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Restenosis after PCI. Part 1: Pathophysiology and risk factors
Abstract
Restenosis is a complex disease for which the pathophysiological mechanisms have not yet been fully elucidated, but are thought to include inflammation, proliferation, and matrix remodeling. Over the years, many predictive clinical, biological, (epi)genetic, lesion-related, and procedural risk factors for restenosis have been identified. These factors are not only useful in risk stratification of patients, they also contribute to our understanding of this condition. Furthermore, these factors provide evidence on which to base treatment tailored to the individual and aid in the development of novel therapeutic modalities. In this Review, we will evaluate the available evidence on the pathophysiological mechanisms of restenosis and provide an overview of the various risk factors, together with the possible clinical application of this knowledge.
... In-stent restenosis (ISR) refers to the re-narrowing of stented coronary artery lesions due to neointimal hyperplasia [1]. The risk factors of ISR are not fully elucidated; however, clinical data indicate that factors including type 2 diabetes mellitus (T2DM), hyperlipidemia (HL), hypertension (HT), advanced age, and male gender may accelerate the occurrence of restenosis [2]. ...
... Numerous studies demonstrated that T2DM represents a pivotal risk factor for restenosis, which is attributable to the inflammatory process initiated by the secretion of cytokines and elevated levels of growth factors. Furthermore, HT and HL have been identified as potential risk factors for restenosis, due to their influence on neointima formation [1,2]. Similarly, the frequency of T2DM (p=0.005), ...
... The association between gender and risk of ISR remains inconclusive. While some studies have reported a higher risk of ISR among men compared to women [1], some have suggested that it is higher in women [40]. In the present study, however, we found similar gender distributions among the study groups, which is consistent with some of the previous studies [41]. ...
Objectives
The peroxisome proliferator-activated receptor gamma ( PPARG ) C161T polymorphism (rs3856806) may be a risk factor for in-stent restenosis (ISR) due to its known associations with type 2 diabetes (T2DM), obesity, and coronary artery disease (CAD). This study aims to investigate the relationship between PPARG -C161T polymorphism and the risk of ISR, considering clinical features.
Methods
According to the results of coronary angiography, the patients who had undergone drug-eluting stent implantation were categorized into two groups: ISR (n=116) and non-ISR (n=265). The control group consisted of 140 healthy subjects with asymptomatic for CAD or any systemic disease. PPARG -C161T genotypes were determined using the real-time polymerase chain reaction melting curve analysis.
Results
T2DM, hypertension, and hyperlipidemia were observed as the main clinical features causing non-ISR and ISR. The 161-CC genotype was associated with an increased risk of ISR compared to both controls (p=0.014) and non-ISR patients (p=0.008). This difference remained statistically significant after multivariate analysis for non-ISR patients (p=0.003) but not for the ISR group. The prevalence of hypertension and hyperlipidemia was higher in ISR patients with T2DM than in non-ISR patients with T2DM (p=0.002 and p=0.009, respectively). Multivariate logistic regression analysis in subgroups based on the presence of T2DM showed that hypertension (p<0.001) was associated with ISR in patients with T2DM.
Conclusions
This study points out the association between the PPARG 161-CC genotype and the risk of ISR, which also means that the PPARG 161-T allele is protective against ISR. However, this effect could be divergent in the presence of the metabolic components of the restenosis phenotype, especially T2DM.
... Restenosis is the artery renarrowing within the first year after the treatment, and it is also referred to as negative or constrictive vessel remodeling (Pasterkamp et al., 2000). It might lead to the need of re-intervention with a reported incidence of 25% to 50% if not accompanied by stent insertion (Jukema et al., 2012). ...
... In fact, restenosis involves two distinct, possibly highly coupled, mechanisms (Jukema et al., 2012;Koskinas et al., 2012). One emphasizes alterations in blood-flow-related shear stresses and thrombogenic risk, while the other focuses on vessel wall damage triggering inflammation and abnormal growth. ...
... However, these therapies have limited direct impact on the VSMCs per se. Percutaneous coronary intervention with a stent has significantly reduced mortality rates in patients with acute coronary syndromes [8], but the development of neo-atherosclerosis, also known as in-stent restenosis, has emerged as a major safety concern due to the increased proliferative VSMCs resulting from phenotypic switching [9]. Therefore, directly targeting the phenotypic switching of VSMCs holds therapeutic promise, particularly for patients with CVDs who have relatively normal cholesterol levels, those who experience recurrent CVDs despite lipid-lowering therapy, and those who develop in-stent restenosis after coronary stent implantation. ...
Phenotypic switching (from contractile to synthetic) of vascular smooth muscle cells (VSMCs) is essential in the progression of atherosclerosis. The damaged endothelium in the atherosclerotic artery exposes VSMCs to increased interstitial fluid shear stress (IFSS). However, the precise mechanisms by which increased IFSS influences VSMCs phenotypic switching are unrevealed. Here, we employed advanced numerical simulations to calculate IFSS values accurately based on parameters acquired from patient samples. We then carefully investigated the phenotypic switching and extracellular vesicles (EVs) secretion of VSMCs under various IFSS conditions. By employing a comprehensive set of approaches, we found that VSMCs exhibited synthetic phenotype upon atherosclerotic IFSS. This synthetic phenotype is the upstream regulator for the enhanced secretion of pro-calcified EVs. Mechanistically, as a mechanotransducer, the epidermal growth factor receptor (EGFR) initiates the flow-based mechanical cues to MAPK signaling pathway, facilitating the nuclear accumulation of the transcription factor krüppel-like factor 5 (KLF5). Furthermore, pharmacological inhibiting either EGFR or MAPK signaling pathway blocks the nuclear accumulation of KLF5 and finally results in the maintenance of contractile VSMCs even under increased IFSS stimulation. Collectively, targeting this signaling pathway holds potential as a novel therapeutic strategy to inhibit VSMCs phenotypic switching and mitigate the progression of atherosclerosis.
... Michael Jonas et al. [28] used the insulin resistance model of the Zucker fatty rat and found that insulin-resistant Zucker fatty rats developed a thicker neointima and a narrower lumen area 2 weeks after implantation of an abdominal aortic stent compared with normal Zucker lean rats. Additionally, Manikandan Panchatcharam et al. [29] established a femoral artery guide wire injury model in hyperglycemic mice and confirmed The current mainstream view is that DM increases the risk of restenosis [31]. Studies have shown that patients with insulin-dependent DM are at particularly high risk for adverse events after percutaneous coronary intervention (PCI) [27]. ...
Importance
Diabetes mellitus (DM) is thought to be closely related to arterial stenotic or occlusive disease caused by atherosclerosis. However, there is still no definitive clinical evidence to confirm that patients with diabetes have a higher risk of restenosis.
Objective
This meta-analysis was conducted to determine the effect of DM on restenosis among patients undergoing endovascular treatment, such as percutaneous transluminal angioplasty (PTA) or stenting.
Data sources and study selection
The PubMed/Medline, EMBASE and Cochrane Library electronic databases were searched from 01/1990 to 12/2022, without language restrictions. Trials were included if they satisfied the following eligibility criteria: (1) RCTs of patients with or without DM; (2) lesions confined to the coronary arteries or femoral popliteal artery; (3) endovascular treatment via PTA or stenting; and (4) an outcome of restenosis at the target lesion site. The exclusion criteria included the following: (1) greater than 20% of patients lost to follow-up and (2) a secondary restenosis operation.
Data extraction and synthesis
Two researchers independently screened the titles and abstracts for relevance, obtained full texts of potentially eligible studies, and assessed suitability based on inclusion and exclusion criteria.. Disagreements were resolved through consultation with a third researcher. Treatment effects were measured by relative ratios (RRs) with 95% confidence intervals (CIs) using random effects models. The quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria.
Main outcomes and measures
The main observation endpoint was restenosis, including > 50% stenosis at angiography, or TLR of the primary operation lesion during the follow-up period.
Results
A total of 31,066 patients from 20 RCTs were included. Patients with DM had a higher risk of primary restenosis after endovascular treatment (RR = 1.43, 95% CI: 1.25–1.62; p = 0.001).
Conclusions and relevance
This meta-analysis of all currently available RCTs showed that patients with DM are more prone to primary restenosis after endovascular treatment.
... Balloon angioplasty was performed on the day of ipsilateral ischemic stroke. * These patients did not proceed to digital subtraction angiography 21 for confirmation immediately when ISR R3 was first detected and were later treated with balloon angioplasty after cerebral infarction. † Refused Categorical and continuous variables are presented as frequencies (%) and median (IQR). ...
Objective
To analyze the relationship between in-stent restenosis (ISR) following carotid artery stenting (CAS) and platelet clopidogrel reactivity confirmed by the P2Y12 reaction unit (PRU) and inhibition rate (IR).
Methods
We retrospectively analyzed 171 patients who underwent CAS with extracranial carotid stenosis from January 2016 to December 2019. Dual antiplatelet therapy with 100 mg aspirin and 75 mg clopidogrel was started ≥5 days before CAS. Clopidogrel resistance was measured with the PRU and IR the day before CAS. The ISR degree was classified into R1, R2, and R3 (moderate to severe luminal stenosis of ≥50% or occlusion) by carotid CT angiography after 24–30 months. The degree of quantitative association between platelet reactivity and ISR R3 was determined by the receiver operating characteristic curve method. The optimal cut-off values of PRU and IR were derived using the maximum Youden index.
Results
There were 33 R3 degrees of ISR (19.3%) and nine ipsilateral ischemic strokes (5.3%). The PRU and IR were different between R1+R2 degrees (176.4±50.1, 27.5±18.7%) and R3 degree (247.5±55.0, 10.3±13.4%) (P<0.001). The areas under the curves of PRU and IR were 0.841 and 0.781, and the optimal cut-off values were 220.0 and 14.5%, respectively. Multivariate logistic regression analysis showed that PRU ≥220 and IR ≤14.5% were significant predictive factors for ISR R3 (P<0.001 and P=0.017, respectively). ISR R3 was independently associated with ipsilateral ischemic stroke after CAS (P=0.012).
Conclusions
High PRU (≥220) and low IR (≤14.5%) are related to ISR R3 following CAS, which may cause ipsilateral ischemic stroke.
Background
Stent restenosis is a relatively common phenomenon among patients with coronary heart disease undergoing percutaneous coronary intervention (PCI). It seems that a set of clinical, laboratory, and even genetic factors make people susceptible to such a phenomenon and in fact, this is multi-factorial. We aimed to first determine the underlying clinical and laboratory risk factors for the occurrence of stent re-stenosis after PCI based on a systematic review study, and after that, through a bioinformatics study, to evaluate the related genes and microRNAs with the occurrence of stent re-stenosis.
Main text
In the first step, the manuscript databases including Medline, Web of Knowledge, Google Scholar, Scopus, and Cochrane were deeply searched by the two blinded investigators for all eligible studies based on the considered keywords to introduce clinical and laboratory determinants of stent re-stenosis. In the bioinformatic phase, and following a review of the literature to identify genes and microRNAs involved in restenosis, the interaction of each gene with other genes associated with stent re-stenosis was determined by GeneMANIA network analysis and Cytoscape software. Overall, 67 articles (including 40,789 patients) on clinical and biochemical predictors for stent restenosis and 25 articles on genetic determinants of this event were eligible for the final analysis. The predictors for this event were categorized into four subgroups patient-based parameters including traditional cardiovascular risk profiles, stent-based parameters including type and diametric characteristics of the stents used, coronary lesion-based parameters including several two target lesions and coronary involvement severity and laboratory-based parameters particularly related to activation of inflammatory processes. In the bioinformatic phase, we uncovered 42 genes that have been described to be involved in such a phenomenon considering a special position for genes encoding inflammatory cytokines. Also, 12 microRNAs have been pointed to be involved in targeting genes involved in stent re-stenosis.
Conclusions
The incidence of stent re-stenosis will be the result of a complex interaction of clinical risk factors, laboratory factors mostly related to the activation of inflammatory processes, and a complex network of gene-to-gene interactions.
Platelets play a pivotal role in many physiological and pathological processes, with their special targeting/adhering properties towards infarcted myocardium, injured or dysfunctional endothelium, and growing thrombus. Leveraging the site-targeting/adhering property, a variety of platelet-inspired targeting delivery（PITD）designs have been developed, the majority of which are reached by hitchhiking live platelets, cloaking nanoparticles with platelet membranes and mimicking platelet functions. With PITD, drugs or regenerative cells can directly reach targeted sites with minimized systematical distribution thus being of great clinical benefits. Coronary heart disease (CHD) is a major health burden worldwide. Plenty of PITD designs have shown promising outcomes for the treatment of CHD in preclinical models, especially in thrombolysis and post-percutaneous coronary intervention (post-PCI) anti-restenosis. Besides, PITD applications in cardiac protection and atherosclerotic plaque imaging are also under investigation. What's more, the potential benefits of PITD in the field of cell-based therapy are also attracting growing attention since it may resolve the problem of low arriving and retention efficiency, which are also particularly discussed in this review. In brief, our focus is putting on PITD strategies designed for the treatment of CHD, which hopefully can facilitate further optimization of this direction.
Objectives:
We examined the relative contributions of inflammation and arterial injury to neointimal formation in a porcine coronary overstretch restenosis model.
Background:
Previous studies established that stents cause neointimal proliferation proportional to injury. Although inflammation has been postulated to be a major contributor to restenosis after angioplasty, there is a paucity of data on the relation between inflammation and subsequent neointimal formation.
Methods:
Twenty-one pigs underwent balloon injury followed by implantation of oversized, tubular, slotted stents (stent/artery ratio 1.2:1) in the left anterior descending coronary artery. Morphometric analysis of the extent of injury (graded as injury score 0 to 3) and inflammation (graded as inflammation score 0 to 3) 1 month later was assessed and correlated with neointimal formation.
Results:
An inflammatory reaction was observed in 20 of 21 pigs, and significant positive correlations were found between the degree of arterial injury and the extent of the inflammatory reaction (r = 0.80, p < 0.01) and between the extent of inflammatory reaction and the neointimal thickness (r = 0.75, p < 0.01), neointimal area (r = 0.53, p = 0.01) and percent area stenosis (r = 0.66, p < 0.01) within the stents. Importantly, there were areas with inflammation only in the absence of injury, and vice versa, that were also associated with neointimal hyperplasia.
Conclusions:
These data suggest that the inflammatory reaction plays an equally important role as arterial injury in neointimal formation after coronary stenting, and that anti-inflammatory approaches may be of value to reduce in-stent restenosis.
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the benefits and harms of drug-eluting stents versus bare-metal stents in participants with acute coronary syndrome.
The purpose of the present study was to test the hypothesis that restenosis is associated with decreased constitutive nitric oxide synthase activity. Male miniswine with moderately elevated serum cholesterol levels underwent cardiac catheterization and oversized balloon injury to the right and left circumflex coronary arteries, followed 2 weeks later by repeat injury on the same coronary segments. After 4 weeks, the coronary arteries were either immediately frozen in liquid nitrogen or pressure-perfusion fixed and prepared for histologic examination. Constitutive nitric oxide synthase activity was quantified using a fibroblast reporter cell method, while constitutive nitric oxide synthase protein was compared between balloon-injured and non-balloon-injured arteries using Western blot analysis. Immunohistochemical studies were performed using a specific antibody against constitutive nitric oxide synthase protein. Following balloon injury, there was decreased constitutive nitric oxide synthase activity in balloon-injured coronary arteries, compared to distal non-balloon-injured segments from the same artery. Histological examination demonstrated an intact endothelium. Specific antibody staining revealed that there was less constitutive nitric oxide synthase protein reactivity by immunohistochemical analysis. Western analysis confirmed less constitutive nitric oxide synthase protein. The data are consistent with the hypothesis that restenosis is associated with decreased endothelial cell nitric oxide production. The data suggest this is secondary to a decreased amount of constitutive nitric oxide synthase enzyme in the endothelium. A deficiency in constitutive nitric oxide synthase enzyme may contribute to the impaired second messenger and paracrine functions of the endothelium observed during restenosis following balloon injury, including abnormal vasomotion, extracellular matrix formation, and platelet aggregation.
Background: Coronary stents are widely used in interventional cardiology, but a current quantitative systematic overview combaring routine coronary stenting with standard percutaneous transluminal coronary angioplasty (PTCA) and restricted stenting provisional stenting) has not been published. Purpose: To summarize results from all randomized clinical trials comparing routine coronary stenting with standard PTCA. Data Sources: Electronic databases were searched by using thej key words angioplasty and stent. References from identified articles were also reviewed. In addition, several prominent general medical and cardiology journals were searched and agencies known to perform systematic reviews were consulted. study Selection: All comparative randomized clinical trials were ncluded, except those involving primary angioplasty for the treatment of acute myocardial infarction. Data Extraction: A specified protocol was followed, and two of the authors independently extracted the data. Outcomes assessed were total mortality, myocardial infarction, angiographic restenosis, coronary artery bypass surgery, repeated PTCA, and freedom from angina. Data Synthesis: The results were synthesized by using a Bayesan hierarchical random-effects model. A total of 29 trials involvng 9918 patients were identified. There was no evidence for a difference between routine coronary stenting and standard PTCA n terms of deaths or myocardial infarctions (odds ratio, 0.90 [95% credible interval [Crl], 0.72 to 1.11]) or the need for coronary artery bypass surgery (odds ratio, 1.01 [Crl, 0.79 to 1.31]). Coronary stenting reduced the rate of restenosis (odds ratio, 0.52 [Crl, 0.37 to 0.69]) and the need for repeated PTCA (odds ratio, 0.59 [Crl, 0.50 to 0.68]). The trials showed a wide range of crossover rates from PTCA to stenting. By use of a multiplicative model, each 10% increase in crossover rate decreased the need for repeated angioplasty by approximately 8% (odds ratio multiplying factor, 1.08 [Crl, 0.98 to 1.18]). Routine stenting probably reduces the need for repeated angioplasty by fewer than 4 to 5 per 100 treated persons compared with PTCA with provisional stenting. Studies were not blinded and suggest a bias with a possible overestimation of this benefit Conclusions: In the controlled environment of randomized clinical trials, routine coronary stenting is safe but probably not associated with important reductions in rates of mortality, acute myocardial infarction, or coronary artery bypass surgery compared with standard PTCA with provisional stenting. Coronary stenting is associated with substantial reductions in angiographic restenosis rates and the subsequent need for repeated PTCA, although this benefit may be overestimated because of trial designs. The incremental benefit of routine stenting for reducing repeated angioplasty diminishes as the crossover rate of stenting with conventional PTCA increases.
Despite the introduction of drug-eluting stents; restenosis remains an important clinical problem. In this review we examine the role of plasminogen activator inhibitor-1 (PAI-1) in controlling restenosis after balloon angioplasty and stent implantation.
Objectives:
We compared the clinical outcomes following coronary stent implantation in insulin-treated diabetes mellitus (IDDM), non-IDDM patients, and nondiabetic patients.
Background:
Diabetic patients have increased restenosis and late morbidity following balloon angioplasty. The impact of diabetes mellitus (DM), especially IDDM, on in-stent restenosis is not known.
Methods:
We studied 954 consecutive patients with native coronary artery lesions treated with elective Palmaz-Schatz stents implantation using conventional coronary angiographic and intravascular ultrasound methodology. Procedural success, major in-hospital complications, and 1-year clinical outcome were compared according to the diabetic status. RESULTS. In-hospital mortality was 2% in IDDM, significantly higher (p <0.02) compared with non-IDDM (0%) and nondiabetics (0.3%). Stent thrombosis did not differ among groups (0.9% in IDDM vs. 0% in non-IDDM and 0% in nondiabetics, p >0.1). During follow-up, target lesion revascularization (TLR) was 28% in IDDM, significantly higher (p <0.05) compared with non-IDDM (17.6%) and nondiabetics (16.3%). Late cardiac event-free survival (including death, myocardial infarction [MI], and any coronary revascularization procedure) was significantly lower (p=0.0004) in IDDM (60%) compared with non-IDDM (70%) and nondiabetic patients (76%). By multivariate analysis, IDDM was an independent predictor for any late cardiac event (OR=2.05, p=0.0002) in general and TLR (odds ratio=2.51, p=0.0001) in particular. CONCLUSIONS. In a large consecutive series of patients treated by elective stent implantation, IDDM patients were at higher risk for in-hospital mortality and subsequent TLR and, as a result, had a significantly lower cardiac event-free survival rate. On the other hand, acute and long-term procedural outcome was found to be similar for non-IDDM compared with nondiabetic patients.