Arterial remodeling after experimental percutaneous injury is highly dependent on adventitial injury and histopathology

Background: The extent and nature of unfavorable geometric remodeling, especially related to the adventitia, has not been studied previously. The purpose of this study was to examine two methods of experimental arterial injury, characterize the extent of remodeling, and determine if remodeling is injury-specific. Methods: Two methods for producing coronary stenoses in pigs were used: heat injury using thermal balloon angioplasty (resulting in adventitial fibrosis), and copper stent implantation (resulting in intense inflammation). Histomorphometric parameters included changes in neointimal thickness (delta neointima) from uninjured to injured sections, and differences in area circumscribed by the internal and external elastic laminas (delta internal elastic lamina area and delta external elastic lamina area, respectively). Remodeling was calculated for each lesion as the enlargement of the external elastic lamina area or internal elastic lamina area for incremental neointimal thickening, expressed as the slopes delta external elastic lamina area/delta neointima and delta internal elastic lamina area/delta neointima. Results: Remodeling indices for the heat lesions were negative (delta internal elastic lamina area/delta neointima=−0.15, delta external elastic lamina area/delta neointima=−0.64) and indicated little remodeling in contrast to copper stent injury (delta internal elastic lamina area/delta neointima=0.95, delta external elastic lamina area/delta neointima=1.20). Conclusions: Remodeling in fibrotic compared to inflammatory lesions differs markedly, and may explain increased restenosis rates observed in thermal balloon angioplasty in patients. This formulation may be useful to study remodeling and restenosis following other interventional technologies.     

Intracoronary ultrasound: A necessary tool for stent implantation? Arguments in favor]

Intracoronary ultrasound (ICUS), as opposed to angiography, provides high resolution, tomographic images of the coronary vessel and lumen. Because of its superior diagnostic sensitivity ICUS is indicated in the evaluation of suboptimal results and complications following stent implantation. Only a few years ago the use of stents was limited by a high incidence of subacute thrombosis. ICUS demonstrated that the deployment technique used at that time was inadequate and that stent expansion could be improved by the routine use of high pressure inflation, leading to a simplification in the anticoagulation regimen and a decrease in the subacute thrombosis rate in elective procedures to < or = 1%. However, the routine use of high balloon pressures does not assure an adequate expansion of the stent. Only about one third of the stents deployed under angiographic guidance are optimally expanded, with intra-stent luminal dimensions similar to the adjacent, reference, luminal sizes. Significantly, these underdeployed stents can be recognized by ICUS and a large proportion adequately expanded. It should be emphasized that the best predictors of stent restenosis are two ICUS parameters, the postprocedural luminal dimensions and the % cross sectional narrowing, and not the angiographic parameters. Likewise, two of the lowest restenosis rates ever reported (12.8% and 7.3%) have occurred in two studies (WEST-2 and MUSIC) in which stent deployment was guided by ICUS. Two trials (AVID and OPTICUS) have been specifically designed to test the hypothesis that routine use of ICUS to guide stent implantation could diminish the restenosis rate, but their final results are not yet available. The CRUISE study was designed to evaluate the impact of routine ICUS not on angiographic restenosis but on the clinical need of revascularization. In this trial, the larger luminal dimensions of the stents implanted under ICUS guidance translated into a 40% reduction in the 6 month revascularization rate (14.8% vs. 8.9%, p < 0.05). Although the final answer is still pending, the available information suggests that the routine use of ICUS might translate into a direct clinical benefit, something remarkable for a diagnostic tool. In any case, the most effective way of using ICUS would probably be identifying those lesions that most benefit from the technique and avoiding its use in lesions with, a priori, excellent results.     

Expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in the pig coronary artery injury model: comparison of plain old balloon angioplasty and stent implantation

OBJECTIVES: Restenosis after coronary intervention usually occurs due to coronary remodeling or neointimal formation, but inflammation is also important especially after stent implantation. Adhesion molecules are important in the recruitment of inflammatory cells into the neointima and in the phenotypical changes of vascular smooth muscle cells. To examine the role of adhesion molecules in the pathogenesis of restenosis, immunohistochemical expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) was investigated in the pig coronary injury model. METHODS: Left anterior descending coronary arteries of pigs were injured using a balloon. Two weeks after the injury, balloon injury was performed again in the balloon group and a Palmaz-Schatz stent was implanted in the stent group. Pigs were sacrificed at 1, 2 and 4 weeks. Immunohistochemical analysis was performed using ICAM-1, VCAM-1, macrophage and alpha-smooth muscle actin antibodies. RESULTS: In non-injured vessels, weak immunoreactivities of ICAM-1 and VCAM-1 were observed in the endothelium and media. In injured sites, ICAM-1 and VCAM-1 were found in the inflammatory cells and smooth muscle cells in the neointima from 1 week, and strong immunoreactivities were seen around the strut in the stent group. Although the immunoreactivities peaked at 2 weeks in the balloon group, strong immunoreactivities were still seen at 4 weeks in the stent group. Regenerated endothelial cells were positive for both antibodies from 2 weeks. CONCLUSIONS: The expression of ICAM-1 and VCAM-1 lasted longer in the stent group than in the balloon group, suggesting the occurrence of late restenosis after stent implantation. Control of the inflammatory response including adhesion molecules is essential for further reduction of restenosis after stent implantation.     

Is intravascular ultrasound after coronary stenting a safe procedure? Three cases of stent damage attributable to ICUS in a tantalum coil stent

The use of coronary stents decreases the morbidity associated with acute closure and restenosis after balloon angioplasty. Intracoronary ultrasound (ICUS) guidance of stent implantation has been advocated to improve stent deployment and thereby to further improve the clinical outcome after stenting, over and above balloon angioplasty. Whereas the merits of intracoronary ultrasound in this respect still remain to be proven, the present paper illustrates that ICUS itself may also entail complications. This paper repoorts on three cases of stent damage induced or aggravated by the ICUS procedure. Cathet. Cardiovasc. Diagn. 40:265–270, 1997. © 1997 Wiley-Liss, Inc.     

Angiotensin-converting enzyme insertion/deletion polymorphism does not influence the restenosis rate after coronary stent implantation

BACKGROUND: Experimental studies have shown an activation of the angiotensin-converting enzyme (ACE) system as a response to endothelial injury. Recent publications have elucidated the hypothesis that the ACE gene polymorphism may influence the level of late luminal loss after coronary stent implantation. It is still unclear whether the polymorphism of the angiotensin gene is a major predictor of the extent of neointimal hyperplasia. In this multicenter study, we therefore tested the relationship between the ACE gene polymorphism and the restenosis rate after coronary stent implantation. METHODS: As a substudy of the optimization with intracoronary ultrasound (ICUS) to reduce stent restenosis (OPTICUS) study, we analyzed ACE serum levels and the ACE gene polymorphism in 154 patients at 9 different centers. All patients underwent elective coronary stent implantation in a stenosis of a major coronary vessel. Balloon inflations were repeated until a satisfactory result was achieved in on-line quantitative coronary angiography or ICUS fulfilling the OPTICUS study criteria. After follow-up of 6 months, all patients underwent reangiography under identical projections as the baseline procedure. A blinded quantitative analysis of the initial procedure as well as the follow-up examinations were performed by an independent core laboratory. ACE gene polymorphism and ACE serum activity were measured at the 6-month follow-up in a double-blinded setting. RESULTS: With respect to the ACE gene polymorphism, there were three subgroups: DD genotype (48 patients), ID (83 patients) and II (23 patients). The subgroups did not differ in regard to age, gender, extent of coronary artery disease, stenosis length, initial degree of stenosis or degree of stenosis after stent implantation. In all, 39 patients (25.3%) had significant restenosis: 12 DD patients (25.0%), 18 ID patients (21.7%) and 9 II patients (39.1%) (odds ratio 2.164, 95% confidence interval 0.853-5.493). We obtained the following results for ACE serum levels: 0.53 micromol/l/s in the DD subgroup, 0.29 micromol/l/s in the ID subgroup and 0.09 micromol/l/s in the II subgroup (p < 0.001). Multivariate logistic regression analysis of the influence of ACE gene polymorphism on the restenosis rate after coronary stent implantation adjusted for lesion length (>12 mm), ACE inhibitor or hydroxymethylglutaryl coenzyme A reductase (CSE) inhibitor treatment, age, male gender, diabetes mellitus, hypertension, high cholesterol, family history, smoking and three-vessel disease did not uncover any statistic significance. CONCLUSIONS: In contrast to other study groups, we were unable to disclose that the DD polymorphism of the ACE gene was associated with a higher rate of restenosis after coronary stent implantation in this multicenter study. In addition, patients with higher ACE serum levels did not show a higher restenosis rate in this trial. We conclude that the pathogenesis of restenosis is a multifactorial process involving various genetic and nongenetic factors.     

Intramural delivery of a specific tyrosine kinase inhibitor with biodegradable stent suppresses the restenotic changes of the coronary artery in pigs in vivo

Objectives. This study was designed to examine whether or not intramural delivery of ST638 (a specific tyrosine kinase inhibitor) with biodegradable stent can suppress the restenotic changes of the coronary artery in vivo.Background. Clinical and animal studies demonstrated that restenosis after coronary intervention results from a combined effect of neointimal formation and geometric remodeling (decrease in total cross-sectional area). Thus, the most effective strategy to prevent the restenosis appears to inhibit both the neointimal formation and geometric remodeling by antiproliferative agent and stent, respectively. We have previously shown that ST638 markedly suppresses the restenotic changes of the porcine coronary artery when applied from the adventitial site.Methods. A poly-l-lactic acid biodegradable stent was coated with either ST638 (0.8 mg) or equimolar of its inactive metabolite, ST494. A pair of these stents were implanted alternatively in the left anterior descending or circumflex coronary artery in pigs (n = 6). Three weeks after the procedure, coronary stenosis was assessed by angiography followed by histological examination.Results. Coronary stenosis was significantly less at the ST638 stent site than at the ST494 stent site (47 ± 5% vs. 25 ± 4%, p < 0.01). Histological examination also showed that the extent of neointimal formation and that of geometric remodeling were significantly less at the ST638 stent site than at the ST494 stent site (p < 0.05).Conclusions. These results indicate that intramural delivery of a specific tyrosine kinase inhibitor with biodegradable stent overcomes the proliferative stimuli caused by balloon injury, the stent itself, and the drug coating on the stent, resulting in the suppression of the restenotic changes of the coronary artery in vivo. This strategy might also be useful in the clinical setting in humans.     

Elevated matrix metalloproteinase expression after stent implantation is associated with restenosis

OBJECTIVE: Matrix metalloproteinases (MMPs) play a key role in intimal growth and is responsible for ventricular remodeling after stent implantation. However, little is known about the relationship between early MMPs expression post-stent implantation and follow-up restenosis. METHODS: We investigated the serial changes of serum MMP-9, MMP-2 and tissue inhibitor of metalloproteinase-1 (TIMP-1) in 16 control subjects with normal coronary angiography (control) and 40 patients before and on the 1st, 3rd and 7th day after uncomplicated stent implantation. Follow-up angiography was performed at 6 months after stent implantation. RESULTS: Serum MMP-2 level was higher in patients with restenosis on the 1st day post-stent implantation and returned to pre-operation level thereafter. Serum MMP-9 levels consistently increased in patients with restenosis up to 7th day post-stent implantation; MMP-9 levels in the 1st, 3rd and 7th day after stent implantation were positively correlated to the late loss index 6 months after stent implantation. CONCLUSIONS: Increased serum MMP-9 level is associated with increased risk of restenosis post-stent implantation.     

E-选择素介导的炎症反应与冠状动脉内支架术后再狭窄

再狭窄是限制冠状动脉内支架术远期成功的重要因素。它是一个由内皮损伤触发的多种因子参与的损伤修复过程,主要包括：机械损伤内皮处非阻塞性血栓形成、新生内膜增生及血管重构等反应。E-选择素仅表达于活化的内皮细胞表面,主要作用是在炎症发生时介导白细胞与血管内皮细胞的起始黏附,以及介导白细胞之间、白细胞与血小板之间的黏附形成血栓,从而对支架置入后损伤的内膜增生过程产生影响。E-选择素的研究对揭示再狭窄发生机制及寻找新的治疗途径均具有重要意义。     

Inflammation as a mechanism and therapeutic target for in-stent restenosis

Restenosis following coronary stenting has long been attributed to neointimal proliferation, thrombosis, and negative remodeling. More recently, the important role of inflammation in vascular healing has also been increasingly well understood. From animal models and from clinical experience, we know that endothelial injury, platelet and leukocyte interactions, and subcellular chemoattractant and inflammatory mediators are pivotal in the development of the inflammatory response following stent implantation. By examining the specific mechanisms governing the inflammatory response to percutaneous coronary intervention, we may gain insight into potential therapeutic targets and strategies to prevent restenosis in clinical practice.     

Stent design-related coronary artery remodeling and patterns of neointima formation following self-expanding and balloon-expandable stent implantation.

The self-expanding Wallstent (WS) and balloon-expandable Palmaz-Schatz stents (PS) display different mechanical and dynamical stent properties. We analyzed the impact of the respective stent design on coronary wall geometry using quantitative coronary angiography (QCA) and intracoronary ultrasound (ICUS) measurements. Serial measurements were performed within the stent and within reference segments of 50 patients (25 WS, 25 PS). Relative changes for each parameter in both stent designs were calculated (Mann-Whitney U-test; 95% CI). The luminal net gain in WS was not significantly higher in WS compared with PS (1.63 +/- 1.11 vs. 1.44 +/- 0.63 mm; P = 0.2554). The respective loss indexes were also similar (0.38 +/- 0.42 vs. 0.36 +/- 0.23; P = 0.8578). The WS segments showed significant postinterventional stent expansion with positive vessel remodeling. The neointima formation was significantly higher in WS segments (4.23 +/- 2.07 vs. 2.22 +/- 2.22 mm(2)). The coronary wall morphology and stent geometry after 6.5 +/- 1.2 months are related to the stent design. In WS segments, the neointima formation was balanced by postinterventional stent expansion, resulting in a comparable relative lumen loss in both stent types. The respective stent design had no impact on the vessel reference segments.     

Metallic biomaterials for coronary stents

The introduction of coronary stents is a milestone in interventional cardiology. Two landmark studies have shown that stainless steel stents significantly decrease the restenosis rate as compared to balloon angioplasty. This fact led to a marked increase of stent implantation since the first stent implantation by Jacques Puel in 1986. Although the concept of coronary stenting significantly improved the interventional therapy of coronary artery disease, restenosis remains a major unsolved drawback of this technique. In addition to procedure and disease related factors like implantation pressure and plaque burden, data suggest that the stent as a medical implant plays a crucial role in the process of neointima formation. Since its introduction in cardiology, more than 50 different stents of different configuration and material have been developed. Although recent publications report of promising results using biodegradable materials, almost all coronary stents commercially available at the moment are made of metallic alloys. Whereas first generation stents were made exclusively from stainless steel and only minor interest was focussed on the stent material in the manufacture of coronary stents, recent studies strongly suggest that the metallic alloy used has a direct impact on the extent of neointima formation. Thus, metallic alloys differ not only with respect to mechanical features, but also by their biocompatible properties. These two factors are of major importance in the induction of vessel wall injury, inflammatory processes and cell proliferation. In the first part, the present paper reviews the metallurgic characteristics of metallic materials, which are currently used or under investigation in the production of coronary stents. In the second part, clinical and experimental results are summarized with respect to their biocompatibility and impact on the process of restenosis formation.     

Adventitial VEGF165 gene transfer prevents lumen loss through induction of positive arterial remodeling after PTCA in porcine coronary arteries

Negative arterial remodeling still plays an important role in the pathogenesis of coronary restenosis even in the era of interventional stenting (e.g. arterial narrowing occurs proximal and distal of a stented segment). Previous studies suggest that increased angiogenesis and inhibited regression of injury-induced adventitial microvessels prevents negative remodeling. We have examined the effect of local vascular endothelial growth factor (VEGF(165)) gene transfer on adventitial microvessel angiogenesis/regression and arterial remodeling after coronary angioplasty. Twenty pigs underwent angioplasty, each one in two major coronary arteries, followed by plasmid liposome gene transfer with either VEGF(165) or control gene LacZ (50 microg DNA with 50 microg of Lipofectine) into the (peri)adventitial space using a needle injection catheter. Arteries were examined at days 1, 7, 14, and 28. Local delivery of VEGF(165) gene into the outer compartments of balloon-injured porcine coronary arteries reduced lumen area loss due to distinct positive remodeling (arterial enlargement). Prevention of adventitial microvessel regression, enhanced adventitial elastin accumulation, reduced adventitial myofibroblast numbers, and a pronounced adventitial inflammatory response considered as a part of arterial healing seem to be the main VEGF-mediated mechanisms indicating the therapeutic potential of VEGF for restenosis prevention.     

Inhibition of neointima formation by tranilast in pig coronary arteries after balloon angioplasty and stent implantation

OBJECTIVES: We evaluated the effect of orally administered tranilast, N-(3,4-dimethoxycinnamoyl) anthranilic acid, on histologic and histomorphometric changes after angioplasty or stent implantation in pig coronary arteries. BACKGROUND: Tranilast, which has antikeloid and antiallergic properties and therefore may modulate the fibrotic and inflammatory tissue responses to angioplasty and stenting, has been shown to inhibit angiographic restenosis in small clinical trials. However, its effect on histomorphometric changes in coronary arteries after angioplasty and stenting is unknown. METHODS: Following initial pharmacokinetic studies in two pigs to determine desirable plasma levels of orally administered tranilast, 36 crossbred juvenile pigs were randomized to placebo or tranilast before undergoing balloon angioplasty in both the left anterior descending and left circumflex plus stent implantation in the right coronary artery. Oral tranilast was administered at 3 g/day starting 3 days before coronary injury and continued for 28 days until euthanasia. Injured vessels were harvested and sections analyzed by computer-assisted microscopic planimetry. RESULTS: In balloon-injured vessels, tranilast was associated with a 37% reduction in neointimal area normalized to fracture length (0.47 +/- 0.01 vs. 0.74 +/- 0.03 mm; p < 0.001) and a 23% reduction in adventitial area normalized to vessel size (0.43 +/- 0.02 vs. 0.56 +/- 0.03; p = 0.003). In stented arteries, neointimal area normalized to injury score was 32% lower in the tranilast-treated group compared to control (1.94 +/- 0.17 vs. 2.86 +/- 0.29; p = 0.01). CONCLUSIONS: In pig coronary arteries, tranilast was associated with a reduction in neointima formation and adventitial reaction after balloon injury. In stented vessels, tranilast was associated with a reduction in neointima formation normalized to injury score.     

Restenosis and the proportional neointimal response to coronary artery injury: results in a porcine model.

Restenosis is a reparative response to arterial injury occurring with percutaneous coronary revascularization. However, the quantitative characteristics of the relation between vessel injury and the magnitude of restenotic response remain unknown. This study was thus performed to determine the relation between severity of vessel wall injury and the thickness of resulting neointimal proliferation in a porcine model of coronary restenosis. Twenty-six porcine coronary artery segments in 24 pigs were subjected to deep arterial injury with use of overexpanded, percutaneously delivered tantalum wire coils. The vessels were studied microscopically 4 weeks after coil implantation to measure the relation between the extent of injury and the resulting neointimal thickness. For each wire site, a histopathologic score proportional to injury depth and the neointimal thicknesses at that site were determined. Mean injury scores were compared with both mean neointimal thickness and planimetry-derived area percent lumen stenosis. The severity of vessel injury strongly correlated with neointimal thickness and percent diameter stenosis (p less than 0.001). Neointimal proliferation resulting from a given wire was related to injury severity in adjacent wires, suggesting an interaction among effects at injured sites. If the results in this model apply to human coronary arteries, restenosis may depend on the degree of vessel injury sustained during angioplasty.     

The role of endothelial progenitor cells in restenosis and stent thrombosis after percutaneous coronary intervention

Background After percutaneous coronary intervention (PCI), some patients may suffer from restenosis and stent thrombosis. Many studies suggest that endothelial progenitor cell (EPC) has an important role in preventing restenosis and stent thrombosis. A novel stent which can attract EPC has been designed to provide a better outcome for these problems. Method The data of the present review was obtained by searching PUBMED and other databases (1994-2011) using the key terms of "endothelial progenitor cell", "reendothelialization", "restenosis", "stent thrombosis", and "percutaneous coronary intervention". Result Rapid reendothelialization is essential in preventing restenosis and stent thrombosis. EPC can differentiate into endothelial cell and accelerate the reendothelialization. After numerous preclinical and clinical researches , the correlation between circulating EPCs to restenosis still remains poorly understood. However , many studies have shown the important role of EPC in diminishing the risk of thrombosis following stent implantation. Some pharmacological agents have been reported can increase the number and / or functions of EPC. Recently , CD34+ antibody coated stent has been developed to attract EPC to the healing endothelium , and has showed favorable results. Conclusion EPC has important role in rapid reendothelialization after vascular injury. EPC can prevent stent thrombosis after PCI , however the effects of EPC in preventing restenosis need further investigations. The capturing CD34+ stent is safe and significantly decreases stent thrombosis.     

Drug-eluting stent: the emerging technique for the prevention of restenosis

Percutaneous coronary interventions (PCI) have surpassed coronary artery bypass grafting as the most common means for treating coronary artery disease, because of materials improvement, the use of stent and pharmacotherapy. However, despite the variety of mechanical techniques such as dilatation, debulking or conventional stent implantation, the incidence of restenosis on short and mid-term follow-up is still representing an important limitation to PCI. Restenosis is mainly due to elastic recoil, negative vessel remodelling and neointimal proliferation, as a response to vessel injury induced by angioplasty devices. The use of conventional stents has provided an efficient method to avoid elastic recoil and negative vessel remodelling, thus partially reducing restenosis as compared to conventional balloon dilatation. However, neointimal proliferation (biological vessel response to injury caused by stent implantation) is not affected by stenting technique. Thus, the extensive use of coronary stent, even in complex lesions, have produced again a "new" disease: the in-stent restenosis especially in some patients' subset (diabetics) or in some lesion subset (bifurcations, long lesions, small vessels, total occlusions, diffuse disease). Therefore, the main target of today's interventional cardiologists is to resolve this problem. The combination between mechanical control of elastic recoil and negative remodelling (stent) and the control of neointimal proliferation - biological response to vessel injury - (antiproliferative drugs) is the emerging approach against restenosis. This emerging approach consists in using the stent as drug carrier to the target site. Local delivery of antiproliferative or immunosuppressive agents using a drug-coated stent is supposed to inhibit in stent restenosis. The first antiproliferative agents being used successfully in clinical trials are sirolimus and paclitaxel and, so far, the data available of these trials demonstrated a marked reduction of restenosis using sirolimus- and paclitaxel-coated stents as compared to conventional stents. However, many questions are still to be answered and several other clinical trials with drug-eluting stents are ongoing, evaluating safety and efficacy of sirolimus and paclitaxel in a larger number of patients and in different subset of coronary lesions type and morphology. Based on the very impressive results available at the present time, we can expect, in the very near future, remarkable changes in our clinical practice and the beginning of a new "era" of interventional cardiology.     

Should every eligible lesion undergo direct stenting?

Although significant coronary artery (CA) calcification is believed to affect stent deployment, the exact impact on stent deployment after high-pressure balloon inflations is unknown. Intracoronary intravascular examination (ICUS) was performed in 27 moderate-severe calcified CA lesions before and after stent implantation. In case of unsatisfactory results (in-stent area < 90%, minimal in-stent diameter/maximal in-stent diameter < 0.8), further inflations up to 20 atm guided by ICUS were applied. Initially, stent expansion was adequate in 10 stents (37%) and symmetric in 19 (70%). After inflation at 20 atm, stents with adequate expansion increased to 16 (59%, P = 0.0036), but stents with symmetry decreased to 13 (48%, P = 0.0045). Stent expansion was inversely correlated to the arc of calcium (r = -0.8, P < 0.0001). There were five patients with clinical restenosis at 6 months (18%). Increases in stent lumen area with high-pressure balloon inflations in moderate-severe calcified CA lesions are at the expense of symmetry. This may affect clinical restenosis.     

Neointimal hyperplasia after stenting in a human mammary artery organ culture

Although the use of stents has limited the incidence of restenosis, in-stent restenosis remains an important problem. In-stent restenosis is the result of a healing process that induced neointimal hyperplasia through mechanisms that are still not understood. The aim of this study was to analyze the histological consequences of the healing process following stent implantation. Internal mammary arteries from atheroslerotic patients undergoing coronary artery bypass surgery were stented and maintained in culture for 0-28 days. Stent implantation after predilatation induced an extensive loss of endothelial cells whereas direct stenting preserved endothelium between the struts. Morphometric analysis shows that stent placement induced neointimal thickening. Smooth muscle alpha-actin labeling indicates that neo-intimal formation was mainly due to proliferation and migration of smooth muscle cells. Smooth muscle cell proliferation, assessed by MIB-1 staining, was maximal at day 14 after stent insertion. Human mammary artery organ culture thus provides valuable information on histological consequences of stent implantation with or without predilatation regarding endothelial cell disappearance and neointimal hyperplasia. These data also demonstrate that neointimal thickening induced by stent implantation comprises an intrinsic component resulting from the vessel wall response to stent insertion and suggest that blood factors could play an amplifying but not necessary role.     

Treatment Strategies for In-Stent Restenosis

In-stent restenosis has become a significant clinical problem. It is estimated that in 1997, up to 100,000 patients with in-stent restenosis were treated worldwide. Serial intravascular ultrasound analysis has shown that neointimal hyperplasia represents the most important cause for in-stent restenosis, while late recoil and remodeling are neglectabe. With the recent explosion in the use of coronary stents, clinical investigation on stent restenosis has lagged behind. For example, the true prevalence of in-stent restenosis varies with the lesion and patient subset. It is much higher in the "real world" than in selected patients who are typically controlled in most studies. Diffuse restenosis can be expected in about two-thirds of stented patients, and it is difficult to treat because of unfavorable long-term results. Conventional catheter-based treatment modalities include plain balloon angioplasty (PTCA), rotational atherectomy (RA), excimer laser coronary angioplasty (ELCA), directional coronary atherectomy (DCA), and additional stent implantation. Exact individual recurrence rates for these approaches are not known and show a considerable degree of variability. Recently, brachytherapy has emerged as the most promising way to treat in-stent restenosis.     

Balloon-artery interactions during stent placement: a finite element analysis approach to pressure, compliance, and stent design as contributors to vascular injury

Endovascular stents expand the arterial lumen more than balloon angioplasty and reduce rates of restenosis after coronary angioplasty in selected patients. Understanding the factors involved in vascular injury imposed during stent deployment may allow optimization of stent design and stent-placement protocols so as to limit vascular injury and perhaps reduce restenosis. Addressing the hypothesis that a previously undescribed mechanism of vascular injury during stent deployment is balloon-artery interaction, we have used finite element analysis to model how balloon-artery contact stress and area depend on stent-strut geometry, balloon compliance, and inflation pressure. We also examined superficial injury during deployment of stents of varied design in vivo and in a phantom model ex vivo to show that balloon-induced damage can be modulated by altering stent design. Our results show that higher inflation pressures, wider stent-strut openings, and more compliant balloon materials cause markedly larger surface-contact areas and contact stresses between stent struts. Appreciating that the contact stress and contact area are functions of placement pressure, stent geometry, and balloon compliance may help direct development of novel stent designs and stent-deployment protocols so as to minimize vascular injury during stenting and perhaps to optimize long-term outcomes.