Vein Graft Failure Research Articles

Prediction of Major Adverse Cardiovascular Events and Slow/No-Reflow by Virtual Histology Imaging After Percutaneous Interventions on Saphenous Vein Grafts.

Saphenous vein grafts disease (SVGD) is a common complication after coronary artery bypass graft (CABG) and usually treated by percutaneous coronary intervention (PCI). In this prospective cohort study, we performed virtual histology-intravascular ultrasound to investigate whether plaque composition and morphological characteristics were associated with post-PCI major adverse cardiac events (MACEs) and slow/no-reflow in patients with SVGD. Patients (n = 90) were studied (76.7% men, mean age 64.9 ± 8.2 years and mean duration of SVG 8.0 ± 3.6 years). There were 77.8% lesions with a plaque burden of at least 70%; 18 MACE incidences accumulated in 14 patients over 12 months post-PCI and slow/no-reflow was observed in 12 patients. On adjusted multivariate analysis, lesion length (hazard ratio [HR] = 1.05; 95% confidence interval [CI]: 1.01-1.08]); age of CABG (HR = 1.51 [95% CI: 1.11-2.05], and absolute necrotic core (NC) area (HR = 8.04 [95% CI: 1.86-34.73]) were independently associated with MACEs. Factors independently associated with slow/no-reflow post-PCI were preprocedure systolic blood pressure (odds ratio [OR] = 0.98; 95% CI: 0.96-0.99) and absolute NC area (OR = 2.47 (95% CI: 1.14-5.36). A cutoff value of absolute NC area at ≥1.1 mm2 may serve as a significant risk predictor for no-reflow after SVG-PCI. Factors associated with MACEs and the slow/no-reflow phenomenon following PCI of the SVG can be used in risk assessment of SVG.

Upregulation of miR‑423 improves autologous vein graft restenosis via targeting ADAMTS‑7.

Coronary artery bypass graft (CABG) is one of the primary methods of treating coronary heart disease (CHD); however, vein graft restenosis is a major limiting factor of the effectiveness of CABG. Emerging evidence has indicated that miR-423 is associated with vascular diseases. Additionally, upregulation of a disintegrin and metalloproteinase with thrombospondin motifs-7 (ADAMTS-7) contributes to neointima formation by promoting the proliferation and migration of vascular smooth muscle cells and inhibiting the proliferation and migration of endothelial cells. The aim of the present study was to examine the effects of miR-423 target, ADAMTS-7, on regulating vein graft disease and identify novel biomarkers for use in therapy of vein graft failure (VGF). Aberrant expression of miR-423 in plasma of patients with CHD prior to and following CABG confirms that miR-423 may be a suitable target for preventing VGF. Furthermore, a dual-luciferase reporter gene assay indicated that miR-423 directly interacted with ADAMTS-7 and suppressed its expression. Ectopic expression of miR-423 suppressed ADAMTS-7, resulting in decreased proliferation and migration rates of human umbilical vein smooth muscle cells by targeting ADAMTS-7, but resulted in increased proliferation and migration of human umbilical vein endothelial cells in vitro. Overexpression of miR-423 also enhanced re-endothelialization and decreased neointimal formation in a rat vein graft model. In conclusion, the results of the present study demonstrated that the miR-423/ADAMTS-7 axis may possess potential clinical value for the prevention and treatment of restenosis in patients with CHD following CABG.

Relevance of SYNTAX score for assessment of saphenous vein graft failure after coronary artery bypass grafting

ObjectiveTo identify risk factors of saphenous vein graft (SVG) failure and to investigate the utility of anatomical SYNTAX score (SS) and SYNTAX score II (SS-II) in predicting SVG failure. MethodsA total of 598 patients who underwent angiography for clinical reasons after coronary artery bypass grafting (CABG) were included. Baseline data and factors related to SVG failure were analyzed at the patient and graft levels. Patients were divided in tertiles by anatomical SS and in three groups by SS-II revascularization recommendation, and SVG patency was analyzed across these groups. ResultsPatency rates were similar in all SS-stratified and SS-II recommendation groups within 1, 5, and 10 years after CABG. At the patient level, fasting blood glucose (FBG) level <7.0 mmol/L was less common in SVG failure (68.0% vs. 76.2%). At the graft level, patients with SVG failure tended to have angiography later (4.0 years vs. 3.0 years), poorer FBG control (FBG <7.0 mmol/L: 68.2% vs. 74.7%), and more grafts anastomosed to the right coronary system (59.2% vs. 47.4%). Longer time interval after CABG was related to SVG failure both at the patient and graft levels, and odds ratio (OR)/P values (OR/P) were 1.282/0.029 and 1.384/0.016, respectively. Using independent graft and grafting to the right artery system as risk factors at the graft level, OR/Ps were 3.094/0.000 and 2.524/0.000, respectively. ConclusionsLonger time interval after CABG, independent grafts, and grafting to the right artery system are associated with SVG failure. Anatomical SS or SS-II may not be reasonable tools for predicting SVG failure.

Perivascular Administration of Atorvastatin Loaded in Microparticles and Hyaluronic Acid Gel to Prevent Intimal Hyperplasia in Venous Graft

Introduction - Following a bypass graft surgery, almost half of the patients are prone to develop stenosis (thickening of the grafted vessel wall) within five years after the procedure. Perivascular delivery of active compounds is an appealing approach to prevent vein graft failure. We developed a single administration formulation to be applied during the surgical procedure on the grafted vessel. The presence of the formulation as well as a sustained release of the drug should be maintained for four weeks Methods - In this work, we developed a single administration drug delivery system, to be applied locally during the surgical procedure, around the vessel at the anastomosis site. Atorvastatin (ATV) was loaded in poly(lactic-co-glycolic acid) microparticles to achieve a sustained release kinetics of the drug, that would correlate with the time course of the development of the pathology (4 weeks). The microparticles were then incorporated into a hydrogel (cross-linked hyaluronic acid) to ensure residence at the site of injury and prolonged in situ delivery of ATV. The cross-linked hyaluronic acid hydrogel was received sterile. For the rodent model, PLGA microparticles were aseptically incorporated into the gel under laminar flow. For the pig model, prior microparticles sterilization using e-beam radiation or gamma rays was performed. Dose extrapolation was performed using interspecies allometric approaches. The formulation was tested on two animal models of intimal hyperplasia: a rodent carotid artery ligature model and a pig model of venous patch on carotid artery placement. Results - The challenges of the translation of a perivascular, implantable, drug delivery system between two animal models, were addressed: (i) drug release kinetics change due to additional sterilization, (ii) allometric dose extrapolation, (iii) viscosity change due to microparticle content increase to comply with dose scaling. In the rodent model the presence of the formulation showed a 63 % reduction in intimal hyperplasia compared to control (Figure1). These results were not reproduced in the porcine model, despite that a three-fold increase in angiogenesis demonstrated the action of ATV on site.Such discrepancy might be attributed to failure of allometric dose scaling in the context of local delivery. Indeed, the allometric dose scaling indicated that if 2 mg of ATV were administered per mouse, 10 mg should be administered per pig. Model differences in terms of implant degradation or metabolization need to be investigated. Additionally, the duration of the drug release decreased by 30% upon sterilization and this might not be optimal for the triggered pathology. Finally, viscosity increase of the implanted device is not optimal for a homogenous application of the formulation Conclusion - Perivascular administration is an appealing approach for the prevention of vein graft failure. Intra-species translation of efficient perivascular formulation remains an important challenge. Despite the encouraging results with an ATV-loaded microparticle/gel formulation applied on a mouse model, the results were still not reproduced on pigs. As a perspective, a dose increase is envisioned, to assess the efficacy of the formulation.

A Meta-Analysis Comparing Aspirin Alone Versus Dual Antiplatelet Therapy for the Prevention of Venous Graft Failure Following Coronary Artery Bypass Surgery

BackgroundAspirin (ASA) monotherapy is the current standard of care after coronary artery bypass grafting (CABG) to prevent saphenous vein graft (SVG) failure. Several small, randomized clinical trials (RCTs) have suggested that dual antiplatelet therapy (DAPT) may be more effective at preventing SVG failure than ASA alone; however, it is unclear whether some P2Y12 inhibitors are more effective than others for the prevention of SVG failure. MethodsScientific databases and websites were searched to find RCTs. Both traditional pairwise meta-analysis using random-effect model and network meta-analysis using mixed-treatment comparison models were performed to compare the efficacy of various anti-platelet strategies for the prevention of SVG failure. ResultsNine RCTs, which included a total of 1677 patients, were analyzed. Compared to ASA alone, DAPT decreased the risk of graft failure by 37% (RR: 0.63, 95% CI: 0.47–0.86; p = 0.003). In the moderator analysis, the decreased risk of graft failure with DAPT was not significantly different in the ASA + clopidogrel group than in the ASA + ticagrelor group (P-interaction = 0.17). The results of the network meta-analysis were consistent with those from pairwise analyses. The risk of major bleeding was not statistically significantly different between DAPT and ASA alone (RR: 1.35, 95% CI: 0.62–2.94; p = 0.45). ConclusionIn post-CABG patients, DAPT seems to be more effective at preventing graft failure than ASA alone. This strategy does not seem to significantly increase major bleeding risk. Clopidogrel- and ticagrelor-based DAPT seem to be equally effective for this indication.

Adventitial Collagen Crosslink Reduces Intimal Hyperplasia in a Rabbit Arteriovenous Graft Model

BackgroundIntimal hyperplasia (IH) is the initial lesion of vein graft failure after coronary artery bypass grafting. The weak venous wall is likely one of the primary reasons for IH after exposure to the arterial environment. We investigate whether adventitial collagen cross-link by glutaraldehyde (GA) reinforces the venous wall and then reduces IH. Materials and methodsAdventitial collagen cross-link by 0.3% GA was performed on the rabbit jugular veins. The degree of cross-link was accessed by tensile test. The jugular vein with or without cross-link was implanted into the carotid artery of rabbit. Vein dilatation at the immediate anastomosis and pathological remodeling of vein graft after 4 wk was assessed. ResultsTensile test indicated that the mechanical property of 3-min cross-linked veins more closely resembled that of the carotid artery. In rabbit arteriovenous graft models, 3-min adventitial collagen cross-link limited overdistension (diameter: 3.24 mm versus 4.65 mm, P < 0.01) at the immediate anastomosis and reduced IH (intima thickness: 78.83 μm versus 140.19 μm, P < 0.01) of vein grafts 4 wk after implantation in the cross-link group as compared with the graft group (without cross-link). Compared with the cross-link group, the expression of proliferating cell nuclear antigen and vascular cell adhesion molecule–1 increased significantly at both the mRNA and protein levels within the graft group (P < 0.01), but the expression of smooth muscle-22α decreased significantly (P < 0.01). ConclusionsAdventitial collagen cross-link by GA increased the vessel stiffness and remarkably reduced IH in a rabbit arteriovenous graft model.

Early Inhibition of P-Selectin/P-Selectin Glycoprotein Ligand-1 Reduces Intimal Hyperplasia in Murine Vein Grafts through Platelet Adhesion.

Inflammatory processes contribute to intimal hyperplasia (IH) and long-term failure of vein grafts used in bypass surgery. Leukocyte recruitment on endothelial cells of vessels during inflammation is regulated by P-selectin and P-selectin glycoprotein ligand-1 (PSGL-1), which also mediates the interaction between platelets and endothelial cells in vein grafts transferred to arteries. However, how this pathway causes IH in vein grafts is unclear. In this study, we used a murine model of vein grafting to investigate P-selectin-mediated platelet adhesion, followed by IH. On the luminal surface of the vein graft, leukocyte recruitment occurred mainly in areas with adhered platelets rather than on endothelial cells without adherent platelets 1 hour after vein grafting. Blockage of either P-selectin or PSGL-1 reduced platelet adhesion and leukocyte recruitment on the luminal surface of vein grafts. Inhibition of the P-selectin pathway in vein grafts significantly reduced platelet-mediated leukocyte recruitment and IH of vein grafts 28 days after surgery. The study demonstrates that functional blockage of the P-selectin/PSGL-1 pathway in the early inflammatory phase after vein grafting reduced leukocyte invasion in the vein graft wall and later IH development. The findings imply an attractive early time window for prevention of vein graft failure by manipulating platelet adhesion.

Heterogeneous and dynamic lumen remodeling of the entire infrainguinal vein bypass grafts in patients

ObjectiveTo examine the regional variation and temporal change in lumen size along the entire autogenous vein bypass graft used for treating arterial occlusive disease in lower extremity and to explore the factors associated with graft expansive or constrictive remodeling. MethodsPatients were prospectively scanned using contrast-enhanced computed tomography at 1 week and 1, 6, and 12 months postoperatively to obtain lumen cross-sectional areas at 1-mm intervals along the entire grafts. Graft lumen remodeling characteristics and the associated demographic and clinical factors were examined. ResultsFifty-six patients with at least two consecutive computed tomography scans were analyzed. Patients with a composite or longer graft, or with diabetes, had a larger lumen cross-sectional area variation along the graft. The mean lumen cross-sectional areas of all the grafts demonstrated no significant changes through 12 months. However, individually, graft remodeling was time dependent and there was a more dramatic change in lumen cross-sectional area within the first postoperative month. At 12 months, a near equal distribution between expansive and constrictive grafts existed. A negative relation between the initial lumen diameters and the subsequent lumen diameter changes was observed. Eleven grafts failed within 12 months; failed and patent grafts had similar mean lumen cross-sectional areas at all four time points, but failed grafts had a larger maximal local cross-sectional area reduction from 1 week to 1 month (58.0 ± 6.7% vs 38.1 ± 3.1%, mean ± standard error of the mean, failed vs patent, P = .004). Black patients had a smaller mean lumen cross-sectional area than white patients at all four time points and also had a higher early percent mean area reduction (−20.5 ± 6.3% vs −1.0 ± 3.7%, black vs white, P = .018). Cilostazol use was associated with early expansive graft remodeling. ConclusionsVein grafts remodel heterogeneously and dynamically. Remodeling is associated with initial graft lumen size, race, and cilostazol use. It is found that remodeling that produces some critical minimum area or maximal percent reduction during the first postoperative month may predispose to vein graft failure. These findings offer insight into further investigation to examine the underlying mechanisms and opportunities to improve graft remodeling and durability.

Antithrombotic treatment after coronary artery bypass graft surgery: systematic review and network meta-analysis

ObjectiveTo assess the effects of different oral antithrombotic drugs that prevent saphenous vein graft failure in patients undergoing coronary artery bypass graft surgery.DesignSystematic review and network meta-analysis.Data sourcesMedline, Embase, Web...

SAPHENOUS VEIN GRAFT PATENCY ON DACRON CONDUITS IS COMPARABLE TO PROXIMAL ANASTOMOSIS CONSTRUCTED ON THE NATIVE AORTA: RESULTS OF A LONGITUDINAL COHORT OF PATIENTS WITH ASCENDING AORTIC REPLACEMENT AND CORONARY ARTERY BYPASS GRAFTS

Coronary artery bypass grafts (CABG) is a well-accepted technique for coronary artery revascularization. Early saphenous vein graft (SVG) failure is reported between 10-20% at one year. However, patency of SVG anastomosed on an ascending aortic Dacron graft remains debated. The purpose of this study is to provide insight on the patency rate of SVG anastomosed on a Dacron graft. We reviewed data on all consecutive adult patients who underwent an ascending aortic replacement with concomitant CABG between 2007 and 2018 and follow-up in a high volume aortic clinic. Operative reports, follow-up enhanced chest computed tomography (CT), and coronary angiograms were reviewed. Primary end-point was SVG patency within one year of CABG. One hundred and seven patients met inclusion criteria (mean age: 66.7±8.0 yo, 10% female, average EuroScore II 7.1±5.6). A total of 171 SVG (159 anastomosis on the dacron graft and 12 veno-venous anastomosis) were evaluated. Concomitant interventions to CABG were aortic valve replacement n=53, Bentall procedure n=22, aortic valve resuspension n=10, valve sparing n=2, total arch replacement n=36, and hemiarch replacement n=13. Ten patients (9%) had one or more SVG occluded. Of the 171 SVG, twelve (7%) SVG were occluded. Among the occluded grafts, 6/12 were on the 67 right coronary artery grafts (9.0% occlusion rate), 4 were on the 64 circumflex grafts (6.3% occlusion rate), 2 on the 40 LAD/diagonal grafts (occlusion rate 4.8%); p=ns between different territories. Only one of the 12 veno-venous grafts was occluded. Overall, occlusion rate of SVG anastomosed on the dacron was 6.9% (11/159). On review of surgical reports, occluded grafts were described as a suboptimal conduit in one patient and a poor vessel quality in 3 other patients. SVG anastomosed on Dacron conduits appear to have a comparable early patency rate (93%) to SVG anastomosed to the native aorta. Considering the good patency of SVG on Dacron grafts, use of veno-venous proximal anastomosis should be limited.

2223Effect of ticagrelor plus aspirin, ticagrelor alone, or aspirin alone on vein-graft patency 1 year after coronary artery bypass grafting with or without diabetes: a post-hoc analysis of the DACAB tria

Abstract Introduction The association of diabetes and vein graft patency after coronary artery bypass grafting (CABG) remains controversial. In patients with diabetes, impaired endothelial function in vein grafts and high platelet turnover might result in early vein graft failure. The DACAB trial showed ticagrelor plus aspirin significantly increased 1-year vein graft patency vs. aspirin alone, while no significant difference between ticagrelor alone and aspirin alone. However, whether the results is different between the patients with or without diabetes is unknown. Purpose To assess the effects of ticagrelor with or without aspirin vs. aspirin alone on 1-year vein grafts patency after CABG in patients with or without diabetes. Methods We examined the subgroups of patients with and without diabetes from DACAB trial (NCT02201771), in which 500 patients were randomized to 1 of 3 antiplatelet regimens (ticagrelor 90mg twice daily plus aspirin 100mg once daily, T+A group; ticagrelor 90mg twice daily, T group; or aspirin 100mg once daily, A group) within 24 hours post-CABG. The primary outcome was 1-year vein graft patency (FitzGibbon grade A) assessed by multi-slice computed tomographic angiography or coronary angiography. Results According to the baseline medical history and/or glycated hemoglobin (HbA1c) ≥6.5%, 283 patients with 818 vein grafts were allocated to the non-diabetes subgroup, remaining 217 patients with 642 vein grafts to the diabetes subgroup. By per-graft analysis, no significant difference on 1-year vein graft patency rate was observed between non-diabetes and diabetes subgroup (84.6% [692/881] for non-diabetes vs. 80.2% [515/642] for diabetes, adjusted odds ratio (OR) =1.39, 95% CI: 0.92–2.09, P=0.116). In T+A group, 1-year vein graft patency rates were 91.0% (244/268) for non-diabetes vs. 85.8% (188/219) for diabetes; In T group, 85.0% (221/260) for non-diabetes vs. 80.3% (183/228) for diabetes; In A group, 78.3% (227/290) for non-diabetes vs. 73.9% (144/195) for diabetes. Ticagrelor plus aspirin showed higher vein graft patency rate than aspirin alone in both non-diabetes and diabetes subgroup (non-diabetes: adjusted OR = 0.34, 95% CI: 0.17–0.69, and diabetes: adjusted OR = 0.42, 95% CI: 0.19–0.91, P for interaction = 0.524), whereas ticagrelor alone did not show improvement on vein graft patency compared with aspirin alone in both subgroups (non-diabetes: adjusted OR=0.62, 95% CI: 0.32–1.20, and diabetes: adjusted OR = 0.65, 95% CI: 0.33–1.31, P for interaction = 0.795). Similar results were showed by per-patient analysis. A total 16 major adverse cardiovascular events occurred, 8 (2.8%) for non-diabetes and 8 (3.7%) for diabetes. Conclusion In the DACAB trial, diabetes was not found to be associated with decreased vein graft patency at 1 year after CABG. The effect of ticagrelor plus aspirin on improvement of 1-year vein graft patency, when compared with aspirin alone, is consistent in patients with or without diabetes. Acknowledgement/Funding AstraZeneca

Validation of randomized controlled trial-derived models for the prediction of postintervention outcomes in chronic limb-threatening ischemia

BackgroundChronic limb-threatening ischemia (CLTI) represents the most severe form of peripheral artery disease and has a large impact on quality of life, morbidity, and mortality. Interventions are aimed at improving tissue perfusion and averting amputation and secondary cardiovascular complications with an optimal risk-benefit ratio. Several prediction models regarding postprocedural outcomes in CLTI patients have been developed on the basis of randomized controlled trials to improve clinical decision-making. We aimed to determine model performance in predicting clinical outcomes in selected CLTI cohorts. MethodsThis study validated the Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL), Finland National Vascular registry (FINNVASC), and Prevention of Infrainguinal Vein Graft Failure (PREVENT III) models in data sets from a peripheral artery disease registry study (Athero-Express) and two randomized controlled trials of CLTI in The Netherlands, Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) and Percutaneous Transluminal Angioplasty and Drug-eluting Stents for Infrapopliteal Lesions in Critical Limb Ischemia (PADI). Receiver operating characteristic (ROC) curve analysis was used to calculate their predictive capacity. The primary outcome was amputation-free survival (AFS); secondary outcomes were all-cause mortality and amputation at 12 months after intervention. ResultsThe BASIL and PREVENT III models showed predictive values regarding postintervention mortality in the JUVENTAS cohort with an area under the ROC curve (AUC) of 81% and 70%, respectively. Prediction of AFS was poor to fair (AUC, 0.60-0.71) for all models in each population, with the highest predictive value of 71% for the BASIL model in the JUVENTAS population. The FINNVASC model showed the highest predictive value regarding amputation risk in the PADI population with AUC of 78% at 12 months. ConclusionsIn general, all models performed poor to fair in predicting mortality and amputation. Because the BASIL model performed best in predicting AFS, we propose use of the BASIL model to aid in the clinical decision-making process in CLTI. However, improvements in performance have to be made for any of these models to be of real additional value in clinical practice.

Total arterial off-pump coronary revascularization: The Holy Grail?

Coronary artery bypass grafting (CABG) remains the standard of care for patients with complex multivessel coronary artery disease. However, conventional CABG utilizing left internal mammary artery and supplemental vein grafts performed on cardiopulmonary bypass is marred by questionable long-term patency of vein grafts and risk of neurological injury. Total arterial off-pump CABG is a strategy associated with avoidance of neurological injury and vein graft failure. The aim of this review is to summarize recent evidence on safety and effectiveness of total arterial off-pump CABG. Two key studies have been published recently. One describes a dual inflow technique that achieves anaortic, off-pump complete revascularization using arterial grafts only. The other is single centre study that reports 10-year survival of 89.33%, rate of freedom from repeat revascularization of 91.33% and early stroke rate of 0.9% after total arterial off-pump CABG. Total arterial off-pump CABG with its advantages of improved survival, enhanced freedom from repeat revascularization and low stroke rate can be regarded as the Holy Grail of myocardial revascularization. However, the results of a large, multicenter, prospective trial are required to substantiate this status.

Saphenous vein grafts in contemporary coronary artery bypass graft surgery.

Myocardial ischaemia resulting from obstructive coronary artery disease is a major cause of morbidity and mortality in the developed world. Coronary artery bypass graft (CABG) surgery is the gold-standard treatment in many patients with complex multivessel coronary artery disease or left main disease. Despite substantial improvements in the outcome of patients undergoing CABG surgery in the past decade, graft patency remains the 'Achilles' heel' of this procedure. Whereas the use of the left internal mammary artery as a conduit is associated with the highest 10-year patency rate (>90%), saphenous vein grafts - the most commonly used conduit in CABG surgery - fail in 40-50% of treated patients by 10 years after surgery. Vein graft disease (VGD) and failure result from complex pathophysiological processes that can lead to complete occlusion of the graft, affecting long-term clinical outcomes. Optimal harvesting techniques, intraoperative preservation strategies and intraoperative patency control have important roles in the prevention of VGD. In addition, several studies published in the past decade have reported similar mid-term patency rates between vein grafts and arterial grafts when veins are used as a composite graft based on the internal mammary artery. In this Review, we present the latest evidence on the utilization of saphenous vein grafts for CABG surgery and provide an overview of the current practices for the prevention of VGD and vein graft failure.

Development of a risk score for early saphenous vein graft failure: An individual patient data meta-analysis

ObjectivesEarly saphenous vein graft (SVG) occlusion is typically attributed to technical factors. We aimed at exploring clinical, anatomical, and operative factors associated with the risk of early SVG occlusion (within 12 months postsurgery). MethodsPublished literature in MEDLINE was searched for studies reporting the incidence of early SVG occlusion. Individual patient data (IPD) on early SVG occlusion were used from the SAFINOUS-CABG Consortium. A derivation (n = 1492 patients) and validation (n = 372 patients) cohort were used for model training (with 10-fold cross-validation) and external validation respectively. ResultsIn aggregate data meta-analysis (48 studies, 41,530 SVGs) the pooled estimate for early SVG occlusion was 11%. The developed IPD model for early SVG occlusion, which included clinical, anatomical, and operative characteristics (age, sex, dyslipidemia, diabetes mellitus, smoking, serum creatinine, endoscopic vein harvesting, use of complex grafts, grafted target vessel, and number of SVGs), had good performance in the derivation (c-index = 0.744; 95% confidence interval [CI], 0.701-0.774) and validation cohort (c-index = 0.734; 95% CI, 0.659-0.809). Based on this model. we constructed a simplified 12-variable risk score system (SAFINOUS score) with good performance for early SVG occlusion (c-index = 0.700, 95% CI, 0.684-0.716). ConclusionsFrom a large international IPD collaboration, we developed a novel risk score to assess the individualized risk for early SVG occlusion. The SAFINOUS risk score could be used to identify patients that are more likely to benefit from aggressive treatment strategies.

Preventing treatment failures in coronary artery disease: what can we learn from the biology of in-stent restenosis, vein graft failure, and internal thoracic arteries?

Coronary artery disease (CAD) remains one of the most important causes of morbidity and mortality worldwide, and the availability of percutaneous or surgical revascularization procedures significantly improves survival. However, both strategies are daunted by complications which limit long-term effectiveness. In-stent restenosis (ISR) is a major drawback for intracoronary stenting, while graft failure is the limiting factor for coronary artery bypass graft surgery (CABG), especially using veins. Conversely, internal thoracic artery (ITA) is known to maintain long-term patency in CABG. Understanding the biology and pathophysiology of ISR and vein graft failure (VGF) and mechanisms behind ITA resistance to failure is crucial to combat these complications in CAD treatment. This review intends to provide an overview of the biological mechanisms underlying stent and VGF and of the potential therapeutic strategy to prevent these complications. Interestingly, despite being different modalities of revascularization, mechanisms of failure of stent and saphenous vein grafts are very similar from the biological standpoint.

MiRMap: Profiling 14q32 microRNA Expression and DNA Methylation Throughout the Human Vasculature.

Aims: MicroRNAs are regulators of (patho)physiological functions with tissue-specific expression patterns. However, little is known about inter-vascular differences in microRNA expression between blood vessel types or vascular beds. Differences in microRNA expression could influence cardiovascular pathophysiology at specific sites in the vasculature. Therefore, we aimed to map expression profiles of vasoactive 14q32 microRNAs throughout the human vasculature, as well as expression of vasoactive target genes of the 14q32 microRNAs. Furthermore, we aimed to map the DNA methylation status of the 14q32 locus, which has been linked to cardiovascular disease.Methods and Results: We collected 109 samples from different blood vessels, dissected during general surgery. Expression of a representative set of 17 14q32 microRNAs was measured in each sample. All 17 microRNAs showed a unique expression pattern throughout the vasculature. 14q32 microRNA expression was highest in lower limb vessels and lowest in head and neck vessels. All 17 microRNAs were expressed more abundantly in arteries than in veins. Throughout the human vasculature, we observed trends toward an inverse correlation between expression levels of the 14q32 microRNAs and their vasoactive target genes. DNA methylation of the 3 Differentially Methylated Regions (DMRs) along the 14q32 locus did not associate with primary or mature microRNA expression. However, hyper-methylation in venous coronary artery bypass grafts compared to arterial bypass grafts was observed in the Intergenic-DMR and MEG3-DMR. In patients with end-stage peripheral arterial disease we found differential DNA methylation throughout all DMRs in their lower limb veins. These findings were confirmed in a mouse model for vein-graft disease in which we found regulated 14q32 DNA methylation during the active phase of vascular remodeling. In ischemic tissues of a murine hind limb ischemia model we observed an increase in DNA methylation associated with increased ischemia over time.Conclusions: We show that 14q32 microRNAs are abundantly expressed in the human vasculature and that expression differs significantly between different blood vessels. 14q32 DNA methylation also varies throughout the vasculature and is associated with vascular health, independently of microRNA levels. These findings could have important implications for future research and for future site-specific targeting of epigenetics-based therapeutics.

Sirtuin 3 Therapy Attenuates Aging Expression, Oxidative Stress Parameters, and Neointimal Hyperplasia Formation in Vein Grafts

Vein graft (VG) failure due to neointimal hyperplasia remains an important and unresolved problem in cardiovascular surgery. Sirtuin3 (SIRT3) is associated with oxidative stress and lifespan. We aimed to measure SIRT3 expression in the veins of humans and rats during aging, explore the inhibitory effects of SIRT3 on vascular smooth muscle cell (VSMC) proliferation and neointimal hyperplasia in VGs, and investigate the underlying mechanisms. SIRT3 mRNA and protein levels in saphenous veins of young and older humans and in veins of young and old rats were measured by quantitative real-time polymerized chain reaction (PCR) and Western blot analysis. Young and old male rats were randomized to the control (control), graft (graft), adenovirus-encoding green fluorescent protein (Ad-GFP), and adenovirus encoding SIRT3 (Ad-SIRT3) groups. At 7days after operation, the mRNA and protein levels of SIRT3 and endothelial nitric oxide synthase (eNOS) were measured by quantitative real-time PCR and Western blot analysis. The mRNA levels and enzyme activity of manganese superoxide dismutase (MnSOD) and catalase (CAT) were measured by quantitative real-time PCR and enzymatic activity assay kits, and total nitric oxide (NO) levels were measured by biochemical assay kits. Histomorphometric analysis of VGs and immunohistochemical staining for proliferative activity were performed at 4weeks after operation. The hemodynamic parameters of the VGs were also measured by ultrasonic examination. SIRT3 mRNA and protein levels were lower in older human and rat veins than in younger human and rat veins. Ad-SIRT3 treatment significantly increased the expression and concentration of SIRT3, MnSOD, CAT, eNOS, and NO in VGs at 7days after operation. Ad-SIRT3 gene transfer reduced the neointimal thickness and neointimal area/media area ratio in the VGs of the Ad-SIRT3 groups compared with the graft and Ad-GFP groups, especially in old rats. Proliferative activity was lower in the Ad-SIRT3 groups than in the other groups. The hemodynamic parameters of VGs were obviously improved in the Ad-SIRT3 groups. SIRT3 expression decreases in the veins of humans and rats during aging. Furthermore, SIRT3 overexpression can significantly reduce VSMC proliferation and neointimal hyperplasia in VGs. Local intravenous delivery of adenovirus encoding SIRT3 may be a promising gene therapy for preventing VG failure.

The Role of MicroRNA-21 in Venous Neointimal Hyperplasia: Implications for Targeting miR-21 for VNH Treatment.

The molecular mechanism of hemodialysis access arteriovenous fistula (AVF) failure due to venous neointimal hyperplasia (VNH) is not known. The role of microRNA-21 (miR-21) in VNH associated with AVF failure was investigated by performing in vivo and in vitro experiments. In situ hybridization results revealed that miR-21 expression increased and was associated with fibroblasts in failed AVFs from patients. In a murine AVF model, qRT-PCR gene expression results showed a significant increase in miR-21 and a decrease in miR-21 target genes in graft veins (GVs) compared to contralateral veins in mouse AVF. miR-21 knockdown in GVs was performed using a lentivirus-mediated small hairpin RNA (shRNA), and this improved AVF patency with a decrease in neointima compared to control GVs. Moreover, loss of miR-21 in GVs significantly decreased the Tgfβ1, Col-Ia, and Col-Iva genes. Immunohistochemistry demonstrated a significant decrease in myofibroblasts and proliferation with an increase in terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining in miR-21-knockdown vessels, along with a decrease in hypoxia-inducible factor-1 alpha (HIF-1α) and phospho-SMAD2 (pSMAD-2) and phospho-SMAD3 (pSMAD-3) and an increase in phosphatase and tensin homolog (PTEN) staining. Hypoxic fibroblast knockdown for miR-21 showed a significant decrease in Tgfβ-1 expression and pSMAD-2 and -3 levels and a decrease in myofibroblasts. These results indicate that miR-21 upregulation causes VNH formation by fibroblast-to-myofibroblast differentiation.

A Five-Parameter Score for Predicting Saphenous Vein Graft Degenerative and/or Occlusive Disease in Recurring Ischemic Symptoms After Coronary Artery Bypass Grafting

Background: The recurrence rate of ischemic symptoms after coronary artery bypass grafting (CABG) is increasing in recent years. How to prevent and treat saphenous vein graft disease (SVGD) has been a clinical challenge to date. Although studies on risk factors for SVGD have been published, there is currently no available score for estimating the risk of SVGD. We sought to develop and validate a scoring system to predict SVGD among patients who recurring ischemia post CABG. Objective: To inform research on patient management including modifiable risk factors for SVGD [symptomatic ≥ 50% stenosis in at least 1 Saphenous vein grafts (SVG)], we sought to develop and validate a simple predictive clinical risk score index for SVGD with recurring ischemia after CABG. Methods and Results: This was a retrospective cohort study and the results were validated using bootstrap resampling on a separate cohort. A nomogram and risk scoring system were developed based on retrospectively collected data from a training cohort of 606 consecutive patients who were readmitted at Tianjin Chest Hospital between March 2015 and December 2017 with recurring ischemia >1 year after CABG. Logistic regression model was used to find the predictive factors and to build a nomogram. The predictive accuracy and discriminative ability of the model for SVGD were determined by concordance (C) index and calibration curve. To assess the generalization, models were validated using bootstrap resampling and an external cohort of 187 consecutive patients enrolled between March 2017 and December 2018 at 4 other local hospitals. In multivariable analysis of the primary cohort, native lesion vessel number, SVG age, recurring ischemia type, very low-density lipoprotein level, and left ventricular end-diastolic diameter were independent predictors of SVGD after CABG. A summary risk score was derived from nomogram, ranging from 0 to 30, with a cutoff value of 15. In internal and external validation, the C-index was 0.82[95%CI, 0.78-0.86] and 0.86 [0.79-0.92] for risk score-based predictions, indicating good overall discrimination. The calibration curve for probability of SVGD showed optimal agreement between actual observations and risk score prediction. Conclusions: A simple-to-use risk scoring system based on five easily obtainable demographic, clinical, biochemical variables was developed and validated to predict the risk of SVGD among patients who recurring ischemia post CABG. This score may be useful for providing patients with individualized estimates of SVGD risk. Funding Statement: This research project was funded by the Key Project of Scientific and Technological Support Plan of Tianjin in 2016 (No.16YFZCSY00800), the Key Project of Healthcare Industry of Tianjin in 2015 (No. 15KG128) and Major Science and Technology Projects of Tianjin Science and Technology Commission in 2016 (No. 16ZXMJSY00150). Declaration of Interests: All authors have no conflicts of interest to declare. Ethics Approval Statement: Ethical approval was obtained from participating institutions through their respective institutional review boards, and all participants provided written informed consent prior to treatment.