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.

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.

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.

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.

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).

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 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.

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.

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.

Restenosis of a drug eluting stent on the previous bioresorbable vascular scaffold successfully treated with a drug-coated balloon: A case report

BACKGROUND The in-stent restenosis(ISR)rates are reportedly inconsistent despite the increased use of second-generation drug eluting stent(DES).Although bioresorbable vascular scaffold(BVS)have substantial advantages with respect to vascular restoration,the rate of scaffold thrombosis is higher with BVS than with DES.Optimal treatment strategies have not been established for DES-ISR to date.CASE SUMMARY We report on a case of a 60-year-old man patient with acute coronary syndrome.He had a history of ST-segment elevation myocardial infarction associated with very late scaffold thrombosis and treated with a DES.Coronary angiography revealed significant stenosis,suggesting DES-ISR on the previous BVS.Optical coherence tomography(OCT)identified a plaque rupture and a disrupted scaffold strut in the neointimal proliferation of DES.To treat the DES-ISR on the previous BVS,we opted for a drug-coated balloon(DCB)after a balloon angioplasty using a semi-compliant and non-compliant balloon.The patient did not experience adverse cardiovascular events on using a DCB following the use of intensive dual antiplatelet therapy and statin for 24 mo.CONCLUSION This case highlights the importance of OCT as an imaging modality for characterizing the mechanism of target lesion failure.The use of a DCB following the administration of optimal pharmacologic therapy may be an optimal strategy for the treatment and prevention of recurrent BVS thrombosis and DES-ISR.

Clinico-Angiographic Profile and Prevalence of Restenosis in Patients Undergoing Percutaneous Transluminal Coronary Angioplasty to Left Main Coronary Artery: An Observational Cohort Study

Background: Patients who underwent percutaneous coronary intervention in left main coronary artery (LMCA) requires special concern, being high risk and increasing patient population. The aim of this study was to assess the clinical profile, angiographic status, and prevalence of restenosis in patients who underwent percutaneous transluminal coronary angioplasty (PTCA) in LMCA. Materials and Methods: This observational cohort study included 17 patients who underwent PTCA in LMCA during one-year study period at tertiary care centers in Government Medical College, Kozhikode, India. Data including various risk factors, clinical and angiographic details, stent used, procedural complications and outcomes including rate of restenosis were analyzed. Results: A total of 17 patients (mean age 53.88 ± 9.80 years) with 76.47% of males were included in the study. Smoking and hypertension were the most common risk factors presented in 52.94% and 47.06% of patients respectively. Single vessel disease (SVD) of LMCA was the most common pattern observed in 47.10%;the rate of restenosis was observed in 11.76% patients. Revascularization was performed in one patient (5.88%) with coronary artery bypass graft and in one patient (5.88%) with PTCA using drug eluting stent (DES). The overall procedural success was 88.24% in this study. Survival rate was 100% at one-year follow-up period. Conclusion: Our study involved patients who underwent PTCA in LMCA, showed smoking as a most prevalent risk factor for coronary artery disease and SVD as a most common pattern, comparatively low rate of restenosis and 100% of survival rate at one-year follow-up period.

Construction and Analysis of an LncRNA-miRNA-mRNA Network Based on Competitive Endogenous RNA Reveal miRNAs Potentially Involved in In-stent Restenosis after Percutaneous Coronary Intervention

Objective:Percutaneous coronary intervention is one of the most common procedures used for the invasive treatment of patients with coronary heart disease;the incidence of in-stent restenosis(ISR)after percutaneous coronary intervention is 5%to 15%.In this study,a competitive endogenous RNA(ceRNA)network was constructed to investigate potential mechanisms involved in ISR.Methods:The expression data for differentially expressed microRNAs(DEmiRNAs)and messenger RNAs(mRNAs)between patients with and without ISR were obtained using limma package.Long noncoding RNAs(lncRNAs)were predicted based on the DEmiRNAs using the miRDB,miRTarBase,and TargetScan databases.An ISR-specific ceRNA network was subsequently constructed and investigated.To verify the key miRNAs of ceRNA,patients with and without ISR were enrolled from Guangdong Provincial Hospital of Chinese Medicine between January 2017 and December 2018(n=8,respectively);plasma was collected from all enrolled patients.Results:Based on the raw data obtained from the Gene Expression Omnibus database,472 DEmiRNAs and 304 differentilly expressed messenger RNAs between patients with and without ISR were identified.A ceRNA network was constructed by combining 270 IncRNAs,3 miRNAs(miR-125,miR-140,and miR-206),and 4 mRNAs(STRADB,TKT,PCTP,and BTG2).The hub genes of the ceRNA network of ISR included the following:miR-125,miR-206,miR-140,PCDHB9,CASC2,BAK1P1,CSPG4P3Y,CSPG4P4Y,STRCP1,and GRIP2.Verification of miRNAs of ceRNA also showed that the expression of miR-206 was upregulated in patients with ISR vs.those without ISR(P<0.05).In contrast,the expression of miR-140 and miR-125 was downregulated in patients with ISR vs.those without ISR(P<0.05).Conclusions:This study constructed noncoding RNA-related ceRNA networks for ISR.The results indicated that miR-206,miR-125,and miR-140 may be biomarkers of ISR.

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.

A novel mechanism of inhibiting in-stent restenosis with arsenic trioxide drug-eluting stent: Enhancing contractile phenotype of vascular smooth muscle cells via YAP pathway

Objective:Arsenic trioxide(ATO or As2O3)has beneficial effects on suppressing neointimal hyperplasia and restenosis,but the mechanism is still unclear.The goal of this study is to further understand the mechanism of ATO's inhibitory effect on vascular smooth muscle cells(VSMCs).Methods and results:Through in vitro cell culture and in vivo stent implanting into the carotid arteries of rabbit,a synthetic-to-contractile phenotypic transition was induced and the proliferation of VSMCs was inhibited by ATO.F-actin filaments were clustered and the elasticity modulus was increased within the phenotypic modulation of VSMCs induced by ATO in vitro.Meanwhile,Yes-associated protein(YAP)nuclear translocation was inhibited by ATO both in vivo and in vitro.It was found that ROCK inhibitor or YAP inactivator could partially mask the phenotype modulation of ATO on VSMCs.Conclusions:The interaction of YAP with the ROCK pathway through ATO seems to mediate the contractile phenotype of VSMCs.This provides an indication of the clinical therapeutic mechanism for the beneficial bioactive effect of ATO-drug eluting stent(AES)on in-stent restenosis(ISR).

Role of plasma C-reactive protein in predicting in-stent restenosis in patients with stable angina after coronary stenting

Background The role of plasma high sensitivity C-reactive protein （hs-CRP） in in-stent restenosis （ISR） remains controversial. We investigated plasma hs-CRP level at both admission and follow-up in patients with stable angina （SA）after successful coronary stenting in order to clarify the predictive value of hs-CRP for ISR.Methods We summarized 303 consecutive chronic SA patients with coronary drug-eluting stent （DES） implantation.The ISR was analyzed by quantitative coronary analysis （QCA） at a mean follow-up of 8 months, and the patients were divided into two groups according to the detected ISR as ISR group （n=48） and non-ISR group （n=255）. Plasma hs-CRP was examined at both admission and 8-month follow-up in all patients, standard medication continued throughout the investigation period.Results QCA presented that 48 patients （15.8%） suffered from ISR at follow-up. The basic clinical characteristics were similar between the two groups, while plasma hs-CRP was higher in ISR group than that in non-ISR group at both admission and follow-up, P 〈0.001 respectively. Multivariate regression analysis indicated that plasma hs-CRP level at either admission or follow-up could independently predict ISR occurrence （OR=5.581, 95% Cl 2.532-12.302, P〈0.001and OR=6.299, 95% CI 2.722-14.577, P 〈0.001, respectively）.Conclusions Our data indicate that plasma hs-CRP level may independently predict ISR at both admission and follow-up in SA patients with coronary DES implantation, which implies that a chronic, sustained systemic inflammatory response might be involved in ISR pathogenesis.

Inflammation inhibitory effects of sirolimus and paclitaxel-eluting stents on interleukin-1β-induced coronary artery in-stent restenosis in pigs

Background Coronary artery in-stent restenosis （ISR） and late stent thrombosis remain as important complications of stenting. The inflammation reactions to sirolimus and paclitaxel-eluting stents were investigated in a swine stenosis model induced by interleukin （IL）-1β.Methods Mini pigs （n=12; 2-3 months old and weighing 25-30 kg） were subjected to thoracotomy. Segments （10 mm）of the mid left anterior descending coronary artery and left circumflex coronary artery were exposed and aseptically wrapped with a cotton mesh soaked with IL-1β （5 μg）. After 2 weeks, the animals were anesthetized and quantitative coronary arteriography （QCA） was performed. The stenosis sites were randomized into three groups for stent insertion： a sirolimus-eluting stent （SES） group （FirebirdTM, n=7）, a paclitaxel-eluting stent （PES） group （TAXUSTM, n=9）, and a bare-metal stent （BMS） group （YINYITM, Dalian Yinyi Biomaterials Development Co., Ltd, China, n=8）. The three different stents were randomly implanted into stenosis segments. Expression of monocyte chemoattractant protein-1 （MCP-1）, tumor necrosis factor-alpha （TNF-α）, P-selectin and vascular cell adhesion molecule-1 （VCAM-1） was determined by reverse transcription-coupled polymerase chain reaction （RT-PCR）.Results QCA showed severe stenosis in IL-1β treated segments. The SES and PES groups showed lower 1-month angiographic late lumen loss （LLL） within the stent and the lesion compared with BMS （P 〈0.05） by follow-up QCA. The SES showed lower LLL than that of PES in reducing 1-month inflammation lesions in pigs by follow-up QCA （（0.15±0.06）mm vs. （0.33±0.01） mm, P 〈0.0001）. The neointimal hyperplasia areas in SES and PES showed lower than those of BMS （SES （11.6±1.7） mm2, PES （27.2±1.6） mm2 vs. BMS （76.2±1.3） mm2, P 〈0.0001）. The mRNA expression of MCP-1 by RT-PCR in SES and PES showed lower than that of BMS at 30 days after stenting （SES 0.20±0.03, PES 0.48±0.49 vs.BMS 0.58±0.07, P 〈0.05）. Levels of VCAM-1 in SES were significantly lower than those of PES and BMS （SES 0.35±0.08 vs. PES 0.65±0.13, BMS 0.70±0.06, P 〈0.05）. Histochemical immunostaining of vessel walls showed lower inflammatory chemokine MCP-1 expression in the SES and PES groups compared with BMS.Conclusion SESs were superior in reducing 1-month angiographic LLL in inflammation lesions in pigs, strongly suggesting that SESs can suppress inflammatory reactions in ISR at multiple points.