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.

Enhanced caveolin-1 expression in smooth muscle cells: Possible prelude to neointima formation

AIM: To study the genesis of neointima formation in pulmonary hypertension(PH), we investigated the role of caveolin-1 and related proteins. METHODS: Male Sprague Dawley rats were given monocrotaline(M, 40 mg/kg) or subjected to hypobaric hypoxia(H) to induce PH. Another group was given M and subjected to H to accelerate the disease process(M + H). Right ventricular systolic pressure, right ventricular hypertrophy, lung histology for medial hypertrophy and the presence of neointimal lesions were examined at 2 and 4 wk. The expression of caveolin-1 and its regulatory protein peroxisome proliferator-activated receptor(PPAR) γ, caveolin-2, proliferative and antiapoptotic factors(PY-STAT3, p-Erk, Bcl-x L), endothelial nitric oxide synthase(e NOS) and heat shock protein(HSP) 90 in the lungs were analyzed, and the results from M + H group were compared with the controls, M and H groups. Double immunofluorescence technique was used to identify the localization of caveolin-1 in pulmonary arteries in rat lungs and in human PH lung tissue. RESULTS: In the M + H group, PH was more severe compared with M or H group. In the 4 wk M+H group, several arteries with reduced caveolin-1 expression in endothelial layer coupled with an increased expression in smooth muscle cells(SMC), exhibited neointimal lesions. Neointima was present only in the arteries exhibiting enhanced caveolin-1 expression in SMC. Lung tissue obtained from patients with PH also revealed neointimal lesions only in the arteries exhibiting endothelial caveolin-1 loss accompanied by an increased caveolin-1 expression in SMC. Reduction in e NOS and HSP90 expression was present in the M groups(2 and 4 wk), but not in the M + H groups. In both M groups and in the M + H group at 2 wk, endothelial caveolin-1 loss was accompanied by an increase in PPARγ expression. In the M + H group at 4 wk, increase in caveolin-1 expression was accompanied by a reduction in the PPARγ expression. In the H group, there was neither a loss of endothelial caveolin-1, eNOS or HSP 90, nor an increase in SMC caveolin-1 expression; or any alteration in PPARγ expression. Proliferative pathways were activated in all experimental groups. CONCLUSION: Enhanced caveolin-1 expression in SMC follows extensive endothelial caveolin-1 loss with subsequent neointima formation. Increased caveolin-1 expression in SMC, thus, may be a prelude to neointima formation.

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.

ROLE OF ENDOGENOUS CARBON MONOXIDE IN NEOINTIMAL FORMATION INDUCED BY BALLOON-INJURY IN RAT AORTA

Objective.The present study investigated the role of endogenous carbon monoxide(CO)in the pathogenesis of neointimal formation induced by balloon injury in rat. Method.Endothelial denudation of the left common carotid artery of rat was carried out by three passages of a Fogarty 2F balloon catheter.DNA,collagen and elastin contents of each intima media were estimated;and heme oxygenase(HO)activity and CO production in vascular smooth muscle cell(VSMC)were measured after administration of HO inhibitor. Result.Our data showed that neointima occurred in the rat on day 7 and day 21 after balloon injury,and at the same time HO activity and CO production in VSMC were markedly increased Administration of HO inhibitor,zinc deuteroporphyrin 2,4 bisglycol(ZnDPBG),could effectively inhibit HO activity and CO production,significantly enhance neointimal formation(aortic intima/media ratio were 21 4±1 8% vs 17 6±2 0%,P<0 05 on day 7;and 30 5±2 4% vs 23 0±2 2%,P<0 01 on day 21,respectively,compared with balloon alone group). Conclusion.We concluded that 1)inhibition of CO production may enhance neointimal formation induced by endothelial denudation,implying endogenous CO play an protective role in response to vascular injury,and 2)induction of HO activity may be applied clinically for preventing restenosis after angioplasty.

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.

Effect of adenoviral vector-mediated rat antisense AT1B gene transfer on neointima proliferation after rat carotid injury

Objective: Angiotensin Ⅱ is a growth-promoting factor for vascular smooth muscle cells in culture andin the intact animal. The biological effects of angiotensin Ⅱ are manifested only by binding to specific receptors oncell membranes. In the study, we observed that the effect of rat antisense AT1B gene transfer mediated by adenoviral vector-on neointimal proliferation following rat carotid injury. Methods: Antisense AT1B gene was transductedinto the carotid by adenoviral vector after carotid bal1oon injury and the restenosis model was established in SD rat.We measured neointima/media area ratio in local artery at day 21 after gene transfer. Results: Rat antisense AT1Bgene was successfully transducted into local carotid after the carotid balloon injury. Neointima/media area ratiowas significantly reduced (47 %, P<0. 01) at day 21 after gene transfer compared with the control group. Conclusion: The results suggest it is possible that antisense AT1B gene transfer as a potential therapeutic approach prevent neointimal hyperplasia.

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.

Loss of cavin1 and expression of p-caveolin-1 in pulmonary hypertension: Possible role in neointima formation

BACKGROUND Pulmonary hypertension(PH) is a progressive disease with a high morbidity and mortality rate; and neointima formation leads to the irreversibility of the disease.We have previously reported that in rats, monocrotaline(MCT) injection leads to progressive disruption of endothelial cells(EC), and endothelial caveolin-1(cav-1) loss, accompanied by the activation of pro-proliferative pathways leading to PH. Four weeks post-MCT, extensive endothelial cav-1 loss is associated with increased cav-1 expression in smooth muscle cells(SMC). Exposing the MCTtreated rats to hypoxia hastens the disease process; and at 4 wk, neointimal lesions and occlusion of the small arteries are observed.AIM To identify the alterations that occur during the progression of PH that lead to neointima formation.METHODS Male Sprague-Dawley rats(150-175 g) were divided in 4 groups(n = 6-8 per group): controls(C); MCT(M, a single sc injection 40 mg/kg); Hypoxia(H,hypobaric hypoxia); MCT + hypoxia(M+H, MCT-injected rats subjected to hypobaric hypoxia starting on day1). Four weeks later, right ventricular systolic pressure(RVSP), right ventricular hypertrophy(RVH), lung histology, and cav-1 localization using immunofluorescence technique were analyzed. In addition, the expression of cav-1, tyrosine 14 phosphorylated cav-1(p-cav-1), caveolin-2(cav-2), cavin-1, vascular endothelial cadherin(VE-Cad) and p-ERK1/2 in the lungs were examined, and the results were compared with the controls.RESULTSSignificant PH and right ventricular hypertrophy were present in M and H groups [RVSP, mmHg, M 54±5~*, H 45±2~*, vs C 20±1, P < 0.05; RVH, RV/LV ratio M 0.57±0.02~*, H 0.50±0.03~*, vs C 0.23±0.007, P < 0.05]; with a further increase in M+H group [RVSP 69±9 mmHg, RV/LV 0.59±0.01 P < 0.05 vs M and H]. All experimental groups revealed medial hypertrophy; but only M+H group exhibited small occluded arteries and neointimal lesions. Immunofluorescence studies revealed endothelial cav-1 loss and increased cav-1 expression in SMC in M group; however, the total cav-1 level in the lungs remained low. In the M+H group, significant endothelial cav-1 loss was associated with increasing expression of cav-1 in SMC; resulting in near normalization of cav-1 levels in the lungs [cav-1, expressed as % control, C 100±0, M 22±4~*, H 96±7, M+H 77±6, ~* = P< 0.05 vs C]. The expression of p-cav-1 was observed in M and M+H groups [M314±4%, M+H 255±22% P < 0.05 vs C]. Significant loss of cav-2 [% control, C100±0, M 15±1.4~*, H 97±7, M+H 15±2~*; M and M+H vs C, ~* = P < 0.05], cavin-1 [%control, C 100±0, M 20±3~*, H 117±7, M+H 20±4~*; M and M+H vs C, P < 0.05] and VE-Cad [% control, C 100±0, M 17±4~*, H 96±9, M+H 8±3~*; M and M+H vs C, P <0.05] was present in M and M+H groups, confirming extensive disruption of EC.Hypoxia alone did not alter the expression of cav-1 or cav-1 related proteins.Expression of p-ERK1/2 was increased in all 3 PH groups [%control, C 100±0, M284±23~*, H 254±25~*, M+H 270±17~*; ~* = P < 0.05 vs C].CONCLUSION Both cavin-1 loss and p-cav-1 expression are known to facilitate cell migration;thus, these alterations may in part play a role in neointima formation in PH.

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.

A Polymer Coated Cicaprost-Eluting Stent Increases Neointima Formation and Impairs Vessel Function in the Rabbit Iliac Artery

Drug-eluting stents have been successful in reducing in-stent restenosis but are not suitable for all lesion types and have been implicated in causing late stent thrombosis due to incomplete regeneration of the endothelial cell layer. In this study we implanted stents coated with cicaprost, a prostacyclin analogue with a long plasma half-life and antiproliferative effects on vascular smooth muscle cells, into the iliac arteries of rabbits. At 28-day follow-up we compared neointima formation within the stented vessels and vascular function in adjacent vessels, to assess if cicaprost could reduce restenosis without impairing vessel function. Arteries implanted with cicaprost eluting stents had significantly more neointima compared to bare metal stents. In adjacent segments of artery, endothelium-dependent relaxation was impaired by the cicaprost-eluting stent but vasodilation to an endothelium-independent vasodilator was maintained. We conclude that the presence of the polymer and sub-optimal release of cicaprost from the stent may be responsible for the increased neointma and impaired functional recovery of the endothelium observed. Further experiments should be aimed at optimising release of cicaprost and exploring different stent polymer coatings.

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.

Endoplasmic Reticulum Stress-induced Endothelial Dysfunction Promotes Neointima Formation after Arteriovenous Grafts in Mice on High-fat Diet

Objective Endothelial dysfunction is one candidate for triggering neointima formation after arteriovenous grafts(AVGs),but the factors mediating this process are unclear.The purpose of this study was to investigate the role of endoplasmic reticulum stress(ERS)-induced endothelial dysfunction in neointima formation following AVGs in high-fat diet(HFD)mice.Methods CCAAT-enhancer-binding protein-homologous protein(CHOP)knockout(KO)mice were created.Mice were fed with HFD to produce HFD model.AVGs model were applied in the groups of WT ND,WT HFD,and CHOP KO HFD.Human umbilical vein endothelial cells(HUVECs)were cultured with oxidized low density lipoprotein(ox-LDL)(40 mg/L)for the indicated time lengths(0,6,12,24 h).ERS inhibitor tauroursodeoxycholic acid(TUDCA)was used to block ERS.Immunohistochemical staining was used to observe the changes of ICAM1.Changes of ERS were detected by real-time RT-PCR.Protein expression levels and ERS activation were detected by Western blotting.Endothellial cell function was determined by endothelial permeability assay and transendothelial migration assay.Results HFD increased neointima formation in AVGs associated with endothelial dysfunction.At the same time,ERS was increased in endothelial cells(ECs)after AVGs in mice consuming the HFD.In vitro,ox-LDL was found to stimulate ERS,increase the permeability of the EC monolayer,and cause endothelial dysfunction.Blocking ERS with TUDCA or CHOP siRNA reversed the EC dysfunction caused by ox-LDL.In vivo,knockout of CHOP(CHOP KO)protected the function of ECs and decreased neointima formation after AVGs in HFD mice.Conclusion Inhibiting ERS in ECs could improve the function of AVGs.

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.

ROLE OF ANTISENSE AND DECOY OLIGONUCLEOTIDE OF NF-κB IN VESSEL STENOSIS AND NEOINTIMA FORMATION IN BALLOON-INJURED RAT ARTERY

Objective To examine antisense and decoy oligonucleotides of nuclear factor kappa B in vivo effects on intima proliferation and balloon-injured monocytes chemotactic protein-1 （ MCP-1 ） and extraceUular signal regulated kinase-2 （ERK2） κexpression in the carotid artery of rats. Methods Sprague-Dawley rats underwent balloon-dilation injury of the left carotid artery. Rats are divided into 7 groups （ n = 18 ） and each group includes6 time points （6 h, 1, 3, 5, 7, 14 d） （n =3）. Uninjured right carotid artery of the same rat was used as controls. Results In model group, sense group and scramble group, vessel intima area , media area and intima/media ratio increased after 5 d and reached the maximum after 7 d. The effect of antisense plus decoy group on intimal hyperplasia was more obvious than that of antisense group and decoy group alone. MCP-1 mRNA expression was increased expression continuously at 3, 5 and 7 d and decreased at 14 d. Compared with model group, sense group and scramble group, antisense group, decoy group and antisense plus decoy group had lowered MCP-1 mRNA expression in each time point （ P 〈 0. 05 ）. NF-KB p65 was dispersed positive stain 6 h after injury and increased after 1 d and peaked at 7 d, but the protein expression was weak at 14 d. ERK2 protein synthesis increased at I d and reached the peak at 7 d, while protein expression after 14 d was similar to that at 7 d. Treatment of antisense group, decoy group and antisense plus decoy group inhibited protein synthesis more significantly than those of model group, sense group and scramble group（ P 〈 0. 05）. Conclusion NF-KB modulates genes expression and protein synthesis of MCP-1 and ERK2. Celluar proliferation in vessel wall was dynamically changed after balloon angioplasty injury. Antisense and decoy oligonucleotide of NF-KB by local lipofectaraine transfer inhibit NF-KB activating gene modulation and neointimal hyperplasia.