Restenosis Process Research Articles

Bare Metal Stents Versus Drug Eluting Stents: Where Do We Stand in 2015?

The development of bare metal stent (BMS) was a major advancement over plain old balloon angioplasty (POBA) in the management of symptomatic coronary artery disease. BMS prevented restenosis by attenuating early arterial recoil and contraction; both seen commonly after POBA. However, the rate of clinically indicated target lesion repeat revascularization due to a process of in-stent restenosis (ISR) at 1year remained relatively high (10 to 20%), often due to excessive neointimal growth (Fischman et al. N Engl J Med. 331:496, 1994; Serruys et al. N Engl J Med. 331:489, 1994; Cutlip et al. J Am Coll Cardiol 40:2082, 2002). Stents with drug elution technology (DES) were developed to reduce the relatively high rate of ISR and subsequent repeat revascularization seen with BMS. Clinical trials have confirmed a reduction of as much as 50 to 70% in target lesion revascularization by DES compared to BMS. These findings have led to the preferential use of DES in the majority of percutaneous coronary intervention (PCI). However, as DES require a longer period of dual antiplatelet therapy (DAPT) to prevent stent thrombosis, DES are not appropriate for all patients.

Hyperglycemia has no effect on development of restenosis after percutaneous transluminal angioplasty (PTA) in a diabetic rabbit model.

It is well known that hyperglycemia is a trigger of atherosclerosis in patients with diabetes mellitus. However, the role of hyperglycemia in restenosis remains unclear. In this study, we investigated the effects of hyperglycemia on restenosis. Stenosis was evaluated in two sets of diabetic rabbit models: i) diabetic restenosis versus nondiabetic restenosis and ii) diabetic atherosclerosis versus nondiabetic atherosclerosis. Our results indicated that there was no difference in rates of stenosis between the diabetic and the nondiabetic groups in restenosis rabbit models. However, the incidence of stenosis was significantly higher in the diabetic atherosclerosis group compared with the nondiabetic atherosclerosis group. Similarly, the intima-media thickness and cell proliferation rate were significantly increased in the diabetic atherosclerosis group compared with the nondiabetic atherosclerosis group, but there was no difference between the diabetic restenosis and the nondiabetic restenosis groups. Our results indicate that hyperglycemia is an independent risk factor for atherosclerosis, but it has no evident effect on restenosis. These findings indicate that the processes of atherosclerosis and restenosis may involve different pathological mechanisms.

Diferenciación geométrica fractal y euclidiana de arterias normales y reestenosadas. Armonía matemática arterial

Background: a methodology was developed that differentiates normality of coronary restenosis in a model of experimentation with porcine, based on fractal geometry and the concept of intrinsic mathematical harmony (AMI). Objective: to develop a methodology that allows the mathematical differentiation of normal and restenosed arteries through the simultaneous application of Euclidean and fractal geometry. Materials and methods: images of histological plaques of three normal and three restenosed arteries were measured, calculating the fractal dimension by means of the box-counting method of three islands delimited by the arterial layers and then the AMI was calculated; At the same time, the number of squares occupying the surface of the three defined islands was calculated and differences were established between groups. Results: the fractal dimension of the normal arteries was between 1.0184 and 1.2578 and in the restenosed ones between 0.6881 and 1.1651; the values ​​of the number of squares occupied by the surface of the arteries oscillated between 34 and 76 for the normal arteries and for the restenosed ones between 91 and 162, thus the islands of the normal arteries always had occupation values ​​less than 100, while the restenosadas always presented a greater or equal value in at least one of their islands. Conclusions: a fractal and Euclidean mathematical self-organization of the arterial restenosis process was revealed, which allows to establish differences between these states, quantifying the progress of arterial occlusion. Abbreviations: AMI, intrinsic mathematical harmony; EAC, coronary artery disease.

Effects of Cardiovascular Stent Design on Wall Shear Stress Distribution in Straight and Curved Arteries

he stent is a major breakthrough in the treatment of coronary artery diseases. The permanent vascular implant of a stent, however, changes the intra-stent blood hemodynamics. There is a growing consensus that the stent implant may change the artery wall shear stress distribution and therefore trigger the restenosis process. Several studies have suggested that low shear stress, particularly the shear stress less than 5 dyne/cm2, may lead to endothelial proliferation of smooth muscle cells. Computational fluid dynamics (CFD) has been widely used to analyze hemodynamics in stented arteries. In this paper, CFD models were developed to investigate the effects of cardiovascular stent design on the wall shear stress distribution in straight and curved arteries. Results show that the stent design pattern alone did not have a significant impact on the stent hemodynamics; however, stenting in curved arteries increased the low shear stress area which may lead to higher restenosis rate. The low shear stress area was almost doubled when the degree of artery curvature increased from 0o to 90o. The proposed methodology and findings will provide great insight for future optimization of stent design to reduce the risk of restenosis.

Antirestenosis Effect of Butein in the Neointima Formation Progression

The development of restenosis involves migration and hyperproliferation of vascular smooth muscle cells (VSMCs). Platelet-derived growth factor (PDGF) is one of the major factors. Butein modulates inflammatory pathways and affects the proliferation and invasion of the tumor. We investigated the hypothesis that butein might prevent the restenosis process via a similar pathway. Our results demonstrated that butein inhibited PDGF-induced VSMC proliferation and migration as determined by BrdU proliferation and two-dimensional migration scratch assay. Butein also concentration-dependently repressed PDGF-induced phosphorylation of PDGF-receptor β, mitogen-activated protein kinases, phosphoinositide 3-kinase/Akt, and phopholipase Cγ/c-Src in VSMCs. In addition, in vivo results showed that butein attenuated neointima formation in balloon-injured rat carotid arteries. These results indicate that butein may inhibit PDGF-induced VSMC proliferation and migration, resulting in attenuation of neointima formation after percutaneous transluminal coronary angioplasty. Our study demonstrates for the first time that systemic administration of butein is able to reduce neointima formation after vascular injury.

Repeat Revascularization Is a Faulty End Point for Clinical Trials

Coronary revascularization is performed to reduce myocardial ischemia and its sequelae of death, myocardial infarction, and anginal symptoms. A successful procedure increases the patient's quality of life, length of life, or both. Clinical trials of coronary revascularization should measure these outcomes to assess progress toward the goals of therapy. Death is an important and unequivocal outcome but, fortunately, is uncommon, and hence, very large studies are needed to assess differences in mortality. Myocardial infarction is also an objective outcome because it requires laboratory measures such as electrocardiography, biomarker levels, and imaging results, but it too is uncommon and can be assessed only in large trials. In contrast to these hard outcomes, angina is a symptom, and its subjectivity has made it less desirable to clinical investigators as an outcome measure. Angina can be measured using standardized approaches, however, and its effect on health status and quality of life has been quantified in many clinical trials. Article see p 267 In addition to these standard outcomes, repeat coronary revascularization has been adopted as an end point in many trials of percutaneous coronary intervention (PCI). Early balloon angioplasty procedures had high rates of restenosis and, consequently, of repeat revascularization procedures, typically another angioplasty. In the early 1980s, most interventional cardiologists accepted repeat procedures as an inevitable consequence of PCI because restenosis proved very difficult to tame, at least by using drug therapy. The disease process of restenosis could be measured using coronary angiography, but the angiographic measures were of uncertain clinical importance. Repeat revascularization became a …

Cardiovascular stent design and wall shear stress distribution in coronary stented arteries

The stent is a major breakthrough in the treatment of coronary artery diseases. The permanent vascular implant of a stent, however, changes the intra-stent blood flow haemodynamics. There is a growing consensus that the stent implant may change the artery wall shear stress distribution and hence trigger the restenosis process. Computational fluid dynamics (CFD) has been widely used to analyse haemodynamics in stented arteries. In this Letter, CFD models were developed to investigate the effects of stent design pattern and strut geometry, respectively, on the wall shear stress distribution in coronary stented arteries. Assessment of the potential restenosis risk was primarily based on the wall shear stress distribution. Results show that the stent design pattern alone does not have a significant impact on the stent haemodynamic behaviour. Wall shear stress is very sensitive to strut thickness, while varying the strut width or crown radius has very little effect. The proposed methodology and findings will provide great insight for future optimisation of stent design to reduce the risk of restenosis.

Hemodynamic Simulation of Intra-stent Blood Flow

The stent has been a major breakthrough for the treatment of atherosclerotic vascular disease. The permanent vascular implant of a stent, however, changes the blood flow hemodynamics and may consequently affect the restenosis process. Computational Fluid Dynamics (CFD) has been widely used to analyze the hemodynamic behavior and wall shear stress (WSS) distribution in stented arteries. The objective of this study is to present a thorough comparison among various CFD models to investigate the effects of rheological properties and pulsatile flow on hemodynamic simulation of the intra-stent blood flow. Several CFD models were developed with various modeling setups – axisymmetric parallel ring vs. 3-D stented artery model, Newtonian vs. non-Newtonian flow, and steady-state vs. pulsatile flow. Simulated results show that the minimum WSS occurs at the recirculation zones located at the downstream or backside of each stent struts. The rheological effect on WWS is minor in the axisymmetric parallel ring model; however, it becomes slightly significant in the 3-D stented artery model, with Newtonian flow being a more conservative assumption. For given pulsatile waveforms, the steady-state and pulsatile flow resulted in fairly similar trends in the WSS distribution. Therefore, it is reasonable to simulate the intra-stent blood flow as a steady-state Newtonian flow, which could be beneficial in more complex simulations and drastically reduce the computational time. These findings will provide great insights for future stent design optimization to reduce restenosis.

Plasma asymmetric dimethylarginine predicts restenosis after coronary angioplasty

IntroductionAsymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of endothelial nitric oxide synthase. Asymmetric dimethylarginine may influence the process of restenosis after coronary angioplasty. The aim of the study was to determine if initial plasma ADMA level could predict restenosis after coronary angioplasty and stenting.Material and methodsThe study group consisted of 60 consecutive patients (10 women and 50 men, average age 58.9 ±10.4 years old), who underwent percutaneous coronary angioplasty with bare metal stenting for stable coronary artery disease. All patients underwent follow-up coronary angiography after a 6-month period. Patients were divided into two groups, one with restenosis (n = 22), and the other one without restenosis (n = 38). In addition to measuring acknowledged restenosis risk factors, plasma ADMA level was measured before initial angiography.ResultsAsymmetric dimethylarginine plasma level was significantly higher in the group with restenosis than in the group without restenosis (1.94 ±0.94 µmol/l vs. 0.96 ±0.67 µmol/l; p < 0.05). L-arginine/ADMA ratio was also decreased in the group with restenosis, when compared with the group without restenosis (p < 0.05). Multivariate logistic regression revealed that independent restenosis risk factors were characterised by an initially high ADMA level (p < 0.01), advanced age (p < 0.05) and low level of HDL cholesterol (p < 0.05).ConclusionsPre-procedural elevated plasma ADMA level increases the risk of restenosis in patients who underwent coronary angioplasty and stenting with bare metal stents.

Theoretical generalization of normal and sick coronary arteries with fractal dimensions and the arterial intrinsic mathematical harmony

BackgroundFractal geometry is employ to characterize the irregular objects and had been used in experimental and clinic applications. Starting from a previous work, here we made a theoretical research based on a geometric generalization of the experimental results, to develop a theoretical generalization of the stenotic and restenotic process, based on fractal geometry and Intrinsic Mathematical Harmony.MethodsStarting from all the possibilities of space occupation in box-counting space, all arterial prototypes differentiating normality and disease were obtained with a computational simulation. Measures from 2 normal and 3 re-stenosed arteries were used as spatial limits of the generalization.ResultsA new methodology in animal experimentation was developed, based on fractal geometric generalization. With this methodology, it was founded that the occupation space possibilities in the stenotic process are finite and that 69,249 arterial prototypes are obtained as a total.ConclusionsThe Intrinsic Mathematical Harmony reveals a supra-molecular geometric self-organization, where the finite and discrete fractal dimensions of arterial layers evaluate objectively the arterial stenosis and restenosis process.

The Effects of Vinblastine on Smooth Muscle Cells In Vitro: Evaluation of a Therapeutic Window for the Treatment of Restenosis

The development of drug-eluting stents (DES) to combat the problem of in-stent restenosis has revolutionized interventional cardiology. However, concerns have emerged about the risk of late angiographic stent thromboses associated with DES. The evaluation and width of the therapeutic window of a particular DES system is of huge importance to its safety and efficacy. In this study, the effects of vinblastine, an antimitotic drug, on smooth muscle cells in vitro is analyzed. The change in levels of proliferation, activity, migration, and viability in human coronary artery smooth muscle cells was measured at a range of concentrations and over a number of time points. These findings were then compared with those of a previous study on the effects of vinblastine on endothelial cells, and an optimum working concentration range was evaluated. This study suggests that the concentration of vinblastine most appropriate in restenosis treatment would be between 0.1 and 1 nM. At this concentration, vinblastine exerts a distinct effect on smooth muscle cell proliferation without detrimental effects on endothelial cell viability. It was also found that vinblastine affects certain cellular activities such as migration in a threshold-independent manner, suggesting that very low doses could be active against the processes of restenosis.

Rosuvastatin reduces neointima formation in a rat model of balloon injury

BackgroundProcesses of restenosis, following arterial injury, are complex involving different cell types producing various cytokines and enzymes. Among those enzymes, smooth muscle cell-derived matrix metalloproteinases (MMPs) are thought to take part in cell migration, degrading of extracellular matrix, and neointima formation. MMP-9, also known as gelatinase B, is expressed immediately after vascular injury and its expression and activity can be inhibited by statins. Using an established in vivo model of vascular injury, we investigated the effect of the HMG-CoA reductase inhibitor rosuvastatin on MMP-9 expression and neointima formation.Materials and methods14-week old male Sprague Dawley rats underwent balloon injury of the common carotid artery. Half of the animals received rosuvastatin (20 mg/kg body weight/day) via oral gavage, beginning 3 days prior to injury. Gelatinase activity and neointima formation were analyzed 3 days and 14 days after balloon injury, respectively. 14 days after vascular injury, proliferative activity was assessed by staining for Ki67.ResultsAfter 14 days, animals in the rosuvastatin group showed a decrease in total neointima formation (0.194 ± 0.01 mm2 versus 0.124 ± 0.02 mm2, p < 0.05) as well as a reduced intima/media ratio (1.26 ± 0.1 versus 0.75 ± 0.09, p < 0.05). Balloon injury resulted in increased activity of MMP-9 3 days after intervention for both rosuvastatin treated animals and controls with no significant difference observed between the groups. There was a trend towards a reduction in the number of Ki67-positive cells 14 days after injury.ConclusionsRosuvastatin attenuates neointima formation without affecting early MMP-9 activity in a rat model of vascular injury.

025 Benefit of Drug Eluting Stents over Bare Metal Stents after Rotational Atherectomy. A propensity score adjusted comparison in revascularization, mortality and MACE

Rotational atherectomy makes possible to attempt small and calcified arteries while Drug Eluting Stents (DES) properties may reduce the restenosis process, rendering this combination attractive in selected cases. We compared 1year clinical outcome after rotational atherectomy following by either DES or Bare Metal Stents (BMS) implantation. Single centre registry including all consecutive cases of rotational atherectomy use. Clinical follow-up was obtained in all patients. Propensity score for being treated with a DES was calculated using 18 clinical, angiographic and procedural variables. Comparison was adjusted on 4 strata of the propensity score. Between 2002 and 2008, 223 patients were treated: 114 with BMS and 110 with DES. Most of the patients with BMS between 2002 and 2004 and later with DES. No significant difference was observed in clinical characteristics between groups: age 70 years, reference diameter 2.40±0.60mm, lesion length 10±9mm. Two cases of coronary perforation occurred, 7 lesion failure, and 12 transcient no-reflow. The use of GP2b3a inhibitors was similar in both groups, but, compared with BMS, patients in the DES group had longer duration of combination of aspirin and Clopidogrel. At one year, significantly lower rates of vessel revascularisation (2% vs 12%, p=0.005), of all cause mortality (5% vs 14%, p=0.05) and of MACE (10% vs 22%, p=0.02) were observed in the DES than in the BMS group. Adjustment on the strata of the propensity score did not change significantly these results (figure). Despite propensity score adjusted, this comparison has limitations. After rotational atherectomy we observed clear benefit for DES implantation over BMS on vessel revascularisation, mortality and MACE rates.

Noninvasive assessment of coronary artery bypass graft with 64-slice CT: comparison with invasive coronary angiography

In composite arterial coronary grafts (CACGs), transport phenomena and geometry may considerably alter blood flow dynamics. CACGs aim at revascularizing pathological arteries according to the human anatomy. However, the exact mechanisms causing the failure of coronary bypass grafting are not yet well elucidated. In the present study, computational fluid dynamics (CFD) techniques are applied for the simulation of multi-branched CACGs under physiologically realistic inflow waveforms. The numerical solution is obtained by a finite-volume method formulated in non-orthogonal, curvilinear coordinates and a multi-grid approach. The geometrical models, consisting of idealized and rigid vessels, include the typical T- and a rather new Π-graft configuration. The stenotic effect is also investigated by comparing computational results for three different degrees of area constriction, namely 25%, 50% and 75%, as well as the case without stenosis. Different grafting distances and various inflow rate ratios are imposed, to give an insight into haemodynamical alterations of CACGs and to study the process of restenosis. The results focus on the interaction between the grafts and coronary flows in terms of spatial and temporal variations of velocity and wall shear stress (WSS) distribution. Prominent variations among the different geometries, concerning the velocity profiles and secondary flow motion, are shown. Moreover, the residual flow emerging from different degrees of area constriction shows that low and oscillating shear stresses may arise for even moderate stenotic fields.

Restenosis After Lower Extremity Interventions:Current Status and Future Directions

The incidence of restenosis after percutaneous peripheral interventions (PPI) varies considerably depending upon the vascular bed but appears to be highest in the femoropopliteal and tibioperoneal arteries. The restenosis process in the periphery does not appear to stop at the 6-month mark, as seen with bare metal stents in the coronary arteries, but continues for a longer time, possibly years, after the intervention. This review evaluates the incidence of restenosis following lower extremity arterial interventions and potential drugs or devices that could alter this process, including nonpharmacological (stents, cryoplasty, Cutting Balloon angioplasty, atherectomy, brachytherapy, and photodynamic therapy) and pharmacological (systemic and direct drug delivery) approaches. A global strategy to achieve optimal outcome with PPI is offered: (1) obtain excellent acute angiographic results with less dissection and recoil, (2) protect the distal tibial vascular bed, and (3) reduce smooth muscle cell proliferation with pharmacological intervention.

A lubricious formulation exhibiting reduced thrombogenicity, cell proliferation, and protein adsorption

The adhesion of human platelets, erythrocytes, and leukocytes, the adsorption of protein, and the proliferation of human umbilical vein endothelial cells (HUVEC) on the surface of electropolished stainless steel and the lumen of polyurethane tubing coated with Hydromer's lubricious Duality T8B formulation was evaluated. Following exposure to a platelet-enriched suspension from citrated human whole blood, stainless steel coated with this formulation exhibited significantly reduced adhesion of platelets, erythrocytes, and granulocytes. This reduction in adhesion was confirmed using an immunohistochemical method utilizing antibodies to CD41, CD235, and CD15, respectively. The proliferation of HUVEC cells were significantly reduced when cultured on coated stainless steel. This formulation was also able to significantly reduce the adsorption of plasma proteins and the major protein in tear fluid (lysozyme) to the surface of stainless steel. The nonthrombogenic properties of Duality T8B after application to the lumen of polyurethane tubing were also examined. Following a short-term (3 h) static exposure to citrated human whole blood, microscopic examination revealed that the adhesion of platelets and erythrocytes was reduced significantly, a finding confirmed using anti-CD41 and anti-CD235 antibodies in the immunohistochemical method. A long-term (12 day) study yielded essentially identical results indicating a significant reduction in the adhesion of blood components on the luminal surface of coated polyurethane tubing. In summary, these data indicate that the application of Duality T8B onto surfaces of medical devices, such as catheters, extracorporeal circuitry, and coronary stents, could aid in reducing or preventing not only thrombus formation but also the process of restenosis.

The role of glucose lowering agents on restenosis after percutaneous coronary intervention in patients with diabetes mellitus

IntroductionThe prevalence of diabetes is increasing rapidly, and individuals with diabetes are at high risk for cardiovascular disorders. Subsequently the percentage of patients with diabetes subjected to revascularisation, i.e. either percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) also rises rapidly. The outcome of patients with diabetes after PCI is worse than for patients without diabetes. Restenosis is the main limiting factor of the long-term success of PCI. Although stents and antithrombotics improved outcome after PCI in both diabetics and non-diabetics, diabetics still have a worse prognosis. This leads to the suggestion that the restenosis mechanism in diabetics might be different from that in non-diabetics.ConclusionSeveral glucose lowering agents have been shown to influence the restenosis process and thus the outcome after PCI. Current data of especially metformin and thiazolidinediones indicate beneficial results as compared to insulin and sulfonylurea on restenosis. However, no large trials have been undertaken in which the effect of glucose lowering agents on restenosis is associated with improved outcome.The purpose of this review is to summarize the effect of diabetes and glucose lowering agents on restenosis.

Assessment of tissue prolapse after balloon-expandable stenting: Influence of stent cell geometry

Restenosis is a re-narrowing or blockage of an artery at the same site where treatment, such as a balloon angioplasty or stent procedure, has already taken place. Several clinical trials have shown a significant reduction in the restenosis rates with endovascular stenting. The purpose of stenting is to maintain the arterial lumen open by a scaffolding action that provides radial support. However, stenting can cause a vascular injury during the deployment. Indeed, in-stent restenosis remains a major problem in percutaneous coronary intervention, requiring patients to undergo repeated procedures and surgery. The loading imposed by the deployment of the stent on the artery is involved in the restenosis process. Furthermore, it is well known that the stent design plays a role in the outcome of the stenting interventional procedure. This study compares the mechanical effects of the expansion of five different designs of balloon-expandable stents in a coronary artery by means of numerical models based on the finite element method. An index for the evaluation of the tissue prolapse based on the expanded configuration reached by the stent cells is proposed. The effects of the balloon inflation and deflation are included in the present study. Wall stresses and tissue prolapse of the vessel wall within the stent cells are evaluated and compared among the different stent designs. Results show that the printed area does not predict prolapse, and that the proposed index ( PI) does correlate with tissue prolapse.

Vascular Wall Responses to Angioplasty and Stenting: Endothelial Injury, Neointimal Hyperplasia and the Process of Restenosis

Vascular Wall Responses to Angioplasty and Stenting: Endothelial Injury, Neointimal Hyperplasia and the Process of Restenosis

Cell adhesion and proliferation are reduced on stainless steel coated with polysaccharide‐based polymeric formulations

Hydromer's polymeric formulations F200 and F202 were evaluated after application to a synthetic substrate for effects on cell adhesion and proliferation. A significant reduction in cell adhesion was observed when cells grown on medical-grade stainless steel coated with these polymers were stained and examined under a fluorescence microscope. This reduction in cell adhesion/proliferation was confirmed when cells were isolated and analyzed by the MTS cell proliferation assay. The rate of growth of cells on F200- and F202-coated stainless steel monitored over a period of 7 days was significantly less than that observed on uncoated stainless steel, suggesting that the rate of growth of cells was reduced. The adhesion/proliferation of human umbilical vein endothelial cells (HUVEC) to coated substrates was also decreased significantly, indicating that the reduction in cell adhesion/proliferation is not restricted to only fibroblasts. Additional studies have indicated that the adhesion/proliferation of murine fibroblasts and human endothelial cells to stainless coated with a modified formulation exhibiting a high degree of lubricity was also significantly reduced. This lubricious formulation was also observed to be effective in reducing platelet adhesion, data supporting the view that lubricity also contributes to a reduction in cell and platelet adhesion. The application of these polymeric coatings on devices designed for medical implantation may not only prevent thrombus formation but may also retard the process of restenosis.