Reduction Of In-stent Restenosis Research Articles

In-Stent Restenosis and Stent Thrombosis: An Elusive Target

In-Stent Restenosis and Stent Thrombosis: An Elusive Target

Intraprocedural endothelial cell seeding of arterial stents via biotin/avidin targeting mitigates in-stent restenosis

Impaired endothelialization of endovascular stents has been established as a major cause of in-stent restenosis and late stent thrombosis. Attempts to enhance endothelialization of inner stent surfaces by pre-seeding the stents with endothelial cells in vitro prior to implantation are compromised by cell destruction during high-pressure stent deployment. Herein, we report on the novel stent endothelialization strategy of post-deployment seeding of biotin-modified endothelial cells to avidin-functionalized stents. Acquisition of an avidin monolayer on the stent surface was achieved by consecutive treatments of bare metal stents (BMS) with polyallylamine bisphosphonate, an amine-reactive biotinylation reagent and avidin. Biotin-modified endothelial cells retain growth characteristics of normal endothelium and can express reporter transgenes. Under physiological shear conditions, a 50-fold higher number of recirculating biotinylated cells attached to the avidin-modified metal surfaces compared to bare metal counterparts. Delivery of biotinylated endothelial cells to the carotid arterial segment containing the implanted avidin-modified stent in rats results in immediate cell binding to the stent struts and is associated with a 30% reduction of in-stent restenosis in comparison with BMS.

In vivo evaluation of a pro-healing polydopamine coated stent through an in-stent restenosis rat model.

Drug-eluting stents have demonstrated efficiency in in-stent restenosis (ISR) but induced a risk of late acute thrombosis by delaying strut re-endothelialization. Polydopamine (PDA), a biocompatible polymer inspired from adhesive proteins of mussels, has been reported to promote endothelial cell (EC) proliferation while limiting SMC proliferation in vitro, thus suggesting the pro-healing potential. This study aimed at evaluating in vivo the impact of the pro-healing PDA-coated stent on ISR and on the quality of the strut re-endothelialization in a rat model. PDA-coated stents demonstrated a significant reduction in ISR in vivo compared to bare metal stents (ratio neointima/media = 0.48 (±0.26) versus 0.83 (±0.42), p < 0.001). Western blot analyses identified a trend towards an increased activation of p38 MAPK phosphorylation and its anti-proliferative effects on vascular SMC that could explain the results observed in morphological analyses. This bioinspired and biocompatible polydopamine layer could intrinsically limit ISR. In addition, according to its latent reactivity, PDA offers the possibility to immobilize some relevant drugs on the PDA-functionalized stent to provide potential synergistic effects.

In vivo and in vitro analyses of the effects of a novel high-nitrogen low-nickel coronary stent on reducing in-stent restenosis.

Currently, percutaneous coronary intervention is an important treatment for coronary heart disease. However, the in-stent restenosis rate is still approximately 10-30% after stenting. Nickel ions from the stent are considered to be associated with in-stent restenosis. Therefore, in the present study, we quantitatively evaluated in-stent restenosis after implanting the novel high-nitrogen low-nickel coronary stent (HNS) and studied the mechanism underlying the reduction in in-stent restenosis by using ELISA and Western blot. The in vivo results showed that the HNS could significantly reduce neointima formation and inflammation as compared to SUS316L stents (316L) at 180 days after implantation in porcine coronary arteries and that vascular endothelial growth factor-A expression in porcine coronary arteries after HNS implantation also decreased. The in vitro results showed that, in the case of the HNS, human umbilical vein endothelial cell (HUVEC) proliferation was lower and lesser IL-6 release was noted from HUVECs at one and three days after culture than in the 316L group. Furthermore, p-STAT3 expression in HUVECs on the HNS surface was downregulated after culture for seven days. Thus, we conclude that the HNS could be a promising alternative coronary stent for percutaneous coronary intervention.

Different Effects of Thiazolidinediones on In-Stent Restenosis and Target Lesion Revascularization after PCI: A Meta-Analysis of Randomized Controlled Trials

In-stent restenosis (ISR) remains the leading problem encountered after percutaneous coronary intervention (PCI). Thiazolidinediones (TZDs) has been shown to be associated with reduced ISR and target lesion revascularization (TLR); however, the results are inconsistent, especially between rosiglitazone and pioglitazone. In this study, fourteen RCTs with a total of 1350 patients were finally included through a systematical literature search of Embase, Pubmed, the Cochrane Library, and ClinicalTrials.gov from inception to January 31, 2017. The follow-up duration of the included trials ranged from 6 months to 18 months. The results demonstrated that TZDs treatment is associated with significantly reduced risk of TLR (RR:0.45, 95%CI 0.30 to 0.67 for pioglitazone, RR:0.68, 95%CI 0.46 to 1.00 for rosiglitazone). Pioglitazone is associated with significantly reduced risks of ISR (RR:0.47, 95%CI 0.27 to 0.81), major adverse cardiac events (MACE) (RR:0.44, 95%CI 0.30 to 0.64) and neointimal area (SMD: −0.585, 95%CI −0.910 to −0.261). No significant relationship was observed between rosiglitazone and ISR (RR:0.91, 95%CI 0.39 to 2.12), MACE (RR:0.73, 95%CI 0.53 to 1.00) and neointimal area (SMD: −0.164, 95%CI −1.146 to 0.818). This meta-analysis demonstrated that TZDs treatment is associated with significant reduction in ISR, TLR and MACE for patients after PCI. Pioglitazone treatment seems to have more beneficial effects than rosiglitazone and no significantly increased cardiovascular risk was detected for both agents.

Reduction of In-Stent Restenosis by Cholesteryl Ester Transfer Protein Inhibition.

Angioplasty and stent implantation, the most common treatment for atherosclerotic lesions, have a significant failure rate because of restenosis. This study asks whether increasing plasma high-density lipoprotein (HDL) levels by inhibiting cholesteryl ester transfer protein activity with the anacetrapib analog, des-fluoro-anacetrapib, prevents stent-induced neointimal hyperplasia. New Zealand White rabbits received normal chow or chow supplemented with 0.14% (wt/wt) des-fluoro-anacetrapib for 6 weeks. Iliac artery endothelial denudation and bare metal steel stent deployment were performed after 2 weeks of des-fluoro-anacetrapib treatment. The animals were euthanized 4 weeks poststent deployment. Relative to control, dietary supplementation with des-fluoro-anacetrapib reduced plasma cholesteryl ester transfer protein activity and increased plasma apolipoprotein A-I and HDL cholesterol levels by 53±6.3% and 120±19%, respectively. Non-HDL cholesterol levels were unaffected. Des-fluoro-anacetrapib treatment reduced the intimal area of the stented arteries by 43±5.6% (P<0.001), the media area was unchanged, and the arterial lumen area increased by 12±2.4% (P<0.05). Des-fluoro-anacetrapib treatment inhibited vascular smooth muscle cell proliferation by 41±4.5% (P<0.001). Incubation of isolated HDLs from des-fluoro-anacetrapib-treated animals with human aortic smooth muscle cells at apolipoprotein A-I concentrations comparable to their plasma levels inhibited cell proliferation and migration. These effects were dependent on scavenger receptor-B1, the adaptor protein PDZ domain-containing protein 1, and phosphatidylinositol-3-kinase/Akt activation. HDLs from des-fluoro-anacetrapib-treated animals also inhibited proinflammatory cytokine-induced human aortic smooth muscle cell proliferation and stent-induced vascular inflammation. Inhibiting cholesteryl ester transfer protein activity in New Zealand White rabbits with iliac artery balloon injury and stent deployment increases HDL levels, inhibits vascular smooth muscle cell proliferation, and reduces neointimal hyperplasia in an scavenger receptor-B1, PDZ domain-containing protein 1- and phosphatidylinositol-3-kinase/Akt-dependent manner.

Diagnosis and management challenges of in-stent restenosis in coronary arteries.

Over the course of the 3 decades, percutaneous coronary intervention (PCI) with stent implantation transformed the practice of cardiology. PCI with stenting is currently the most widely performed procedure for the treatment of symptomatic coronary disease. In large trials, drug-eluting stents (DES) have led to a significant reduction in in-stent restenosis (ISR) rates, one of the major limitations of bare-metal stents. Due to these favorable findings, DES was rapidly and widely adopted enabling more complex coronary interventions. Nevertheless, ISR remains a serious concern as late stent complications. ISR mainly results from aggressive neointimal proliferation and neoatherosclerosis. DES-ISR treatment continues to be challenging complications for interventional cardiologists.

Biomimetic titania/hydroxyapatite coating of CrCoMo microimplants enhances biocompatibility and reduces metal-associated toxicity

Currently, percutaneous coronary intervention (PCI) with drug-eluting stents (DES) is the most commonly employed modality in the treatment of patients with coronary artery disease. PCI has come of age over the last four decades with enormous forays in the technology and drugs which have greatly enhanced its capability. Angioplasty and bare metal stents were plagued by high failure rates on account of restenosis leading to repeat revascularization procedures. Insights into pathophysiology of instent restenosis (ISR) and neointimal hyperplasia triggered the development of DES. The dreamlike remarkable reduction in ISR with DES was enthusiastically welcomed. Soon thereafter emerged the spectre of very late stent thrombosis (VLST) with DES. VLST was a new entity seen predominantly with DES and pathological insights as to the cause was instrumental in the development and efficacy of new generation DES. This review will highlight the evolution and present day DES for coronary interventions.

Effect of Pioglitazone in Preventing In-Stent Restenosis after Percutaneous Coronary Intervention in Patients with Type 2 Diabetes: A Meta-Analysis.

BackgroundThe benefits of pioglitazone in patients with type 2 diabetes mellitus (T2DM) after percutaneous coronary intervention (PCI) is unclear.ObjectivesTo evaluate the effect of pioglitazone on prevention of in-stent restenosis (ISR) in patients with T2DM after PCI.MethodsAll full-text published relevant studies compared the effect of pioglitazone with control group (placebo or no pioglitazone treatment) on ISR in patients with T2DM after PCI were identified by searching the databases including PubMed, EMBASE, Cochrane Library and ISI Web of Science through October 2015. The endpoints were defined as the rate of ISR, late lumen loss, in-stent neointimal volume, target lesion revascularization (TLR) and major adverse cardiac events (MACE).ResultsSix studies (5 RCTs and 1 retrospective study), comprising 503 patients, were included into this meta-analysis. In the pioglitazone group, as compared with the control group, the risk ratio for ISR was 0.48 (I2 = 14.5%, P = 0.322; 95%CI 0.35 to 0.68, P<0.001), the risk ratio for TLR was 0.58 (I2 = 6.0%, P = 0.363; 95%CI 0.38 to 0.87, P = 0.009). The result showed there was no association between the use of pioglitazone and the events of MACE (I2 = 36.7%, P = 0.209; RR 0.56, 95%CI 0.30 to 1.05, P = 0.071). For the considerable heterogeneity, further analysis was not suitable for the endpoints of late lumen loss (I2 = 81.9%, P<0.001) and neointimal volume (I2 = 75.9%, P = 0.016).ConclusionsThe treatment of pioglitazone was associated with a reduction in ISR and TLR in T2DM patients suffering from PCI, except the incidence of MACE.

Abstract 281: Local MicroRNA Modulation Using a Novel Anti-mir-21-eluting Stent Effectively Prevents In-stent Restenosis

The major limitation of vascular angioplasty remains the occurrence of in-stent restenosis (ISR). The central role of miRNAs in the pathophysiology of the proliferative response in cardiovascular disease offers attractive concepts for possible therapeutic interventions, with systemic miRNA modulation however potentially causing substantial off-target effects. Aim of the current study was to test the feasibility of local miRNA modulation using drug eluted stent (DES) technology. Utilizing human ISR tissue samples, as well as a humanized rodent model of balloon-injured human internal mammary arteries with subsequent stent implantation in RNU rats, we were able to identify several miRNAs dys-regulated, including the well-characterized miR-21. We inhibited miR-21 (with a FAM-tagged-LNA-anti-miR-21), using either systemic or local delivery via DES. Systemic suppression of miR-21 showed a dose-dependent reduction of luminal obliteration, while not impeding vascular re-endothelialization. However, miR-21 expression in liver, heart, lung, and kidney appeared significantly reduced, with increased levels of serum creatinine, pointing towards the expected off-target effects of systemic miRNA modulation. Local mir-21 suppression, using the anti-miR-21-DES, effectively reduced myointimal hyperplasia and ISR compared to bare metal stents, while not exerting detectable off-target effects on any other organ we investigated. Additional in vitro experiments in cultured human coronary artery smooth muscle and endothelial cells further confirmed the ability of anti_miR-21 to limit SMC proliferation and migration by repressing mRNA and protein levels of its established target PTEN, while not affecting the proliferative response in the ECs. This is the first experimental study to demonstrate the efficacy, feasibility and suitability of an anti-miRNA-eluting stent (anti-miR-21-DES) for the reduction of ISR through dominant inhibition of SMC proliferation.

Rationale and design: Impact of intravascular ultrasound guidance on long-term clinical outcomes of everolimus-eluting stents in long coronary lesions

BackgroundAlthough the use of drug-eluting stents (DESs) in patients with coronary artery disease has contributed to a significant reduction in in-stent restenosis and repeat revascularization, treating diffuse long lesions using DESs remains challenging due to the high rates of in-stent restenosis and stent thrombosis. Intravascular ultrasound (IVUS) provides tomographic images of coronary vascular structure and is useful for evaluating lesion morphology and stent optimization during percutaneous coronary intervention. However, it remains controversial whether IVUS guidance in DES implantation for long coronary lesions could reduce adverse clinical outcomes. HypothesisWe hypothesize that the long-term clinical outcomes of IVUS-guided DES implantation would be superior to those of angiography-guided DES implantation in a subset of patients with long coronary lesions. Study designThis study is a randomized, prospective, multi-center trial comparing the long-term clinical outcomes of IVUS-guided and angiography-guided everolimus-eluting stent implantation in patients with long coronary lesions (implanted stent ≥28mm in length). The primary end point is a composite of major adverse cardiac events, including cardiac death, target lesion-related myocardial infarction, or target lesion revascularization at 1year following intervention. A total of 1,400 patients will be required to be enrolled according to sample size calculations. ConclusionThis study will test the hypothesis that IVUS guidance improves long-term clinical outcomes in patients treated with everolimus-eluting stents for long coronary lesions compared with angiographic guidance.

Accelerated endothelialization with a polymer-free sirolimus-eluting antibody-coated stent

Drug-eluting stents have shown an impressive reduction of in-stent restenosis for many years. However, stent thrombosis due to incomplete/late endothelialization has raised major safety concerns. To overcome these problems, we developed for the first time a polymer-free sirolimus-eluting antibody-coated stent (PFSEACS) by combining polymer free and endothelial progenitor cell-capture pro-healing approaches. In the first phase, the stents were prepared by loading sirolimus on the porous outer stent surface and directly fixing the anti-CD34 antibodies without any medium carriers on the blood contacting surface. The dose and elution of sirolimus, the amount and stability of anti-CD34 antibody immobilization, and the rate of CD34+ cell capture were evaluated. In the second phase, the stents were validated in an animal model of coronary arteries in pigs. The stent was observed to start collecting endothelial progenitor cells ~2 h after stent implantation and exhibited greatly enhanced endothelialization while maintaining an excellent anti-restenosis activity comparable to the polymer-free sirolimus-eluting stents. Overall, both in vitro and in vivo evaluations indicated that novel PFSEACSs exhibited facilitated endothelialization with excellent anti-restenosis activity and thus should merit further clinical studies.

Myokardrevaskularisation

Coronary artery disease (CAD) is a leading cause of morbidity and mortality in western countries and is of significant socio-economic importance due to its increasing prevalence. Until percutaneous coronary interventions (PCI) were established, CAD could only be treated by surgical revascularization or pharmacological therapy. In-stent restenosis remains a major problem after stent implantation. However, the use of new materials and stent coatings have led to a significant reduction in in-stent restenosis. Thus, surgical revascularization and PCI are currently of equal value for the treatment of CAD. The decision-making for PCI or surgical revascularization depends on various factors such as number of diseased vessels, complexity of the coronary stenoses, concomitant diseases, and the patient's general condition. The therapeutic regime of every patient should be adjusted to the recommendations of the European and German Society for Cardiology, while controversial and complex cases should be discussed in an interdisciplinary case conference ("heart team").

Combination treatment with asiaticoside and rapamycin: A new hope for in-stent restenosis

The aim of this study was to investigate and characterize the efficacy and mechanism of action of asiaticoside in combination with rapamycin in the inhibition of in-stent restenosis (ISR). The effects of asiaticoside combined with rapamycin on cell proliferation in vitro were evaluated by MTT assay. The mRNA expression was analyzed by quantitative polymerase chain reaction (qPCR). Enzyme-linked immunosorbent assay (ELISA) was used to confirm protein synthesis. The cell growth inhibition rate in the combination group was significantly higher compared with those in the asiaticoside and rapamycin groups for human aortic fibroblasts (HAFs; 63.50±3.83, 53.06±8.10 and 60.34±4.9%, respectively) and human aortic smooth muscle cells (HASMCs; 33.12±1.35, 26.21±7.59 and 28.27±4.92, respectively; P<0.05). However, for human coronary artery endothelial cells (HCAECs), the cell growth inhibition rates in the combination, asiaticoside and rapamycin groups were 11.09±1.17, 26.22±4.24 and 34.80±2.80%, respectively (P<0.05), as detected by MTT assay. The qPCR assay showed that in the combination group the level of von Willebrand factor (vWF) mRNA was downregulated, while platelet endothelial cell adhesion molecule (PECAM-1) and endothelial nitric oxide synthase (eNOS) mRNAs were upregulated in HCAECs compared with the rapamycin group (P<0.05). Transforming growth factor (TGF)-β1 and TIMP1 mRNAs were downregulated while Smad7 and matrix metalloproteinase 1 (MMP1) mRNAs were upregulated in HAFs compared with the rapamycin and AT groups (P<0.05). The ELISA showed that the type I collagen level was significantly reduced in HASMCs and HAFs (P<0.05). The data suggest that asiaticoside combined with rapamycin may be effective in the reduction of ISR.

The impact of successful manual thrombus aspiration on in-stent restenosis after primary PCI

This study sought to investigate the impact of successful manual thrombus aspiration on angiographic in-stent restenosis and clinical outcome in patients treated by bare metal stent implantation for ST-segment elevation acute myocardial infarction. There are very limited data on the impact of manual thrombus aspiration on the occurrence of in-stent restenosis after bare metal stent implantation. This was a prospective, randomized, single-center study. Patients (N=60) presenting within 12 h of ST-segment elevation acute myocardial infarction symptom onset were randomized to primary percutaneous coronary intervention (PCI) with (N=30) or without (N=30) upfront manual thrombus aspiration using the Export aspiration catheter. All patients underwent control coronary angiography after 6 months. Baseline, clinical, and angiographic preprocedural findings did not differ between the two groups. Patients who underwent successful manual thrombus aspiration had significantly higher minimal lumen diameter after 6 months (2.25±0.90 vs. 1.63±0.76, P=0.005), significantly lower percentage diameter stenosis (28.81 vs. 45.03%, P=0.017), and significantly lower late lumen loss (0.73±0.84 vs. 1.18±0.79, P=0.035). There was a trend for lower rate of major adverse cardiocerebrovascular events such as death, myocardial reinfarction, stroke, and target lesion revascularization in the same group of patients (16.67 vs. 26.67%, P=0.347). Successful upfront manual thrombus aspiration during primary PCI showed beneficial effects on the reduction of in-stent restenosis after bare metal stent implantation compared with standard PCI.

Myokardrevaskularisation

Coronary artery disease (CAD) is a leading cause of morbidity and mortality in western countries and is of significant socio-economic importance due to its increasing prevalence. Until percutaneous coronary interventions (PCI) were established, CAD could only be treated by surgical revascularization or pharmacological therapy. In-stent restenosis remains a major problem after stent implantation. However, the use of new materials and stent coatings have led to a significant reduction in in-stent restenosis. Thus, surgical revascularization and PCI are currently of equal value for the treatment of CAD. The decision-making for PCI or surgical revascularization depends on various factors such as number of diseased vessels, complexity of the coronary stenoses, concomitant diseases, and the patient's general condition. The therapeutic regime of every patient should be adjusted to the recommendations of the European and German Society for Cardiology, while controversial and complex cases should be discussed in an interdisciplinary case conference ("heart team").

Effects of renin-angiotensin system inhibitors on coronary in-stent restenosis: a meta-analysis of randomised controlled trials

BackgroundRAS inhibitors have been proved to antiproliferative effect on neointimal hyperplasia so as to prevent in-stent restenosis (ISR) in animal models. However whether RAS inhibitors could prevent ISR in human...

AS-075 Effects of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker on Coronary Endothelial Function after First Generation Drug-Eluting Stent Implantation

Drug-eluting stent (DES) has shown further reduction of in-stent restenosis and repeated revascularization compared with bare-metal stent. However, DES still has some concerns. Local coronary endothelial dysfunction after first generation DES implantation was reported. Endothelial dysfunction has been related to future cardiovascular events. On the other hand, renin-angiotensin system inhibitors (RAS-I) are widely administered to patients with DES implantation as antihypertensive drugs. The aim of this study is to determine whether endothelial function of the patients with DES implantation and RAS-I is different between angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin receptor blocker (ARB).

Drug eluting versus bare metal stents in cardiac allograft vasculopathy

Cardiac allograft vasculopathy (CAV) is a distinct pathological condition characterized by diffuse and progressive arteriopathy and it is an important determinant of long-term graft survival. Definitive CAV treatment is retransplantation but palliation with stenting might temporarily alleviate it. The benefit of drug eluting stents (DES) over bare metal stents (BMS) in the treatment of such lesions is debatable. We therefore sought to do a literature search to review the available evidence comparing DES to BMS. We conducted Pub Med, EMBASE, Cochrane database review, Web of Science search of studies comparing DES with BMS in CAV. Available studies were retrospective in nature with either direct comparison groups (n = 5) or historical controls (n = 1). The main outcomes analyzed were in stent restenosis (ISR) during follow-up and clinical outcomes. A total of 312 patients from six studies were included in the review (1995-2007). Most commonly used DES were sirolimus eluting stent. DES appeared to reduce the long-term risk of ISR compared with BMS. Three of the five studies showed a statistically significant reduction in ISR at 12 months while the one study assessing ISR at 6 months showed no significant difference. Clinical endpoints such as death and major adverse cardiac events were not statistically different. DES appear to reduce the incidence of ISR in CAV as compared with BMS. Prospective randomized clinical trials are needed to determine the clinical benefit of DES beyond a reduction in ISR.

Role of Pioglitazone in the Prevention of Restenosis and Need for Revascularization After Bare-Metal Stent Implantation: A Meta-Analysis

We performed a meta-analysis to evaluate the impact of pioglitazone in the prevention of in-stent restenosis (ISR) and need for revascularization after bare-metal stent (BMS) implantation. BMS use is associated with a significant incidence of restenosis. Pioglitazone, a thiazolidinedione (TZD), has been shown in small studies to be associated with decreased neointimal formation after BMS implantation. The meta-analysis included randomized controlled trials that randomized patients undergoing BMS implantation into pioglitazone treatment in combination with standard treatment or standard treatment only. All randomized controlled trials followed patients for 6 months with baseline and follow-up angiographies. The ISR and revascularization rate were considered primary outcomes. We identified 6 eligible studies involving 373 patients (187 in the pioglitazone group and 186 in the control group). Use of pioglitazone was associated with decreased late loss, a larger minimal lumen diameter, and a lower percentage diameter stenosis (p < 0.01). The angiographic ISR rate was decreased with pioglitazone (p < 0.01), and patients who received pioglitazone were significantly less likely to undergo revascularization (p < 0.01). Intravascular ultrasound analysis also demonstrated decreased neointima formation in the pioglitazone group. Subgroup analysis showed significant reduction in ISR and need for revascularization for studies involving only diabetic patients, whereas analysis of the remaining studies demonstrated nonsignificant reduction. This meta-analysis suggests that treatment with pioglitazone is effective in decreasing ISR and need for revascularization after BMS implantation in patients with diabetes. A randomized clinical trial evaluating the hypothesis that administration of pioglitazone reduces restenosis in diabetic patients after BMS implantation seems warranted.