The association between the triglyceride-glucose index and in-stent restenosis in patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis.

BACKGROUND: Insulin resistance (IR) can lead to cellular metabolic disorders, activation of oxidative stress, and endothelial dysfunction, contributing to in-stent restenosis (ISR). The triglyceride-glucose index (TyG index), a new indicator reflecting IR, is extensively researched in the cardiovascular field. This study, through a meta-analysis, aimed to utilize a larger combined sample size and thereby enhance the overall test efficacy to explore the TyG index-ISR relationship. METHODS: A thorough search was conducted in the PubMed, EMBASE, Web of Science, and Cochrane Library databases to find original papers and their references published between 1990 and January 2024. This search included both prospective and retrospective studies detailing the correlation between the TyG index and ISR in individuals with coronary heart disease (CHD). OUTCOMES: The five included articles comprised 3,912 participants, and the odds ratio (OR) extracted from each study was combined using the Inverse Variance method. Results showed that, in the context of CHD patients, each incremental unit in the TyG index, when treated as a continuous variable, corresponded to a 42% elevation in ISR risk (95% CI 1.26-1.59, I²=13%, p < 0.005). When analyzing the TyG index categorically, the results revealed a higher ISR risk in the highest TyG index group compared to the lowest group (OR: 1.69, 95% CI 1.32-2.17, I²=0). Additionally, in patients with chronic coronary syndrome (CCS), each unit increase in the TyG index, the risk of ISR in patients increased by 37% (95% CI 1.19-1.57, I²=0%, p < 0.005). This correlation was also observable in acute coronary syndrome (ACS) patients (OR:1.48, 95% CI 1.19-1.85, I²=0, p < 0.005). CONCLUSIONS: The TyG index, an economical and precise surrogate for IR, is significantly linked with ISR. Furthermore, this correlation is unaffected by the type of coronary heart disease.

Identification of key molecular markers of acute coronary syndrome using peripheral blood transcriptome sequencing analysis and mRNA-lncRNA co-expression network construction.

Acute coronary syndrome (ACS) is a term used to describe major cardiovascular diseases, and treatment of in-stent restenosis in patients with ACS remains a major clinical challenge. Further investigation into molecular markers of ACS may aid early diagnosis, and the treatment of ACS and post-treatment recurrence. In the present study, total RNA was extracted from the peripheral blood samples of 3 patients with ACS, 3 patients with percutaneous coronary intervention (PCI)_non-restenosis, 3 patients with PCI_restenosis and 3 healthy controls. Subsequently, RNA library construction and high-throughput sequencing were performed. DESeq2 package in R was used to screen genes that were differentially expressed between the different samples. Moreover, the intersection of the differentially expressed mRNAs (DEmRNAs) and differentially expressed long noncoding RNAs (DElncRNAs) obtained. GeneCodis4.0 was used to perform function enrichment for DEmRNAs, and lncRNA-mRNA co-expression network was constructed. The GSE60993 dataset was utilized for diagnostic analysis, and the aforementioned investigations were verified using in vitro studies. Results of the present study revealed a large number of DEmRNAs and DElncRNAs in the different groups. We selected genes in the top 10 of differential expression and also involved in the co-expression of lncRNA-mRNA for diagnostic analysis in the GSE60993 dataset. The area under curve (AUC) of PDZK1IP1 (0.747), PROK2 (0.769) and LAMP3 (0.725) were all >0.7. These results indicated that the identified mRNAs and lncRNAs may act as potential clinical biomarkers, and more specifically, PDZK1IP1, PROK2 and LAMP3 may act as potential biomarkers for the diagnosis of ACS.

Roles of MicroRNAs in Peripheral Artery In-Stent Restenosis after Endovascular Treatment.

Endovascular repair including percutaneous transluminal angioplasty (PTA) and stent implantation has become the standard approach for the treatment of peripheral arterial disease; however, restenosis is still the main limited complication for the long-term success of the endovascular repair. Endothelial denudation and regeneration, inflammatory response, and neointimal hyperplasia are major pathological processes occurring during in-stent restenosis (ISR). MicroRNAs exhibit great potential in regulating several vascular biological events in different cell types and have been identified as novel therapeutic targets as well as biomarkers for ISR prevention. This review summarized recent experimental and clinical studies on the role of miRNAs in ISR modification, with the aim of unraveling the underlying mechanism and potential therapeutic strategy of ISR.

Blood biomarkers of progressive atherosclerosis and restenosis after stenting of symptomatic intracranial artery stenosis.

In-stent restenosis (ISR) represents a major complication after stenting of intracranial artery stenosis (ICAS). Biomarkers derived from routine blood sampling including C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and mean platelet volume (MPV) have been associated with progressive atherosclerosis. We investigated the role of CRP, NLR, PLR and MPV on the development of intracranial ISR and recurrent stroke risk. We retrospectively included all patients who had undergone stenting of symptomatic ICAS at our university hospital between 2005 and 2016. ISR (≥ 50% stenosis) was diagnosed by regular Duplex sonography follow-up studies and confirmed by digital subtraction angiography or computed tomography angiography (mean follow-up duration: 5 years). Laboratory parameters were documented before stenting, at the time of restenosis and at last clinical follow-up. Of 115 patients (mean age: 73 ± 13 years; female: 34%), 38 (33%) developed ISR. The assessed laboratory parameters did not differ between patients with ISR and those without (p > 0.1). While ISR was associated with the occurrence of recurrent ischemic stroke (p = 0.003), CRP, NLR, PLR and MPV were not predictive of such events (p > 0.1). Investigated blood biomarkers of progressive atherosclerosis were not predictive for the occurrence of ISR or recurrent ischemic stroke after ICAS stenting during a 5-year follow-up.

Triglyceride-glucose index is associated with in-stent restenosis in patients with acute coronary syndrome after percutaneous coronary intervention with drug-eluting stents.

BACKGROUND: The triglyceride-glucose (TyG) index is an alternative marker of insulin resistance (IR) and is closely associated with the prevalence and prognosis of atherosclerotic cardiovascular disease (ASCVD). However, the association between the TyG index and in-stent restenosis (ISR) after drug-eluting stent (DES) implantation in patients with acute coronary syndrome (ACS) remains unknown. METHODS: The present study retrospectively recruited patients who were admitted for ACS and underwent coronary angiography at 6 to 24 months after successful DES-based percutaneous coronary intervention (PCI). In addition, we calculated the TyG index with the following formula: Ln(fasting triglyceride [mg/dL] × fasting blood glucose [mg/dL]/2) and divided patients into 3 groups according to the tertile of the TyG index. Most importantly, multivariate logistic regression analysis models were also constructed to assess the association between the TyG index and DES-ISR in patients with ACS. RESULTS: A total of 1574 patients with ACS (58.4 ± 9.4 years, 77.4% male) were included in this study. At the median follow-up time of 12 (9-14) months, the prevalence of DES-ISR increased stepwise with the increasing tertile of the TyG index (11.6% vs 17.3% vs 19.4%, p = 0.002), and the TyG index was also higher in the ISR group than in the non-ISR group (9.00 ± 0.58 vs 8.84 ± 0.61, p < 0.001). In addition, the positive association between the TyG index and the prevalence of DES-ISR was also determined in the fully adjusted model (TyG, per 1-unit increase: OR 1.424, 95% CI 1.116 to 1.818, p = 0.005; tertile of TyG, the OR (95% CI) values for tertile 2 and tertile 3 were 1.454 (1.013 to 2.087) and 1.634 (1.125 to 2.374), respectively, with tertile 1 as a reference). The association was also reflected in most subgroups. Moreover, adding the TyG index to the predictive model for DES-ISR in patients with ACS could contribute to an increase in C-statistics (0.675 vs 0.659, p = 0.010), categorical net reclassification improvement (0.090, p < 0.001), and integrated discrimination improvement (0.004, p = 0.040). CONCLUSION: An elevated TyG index was independently and positively associated with DES-ISR in patients with ACS who underwent PCI. However, the incremental predictive value of the TyG index for DES-ISR was slight. To further confirm our findings, future studies are needed.

Differentially expressed miR-152, a potential biomarker for in-stent restenosis (ISR) in peripheral blood mononuclear cells (PBMCs) of coronary artery disease (CAD) patients.

BACKGROUND AND AIMS: In-stent restenosis (ISR) remains the most daunting challenge of current treatments of coronary artery disease (CAD). MicroRNAs (miRNAs) are prominent regulators of key pathological processes leading to restenosis and used as diagnostic tools in different studies. miR-152 and miR-148a are implicated to contribute in the putative intracellular mechanisms of ISR. The aim of present study is to investigate the potential early-stage diagnostic role of miR-152 and miR-148a expression levels for ISR in peripheral blood mononuclear cells (PBMCs) of patients who underwent stent implantation. METHODS AND RESULTS: The miRNAs that are supposed to be involved in the ISR were nominated by bioinformatics approach mainly using miRWalk3. Then by quantitative real-time PCR, we determined the relative expression of miR-152 and miR-148a of PBMCs from ISR patients with their age/sex-matched controls. RESULTS: The presence of ISR significantly coincided with a decrease in the relative expression of miR-152. The area under the curve (AUC) for miR-152 receiver operating characteristic (ROC) curve was 0.717 (95% CI; 0.60-0.83) with a sensitivity of 70% and a specificity of 67%, suggesting that the miRNA expression level might be employed to identify patients at risk of ISR. CONCLUSIONS: To the best of our knowledge, this is the first work to show that the miR-152 expression level can possibly be applied to predict CAD patients at risk of ISR. The results suggest that the expression levels of miR-152 in PBMCs may serve as a biomarker for ISR. Our finding suggests the importance of miRNA levels in PBMCs as a novel biological tool to detect diseases in their early clinical stages.

Predictive value of inflammatory factors on coronary restenosis after percutaneous coronary intervention in patients with coronary heart disease: A protocol for systematic review and meta-analysis.

BACKGROUND: Evidence reveals that inflammatory factors can predict coronary restenosis in patients suffering from coronary heart disease (CHD) after percutaneous coronary intervention (PCI). Perhaps, inflammatory factors are promising biomarkers for the diagnosis of coronary restenosis after PCI. However, the accuracy of inflammatory factors has not been systematically evaluated. Therefore, it is necessary to perform a meta-analysis to certify the diagnostic values of inflammatory factors on coronary restenosis after PCI. METHODS: China National Knowledge Infrastructure (CNKI), Wanfang, VIP, China Biology Medicine disc (CBM), PubMed, EMBASE, Cochrane Library and Web of Science were searched for relevant studies to explore the potential diagnostic values of inflammatory factors on coronary restenosis after PCI from inception to January 2021. All data were extracted by 2 experienced researchers independently. The risk of bias about the meta-analysis was confirmed by the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). The data extracted were synthesized and heterogeneity was investigated as well. All of the above statistical analyses were carried out with Stata 16.0. RESULTS: The results of this meta-analysis will be submitted to a peer-reviewed journal for publication. CONCLUSION: This study clarified confusions about the specificity and sensitivity of inflammatory factors on coronary restenosis after PCI, thus further guiding their promotion and application. ETHICS AND DISSEMINATION: Ethical approval will not be necessary since this systematic review and meta-analysis will not contain any private information of participants or violate their human rights. TRIAL REGISTRATION NUMBER: DOI 10.17605/OSF.IO/N28JX.

Circulating level of microRNA-142-5p is a potential biomarker for predicting in-stent restenosis: a case-control study.

BACKGROUND: Patients who receive percutaneous coronary intervention (PCI) have different chances of developing in-stent restenosis (ISR). To date, no predictable biomarker can be applied in the clinic. MicroRNAs (miRNAs or miRs) play critical roles in transcription regulation, and their circulating levels were reported to have potential as clinical biomarkers. METHODS: In total, 93 coronary stent-implanted patients without pregnancy, liver or renal dysfunction, malignancy, hemophilia, or autoimmune diseases were recruited in this clinical study. All recruited participants were divided into an ISR group (n = 45) and a non-ISR group (n = 48) based on their restenotic status as confirmed by cardiologists at the first follow-up visit (6 months after surgery). Blood samples of all participants were harvested to measure circulating levels of miRNA candidates (miR-132, miR-142-5p, miR-15b, miR-24-2, and miR-424) to evaluate whether these circulating miRNAs can be applied as predictive biomarkers of ISR. RESULTS: Our data indicated that circulating levels of miR-142-5p were significantly higher in the ISR population, and results from the receiver operating characteristic (ROC) curve analysis also demonstrated superior discriminatory ability of miR-142-5p in predicting patients' restenotic status. In addition, circulating levels of miR-15b, miR-24-2, and miR-424 had differential expressions in participants with diabetes, hyperlipidemia, and hypertension, respectively. CONCLUSIONS: The current study revealed that the circulating level of miR-142-5p has potential application as a clinical biomarker for predicting the development of ISR in stent-implanted patients.

Predictive value of LncRNA on coronary restenosis after percutaneous coronary intervention in patients with coronary heart disease: A protocol for systematic review and meta-analysis.

BACKGROUND: Evidence shows that long-stranded non-coding RNA (LncRNA) can predict coronary artery restenosis in patients suffering from coronary heart disease after percutaneous coronary intervention, suggesting that LncRNA may become a promising biomarker for the diagnosis of coronary artery restenosis after percutaneous coronary intervention. However, its accuracy has not been systematically evaluated. Therefore, it is necessary to perform meta-analysis to certify the diagnostic value of LncRNA on coronary artery restenosis after percutaneous coronary intervention. METHODS: PubMed, EMBASE, Cochrane Library, and Web of Science were searched for relevant studies to explore the potential diagnostic values of LncRNA on coronary artery restenosis after percutaneous coronary intervention from inception to December 2020. Data were extracted by two experienced researchers independently. The risk of bias about the meta-analysis was confirmed by the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). Data was synthesized and heterogeneity was investigated as well. All of the above statistical analysis was carried out with Stata 14.0. RESULTS: This study proved the pooled diagnostic performance of LncRNA on coronary artery restenosis after percutaneous coronary intervention. CONCLUSION: This study clarified confusions about the specificity and sensitivity of LncRNA on coronary artery restenosis after percutaneous coronary intervention, thus further guiding their promotion and application. ETHICS AND DISSEMINATION: Ethical approval is not required for this study. The systematic review will be published in a peer-reviewed journal, presented at conferences, and shared on social media platforms. This review would be disseminated in a peer-reviewed journal or conference presentations. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/4QT2P.

Characteristics of recurrent in-stent restenosis after second- and third-generation drug-eluting stent implantation.

BACKGROUND: In second- and third-generation drug-eluting stent (DES) era, in-stent restenosis (ISR) is not commonly seen. However, a few patients still need repeat revascularizations for recurrent ISR even after second- and third-generation DES implantation. METHODS: From January 2012 to March 2017, 2339 lesions underwent second- and third-generation DES (Nobori, Promus Element, Resolute Integrity, Xience, Ultimaster and Synergy) implantation, of which 95 lesions (4.1%) underwent revascularization for first ISR. All lesions were divided into two groups of recurrent ISR group and non-recurrent ISR group. After successful optical coherence tomography (OCT) guided revascularization for all lesions, we investigated characteristics of recurrent ISR, and 2 years follow-up were completed. RESULTS: The mean age was 70.8 ± 11.7 years, and 73.2% were males. Among 56 DES-ISR lesions which were assessed by OCT, recurrent ISR was seen in 33.9% (N = 19) at 2 years follow-up after revascularization for first ISR. Serum low-density lipoprotein-cholesterol (LDL-C) level was higher in recurrent ISR group compared with non-recurrent ISR group (114.1 ± 53.9 mg/dl vs. 90.9 ± 27.8 mg/dl, P = 0.04) and heterogeneous tissue pattern was more frequently found in recurrent ISR group compared with non-recurrent ISR group (63.2% vs. 27.0%, P = 0.03). Multivariate analysis identified a heterogeneous tissue pattern (odds ratio 3.71; 95% confidence interval 1.09-12.59; P = 0.03) as an independent predictor of recurrent restenosis. CONCLUSION: Recurrent ISR of second- and third-generation DES was associated with heterogeneous tissue pattern of first ISR, and high LDL-C level was associated with recurrence.

High low-density lipoprotein cholesterol as an independent risk factor for coronary restenosis in hemodialysis patients undergoing percutaneous coronary interventions.

HD patients have been reported to have a higher risk of restenosis after percutaneous coronary intervention (PCI). The aim of this study was to investigate the risk factors of coronary restenosis in HD patients. We enrolled 54 HD patients (mean age: 66.5 ± 10.1 years; 72.2% men; mean HD duration: 3.7 years), who received PCI and follow-up coronary angiography. Of the patients, 22 (40.7%) had restenosis within 3 to 12 months of PCI. Univariate logistic analysis showed low-density lipoprotein cholesterol (LDL-C)/high-density lipoprotein cholesterol (HDL-C) ratio, LDL-C, non-HDL-C, and history of major adverse cardiovascular events were significantly associated with coronary restenosis (OR]: 1.89, 1.27, 1.22, and 5.79, respectively). Multivariate analysis showed that LDL-C was significantly associated with coronary restenosis (OR: 1.43). These data suggest that LDL-C is an independent risk factor for coronary restenosis in HD patients undergoing PCI, and strict lipid management may be required.

Biomarkers of platelet activation and cardiovascular risk in the DAPT trial.

Prolonged use of dual antiplatelet therapy (DAPT) post-percutaneous coronary intervention (PCI) has been shown to reduce the risk of major adverse cardiovascular events (MACE), but with increased bleeding. It remains unknown whether biomarkers of platelet activation may be useful for identifying patients at increased risk of MACE. The DAPT study was a randomized trial of 12 versus 30 months of DAPT in patients who underwent PCI. Serum biomarkers [myeloid-related protein (MRP)-8/14, P-selectin, soluble CD-40 ligand (sCD40L)] were assessed in 1399 patients early post-PCI. On-treatment platelet reactivity index (PRI) using VASP phosphorylation was assessed in 443 patients randomized to continued DAPT at 1 year. MACE was defined as CV death, MI, or ischemic stroke. Multivariable models were adjusted for baseline characteristics, index event, and stent type. A stepwise increase in the risk of MACE was observed with increasing tertiles of both MRP-8/14 and P-selectin (p-trend = 0.04 for both). After multivariable adjustment, the adjusted HR (95% CI) for MACE in patients in the top tertile was 1.94 (1.14-3.30) for MRP-8/14 and 1.62 (0.99-2.64) for P-selectin. In contrast, baseline sCD40L was not associated with CV risk. Among patients randomized to continued DAPT, higher on-treatment platelet reactivity was not significantly associated with risk of MACE (p-trend = 0.32; adj-HR T3 vs. T1 1.54, 95% CI 0.20-12.18) or bleeding (P-trend = 0.17; adj-HR 0.25, 95% CI 0.05-1.21). MRP-8/14 and soluble P-selectin may be useful for identifying patients at increased risk of MACE after PCI. The utility of on-treatment platelet function testing requires further study.Clinical Trial Registration https://www.clinicaltrials.gov . Unique identifier NCT00977938.

Circulating microRNA-21 as Stable Blood-Based Markers for Patients With ISR After PCI.

It recently has been reported that the in-stent restenosis (ISR) of expanded area after percutaneous coronary intervention (PCI) within six months can become a serious postoperative complication. A real-time quantitative PCR was used to analyze the expression of serum miR-21 in 33 ISR and 37 non-ISR patients after PCI. Expression of miR-21 was significantly higher in the ISR group compared with that in the NISR group, and a similar trend also occurred in factor- (TNF-α) level, Interleukin -6 (IL-6) level, and plaque area (PLA). However, a contrary trend occurred in the external elastic membrane area (EEM) and minimal lumen area (MLA). This study suggests that the increased expression of serum miR-21 is related to ISR after PCI, and miR-21 can be a new predictor of ISR.

Circulating miRNA-23b and miRNA-143 Are Potential Biomarkers for In-Stent Restenosis.

In-stent restenosis (ISR) is one of the main complications in patients undergoing percutaneous coronary angioplasty, and microRNAs participate in the contractile-to-synthetic phenotypic switch of vascular smooth muscle cells, a hallmark of restenosis development. MicroRNAs (miRNAs) can be released into circulation from injured tissues, enticing a potential role as noninvasive biomarkers. We aimed to evaluate circulating levels of miRNA-23b, miRNA-143, and miRNA-145 as diagnostic markers of ISR. 142 patients with coronary artery disease undergoing successful angioplasty and a follow-up angiography were included. Subjects were classified according to the degree of obstruction at the angioplasty site into cases (≥50%) or controls (<50%). Total RNA was isolated from plasma to quantify circulating miRNAs levels, and the ROC curves were constructed. Among circulating miRNAs assessed, miRNA-23b and miRNA-143 were significantly lower in cases (miRNA-23b: 18.4x10-5 and miRNA-143: 13.7x10-5) than controls (miRNA-23b: 5.2x10-5, p < 0.0001; miRNA-143: 4.0x10-5, p < 0.0001). Plasma levels of miRNA-145 showed no significant differences. The analysis of the ROC curves showed an area under the curve for miRNA-23b of 0.71 (95% CI: 0.62-0.80, p < 0.0001) and 0.69 for miRNA-143 (95% CI: 0.60-0.78; p < 0.0001). Our data suggest that plasma levels of miRNA-23b and miRNA-143 could be useful as noninvasive biomarkers of ISR.

miR-18a-5p Promotes Proliferation and Migration of Vascular Smooth Muscle Cells by Activating the AKT/Extracellular Regulated Protein Kinases (ERK) Signaling Pathway.

BACKGROUND microRNAs (miRNAs) play important roles in abnormal proliferation and migration of vascular smooth muscle cells (VSMCs), which lead to restenosis in coronary artery disease. Nevertheless, the role of miR-18a-5p and how it works in VSMCs remain unknown. MATERIAL AND METHODS miR-18a-5p expression was determined by fluorescence quantitative real-time polymerase chain reaction (qRT-PCR) analysis of tissues from 20 patients with stent restenosis, and rats with carotid artery injury, as well as VSMCs. A cell viability assay was used to measure cell proliferation. Cell migration abilities were assessed by transwell migration assay and wound healing assays. To identify miR-18a-5p targets, a dual-luciferase reporter assay was performed. Western blot analysis and immunofluorescence techniques were used to assess the protein expression levels of AKT and ERK. The rescue effects of miR-18a-5p on the proliferation or migration of VSMCs were evaluated after exposure to the AKT inhibitor MK-2206 and ERK inhibitor PD98059. RESULTS The expression level of miR-18a-5p was significantly higher in the blood serum of patients with stent restenosis and in rats with carotid artery injury, and the expression of AKT and ERK was higher after carotid artery injury. The proliferation and migration abilities of VSMCs were accelerated by the overexpression of miR-18a-5p. It was found that miR-18a-5p directly modulates AKT/ERK signaling. Upregulated miR-18a-5p increased the protein expression levels of AKT and ERK and we found a positive correlation between miR-18a-5p expression level and expression of AKT and ERK. Additionally, the promoting effect of miR-18a-5p on VSMCs proliferation, migration, and invasion was reversed by ERK inhibitor or AKT inhibitor. CONCLUSIONS miR-18a-5p can promote proliferation of VSMCs by activating the AKT/ERK signaling pathway.

The relationship between fibrinogen-to-albumin ratio and in-stent restenosis in patients with coronary artery disease undergoing drug-eluting stenting.

BACKGROUND: In-stent restenosis (ISR) remains a significant clinical problem in patients with coronary artery disease (CAD) treated with percutaneous coronary intervention (PCI). Recent studies identified the fibrinogen-to-albumin ratio (FAR) as a novel inflammatory marker to predict inflammation in chronic diseases. This study aimed to investigate the relationship between FAR and ISR in patients with DES implantation. METHODS: A total of 506 consecutive CAD patients were enrolled. Subjects history of successful native vessel PCI with DES at least 12 months prior to undergoing repeat angiography for chest pain. Patients were divided between ISR group (n = 125) and no-ISR group (n = 381). ISR was defined as luminal stenosis ≥50% located within the stent or up to 5 mm beyond the stent edges by the quantitative coronary analysis. Laboratory parameters were measured before angiography. Significant factors associated with ISR were evaluated by multivariate logistic regression analysis. RESULTS: Baseline characteristics were similar between the ISR and no-ISR groups. The ISR group had significantly higher FAR level compared with the no-ISR group (73.26 ± 17.68 vs. 64.90 ± 15.88, P < 0.05). Furthermore, the ISR group had significantly lower albumin level and higher prevalence of diabetes mellitus compared to no-ISR (P < 0.05). In a multivariate analysis, FAR (odds ratio [OR] = 1.039, 95% confidence interval (CI) = 1.024-1.054), albumin (OR = 0.923, 95% CI = 0.389-0.977) and diabetes mellitus (OR = 2.663, 95% CI = 1.587-4.468) were significantly associated with ISR. CONCLUSION: FAR is significantly associated with the development of ISR in CAD patients undergoing PCI with DES implantation.

Osteoprotegerin promotes intimal hyperplasia and contributes to in-stent restenosis: Role of an αVß3/FAK dependent YAP pathway.

OBJECTIVE: Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are related to in-stent-restenosis (ISR) following percutaneous coronary intervention (PCI). Osteoprotegerin (OPG) has been implicated in various vascular diseases. However, the effects of OPG on ISR and the underlying mechanism remained elusive. We here investigated the association between OPG and ISR, and to demonstrate the role and potential mechanisms of OPG in neointimal hyperplasia. APPROACH AND RESULTS: From 2962 patients who received coronary angiography and follow-up coronary angiography at approximately one year, 291 patients were diagnosed with ISR, and another 291 gender- and age- matched patients without ISR were selected as controls. Serum OPG levels were significantly increased in patients with ISR. Multivariable logistic regression analysis indicated that OPG level was independently associated with the increased risk of ISR. In a mouse femoral artery wire injury model, upregulated OPG was evidenced in vascular tissue after injury. OPG deletion attenuated the vascular injury-induced neointimal hyperplasia and related gene expression in mice. OPG promoted neointimal hyperplasia and human aortic smooth muscle cell (hASMC) proliferation and migration through activation of yes-associated protein (YAP), a major downstream effector of the Hippo signaling pathway, whereas knockdown or inhibition of YAP in hASMCs blunted OPG-induced above effects. Moreover, we found that OPG, as a ligand for integrin αVß3, mediated phosphorylation of focal adhesion kinase (FAK) and actin cytoskeleton reorganization, resulting in YAP dephosphorylation in hASMCs. OPG-dependent YAP and VSMC activation was prevented by treatment with αVß3-blocking antibodies and inhibitors of FAK and actin stress fibers. CONCLUSIONS: Increased serum OPG levels are associated with increased risk of ISR following PCI and OPG could promote neointimal hyperplasia in response to injury through integrin αVß3 mediated FAK and YAP activation, indicating OPG/YAP inhibition might serve as an attractive novel target for the prevention of ISR after PCI.

Potential of circulating pro-angiogenic microRNA expressions as biomarkers for rapid angiographic stenotic progression and restenosis risks in coronary artery disease patients underwent percutaneous coronary intervention.

BACKGROUND: This study aimed to investigate the correlation of pro-angiogenic microRNA (miRNA) expressions with rapid angiographic stenotic progression (RASP) and restenosis risks in coronary artery disease (CAD) patients underwent percutaneous coronary intervention (PCI) with drug-eluting stents (DES). METHODS: A total of 286 CAD patients underwent PCI with DES were consecutively recruited in this study. Plasma samples were collected before PCI operation, and 14 pro-angiogenic miRNAs were measured by real-time quantitative reverse transcription-polymerase chain reaction. Rapid angiographic stenotic progression at nontarget lesions and restenosis at stented lesions were evaluated by quantitative coronary angiography at 12 months after PCI operation. RESULTS: The occurrence rates of RASP and restenosis were 39.5% and 22.4%, respectively. Let-7f, miR-19a, miR-19b-1, miR-92a, miR-126, miR-210, and miR-296 were decreased in RASP patients than non-RASP patients, among which let-7f, miR-19a, miR-126, miR-210, and miR-296 independently correlated with lower RASP occurrence by multivariate analysis, followed by receiver-operating characteristic (ROC) curve exhibited that these five miRNAs showed great value in predicting RASP risk with area under curve (AUC) 0.879 (95% CI: 0.841-0.917). Besides, let-7f, miR-19a, miR-92a, miR-126, miR-130a, and miR-210 were reduced in restenosis patients than non-restenosis patients, among them miR-19a, miR-126, miR-210, and miR-378 independently correlated with lower restenosis occurrence by multivariate analysis, followed by ROC curve disclosed that these four miRNAs had good value in predicting restenosis risk with AUC 0.776 (95% CI: 0.722-0.831). CONCLUSIONS: Circulating let-7f, miR-19a, miR-126, miR-210, and miR-296 independently correlate with reduced RASP risk, while miR-19a, miR-126, miR-210, and miR-378 independently correlate with decreased restenosis risk in CAD patients underwent PCI with DES.

Platelets in In-stent Restenosis: From Fundamental Role to Possible Prognostic Application.

BACKGROUND: Introduction of new generations of stents has decreased the percentage of patients experiencing in-stent restenosis (ISR) following the implantation of stent. However, a large number of patients are still afflicted with this phenomenon, which necessitates further study of ISR pathophysiology. METHODS: Relevant English literature was searched up to 2018 and retrieved form the PubMed database and Google Scholar search engine. The following keywords were used: "In-stent restenosis", "Platelet", "Chemokine", "Inflammation", "Vascular smooth muscle cell" and "Neointima". RESULTS: Previous studies have shown that ISR is a pathophysiologic response to damage of the artery wall after its elongation and separation of the atherosclerotic plaque. Development of neointimal hyperplasia (NIH) following this pathophysiologic response is a function of inflammation caused by platelets, monocytes, macrophages, and lymphocytes, as well as rapid migration and proliferation of generally quiescent cells in the median layer of the artery wall. CONCLUSION: After damage to the artery wall, platelets play an essential role in the incidence of NIH by contributing to inflammation and migration of vascular smooth muscle cells and extracellular matrix remodeling, especially via secretion of different chemokines; therefore, developing therapeutic strategies for platelet inhibition in a controlled manner could be the basis of preventive treatments in the near future. In this study, for the first time, we hypothesize that evaluation of platelet activity profile in patients before and after stent implantation may determine the prognosis and likelihood of ISR.

Correlation of pre-operative circulating inflammatory cytokines with restenosis and rapid angiographic stenotic progression risk in coronary artery disease patients underwent percutaneous coronary intervention with drug-eluting stents.

BACKGROUND: This study aimed to explore the associations of common inflammatory cytokine levels with restenosis and rapid angiographic stenotic progression (RASP) risk in coronary artery disease (CAD) patients underwent percutaneous coronary intervention (PCI) with drug-eluting stents (DES). METHODS: Two hundred and ten CAD patients underwent PCI with DES were consecutively recruited, then pre-operative serum levels of TNF-α, IL-1ß, IL-4, IL-6, IL-8, IL-10, IL-17A, IL-21, and IL-23 were determined by ELISA. The 12-month in-stent restenosis and RASP of non-intervened lesion were assessed by quantitative coronary angiography analysis. RESULTS: The pre-operative TNF-α, IL-6, IL-17A, and IL-23 expressions were increased while IL-4 expression was decreased in restenosis patients compared with non-restenosis patients. Further analysis revealed that IL-6, IL-8, hypercholesteremia, diabetes mellitus, and HsCRP could independently predict restenosis risk, and subsequent ROC curve revealed that their combination was able to differentiate restenosis patients from non-restenosis patients with an AUC of 0.951 (95%CI: 0.925-0.978). Meanwhile, the pre-operative TNF-α, IL-6, IL-17A, IL-21, and IL-23 expressions were increased whereas IL-4 level was decreased in RASP patients compared with non-RASP patients. Further analysis revealed that TNF-α, IL-6, IL-23, hypercholesteremia, SUA, HsCRP, and multivessel artery lesions could independently predict RASP risk, and subsequent ROC curve disclosed that their combination could discriminate RASP patients from non-RASP patients with an AUC of 0.886 (95%CI: 0.841-0.931). CONCLUSIONS: This study unveils the potentiality of pre-operative circulating inflammatory cytokines as markers for predicting restenosis and RASP risk in CAD patients underwent PCI with DES.