The development of coronary stents represents a major step forward in the treatment of obstructive coronary artery disease since the introduction of percutaneous coronary intervention. The initial enthusiasm for bare metal stents was, however, tempered by a significant incidence of in-stent restenosis, the manifestation of excessive neointima hyperplasia within the stented vessel segment, ultimately leading to target vessel revascularization. Later, drug-eluting stents, with controlled local release of antiproliferative agents, consistently reduced this need for repeat revascularization. In turn, the long-term safety of first-generation drug-eluting stents was brought into question with the observation of an increased incidence of late stent thrombosis, often presenting as myocardial infarction or sudden death. Since then, new drugs, polymers, and platforms for drug elution have been developed to improve stent safety and preserve efficacy. Development of a novel platinum chromium alloy with high radial strength and high radiopacity has enabled the design of a new, thin-strut, flexible, and highly trackable stent platform, while simultaneously improving stent visibility. Significant advances in polymer coating, serving as a drug carrier on the stent surface, and in antiproliferative agent technology have further improved the safety and clinical performance of newer-generation drug-eluting stents. This review will provide an overview of the novel platinum chromium everolimus-eluting stents that are currently available. The clinical data from major clinical trials with these devices will be summarized and put into perspective.
drug-eluting stent; restenosis; Promus Element; Synergy
The 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.
Several 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.
Drug-eluting stents (DES) reduce coronary restenosis significantly; however, late stent thrombosis (LST) occurs, which requires long-term antiplatelet therapy. Angioscopic grading of neointimal coverage of coronary stent struts was established, and it was revealed that neointimal formation is incomplete and prevalence of LST is higher in DES when compared to bare-metal stents. It was also observed that the neointima is thicker and LST is less frequent in paclitaxel-eluting and zotarolimus-eluting stents than in sirolimus-eluting stents. Many new stents were devised and they are now under experimental or clinical investigations to overcome the shortcomings of the stents that have been employed clinically. Endothelial cells are highly anti-thrombotic. Neo-endothelial cell damage is considered to be caused by friction between the cells and stent struts due to the thin neointima between them which might act as a cushion. Therefore, development of a DES that causes an appropriate thickness (around 100 μm) of the neointima is a potential option with which to prevent neo-endothelial cell damage and consequent LST while preventing restenosis.
Bare-metal stent; Drug-eluting stent; Neointimal coverage; Late stent thrombosis; Neo-endothelial cell damage; Angioscopy
Animal models of stenting are mostly limited to larger animals or involve substantial abdominal surgery in rodents. We aimed to develop a simple, direct model of murine stenting.
Methods and results
We designed a miniature, self-expanding, nitinol wire coil stent that was pre-loaded into a metal stent sheath. This was advanced into the abdominal aorta of the mouse, via femoral access, and the stent deployed. In-stent restenosis was investigated at 1, 3, 7, and 28 days post-stenting. The model was validated by investigation of neointima formation in mice deficient in signalling via the interleukin-1 receptor (IL-1R1), compared with other injury models. Ninety-two per cent of mice undergoing the procedure were successfully stented. All stented vessels were patent. Inflammatory cells were seen in the adventitia and around the stent strut up to 3 days post-stenting. At 3 days, an early neointima was present, building to a mature neointima at 28 days. In mice lacking IL-1R1, the neointima was 64% smaller than that in wild-type controls at the 28-day timepoint, in agreement with other models.
This is the first description of a successful model of murine in situ stenting, using a stent specifically tailored for use in small thin-walled arteries. The procedure can be undertaken by a single operator without the need for an advanced level of microsurgical skill and is reliable and reproducible. The utility of this model is demonstrated by a reduction in in-stent restenosis in IL-1R1-deficient mice.
Mouse stent model
In the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS), early recurrent carotid stenosis was more common in patients assigned to endovascular treatment than it was in patients assigned to endarterectomy (CEA), raising concerns about the long-term effectiveness of endovascular treatment. We aimed to investigate the long-term risks of restenosis in patients included in CAVATAS.
413 patients who were randomly assigned in CAVATAS and completed treatment for carotid stenosis (200 patients had endovascular treatment and 213 patients had endarterectomy) had prospective clinical follow-up at a median of 5 years and carotid duplex ultrasound at a median of 4 years. We investigated the cumulative long-term incidence of carotid restenosis after endovascular treatment and endarterectomy, the effect of the use of stents on restenosis after endovascular treatment, risk factors for the development of restenosis, and the effect of carotid restenosis on the risk of recurrent cerebrovascular events. Analysis was by intention to treat. This study is registered, number ISRCTN01425573.
Severe carotid restenosis (≥70%) or occlusion occurred significantly more often in patients in the endovascular arm than in patients in the endarterectomy arm (adjusted hazard ratio [HR] 3·17, 95% CI 1·89–5·32; p<0·0001). The estimated 5-year incidence of restenosis was 30·7% in the endovascular arm and 10·5% in the endarterectomy arm. Patients in the endovascular arm who were treated with a stent (n=50) had a significantly lower risk of developing restenosis of 70% or greater compared with those treated with balloon angioplasty alone (n=145; HR 0·43, 0·19–0·97; p=0·04). Current smoking or a history of smoking was a predictor of restenosis of 70% or more (2·32, 1·19–4·54; p=0·01) and the early finding of moderate stenosis (50–69%) up to 60 days after treatment was associated with the risk of progression to restenosis of 70% or more (3·76, 1·88–7·52; p=0·0002). The composite endpoint of ipsilateral non-perioperative stroke or transient ischaemic attack occurred more often in patients in whom restenosis of 70% or more was diagnosed in the first year after treatment compared with patients without restenosis of 70% or more (5-year incidence 23% vs 11%; HR 2·18, 1·04–4·54; p=0·04), but the increase in ipsilateral stroke alone was not significant (10% vs 5%; 1·67, 0·54–5·11).
Restenosis is about three times more common after endovascular treatment than after endarterectomy and is associated with recurrent ipsilateral cerebrovascular symptoms; however, the risk of recurrent ipsilateral stroke is low. Further data are required from on-going trials of stenting versus endarterectomy to ascertain whether long-term ultrasound follow-up is necessary after carotid revascularisation.
British Heart Foundation; UK National Health Service Management Executive; UK Stroke Association.
One of the most common medical interventions to reopen an occluded vessel is the implantation of a coronary stent. While this method of treatment is effective initially, restenosis, or the re-narrowing of the artery frequently occurs largely due to neointimal hyperplasia of smooth muscle cells. Drug eluting stents were developed in order to provide local, site-specific, controlled release of drugs that can inhibit neointima formation. By implementing a controlled release delivery system it may be possible to control the time release of the pharmacological factors and thus be able to bypass some of the critical events associated with stent hyperplasia and prevent the need for subsequent intervention. However, since the advent of first-generation drug eluting stents, long-term adverse effects have raised concerns regarding their safety. These limitations in safety and efficacy have triggered considerable research in developing biodegradable stents and more potent drug delivery systems. In this review, we shed light on the current state-of-the-art in drug eluting stents, problems related to them and highlight some of the ongoing research in this area.
drug eluting stent; stent; controlled release; restenosis; sirolimus
The development of stent has been a major advance in the treatment of obstructive coronary artery disease since the introduction of balloon angioplasty. However, neointimal hyperplasia occurring within the stent leading to in-stent restenosis is a main obstacle in the long-term success of percutaneous coronary intervention (PCI). The recent introduction of drug-eluting stents (DES) contributes a major breakthrough to interventional cardiology. Many large randomized clinical trials using DES have shown a remarkable reduction in angiographic restenosis and target vessel revascularization when compared with bare metal stents. The results of these trials also appear to be supported by evidence from everyday practice and noncontrolled clinical trials. However, the expanded applications of DES, especially in treating complex lesions such as left main trunk, bifurcation, saphenous vein graft lesions, or in-stent restenosis, are still under evaluation with ongoing studies. With the availability of different types of DES in the market, the issue of cost should not be a deterrent and DES will eventually be an economically viable option for all patients. The adoption of DES in all percutaneous coronary intervention may become a reality in the near future. In this review article, we summarize the recent development and progress of DES as well as compare and update the results of clinical trials.
drug-eluting stent; percutaneous transluminal coronary angioplasty; in-stent restenosis
The present review assesses the data on long-term outcome after coronary stenting. Histological, angiographical and intravascular imaging data have shown that the insertion of stents constitutes only a transient stimulus to lumen renarrowing, that this process is almost complete at 6 months and that a certain degree of neointima regression is also possible after this time. Clinical data have confirmed the sustained benefit of stenting in the long term. Careful selection of optimal stent designs and application of the recent advances in adjunctive pharmacological therapy are currently effective strategies to improve both short-and long-term results with coronary stenting. However, further efforts are needed and are ongoing to combat restenosis, a process that counters the excellent short-term results of stenting in the long term.
coronary artery disease; long-term outcome; restenosis; stents; thrombosis
Preclinical models of restenosis are essential to unravel the pathophysiological processes that lead to in-stent restenosis and to optimize existing and future drug-eluting stents.
A variety of antibodies and transgenic and knockout strains are available in rats. Consequently, a model for in-stent restenosis in the rat would be convenient for pathobiological and pathophysiological studies.
In this video, we present the full procedure and pit-falls of a rat stent model suitable for high throughput stent research. We will show the surgical procedure of stent deployment, and the assessment of in-stent restenosis using the most elegant technique of OCT (Optical Coherence Tomography). This technique provides high accuracy in assessing plaque CSAs (cross section areas) and correlates well with histological sections, which require special and time consuming embedding and sectioning techniques. OCT imaging further allows longitudinal monitoring of the development of in-stent restenosis within the same animal compared to one-time snapshots using histology.
Percutaneous coronary intervention (PCI) has become the most common revascularization procedure for coronary artery disease. The use of stents has reduced the rate of restenosis by preventing elastic recoil and negative remodeling. However, in-stent restenosis remains one of the major drawbacks of this procedure. Drug-eluting stents (DESs) have proven to be effective in reducing the risk of late restenosis, but the use of currently marketed DESs presents safety concerns, including the non-specificity of therapeutics, incomplete endothelialization leading to late thrombosis, the need for long-term anti-platelet agents, and local hypersensitivity to polymer delivery matrices. In addition, the current DESs lack the capacity for adjustment of the drug dose and release kinetics appropriate to the disease status of the treated vessel. The development of efficacious therapeutic strategies to prevent and inhibit restenosis after PCI is critical for the treatment of coronary artery disease. The administration of drugs using biodegradable polymer nanoparticles as carriers has generated immense interest due to their excellent biocompatibility and ability to facilitate prolonged drug release. Despite the potential benefits of nanoparticles as smart drug delivery and diagnostic systems, much research is still required to evaluate potential toxicity issues related to the chemical properties of nanoparticle materials, as well as to their size and shape. This review describes the molecular mechanism of coronary restenosis, the use of DESs, and progress in nanoparticle drug- or gene-eluting stents for the prevention and treatment of coronary restenosis.
Coronary artery disease; Stenosis; Restenosis; Stents; Nanoparticle.
The introduction of drug eluting stents has resulted in dramatic reductions in the rates of restenosis and the need for repeat revascularization. In the last several years, concern has been raised regarding the long-term safety of this technology, particularly in the area of late restenosis and stent thrombosis. The development of newer anti-restenotic drug coatings, biodegradable polymers and even completely bioabsorbable stents offer the potential to address these limitations. Additional questions that have recently come to the forefront include the optimal duration of dual antiplatelet therapy, the use of platelet reactivity assays and genetic testing and drug eluting stent use in the treatment of acute myocardial infarction. This article will attempt to address these and other areas of controversy in the use and implementation of drug eluting stents.
Bare metal stents (BMS); drug eluting stents (DES); rates of restenosis; revascularization
The optimal treatment of chronic middle cerebral artery (MCA) occlusion is unclear. Angioplasty and stenting may be an alternative treatment for patients with recurrent ischemic symptoms despite medical therapy. Two patients with chronic right MCA occlusion successfully treated with stenting are reported, together with their long term follow-up to illustrate the feasibility of endovascular recanalization. One patient remained asymptomatic at the 29-month follow-up. Another patient developed symptomatic in-stent restenosis at 12 months which resolved after repeat angioplasty. Further larger scale pilot studies are needed to determine the efficacy and long term outcome of this treatment.
Purpose. The long-term efficacy of carotid artery stenting is debated. Predictors of stent restenosis are not fully investigated. Our aim was to assess the incidence of long term restenosis after CAS and to identify some predictors of restenosis. Methods. We retrospectively selected 189 treated patients and we obtained the survival Kaplan-Meier curves for overall survival, for freedom from stroke or death and from restenosis. To correlate clinical, radiological, and procedural variables to stent restenosis, an univariate analysis was performed while to determine independent predictors of restenosis, a multivariate analysis was applied. Results. At 1, 3, and 5 years, the cumulative overall survival rate was 98%, 94%, and 92% with a cumulative primary patency rate of 87%, 82.5%, and 82.5%. The percentage residual stenosis after CAS and multiple stents deployment were independent predictors of restenosis, while diabetes and tumors are suggestive but not significant predictors of restenosis. Conclusions. In our CAS experience, encouraging long-term results seem to derive from both neurological event free rate and restenosis incidence. Adequate recanalization of the treated vessel is important to limit the development of stent restenosis. Multiple stents deployment, and with less evidence, diabetes, or neoplasms has to be considered to facilitate restenosis.
The biomechanical interaction of stents and the arteries into which they are deployed is a potentially important consideration for long-term success. Adverse arterial reactions to excessive stress and the resulting damage have been linked to the development of restenosis. Complex geometric features often encountered in these procedures can confound treatment. In some cases, it is desirable to deploy a stent across a region in which the diameter decreases significantly over the length of the stent. This study aimed to assess the final arterial diameter and circumferential stress in tapered arteries into which two different stents were deployed (one stiff and one less stiff). The artery wall was assumed to be made of a strain stiffening material subjected to large deformations, with a 10% decrease in diameter over the length of the stent. A commercially available finite element code was employed to solve the contact problem between the two elastic bodies. The stiffer stent dominated over arterial taper, resulting in a nearly constant final diameter along the length of the stent, and very high stresses, particularly at the distal end. The less stiff stent followed more closely the tapered contour of the artery, resulting in lower artery wall stresses. More compliant stents should be considered for tapered artery applications, perhaps even to the exclusion of tapered stents.
Stress; Restenosis; Vascular Interventions; Finite Element Analysis
The development of stent has been a major advance in the treatment of obstructive coronary artery disease since the introduction of balloon angioplasty. Subsequently, neointimal hyperplasia within the stent leading to in-stent restenosis emerged as a major obstacle in long-term success of percutaneous coronary intervention. Recent introduction of drug-eluting stents is a major breakthrough to tackle this problem. This review article summarizes stent technology, reviews progress of drug-eluting stents and discusses quality of life, patient satisfaction, and acceptability of percutaneous coronary intervention.
drug-eluting stent; coronary intervention; patient outcomes
We report the results of an independent laboratory’s tests of novel agents to prevent or reverse type 1 diabetes (T1D) in the non-obese diabetic (NOD) mouse, BioBreeding diabetes prone (BBDP) rat, and multiple autoimmune disease prone (MAD) rat models. Methods were developed to better mimic human clinical trials, including: prescreening, randomization, blinding, and improved glycemic care of the animals. Agents were suggested by the research community in an open call for proposals, and selected for testing by an NIDDK appointed independent review panel. Agents selected for testing to prevent diabetes at later stages of progression in a rodent model were a STAT4 antagonist (DT22669), alpha1 anti-trypsin (Aralast NP), celastrol (a natural product with anti-inflammatory properties), and a Macrophage Inflammatory Factor inhibitor (ISO-092). Agents tested for reversal of established T1D in rodent models were: alpha1 anti-trypsin (Aralast NP), tolerogenic peptides (Tregitopes), and a long-acting formulation of GLP-1 (PGC-GLP-1). None of these agents were seen to prevent or reverse type 1 diabetes, while the positive control interventions were effective: anti-CD3 treatment provided disease reversal in the NOD mouse, dexamethasone prevented T1D induction in the MAD rat, and cyclosporin prevented T1D in the BBDP rat. For some tested agents, details of previous formulation, delivery, or dosing, as well as laboratory procedure, availability of reagents and experimental design, could have impacted our ability to confirm prior reports of efficacy in preclinical animal models. In addition, the testing protocols utilized here provided detection of effects in a range commonly used in placebo controlled clinical trials (for example, 50% effect size), and thus may have been underpowered to observe more limited effects. That said, we believe the results compiled here, showing good control and repeatability, confirm the feasibility of screening diverse test agents in an independent laboratory.
To investigate the effect of reducing stent length on the rate of target lesion restenosis.
In a prospective investigation, acute and long term results of a short stenting procedure were analysed by quantitative angiography and compared with results of a conventional stenting procedure selected according to a matched pairs analysis.
Short stents were implanted in 400 consecutive patients with 464 lesions and conventional stents in 430 patients. Demographic and lesion characteristics were comparable between groups.
In short stenting, the shortest stent length to cover only segments with > 30% reduction in vessel diameter was used. In conventional stenting, full coverage of a stenotic vessel segment was intended.
Main outcome measures
The mean stent lengths of the short stent group (9.8 (4) mm) and the conventional stent group (16.3 (7) mm) differed significantly (p < 0.0001); all other procedural and angiographic parameters were the same. Procedural success was similar for both groups. Control angiography after six months was conducted in 92% of patients.
Short stenting resulted in both less restenosis (68 of 431 (15.8%)) than conventional stenting (93 of 381 (24.4%), p = 0.007) and less late lumen loss (0.6 (0.6) mm v 0.75 (0.5) mm, p = 0.0001). Residual stenosis (< 45%) in adjacent vessel segments after short stenting did not affect the restenosis rate. Only the implantation of a ⩽ 9 mm stent predicted the absence of restenosis in a multivariate analysis.
Shortening the length of bare metal stents reduces the restenosis rate as compared with conventional stenting.
stent; balloon dilatation; restenosis
This study is to explore the effect of valsartan-eluting stents on neointima formation after stenting and to elucidate possible mechanisms how locally used valsartan prevents in-stent restenosis (ISR). METHOD: valsartan- and carriereluting stents were manufactured by using multi-layer-coated technology. Bare stents, carrier-eluting stents and valsartan– eluting stents were implanted into the abdominal aortas of the rabbits respectively. Quantitative angiography (QA) before, immediately after and 3 months after stent implantation were compared between the groups of bare (n=8), carrier-eluting (n=8) and valsartan-eluting stent (n=10), which allows the comparison of vascular diameters of aortas as well as indices of vascular neointimal formation, i.e. luminal area (LA), neointimal area (NIA), inner elastic membrane luminal area (IELA) and the maximal inner-membrane thickness (MIT) in 15 rabbits. α-Actin protein expression were detected by Envision two-step immunohistochemistry. Mean positive indices (MPI) of the above protein were analyzed semi-quantatively by IMS(Information Management System) cell image analysis system. MPI=positive area×OD (optical density). Collagen deposition in neointima was observed through MASSON stain among the three groups.
the mean aortic diameters were similar in the three groups:bare stents group(n=8), carrier-eluting stents group(n=8) and valsartan eluting stents group(n=10) measured by QA at different time. A larger luminal area and a less neointimal hyperplasia in valsartan eluting-stents group was found compared with the other two groups. The mean luminal areas were 4345548±125822um2; 4302061±167952 um2; 5016269±207934um2 respectively. The mean neointimal areas were 1119635±163503um2; 1135636±136555um2; 441577±74099um2 and the mean maximal inner-membrane thickness were 210±30um;192±21um; 116±12um respectively. α-Actin protein expression was significantly lower in neointima of valsartan eluting-stents group than the other two groups. Through MASSON stain we found that Collagen was much richer in neointima of bare stents group and carrier-eluting stents group than valsartan eluting-stents group.
Valsartan eluting-stents inhibited neointimal hyperplasia after stenting by decreasing collagen deposition and smooth muscle cell proliferation. Therefore it would be potentially effective in preventing in-stent restenosis.
Quantitative angiography (QA), luminal area (LA), neointimal area (NIA), inner elastic membrane luminal area (IELA), the maximal inner-membrane thickness (MIT), Mean positive indices (MPI), optical density (OD), Drugeluting stents (DES), in-stent restenosis(ISR), percutaneous transluminal coronary angioplasty (PTCA), angiotensin α type 2 receptor (AT2).
eluting stent; valsartan; restenosis; collagen; AT2 receptor
Percutaneous angioplasty and stenting for the treatment of extracranial vertebral artery (VA) stenosis seems a safe, effective and useful technique for resolving symptoms and improving blood flow to the posterior circulation, with a low complication rate and good long-term results. In patients with severe tortuosity of the vessel, stent placement is a real challenge. The new coronary balloon-expandable stents may be preferred. A large variability of restenosis rates has been reported. Drug-eluting stents may be the solution. After a comprehensive review of the literature, it can be concluded that percutaneous angioplasty and stenting of extracranial VA stenosis is technically feasible, but there is insufficient evidence from randomized trials to demonstrate that endovascular management is superior to best medical management.
Vertebral artery stenosis; Endovascular treatment; Stent; Angioplasty
OBJECTIVE—To analyse the variables involved in the high restenosis rate following stent implantation in coronary artery bypass grafts.
DESIGN—A retrospective analysis of a consecutive group of patients attending a tertiary centre.
PATIENTS—The long term angiographic outcome of 219 stent implantations for individual lesions performed in 191 patients was investigated. Multivariate analysis correlated clinical, procedural, and angiographic variables with the incidence of angiographic restenosis, defined as diameter stenosis > 50% at follow up.
RESULTS—Angiographic restenosis was observed in 34% of lesions treated. Multiple logistic regression analysis defined diabetes mellitus (odds ratio 6.91, 95% confidence interval (CI) 2.43 to 9.69), graft recanalisation (2.89, 95% CI 1.18 to 6.63), lesion at the aortic anastomosis (6.98, 95% CI 2.77 to 21.31), lesion at the coronary anastomosis (3.01, 95% CI 1.19 to 7.69), high diameter stenosis after stent placement (7.21, 95% CI 2.66 to 16.81), placement of long stents (2.73, 95% CI 1.09 to 7.39), and implantation of more than one stent (7.31, 95% CI 2.08 to 19.96) as independent predictors of graft in-stent restenosis.
CONCLUSIONS—There appears to be a specific risk factor constellation contributing to the high restenosis rate following stent implantation in venous bypass grafts. Critical consideration of these variables may help identify patients who are poor candidates for stent implantation and who may benefit from a different approach.
Keywords: coronary artery bypass graft; stent; restenosis
Neointimal hyperplasia, a process of smooth muscle cell re-growth, is the result of a natural wound healing response of the injured artery after stent deployment. Excessive neointimal hyperplasia following coronary artery stenting results in in-stent restenosis (ISR). Regardless of recent developments in the field of coronary stent design, ISR remains a significant complication of this interventional therapy. The influence of stent design parameters such as strut thickness, shape and the depth of strut deployment within the vessel wall on the severity of restenosis has already been highlighted but the detail of this influence is unclear. These factors impact on local haemodynamics and vessel structure and affect the rate of neointima formation. This paper presents the first results of a multi-scale model of ISR. The development of the simulated restenosis as a function of stent deployment depth is compared with an in vivo porcine dataset. Moreover, the influence of strut size and shape is investigated, and the effect of a drug released at the site of injury, by means of a drug-eluting stent, is also examined. A strong correlation between strut thickness and the rate of smooth muscle cell proliferation has been observed. Simulation results also suggest that the growth of the restenotic lesion is strongly dependent on the stent strut cross-sectional profile.
in-stent restenosis; multi-scale modelling; complex automata; strut thickness; strut shape
Bare metal stents have a proven safety record, but limited long-term efficacy due to in-stent restenosis. First-generation drug-eluting stents successfully countered the restenosis rate, but were hampered by concerns about their long-term safety. Second generation drug-eluting stents have combined the low restenosis rate of the first generation with improved long-term safety. We review the evolution of drug-eluting stents with a focus on the safety, efficacy, and unique characteristics of everolimus-eluting stents.
everolimus-eluting stents; safety; efficacy
Gimap5 (GTPase of the immunity-associated protein 5) has been linked to the regulation of T cell survival, and polymorphisms in the human GIMAP5 gene associate with autoimmune disorders. The BioBreeding diabetes-prone (BBDP) rat has a mutation in the Gimap5 gene that leads to spontaneous apoptosis of peripheral T cells by an unknown mechanism. Because Gimap5 localizes to the endoplasmic reticulum (ER), we hypothesized that absence of functional Gimap5 protein initiates T cell death through disruptions in ER homeostasis. We observed increases in ER stress-associated chaperones in T cells but not thymocytes or B cells from Gimap5−/− BBDP rats. We then discovered that ER stress-induced apoptotic signaling through C/EBP-homologous protein (CHOP) occurs in Gimap5−/− T cells. Knockdown of CHOP by siRNA protected Gimap5−/− T cells from ER stress-induced apoptosis, thereby identifying a role for this cellular pathway in the T cell lymphopenia of the BBDP rat. These findings indicate a direct relationship between Gimap5 and the maintenance of ER homeostasis in the survival of T cells.
Coronary artery disease remains one of the leading causes of death in the United States. Over the last 30 years, the development of coronary artery angioplasty and stenting has drastically reduced mortality during acute coronary syndromes while also reducing symptoms of chronic coronary artery disease. Unfortunately, the placement of stents in a coronary artery can be complicated by in-stent thrombosis or restenosis. In 2003–2004, a new generation of stents was introduced to the market with the goal of reducing the rate of restenosis. These stents, called drug eluting stents (DES), are coated with a pharmacological agent designed to reduce the neointimal hyperplasia associated with restenosis. Within a year, approximately 80% of all percutaneous coronary interventions performed within the US involved placement of a DES. In 2006, a controversy arose about the possibility of a statistically significant increased risk of acute stent thrombosis associated with DES especially when used for an “off label” indication. This risk was attributed to delayed endothelization. This controversy has led to a reduction in the use of DES along with longer use of dual platelet inhibition with aspirin and clopidogrel. Recently Medtronic introduced a new DES to the market called the Endeavor® stent – a zotarolimus eluting stent.
Endeavor® stent; zotarolimus stent; drug eluting stent
Patients with diabetes mellitus (DM) are prone to a diffuse and rapidly progressive form of atherosclerosis, which increases their likelihood of requiring revascularization. However, the unique pathophysiology of atherosclerosis in patients with DM modifies the response to arterial injury, with profound clinical consequences for patients undergoing percutaneous coronary intervention (PCI). Multiple studies have shown that DM is a strong risk factor for restenosis following successful balloon angioplasty or coronary stenting, with greater need for repeat revascularization and inferior clinical outcomes. Early data suggest that drug eluting stents reduce restenosis rates and the need for repeat revascularization irrespective of the diabetic state and with no significant reduction in hard clinical endpoints such as myocardial infarction and mortality. For many patients with 1- or 2-vessel coronary artery disease, there is little prognostic benefit from any intervention over optimal medical therapy. PCI with drug-eluting or bare metal stents is appropriate for patients who remain symptomatic with medical therapy. However, selection of the optimal myocardial revascularization strategy for patients with DM and multivessel coronary artery disease is crucial. Randomized trials comparing multivessel PCI with balloon angioplasty or bare metal stents to coronary artery bypass grafting (CABG) consistently demonstrated the superiority of CABG in patients with treated DM. In the setting of diabetes CABG had greater survival, fewer recurrent infarctions or need for re-intervention. Limited data suggests that CABG is superior to multivessel PCI even when drug-eluting stents are used. Several ongoing randomized trials are evaluating the long-term comparative efficacy of PCI with drug-eluting stents and CABG in patients with DM. Only further study will continue to unravel the mechanisms at play and optimal therapy in the face of the profoundly virulent atherosclerotic potential that accompanies diabetes mellitus.
Coronary artery bypass graft; Diabetes mellitus; Percutaneous coronary intervention; Revascularization; Stents