Circulating monocytes and in-stent neointima after coronary stent implantation

OBJECTIVES: The aim of this study was to investigate the relationship between circulating monocytes and in-stent neointimal volume at six-month follow-up. BACKGROUND: In-stent neointimal hyperplasia is the main contributing factor to in-stent restenosis. There is increasing evidence that white blood cells (WBCs), especially monocytes, play a central role in restenosis after stent implantation. METHODS: We performed coronary stent implantation in 107 patients (107 lesions). Peripheral blood was obtained from all patients immediately before coronary angiography and every day for seven days after the intervention, and each WBC fraction count was analyzed. At scheduled six-month follow-up, all patients received angiographic and volumetric intravascular ultrasound analysis. RESULTS: The circulating monocyte count increased and reached its peak two days after stent implantation (from 350 +/- 167 to 515 +/- 149/mm3, p < 0.01). The maximum monocyte count after stent implantation showed a significant positive correlation with in-stent neointimal volume at six-month follow-up (r = 0.44, p < 0.0001). Other fractions showed neither significant serial changes nor a correlation with in-stent neointimal volume. Multiple regression analysis revealed that in-stent neointimal volume was independently correlated with stent volume immediately after implantation (r = 0.45, p < 0.0001) and maximum monocyte count (r = 0.35, p < 0.001). Angiographic restenosis, defined as percent diameter stenosis >50%, was observed in 22 patients (21%), and these patients showed a significantly larger maximum monocyte count than patients without restenosis (642 +/- 110 vs. 529 +/- 77/mm3, p < 0.01). CONCLUSIONS: Circulating monocytes increased after coronary stent implantation, and the peak monocyte count related to in-stent neointimal volume. Our results suggest that circulating monocytes play a role in the process of in-stent neointimal hyperplasia.     

Thiazolidinedione treatment attenuates diffuse neointimal hyperplasia in restenotic lesions after coronary stent implantation in type 2 diabetic patients: an intravascular ultrasound study

OBJECTIVES: Thiazolidinedione treatment reduces neointimal tissue proliferation after coronary stent implantation in diabetic patients. However, in-stent restenosis still persists in patients treated with thiazolidinedione. The effect of thiazolidinedione treatment on the pattern of in-stent restenosis remains unclear. This study investigated whether thiazolidinedione treatment attenuates diffuse neointimal hyperplasia in restenotic lesions after coronary stent implantation in diabetic patients. METHODS: Volumetric intravascular ultrasound was performed at 6 months after coronary stent implantation in 76 patients with restenotic lesions who received either conventional anti-diabetic treatment (control group, n = 56) or thiazolidinedione treatment (thiazolidinedione group, n = 20). RESULTS: There were no significant differences between the two groups in stent volume (99 +/- 32 vs 90 +/- 20 mm3, respectively, p = 0.26) or in minimal lumen area in the stent (1.4 +/- 0.6 vs 1.6 +/- 0.5 mm2, respectively, p = 0.11). However, there were significant reductions in neointimal volume (56 +/- 25 vs 36 +/- 11 mm3, respectively, p < 0.01)and neointimal index (56 +/- 11% vs 41 +/- 8%, respectively, p < 0.01) in the thiazolidinedione group. Coefficient of variation of neointimal tissue accumulation was greater in the thiazolidinedione group (45.5%) than in the control group (25.2%). CONCLUSIONS: Intravascular ultrasound study demonstrated that together with reduction of overall neointimal tissue proliferation, thiazolidinedione treatment caused greater point-to-point heterogeneity in the neointimal tissue accumulation in restenotic lesions after coronary stent implantation. This finding strongly suggests that thiazolidinedione treatment attenuates diffuse in-stent restenosis in diabetic patients.     

Mechanisms of acute lumen gain and recurrent restenosis after rotational atherectomy of diffuse in-stent restenosis: a quantitative angiographic and intravascular ultrasound study.

OBJECTIVES: This quantitative angiographic and intravascular ultrasound study determined the mechanisms of acute lumen enlargement and recurrent restenosis after rotational atherectomy (RA) with adjunct percutaneous transluminal coronary angioplasty in the treatment of diffuse in-stent restenosis (ISR). BACKGROUND: In-stent restenosis remains a significant clinical problem for which optimal treatment is under debate. Rotational atherectomy has become an alternative therapeutic approach for the treatment of diffuse ISR based on the concept of "tissue-debulking." METHODS: Rotational atherectomy with adjunct angioplasty of ISR was used in 45 patients with diffuse lesions. Quantitative coronary angiographic (QCA) analysis and sequential intravascular ultrasound (IVUS) measurements were performed in all patients. Forty patients (89%) underwent angiographic six-month follow-up. RESULTS: Rotational atherectomy lead to a decrease in maximal area of stenosis from 80+/-32% before intervention to 54+/-21% after RA (p < 0.0001) as a result of a significant decrease in intimal hyperplasia cross-sectional area (CSA). The minimal lumen diameter after RA remained 15+/-4% smaller than the burr diameter used, indicating acute neointimal recoil. Additional angioplasty led to a further decrease in area of stenosis to 38+/-12% due to a significant increase in stent CSA. At six-month angiographic follow-up, recurrent restenosis rate was 45%. Lesion and stent length, preinterventional diameter stenosis and amount of acute neointimal recoil were associated with a higher rate of recurrent restenosis. CONCLUSIONS: Rotational atherectomy of ISR leads to acute lumen gain by effective plaque removal. Adjunct angioplasty results in additional lumen gain by further stent expansion and tissue extrusion. Stent and lesion length, severity of ISR and acute neointimal recoil are predictors of recurrent restenosis.     

The effect of paclitaxel-eluting stents on restenosis]

OBJECTIVE: In our study we aimed to investigate the effects of paclitaxel-eluting stent on restenosis. METHODS: Sixteen porcine were randomly assigned to two groups (n=8 per group): control group animals received conventional stent implantation and study group animals -paclitaxel-eluting stent implantation. Both groups were treated with 300 mg acetylsalicylic acid and 75 mg clopidogrel daily. The degree of neointimal proliferation and effect of drug-eluting stent on restenosis were evaluated 6 weeks after by angiography and intravascular ultrasound (IVUS). RESULTS: Angiographic in-stent restenosis was lower in paclitaxel-eluting stent group (12.50 +/- 7.07% versus 41.25 +/- 28.50%, p=0.001). The IVUS data demonstrated that paclitaxel group animals had larger minimal lumen area (8.76 +/- 1.09 mm2 versus 6.23 +/- 3.10 mm2, p=0.028), smaller mean neointimal proliferation area (1.03 +/- 0.75 mm2 versus 3.55 +/- 2.86 mm2, p=0.01) and mean percent stenosis (10.71 +/- 8.10% versus 36.85 +/- 30.93%, p=0.01). CONCLUSION: This study suggests that drug-eluting stents may also have a preventive effect for the in-stent restenosis.     

Saline infusion via local drug delivery catheters is associated with increased neointimal hyperplasia in a porcine coronary in-stent restenosis model

BACKGROUND: Catheter-based local drug delivery at the site of stent implantation has been proposed to reduce in-stent restenosis. We examined whether local delivery itself may cause additional vessel wall injury and negate the potential benefit of local drug delivery in a porcine coronary in-stent restenosis model. METHODS: Pigs were randomly assigned to no local delivery (controls, n = 10) or local saline infusion (5 ml) using commercially available catheters (n = 39; Dispatch catheter, Microporous Infusion catheter, and InfusaSleeve) prior to oversized (stent:artery ratio 1.2) coronary stent implantation. The amount of in-stent neointima was evaluated 4 weeks later with angiography and histology. RESULTS: There was no difference in vessel size or stent: artery ratio. However, at follow-up the local saline delivery group had significantly greater diameter stenosis (50 +/- 19% versus 25 +/- 17% in the controls, P < 0.01). Histology revealed similar injury scores but significantly greater neointimal area in the local saline group (3.61 +/- 1.11 mm2 versus 1.96 +/- 0.82 mm2 in the controls, P < 0.01). In a multivariate linear regression analysis, the use of the local delivery catheter was the only independent variable which was positively correlated with the amount of neointima (P = 0.0001). CONCLUSIONS: In this in-stent restenosis model, catheter-based local saline delivery was associated with significantly increased neointimal hyperplasia. Thus, for local drug delivery to reduce in-stent restenosis, the antiproliferative agent should be potent enough to compensate for the additional neointimal hyperplasia from the infusion itself.     

Comparison between sirolimus-eluting stents and intracoronary catheter-based beta radiation for the treatment of in-stent restenosis

We report the outcomes of patients who had in-stent restenosis (IRS) that was treated with intravascular brachytherapy (IVBT) or sirolimus-eluting stent (SES) implantation. The benefit of IVBT for treating ISR is well documented. SES implantation decreases first-time ISR and, in preliminary reports, has been used to treat ISR. Fifty consecutive patients who had ISR were treated; the first 25 patients underwent SES implantation and the next 25 patients were treated with IVBT using a beta-Cath System (a 40-mm strontium-90/yttrium-90 source). Quantitative angiographic and intravascular ultrasound follow-up were performed at 5.2 +/- 1.1 and 12.1 +/- 1.2 months; clinical follow-up was performed at 15 months. SES deployment and IVBT were successful in all patients. At 12-month follow-up, 8 patients who underwent IVBT had angiographic recurrence (4 in the stent and 4 at the stent edge); only 1 patient who underwent SES implantation developed recurrent ISR. At 12 months, in-stent late luminal loss was similar between the SES and IVBT groups (0.35 +/- 0.45 vs 0.34 +/- 0.46 mm, p = 0.9); however, in-stent net luminal gain was higher in the SES group than in the IVBT group (1.32 +/- 0.13 vs 0.57 +/- 0.19 mm, p <0.0001), and in-lesion late luminal loss was higher in the IVBT group (0.48 +/- 0.32 vs 0.16 +/- 0.42 mm, p = 0.004). At 12 months, intravascular ultrasound stent volume obstruction was higher after IVBT versus than after SES implantation (38.7% vs 6.7%, p <0.0001). At 15-month clinical follow-up, 64% and 96% (p <0.01) of patients who underwent IVBT and SES implantation, respectively, were free of major adverse cardiac events. In conclusion SES implantation for the treatment of ISR was effective and superior to catheter-based IVBT in preventing recurrent neointimal proliferation and angiographic restenosis at 1-year follow-up.     

Presence of bone-marrow- and neural-crest-derived cells in intimal hyperplasia at the time of clinical in-stent restenosis

OBJECTIVE: Intralesional data of coronary target lesions following stent implantation are infrequent. In addition, there is ongoing controversy on the origin of neointimal cells. In this respect, several lines of evidence revealed bone-marrow-derived endothelial progenitor and dendritic cells (DCs) as well as neural-crest-derived cells (NCCs) to contribute to atherosclerosis. Therefore, the objective of the present study was to assess cellularity, cell type and origin of neointimal cells in in-stent restenosis (ISR). METHODS: Atherectomy specimens from 17 patients with coronary in-stent restenosis (n=10; time post-stenting 5+/-3 months) and with peripheral in-stent restenosis (n=7; 7+/-3 months) versus those from 10 patients with primary lesions were immunohistochemically examined for the presence of the determinants CD34, AC133, S100, glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), nerve growth factor receptor (NGFR) and alpha-smooth muscle actin followed by computer-assisted morphometry. RESULTS: In-stent restenosis probes consistently demonstrated homogeneous hypercellularity (942+/-318 cells/mm(2)) compared to de novo lesions (347+/-120 cells/mm(2), P<0.001). alpha-smooth muscle actin positive cells occupied 67% of intimal cells in in-stent restenosis. As a key finding, expression of endothelial progenitor cells (CD34: 7.1+/-2.5% positive/total cells vs. 0.6+/-0.7%, P<0.001; AC133: 7.0+/-3.4% vs. 1.0+/-0.7%, P<0.001), dendritic cells (S100: 9.8+/-5.6% vs. 1.4+/-1.1%, P<0.001) and neural-crest-derived cells (GFAP: 7.9+/-2.4% vs. 3.1+/-1.0%; NSE: 4.4+/-2.6% vs. 1.3+/-1.6%; NGFR: 4.2+/-2.5% vs. 1.1+/-0.7%; each P<0.001) was significantly increased in in-stent restenosis compared to primary lesions. CONCLUSIONS: Bone-marrow- and neural-crest-derived cells, the most dendritic cells, are consistently present in in-stent restenosis, whereas alpha-smooth muscle actin positive cells constitute the largest intimal cell pool. Our data suggest the recruitment of primarily extravascular cells within neointima formation in human in-stent restenosis.     

Neointimal expression of rapamycin receptor FK506-binding protein FKBP12: postinjury animal and human in-stent restenosis tissue characteristics

Despite excellent clinical results for sirolimus (rapamycin)-eluting stents, the exact mechanisms of antirestenotic activity and affected cellular targets are incompletely understood. Therefore, we determined the presence and tem- porospatial expression pattern of FKBP12, the primary intracellular receptor of rapamycin, in rat carotid arteries after balloon injury, as well as in human in-stent restenosis and primary stable coronary atheroma. FKBP12 expression was assessed by immunohistochemistry. Rat carotid arteries revealed maximal expression in 57.7 +/- 4.0% of neointimal cells at day 7. A large proportion of these FKBP12+ cells showed luminally confined co-expression with dendritic cell markers. Despite a considerably thicker neointima at day 28, presence of FKBP12 decreased (8.5 +/- 1.9%, p = 0.02) with a scattered pattern in luminal and deep neointima. Likewise, human in-stent restenosis atherectomy specimens (time after stent implantation 2-12 months) revealed a comparable extent of cellular rapamycin receptor expression (9.3 +/- 1.0%) that significantly differed from that found in primary stable atheroma (1.3 +/- 0.4%, p < 0.001). In conclusion, the rapamycin receptor is predominantly present during early neointima formation, while mature neointimal atheromas show a relatively low expression without confinement to luminal areas. Co-expression of FKBP12 and dendritic cell markers suggests that dendritic cells may be another important target for early and long-term rapamycin effects.     

Polymer-based paclitaxel-eluting stents reduce in-stent neointimal tissue proliferation: a serial volumetric intravascular ultrasound analysis from the TAXUS-IV trial

OBJECTIVES: The aim of this study was to use serial volumetric intravascular ultrasound (IVUS) to evaluate the effects of polymer-based, paclitaxel-eluting stents on in-stent neointima formation and late incomplete stent apposition. BACKGROUND: The TAXUS-IV trial demonstrated that the slow-release, polymer-based, paclitaxel-eluting stent reduces angiographic restenosis and the need for repeat revascularization procedures. Serial IVUS studies reveal details of the pattern of vascular responses provoked by stent implantation that provide insight into device safety and efficacy. METHODS: In the TAXUS-IV trial, patients were randomized to the slow-release, polymer-based, paclitaxel-eluting TAXUS stent or a bare-metal EXPRESS stent (Boston Scientific Corp., Natick, Massachusetts). As part of a formal substudy, complete volumetric IVUS data were available in 170 patients, including 88 TAXUS patients and 82 controls, at implantation and at nine-month follow-up. RESULTS: No baseline differences were present in the clinical characteristics or IVUS parameters between the control and TAXUS groups. At nine-month follow-up, IVUS lumen volumes were larger in the TAXUS group (123 +/- 43 mm(3) vs. 104 +/- 44 mm(3), p = 0.005), due to a reduction in neointimal volume (18 +/- 18 mm(3) vs. 41 +/- 23 mm(3), p < 0.001). Millimeter-by-millimeter analysis within the stent demonstrated uniform suppression of neointimal growth along the entire stent length. Late lumen loss was similar at the proximal edge of the stent between the two groups, and reduced with the TAXUS stent at the distal edge (p = 0.004). Incomplete stent apposition at nine months was observed in only 3.0% of control and 4.0% of TAXUS stents (p = 0.12). CONCLUSIONS: Polymer-based, paclitaxel-eluting TAXUS stents are effective in inhibiting neointimal tissue proliferation, and do not result in late incomplete stent apposition.     

An intravascular ultrasound analysis of the mechanisms of restenosis comparing drug-eluting stents with brachytherapy

There are treatment failures after de novo drug-eluting stent (DES) implantation and after treatment with DESs or vascular brachytherapy (VBT) of in-stent restenosis (ISR) lesions. We studied 38 patients who presented with DES failure (26 patients after de novo DES implantation and 12 patients after DES treatment of ISR) and 30 patients who presented with VBT failure (all after treatment of ISR). Standard clinical data were collected and volumetric intravascular ultrasound was measured. Patients who presented with DES failures were 58.8 +/- 9.6 years of age and those who presented with VBT failures were 59.8 +/- 8.7 years of age; 60.5% of DES and 58.6% of VBT failures were in men; 31.5% of DES failures and 46.6% of VBT failures occurred in diabetic patients; and times to presentation were 210 +/- 101 days in DES failures and 510 +/- 527 days in VBT failures (p = 0.001). Minimal stent area was significantly larger in VBT than in the 2 DES failure groups (de novo DES implantation and DES treatment of ISR, p <0.0001); this was associated with more neointimal hyperplasia in VBT failures (p <0.0001). After it was normalized to stent length, intimal hyperplasia was diffusely distributed in VBT failures; conversely, DES failures were associated with less intimal hyperplasia and the intimal hyperplasia was mostly focal, with greater accumulation in the proximal and mid segments. In conclusion, VBT failures were caused by significant, recurrent, and diffuse intimal hyperplasia in the setting of adequate stent expansion, whereas DES failures were caused by only modest, but focal, intimal hyperplasia in the setting of DES underexpansion.     

Tyrphostin AGL-2043 eluting stent reduces neointima formation in porcine coronary arteries

OBJECTIVE: Tyrphostin AGL-2043 is a potent tricyclic quinoxaline inhibitor of PDGF beta-receptor tyrosine kinase (PTK), Kit, and Flt3. We have shown previously that selective inhibition of PDGF beta-receptor PTK by tyrphostins markedly reduces SMC proliferation and migration in vitro, reduces neointima formation in balloon-injured porcine femoral arteries, and reduces neointimal stenosis in stented porcine coronary arteries when administered intramurally within biodegradable nanoparticles. The present study was designed to determine the effect of AGL-2043 delivered from a stent-based, biodegradable polymeric coating on neointima formation in the porcine coronary artery model. METHODS AND RESULTS: Stents coated with biodegradable, polylactic/glycolic acid (PLGA) polymer, with (n=13) or without (n=11) 180 mcg AGL-2043 were implanted into the proximal LAD of 24 Sinclair mini-pigs (34+/-4 kg) to achieve a 1.1:1 stent/artery diameter ratio. The delivery of drug from stent to tissue was confirmed by high-performance liquid chromatography. After 28 days, histomorphometric analysis showed that in-stent stenosis in animals treated with AGL-2043 was reduced by 50% (51+/-21% versus 26+/-10%, p=0.001), the absolute neointimal area was reduced by 44% (2.38+/-1.04 versus 1.31+/-0.43 mm(2), p=0.004), and the absolute luminal area was increased by 57% (2.19+/-1.09 versus 3.39+/-0.59 mm(2), p=0.003). There were no significant differences between control and AGL-2043 in injury score (1.24+/-0.11 vs. 1.15+/-0.12, p=0.07) or inflammation score (1.19+/-0.35 vs. 1.07+/-0.33, p=0.41). Moreover, the difference in % in-stent stenosis between control and treated animals remained highly significant even after normalizing the % stenosis to the degree of injury (p=0.0008) or to the inflammation score (p=0.001). Mortality for this study was zero. Tissue concentration in segments 1 cm proximal and distal to the stents, were negligible or zero at 1 h, 24 h, and 4 weeks after stent implantation. CONCLUSION: Stent-based delivery of tyrphostin AGL-2043 from a biodegradable polymeric coating reduces in-stent neointimal hyperplasia in porcine coronary arteries by 50% after 28 days and preserves lumen area. Long-term studies should be the next step in testing applicability to the human interventional setting.     

Predictors of diffuse-type in-stent restenosis after coronary stent implantation

Diffuse-type in-stent restenosis (ISR) is associated with higher rate of restenosis after balloon angioplasty, requiring new therapeutic modalities; therefore, it is clinically important to identify the determinants of diffuse-type ISR. We evaluate the clinical and angiographic variables to predict diffuse-type ISR after coronary stent placement. Two hundred and ten ISR lesions in 196 patients (diffuse ISR, 114 lesions; focal ISR, 96 lesions) were reviewed in this study. Clinical, procedural and quantitative coronary angiographic parameters were analyzed. Diffuse-type ISR was defined as a ≥50% lumen narrowing and ≥10-mm length. Univariate analysis revealed that initial lesion length, smaller vessel size, diabetes, multivessel disease, multiple stents, and long stent were significantly associated with diffuse-type ISR. However, diabetes was the only independent predictor of diffuse-type ISR by stepwise multiple regression analysis (OR, 3.3; 95% CI, 1.4–7.4, P = 0.001). Diabetes was associated with diffuse-type ISR after coronary stent placement. It may reflect enhanced rate of neointimal hyperplasia within the stent in diabetic patients. Cathet. Cardiovasc. Intervent. 47:406–409, 1999. © 1999 Wiley-Liss, Inc.     

长链非编码RNA牛磺酸上调基因1与冠状动脉支架内再狭窄的相关性

目的:探讨长链非编码RNA(LncRNA)牛磺酸上调基因1(TUG1)在冠状动脉(冠脉)支架内再狭窄(ISR)患者外周血中的表达水平,研究TUG1对支架内再狭窄的诊断价值。方法:选取2019年5月-2021年6月于济宁医学院附属医院心内科住院且既往置入过冠脉支架的患者,入院复查冠脉造影评估冠脉支架是否狭窄,根据冠脉造影结果分为支架内再狭窄(ISR)组(26例)和支架内非狭窄(N-ISR)组(26例)。首先收集患者外周血,用单核细胞分离液提取单核细胞,从上述细胞中提取RNA,然后采用实时荧光定量聚合酶链式反应(qRT-PCR)法检测LncRNA TUG1表达水平;采用多因素logistic回归分析研究ISR患者的独立危险因素,采用受试者工作特征曲线(ROC曲线)来评估TUG1对ISR的诊断价值。结果:ISR组TUG1表达量高于N-ISR组[(0.1982±0.2276)∶(0.0704±0.0869),P<0.05],差异有统计学意义。多因素logistic回归分析表明,TUG1为ISR的独立危险因素(OR=1.934,95%CI1.017~3.677,P=0.044)。TUG1的ROC曲线下面积为0.703,灵敏度为65.4%,特异度为73.1%。结论:ISR组患者TUG1的表达水平增高。高表达的TUG1是ISR的独立危险因素,TUG1可能是预测经皮冠脉介入治疗术后发生ISR的新型生物标志物。     

The relationship between preprocedural platelet size and subsequent in-stent restenosis

OBJECTIVE: Elevated mean platelet volume predicts restenosis after percutaneous transluminal coronary angioplasty but its effect on the development of in-stent restenosis is not known. We assessed the effect of mean platelet volume measured before coronary stent implantation for stable angina pectoris on subsequent development of in-stent restenosis. METHODS AND RESULTS: We retrospectively analysed the data of 60 patients who had stent implantation on one native coronary artery for stable angina pectoris and control angiographies for clinically suspected restenosis within 6 months. Mean platelet volume was measured by auto analyzer one day before stent implantation. Clinical and demographic data and laboratory results were obtained from the hospital charts of the patients. In-stent restenosis was evaluated visually from control angiograms. Angiographic in-stent restenosis was present in 35 (58%) of 60 patients and 25 (42%) patients had no restenosis. Mean platelet volume in the in-stent restenosis group was 8.28 +/- 0.71 fl compared to 7.63 +/- 0.74 fl in the no-restenosis group (p = 0.001). There was a positive correlation between preprocedural mean platelet volume and development of in-stent restenosis (r = 0.44; p < 0.001). A mean platelet volume value of > or = 8.4 fl was associated with an odds ratio of 16.0 for development of in-stent restenosis, with high specificity and positive predictivity but poor sensitivity and negative predictivity (96%, 93%, 40% and 53%, respectively). CONCLUSIONS: Mean platelet volume measured before stent implantation is correlated with subsequent development of in-stent restenosis. If preprocedural mean platelet volume is greater than 8.4 fl, in-stent restenosis is more probable to occur.     

Chest pain after coronary artery stent implantation

A sizeable proportion of patients who undergo successful coronary artery stent implantation experiences chest pain immediately after the procedure and/or in the following months in the absence of in-stent restenosis. We investigated this phenomenon in 57 consecutive patients with stable angina who underwent successful stent implantation. Chest pain characteristics were assessed before stent implantation and during 6-month follow-up. All patients underwent coronary angiography within 6 months of the procedure 48 hours after exercise thallium-201 perfusion scintigraphy. Patients who did not exhibit in-stent restenosis underwent an ergonovine test at the end of routine coronary angiography. During follow-up, 15 patients complained of chest pain. Six of these patients exhibited scintigraphic evidence of myocardial ischemia and in-stent restenosis at angiography. In the remaining 9 patients, chest pain occurred in the absence of in-stent restenosis at angiography. In 8 of these patients intracoronary ergonovine administration reproduced their habitual pain, whereas it did not cause any pain in the 42 patients who were completely asymptomatic at follow-up and without in-stent restenosis. Ergonovine caused more intense vasoconstriction and nitroglycerin caused more intense vasodilation of the reference coronary diameter in patients with than in patients without ergonovine-induced pain (-17 +/- 3 vs -9 +/- 3%, p <0.001; 9 +/- 6 vs 5 +/- 4%, p <0.02, respectively). In conclusion, chest pain with features similar to habitual angina occurs in the absence of in-stent restenosis in 1/5 of patients after stent implantation and appears to be associated with more intense coronary vasoreactivity.     

长链非编码RNA牛磺酸上调基因1与冠状动脉支架内再狭窄的相关性

目的:探讨长链非编码RNA(LncRNA)牛磺酸上调基因1(TUG1)在冠状动脉(冠脉)支架内再狭窄(ISR)患者外周血中的表达水平,研究TUG1对支架内再狭窄的诊断价值。方法:选取2019年5月-2021年6月于济宁医学院附属医院心内科住院且既往置入过冠脉支架的患者,入院复查冠脉造影评估冠脉支架是否狭窄,根据冠脉造影结果分为支架内再狭窄(ISR)组(26例)和支架内非狭窄(N-ISR)组(26例)。首先收集患者外周血,用单核细胞分离液提取单核细胞,从上述细胞中提取RNA,然后采用实时荧光定量聚合酶链式反应(qRT-PCR)法检测LncRNA TUG1表达水平;采用多因素logistic回归分析研究ISR患者的独立危险因素,采用受试者工作特征曲线(ROC曲线)来评估TUG1对ISR的诊断价值。结果:ISR组TUG1表达量高于N-ISR组[(0.1982±0.2276)∶(0.0704±0.0869),P<0.05],差异有统计学意义。多因素logistic回归分析表明,TUG1为ISR的独立危险因素(OR=1.934,95%CI1.017~3.677,P=0.044)。TUG1的ROC曲线下面积为0.703,灵敏度为65.4%,特异度为73.1%。结论:ISR组患者TUG1的表达水平增高。高表达的TUG1是ISR的独立危险因素,TUG1可能是预测经皮冠脉介入治疗术后发生ISR的新型生物标志物。     

A randomized comparison of repeat stenting with balloon angioplasty in patients with in-stent restenosis

OBJECTIVES: This randomized trial compared repeat stenting with balloon angioplasty (BA) in patients with in-stent restenosis (ISR). BACKGROUND: Stent restenosis constitutes a therapeutic challenge. Repeat coronary interventions are currently used in this setting, but the recurrence risk remains high. METHODS: We randomly assigned 450 patients with ISR to elective stent implantation (224 patients) or conventional BA (226 patients). Primary end point was recurrent restenosis rate at six months. Secondary end points included minimal lumen diameter (MLD), prespecified subgroup analyses, and a composite of major adverse events. RESULTS: Procedural success was similar in both groups, but in-hospital complications were more frequent in the balloon group. After the procedure MLD was larger in the stent group (2.77 +/- 0.4 vs. 2.25 +/- 0.5 mm, p < 0.001). At follow-up, MLD was larger after stenting when the in-lesion site was considered (1.69 +/- 0.8 vs. 1.54 +/- 0.7 mm, p = 0.046). However, the binary restenosis rate (38% stent group, 39% balloon group) was similar with the two strategies. One-year event-free survival (follow-up 100%) was also similar in both groups (77% stent vs. 71% balloon, p = 0.19). Nevertheless, in the prespecified subgroup of patients with large vessels (> or =3 mm) the restenosis rate (27% vs. 49%, p = 0.007) and the event-free survival (84% vs. 62%, p = 0.002) were better after repeat stenting. CONCLUSIONS: In patients with ISR, repeat coronary stenting provided better initial angiographic results but failed to improve restenosis rate and clinical outcome when compared with BA. However, in patients with large vessels coronary stenting improved the long-term clinical and angiographic outcome.     

Eosinophilic infiltration in restenotic tissue following coronary stent implantation

OBJECTIVES: The aim of our study was to compare the histopathological features of restenotic tissue after balloon angioplasty and after stent placement. We emphasized on specific types of inflammatory cells to evaluate the type of tissue immune response in both situations. METHODS: A total of 32 patients underwent elective directional coronary atherectomy; 16 patients had restenosis after balloon angioplasty, 16 patients had in-stent restenosis (ISR). Atherectomy specimens were stained with antibodies against T cells, eosinophils, smooth muscle cell actin, macrophages and with antibodies against T cell activation markers. Quantitative morphometric analysis was performed using image analysis software. RESULTS: In-stent restenotic tissue contained more smooth muscle cells (P < 0.001), anti-CD3 positive T cells (P < 0.001) and eosinophils (P = 0.012). Anti-CD40L positive activated T cells were more numerous in ISR lesions (P = 0.003) and were frequently clustered around stent imprints in the tissue. Five ISR specimens contained grossly visible stent fragments amidst the restenotic tissue. In all cases of balloon restenosis, T cells and eosinophils (if present) were concentrated around lipid rich tissue. CONCLUSIONS: Our study indicates involvement of inflammatory responses in both types of restenosis, with significantly more eosinophils encountered in case of in-stent restenosis. In contrast with clustering of inflammatory cells around stent struts after stent placement, the inflammatory cells in balloon restenosis were located in association with lipid rich tissue, suggesting different inflammatory triggers in balloon restenosis and in-stent restenosis.     

Impact of preinterventional arterial remodeling on in-stent neointimal hyperplasia and in-stent restenosis after coronary stent implantation.

BACKGROUND: Patterns of arterial remodeling during the course of plaque development have been shown to play an important role in both the progression of de novo atherosclerosis and in the restenotic process following coronary intervention. The aim of the present prospective study was to evaluate the effect of pre-interventional arterial remodeling on in-stent neointimal hyperplasia (NIH) and in-stent restenosis (ISR) after stenting. METHODS AND RESULTS: Pre-interventional arterial remodeling was assessed in 85 native coronary lesions by using intravascular ultrasound (IVUS). The remodeling index (RI) was 1.09+/-0.20 in the positive remodeling (PR)/intermediate remodeling (IR) group and 0.84+/-0.12 in the negative remodeling (NR) group. The plaque plus media cross sectional area (P&M CSA) at pre-intervention and NIH CSA at follow-up in the minimal lumen CSA were significantly larger in the PR/IR group (9.2+/-2.9 mm2 vs 6.2+/-1.8 mm2, 3.3+/-1.2 mm2 vs 1.5+/-0.9 mm2; p = 0.001, p = 0.001, respectively). On 3-dimensional analysis of IVUS images at follow-up, the lumen volume was significantly smaller in the PR/IR group than that in the NR group (62+/-15 mm3 vs 75 +/-20 mm3; p = 0.001), and neointima hyperplasia volume was significantly larger in the PR/IR group than that in the NR group (46+/-15 mm3 vs 26+/-10 mm3; p = 0.001). A significant positive correlation was found between pre-interventional RI and follow-up NIH CSA (r = 0.25, p = 0.022). The incidence of ISR and repeat intervention was significantly higher in the PR/IR group (30.8% vs 18.2%, 28.8% vs 15.2%; p = 0.032, 0.035, respectively). CONCLUSION: Measuring pre-interventional arterial remodeling patterns by IVUS may be helpful to stratify lesions at high-risk of ISR.     

Therapeutic implications of in-stent restenosis located at the stent edge. Insights from the restenosis intra-stent balloon angioplasty versus elective stenting (RIBS) randomized trial.

AIMS: In patients with in-stent restenosis (ISR) several anatomic subgroups have been identified. ISR affecting the stent edge (EDG) is a poorly characterised subgroup with undefined therapeutic implications. We sought to determine the implications of ISR affecting the stent EDG. METHODS AND RESULTS: 450 patients included in the "Restenosis Intra-stent: Balloon angioplasty vs elective Stenting" (RIBS) randomized study, were analysed. EDG ISR was predefined in the protocol and the pattern of ISR analysed in a centralized core-lab. Fifty-two patients (12%) had EDG ISR (29 stent group, 23 balloon arm). Patients with EDG ISR had less severe [minimal lumen diameter (MLD) (0.78+/-0.3 vs 0.66+/-0.3 mm, p=0.05)] and shorter lesions (lesion length 10.2+/-6 vs 13.2+/-7 mm, p=0.003). Patients with EDG ISR more frequently required crossover (12% vs 3%, p=0.006) but eventually the immediate angiographic result and the long-term clinical and angiographic outcome was similar to that found in patients without EDG ISR. Patients with EDG ISR treated in the balloon and stent arms had similar baseline characteristics. However, after intervention, the immediate angiographic result was better in the stent arm (MLD 2.79+/-0.4 vs 2.35+/-0.3 mm, p=0.001). This difference persisted at late follow-up: MLD (1.93+/-0.7 vs 1.39+/-0.7 mm, p=0.01), recurrent restenosis (20% vs 50%, p=0.03). In addition, the 1-year event-free survival was significantly better (83% vs 52%, log rank p=0.01; Cox HR 0.28, 95%CI 0.09-0.79) in the stent arm. Moreover, stent implantation was an independent predictor of freedom from target vessel revascularization (HR 0.15, 95%CI 0.03-0.67, p=0.003). CONCLUSIONS: EDG ISR constitutes a specific subgroup with relevant therapeutic implications. In patients with EDG ISR, repeat stent implantation provides better clinical and angiographic outcome than conventional balloon angioplasty.