrow or blood compartments are mobilized by cytokine activation,¹⁸⁰ home to sites of vascular damage, proliferate, and form arterial lesions in conjunction with resident arterial cells. Evidence in support of these hypotheses comes from animal models of allograft vasculopathy and diet-induced atherosclerosis, in which bone marrow–derived cells may give rise to a substantial percentage of lesional vascular SMCs.^180–182

Recent experimental findings from the laboratory of Nabel and colleagues strongly suggest that vascular repair and regeneration is regulated by the proliferation of bone marrow–derived hematopoietic and nonhematopoietic cells through a p27^Kip1-dependent mechanism and that immune cells largely mediate these effects.⁵⁴ Exploiting the power of genetically deficient mice and bone marrow transplantation, they reported that lesion formation after mechanical arterial injury was markedly increased in p27^Kip1-deficient mice, characterized by prominent vascular infiltration by immune and inflammatory cells. Vascular occlusion was substantially increased when bone marrow–derived cells from p27-deficient mice repopulated vascular lesions induced by mechanical injury in wild-type recipients, in contrast to wild-type bone marrow donors.

The contribution and importance of bone marrow–derived cells to human vascular disease is largely unproven. Histological analyses of vessels from sex-mismatched hearts after orthotopic cardiac transplantation have revealed that 10% of arterioles contained cells of host origin¹⁸³ and that 2.6% of the SMCs examined were host derived,¹⁸⁴ observations consistent with the migration of putative stem/progenitor cells from the recipient to the grafted heart. Similarly, human muscle cells of host origin were identified in the vascular lesions of renal allografts.¹⁸⁵

The use of antibodies against membrane receptors of circulating progenitor endothelial cells to attract these cells to the site of vascular injury has been proposed by Kutryk and coworkers. These investigators coated surface-modified stainless steel stents with anti-CD34 antibodies. They have found CD34⁺ cells covering 70% of the stent surface 1 hour after antibody-coated stent deployment in pig coronary arteries versus no cell coverage of stainless steel stents (M.J. Kutryk, MD, unpublished data, 2002). These antibody-coated stents have been implanted in human coronaries in a multicenter pilot study (Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth [HEALING]) without adverse reactions, but long-term outcomes are pending.

Transcription Factor Decoy Oligonucleotides
Oligodeoxynucleotides (ODNs) bearing the consensus binding sequence of a specific transcription factor are capable of manipulating gene expression in living cells. This strategy involves the intracellular delivery of such "decoy" ODNs, which are then recognized and bound by the target factor. Occupation of the transcription factor’s DNA-binding site by the decoy renders the protein incapable of subsequently binding to the promoter regions of target genes. The use of decoy ODNs for the therapeutic manipulation of gene expression was first described by Dzau’s laboratory in 1995. Morishita et al¹⁸⁶ reported the treatment of rat carotid arteries at the time of balloon injury, with ODNs bearing the consensus binding site for the E2F family of transcription factors. Although as many as 6 E2F isoforms are known to play differing roles in cell cycle progression and cell growth,¹⁸⁷ release of the predominant E2F-1 isoform at a critical point in the late G₁ phase of the cell cycle coordinately upregulates expression of multiple genes that help speed the cell through DNA synthesis and mitosis. They found that a decoy specific to E2F-1 prevented this upregulation and blocked smooth muscle proliferation and neointimal hyperplasia in injured vessels.¹⁸⁶ On the basis of these preclinical data, these investigators examined the safety and biological efficacy of E2F decoy transfection in patients receiving human vein bypass grafts for peripheral vascular disease. Treatment with E2F decoy was associated with a >70% reduction in cellular proliferation markers, and at 12 months, fewer graft occlusions, revisions, or critical stenosis as compared with the untreated group (hazard ratio 0.34 [95% CI 0.12 to 0.99]). Application of this genetic-engineering strategy to PCI likely depends on the results of 2 large phase III trials designed to lower clinical failure rates after coronary artery bypass grafting and peripheral revascularization. There are significant challenges with ODN therapy because of issues of target specificity, uptake across cell membranes, and rapid intracellular degradation of the ODN. Indeed, the only randomized restenosis study in humans with antisense ODN directed against the nuclear protooncogene c-myc demonstrated no reduction in angiographic or clinical restenosis after bare-metal stenting.¹⁸⁸

Combination Chemotherapy
Combination chemotherapy—namely, the use of multiple agents to optimize efficacy and limit toxicity—is the principal treatment strategy in oncology. To date, single-drug approaches have dominated antirestenosis programs, but emerging experimental evidence indicates that combination therapies also may be effective in reducing neointimal thickening after stenting. A combination of hirudin and iloprost was blended with a polylactic acid polymer and loaded onto a stent. Although iloprost was slowly released by the breakdown of the polymer, 60% of the hirudin was eluted in the first 24 hours.¹⁸⁹ Decreased neointimal formation was observed in sheep and pig injury models treated with this antithrombotic-eluting stent. Paclitaxel–NO donor conjugate–eluting stent was found to be more beneficial than was paclitaxel-eluting stent alone.¹⁹⁰ Gene therapy also may be combined with pharmacological therapy to modulate distinct ligand-receptor signaling systems. Leppanen and coworkers¹⁹¹ recently reported that oral imatinib mesylate (STI571/gleevec) improves the efficacy of local intravascular VEGEF-C gene transfer in reducing neointimal growth. Theoretical advantages of such combination approaches over single-drug antiproliferative therapy alone include larger reductions in neointimal growth by targeting multiple cell cycle checkpoints, diminished likelihood of resistance, and enhanced endothelial recovery.

Customized stents for drug delivery have been developed. These stents may allow both temporal and spatial control of drug release. Thus, an antithrombotic, prohealing agent could be released in the luminal surface early after implantation, whereas an antiproliferative agent could be released intramurally. The Conor stent¹⁹² has individual polymer inlays for drug reservoirs that can be loaded with different compounds.

Biodegradable Stents
Polymeric biodegradable stents, which "dissolve" slowly after implantation, are promising stent technologies that can be loaded with large amounts of drug or multiple agents. Biodegradable stents fulfill the ideal requirement for endovascular prosthesis by providing initial scaffolding support to prevent vessel recoil and negative remodeling, without the undesirable continuous vessel trauma caused by a permanent rigid foreign body. Still, polymeric stents have yet to achieve the mechanical strength or surface properties of stainless steel stents. In addition, vessel toxicity remains a major limitation for polymeric biodegradable stents.¹⁹³ The Igaki-Tamai stents have been tested in human coronary arteries with satisfactory results,¹⁹⁴ but stents were still visible by IVUS 6 months after implantation. Stents made of magnesium alloys have been developed recently. Biocorrosion of magnesium AE21 alloy containing 2% aluminum atoms and 1% rare earth elements (cerium, praseodymium, neodymium) was well tolerated in pig coronary arteries.¹⁹⁵ Inflammatory reaction, albeit not extensive, was induced by corrosion of the stent, which lost its integrity 35 days after implantation. Positive vessel remodeling was observed after this period, which may be related to the inflammatory reaction. The ability of this metallic stent to carry medication, with or without a biodegradable polymer coating, remains to be demonstrated. Further experiments are required to exclude potential vessel toxicity and hydrogen formation that may be associated with the corrosion of magnesium.

	Conclusion

Top Introduction Restenosis: Definitions and... An Integrated View of... Animal Model and Human... Molecular Mechanisms of... Antiinflammatory Approaches to... Human Evidence for the... Cell Cycle and Restenosis Local Drug Pharmacokinetics Clinical Aspects of Restenosis... Mechanism of Restenosis after... DES: Future Approaches Conclusion References

 
The elucidation of the molecular and cellular mechanisms of inflammation and cellular proliferation in vascular injury and repair powered the development of DES technology. Despite across-the-board benefits with DES as compared with bare-metal stents in randomized clinical trials and registries, significant challenges remain. Advances in drugs and devices are needed for the treatment of small vessels, left main and bifurcation lesions, and patients with diabetes mellitus. Combination chemotherapy, biodegradable stents, and cell-based therapies are likely to provide effective solutions for the prevention of restenosis in complex lesions and patients.

	References

Top Introduction Restenosis: Definitions and... An Integrated View of... Animal Model and Human... Molecular Mechanisms of... Antiinflammatory Approaches to... Human Evidence for the... Cell Cycle and Restenosis Local Drug Pharmacokinetics Clinical Aspects of Restenosis... Mechanism of Restenosis after... DES: Future Approaches Conclusion References

 
1. Forrester JS, Fishbein M, Helfant R, Fagin J. A paradigm for restenosis based on cell biology: clues for the development of new preventive therapies. J Am Coll Cardiol. 1991; 17: 758–769.[Abstract]

2. Libby P, Schwartz D, Brogi E, Tanaka H, Clinton SK. A cascade model for restenosis: a special case of atherosclerosis progression. Circulation. 1992; 86: III-47–III-52.[Medline] [Order article via Infotrieve]

3. Schwartz RS, Topol EJ, Serruys PW, Sangiorgi G, Holmes DR Jr. Artery size, neointima, and remodeling: time for some standards. J Am Coll Cardiol. 1998; 32: 2087–2094.[Free Full Text]

4. Di Mario C, Gil R, Camenzind E, Ozaki Y, von Birgelen C, Umans V, de Jaegere P, de Feyter PJ, Roelandt JR, Serruys PW. Quantitative assessment with intracoronary ultrasound of the mechanisms of restenosis after percutaneous transluminal coronary angioplasty and directional coronary atherectomy. Am J Cardiol. 1995; 75: 772–777.[CrossRef][Medline] [Order article via Infotrieve]

5. Mintz G, Popma J, Pichard A, Kent K, Satler L, Wong C, Hong M, Kovach J, Leon M. Arterial remodeling after coronary angioplasty: a serial intravascular ultrasound study. Circulation. 1996; 94: 35–43.[Abstract/Free Full Text]

6. Staab ME, Srivatsa SS, Lerman A, Sangiorgi G, Jeong MH, Edwards WD, Holmes DR Jr, Schwartz RS. Arterial remodeling after experimental percutaneous injury is highly dependent on adventitial injury and histopathology. Int J Cardiol. 1997; 58: 31–40.[CrossRef][Medline] [Order article via Infotrieve]

7. Labinaz M, Pels K, Hoffert C, Aggarwal S, O’Brien ER. Time course and importance of neoadventitial formation in arterial remodeling following balloon angioplasty of porcine coronary arteries. Cardiovasc Res. 1999; 41: 255–266.[Abstract/Free Full Text]

8. Costa MA, de Wit LE, de Valk V, Serrano P, Wardeh AJ, Serruys PW, Sluiter W. Indirect evidence for a role of a subpopulation of activated neutrophils in the remodelling process after percutaneous coronary intervention. Eur Heart J. 2001; 22: 580–586.[Abstract/Free Full Text]

9. Dussaillant G, Mintz G, Pichard A, Kent K, Satler L, Popma J, Wong S, Leon M. Small stent size and intimal hyperplasia contribute to restenosis: a volumetric intravascular ultrasound analysis. J Am Coll Cardiol. 1995; 26: 720–724.[Abstract]

10. Costa MA, Sabate M, Kay IP, de Feyter PJ, Kozuma K, Serrano P, de Valk V, Albertal M, Ligthart JM, Disco C, Foley DP, Serruys PW. Three-dimensional intravascular ultrasonic volumetric quantification of stent recoil and neointimal formation of two new generation tubular stents. Am J Cardiol. 2000; 85: 135–139.[CrossRef][Medline] [Order article via Infotrieve]

11. Welt FG, Rogers C. Inflammation and restenosis in the stent era. Arterioscler Thromb Vasc Biol. 2002; 22: 1769–1776.[Abstract/Free Full Text]

12. Riessen R, Isner JM, Blessing E, Loushin C, Nikol S, Wight TN. Regional differences in the distribution of the proteoglycans biglycan and decorin in the extracellular matrix of atherosclerotic and restenotic human coronary arteries. Am J Pathol. 1994; 144: 962–974.[Abstract]

13. Schwartz RS, Huber KC, Murphy JG, Edwards WD, Camrud AR, Vlietstra RE, Holmes DR. Restenosis and proportional neointimal response to coronary artery injury: results in a porcine model. J Am Coll Cardiol. 1992; 19: 267–274.[Abstract]

14. Strauss BH, Robinson R, Batchelor WB, Chisholm RJ, Ravi G, Natarajan MK, Logan RA, Mehta SR, Levy DE, Ezrin AM, Keeley FW. 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]

15. Bauters C, Marotte F, Hamon M, Oliviero P, Farhadian F, Robert V, Samuel JL, Rappaport L. Accumulation of fetal fibronectin mRNAs after balloon denudation of rabbit arteries. Circulation. 1995; 92: 904–911.[Abstract/Free Full Text]

16. Farb A, Kolodgie FD, Hwang JY, Burke AP, Tefera K, Weber DK, Wight TN, Virmani R. Extracellular matrix changes in stented human coronary arteries. Circulation. 2004; 110: 940–947.[Abstract/Free Full Text]

17. Tanaka H, Sukhova GK, Swanson SJ, Clinton SK, Ganz P, Cybulsky MI, Libby P. Sustained activation of vascular cells and leukocytes in the rabbit aorta after balloon injury. Circulation. 1993; 88: 1788–1803.[Abstract/Free Full Text]

18. Rogers C, Welt FG, Karnovsky MJ, Edelman ER. Monocyte recruitment and neointimal hyperplasia in rabbits: coupled inhibitory effects of heparin. Arterioscler Thromb Vasc Biol. 1996; 16: 1312–1318.[Abstract/Free Full Text]

19. Rogers C, Edelman ER, Simon DI. A mAb to the beta2-leukocyte integrin Mac-1 (CD11b/CD18) reduces intimal thickening after angioplasty or stent implantation in rabbits. Proc Natl Acad Sci U S A. 1998; 95: 10134–10139.[Abstract/Free Full Text]

20. Bishop GG, McPherson JA, Sanders JM, Hesselbacher SE, Feldman MJ, McNamara CA, Gimple LW, Powers ER, Mousa SA, Sarembock IJ. Selective alpha(v)beta(3)-receptor blockade reduces macrophage infiltration and restenosis after balloon angioplasty in the atherosclerotic rabbit. Circulation. 2001; 103: 1906–1911.[Abstract/Free Full Text]

21. Barringhaus KG, Phillips JW, Thatte JS, Sanders JM, Czarnik AC, Bennett DK, Ley KF, Sarembock IJ. Alpha4beta1 integrin (VLA-4) blockade attenuates both early and late leukocyte recruitment and neointimal growth following carotid injury in apolipoprotein E (–/–) mice. J Vasc Res. 2004; 41: 252–260.[CrossRef][Medline] [Order article via Infotrieve]

22. Moreno PR, Bernardi VH, Lopez-Cuellar J, Newell JB, McMellon C, Gold HK, Palacios IF, Fuster V, Fallon JT. Macrophage infiltration predicts restenosis after coronary intervention in patients with unstable angina. Circulation. 1996; 94: 3098–3102.[Abstract/Free Full Text]

23. Chen Z, Keaney JF Jr, Schulz E, Levison B, Shan L, Sakuma M, Zhang X, Shi C, Hazen SL, Simon DI. Decreased neointimal formation in Nox2-deficient mice reveals a direct role for NADPH oxidase in the response to arterial injury. Proc Natl Acad Sci U S A. 2004; 101: 13014–13019.[Abstract/Free Full Text]

24. Assoian RK, Fleurdelys BE, Stevenson HC, Miller PJ, Madtes DK, Raines EW, Ross R, Sporn MB. Expression and secretion of type beta transforming growth factor by activated human macrophages. Proc Natl Acad Sci U S A. 1987; 84: 6020–6024.[Abstract/Free Full Text]

25. Garbisa S, Ballin M, Daga-Gordini D, Fastelli G, Naturale M, Negro A, Semenzato G, Liotta LA. Transient expression of typeIV collagenolytic metalloproteinase produced by human mononuclear phagocytes. J Biol Chem. 1986; 261: 2369–2375.[Abstract/Free Full Text]

26. Sukhova GK, Shi G-P, Simon DI, Chapman HA, Libby P. Expression of the elastinolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells. J Clin Invest. 1998; 102: 576–583.[Medline] [Order article via Infotrieve]

27. Farb A, Weber DK, Kolodgie FD, Burke AP, Virmani R. Morphological predictors of restenosis after coronary stenting in humans. Circulation. 2002; 105: 2974–2980.[Abstract/Free Full Text]

28. Gaspardone A, Crea F, Versaci F, Tomai F, Pellegrino A, Chiariello L, Gioffre PA. Predictive value of C-reactive protein after successful coronary-artery stenting in patients with stable angina. Am J Cardiol. 1998; 82: 515–518.[CrossRef][Medline] [Order article via Infotrieve]

29. Inoue T, Sakai Y, Morooka S, Hayashi T, Takayanagi K, Takabatake Y. Expression of polymorphonuclear leukocyte adhesion molecules and its clinical significance in patients treated with percutaneous transluminal coronary angioplasty. J Am Coll Cardiol. 1996; 28: 1127–1133.[Abstract]

30. Mickelson JK, Lakkis NM, Villarreal-Levy G, Hughes BJ, Smith CW. Leukocyte activation with platelet adhesion after coronary angioplasty: a mechanism for recurrent disease? J Am Coll Cardiol. 1996; 28: 345–353.[Abstract]

31. Neumann FJ, Ott I, Gawaz M, Puchner G, Schomig A. Neutrophil and platelet activation at balloon-injured coronary artery plaque in patients undergoing angioplasty. J Am Coll Cardiol. 1996; 27: 819–824.[Abstract]

32. Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 1994; 76: 301–314.[CrossRef][Medline] [Order article via Infotrieve]

33. Smith CW, Marlin SD, Rothlein R, Toman C, Anderson DC. Cooperative interactions of LFA-1 and Mac-1 with intercellular adhesion molecule-1 in facilitating adherence and transendothelial migration of human neutrophils in vitro. J Clin Invest. 1989; 83: 2008–2017.[Medline] [Order article via Infotrieve]

34. Languino LR, Duperray A, Joganic KJ, Fornaro M, Thornton GB, Altieri DC. Regulation of leukocyte-endothelium interaction and leukocyte transendothelial migration by intercellular adhesion molecule 1-fibrinogen recognition. Proc Natl Acad Sci U S A. 1995; 92: 1505–1509.[Abstract/Free Full Text]

35. Diamond MS, Alon R, Parkos CA, Quinn MT, Springer TA. Heparin is an adhesive ligand for the leukocyte integrin Mac-1. (CD11b/CD18). J Cell Biol. 1995; 130: 1473–1482.[Abstract/Free Full Text]

36. McEver RP, Cummings RD. Role of PSGL-1 binding to selectins in leukocyte recruitment. J Clin Invest. 1997; 100: S97–S103.[Medline] [Order article via Infotrieve]

37. Diacovo TG, Roth SJ, Buccola JM, Bainton DF, Springer TA. Neutrophil rolling, arrest, and transmigration across activated, surface-adherent platelets via sequential action of P-selectin and the beta 2-integrin CD11b/CD18. Blood. 1996; 88: 146–157.[Abstract/Free Full Text]

38. Simon DI, Chen Z, Xu H, Li CQ, Dong J, McIntire LV, Ballantyne CM, Zhang L, Furman MI, Berndt MC, Lopez JA. Platelet glycoprotein Ibalpha is a counterreceptor for the leukocyte integrin Mac-1 (CD11b/CD18). J Exp Med. 2000; 192: 193–204.[Abstract/Free Full Text]

39. Welt FG, Tso C, Edelman ER, Kjelsberg MA, Paolini JF, Seifert P, Rogers C. Leukocyte recruitment and expression of chemokines following different forms of vascular injury. Vasc Med. 2003; 8: 1–7.[Abstract/Free Full Text]

40. Horvath C, Welt FG, Nedelman M, Rao P, Rogers C. Targeting CCR2 or CD18 inhibits experimental in-stent restenosis in primates: inhibitory potential depends on type of injury and leukocytes targeted. Circ Res. 2002; 90: 488–494.[Abstract/Free Full Text]

41. Simon DI, Chen Z, Seifert P, Edelman ER, Ballantyne CM, Rogers C. Decreased neointimal formation in Mac-1(-/-) mice reveals a role for inflammation in vascular repair after angioplasty. J Clin Invest. 2000; 105: 293–300.[Medline] [Order article via Infotrieve]

42. Kubo N, Boisvert WA, Ballantyne CM, Curtiss LK. Leukocyte CD11b expression is not essential for the development of atherosclerosis in mice. J Lipid Res. 2000; 41: 1060–1066.[Abstract/Free Full Text]

43. Gu L, Okada Y, Clinton SK, Gerard C, Sukhova GK, Libby P, Rollins BJ. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor–deficient mice. Mol Cell. 1998; 2: 275–281.[CrossRef][Medline] [Order article via Infotrieve]

44. Boring L, Gosling J, Cleary M, Charo IF. Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature. 1998; 394: 894–897.[CrossRef][Medline] [Order article via Infotrieve]

45. Roque M, Kim WJ, Gazdoin M, Malik A, Reis ED, Fallon JT, Badimon JJ, Charo IF, Taubman MB. CCR2 deficiency decreases intimal hyperplasia after arterial injury. Arterioscler Thromb Vasc Biol. 2002; 22: 554–559.[Abstract/Free Full Text]

46. Bienvenu JG, Tanguay JF, Theoret JF, Kumar A, Schaub RG, Merhi Y. Recombinant soluble p-selectin glycoprotein ligand-1-Ig reduces restenosis through inhibition of platelet-neutrophil adhesion after double angioplasty in swine. Circulation. 2001; 103: 1128–1134.[Abstract/Free Full Text]

47. Cipollone F, Marini M, Fazia M, Pini B, Iezzi A, Reale M, Paloscia L, Materazzo G, D’Annunzio E, Conti P, Chiarelli F, Cuccurullo F, Mezzetti A. Elevated circulating levels of monocyte chemoattractant protein-1 in patients with restenosis after coronary angioplasty. Arterioscler Thromb Vasc Biol. 2001; 21: 327–334.[Abstract/Free Full Text]

48. Danenberg HD, Golomb G, Groothuis A, Gao J, Epstein H, Swaminathan RV, Seifert P, Edelman ER. Liposomal alendronate inhibits systemic innate immunity and reduces in-stent neointimal hyperplasia in rabbits. Circulation. 2003; 108: 2798–2804.[Abstract/Free Full Text]

49. Versaci F, Gaspardone A, Tomai F, Ribichini F, Russo P, Proietti I, Ghini AS, Ferrero V, Chiariello L, Gioffre PA, Romeo F, Crea F. Immunosuppressive Therapy for the Prevention of Restenosis after Coronary Artery Stent Implantation (IMPRESS Study). J Am Coll Cardiol. 2002; 40: 1935–1942.[Abstract/Free Full Text]

50. Berk BC, Gordon JB, Alexander RW. Pharmacologic roles of heparin and glucocorticoids to prevent restenosis after coronary angioplasty. J Am Coll Cardiol. 1991; 17: 111B–117B.[Medline] [Order article via Infotrieve]

51. Pepine CJ, Hirshfeld JW, Macdonald RG, Henderson MA, Bass TA, Goldberg S, Savage MP, Vetrovec G, Cowley M, Taussig AS, Whitworth HB, Margolis JR, Hill JA, Bove AA, Jugo R. A controlled trial of corticosteroids to prevent restenosis after coronary angioplasty. Circulation. 1990; 81: 1753–1761.[Abstract/Free Full Text]

52. de Scheerder I, Wang K, Wilczek K, van Dorpe J, Verbeken E, Desmet W, Schacht E, Piessens J. Local methylprednisolone inhibition of foreign body response to coated intracoronary stents. Coron Artery Dis. 1996; 7: 161–166.[Medline] [Order article via Infotrieve]

53. Holmes D, Savage M, La BJ, Grip L, Serruys P, Fitzgerald P, Fischman D, Goldberg S, Brinker J, Zeiher A, Shapiro L, Willerson J, Davis B, Ferguson J, Popma J, King S, Lincoff A, Tcheng J, Chan R, Granett J, Poland M. Results of Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) trial. Circulation. 2002; 106: 1243–1250.[Abstract/Free Full Text]

54. Boehm M, Olive M, True AL, Crook MF, San H, Qu X, Nabel EG. Bone marrow–derived immune cells regulate vascular disease through a p27(Kip1)-dependent mechanism. J Clin Invest. 2004; 114: 419–426.[CrossRef][Medline] [Order article via Infotrieve]

55. Kearney M, Pieczek A, Haley L, Losordo DW, Andres V, Schainfeld R, Rosenfield K, Isner JM. Histopathology of in-stent restenosis in patients with peripheral artery disease. Circulation. 1997; 95: 1998–2002.[Abstract/Free Full Text]

56. O’Brien ER, Urieli-Shoval S, Garvin MR, Stewart DK, Hinohara T, Simpson JB, Benditt EP, Schwartz SM. Replication in restenotic atherectomy tissue. Atherosclerosis. 2000; 152: 117–126.[CrossRef][Medline] [Order article via Infotrieve]

57. Sousa J, Costa M, Sousa A, Abizaid A, Seixas A, Abizaid A, Feres F, Mattos L, Falotico R, Jaeger J, Popma J, Serruys P. Two-year angiographic and intravascular ultrasound follow-up after implantation of sirolimus-eluting stents in human coronary arteries. Circulation. 2003; 107: 381–383.[Abstract/Free Full Text]

58. Tanner FC, Yang ZY, Duckers E, Gordon D, Nabel GJ, Nabel EG. Expression of cyclin–dependent kinase inhibitors in vascular disease. Circ Res. 1998; 82: 396–403.[Abstract/Free Full Text]

59. Nabel EG. CDKs and CKIs: molecular targets for tissue remodelling. Nat Rev Drug Discov. 2002; 1: 587–598.[CrossRef][Medline] [Order article via Infotrieve]

60. Morgan DO. Principles of CDK regulation. Nature. 1995; 374: 131–134.[CrossRef][Medline] [Order article via Infotrieve]

61. Sherr CJ. Cancer cell cycles. Science. 1996; 274: 1672–1677.[Abstract/Free Full Text]

62. Ekholm SV, Reed SI. Regulation of G(1) cyclin-dependent kinases in the mammalian cell cycle. Curr Opin Cell Biol. 2000; 12: 676–684.[CrossRef][Medline] [Order article via Infotrieve]

63. Pagano M, Tam SW, Theodoras AM, Beer-Romero P, Del Sal G, Chau V, Yew PR, Draetta GF, Rolfe M. Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science. 1995; 269: 682–685.[Abstract/Free Full Text]

64. Polyak K, Lee MH, Erdjument-Bromage H, Koff A, Roberts JM, Tempst P, Massague J. Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell. 1994; 78: 59–66.[CrossRef][Medline] [Order article via Infotrieve]

65. Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999; 13: 1501–1512.[Free Full Text]

66. Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massague J, Roberts JM, Koff A. p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev. 1994; 8: 9–22.[Abstract/Free Full Text]

67. Yang ZY, Simari RD, Perkins ND, San H, Gordon D, Nabel GJ, Nabel EG. Role of the p21 cyclin–dependent kinase inhibitor in limiting intimal cell proliferation in response to arterial injury. Proc Natl Acad Sci U S A. 1996; 93: 7905–7910.[Abstract/Free Full Text]

68. Chen D, Krasinski K, Sylvester A, Chen J, Nisen PD, Andres V. 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.[Medline] [Order article via Infotrieve]

69. Coats S, Flanagan WM, Nourse J, Roberts JM. Requirement of p27Kip1 for restriction point control of the fibroblast cell cycle. Science. 1996; 272: 877–880.[Abstract]

70. Nakayama K, Ishida N, Shirane M, Inomata A, Inoue T, Shishido N, Horii I, Loh DY, Nakayama K-I. Mice lacking p27Kip1 display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell. 1996; 85: 707–720.[CrossRef][Medline] [Order article via Infotrieve]

71. Kiyokawa H, Kineman RD, Manova-Todorova KO, Soares VC, Hoffman ES, Ono M, Khanam D, Hayday AC, Frohman LA, Koff A. Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27(Kip1). Cell. 1996; 85: 721–732.[CrossRef][Medline] [Order article via Infotrieve]

72. Fero ML, Rivkin M, Tasch M, Porter P, Carow CE, Firpo E, Polyak K, Tsai L-H, Broudy V, Perlmutter RM. A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27Kip1-deficient mice. Cell. 1996; 85: 733–744.[CrossRef][Medline] [Order article via Infotrieve]

73. Koyama H, Raines EW, Bornfeldt KE, Roberts JM, Ross R. Fibrillar collagen inhibits arterial smooth muscle proliferation through regulation of Cdk2 inhibitors. Cell. 1996; 87: 1069–1078.[CrossRef][Medline] [Order article via Infotrieve]

74. Boehm M, Nabel EG. Cell cycle and cell migration: new pieces to the puzzle. Circulation. 2001; 103: 2879–2881.[Free Full Text]

75. Sun J, Marx SO, Chen HJ, Poon M, Marks AR, Rabbani LE. Role for p27(Kip1) in vascular smooth muscle cell migration. Circulation. 2001; 103: 2967–2972.[Abstract/Free Full Text]

76. Sousa JE, Costa MA, Tuzcu EM, Yadav JS, Ellis S. New frontiers in interventional cardiology. Circulation. 2005; 111: 671–681.[Free Full Text]

77. Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell. 1994; 78: 35–43.[CrossRef][Medline] [Order article via Infotrieve]

78. Marx SO, Jayaraman T, Go LO, Marks AR. Rapamycin-FKBP inhibits cell cycle regulators of proliferation in vascular smooth muscle cells. Circ Res. 1995; 76: 412–417.[Abstract/Free Full Text]

79. Schmelzle T, Hall MN. TOR, a central controller of cell growth. Cell. 2000; 103: 253–262.[CrossRef][Medline] [Order article via Infotrieve]

80. Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell. 2002; 110: 163–175.[CrossRef][Medline] [Order article via Infotrieve]

81. Kim DH, Sarbassov dos D, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, Tempst P, Sabatini DM. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell. 2003; 11: 895–904.[CrossRef][Medline] [Order article via Infotrieve]

82. Braun-Dullaeus RC, Ziegler A, Bohle RM, Bauer E, Hein S, Tillmanns H, Haberbosch W. Quantification of the cell-cycle inhibitors p27(Kip1) and p21(Cip1) in human atherectomy specimens: primary stenosis versus restenosis. J Lab Clin Med. 2003; 141: 179–189.[CrossRef][Medline] [Order article via Infotrieve]

83. Nourse J, Firpo E, Flanagan WM, Coats S, Polyak K, Lee MH, Massague J, Crabtree GR, Roberts JM. Interleukin-2–mediated elimination of the p27Kip1 cyclin-dependent kinase inhibitor prevented by rapamycin. Nature. 1994; 372: 570–573.[CrossRef][Medline] [Order article via Infotrieve]

84. Suzuki T, Kopia G, Hayashi S, Bailey L, Llanos G, Wilensky R, Klugherz B, Papandreou G, Narayan P, Leon M, Yeung A, Tio F, Tsao P, Falotico R, Carter A. Stent-based delivery of sirolimus reduces neointimal formation in a porcine coronary model. Circulation. 2001; 104: 1188–1193.[Abstract/Free Full Text]

85. Sousa JE, Costa MA, Farb A, Abizaid A, Sousa A, Seixas AC, da Silva LM, Feres F, Pinto I, Mattos LA, Virmani R. Vascular healing 4 years after the implantation of sirolimus-eluting stent in humans: a histopathological examination. Circulation. 2004; 110: e5–e6.[Free Full Text]

86. Poon M, Marx SO, Gallo R, Badimon JJ, Taubman MB, Marks AR. Rapamycin inhibits vascular smooth muscle cell migration. J Clin Invest. 1996; 98: 2277–2283.[Medline] [Order article via Infotrieve]

87. Martin KA, Rzucidlo EM, Merenick BL, Fingar DC, Brown DJ, Wagner RJ, Powell RJ. The mTOR/p70 S6K1 pathway regulates vascular smooth muscle cell differentiation. Am J Physiol Cell Physiol. 2004; 286: C507–C517.[Abstract/Free Full Text]

88. Morice M, Serruys P, Sousa J, Fajadet J, Ban HE, Perin M, Colombo A, Schuler G, Barragan P, Guagliumi G, Molnar F, Falotico R. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med. 2002; 346: 1773–1780.[Abstract/Free Full Text]

89. Moses J, Leon M, Popma J, Fitzgerald P, Holmes D, O’Shaughnessy C, Caputo R, Kereiakes D, Williams D, Teirstein P, Jaeger J, Kuntz R. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med. 2003; 349: 1315–1323.[Abstract/Free Full Text]

90. Gallo R, Padurean A, Jayaraman T, Marx S, Roque M, Adelman S, Chesebro J, Fallon J, Fuster V, Marks A, Badimon JJ. Inhibition of intimal thickening after balloon angioplasty in porcine coronary arteries by targeting regulators of the cell cycle. Circulation. 1999; 99: 2164–2170.[Abstract/Free Full Text]

91. Klugherz B, Llanos G, Lieuallen W, Kopia G, Papandreou G, Narayan P, Sasseen B, Adelman S, Falotico R, Wilensky R. Twenty-eight-day efficacy and phamacokinetics of the sirolimus-eluting stent. Coron Artery Dis. 2002; 13: 183–188.[CrossRef][Medline] [Order article via Infotrieve]

92. Gregory CR, Huang X, Pratt RE, Dzau VJ, Shorthouse R, Billingham ME, Morris RE. Treatment with rapamycin and mycophenolic acid reduces arterial intimal thickening produced by mechanical injury and allows endothelial replacement. Transplantation. 1995; 59: 655–661.[Medline] [Order article via Infotrieve]

93. Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT. Plant antitumor agents. VI. The isolation and structure of Taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J Am Chem Soc. 1971; 93: 2325–2327.[CrossRef][Medline] [Order article via Infotrieve]

94. Nicolaou KC, Yang Z, Liu JJ, Ueno H, Nantermet PG, Guy RK, Claiborne CF, Renaud J, Couladouros EA, Paulvannan K, et al. Total synthesis of Taxol. Nature. 1994; 367: 630–634.[CrossRef][Medline] [Order article via Infotrieve]

95. Rowinsky EK, Donehower RC. Paclitaxel (Taxol). N Engl J Med. 1995; 332: 1004–1014.[Free Full Text]

96. Arnal I, Wade RH. How does Taxol stabilize microtubules? Curr Biol. 1995; 5: 900–908.[CrossRef][Medline] [Order article via Infotrieve]

97. Caplow M, Shanks J, Ruhlen R. How Taxol modulates microtubule disassembly. J Biol Chem. 1994; 269: 23399–23402.[Abstract/Free Full Text]

98. Sollott SJ, Cheng L, Pauly RR, Jenkins GM, Monticone RE, Kuzuya M, Froehlich JP, Crow MT, Lakatta EG, Rowinsky EK, et al. Taxol inhibits neointimal smooth muscle cell accumulation after angioplasty in the rat. J Clin Invest. 1995; 95: 1869–1876.[Medline] [Order article via Infotrieve]

99. Zhou X, Li J, Kucik DF. The microtubule cytoskeleton participates in control of beta2 integrin avidity. J Biol Chem. 2001; 276: 44762–44769.[Abstract/Free Full Text]

100. Axel DI, Kunert W, Goggelmann C, Oberhoff M, Herdeg C, Kuttner A, Wild DH, Brehm BR, Riessen R, Koveker G, Karsch KR. Paclitaxel inhibits arterial smooth muscle cell proliferation and migration in vitro and in vivo using local drug delivery. Circulation. 1997; 96: 636–645.[Abstract/Free Full Text]

101. Manthey CL, Perera PY, Salkowski CA, Vogel SN. Taxol provides a second signal for murine macrophage tumoricidal activity. J Immunol. 1994; 152: 825–831.[Abstract]

102. Jun CD, Choi BM, Kim HM, Chung HT. Involvement of protein kinase C during Taxol-induced activation of murine peritoneal macrophages. J Immunol. 1995; 154: 6541–6547.[Abstract]

103. Bhat N, Perera PY, Carboni JM, Blanco J, Golenbock DT, Mayadas TN, Vogel SN. Use of a photoactivatable Taxol analogue to identify unique cellular targets in murine macrophages: identification of murine CD18 as a major Taxol-binding protein and a role for Mac-1 in Taxol-induced gene expression. J Immunol. 1999; 162: 7335–7342.[Abstract/Free Full Text]

104. Mullins DW, Walker TM, Burger CJ, Elgert KD. Taxol-mediated changes in fibrosarcoma-induced immune cell function: modulation of antitumor activities. Cancer Immunol Immunother. 1997; 45: 20–28.[CrossRef][Medline] [Order article via Infotrieve]

105. Mullins DW, Burger CJ, Elgert KD. Paclitaxel enhances macrophage IL-12 production in tumor-bearing hosts through nitric oxide. J Immunol. 1999; 162: 6811–6818.[Abstract/Free Full Text]

106. Cabral FR. Isolation of Chinese hamster ovary cell mutants requiring the continuous presence of Taxol for cell division. J Cell Biol. 1983; 97: 22–29.[Abstract/Free Full Text]

107. Zaffaroni N, Pennati M, Colella G, Perego P, Supino R, Gatti L, Pilotti S, Zunino F, Daidone MG. Expression of the anti-apoptotic gene survivin correlates with Taxol resistance in human ovarian cancer. Cell Mol Life Sci. 2002; 59: 1406–1412.[CrossRef][Medline] [Order article via Infotrieve]

108. Anand S, Penrhyn-Lowe S, Venkitaraman AR. AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol. Cancer Cell. 2003; 3: 51–62.[CrossRef][Medline] [Order article via Infotrieve]

109. McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, Clarke-Pearson DL, Davidson M. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med. 1996; 334: 1–6.[Abstract/Free Full Text]

110. Seidman AD. One-hour paclitaxel via weekly infusion: dose-density with enhanced therapeutic index. Oncology. 1998; 12: 19–22.[CrossRef]

111. Drachman DE, Edelman ER, Seifert P, Groothuis AR, Bornstein DA, Kamath KR, Palasis M, Yang D, Nott SH, Rogers C. Neointimal thickening after stent delivery of paclitaxel: change in composition and arrest of growth over six months. J Am Coll Cardiol. 2000; 36: 2325–2332.[Abstract/Free Full Text]

112. Farb A, Heller PF, Shroff S, Cheng L, Kolodgie FD, Carter AJ, Scott DS, Froehlich J, Virmani R. Pathological analysis of local delivery of paclitaxel via a polymer-coated stent. Circulation. 2001; 104: 473–479.[Abstract/Free Full Text]

113. Park S, Shim W, Ho D, Raizner A, Park S, Hong M, Lee C, Choi D, Jang Y, Lam R, Weissman N, Mintz G. A paclitaxel-eluting stent for the prevention of coronary restenosis. N Engl J Med. 2003; 348: 1537–1545.[Abstract/Free Full Text]

114. Gershlick A, De Scheerder I, Chevalier B, Stephens-Lloyd A, Camenzind E, Vrints C, Reifart N, Missault L, Goy JJ, Brinker JA, Raizner AE, Urban P, Heldman AW. Inhibition of restenosis with a paclitaxel-eluting, polymer-free coronary stent: the European evaLUation of pacliTaxel Eluting Stent (ELUTES) trial. Circulation. 2004; 109: 487–493.[Abstract/Free Full Text]

115. Kataoka T, Grube E, Honda Y, Morino Y, Hur S, Bonneau H, Colombo A, Di MC, Guagliumi G, Hauptmann K, Pitney M, Lansky A, Stertzer S, Yock P, Fitzgerald P. 7-Hexanoyltaxol-eluting stent for prevention of neointimal growth: an intravascular ultrasound analysis from the Study to COmpare REstenosis rate between QueST and QuaDS-QP2 (SCORE). Circulation. 2002; 106: 1788–1793.[Abstract/Free Full Text]

116. Grube E, Silber S, Hauptmann K, Mueller R, Buellesfeld L, Gerckens U, Russell M. TAXUS I: six- and twelve-month results from a randomized, double-blind trial on a slow-release paclitaxel-eluting stent for de novo coronary lesions. Circulation. 2003; 107: 38–42.[Abstract/Free Full Text]

117. Colombo A, Sangiorgi G. The monocyte: the key in the lock to reduce stent hyperplasia? J Am Coll Cardiol. 2004; 43: 24–26.[Free Full Text]

118. Stone G, Ellis S, Cox D, Hermiller J, O’Shaughnessy C, Mann J, Turco M, Caputo R, Bergin P, Greenberg J, Popma J, Russell M. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med. 2004; 350: 221–231.[Abstract/Free Full Text]

119. Hwang CW, Edelman ER. Arterial ultrastructure influences transport of locally delivered drugs. Circ Res. 2002; 90: 826–832.[Abstract/Free Full Text]

120. Hwang CW, Wu D, Edelman ER. Physiological transport forces govern drug distribution for stent-based delivery. Circulation. 2001; 104: 600–605.[Abstract/Free Full Text]

121. Panse N, Brett S, Panse P, Kareti K, Rewis D, Gilmore P, Zenni MM, Wilke N, Bass T, Costa MA. Multiple plaque morphologies in a single coronary artery: insights from volumetric intravascular ultrasound. Catheter Cardiovasc Interv. 2004; 61: 376–380.[CrossRef][Medline] [Order article via Infotrieve]

122. Levin AD, Vukmirovic N, Hwang CW, Edelman ER. Specific binding to intracellular proteins determines arterial transport properties for rapamycin and paclitaxel. Proc Natl Acad Sci U S A. 2004; 101: 9463–9467.[Abstract/Free Full Text]

123. Gruentzig AR, Meier B. Percutaneous transluminal coronary angioplasty: the first five years and the future. Int J Cardiol. 1983; 2: 319–323.[CrossRef][Medline] [Order article via Infotrieve]

124. Cutlip D, Chauhan M, Baim D, Ho K, Popma J, Carrozza J, Cohen D, Kuntz R. Clinical restenosis after coronary stenting: perspectives from multicenter clinical trials. J Am Coll Cardiol. 2002; 40: 2082–2089.[Abstract/Free Full Text]

125. Teirstein P, Massulo V, Jani S, Popma JJ, Russo RJ, Schatz RA, Guarneri EM, Steuterman S, Sirkin K, Cloutier DA, Leon MB, Tripuraneni P. Three-year clinical and angiographic follow-up after intracoronary radiation: results of a randomized clinical trial. Circulation. 2000; 101: 360–365.[Abstract/Free Full Text]

126. Kay IP, Ligthart JM, Virmani R, van Beusekom HM, Kozuma K, Carter AJ, Sianos G, van der Giessen WJ, Wardeh AJ, de Feyter PJ, Serruys PW. The black hole: echolucent tissue observed following intracoronary radiation. Int J Cardiovasc Intervent. 2003; 5: 137–142.[CrossRef][Medline] [Order article via Infotrieve]

127. Serruys PW, Strauss BH, Beatt KJ, Bertrand ME, Puel J, Rickards AF, Meier B, Goy J-J, Vogt P, Kappenberger L, Sigwart U. Angiographic follow-up of a self-expanding coronary-artery stent. N Engl J Med. 1991; 324: 13–17.[Abstract]

128. Kuntz RE, Baim DS. Defining coronary restenosis: newer clinical and angiographic paradigms. Circulation. 1993; 88: 1310–1323.[Free Full Text]

129. Sabate M, Costa MA, Kozuma K, Kay IP, van der Wiel CJ, Verin V, Wijns W, Serruys PW. Methodological and clinical implications of the relocation of the minimal luminal diameter after intracoronary radiation therapy. Dose Finding Study Group. J Am Coll Cardiol. 2000; 36: 1536–1541.[Abstract/Free Full Text]

130. Costa MA, Kozuma K, Gaster AL, van Der Giessen WJ, Sabate M, Foley DP, Kay IP, Ligthart JM, Thayssen P, van Den Brand MJ, de Feyter PJ, Serruys PW. Three dimensional intravascular ultrasonic assessment of the local mechanism of restenosis after balloon angioplasty. Heart. 2001; 85: 73–79.[Abstract/Free Full Text]

131. Mauri L, Orav EJ, O’Malley AJ, Moses JW, Leon MB, Holmes DR Jr, Teirstein PS, Schofer J, Breithardt G, Cutlip DE, Kereiakes DJ, Shi C, Firth BG, Donohoe DJ, Kuntz RE. Relationship of late loss in lumen diameter to coronary restenosis in sirolimus-eluting stents. Circulation. 2005; 111: 321–327.[Abstract/Free Full Text]

132. Nissen SE, Gurley JC, Grines CL, Booth DC, McClure R, Berk M, Fischer C, DeMaria AN. Intravascular ultrasound assessment of lumen size and wall morphology in normal subjects and patients with coronary artery disease. Circulation. 1991; 84: 1087–1099.[Abstract/Free Full Text]

133. Castagna MT, Mintz GS, Leiboff BO, Ahmed JM, Mehran R, Satler LF, Kent KM, Pichard AD, Weissman NJ. The contribution of "mechanical" problems to in-stent restenosis: an intravascular ultrasonographic analysis of 1090 consecutive in-stent restenosis lesions. Am Heart J. 2001; 142: 970–974.[CrossRef][Medline] [Order article via Infotrieve]

134. Sabate M, Costa MA, Kozuma K, Kay IP, van der Giessen WJ, Coen VL, Ligthart JM, Serrano P, Levendag PC, Serruys PW. Geographic miss: a cause of treatment failure in radio-oncology applied to intracoronary radiation therapy. Circulation. 2000; 101: 2467–2471.[Abstract/Free Full Text]

135. Lemos PA, van Mieghem CA, Arampatzis CA, Hoye A, Ong AT, McFadden E, Sianos G, van der Giessen WJ, de Feyter PJ, van Domburg RT, Serruys PW. Post–sirolimus-eluting stent restenosis treated with repeat percutaneous intervention: late angiographic and clinical outcomes. Circulation. 2004; 109: 2500–2502.[Abstract/Free Full Text]

136. Carter AJ, Aggarwal M, Kopia GA, Tio F, Tsao PS, Kolata R, Yeung AC, Llanos G, Dooley J, Falotico R. Long-term effects of polymer-based, slow-release, sirolimus-eluting stents in a porcine coronary model. Cardiovasc Res. 2004; 63: 617–624.[Abstract/Free Full Text]

137. Lemos PA, Saia F, Ligthart JM, Arampatzis CA, Sianos G, Tanabe K, Hoye A, Degertekin M, Daemen J, McFadden E, Hofma S, Smits PC, de Feyter P, van der Giessen WJ, van Domburg RT, Serruys PW. Coronary restenosis after sirolimus-eluting stent implantation: morphological description and mechanistic analysis from a consecutive series of cases. Circulation. 2003; 108: 257–260.[Abstract/Free Full Text]

138. Colombo A, Orlic D, Stankovic G, Corvaja N, Spanos V, Montorfano M, Liistro F, Carlino M, Airoldi F, Chieffo A, Di Mario C. Preliminary observations regarding angiographic pattern of restenosis after rapamycin-eluting stent implantation. Circulation. 2003; 107: 2178–2180.[Abstract/Free Full Text]

139. Fishman JA, Ryan GB, Karnovsky MJ. 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.[Medline] [Order article via Infotrieve]

140. Clowes AW, Karnovsky MJ. Suppression by heparin of smooth muscle cell proliferation in injured arteries. Nature (London). 1977; 265: 625–626.[CrossRef][Medline] [Order article via Infotrieve]

141. Castellot JJJ, Addonizio ML, Rosenberg RD, Karnovsky MJ. Cultured endothelial cells produce a heparin-like inhibition of smooth muscle growth. J Cell Biol. 1981; 90: 372–379.[Abstract/Free Full Text]

142. Edelman ER, Nugent MA, Karnovsky MJ. Perivascular and intravenous administration of basic fibroblast growth factor: vascular and solid organ deposition. Proc Natl Acad Sci U S A. 1993; 90: 1513–1517.[Abstract/Free Full Text]

143. van Beusekom HM, Whelan DM, Hofma SH, Krabbendam SC, van Hinsbergh VW, Verdouw PD, van der Giessen WJ. Long-term endothelial dysfunction is more pronounced after stenting than after balloon angioplasty in porcine coronary arteries. J Am Coll Cardiol. 1998; 32: 1109–1117.[Abstract/Free Full Text]

144. Guagliumi G, Farb A, Musumeci G, Valsecchi O, Tespili M, Motta T, Virmani R. Sirolimus-eluting stent implanted in human coronary artery for 16 months: pathological findings. Circulation. 2003; 107: 1340–1341.[Free Full Text]

145. Jeremias A, Sylvia B, Bridges J, Kirtane AJ, Bigelow B, Pinto DS, Ho KK, Cohen DJ, Garcia LA, Cutlip DE, Carrozza JP Jr. Stent thrombosis after successful sirolimus-eluting stent implantation. Circulation. 2004; 109: 1930–1932.[Abstract/Free Full Text]

146. Rogers C, Parikh S, Seifert P, Edelman ER. Endogenous cell seeding: remnant endothelium after stenting enhances vascular repair. Circulation. 1996; 94: 2909–2914.[Abstract/Free Full Text]

147. Nugent MA, Nugent HM, Iozzo RV, Sanchack K, Edelman ER. Perlecan is required to inhibit thrombosis after deep vascular injury and contributes to endothelial cell-mediated inhibition of intimal hyperplasia. Proc Natl Acad Sci U S A. 2000; 97: 6722–6727.[Abstract/Free Full Text]

148. Nugent HM, Edelman ER. Tissue engineering therapy for cardiovascular disease. Circ Res. 2003; 92: 1068–1078.[Abstract/Free Full Text]

149. von der Leyen H, Gibbons G, Morishita R, Lewis N, Zhang L, Nakajima M, Kaneda Y, Cooke J, Dzau V. Gene therapy inhibiting neointimal vascular lesion: in vivo transfer of endothelial cell nitric oxide synthase gene. Proc Natl Acad Sci U S A. 1995; 92: 1137–1141.[Abstract/Free Full Text]

150. Geraldes P, Sirois MG, Bernatchez PN, Tanguay JF. Estrogen regulation of endothelial and smooth muscle cell migration and proliferation: role of p38 and p42/44 mitogen-activated protein kinase. Arterioscler Thromb Vasc Biol. 2002; 22: 1585–1590.[Abstract/Free Full Text]

151. New G, Moses J, Roubin G, Leon M, Colombo A, Iyer S, Tio F, Mehran R, Kipshidze N. Estrogen-eluting, phosphorylcholine-coated stent implantation is associated with reduced neointimal formation but no delay in vascular repair in a porcine coronary model. Catheter Cardiovasc Interv. 2002; 57: 266–271.[CrossRef][Medline] [Order article via Infotrieve]

152. Abizaid A, Albertal M, Costa MA, Abizaid AS, Staico R, Feres F, Mattos LA, Sousa AG, Moses J, Kipshidize N, Roubin GS, Mehran R, New G, Leon MB, Sousa JE. First human experience with the 17-beta-estradiol–eluting stent: the Estrogen And Stents To Eliminate Restenosis (EASTER) trial. J Am Coll Cardiol. 2004; 43: 1118–1121.[Abstract/Free Full Text]

153. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995; 1: 27–31.[CrossRef][Medline] [Order article via Infotrieve]

154. Baumgartner I, Isner JM. Somatic gene therapy in the cardiovascular system. Annu Rev Physiol. 2001; 63: 427–450.[CrossRef][Medline] [Order article via Infotrieve]

155. Van Belle E, Tio FO, Couffinhal T, Maillard L, Passeri J, Isner JM. Stent endothelialization: time course, impact of local catheter delivery, feasibility of recombinant protein administration, and response to cytokine administration. Circulation. 1997; 95: 438–448.[Abstract/Free Full Text]

156. Van Belle E, Tio FO, Chen D, Maillard L, Kearney M, Isner JM. Passivation of metallic stents after arterial gene transfer of phVEGF165 inhibits thrombus formation and intimal thickening. J Am Coll Cardiol. 1997; 29: 1371–1379.[Abstract]

157. Van Belle E, Maillard L, Tio FO, Isner JM. Accelerated endothelialization by local delivery of recombinant human vascular endothelial growth factor reduces in-stent intimal formation. Biochem Biophys Res Commun. 1997; 235: 311–316.[CrossRef][Medline] [Order article via Infotrieve]

158. Asahara T, Bauters C, Pastore C, Kearney M, Rossow S, Bunting S, Ferrara N, Symes JF, Isner JM. Local delivery of vascular endothelial growth factor accelerates reendothelialization and attenuates intimal hyperplasia in balloon-injured rat carotid artery. Circulation. 1995; 91: 2793–2801.[Abstract/Free Full Text]

159. Asahara T, Chen D, Tsurumi Y, Kearney M, Rossow S, Passeri J, Symes JF, Isner JM. Accelerated restitution of endothelial integrity and endothelium-dependent function after phVEGF165 gene transfer. Circulation. 1996; 94: 3291–3302.[Abstract/Free Full Text]

160. Isner JM. Still more debate over VEGF. Nat Med. 2001; 7: 639–641.[CrossRef][Medline] [Order article via Infotrieve]

161. Inoue M, Itoh H, Ueda M, Naruko T, Kojima A, Komatsu R, Doi K, Ogawa Y, Tamura N, Takaya K, Igaki T, Yamashita J, Chun TH, Masatsugu K, Becker AE, Nakao K. Vascular endothelial growth factor (VEGF) expression in human coronary atherosclerotic lesions: possible pathophysiological significance of VEGF in progression of atherosclerosis. Circulation. 1998; 98: 2108–2116.[Abstract/Free Full Text]

162. Shibata M, Suzuki H, Nakatani M, Koba S, Geshi E, Katagiri T, Takeyama Y. The involvement of vascular endothelial growth factor and flt-1 in the process of neointimal proliferation in pig coronary arteries following stent implantation. Histochem Cell Biol. 2001; 116: 471–481.[CrossRef][Medline] [Order article via Infotrieve]

163. Barleon B, Sozzani S, Zhou D, Weich HA, Mantovani A, Marme D. Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood. 1996; 87: 3336–3343.[Abstract/Free Full Text]

164. Kim I, Moon SO, Kim SH, Kim HJ, Koh YS, Koh GY. Vascular endothelial growth factor expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin through nuclear factor-kappa B activation in endothelial cells. J Biol Chem. 2001; 276: 7614–7620.[Abstract/Free Full Text]

165. Marumo T, Schini-Kerth VB, Busse R. Vascular endothelial growth factor activates nuclear factor-kappaB and induces monocyte chemoattractant protein-1 in bovine retinal endothelial cells. Diabetes. 1999; 48: 1131–1137.[Abstract]

166. Yonemitsu Y, Kaneda Y, Morishita R, Nakagawa K, Nakashima Y, Sueishi K. Characterization of in vivo gene transfer into the arterial wall mediated by the Sendai virus (hemagglutinating virus of Japan) liposomes: an effective tool for the in vivo study of arterial diseases. Lab Invest. 1996; 75: 313–323.[Medline] [Order article via Infotrieve]

167. Luttun A, Tjwa M, Moons L, Wu Y, Angelillo-Scherrer A, Liao F, Nagy JA, Hooper A, Priller J, De Klerck B, Compernolle V, Daci E, Bohlen P, Dewerchin M, Herbert JM, Fava R, Matthys P, Carmeliet G, Collen D, Dvorak HF, Hicklin DJ, Carmeliet P. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med. 2002; 8: 831–840.[CrossRef][Medline] [Order article via Infotrieve]

168. Celletti FL, Waugh JM, Amabile PG, Brendolan A, Hilfiker PR, Dake MD. Vascular endothelial growth factor enhances atherosclerotic plaque progression. Nat Med. 2001; 7: 425–429.[CrossRef][Medline] [Order article via Infotrieve]

169. Kendall RL, Wang G, Thomas KA. Identification of a natural soluble form of the vascular endothelial growth factor receptor, FLT-1, and its heterodimerization with KDR. Biochem Biophys Res Commun. 1996; 226: 324–328.[CrossRef][Medline] [Order article via Infotrieve]

170. Ohtani K, Egashira K, Hiasa K-I, Zhao Q, Kitamoto S, Ishibashi M, Usui M, Inoue S, Yonemitsu Y, Sueishi K, Sata M, Shibuya M, Sunagawa K. Blockade of vascular endothelial growth factor suppresses experimental restenosis after intraluminal injury by inhibiting recruitment of monocyte lineage cells. Circulation. 2004; 110: 2444–2452.[Abstract/Free Full Text]

171. Hedman M, Hartikainen J, Syvanne M, Stjernvall J, Hedman A, Kivela A, Vanninen E, Mussalo H, Kauppila E, Simula S, Narvanen O, Rantala A, Peuhkurinen K, Nieminen MS, Laakso M, Yla-Herttuala S. Safety and feasibility of catheter-based local intracoronary vascular endothelial growth factor gene transfer in the prevention of postangioplasty and in-stent restenosis and in the treatment of chronic myocardial ischemia: phase II results of the Kuopio Angiogenesis Trial (KAT). Circulation. 2003; 107: 2677–2683.[Abstract/Free Full Text]

172. Walter DH, Cejna M, Diaz-Sandoval L, Willis S, Kirkwood L, Stratford PW, Tietz AB, Kirchmair R, Silver M, Curry C, Wecker A, Yoon YS, Heidenreich R, Hanley A, Kearney M, Tio FO, Kuenzler P, Isner JM, Losordo DW. Local gene transfer of phVEGF-2 plasmid by gene-eluting stents: an alternative strategy for inhibition of restenosis. Circulation. 2004; 110: 36–45.[Abstract/Free Full Text]

173. Kalka C, Masuda H, Takahashi T, Kalka-Moll WM, Silver M, Kearney M, Li T, Isner JM, Asahara T. Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci U S A. 2000; 97: 3422–3427.[Abstract/Free Full Text]

174. Kawamoto A, Gwon HC, Iwaguro H, Yamaguchi JI, Uchida S, Masuda H, Silver M, Ma H, Kearney M, Isner JM, Asahara T. Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischemia. Circulation. 2001; 103: 634–637.[Abstract/Free Full Text]

175. Iwaguro H, Yamaguchi J, Kalka C, Murasawa S, Masuda H, Hayashi S, Silver M, Li T, Isner JM, Asahara T. Endothelial progenitor cell vascular endothelial growth factor gene transfer for vascular regeneration. Circulation. 2002; 105: 732–738.[Abstract/Free Full Text]

176. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997; 275: 964–966.[Abstract/Free Full Text]

177. Yamashita J, Itoh H, Hirashima M, Ogawa M, Nishikawa S, Yurugi T, Naito M, Nakao K, Nishikawa S-I. Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors. Nature. 2000; 408: 92–96.[CrossRef][Medline] [Order article via Infotrieve]

178. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature. 2002; 418: 41–49.[CrossRef][Medline] [Order article via Infotrieve]

179. Hillebrands J-L, Klatter FA, van den Hurk BMH, Popa ER, Nieuwenhuis P, Rozing J. Origin of neointimal endothelium and alpha-actin–positive smooth muscle cells in transplant arteriosclerosis. J Clin Invest. 2001; 107: 1411–1422.[CrossRef][Medline] [Order article via Infotrieve]

180. Sata M, Saiura A, Kunisato A, Tojo A, Okada S, Tokuhisa T, Hirai H, Makuuchi M, Hirata Y, Nagai R. Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med. 2002; 8: 403–409.[CrossRef][Medline] [Order article via Infotrieve]

181. Shimizu K, Sugiyama S, Aikawa M, Fukumoto Y, Rabkin E, Libby P, Mitchell RN. Host bone-marrow cells are a source of donor intimal smooth-muscle–like cells in murine aortic transplant arteriopathy. Nat Med. 2001; 7: 738–741.[CrossRef][Medline] [Order article via Infotrieve]

182. Saiura A, Sata M, Hirata Y, Nagai R, Makuuchi M. Circulating smooth muscle progenitor cells contribute to atherosclerosis. Nat Med. 2001; 7: 382–383.[CrossRef][Medline] [Order article via Infotrieve]

183. Quaini F, Urbanek K, Beltrami AP, Finato N, Beltrami CA, Nadal-Ginard B, Kajstura J, Leri A, Anversa P. Chimerism of the transplanted heart. N Engl J Med. 2002; 346: 5–15.[Abstract/Free Full Text]

184. Glaser R, Lu MM, Narula N, Epstein JA. Smooth muscle cells, but not myocytes, of host origin in transplanted human hearts. Circulation. 2002; 106: 17–19.[Abstract/Free Full Text]

185. Grimm PC, Nickerson P, Jeffery J, Savani RC, Gough J, McKenna RM, Stern E, Rush DN. Neointimal and tubulointerstitial infiltration by recipient mesenchymal cells in chronic renal-allograft rejection. N Engl J Med. 2001; 345: 93–97.[Abstract/Free Full Text]

186. Morishita R, Gibbons GH, Horiuchi M, Ellison KE, Nakama M, Zhang L, Kaneda Y, Ogihara T, Dzau VJ. A gene therapy strategy using a transcription factor decoy of the E2F binding site inhibits smooth muscle proliferation in vivo. Proc Natl Acad Sci U S A. 1995; 92: 5855–5859.[Abstract/Free Full Text]

187. Mann MJ, Dzau VJ. Therapeutic applications of transcription factor decoy oligonucleotides. J Clin Invest. 2000; 106: 1071–1075.[Medline] [Order article via Infotrieve]

188. Kutryk MJ, Foley DP, van den Brand M, Hamburger JN, van der Giessen WJ, deFeyter PJ, Bruining N, Sabate M, Serruys PW. Local intracoronary administration of antisense oligonucleotide against c-myc for the prevention of in-stent restenosis: results of the randomized investigation by the Thoraxcenter of antisense DNA using local delivery and IVUS after coronary stenting (ITALICS) trial. J Am Coll Cardiol. 2002; 39: 281–287.[Abstract/Free Full Text]

189. Alt E, Haehnel I, Beilharz C, Prietzel K, Preter D, Stemberger A, Fliedner T, Erhardt W, Schomig A. Inhibition of neointima formation after experimental coronary artery stenting: a new biodegradable stent coating releasing hirudin and the prostacyclin analogue iloprost. Circulation. 2000; 101: 1453–1458.[Abstract/Free Full Text]

190. Lin CE, Garvey DS, Janero DR, Letts LG, Marek P, Richardson SK, Serebryanik D, Shumway MJ, Tam SW, Trocha AM, Young DV. Combination of paclitaxel and nitric oxide as a novel treatment for the reduction of restenosis. J Med Chem. 2004; 47: 2276–2282.[CrossRef][Medline] [Order article via Infotrieve]

191. Leppanen O, Rutanen J, Hiltunen MO, Rissanen TT, Turunen MP, Sjoblom T, Bruggen J, Backstrom G, Carlsson M, Buchdunger E, Bergqvist D, Alitalo K, Heldin CH, Ostman A, Yla-Herttuala S. Oral imatinib mesylate (STI571/gleevec) improves the efficacy of local intravascular vascular endothelial growth factor-C gene transfer in reducing neointimal growth in hypercholesterolemic rabbits. Circulation. 2004; 109: 1140–1146.[Abstract/Free Full Text]

192. Finkelstein A, McClean D, Kar S, Takizawa K, Varghese K, Baek N, Park K, Fishbein MC, Makkar R, Litvack F, Eigler NL. Local drug delivery via a coronary stent with programmable release pharmacokinetics. Circulation. 2003; 107: 777–784.[Abstract/Free Full Text]

193. Vogt F, Stein A, Rettemeier G, Krott N, Hoffmann R, vom Dahl J, Bosserhoff AK, Michaeli W, Hanrath P, Weber C, Blindt R. Long-term assessment of a novel biodegradable paclitaxel-eluting coronary polylactide stent. Eur Heart J. 2004; 25: 1330–1340.[Abstract/Free Full Text]

194. Tamai H, Igaki K, Kyo E, Kosuga K, Kawashima A, Matsui S, Komori H, Tsuji T, Motohara S, Uehata H. Initial and 6-month results of biodegradable poly-l-lactic acid coronary stents in humans. Circulation. 2000; 102: 399–404.[Abstract/Free Full Text]

195. Heublein B, Rohde R, Kaese V, Niemeyer M, Hartung W, Haverich A. Biocorrosion of magnesium alloys: a new principle in cardiovascular implant technology? Heart. 2003; 89: 651–656.[Abstract/Free Full Text]

This article has been cited by other articles:

				N. Rosenthal and M. A. Costa Unravelling the endovascular microenvironment by optical coherence tomography Eur. Heart J., November 19, 2009; (2009) ehp481v1. [Full Text] [PDF]

				B. D. Horne and J. L. Anderson Irrelevance of the Chromosome 9p21.3 Locus for Acute Cardiovascular Events and Restenosis J. Am. Coll. Cardiol. Intv., November 1, 2009; 2(11): 1156 - 1157. [Full Text] [PDF]

				C. M. van Tiel, P. I. Bonta, S. Z.H. Rittersma, M. A.M. Beijk, E. J. Bradley, A. M. Klous, K. T. Koch, F. Baas, J. W. Jukema, D. Pons, et al. p27kip1-838C>A Single Nucleotide Polymorphism Is Associated With Restenosis Risk After Coronary Stenting and Modulates p27kip1 Promoter Activity Circulation, August 25, 2009; 120(8): 669 - 676. [Abstract] [Full Text] [PDF]

				K.-J. Lee, A. Hinek, R. R. Chaturvedi, C. L. Almeida, O. Honjo, G. Koren, and L. N. Benson Rapamycin-Eluting Stents in the Arterial Duct: Experimental Observations in the Pig Model Circulation, April 21, 2009; 119(15): 2078 - 2085. [Abstract] [Full Text] [PDF]

				R. A. Byrne, R. Iijima, J. Mehilli, S. Pinieck, O. Bruskina, A. Schomig, and A. Kastrati Durability of Antirestenotic Efficacy in Drug-Eluting Stents With and Without Permanent Polymer J. Am. Coll. Cardiol. Intv., April 1, 2009; 2(4): 291 - 299. [Abstract] [Full Text] [PDF]

				S. Verheye, P. Agostoni, K. D. Dawkins, J. Dens, W. Rutsch, D. Carrie, J. Schofer, C. Lotan, C. L. Dubois, S. A. Cohen, et al. The GENESIS (Randomized, Multicenter Study of the Pimecrolimus-Eluting and Pimecrolimus/Paclitaxel-Eluting Coronary Stent System in Patients with De Novo Lesions of the Native Coronary Arteries) Trial J. Am. Coll. Cardiol. Intv., March 1, 2009; 2(3): 205 - 214. [Abstract] [Full Text] [PDF]

				M. A Ostovan, R. Mollazadeh, J. Kojuri, and M. Mirabadi Experience with Paclitaxel-Eluting Infinnium Coronary Stents Asian Cardiovasc Thorac Ann, December 1, 2008; 16(6): 454 - 458. [Abstract] [Full Text] [PDF]

				A.-L. Levonen, E. Vahakangas, J. K. Koponen, and S. Yla-Herttuala Antioxidant Gene Therapy for Cardiovascular Disease: Current Status and Future Perspectives Circulation, April 22, 2008; 117(16): 2142 - 2150. [Abstract] [Full Text] [PDF]

				G. M. Howard-Alpe, J. de Bono, L. Hudsmith, W. P. Orr, P. Foex, and J. W. Sear Coronary artery stents and non-cardiac surgery Br. J. Anaesth., May 1, 2007; 98(5): 560 - 574. [Abstract] [Full Text] [PDF]

				A.-L. Levonen, M. Inkala, T. Heikura, S. Jauhiainen, H.-K. Jyrkkanen, E. Kansanen, K. Maatta, E. Romppanen, P. Turunen, J. Rutanen, et al. Nrf2 Gene Transfer Induces Antioxidant Enzymes and Suppresses Smooth Muscle Cell Growth In Vitro and Reduces Oxidative Stress in Rabbit Aorta In Vivo Arterioscler Thromb Vasc Biol, April 1, 2007; 27(4): 741 - 747. [Abstract] [Full Text] [PDF]

				D. I. Simon and V. J. Pompili Far-Fetched Benefit of Inflammation Circulation, February 6, 2007; 115(5): 548 - 549. [Full Text] [PDF]

				T. Nomiyama, T. Nakamachi, F. Gizard, E. B. Heywood, K. L. Jones, N. Ohkura, R. Kawamori, O. M. Conneely, and D. Bruemmer The NR4A Orphan Nuclear Receptor NOR1 Is Induced by Platelet-derived Growth Factor and Mediates Vascular Smooth Muscle Cell Proliferation J. Biol. Chem., November 3, 2006; 281(44): 33467 - 33476. [Abstract] [Full Text] [PDF]

				C. Patterson, S. Mapera, H.-H. Li, N. Madamanchi, E. Hilliard, R. Lineberger, R. Herrmann, and P. Charles Comparative Effects of Paclitaxel and Rapamycin on Smooth Muscle Migration and Survival: Role of Akt-Dependent Signaling Arterioscler Thromb Vasc Biol, July 1, 2006; 26(7): 1473 - 1480. [Abstract] [Full Text] [PDF]

				R. Seabra-Gomes Percutaneous coronary interventions with drug eluting stents for diabetic patients. Heart, March 1, 2006; 92(3): 410 - 419. [Full Text] [PDF]

				Y. Wang, M. Sakuma, Z. Chen, V. Ustinov, C. Shi, K. Croce, A. C. Zago, J. Lopez, P. Andre, E. Plow, et al. Leukocyte Engagement of Platelet Glycoprotein Ib{alpha} via the Integrin Mac-1 Is Critical for the Biological Response to Vascular Injury Circulation, November 8, 2005; 112(19): 2993 - 3000. [Abstract] [Full Text] [PDF]

This Article Extract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Costa, M. A. Articles by Simon, D. I. Search for Related Content PubMed PubMed Citation Articles by Costa, M. A. Articles by Simon, D. I. Related Collections Restenosis Smooth muscle proliferation and differentiation Catheter-based coronary interventions: stents