**4. Saphenous vein graft failure**

Studies of saphenous veins harvested for bypass procedures have shown that many have abnormal histological and physical attributes. [23,24] Moreover, the quality of the saphenous vein can have significant clinical consequences. Therefore, vein grafts in the arterial circulation must be considered as a viable, constantly adapting and evolving conduit.

Several intrinsic and extrinsic factors may play a role in the mechanism of SVG failure. At the time of harvest, the quality of the saphenous veins may be poor, demonstrating a spectrum of pre-existing pathological conditions ranging from significantly thickened walls to post phlebitic changes and varicosities. Between 2% and 5% of saphenous veins are unusable and up to 12% can be considered diseased which reduce the patency rate by one half compared to non-diseased veins. [25] In addition, the inevitable vascular trauma that occurs during SVG harvesting itself can also lead to damage to the endothe‐ lium and SMC and thereby contribute to graft failure. Surgical manipulation and highpressure distension to reverse spasm during harvesting leads to loss of endothelial integrity and the antithrombogenic attributes of the endothelium, rendering the SVG prone to subsequent occlusive intimal hyperplasia and/or thrombus formation. [26] Dur‐ ing harvesting the vasa vasorum and nervous network of the SVG are devided, making the graft dependent on diffusion for weeks until adequate circulation is esthablished. [27-32] Ischemic insult and decreased production of nitric oxide and adenosine may cause SMC proliferation. [33] As it has been demonstrated that intimal hyperplasia does not occur in vein-to-vein isografts, it can be stated that pathologic changes seen in SVG in the arterial circulation are predominantly caused by hemodynamic and physiochemical changes. [34]

In a later stage atherosclerotic lesions may be complicated by aneurysmal dilatation which is found to correlate with thrombosed SVG. (66) The occurrence of atheroembo‐ lism form the diseased graft or plaque rupture may cause late thrombosis necessitating revascularization therapy. [57,58] In general, SVG thrombosis is the major cause of mor‐

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Predictors of graft patency 3 years after CABG were evaluated by Veterans Affairs Cooperative Study Group. [59] Multivariable analysis showed that the only factors that were predictive were vein preservation solution temperature ≤5ºC, serum cholesterol, the number of proximal anastomoses ≤2, and recipient artery diameter >5 mm. Thus, predictors of 3-year graft patency are most closely related to operative techniques and the underlying disease. In another study, factors that predict the late progression of SVG atherosclerosis were evaluated in 1248 patients in the Post-CABG trial. [47] Factors independently associated with the progression of disease were maximum stenosis of the graft at baseline angiography, years after CABG, moderate therapy to lower LDL cholesterol, prior MI, high triglyceride levels, small minimum graft diameter, low HDL concentration, high LDL concentration, high mean arterial pressure, low left ventricular ejection fraction, male gender, and current cigarette smoking. Finally, concerns have been raised about the possibility of worse outcomes when a SVG is used for multiple distal anastomosis compared to single anastomosis. In a substudy of the PREVENT IV trial, the use of SVG conduits with multiple distal anastomoses was associated with a significantly higher rate of ≥75 percent stenosis of the SVG on angiography at one year. [60] Moreover, clinical follow-up showed a trend towards a higher rate of the adjusted composite of death,

Noteworthy, the clinical impact of SVG failure is still debated. Not all grafts that have angiographic stenosis or occlusion will cause symptoms, and probably a substantial of SVG

Several arterial conduits are suitable for myocardial revascularization and the arterial conduits can be divided into 3 types according to functional class (Table 1). Type I arterial grafts are the somatic arteries including the IMA, IEA, and subscapular artery. Type II arterial grafts are the splanchnic arteries including the GEA, splenic artery, and inferior mesenteric artery. Type III arterial grafts are the limb arteries including the RA, ulnar artery, and lateral femoral circum‐ flex artery. Compared to functional class type II and III, type I is less spastic. [61] Although the full length of arterial grafts is reactive, the major muscular components are located at the two ends of the artery (muscular regulator). [62] Therefore, in terms of preventing vasospasm of arterial grafts, trimming off the small and highly reactive distal end of the grafts (IMA, GEA,

Studies have demonstrated that there are differences between arterial and venous grafts: 1) arterial grafts are less susceptible to vasoactive substances then veins [63]; 2) the arterial wall

bidity and mortality. [19,41]

MI, or revascularization at five years.

that fail do not impact outcomes.

**5. Histology of arterial grafts**

IEA, or other grafts) may be important and clinically feasible.

SVG failure can be divided into three temporal categories: early (0 to 30 days), midterm (30 days to 1 year) or late (after 1 year). Early SVG failure due to thrombotic complica‐ tions is mainly attributable to technical errors during harvesting, anastomosis or com‐ prised anatomic runoff. [19,35-37] It occurs in 15% to 18% of VG during the 1st month. [38-40] Early thrombotic complications in SVG in the arterial circulation are caused by a reduction of tissue plasminogen activator, attenuation of thrombomudulin and reduced expression of heparin sulphate. [41]

Midterm SVG failure is mainly caused by fibrointimal hyperplasia as it serves as the founda‐ tion for subsequent graft atheroma leading to occlusive stenosis. The release of a variety of mediators, growth factors, and cytokines by the injured endothelium, platelets and activated macrophages will cause migration and proliferation of SMC. Diminished production of endothelial nitric oxide (NO), prostaglandin 12 and adenosine will further contribute to and enhanced SMC proliferation, leading to development of neointimal hyperplasia. [19,33,37,42-44] Changes in the flow pattern within the vessel (shear stress) an ischemic insults may contribute to changes in the SVG at this stage. SVG are exposed to much higher mechanical pressure that they were adapted to (arterial versus venous blood pressure) which can poten‐ tially stimulate SMC proliferation. Moreover, after encountering arterial flow patterns increased levels of intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and monocyte chemotactic protein-1 will facilitate leukocyte-endothelial interactions so that leukocyte infiltration of the lesions will ensue. [34] Finally, the adaptive response to hemody‐ namic factors, i.e. wall shear stress, may affect the distal site of the anastomosis leading to SVG failure. [45,46] Midterm SVG failure accounts for an additional 15% to 30%. [47,48] In the course of vessel remodelling, late SVG failure is characterized by progression of intimal fibrosis at the cost of a reduction in cellularity which may contribute to progression of SMC apoptosis. [19,34,41,44] In addition, perivascular fibroblasts may also be involved in neointimal formation and matrix deposition as these cells may exhibit contractile elements while migrating from the adventitia towards the media. [49] After 1 year most SVG stenosis is due to atherosclerosis but although vein graft atherosclerosis is accelerated compared to arteries, evidence show that a fully evolved plaque appear after 3 to 5 years of implantation. [35,47,50] In SVG there is no focal compensatory enlargement in the stenotic segments which is in contrast to native atherosclerotic arteries in which the development of an atherosclerotic plaque is associated with enlargement of the vessel and preservation of the lumen area until plaque progression exceeds the compensatory mechanism of the vessel. [51] Several studies show that SVG patency at 10 years is no more than 50% to 60%. [19,41,52,53] Finally, several studies have suggested a role of immune cells in neointimal formation as macrophages are found in the intima, while T-lymphocytes are present in the adventitia of neointimal lesions wit a predom‐ inance of CD4+ cells. [54-56]

In a later stage atherosclerotic lesions may be complicated by aneurysmal dilatation which is found to correlate with thrombosed SVG. (66) The occurrence of atheroembo‐ lism form the diseased graft or plaque rupture may cause late thrombosis necessitating revascularization therapy. [57,58] In general, SVG thrombosis is the major cause of mor‐ bidity and mortality. [19,41]

Predictors of graft patency 3 years after CABG were evaluated by Veterans Affairs Cooperative Study Group. [59] Multivariable analysis showed that the only factors that were predictive were vein preservation solution temperature ≤5ºC, serum cholesterol, the number of proximal anastomoses ≤2, and recipient artery diameter >5 mm. Thus, predictors of 3-year graft patency are most closely related to operative techniques and the underlying disease. In another study, factors that predict the late progression of SVG atherosclerosis were evaluated in 1248 patients in the Post-CABG trial. [47] Factors independently associated with the progression of disease were maximum stenosis of the graft at baseline angiography, years after CABG, moderate therapy to lower LDL cholesterol, prior MI, high triglyceride levels, small minimum graft diameter, low HDL concentration, high LDL concentration, high mean arterial pressure, low left ventricular ejection fraction, male gender, and current cigarette smoking. Finally, concerns have been raised about the possibility of worse outcomes when a SVG is used for multiple distal anastomosis compared to single anastomosis. In a substudy of the PREVENT IV trial, the use of SVG conduits with multiple distal anastomoses was associated with a significantly higher rate of ≥75 percent stenosis of the SVG on angiography at one year. [60] Moreover, clinical follow-up showed a trend towards a higher rate of the adjusted composite of death, MI, or revascularization at five years.

Noteworthy, the clinical impact of SVG failure is still debated. Not all grafts that have angiographic stenosis or occlusion will cause symptoms, and probably a substantial of SVG that fail do not impact outcomes.
