Research Progress on the Pathogenesis and Treatment of Neoatherosclerosis

Neoatherosclerosis(NA)within stents has become an important clinical problem after coronary artery stent implantation.In-stent restenosis and in-stent thrombosis are the two major complications following coronary stent placement and seriously affect patient prognosis.As the common pathological basis of these two complications,NA plaques,unlike native atherosclerotic plaques,often grow around residual oxidized lipids and stent struts.The main components are foam cells formed by vascular smooth muscle cells(VSMCs)engulfing oxidized lipids at lipid residue sites.Current research mainly focuses on optical coherence tomography(OCT)and intravascular ultrasound(IVUS),but the specific pathogenesis of NA is still unclear.A thorough understanding of the pathogenesis and pathological features of NA provides a theoretical basis for clinical treatment.This article reviews the previous research of our research group and the current situation of domestic and foreign research.

Neoatherosclerosis:Coronary stents seal atherosclerotic lesions but result in making a new problem of atherosclerosis

Chronic inflammation of the native vessel wall with infiltration of lipid-laden foamy macrophages through impaired endothelium results in atherosclerosis. Percutaneous coronary intervention, including metallic stent implantation, is now widely utilized for the treatment of atherosclerotic lesions of the coronary artery. Baremetal stents and the subsequently developed drugeluting stents seal the atherosclerosis and resolve lumen stenosis or obstruction of the epicardial coronary artery and myocardial ischemia. After stent implantation, neointima proliferates within the stented segment. Chronic inflammation caused by a foreign body reaction to the implanted stent and subsequent neovascularization, which is characterized by the continuous recruitment of macrophages into the vessel, result in the transformation of the usual neointima into an atheromatous neointima. Neointima with an atherosclerotic appearance, such as that caused by thin-cap fibroatheromas, is now recognized as neoatherosclerosis, which can sometimes cause in-stent restenosis and acute thrombotic occlusion originating from the stent segment following disruption of the atheroma. Neoatherosclerosis is emerging as a new coronary stent-associated problem that has not yet been resolved. In this review article, we will discuss possible mechanisms, clinical challenges, and the future outlook of neoatherosclerosis.

Clinical Value of the Quantitative Flow Ratio to Predict Long-term Target Vessel Failure in Patients with In-stent Restenosis after Drug-coated Balloon Angioplasty

Objective The study sought to investigate the clinical predictive value of quantitative flow ratio(QFR)for the long-term target vessel failure(TVF)outcome in patients with in-stent restenosis(ISR)by using drug-coated balloon(DCB)treatment after a long-term follow-up.Methods This was a retrospective study.A total of 186 patients who underwent DCB angioplasty for ISR in two hospitals from March 2014 to September 2019 were enrolled.The QFR of the entire target vessel was measured offline.The primary endpoint was TVF,including target vessel-cardiac death(TV-CD),target vessel-myocardial infarction(TV-MI),and clinically driven-target vessel revascularization(CD-TVR).Results The follow-up time was 3.09±1.53 years,and 50 patients had TVF.The QFR immediately after percutaneous coronary intervention(PCI)was significantly lower in the TVF group than in the no-TVF group.Multivariable Cox regression analysis indicated that the QFR immediately after PCI was an excellent predictor for TVF after the long-term follow-up[hazard ratio(HR):5.15×10−5(6.13×10−8−0.043);P<0.01].Receiver-operating characteristic(ROC)curve analysis demonstrated that the optimal cut-off value of the QFR immediately after PCI for predicting the long-term TVF was 0.925(area under the curve:0.886,95%confidence interval:0.834–0.938;sensitivity:83.40%,specificity:88.00;P<0.01).In addition,QFR≤0.925 post-PCI was strongly correlated with the TVF,including TV-MI and CD-TVR(P<0.01).Conclusion The QFR immediately after PCI showed a high predictive value of TVF after a long-term follow-up in ISR patients who underwent DCB angioplasty.A lower QFR immediately after PCI was associated with a worse TVF outcome.

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, drugeluting 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.

Treatment of coronary in-stent restenosis： a systematic review

Coronary stem implantation has significantly improved percutaneous coronary intervention and enabled the management of early complications of plain balloon angioplasty. However, a new complication has accompanied these improvements： in-stent restenosis （ISR） arising from neointimal hyperplasia. ISR after coronary angioplasty is currently one of the main limitations of this method, leading to the recurrence of exertional angina pectoris or acute coronary syndromes. The clinical incidence of ISR after bare-metal stent （BMS） implantation is approximately 20%35%. The use of drug-eluting stents （DES） has led to a further decrease in the occurrence of ISR to 5%-10%. Evidence resulting from controlled clinical studies suggests that DES and drug-eluting balloon catheters （DEB） provide the best clinical and angiographic results in the treatment of ISR. We undertook a systematic review of the pathophysiology, diagnostics and treatment options for BMS- and DES-ISR. We discuss recent randomised studies, comparing different DES or DEB used for BMS or DES-ISR treatment, as well as the use of new biovascular scafolds and the topic of scafold restenosis.

New predictors of in-stent restenosis in patients with diabetes mellitus undergoing percutaneous coronary intervention with drug-eluting stent

Background Percutaneous coronary intervention （PCI） had become the major therapeutic procedure for coronary artery disease （CAD）, but the high rate of in-stent restenosis （ISR） still remained an unsolved clinical problem in clinical practice. Increasing evidences suggested that diabetes mellitus （DM） was a major risk factor for ISR, but the risk predictors of ISR in CAD patients with DM had not been well characterized. The aim of this study was to investigate the clinical and angiographic characteristic predictors significantly associated with the occurrence of ISR in diabetic patients following coronary stenting with drug-eluting stent （DES）. Methods A total of 920 patients with diabetes who diagnosed CAD and underwent coronary DES implantation at Beijing Anzhen Hospital in China were consecutively enrolled from January 2012 to December 2012. Of these, 440 patients underwent the second angiography within ≥ 6 months due to the progression of treated target lesions. Finally, 368 of these patients who met the inclusion and exclusion criteria were followed up by angiography after baseline PCI. According to whether ISR was detected at follow-up angiography, patients were divided into the ISR group （n = 74） and the non-ISR group （n = 294）. The independent predictors of ISR in patients with DM were explored by multivariate Cox＇s proportional hazards regression models. Results A total of 368 patients （260 women and 108 men） with a mean ages of 58.71 ± 10.25 years were finally enrolled in this study. Of these, ISR occurred in 74/368 diabetic patients （20.11%） by follow-up angiography. Univariate analysis showed that most baseline characteristics of the ISR and non-ISR group were similar. Patients in the ISR group had significantly higher serum very low density lipoprotein cholesterol （VLDL-C）, triglyceride （TG） and uric acid （UA） levels, more numbers of target vessel lesions, higher prevalence of multi-vessel disease, higher SYNTAX score, higher rate of previous but lower rate of drinking compared with patients in the non-ISR group. The independent predictors of ISR in patients with DM after DES implantation included VLDL-C （HR = 1.85, 95% CI： 1.24-2.77, P = 0.002）, UA （per 50 μmol/L increments, HR = 1.19, 95% CI： 1.05 1.34, P = 0.006）, SYNTAX score （per 5 increments, HR = 1.34, 95% CI： 1.03-1.74, P = 0.031） and the history ofPCI （HR = 3.43, 95% CI： 1.57-7.80, P = 0.003） by the multivariate Cox＇s proportional hazards regression analysis. Conclusions The increased serum VLDL-C and UA level, higher SYNTAX score and the history of previous PCI were independent predictors of ISR in patients with DM after coronary DES implantation. It provided new evidence for physi- cians to take measures to lower the risk oflSR for the better management of diabetic patients after PCI.

Assessment of Coronary Stents by 64-slice Computed Tomography: In-stent Lumen Visibility and Patency

Objective To assess lumen visibility of coronary stents by 64-slice computed tomography （CT） coronary angiography, and determine the value of 64-slice CT in non-invasive detecting of in-stent restenosis after coronary artery stent implantation. Methods Totally, 60 patients （54 males, aged 57.0±12.7 years） and /05 stents were investigated by 64-slice CT at a mean interval of 20.0±16.6 months after coronary stents implantation. Axial multi-planar reconstruction images of the stents and curved-planar reconstruction images through the median of the stents were reconstructed for evaluating stent image quality on a 5-point scale （1=excellent, 5=nonassessable）, and stent lumen diameter was detected. Conventional coronary angiography was performed in 18 patients, and 32 stents were evaluated. Results Image quality was good to excellent on average （score 1.71±0.76）. Stent image quality score was correlated to heart rate （r=0. 281, P〈0.01） and stent diameter （r=-0.480, P〈0.001）. All the stents were assessable in lumen visibility with an average visible lumen diameter percentage of 60.7%±13.6%. Visible lumen diameter percentage was correlated to heart rate （r=-0.193, P〈0.05）, stent diameter （r=0.403, P〈0.001）, and stent image quality score （r=-0.500, P〈0.001）. Visible lumen diameter percentage also varied depending on the stent type. In comparison with the conventional coronary angiography, 4 of 6 in-stent stenoses were correctly detected. The sensitivity and specificity for the detection of in-stent stenosis were 66.7% and 84.6%, respectively. Conclusions Using a 64-slice CT, the stent lumen is partly visible in most of the stents. And 64-slice CT may be useful in the assessment of stent patency.

Drug-eluting balloons versus new generation drug-eluting stents for the management of in-stent restenosis: an updated meta-analysis of randomized studies

Background New-generation drug-eluting stents (DES) was more effective in the treatment of in-stent restenosis (ISR) compared with the first-generation DES. Drug-eluting balloons (DEB) and new-generation DES had been available strategies in treatment of bare-metal stents/DES ISR (BMS/DES-ISR). Six new randomized trials have recently examined the angiographic outcomes and one-year clinical outcomes of DEB and new generation DES in BMS/DES-ISR. However, the optimal management for BMS/DES-ISR lesions remains controversial. Methods We searched the randomized clinical trials evaluating the angiographic outcomes and one-year clinical outcomes of DEB and new-generation DES in patients with BMS/DES-ISR. The primary endpoints were the angiographic outcomes, including the minimal luminal diameter (MLD), diameter stenosis %(DS%), late lumen loss (LLL), and binary restenosis (BR). Results A total of six randomized clinical trials with 1177 BMS/DES-ISR patients were included in our meta-analysis. For angiographic outcomes, there were significantly less MLD and more DS% with DEB compared to new-generation DES (MLD: MD =?0.18, 95% CI:?0.31– ?0.04, P < 0.001;DS%: MD = 5.68, 95% CI: 1.00–10.37, P < 0.001). Moreover, for one-year clinical outcomes, DEB was associated with a significant increase risk in target lesion revascularization (TLR)(RR = 2.93, 95% CI: 1.50–5.72, P = 0.002). However, DEB was associated with higher risks of major adverse cardiac event, target vessel revascularization, TLR, BR, and more DS% only in DES-ISR group. Conclusions DEB and new-generation DES have the similar clinical efficacy for the treatment of BMS-ISR. However, DES showed more MLD, less DS%, and a decreased risk of TLR for the treatment of DES-ISR.

Recent advances in cardiovascular stent for treatment of in-stent restenosis:Mechanisms and strategies

Treatments of atherogenesis,one of the most common cardiovascular diseases(CVD),are continuously being made thanks to innovation and an increasingly in-depth knowledge of percutaneous transluminal coronary angioplasty(PTCA),the most revolutionary medical procedure used for vascular restoration.Combined with an expanding balloon,vascular stents used at stricture sites enable the long-time restoration of vascular permeability.However,complication after stenting,in-stent restenosis(ISR),hinders the advancement of vascular stents and are associated with high medical costs for patients for decades years.Thus,the development of a high biocompatibility stent with improved safety and efficiency is urgently needed.This review provides an overview of current advances and potential technologies for the modification of stents for better treatment and prevention of ISR.In particular,the mechanisms of in-stent restenosis are investigated and summarized with the aim to comprehensively understanding the pathogenesis of stent complications.Then,according to different therapeutic functions,the current stent modification strategies are reviewed,including polymeric drug eluting stents,biological friendly stents,prohealing stents,and gene stents.Finally,the review provides an outlook of the challenges in the design of stents with optimal properties.Therefore,this review is a valuable and practical guideline for the development of cardiovascular stents.

COMPARISON OF SHORT- AND LONG-TERM OUTCOMES BETWEEN CYPHER AND TAXUS DRUG-ELUTING STENTS FOR IN-STENT RESTENOSIS

Objective To compare the short- and long-term clinical outcomes between sirolimus-eluting stent （ Cypher stent） and paclitaxel-eluting stent （TAXUS stent） in patients with in-stent restenosis （ISR） lesions of the coronary arteries. Methods From December 2002 to March 2005, 253 patients with ISR lesions of the coronary arteries were selected and divided into two groups. Cypher group （152 cases） was treated with Cypher or Cypher Select stents, and TAXUS group （101 cases） with TAXUS stents. A total of 262 ISR lesions in these patients were treated with 308 drog-eluring stents （DESs）, including 176 Cypher or Cypher Select stents and 132 TAXUS stents. All patients were followed up for 10 months. Procedure success rates of DES implantation in both groups were observed. Major adverse cardiac events （MACE） rates in hospital and at 10 months follow-up, as well as in-DES restenosis observed using coronary angiography at follow-up were compared between two groups. Results Success rate of DES implantation was 100% in both groups. No significant difference in MACE rate during hospitalization was found between the two groups. However, at 10 months follow-up, MACE rate was higher in TAXUS group than in Cypher group （ 16.00% vs. 6.67%, P =0. 031 ）. As for coronary angiography at 10 months follow-up, we observed an increasing tendency of in-DES restenosis rate in TAXUS group compared with Cypher group （29.41% vs. 14.04%, P=0.075）. Conclusions Cypher and TAXUS DESs both have good short- and long-term outcomes in treating ISR. Cypher DES proved better long-term clinical outcome than TAXUS DES.

Comparison of the efficacy of drug-eluting balloon for de novo lesions and in-stent restenosis lesions of the femoropopliteal arteries

Objective:To compare the efficacy of drug-eluting balloons for de novo and in-stent restenosis(ISR)for lesions of the femoropopliteal arteries during 12-month follow-up.Materials and methods:A retrospective analysis of 66 patients was performed.These patients had lower extremity atherosclerosis obliterans and were treated with drug-eluting balloons from June 2016 to June 2017.All the lesions were femoropopliteal,including 47 de novo lesions and 19 ISR lesions.Clinical results were followed up at 6 months and 12 months postoperatively.The primary patency rate,target lesion revascularization,Rutherford classification,ankle-brachial index,amputation rate and mortality were compared between the two groups.Results:All the 66 patients underwent the treatment of femoropopliteal artery lesions with unilateral limbs.The surgical success rates were 100%.No adverse events such as acute ischemia or amputation occurred in the hospital.There was no difference between the two groups'Rutherford classification and the ankle-brachial index at the 6-month follow-up(p>0.05).At the 12-month follow-up,the de novo group's Rutherford classification was lower than the ISR group(p=0.026),and the ankle-brachial index of the ISR group was lower(0.66±0.033 vs 0.52±0.056,p=0.036).There was no difference between the patency rate of the de novo group and the ISR group(93.6%vs 84.2%,p=0.229)at the 6-month follow-up.However,the ISR group patency rate was lower at the 12-month follow-up(63.2%vs 85.1%,p=0.048).As for revascularization there was no significant difference between the two groups at the 6-month follow-up(4.2%vs 10.5%,p=0.334),but a higher rate occurred in the ISR group at the 12-month follow-up(26.3%vs 6.4%,p=0.025).There were no significant differences in the mortality or amputation rate between the two groups(p>0.05).Conclusions:Drug-eluting balloons were effective in treating both de novo lesions and ISR lesions in the atherosclerotic femoropopliteal artery,but the 12-month follow-up results of ISR lesions were less favorable than the de novo lesions.

Comparison of the safety and efficacy of two types of drug-eluting balloons （RESTORE DEB and SeQuent Please） in the treatment of coronary in-stent restenosis： study protocol for a randomized controlled trial （RESTORE ISR China）

1 Introduction In-stent restenosis （ISR）, characterized by neointimal proliferation and/or neoatherosclerosis in the vessel of the stent, can cause a reduction in lumen diameter after stent implantation, which can directly induce the recurrence of angina symptoms or an acute coronary syndrome in patients and is usually life-threatening.

Intracoronary brachytherapy for the treatment of recurrent drugeluting stent in-stent restenosis:A systematic review and metaanalysis

BACKGROUND We performed a meta-analysis on observational studies since randomized control trials are not available.We studied intracoronary brachytherapy(ICBT)and recurrent drug eluting stent in-stent restenosis(DES-ISR)to evaluate the procedural success,target lesion revascularization(TLR),incidence of myocardial infarction(MI)and all-cause mortality at 2 years follow-up.AIM To perform meta-analysis for patients undergoing ICBT for recurrent DES-ISR.METHODS We performed a systematic search of the PubMed/MEDLINE,Cochrane and DARE databases to identify relevant articles.Studies were excluded if intracoronary brachytherapy was used as a treatment modality for initial ISR and studies with bare metal stents.We used a random-effect model with DerSimonian&Laird method to calculate summary estimates.Heterogeneity was assessed using I2 statistics.RESULTS A total of 6 observational studies were included in the final analysis.Procedural angiographic success following intra-coronary brachytherapy was 99.8%.Incidence of MI at 1-year was 2%and 4.1%at 2-years,respectively.The incidence of TLR 14.1%at 1-year and 22.7%at 2-years,respectively.All-cause mortality at 1-and 2-year follow-up was 3%and 7.5%,respectively.CONCLUSION Given the observational nature of the studies included in the analysis,heterogeneity was significantly higher for outcomes.While there are no randomized controlled trials or definitive guidelines available for recurrent ISR associated with DES,this analysis suggests that brachytherapy might be the alternative approach for recurrent DES-ISR.Randomized controlled trials are required to confirm results from this study.

Increased serum TREM-1 level is associated with in-stent restenosis,and activation of TREM-1 promotes inflammation,proliferation and migration in vascular smooth muscle cells

Background and Objective In-stent restenosis(ISR)remains a major limitation of percutaneous coronary intervention despite improvements in stent design and pharmacological agents,whereas the mechanism of ISR has not been fully clarified.In the present study,we sought to investigate the potential association of serum soluble TREM-1(sTREM-1)levels with the incidence of ISR.The role of TREM-1 was evaluated in cultured vascular smooth muscle cells(VSMCs).

Finite Element Simulation of In-Stent Restenosis with Tissue Growth Model

In this study, a finite element simulation of in-stent restenosis (ISR) is conducted to simulate the deployment and expansion of a stent in an occluded artery with a contact model and a mechanics-based growth model. A tissue growth model based on the multiplicative decomposition of deformation is applied to investigate the growth of the plaque and artery wall upon the stent’s implantation. Due to the high stresses at the contact points between the stent struts and the tissue, further tissue injury or restenosis is observed. The simulation results show that after the stent deployment, the von Mises stress is significantly larger in the plaque compared to the artery wall, especially in the region that is in contact with the stent. However, the growth of the plaque and artery tends to even out the stress concentration over time. The tissue growth is found to be more significant near the inner wall than the outer layer. A 0.77 mm restenosis is predicted, which agrees with published clinical observations. The features of the artery growth are carefully analyzed, and the underlying mechanism is discussed. This study is the first attempt to apply finite element analysis to artery restenosis, which establishes a framework for predicting ISR’s occurrence and severity. The results also provide insights into understanding the underlying mechanism of in-stent restenosis.

Clinical study about the effect of Simiao Yong'an Decoction on preventing in-stent restenosis and regulating inflammation and oxidative stress after lower extremity stent angioplasty stenting

Objective:To study the effect of Simiao Yong'an Decoction on the prevention of in-stent restenosis and the regulation of inflammation and oxidative stress after lower extremity stent angioplasty.Methods:A prospective study was conducted on 60 ASO patients who underwent lower extremity stent angioplasty in our hospital between January 2014 and January 2018.The patients were randomly divided into observation group receiving postoperative Simiao Yong'an Decoction combined with antiplatelet drug treatment and control group receiving postoperative antiplatelet drug treatment.The conditions of in-stent restenosis were followed up,and the indicators of coagulation,inflammation and oxidative stress were detected.Results:The incidence of in-stent restenosis in observation group 1 year after operation was significantly lower than that in control group;6 months and 12 months after operation,the ankle brachial index(ABI)levels,minimal lumen diameter(MLD)levels at the stent and superoxide dismutase(SOD)contents of observation group were significantly higher than those of control group,whereas D-dimer(D-D)and fibrinogen degradation product(FDP)levels as well as P-selectin,C-reactive protein(CRP),tumor necrosis factor-α(TNF-α),malondialdehyde(MDA)and inducible nitric oxide synthase(iNOS)contents were significantly lower than those of control group.Conclusions:Simiao Yong'an Decoction can prevent the in-stent restenosis and inhibit the inflammation and oxidative stress after lower extremity stent angioplasty.

炎症因子在支架内再狭窄发生发展中的作用

介入治疗术后支架内再狭窄(ISR)是影响远期预后的重要原因之一,而炎症反应在ISR的发生发展中具有重要作用。不同于传统动脉粥样硬化的慢性炎症刺激进程,ISR在数月甚至数年内即可出现急性冠状动脉事件,且ISR的炎症机制更为复杂。炎症因子通过调控经皮冠状动脉介入治疗(PCI)术后单核巨噬细胞增殖分化、内皮细胞损伤修复、泡沫细胞形成、平滑肌细胞增殖迁移等众多机制参与ISR的发生发展。文章简述了ISR的分型及影响因素,着重阐述了不同炎症因子在ISR中的作用,以期为ISR的炎症机制研究及临床干预提供新思路。

支架内新生动脉粥样硬化的研究进展

支架内再狭窄(in-stent restenosis,ISR)和支架内血栓(in-stent thrombosis,IST)是目前经皮冠状动脉介入(percutaneous coronary intervention,PCI)治疗的两大主要并发症,也是阻塞性冠脉病变介入治疗的主要限制因素。支架内新生动脉粥样硬化(in-stent neoatherosclerosis,ISNA)是ISR和IST共同的病理基础,目前研究主要基于光学干涉断层显像(optical coherence tomography,OCT)、血管镜、血管内超声(intravascular ultrasonography,IVUS)等临床影像学观察及尸检报告研究,其具体体机制及治疗手段尚不清楚。全面透彻地理解ISNA的流行病学特征、病理学特征及病因机制不仅有助于预防和治疗支架后并发症,也能为新一代冠脉支架开发奠定基础。该文就ISNA与支架发展史、ISNA病理特征及ISNA病因机制的研究进展进行综述。

冠状动脉支架内再狭窄发生机制的研究进展

经皮冠状动脉介入术是目前治疗冠状动脉粥样硬化性心脏病的主要有效的治疗手段,血管支架尤其是药物洗脱支架极大程度上改善了冠心病患者的疗效和预后。与支架相关的病理主要表现为支架内再狭窄引起的进行性心绞痛和支架内血栓导致的急性心肌梗死。支架内再狭窄是由生物、机械、技术及与患者自身相关的复杂相互作用介导形成的病理性新生内膜增生,有关其发病机制的研究正不断深入。本文通过血管内皮损伤、血管平滑肌细胞增殖迁移、血管外基质重构、炎症反应以及新生动脉内膜粥样硬化等方面对其进行综述,深入探讨其形成的影响因素及临床意义。

下肢动脉粥样硬化闭塞支架术后再狭窄研究进展

下肢动脉硬化闭塞症（ASO）是由动脉粥样硬化引起动脉狭窄、闭塞性疾病。血管内支架成形术作为一种微创、安全及有效的方法,近年来已广泛应用于股腘动脉ASO治疗,但术后支架内再狭窄（ISR）发生率高,严重影响患者临床预后。支架内再狭窄问题依然是支架应用所面临的主要问题。文章对支架置入后再狭窄的发生机制、危险因素及最新的治疗进展做一综述,对支架内再狭窄防治具有一定的意义。