Review of risk factors,treatment,and prevention of saphenous vein graft disease after coronary artery bypass grafting

Abstract

Saphenous vein graft disease (SVGD) is a type of vascular disease that may develop after coronary artery bypass grafting (CABG). SVGD seriously affects the short-term and long-term effects of CABG and increases the incidence of major adverse cardiovascular events. It is very important to identify patients at greatest risk and carry out prevention and treatment measures to determine the risk factors for SVGD. Many factors contribute to SVGD when the vein is grafted into an arterial environment, such as surgery-related factors, smoking, diabetes mellitus, hyperlipidemia, and others. In this review, we discuss the risk factors for SVGD, current surgical and pharmacologic therapies with which to manage SVGD, and the prevention of SVGD.

Keywords

Saphenous vein graft disease coronary artery bypass grafting risk factor intimal hyperplasia major adverse cardiovascular events China

Introduction

According to data from the China Cardiovascular Disease Report 2015,¹ coronary artery bypass grafting (CABG) is one of the most important cardiovascular surgical procedures in China, and the number of CABG procedures performed has exceeded 40,000 annually. Owing to population aging and the development of various risk factors in China, the performance of CABG is increasing at a rate of 10% annually. At present, the saphenous vein graft (SVG) is still the main graft material used in CABG; however, the long-term patency rate seriously affects the long-term efficacy of CABG. The 1-, 5-, and 10-year postoperative patency rates are 93%, 74%, and 41%, respectively.² In addition, some studies have shown that up to 12% of SVGs become occluded within the first 6 months after CABG, with 3.4% occluding as early as 2 to 3 weeks.^3,4 Thrombosis formation is the main cause of SVG failure in the early period (<1 month) after CABG; however, abnormal hyperplasia of the neointima is the main cause of SVG failure in the subacute phase (1–12 months) after CABG, and atherosclerosis formation is the main cause of SVG occlusion in the later period (>1 year) after CABG.⁵ Scholars have recently clarified the definition of SVG disease (SVGD) for the first time. In SVGD, the SVG exhibits ≥50% stenosis, which is associated with the recurrence of ischemic symptoms (excluding distal anastomotic occlusion).^6–8 The annual rate of revascularization due to relapse of ischemic symptoms after CABG ranges from 8.6% to 10.4%.⁹ How to treat and prevent SVGD is thus a major clinical challenge. The objective of this review is to discuss the risk factors for SVGD, current surgical and pharmacologic therapies with which to manage SVGD, and prevention techniques for SVGD and provide a theoretical basis for the prevention and treatment of SVGD in daily clinical practice.

Risk factors for SVGD

The long-term life of an SVG is far inferior to that of an arterial graft bridge. Arteries have the advantage of thick elastic fibers and a smooth muscle layer; however, the diameter of veins is only 4 to 5 mm. Blood stagnation, lipid accumulation, and thrombosis are prone to occur in SVGs. The risk factors for SVGD include the following.

1. Surgery-related factors: Deppe et al.¹⁰ conducted a meta-analysis of 51 studies and found that CABG under non-extracorporeal circulation conditions has a relatively high incidence of postoperative graft occlusion and revascularization. Kim et al.¹¹ analyzed the efficacy of CABG in which different saphenous vein acquisition methods were used and found that the early (<1-month) and 1-year patency rates of the traditional acquisition method were significantly lower than those of the No-Touch technique. Compared with the conventional acquisition method, the No-Touch technique can reduce surgical injury/trauma from vein harvesting, improve the integrity of the vascular endothelium, reduce atherosclerosis progression, preserve the intact vasa vasorum and the perivascular adipose tissue and collagen fibers, and avoid high-pressure vein distension.^12,13 Several studies have demonstrated that the No-Touch technique is associated with improved morphological architecture, improved endothelial function indices, preservation of endothelial nitric oxide synthase, and a reduction in adhesion molecule expression and neutrophil adhesion.^14,15 A study by Verma et al.¹⁶ also showed that the No-Touch technique exhibited an early molecular and morphological pattern consistent with decreased vascular smooth muscle cell activation compared with conventional harvesting. The types of target vessels, extent of the lesion, vascular diameter, and anastomosis all affect the SVG patency rate after CABG.¹⁷ SVG patency to the left anterior descending artery is better than that to the right coronary or circumflex artery. Studies have shown that when an SVG is grafted to the right coronary artery, the long-term patency rate is relatively favorable when the SVG–right coronary artery diameter ratio is ≤2.8.^18,19 In the 2016 ORACLE-NIRS study by Danek et al.,²⁰ intravascular ultrasound and optical coherence tomography were used to evaluate SVG outcomes. The study showed that older SVGs were associated with a higher lipid core burden index and smaller lumen area and diameter, which significantly affected the long-term patency of the SVG. Hess et al.²¹ reported that a long surgical time, endoscopic vein harvesting, and low quality of target arteries were risk factors for SVG failure.

2. Smoking: Smoking increases the risk of SVG calcification²² and induces the expression of matrix metalloproteinases 2 and 9 to reduce the patency of the SVG.^23,24 An in vitro study conducted by Sharif et al.²⁵ showed that smoking impairs endothelium-dependent vasodilation. Muir et al.²⁶ investigated the correlation between saphenous vein and internal mammary artery endothelial relaxation in patients undergoing CABG. The authors found that the endothelium-dependent relaxation response of the internal mammary artery in patients who smoked was significantly weakened, while the saphenous vein relaxation response increased significantly. Higman et al.²⁷ showed that smoking impairs the endothelium-dependent vasodilatation of veins and increases vascular tension, platelet aggregation, and the proliferation of smooth muscle cells; all of these effects increase the risk of graft occlusion. On the basis of their multivariate regression analysis, Sen et al.²⁸ also suggested that smoking is an independent risk factor for SVGD.

3. Diabetes mellitus: SVG restenosis in patients with diabetes mellitus undergoing CABG is a pathophysiologic process involving both immune and non-immune factors. The metabolic disorders that occur in patients with type 2 diabetes mellitus lead to long-term dysfunction of vascular endothelial cells.²⁹ Large numbers of inflammatory and growth factors are released after endothelial injury, which further induces the abnormal proliferation and migration of vascular smooth muscle cells and causes restenosis.³⁰ Aberrancies of endothelial cell function may help to explain the increased risk of SVG failure in patients with type 2 diabetes mellitus.³¹ Koshizaka et al.³² evaluated the association of diabetes and its treatment with 1-year angiographic graft failure and 5-year clinical outcomes in patients undergoing CABG. The authors found that the 1-year rates of vein graft failure were similar in patients with and without diabetes, and at 5 years, the rates of death, myocardial infarction, or revascularization were higher among patients with than without diabetes (adjusted hazard ratio, 1.57; 95% confidence interval, 1.26–1.96; P < 0.001). Further studies are needed to better understand the mechanisms behind these findings.

4. Hyperlipidemia: Studies have shown that a low level of high-density lipoprotein (HDL) is associated with graft vascular occlusion and intimal hyperplasia; specifically, the lower the HDL level, the higher the risk of SVGD.³³ Another study showed that if low-density lipoprotein cholesterol (LDL-C) was controlled to <80 mg/dL and the LDL/HDL ratio is <1.5 after CABG, eccentric plaques, yellow plaques, and thrombosis could largely be prevented.³⁴ In contrast, eccentric plaque formation occurred in 78.6%, yellow plaque occurred in 100%, and thrombosis occurred in 78.6% of patients whose blood lipid levels were not well-controlled (LDL-C, 130.2 mg/dL; LDL/HDL ratio, 2.64).³⁴ Therefore, active lipid control after CABG is believed to reduce the risk of SVGD.

5. Other risk factors: A retrospective study conducted by Akboga et al.³⁵ in 2016 included 112 patients with SVGD and 145 patients without SVGD. The study showed that a low level of albumin and high ratio of monocytes to HDL cholesterol were risk factors for the development of SVG atherosclerosis. Cagirci et al.³⁶ determined the level of asymmetric dimethylarginine in 42 patients with SVGD and 61 patients without SVGD using an enzyme-linked immunosorbent assay. The authors found that a high level of asymmetric dimethylarginine and the average platelet volume were independent risk factors for SVGD. Another study showed that a 1% increase in the red blood cell distribution width increased the risk of SVGD by 2.388-fold (95% confidence interval, 1.287–4.432).³⁷ Furthermore, the platelet count, average platelet volume, plateletcrit, platelet distribution width, and platelet-to-lymphocyte ratio or neutrophil-to-lymphocyte ratio all predicted the occurrence of SVGD.^38–43 Sun et al.⁴⁴ reported that a red blood cell distribution width of >0.1275 and a neutrophil-to-lymphocyte ratio of >3.34 were independent risk factors for late SVGD with odds ratios of 4.905 and 4.013, respectively. A low level of adropin protein, HDL, and 25-hydroxyvitamin D; a high level of erythropoietin; and elevated expression of matrix metalloproteinases were also shown to be associated with SVGD.^2,45–47 Perek et al.^48,49 reported that thickening of the saphenous vein tunica media, chunky smooth muscle cell nuclei, and increased expression of cytokeratin 8 accompanied by calponin underexpression in the saphenous vein tunica media were independent risk factors for venous graft failure.

Treatment of SVGD

Determination of the optimal treatment of SVGD is challenging. The annual revascularization rate after CABG ranges from 8.6% to 10.4% because of recurrent ischemic symptoms. Because patients with SVGD are generally older and the underlying coronary artery disease is often severe, many SVGs exhibit the effects of aging after 3 years, and these patients are susceptible to severe ischemic events and refractory heart failure.^50,51 Therefore, post-CABG revascularization is complex and should be managed on an individual basis.

1. Drug treatment: Anticoagulants, such as urokinase, unfractionated heparin, low-molecular-weight heparin, and abciximab, are often used with unsatisfactory effects. For example, Harskamp et al.⁵² found that the use of abciximab in SVG intervention did not improve clinical outcomes; rather, abciximab was associated with more bleeding. Contraindications for these treatments in patients with comorbidities undergoing CABG are also important to consider. For example, abciximab is contraindicated in patients with renal insufficiency and should be used as an adjuvant, not as a single drug.

2. Redo-CABG: The surgical difficulty, perioperative complications, and mortality of redo-CABG are all much higher than those of primary CABG. The symptom relief rate is low, and the 1-year postoperative graft occlusion rate is as high as 41%.⁵³ Event-free survival is also low. Redo-CAGB treatment has decreased in the last two decades. Therefore, redo-CABG is not recommended as a first choice for SVGD treatment.

3. Percutaneous coronary intervention (PCI): PCI is still the first choice for myocardial ischemia after CABG. In China, most revascularization procedures are performed by PCI. With respect to revascularization strategies, both the feasibility of PCI and the blood flow competition between reconstructed vessels and the SVG should be taken into account. Intervention sites include the SVG and native vessel (NV). The efficacy of bare metal stents in SVGs is inferior to the efficacy in NVs. The long-term efficacy of stent implantation is poor, and the restenosis rate ranges from 30% to 60%. A recent meta-analysis⁵⁴ suggested that drug-eluting stents (DESs) are better than bare metal stents when used in SVGs. DESs in SVGs yield the same effect as in NVs; however, the long-term safety, particularly late thrombosis associated with DESs, needs further evaluation.⁵⁵ In a meta-analysis conducted by Lupi et al.,⁵⁶ DESs were shown to significantly reduce target vessel revascularization; however, there is no clear evidence to confirm that DESs can reduce mortality and myocardial infarction. Thus far, DESs have proven to be an acceptable method for SVGD. Covered stents, including self-expanding stents, are not recommended.

3.1 NV PCI: NV PCI-associated procedures are relatively simple, surgeons are more experienced, and instruments are complete. The treatment has a relatively high success rate, and its efficacy for complex coronary artery disease has improved. The advantage of NV PCI is that the coronary arteries are open to replace aging SVGs and supply blood; the long-term efficacy is more reliable.⁵⁷ Notably, the complexity of NV lesions will inevitably affect the success rate of PCI.⁵⁸

3.2 SVG PCI: SVG PCI is more effective than redo-CABG but is associated with the risk of intraoperative distal embolization and postoperative restenosis; the long-term effect of SVG PCI is inconclusive. Current guidelines do not recommend PCI for use in fully occluded SVGs.^59,60 The intracoronary administration of nitroglycerin, diltiazem, or tirofiban has no significant effect on no reflow; the efficacy of distal protection devices is also controversial. Virtual histology intravascular ultrasound (VH-IVUS) is a recently developed imaging technique for detecting atherosclerotic plaques. A recent study⁶¹ used VH-IVUS to examine 125 patients with SVGD undergoing PCI before and after stent implantation. The study showed that in 19 patients with no reflow, the incidences of intraluminal masses, multiple plaque ruptures, plaque irregularities, and tissue prolapse were significantly higher than in patients with normal angiography findings. VH-IVUS can further identify plaque components, which is valuable in predicting slow flow and no reflow after PCI. The information obtained by VH-IVUS is also of significance in guiding PCI surgery, optimizing the treatment strategy, reducing operative risk, and improving patient prognosis.

Prevention of SVGD

1. No-Touch technique: Souza⁶² was the first to design the No-Touch technique to harvest the great saphenous vein in the 1990s. Johansson et al.⁶³ conducted short-term (18 months) and long-term (8.5 years) randomized controlled trials to compare the efficacy of the No-Touch versus traditional techniques. The SVG stenosis rate, intimal thickness, and intimal hyperplasia were better in the No-Touch group than in the traditional group, while the vascular lumen diameter was greater in the No-Touch group than in the traditional group. A long-term study showed that the No-Touch group had fewer intravenous plaques. Rueda et al.⁶⁴ also showed that the short-term patency rate and endothelial integrity were higher in the No-Touch group than in the traditional group. Kim et al.⁶⁵ reported that the short-term and 1-year SVG patency rates of the No-Touch technique were significantly higher than those of traditional techniques. Harvesting the saphenous vein with surrounding tissues may increase SVG patency rates in a likely mechanism similar to the No-Touch technique.⁶⁶ These findings favor the advantages of the No-Touch technique in preventing SVGD.

2. External stenting: The anti-expansion and anti-tension effects of external stents can influence SVG remodeling. Zurbrugg et al.⁶⁷ encased SVGs implanted into the carotid arteries of pigs with biosynthetic external stents. After 4 weeks, Taggart et al.⁶⁸ found that the wall thicknesses of the medial and intimal layers were significantly lower than those in the control group, suggesting that external stents can prevent excessive expansion of grafts and mitigate intimal hyperplasia. Zheng et al.⁶⁹ found that external stents after CABG improved lumen uniformity and reduced intimal hyperplasia. Different stents may have different preventive effects. Animal studies have shown that external restrictive polyester⁵⁶ and nonrestrictive P(3HB-co-3HV) stents⁷⁰ can prevent SVG intimal hyperplasia and restenosis. Porous silicone tube stents are superior to autologous neck fascia and cyanoacrylate adhesive stents in terms of vascular patency and intimal hyperplasia.⁷¹ Therefore, it may be more important to select appropriate stents in the prevention of restenosis.

Drug prevention

3.1 Anti-platelet aggregation drugs: Aspirin has been shown to improve the 1-year SVG patency rate and reduce the incidence of adverse cardiovascular events.⁷² Administration of aspirin within 6 to 24 hours after surgery can effectively prevent SVG occlusion. Aspirin is not beneficial if administered 48 hours after surgery.^73,74 A meta-analysis showed that the best time for administration of aspirin was 6 hours after surgery; this timing did not increase the risk of bleeding.⁷⁵ Wu et al.⁷⁶ reported that aspirin at 100 mg/day significantly improved the perioperative vein patency after non-extracorporeal circulation CABG. Early application of aspirin after CABG has a positive effect on the prevention of SVG stenosis and long-term cardiovascular events. The current guideline recommends a routine daily aspirin dose of 75 to 150 mg.

3.2 Dual anti-platelet therapy (DAPT): Aspirin resistance is an important mechanism underlying early occlusion of CABG grafts. For patients who are suspected to be aspirin-resistant or -intolerant or in whom aspirin is contraindicated, early administration of low-dose clopidogrel (75 mg/d) is an alternative.⁷⁷ With respect to clopidogrel or aspirin alone or in combination, Gao et al.⁷⁸ found that there was no significant difference in the 1- and 12-month SVG patency rates after off-pump CABG between clopidogrel alone and clopidogrel combined with aspirin. Kulik et al.⁷⁹ also showed that the combination of clopidogrel and aspirin did not significantly reduce SVG intimal hyperplasia; there was no significant difference in SVG patency between clopidogrel alone and the combination of the two drugs. Whether the combination of aspirin and clopidogrel can reduce perioperative myocardial infarction and improve long-term SVG patency remains controversial; however, the 2017 European Society of Cardiology guidelines updated the application of DAPT. Specifically, regardless of the revascularization method (PCI or CABG), the recommended regular DAPT course is 12 months. Six months of DAPT can be considered for patients at high risk of bleeding, while DAPT can be extended to >12 months for treatment-tolerant patients with no bleeding complications.

3.3 Statins: According to CABG surgery guidelines, all patients receiving CABG should be target subjects for lipid-lowering therapy. All patients should be administered statins unless contraindications exist. In a large-scale study, post-CABG coronary angiography showed that lovastatin significantly delayed atherosclerosis of the SVG. Patients in the aggressive-treatment group had a lower revascularization rate.⁸⁰ Ouattara et al.⁸¹ showed that perioperative administration of statins reduced the incidence of adverse cardiac events after CABG and that the effect was dose-dependent. Kulik et al.⁸² found that early treatment with statins (within 1 month after discharge) independently reduced all-cause mortality and major adverse cardiac events. The targets of lipid-lowing therapy are a total cholesterol level of <4.68 mmol/L, an LDL-C level of <2.60 mmol/L, a triglyceride level of <1.70 mmol/L, and an HDL-C level of >1 mmol/L. Simvastatin was also shown to inhibit the endothelial prothrombotic shift in the SVG in patients with well-controlled diabetes.⁸³ A post-CABG follow-up study of 1 to 11 years in length showed that active reduction in the LDL-C level reduced the development of atherosclerosis in the SVG.⁸⁰ Kang et al.⁸⁴ agreed that long-term and active control of the LDL-C level with statins significantly delayed the progression of atherosclerosis in SVG and reduced the risk of atherosclerosis and post-CABG revascularization. For patients undergoing CABG, treatment with statins should be initiated during hospitalization. The perioperative application of statins significantly decreases the incidence of atrial fibrillation after surgery. Aggressive lipid-lowing therapy also decreases major end-point events and achieves greater clinical benefits.⁸⁵ PROVE-IT suggested that in patients undergoing CABG with high-risk factors, the LDL-C level should be reduced to 1.82 mmol/L.⁸⁶

3.4 Other drugs: Animal model studies have shown that tacrolimus,⁸⁷ tranilast,⁸⁸ and ursolic acid⁸⁹ can also inhibit SVG restenosis.

4. Gene technology: Gene technology can be used to prevent SVGD in two ways: by introducing a specific protein through gene-transfected cells or by suppressing the production of a specific protein with an antisense oligonucleotide.⁹⁰ Safe and effective vectors are the basis of gene therapy. Current commonly used vectors include adenovirus, lentivirus, and non-viral vectors. In 1994, Chen et al.⁹¹ first reported soluble vascular cell adhesion molecule transgenic treatment of a porcine SVGD model mediated by adenovirus vector. Although the SVG was successfully transfected by soluble vascular cell adhesion molecule, no positive effect was observed. Mann et al.⁹² first reported the use of antisense oligonucleotides to inhibit intimal hyperplasia and atherosclerosis by regulating the cell cycle. Multiple studies have shown transfection with the tissue inhibitor of metalloproteinase 1, 2, and 3 genes inhibited vascular smooth muscle cell proliferation and intimal thickening.⁹³ Additionally, the proliferation of vascular smooth muscle cells and intimal hyperplasia in SVGs is inhibited by transfection with microRNA-145, microRNA-221, Jag1, the early growth response factor 1 decoy oligonucleotide, and the Girdin gene.^94–98 Transgenic treatment with endothelial nitric oxide synthase and inducible nitric oxide synthase has been shown to effectively inhibit inflammatory cell proliferation and intimal hyperplasia in the SVG and has a certain preventive effect against SVGD.⁹⁹

In summary, SVGD has a complex pathogenic mechanism. SVGD is closely associated with thrombosis, SVG intimal hyperplasia, and the formation of atherosclerosis. The pathogenesis and development of SVGD are associated with many factors, including common cardiovascular risk factors, surgery-related factors, and biochemical indicators. Some preventive measures targeting the SVGD mechanism and risk factors have been developed and clinically applied. For example, cardiac surgeons using No-Touch technology for CABG as well as physicians using anti-platelet aggregation, anticoagulation, and lipid-lowering therapy after CABG have achieved significant efficacy. The application of gene technology provides new strategies for SVGD prevention. The current treatment of SVGD includes anticoagulation, redo-CABG, and PCI. The strategy of post-CABG revascularization should be implemented based on individual needs.

Footnotes

Declaration of conflicting interest

The authors declare that there is no conflict of interest.

Funding

This research 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 the Municipal Health Planning Committee Science and Technology Fund Project of Tianjin in 2015 (No. 2015KY35).

References

Chen

Gao

Liu

et a1 . Summary of China cardiovascular disease report 2015. Chin Circul J 2016; 31: 521–528.

Goldman

Zadina

Moritz

et a1 . Long-term patency of saphenous vein and left internal mammary artery grafts after coronary artery bypass surgery: results from a department of veterans affairs cooperative study. J Am Coil Cardiol 2004; 44: 2149–2156.

Fitzgibbon

Kafka

Leach

et al . Coronary bypass graft fate and patient outcome: angiographic follow-up of 5,065 grafts related to survival and reoperation in 1,388 patients during 25 years. J Am Coll Cardiol 1996: 28: 616–626.

Bourassa

MG.

Fate of venous grafts: the past, the present and the future.

J Am Coll Cardiol. 1991: 17: 1081–1083.

Wiedemann

Kocher

Bonaros

et al . Perivascular administration of drugs and genes as a means of reducing vein graft failure. Curr Opin Pharmacol 2012: 12: 203–216.

Yayla

Canpolat

Akyel

et al . Association between platelet to lymphocyte ratio and saphenous vein graft disease. Angiology 2016; 67: 133–188. pii: 000331971557825

Demircelik

Cakmak

Nazli

et al . Adropin: a new marker for predicting late saphenous vein graft disease after coronary artery bypass grafting. Clin Invest Med 2014; 37: E338–E344.

Doğan

Akyel

Cimen

et al . Relationship between neutrophil-to-lymphocyte ratio and saphenous vein graft disease in patients with coronary bypass. Clin Appl Thromb Hemost 2015: 21: 25–29.

Lee

Park

Kandzari

et al . Saphenous vein graft intervention. JACC Cardiovasc Interv 2011; 4: 831–843.

10.

Deppe

Arbash

Kuhn

et al . Current evidence of coronary artery bypass grafting off-pump versus on-pump: a systematic review with meta-analysis of over 16,900 patients investigated in randomized controlled trials. Eur J Cardiothorac Surg 2016: 49: 1031–1041.

11.

Kim

Choi

et al . No-touch saphenous vein harvesting may improve further the patency of saphenous vein composite grafts: early outcomes and 1-year angiographic results. Ann Thorac Surg 2017: 103: 1489–1497.

12.

Dreifaldt

Souza

Loesch

et al . The “no-touch” harvesting technique for vein grafts in coronary artery bypass surgery preserves an intact vasa vasorum. Thorac Cardiovasc Surg 2011: 141: 145–150.

13.

Souza

A new no-touch preparation technique. Technical notes.

Scand J Thorac Cardiovasc Surg 1996: 30: 41–44.

14.

Khaleel

Dorheim

Duryee

et al . High-pressure distention of the saphenous vein during preparation results in increased markers of inflammation: a potential mechanism for graft failure. Ann Thorac Surg 2012: 93: 552–558.

15.

Nolte

Secker

Walker

et al.

Veins are no arteries: even moderate arterial pressure induces significant adhesion molecule expression of vein grafts in an ex vivo circulation model. J Cardiovasc Surg 2011: 52: 251–259.

16.

Verma

Lovren

Pan

et al . Pedicled no-touch saphenous vein graft harvest limits vascular smooth muscle cell activation: the PATENT saphenous vein graft study. Eur J Cardiothorac Surg 2014: 45: 717–725.

17.

Perek

Malinska

Stefaniak

et al . Predictive factors of late venous aortocoronary graft failure: ultrastructural studies. PLoS One 2013: 8: e70628.

18.

Goldman

Zadina

Moritz

et al . Long-term patency of saphenous vein and left internal mammary artery grafts after coronary artery bypass surgery: results from a department of Veterans affairs cooperative study. J Am Coll Cardiol 2004: 44: 2149–2156.

19.

Yamane

Uchida

Okubo

et al . Impact of the size mismatch between saphenous vein graft and coronary artery on graft patency. Gen Thorac Cardiovasc Surg 2017; 65: 25–31.

20.

Danek

B A

Karatasakis

Alame

A J

et al.

Saphenous vein graft near-infrared spectroscopy imaging insights from the lipid core plaque association with clinical events near-infrared spectroscopy (ORACLE-NIRS) registry. Catheter Cardiovasc Interv 2017; 89: E172–E180.

21.

Hess

Lopes

Gibson

et al . Saphenous vein graft failure after coronary artery bypass surgery: insights from PREVENT IV. Circulation 2014: 130: 1445–1451.

22.

Castagna

Mintz

Ohlmann

et al . Incidence, location, magnitude, and clinical correlates of saphenous vein graft calcification: an intravascular ultrasound and angiographic study. Circulation 2005: 11: 1148–1152.

23.

Sun

Lin

Ding

et al . Secondhand smoking and matrix metalloproteinase-2 and -9 gene expression in saphenous veins of women nonsmokers. Ann Thorac Surg 2014: 98: 556–562.

24.

Yongxin

Wenjun

Qiang

et al . Heavy smoking before coronary surgical procedures affects the native matrix metalloproteinase-2 and matrix metalloproteinase-9 gene expression in saphenous vein conduits. Ann Thorac Surg 2013: 95: 55–61.

25.

Sharif

Bayraktutan

Arya

et al . Smoking impairs endothelial function in human saphenous vein in an ex vivo model. Ann Vasc Surg 2009: 23: 116–121.

26.

Muir

McKeown

Bayraktutan

Role of gender, smoking profile, hypertension, and diabetes on saphenous vein and internal mammary artery endothelial relaxation in patients with coronary artery bypass grafting.

Oxid Med Cell Longev 2010: 3: 199–205.

27.

Higman

Greenhalgh

Powell

JT.

Smoking impairs endothelium-dependent relaxation of saphenous vein

. Br J Surg 1993: 80: 1242–1245.

28.

Sen

Yilmaz

Balci

et al . The relationship between vitamin D levels and saphenous vein graft patency. Coron Artery Dis 2015: 26: 328–332.

29.

Radenković

Pioglitazone and endothelial dysfunction pleiotropic effects and possible therapeutic implications.

Sci Pharm 2014: 82: 709–721.

30.

Muto

Model

Ziegler

et al . Mechanisms of vein graft adaptation to the arterial circulation: insights into the neointimal algorithm and management strategies. Circ J 2010: 74: 1501–1512.

31.

Roberts

Gohil

Hudson

et al . Aberrant phenotype in human endothelial cells of diabetic origin: implications for saphenous vein graft failure? J Diabetes Res 2015: 2015: 409432.

32.

Koshizaka

Lopes

Reyes

et al . Long-term clinical and angiographic outcomes in patients with diabetes undergoing coronary artery bypass graft surgery: results from the project of Ex-vivo Vein graft engineering via transfection IV trial. Am Heart J 2015: 169: 175–184.

33.

Jerzewski

Ruel

Voisine

et al . Does high-density lipoprotein influence the development of saphenous vein graft disease after coronary bypass surgery?: exploratory analysis from the CASCADE trial. J Cardiothorac Surg 2013: 8: 172.

34.

Hata

Takayama

Sezai

et al . Efficacy of aggressive lipid controlling therapy for preventing saphenous vein graft disease. Ann Thorac Surg 2009: 88: 1440–1444.

35.

Akboga

Yayla

Balci

et al.

Relationship between serum albumin level and monocyte-to-high-density lipoprotein cholesterol ratio with saphenous vein graft disease in coronary bypass. Thorac Cardiovasc Surg 2017; 65: 315–321.

36.

Cagirci

Cay

Karakurt

et al . Association between plasma asymmetrical dimethylarginine activity and saphenous vein graft disease in patients with coronary bypass. Coron Artery Dis 2010: 21: 20–25.

37.

Akyel

Çelik

İ E

Öksüz

et al . Red blood cell distribution width in saphenous vein graft disease. Can J Cardiol 2013: 29: 448–451.

38.

Fuentes

Andrés

et al . Role of platelets as mediators that link inflammation and thrombosis in atherosclerosis. Platelets 2013: 24: 255–262.

39.

Tavil

Şen

Yazici

et al . Relationship between elevated platelet volume and saphenous vein graft disease. Clin Invest Med 2010: 33: 161–167.

40.

Akpinar

Sayin

Gursoy

et al . Plateletcrit. A platelet marker associated with saphenous vein graft disease. Herz 2014; 39: 142–148.

41.

Ege

Guray

et al . Platelet distribution width and saphenous vein disease in patients after CABG. Herz 2013: 38: 197–201.

42.

Yayla

Canpolat

Akyel

et al . Association between platelet to lymphocyte ratio and saphenous vein graft disease. Angiology 2016: 67 133–138.

43.

Doğan

Akyel

Cimen

et al . Relationship between neutrophil-to-lymphocyte ratio and saphenous vein graft disease in patients with coronary bypass. Clin Appl Thromb Hemost 2015: 21: 25–29.

44.

Sun

Liu

Gao

et al.

The relation between blood routine test indicators and advanced saphenousvein graft disease in patients with coronary artery bypass grafting. Tianjin Med J 2017: 45: 191–196.

45.

Kocaoğlu

Arslan

Koza

et al . Saphenous vein graft disease is associated with a low serum erythropoietin level. Med Princ Pract 2015: 24: 544–547.

46.

Sen

Yilmaz

Balci

K G

et al . The relationship between vitamin D levels and saphenous vein graft patency. Coron Artery Dis 2015; 26: 328–332.

47.

Perek

Malinska

Misterski

et al . Preexisting high expression of matrix metalloproteinase-2 in tunica media of saphenous vein conduits is associated with unfavorable long-term outcomes after coronary artery bypass grafting. Biomed Res Int 2013: 2013: 730–721.

48.

Perek

Malinska

Stefaniak

et al . Predictive factors of late venous aortocoronary graft failure: ultrastructural studies. PLoS One 2013: 8:e70628.

49.

Perek

Malińska

Ostalska-Nowicka

et al . Cytokeratin 8 in venous grafts: a factor of unfavorable long-term prognosis in coronary artery bypass grafting patients. Cardiol J 2013: 20: 583–591.

50.

Runyan

Gorges

Feldman

et al.

Long-term follow-up of lesion-specific outcomes comparing drug-eluting stents and bare metal stents in diseased saphenous vein grafts.

Rev Cardiovasc Med 2013; 14: 1–6.

51.

Gupta

Cigarroa

: The quest for optimal interventional strategy in saphenous vein graft interventions - are we there yet? Catheter Cardiovasc Interv 2012; 80: 1118–1119.

52.

Harskamp

Hoedemaker

Newby

et al . Procedural and clinical outcomes after use of the glycoprotein IIb/IIIa inhibitor abciximab for saphenous vein graft interventions. Cardiovasc Revasc Med 2016: 17: 19–23.

53.

Widimsky

Straka

Stros

et al . One-year coronary bypass graft patency: a randomized comparison between off-pump and on-pump surgery angiographic results of the PRAGUE-4 trial. Circulation 2004: 110: 3418–3423.

54.

Hakeem

Helmy

Munsif

et al : Safety and efficacy of drug eluting stents compared with bare metal stents for saphenous vein graft interventions: a comprehensive meta-analysis of randomized trials and observational studies comprising 7,994 patients. Catheter Cardiovasc Interv 2011: 77: 343–355.

55.

Goswami

Gaffigan

Berrio

et al . Long-term outcomes of drug-eluting stents versus bare-metal stents in saphenous vein graft disease: results from the prairie ‘real world’ stent registry. Catheter Cardiovasc Interv 2010: 75: 93–100.

56.

Lupi

Navarese

Lazzero

et al . Drug-eluting stents vs. bare metal stents in saphenous vein graft disease. Insights from a meta-analysis of 7,090 patients. Circ J 2011: 75: 280–289.

57.

Mavroudis

Kotecha

Chehab

et al . Superior long term outcome associated with native vessel versus graft vessel PCI following secondary PCI in patients with prior CABG. Int J Cardiol 2017: 228: 563–569.

58.

Sturm

Goldberg

Embolic protection devices in saphenous vein graft and native vessel percutaneous intervention: a review.

Curr Cardiol Rev 2012: 8: 192–199.

59.

Guo

Wijeysundera

et al . Long-term safety and effectiveness of drug-eluting stents for the treatment of saphenous vein grafts disease: a population-based study. JACC Cardiovasc Interv 2011: 4: 965–973.

60.

Hindnavis

Cho

Goldberg

Saphenous vein graft intervention: a review.

J Invasive Cardiol 2012: 24: 64–71.

61.

Hong

Jeong

Ahn

et al . Intravascular ultrasound findings that are predictive of no reflow after percutaneous coronary intervention for saphenous vein graft disease. Am J Cardiol 2012: 109: 1576–1581.

62.

Souza

A new no-touch preparation technique. Technical notes

. Scand J Thorac Cardiovasc Surg 1996: 30: 41–44.

63.

Johansson

Souza

Bodin

et al . Slower progression of atherosclerosis in vein grafts harvested with ‘no touch' technique compared with conventional harvesting technique in coronary artery bypass grafting: an angiographic and intravascular ultrasound study. Eur J Cardiothorac Surg 2010; 38: 414–419.

64.

Rueda

Souza

Lima Rde

et al . Novel no-touch technique of harvesting the saphenous vein for coronary artery bypass grafting. Arq Bras Cardiol 2008; 90: 356–362.

65.

Kim

Choi

et al . No-touch saphenous vein harvesting may improve further the patency of saphenous vein composite grafts: early outcomes and 1-year angiographic results. Ann Thorac Surg 2017: 103: 1489–1497.

66.

Verma

Lovren

Pan

et al . Pedicled no-touch saphenous vein graft harvest limits vascular smooth muscle cell activation: the PATENT saphenous vein graft study. Eur J Cardiothorac Surg 2014: 45: 717–725.

67.

Zurbrugg

Wied

Angelini

GD.

Reduction of intimal and medial thickening in sheathed vein grafts.

Ann Thorac Surg 1999: 68: 79–83.

68.

Taggart

Ben Gal

Lees

et al . A randomized trial of external stenting for saphenous vein grafts in coronary artery bypass grafting. Ann Thorac Surg 2015: 99: 2039–2045.

69.

Zheng

Pang

et al.

Experimental study of external stents preventing porcine saphenous vein grafts restenosis. Chin J Clin Thorac Cardiovasc Surg 2006: 13: 405–408.

70.

Qiu

Dong

et al.

A novel external stent prepared by electrospinning reduces neointimal hyperplasia of vein grafts. Chin J Exp Surg 2009: 26: 556–558.

71.

Guo

Liang

Sun

et al.

A comparison study of three kinds of external stent on preventing restenosis after vein graft. Modern Journal of Integrated Traditional Chinese and Western Medicine 2015: 24: 1369–1371, 1374.

72.

Harskamp

Beijk

Damman

et al . Prehospitalization antiplatelet therapy and outcomes after saphenous vein graft intervention. Am J Cardiol 2013: 111: 153–158.

73.

Gukop

Gutman

Bilkhu

et al . Who might benefit from early aspirin after coronary artery surgery? Interact Cardiovasc Thorac Surg 2014: 19: 505–511.

74.

Khan

Jalal

et al . Risks and benefits of giving early aspirin within 6 hours of CABG: a retrospective analysis. Pak J Med Sci 2017: 33: 106–110.

75.

Fremes

Levinton

Naylor

et al . Optimal antithrombotic therapy following aortocoronary bypass: a meta-analysis. Eur J Cardiothorac Surg 1993: 7: 169–180.

76.

Wang

Sun

et al . Preoperative continuation of aspirin therapy may improve perioperative saphenous venous graft patency after off-pump coronary artery bypass grafting. Ann Thorac Surg 2015: 99: 576–580.

77.

Kim

Daskalakis

Silvestry

et al . Aspirin and clopidogrel use in the early postoperative period following on-pump and off pump coronary artery bypass grafting. J Thorac Cardiovasc Surg 2009: 138: 1377–1384.

78.

Gao

Ren

et al . Clopidogrel and aspirin versus clopidogrel alone on graft patency after coronary artery bypass grafting. Ann Thorac Surg 2009; 88: 59–63.

79.

Kulik

Le May

Wells

et al.

The clopidogrel after surgery for coronary artery disease (CASCADE) randomized controlled trial: clopidogrel and aspirin versus aspirin alone after coronary bypass surgery. Curr Control Trials Cardiovasc Med. 2005: 6: 15.

80.

Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med 1997: 336: 153–162.

81.

Ouattara

Benhaoua

Le Manach

et al . Perioperative statin therapy is associated with a significant and dose-dependent reduction of adverse cardiovascular outcomes after coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth 2009; 23: 633–638.

82.

Kulik

Brookhart

Levin

et al . Impact of statin use on outcomes after coronary artery bypass graft surgery. Circulation 2008: 118: 1785–1792.

83.

Spadaccio

De Marco

Di Domenico

et al . Simvastatin attenuates the endothelial pro-thrombotic shift in saphenous vein grafts induced by advanced glycation endproducts. Thromb Res 2014: 133: 418–425.

84.

Kang

Liu

XB.

Effects of aggressive statin therapy on patients with coronary saphenous vein bypass grafts: a systematic review and meta-analysis of randomized, controlled trials.

Clin Ther 2013: 35: 1125–1136.

85.

Liakopoulos

Choi

Kuhn

et al . Statins for prevention of atrial fibrillation after cardiac surgery: a systematic literature review. J Thorac Cardiovasc Surg 2009; 138: 678–686.

86.

Brilakis

de Lemos

Cannon

et al . Outcomes of patients with acute coronary syndrome and previous coronary artery bypass grafting (from the pravastatin or atorvastatin evaluation and infection therapy [PROVE IT-TIMI 22] and the Aggrastat to Zocor [A to Z]trials). Am J Cardiol 2008: 102: 552–558.

87.

Huo

Jia

Liang

et al.

Effect of tacrolimus on intimal hyperplasia in autogenous vein grafts of rats. Intern Med 2016: 11: 335–338, 385.

88.

Sun

CL.

Effect of tranilast on restenosis after canine autologous vein transplantation. Journal of Practical Hand Surgery 2016: 30: 469–471.

89.

Liu

et al.

Study the effects of ursolic acid inhibition of inflammation in the autologous vein graft restenosis rat model. Chinese Journal of Cardiovascular Research 2016: 14: 755–757.

90.

Akowuah

Sheridan

Cooper

et al . Preventing saphenous vein graft failure: does gene therapy have a role? Ann Thorac Surg 2003; 76: 959–966.

91.

Chen

Wilson

Muller

DW.

Adenovirus-mediated gene transfer of soluble vascular cell adhesion molecule to porcine interposition vein grafts.

Circulation 1994: 89: 1922–1928.

92.

Mann

Gibbons

Tsao

et al . Cell cycle inhibition preserves endothelial function in genetically engineered rabbit vein grafts. Clin Invest 1997: 99: 1295–1301.

93.

Akowuah

Gray

Lawrie

et a1 . Ultrasound-mediated delivery of TIMP-3 plasmid DNA into saphenous vein leads to increased lumen size in a porcine interposition graft model. Gene Ther 2005: 12: 1154–1157.

94.

Wang

Lee

et al . MicmRNA-221 sponge therapy attenuates neointimal hyperplasia and improves blood flows in vein grafts. Int J Cardiol 2016; 208: 79–86.

95.

Ohnaka

Marui

Yamahara

et al . Effect of microRNA-145 to prevent vein graft disease in rabbits by regulation of smooth muscle cell phenotype. J Thorac Cardiovasc Surg 2014; 148: 676–682.

96.

Wang

Mei

et al . Early growth response gene-1decoy oligonucleotides inhibit vascular smooth muscle cell proliferation and neointimal hyperplasia of autogenous vein graft in rabbits. Interact Cardiovasc Thorac Surg 2015; 21: 50–54.

97.

Zhou

Xiao

Mao

et al . Soluble Jagged-1 inhibits restenosis of vein graft by attenuating notch signaling. Micmvasc Res 2015; 100: 9–16.

98.

Miyachi

Takahashi

Komori

A novel approach against vascular intimal hyperplasia through the suppression of Girdin.

Ann Vasc Dis 2015; 8: 69–73.

99.

Mcilhenny

Zhang

Tulenko

et al . eNOS transfection of adipose-derived stem cells yields bioactive nitric oxide production and improved results in vascular tissue engineering. J Tissue Eng Regen Med 2015; 9: 1277–1285.