Pathology of in-stent restenosis

The process of in-stent restenosis parallels wound healing responses. Stent deployment results in early thrombus deposition and acute inflammation, granulation tissue development, and ultimately smooth muscle cell proliferation and extracellular matrix synthesis. The severity of arterial injury during stent placement correlates with increased inflammation and late neointimal growth. These pathological findings provide useful targets for therapies aimed at reducing the incidence of in-stent restenosis.     

A multi-scale mechanobiological model of in-stent restenosis: deciphering the role of matrix metalloproteinase and extracellular matrix changes

Since their first introduction, stents have revolutionised the treatment of atherosclerosis; however, the development of in-stent restenosis still remains the Achilles' heel of stent deployment procedures. Computational modelling can be used as a means to model the biological response of arteries to different stent designs using mechanobiological models, whereby the mechanical environment may be used to dictate the growth and remodelling of vascular cells. Changes occurring within the arterial wall due to stent-induced mechanical injury, specifically changes within the extracellular matrix, have been postulated to be a major cause of activation of vascular smooth muscle cells and the subsequent development of in-stent restenosis. In this study, a mechanistic multi-scale mechanobiological model of in-stent restenosis using finite element models and agent-based modelling is presented, which allows quantitative evaluation of the collagen matrix turnover following stent-induced arterial injury and the subsequent development of in-stent restenosis. The model is specifically used to study the influence of stent deployment diameter and stent strut thickness on the level of in-stent restenosis. The model demonstrates that there exists a direct correlation between the stent deployment diameter and the level of in-stent restenosis. In addition, investigating the influence of stent strut thickness using the mechanobiological model reveals that thicker strut stents induce a higher level of in-stent restenosis due to a higher extent of arterial injury. The presented mechanobiological modelling framework provides a robust platform for testing hypotheses on the mechanisms underlying the development of in-stent restenosis and lends itself for use as a tool for optimisation of the mechanical parameters involved in stent design.     

Modelling the Effect of a Functional Endothelium on the Development of In-Stent Restenosis

Treatment of stenosed coronary arteries by balloon angioplasty and stenting results in arterial injury including severe damage to the endothelium at the site of treatment and initiates a complex cascade of inflammatory processes that may lead to the development of in-stent restenosis (ISR). Many clinical and biological factors involved in the progression of restenotic lesions have been studied in detail over the past few years but the mystery behind the pathophysiological mechanisms of this disease is still unresolved. In the present work, the effects of re-endothelialization and nitric oxide release on neointimal growth are investigated in-silico using a two dimensional multi-scale model of ISR. The effect of stent deployment depths on the development of ISR is studied as a function of time after stenting. Two dimensional domains were prepared by deploying bare metal stent struts at three different deployment depths into the tissue. Shear stress distribution on endothelial cells, obtained by blood flow simulations, was translated into nitric oxide production that keeps the smooth muscle cells in quiescent state. The cellular growth trends were plotted as a function of time and the data indicate a positive correlation between the neointimal growths and strut deployment depths in the presence of a functional endothelium, in qualitative agreement with in-vivo data. Additionally, no ISR is observed if a functional endothelium appears much earlier.     

Mechanistic evaluation of long-term in-stent restenosis based on models of tissue damage and growth

Development and application of advanced mechanical models of soft tissues and their growth represent one of the main directions in modern mechanics of solids. Such models are increasingly used to deal with complex biomedical problems. Prediction of in-stent restenosis for patients treated with coronary stents remains a highly challenging task. Using a finite element method, this paper presents a mechanistic approach to evaluate the development of in-stent restenosis in an artery following stent implantation. Hyperelastic models with damage, verified with experimental results, are used to describe the level of tissue damage in arterial layers and plaque caused by such intervention. A tissue-growth model, associated with vessel damage, is adopted to describe the growth behaviour of a media layer after stent implantation. Narrowing of lumen diameter with time is used to quantify the development of in-stent restenosis in the vessel after stenting. It is demonstrated that stent designs and materials strongly affect the stenting-induced damage in the media layer and the subsequent development of in-stent restenosis. The larger the artery expansion achieved during balloon inflation, the higher the damage introduced to the media layer, leading to an increased level of in-stent restenosis. In addition, the development of in-stent restenosis is directly correlated with the artery expansion during the stent deployment. The correlation is further used to predict the effect of a complex clinical procedure, such as stent overlapping, on the level of in-stent restenosis developed after percutaneous coronary intervention.

     

Long period of balloon inflation and the implantation of stents potentiate smooth muscle cell death. Possible role of chronic vascular injury in restenosis

BACKGROUND: It has been suggested that the severity of acute vascular injury immediately after percutaneous transluminal coronary angioplasty (PTCA) or stent implantation correlates with the extent of neointimal hyperplasia and restenosis. However, the influence of prolonged or chronic vessel injury on the pathogenesis of restenosis is unclear. METHODS: Rabbit iliac arteries were balloon dilated for a short (1 min) or prolonged (10 min) period of time, or were chronically dilated and received a Palmaz-Schatz stent (balloon inflation for 1 min). All arteries were overexpanded to a balloon:artery ratio of 1.2:1 as determined by angiography. The arteries were removed 30 min and 4 weeks after the angioplasty procedures. The sites of injury were evaluated by gross histology and transmission electron microscopy (TEM). Cell death of medial smooth muscle cells (SMCs) was specified by TEM images 30 min after the procedures. Computer-assisted quantification of the neointimal cross-sectional areas was performed after 4 weeks using a light microscope connected to a digital image analyser. RESULTS: The results show that prolonged balloon dilatation and stent implantation increased necrotic SMC death compared with balloon dilatation for 1 min. After 30 min, increased staining of SMC nuclei, enlarged intercellular spaces and changes in SMC shape in the media indicated cell death induced by prolonged balloon dilatation or chronic stent injury. Stent implantation markedly augmented vessel damage by persistent compression of the media, compared with a balloon dilatation for 1 or 10 min. Both prolonged balloon dilatation and stent implantation increased neointimal hyperplasia at 4 weeks compared with balloon dilatation for 1 min (0.6 3 0.2 and 1.0 3 0.2 mm(2) versus 0.2 3 0.1 mm(2), P < 0.001 versus dilatation for 1 min). CONCLUSION: Prolonged or chronic vascular expansion due to long balloon-inflation periods or the implantation of stents increases medial SMC death, which subsequently stimulates neointimal growth in this restenosis model. Chronic vascular injury may be an important stimulus for restenosis after angioplasty procedures.     

Numerical study of the uniformity of balloon-expandable stent deployment

Stents are small tubelike structures, implanted in coronary and peripheral arteries to reopen narrowed vessel sections. This endovascular intervention remains suboptimal, as the success rate is limited by restenosis. This renarrowing of a stented vessel is related to the arterial injury caused by stent-artery and balloon-artery interactions, and a local subsequent inflammatory process. Therefore, efforts to optimize the stent deployment remain very meaningful. Several authors have studied with finite element modeling the mechanical behavior of balloon-expandable stents, but none of the proposed models incorporates the folding pattern of the balloon. We developed a numerical model in which the CYPHER stent is combined with a realistic trifolded balloon. In this paper, the impact of several parameters such as balloon length, folding pattern, and relative position of the stent with respect to the balloon catheter on the free stent expansion has been investigated. Quantitative validation of the modeling strategy shows excellent agreement with data provided by the manufacturer and, therefore, the model serves as a solid basis for further investigations. The parametric analyses showed that both the balloon length and the folding pattern have a considerable influence on the uniformity and symmetry of the transient stent expansion. Consequently, this approach can be used to select the most appropriate balloon length and folding pattern for a particular stent design in order to optimize the stent deployment. Furthermore, it was demonstrated that small positioning inaccuracies may change the expansion behavior of a stent. Therefore, the placement of the stent on the balloon catheter should be accurately carried out, again in order to decrease the endothelial damage.     

Monitoring the wall mechanics during stent deployment in a vessel

Clinical trials have reported different restenosis rates for various stent designs. It is speculated that stent-induced strain concentrations on the arterial wall lead to tissue injury, which initiates restenosis. This hypothesis needs further investigations including better quantifications of non-uniform strain distribution on the artery following stent implantation. A non-contact surface strain measurement method for the stented artery is presented in this work. ARAMIS stereo optical surface strain measurement system uses two optical high speed cameras to capture the motion of each reference point, and resolve three dimensional strains over the deforming surface. As a mesh stent is deployed into a latex vessel with a random contrasting pattern sprayed or drawn on its outer surface, the surface strain is recorded at every instant of the deformation. The calculated strain distributions can then be used to understand the local lesion response, validate the computational models, and formulate hypotheses for further in vivo study.     

Murine Model of Femoral Artery Wire Injury with Implantation of a Perivascular Drug Delivery Patch

Percutaneous interventions including balloon angioplasty and stenting have been used to restore blood flow in vessels with occlusive vascular disease. While these therapies lead to the rapid restoration of blood flow, these technologies remain limited by restenosis in the case of bare metal stents and angioplasty, or reduced healing and possibly enhanced risk of thrombosis in the case of drug eluting stents. A key pathophysiological mechanism in the formation of restenosis is intimal hyperplasia caused by the activation of vascular smooth muscle cells and inflammation due to arterial stretch and injury. Surgeries that induce arterial injury in genetically modified mice are useful for the mechanistic study of the vascular response to injury but are often technically challenging to perform in mouse models due to the their small size and lack of appropriate sized devices. We describe two approaches for a surgical technique that induces endothelial denudation and arterial stretch in the femoral artery of mice to produce robust neointimal hyperplasia. The first approach creates an arteriotomy in the muscular branch of the femoral artery to obtain vascular access. Following wire injury this arterial branch is ligated to close the arteriotomy. A second approach creates an arteriotomy in the main femoral artery that is later closed through localized cautery. This method allows for vascular access through a larger vessel and, consequently, provides a less technically demanding procedure that can be used in smaller mice. Following either method of arterial injury, a degradable drug delivery patch can be placed over or around the injured artery to deliver therapeutic agents.     

Simulation of a balloon expandable stent in a realistic coronary artery—Determination of the optimum modelling strategy

Computational models of stent deployment in arteries have been widely used to shed light on various aspects of stent design and optimisation. In this context, modelling of balloon expandable stents has proved challenging due to the complex mechanics of balloon–stent interaction and the difficulties involved in creating folded balloon geometries. In this study, a method to create a folded balloon model is presented and utilised to numerically model the accurate deployment of a stent in a realistic geometry of an atherosclerotic human coronary artery. Stent deployment is, however, commonly modelled by applying an increasing pressure to the stent, thereby neglecting the balloon. This method is compared to the realistic balloon expansion simulation to fully elucidate the limitations of this procedure. The results illustrate that inclusion of a realistic balloon model is essential for accurate modelling of stent deformation and stent stresses. An alternative balloon simulation procedure is presented however, which overcomes many of the limitations of the applied pressure approach by using elements which restrain the stent as the desired diameter is achieved. This study shows that direct application of pressure to the stent inner surface may be used as an optimal modelling strategy to estimate the stresses in the vessel wall using these restraining elements and hence offer a very efficient alternative approach to numerically modelling stent deployment within complex arterial geometries. The method is limited however, in that it can only predict final stresses in the stented vessel and not those occurring during stent expansion, in which case the balloon expansion model is required.     

The involvement of vascular endothelial growth factor and flt-1 in the process of neointimal proliferation in pig coronary arteries following stent implantation

To clarify the role of vascular endothelial growth factor (VEGF) in the process of restenosis, a Palmaz-Schatz stent was implanted in the left anterior descending coronary artery of male pigs at 2 weeks after balloon injury (balloon/artery ratio 1.2:1). The animals were euthanized at 1, 2, and 4 weeks after stenting, and western blot and immunohistochemical analysis were performed using VEGF, fms-like tyrosine kinase (flt)-1, and platelet-derived growth factor (PDGF) antibodies. The expressions of VEGF and flt-1 protein in the neointima were observed as early as 1 week after stenting and remained for up to 4 weeks, while re-endothelialization was complete at 2 weeks. These protein expressions were demonstrated in proliferated smooth muscle cells throughout the entire period after stenting and, in addition, they were observed in the macrophages and endothelial cells of microvessels around stent struts at 4 weeks. The expression pattern of VEGF corresponded with that of PDGF, a growth factor well-known to induce neointimal proliferation. The cell proliferative activity, measured by the proliferating cell nuclear antigen index, around the struts remained high until 4 weeks after stenting, while that in the other areas declined at 4 weeks. These results suggest that VEGF is involved in the process of restenosis not only through its angiogenic properties and induction of monocyte chemotaxis, but also by a synergistic effect with PDGF.     

Modelling drug elution from stents: effects of reversible binding in the vascular wall and degradable polymeric matrix

Today the most popular approach for the prevention of the restenosis consists in the use of the drug eluting stents. The stent acts as a source of drug, from a coating or from a reservoir, which is transported into and through the artery wall. In this study, the behaviour of a model of a hydrophilic drug (heparin) released from a coronary stent into the arterial wall is investigated. The presence of the specific binding site action is modelled using a reversible chemical reaction that explains the prolonged presence of drug in the vascular tissue. An axi-symmetric model of a single stent strut is considered. First an advection-diffusion problem is solved using the finite element method. Then a simplified model with diffusion only in the arterial wall is compared with: (i) a model including the presence of reversible binding sites in the vascular wall and (ii) a model featuring a drug reservoir made of a degradable polymeric matrix. The results show that the inclusion of a reversible binding for the drug leads to delayed release curves and that the polymer erosion affects the drug release showing a quicker elution of the drug from the stent.     

Modelling drug elution from stents: effects of reversible binding in the vascular wall and degradable polymeric matrix

Today the most popular approach for the prevention of the restenosis consists in the use of the drug eluting stents. The stent acts as a source of drug, from a coating or from a reservoir, which is transported into and through the artery wall. In this study, the behaviour of a model of a hydrophilic drug (heparin) released from a coronary stent into the arterial wall is investigated. The presence of the specific binding site action is modelled using a reversible chemical reaction that explains the prolonged presence of drug in the vascular tissue. An axi-symmetric model of a single stent strut is considered. First an advection–diffusion problem is solved using the finite element method. Then a simplified model with diffusion only in the arterial wall is compared with: (i) a model including the presence of reversible binding sites in the vascular wall and (ii) a model featuring a drug reservoir made of a degradable polymeric matrix. The results show that the inclusion of a reversible binding for the drug leads to delayed release curves and that the polymer erosion affects the drug release showing a quicker elution of the drug from the stent.     

Efficiency of endovascular re-interventions for evolving restenosis of different types of stents

The paper compares the results of different treatment options (balloon angioplasty and restenting) for in-stent restenosis in case of evolving restenosis of drug- and nondrug eluting stents. The investigation enrolled 496 coronary heart disease patients with clinical presentation of angina pectoris and/or signs of myocardial ischemia, as well as hemodynamic restenosis of a previously implanted stent. Of them, 216 and 280 patients had restenosis of previously implanted drug- and nondrug-eluting stents, respectively. In the patients with non-drug-eluting stent restenosis, recurrent angina pectoris and the frequency of repeated restenosis were significantly more frequently observed after balloon dilatation than after drug-eluting stent implantation (28.4 and 10.2%; p < 0.05; 19.9 and 8.7%; p < 0.05). In those with drug-eluting stent restenosis, recurrent angina pectoris and the frequency of repeated restenosis did not differ significantly between balloon dilatation of restenosis and implantation of a second drug-eluting stent.     

An argument for the use of multiple segment stents in curved arteries

Stenting of curved arteries is generally perceived to be more challenging than straight vessels. Conceptually implanting multiple shorter stents rather than a single longer stent into such a curved artery represents a promising concept, but little is known about the impact of such an approach. The objective of this study is to evaluate the effectiveness of using a multiple segment stent rather than a single long stent to dilate a curved artery using the finite element method. A double segment stent (DSS) and a single segment stent (SSS) were modeled. The stents were compared when expanded into a model of a curved artery. The model predicts that the DSS provides higher flexibility, more conformity, and lower recoil in comparison to the SSS. The volume of arterial tissue experiencing high levels of stress due to stent implantation is also reduced for the DSS. It is suggested that a multiple segment stenting system is a potential solution to the problem of higher rates of in-stent restenosis in curved arteries and mechanically challenging environments.     

Adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene inhibits vascular smooth muscle cell proliferation and neointima formation following balloon angioplasty of the rat carotid artery.

BACKGROUND: Vascular smooth muscle cell (VSMC) proliferation following arterial injury plays a critical role in a variety of vascular proliferative disorders, including atherosclerosis and restenosis after balloon angioplasty. In this study, we tested the hypothesis that localized arterial infection at the time of balloon angioplasty with an adenovirus (ADV-tk) encoding the herpes simplex virus thymidine kinase gene (HSV-tk), followed by systemic ganciclovir administration, can inhibit VSMC proliferation and neointima formation in a well-characterized model of arterial injury and restenosis. MATERIALS AND METHODS: The left carotid arteries of 31 male Sprague-Dawley rats were subjected to balloon angioplasty and immediately infected with 2 x 10(9) pfu of either ADV-tk or a control adenovirus that does not encode a recombinant protein (ADV-delta E1). Twenty-four hours after injury, animals from each experimental group were randomized to receive a course of systemic ganciclovir (ADV-tk/+GC, ADV delta E1/+GC) or saline (ADV-tk/-GC, ADV-delta E1/-GC). VSMC DNA synthesis was measured by 5'-bromodeoxuridine (BrdU) incorporation 2-4 days after balloon injury. The extent of restenosis, expressed as the neointima to media (I/M) area ratio was determined by digital planimetry 20 days after balloon injury in each of the four treatment groups. Immunohistochemistry using a mAb to von Willebrand factor (vWF) was used to determine the effects of ADV-tk infection and ganciclovir treatment on re-endothelialization of the carotid arteries 20 days following balloon angioplasty. RESULTS: Forty-one percent of the medial VSMCs in the ADV-tk/-GC arteries were labeled with BrdU 4 days after balloon injury. In contrast, ADV-tk infected animals that were treated with systemic ganciclovir (ADV-tk/+GC) displayed a 40% reduction in BrdU-staining medial VSMCs (p < 0.03). I/M area ratios of the three control groups were 1.17 +/- 0.18 (ADV-tk/-GC, n = 5), 1.15 +/- 0.10 (ADV-delta E1/+GC, n = 6), and 0.91 +/- 0.08 (ADV-delta E1/-GC, n = 6). These differences were not statistically significant (p > 0.05). In contrast, the ADV-tk/+GC animals (n = 6) displayed an I/M area ratio of 0.49 +/- 0.13 which was significantly lower than that seen in each of the three control groups (p < 0.02). None of the treated animals showed evidence of significant organ toxicity at autopsy. A regenerated endothelium was observed in the ADV-tk/+GC animals 20 days after balloon injury. CONCLUSIONS: Localized arterial infection with ADV-tk at the time of balloon angioplasty followed by systemic ganciclovir therapy reduces VSMC proliferation and neointimal expansion in the rat carotid artery injury model. Moreover, combined treatment with ADV-tk and systemic ganciclovir does not result in systemic toxicity and appears to selectively eliminate proliferating VSMCs, while preserving the capacity of the injured arterial segments to re-endothelialize within 3 weeks of injury. Taken together, these results support the feasibility of using this gene therapy approach for the treatment of human vascular proliferative disorders.     

Sequential structural and fluid dynamic numerical simulations of a stented bifurcated coronary artery

Despite their success, stenting procedures are still associated to some clinical problems like sub-acute thrombosis and in-stent restenosis. Several clinical studies associate these phenomena to a combination of both structural and hemodynamic alterations caused by stent implantation. Recently, numerical models have been widely used in the literature to investigate stenting procedures but always from either a purely structural or fluid dynamic point of view. The aim of this work is the implementation of sequential structural and fluid dynamic numerical models to provide a better understanding of stenting procedures in coronary bifurcations. In particular, the realistic geometrical configurations obtained with structural simulations were used to create the fluid domains employed within transient fluid dynamic analyses. This sequential approach was applied to investigate the final kissing balloon (FKB) inflation during the provisional side branch technique. Mechanical stresses in the arterial wall and the stent as well as wall shear stresses along the arterial wall were examined before and after the FKB deployment. FKB provoked average mechanical stresses in the arterial wall almost 2.5 times higher with respect to those induced by inflation of the stent in the main branch only. Results also enlightened FKB benefits in terms of improved local blood flow pattern for the side branch access. As a drawback, the FKB generates a larger region of low wall shear stress. In particular, after FKB the percentage of area characterized by wall shear stresses lower than 0.5?Pa was 79.0%, while before the FKB it was 62.3%. For these reasons, a new tapered balloon dedicated to bifurcations was proposed. The inclusion of the modified balloon has reduced the mechanical stresses in the proximal arterial vessel to 40% and the low wall shear stress coverage area to 71.3%. In conclusion, these results show the relevance of the adopted sequential approach to study the wall mechanics and the hemodynamics created by stent deployment.     

同源异型盒基因对血管平滑肌细胞的调控作用

同源异型盒基因是一类对生物体的生长、发育和分化从时间和空间上进行协调的调控基因。构成血管中膜的血管平滑肌细胞表型具有极大的可塑性。在一些病理性血管重构时,血管平滑肌细胞可发生表型调变,从分化型调变为去分化型,具备增殖和迁移能力。在此过程中,多种同源异型盒基因的表达发挥了重要的调控作用。现就同源异型盒基因与血管平滑肌细胞的表型调变、增殖和迁移的关系等方面的研究进展作一综述。     

Rat carotid artery dilation by PTCA balloon catheter induces neointima formation in presence of IEL rupture

The best animal angioplasty model is the porcine model, which is expensive and not available in all laboratories. The aim of this study was to describe a new rat model of angioplasty. An injury was induced with the use of a standard percutaneous transluminal coronary angioplasty (PTCA) 1.5-mm balloon catheter. The neointimal tissue, arterial dimensions, and the injury index were assessed following angioplasty. Ki-67 expression was detected to evaluate cell turnover after balloon angioplasty. In contrast with the standard Clowes model, a significant neointimal formation was detected only in the presence of ruptured internal elastic lamina (IEL). A positive correlation between the percentage of ruptured IEL and the amount of neointimal tissue was also demonstrated. The percentage of IEL fracture correlates with the proliferation index by anti-Ki-67 immunolabeling 7 and 14 days after the angioplasty. Significant arterial negative remodeling was observed following PTCA balloon dilation. In conclusion, our inexpensive animal model of restenosis after angioplasty may have great relevance toward a better understanding of the mechanisms and toward assessment of new therapeutical strategies for this phenomenon.     

Modelling intravascular delivery from drug-eluting stents with biodurable coating: investigation of anisotropic vascular drug diffusivity and arterial drug distribution

In-stent restenosis occurs in coronary arteries after implantation of drug-eluting stents with non-uniform restenosis thickness distribution in the artery cross section. Knowledge of the spatio-temporal drug uptake in the arterial wall is useful for investigating restenosis growth but may often be very expensive/difficult to acquire experimentally. In this study, local delivery of a hydrophobic drug from a drug-eluting stent implanted in a coronary artery is mathematically modelled to investigate the drug release and spatio-temporal drug distribution in the arterial wall. The model integrates drug diffusion in the coating and drug diffusion with reversible binding in the arterial wall. The model is solved by the finite volume method for both high and low drug loadings relative to its solubility in the stent coating with varied isotropic–anisotropic vascular drug diffusivities. Drug release profiles in the coating are observed to depend not only on the coating drug diffusivity but also on the properties of the surrounding arterial wall. Time dependencies of the spatially averaged free- and bound-drug levels in the arterial wall on the coating and vascular drug diffusivities are discussed. Anisotropic vascular drug diffusivities result in slightly different average drug levels in the arterial wall but with very different spatial distributions. Higher circumferential vascular diffusivity results in more uniform drug loading in the upper layers and is potentially beneficial in reducing in-stent restenosis. An analytical expression is derived which can be used to determine regions in the arterial with higher free-drug concentration than bound-drug concentration.