Saphenous vein grafts: to use or not to use?

The choice of the graft conduit is crucial to the success of coronary artery bypass grafting (CABG) because the patency of a coronary conduit is closely associated with an uneventful postoperative course and better long-term patient survival. From the beginning of coronary bypass surgery venous conduits particularly the great saphenous veins (GSV) have been the most frequently used coronary conduit from the beginning of the coronary bypass surgery. However, over the last decade or so, coronary bypass graft surgery with arterial revascularization of all diseased coronaries has shown to be efficient because arterial grafts have better long-term patency, especially left internal mammary artery (LIMA), compared with venous grafts. Early vein graft failure coupled with occlusion is the most important limitation of saphenous vein grafts. Nevertheless, vein grafting is still an integral part of cardiac surgical practice. This review provides a summary of the patency rates, technical features and certain characteristics of the venous conduits. It also examines the current understanding and knowledge of venous histology, vein graft pathology and the associated endothelial and smooth muscle cell physiology and pharmacology. In addition, the existing and the emerging strategies to combat and control vein graft intimal hyperplasia and accelerated atherosclerosis are reviewed in detail.     

Decellularized tissue-engineered blood vessel as an arterial conduit

Arterial tissue-engineering techniques that have been reported previously typically involve long waiting times of several months while cells from the recipient are cultured to create the engineered vessel. In this study, we developed a different approach to arterial tissue engineering that can substantially reduce the waiting time for a graft. Tissue-engineered vessels (TEVs) were grown from banked porcine smooth muscle cells that were allogeneic to the intended recipient, using a biomimetic perfusion system. The engineered vessels were then decellularized, leaving behind the mechanically robust extracellular matrix of the graft wall. The acellular grafts were then seeded with cells that were derived from the intended recipient--either endothelial progenitor cells (EPC) or endothelial cell (EC)--on the graft lumen. TEV were then implanted as end-to-side grafts in the porcine carotid artery, which is a rigorous testbed due to its tendency for graft occlusion. The EPC- and EC-seeded TEV all remained patent for 30 d in this study, whereas the contralateral control vein grafts were patent in only 3/8 implants. Going along with the improved patency, the cell-seeded TEV demonstrated less neointimal hyperplasia and fewer proliferating cells than did the vein grafts. Proteins in the mammalian target of rapamycin signaling pathway tended to be decreased in TEV compared with vein grafts, implicating this pathway in the TEV's resistance to occlusion from intimal hyperplasia. These results indicate that a readily available, decellularized tissue-engineered vessel can be seeded with autologous endothelial progenitor cells to provide a biological vascular graft that resists both clotting and intimal hyperplasia. In addition, these results show that engineered connective tissues can be grown from banked cells, rendered acellular, and then used for tissue regeneration in vivo.     

Saphenous vein grafts: to use or not to use?

The choice of the graft conduit is crucial to the success of coronary artery bypass grafting (CABG) because the patency of a coronary conduit is closely associated with an uneventful postoperative course and better long-term patient survival. From the beginning of coronary bypass surgery venous conduits particularly the great saphenous vein (GSV) has been the most frequently used coronary conduit. However, over the last decade or so, coronary bypass graft surgery with arterial revascularization of all diseased coronaries has shown to be efficient because arterial grafts have better long-term patency, especially left internal mammary artery (LIMA), compared with venous grafts. Early vein graft failure coupled with occlusion is the most important limitation of saphenous vein grafts. Nevertheless, vein grafting is still an integral part of cardiac surgical practice. This review provides a summary of the patency rates, technical features and certain characteristics of the venous conduits. It also examines the current understanding and knowledge of venous histology, vein graft pathology and the associated endothelial and smooth muscle cell physiology and pharmacology. In addition, the existing and the emerging strategies to combat and control vein graft intimal hyperplasia and accelerated atherosclerosis are reviewed in detail.     

Preservation of the Endothelium in Venous Bypass Grafts: Relevance for Graft Patency

Veins continue to be a main choice for arterial bypass grafts, but postoperative graft occlusion rates continue to be a problem, with up to 40% of aortocoronary bypass operations in the U.S.A. now being “redo” or “revision” procedures. An understanding of the factors contributing to the problem of endothelial pathology, and possible strategies for preventing it, include surgical, pharmacological and molecular factors. The endothelial cell is central to vascular wall biology, coordinating vascular wall modelling through the synthesis of key elements which influence smooth muscle cell behaviour. Removal of the endothelium leads to an imbalance in the components of the vasculature, with proliferation of vascular smooth muscle cells resulting in intimal hyperplasia. Endeavours to preserve endothelial cell presence and function may minimise implantation injury (and subsequent early vein graft failure), and may also minimise intimal hyperplasia (the cause of short to intermediate term vein graft failure). The pathophysiology of vein graft failure is still poorly understood. With the advent of new technologies, it is expected that a rational approach to the prevention of intimal hyperplasia (through methods such as gene transfer) may soon be feasible. Even before the full potential of such new technologies is realised, meticulous and continuous efforts to preserve endothelium at the stages of vein harvest, storage and graft implantation should be implemented to maximise the patency of venous grafts.     

VCAM-1 expression precedes macrophage infiltration into subendothelium of vein grafts interposed into carotid arteries in hypercholesterolemic rabbits--a potential role in vein graft atherosclerosis

Intimal hyperplasia and atherosclerosis are major causes of late vein graft failure after coronary artery bypass surgery. Hypercholesterolemia appears to be a key risk factor for atherosclerosis in vein grafts as well as in native arteries. We used a rabbit model of interposition jugular vein graft to the carotid artery and compared intimal thickening, macrophage accumulation, and VCAM-1 expression between hypercholesterolemic (H group) and normocholesterolemic (N group) rabbits. Fifty-nine rabbits were divided into H and N groups. Intimal thickening in vein grafts was approximately three times more prominent in the H group than in the N group. Macrophage accumulation progressively increased with time in H group vein grafts, although it was negligible in the N group. In the H group, moreover, macrophages were initially more abundant in deep intima, and subsequently accumulated in subendothelium of the grafted vein. VCAM-1 expression in luminal endothelial cells of the grafted veins was time-dependently increased after the vein graft surgery in both the H and N groups, and was more prominent in the H group. Comparison of the time-courses between macrophage accumulation and VCAM-1 expression revealed that VCAM-1 expression in luminal endothelium preceded subendothelial accumulation of macrophages. VCAM-1 expression and macrophage accumulation may be key factors which regulate progression of vein graft atherosclerosis.     

Neovascularization in intimal hyperplasia is associated with vein graft failure after coronary artery bypass surgery

Vein graft atherosclerosis is the major limitation of arterial bypass surgery. This study was carried out to determine if the number of microvessels per area of intimal hyperplasia correlated with vein graft disease. Vein grafts (n=24, graft age range 2-19 years) were taken from 22 patients undergoing redo-coronary artery bypass surgery. Mean age of the patients was 68 +/- 9 years; 92% were males. Samples were divided into three groups (n=8 per group): in group I segments were from grafts without angiographic or histologic disease, in groups II and III segments were from grafts with significant angiographic stenosis, without (group II) and with (group III) atheroma. Intimal hyperplasia was identified by Masson staining, morphometric analysis was performed with NIH image analysis software. Microvessels in the intimal hyperplasia were identified using immunohistochemical techniques. Significance was determined by single-factor ANOVA p < 0.05. The mean area of intimal hyperplasia was similar in groups I and II at 1.06 +/- 0.25 mm2 and 0.97 +/- 0.37 mm2, respectively. The extent of intimal hyperplasia was significantly greater in group III, 1.70 +/- 0.62 mm2 (p < 0.01). In group I, the microvessel count in the intimal hyperplasia was 5.62 +/- 3.89 vessels/mm2, while in group III it was 15.26 +/- 3.66/mm2 (p < 0.01 versus group I). Interestingly the number of microvessels per area of intimal hyperplasia in group II was similar to that in group III). In this study, the extent of neovascularization in intimal hyperplasia correlated with stenoses in human vein grafts. Strategies designed to limit neovascularization in intimal hyperplasia may lead to novel therapies to prevent vein graft failure.     

兔自体静脉移植物粥样硬化模型的建立

为研究自体静脉移植物粥样硬化的发病机制以进行干预研究，建立家兔动物模型。将30只雄性新西兰大白兔随机分为正常对照组(n=6)、单纯移植组(n=12)和高脂移植组(n=12)，分别给予普通饲料喂养、单纯自体颈外静脉移植加普通饲料喂养和自体颈外静脉移植加高脂饲料喂养。实验12周末处死动物，检测血脂水平，同时观察静脉移植段的形态特征。结果发现，高脂移植组出现明显的高脂血症，其颈静脉移植段出现较典型的粥样硬化病变。包括内皮细胞脱落、内膜增生、平滑肌细胞移行增殖、脂质沉积和泡沫细胞形成等；单纯移植组的颈静脉移植段仅有明显的内膜增生和平滑肌细胞表型转换及增殖，未见明显脂质沉积；而正常对照组及各移植组对侧颈外静脉未见明显异常。结果提示，自体颈外静脉移植结合高脂饲料喂养可成功建立兔自体静脉移植物粥样硬化模型，此模型可用于人自体静脉移植物粥样硬化发生机理及防治措施等的研究。     

冠状动脉搭桥术后静脉桥狭窄和新生易损斑块形成机制的研究进展

冠状动脉搭桥术术后发生桥血管病变是一种常见的现象,血栓形成、内皮功能障碍、血管痉挛和氧化应激是导致病变的重要机制。相比于动脉桥,静脉桥更易于发生病变,这与静脉本身的解剖形态和功能特征有着很大的关系。急性血栓形成、血管内膜增生和易损斑块形成是静脉桥不同时期发生病变的重要机制。使用抗血小板和调脂药物等冠心病二级预防药物有助于提高桥血管的开通率。寻找桥血管病变的预测因子及相关基因通路有望从细胞及分子学水平为静脉桥疾病提供新的研究方向。本文拟对冠状动脉搭桥术后发生静脉桥狭窄和新生易损斑块病变形成机制的研究进展作一综述。     

Antithrombotic therapy in the coronary vein graft patient

Coronary artery bypass grafting is an important therapeutic modality in the treatment of the patient with coronary artery disease; however, long-term results are limited by the development of saphenous vein graft disease early and late after operation. The pathogenesis of early vein graft occlusion is primarily thrombotic, while that occurring later frequently involves thrombosis superimposed on intimal hyperplasia or vein graft atherosclerosis. We describe the role of various platelet inhibitors and anticoagulants in the prevention of saphenous vein graft occlusion following coronary artery bypass grafting.     

Radial artery as graft for coronary artery bypass surgery: Advantages and disadvantages for its usage focused on structural and biological characteristics

Radial artery (RA) is the most popular arterial graft after the left internal thoracic artery in both low- and high-risk patients undergoing coronary artery bypass grafting. Various arterial grafts such as the right internal thoracic artery, the right gastroepiploic artery, and the inferior epigastric artery have also gained ground over the past 30 years because of the intimal hyperplasia and atherosclerosis of the saphenous vein leading to late graft occlusion. In this review article we would like to present the utility of the RA as a graft, focused mainly on its structural and biological characteristics.     

Accelerated atherosclerosis and calcification in vein grafts: a study in APOE*3 Leiden transgenic mice

Vein grafts fail due to development of intimal hyperplasia and accelerated atherosclerosis. Many murine genetic models in which genes are overexpressed, deleted, or mutated have been introduced recently. Therefore, mouse models are very well suited to dissect the relative contribution of different genes in the development of accelerated atherosclerosis. In the present study, we evaluated whether accelerated atherosclerosis in human vein grafts could be mimicked in hypercholesterolemic APOE*3 Leiden transgenic mice. Venous bypass grafting was performed in the carotid artery in APOE*3 Leiden mice fed either a standard chow diet or a high cholesterol-rich diet for 4 weeks. At several time points (0 hour to 28 days), mice were euthanized and the morphology of the vein grafts was analyzed. In normocholesterolemic mice, vein graft thickening up to 10-fold original thickness, predominantly consisting of alpha-smooth muscle cell actin-positive cells, was observed after 28 days. In hypercholesterolemic mice, accelerated atherosclerosis with accumulation of lipid-loaded foam cells was observed within 7 days after surgery. This accelerated atherosclerosis progressed in time and resulted in significant increase in vein graft thickening up to 50 times original thickness with foam cell-rich lesions and calcification within 28 days after surgery. The atherosclerotic lesions observed in these murine grafts show high morphological resemblance with the atherosclerotic lesions observed in human vein grafts. This accelerated, diet-dependent induction of atherosclerotic-like lesions in murine vein grafts provides a valuable tool in evaluating the mechanisms of accelerated atherosclerosis and therapeutic interventions of vein graft disease.     

Measures to increase the number of mammary artery coronary artery anastomoses

Patients with single internal mammary artery (IMA) grafts along with saphenous vein grafts have been found to have fewer coronary events and longer survival after operation. To reduce bypass graft failure from intimal hyperplasia and atherosclerosis, as well as to improve results, three or more IMA grafts were placed in 215 patients from October 1982 through May 1985. Careful planning helped in bypassing the maximum number of coronary artery obstructions with arterial conduits. By using bilateral IMA grafts, sequential, and Y grafts, the number of IMA coronary artery anastomoses increases and the need for saphenous vein grafts decreases. Meticulous dissection and preparation of the entire IMA and proper construction of the anastomosis are essentials for these procedures to be successful. Two of the 215 patients died early and four died late. Ninety-five percent of the postoperative stress tests were negative and 92% of the 39 IMA grafts visualized in 13 patients studied postoperatively were patent. We found this to be a safe, challenging procedure that improved late bypass conduit success and prolonged survival.     

Cardiac saphenous vein bypass graft disease

Coronary artery bypass grafting is an effective treatment for myocardial ischaemia and is particularly important in patients with multivessel disease and diabetes. However, up to 40% of saphenous vein grafts will occlude within 10 years of surgery. The predominant mechanisms for saphenous vein graft disease are thrombosis, intimal hyperplasia, and accelerated atherosclerosis. The pathology of these changes and the role of key factors such as nitric oxide, cellular proliferation, and the role of hypercholesterolemia and hypertriglyceridaemia, are reviewed. Saphenous vein graft disease is among the first cardiovascular conditions to show significant benefit from gene therapy and promises to show remarkable developments in the near future.     

Intravascular ultrasound imaging of saphenous vein grafts in vitro: comparison with histologic and quantitative angiographic findings.

The ubiquity of coronary artery disease and the resultant widespread use of saphenous veins for coronary artery bypass surgery has stimulated considerable interest in the morphologic and pathophysiologic alterations these vessels undergo after implantation. This study was undertaken to determine the ability of intravascular ultrasound to identify and characterize abnormalities in saphenous vein grafts. Ten saphenous vein grafts excised at autopsy and nine saphenous vein segments harvested during coronary artery bypass surgery were examined with intravascular ultrasound imaging, quantitative coronary angiographic techniques and histologic analysis. Intravascular ultrasound lumen measurements were strongly correlated with quantitative coronary arteriographic measurements (r 0.91, SEE 0.5 mm). Wall thickness was significantly greater in the vein grafts after long-term implantation than in the freshly harvested veins (average thickness 1.4 +/- 0.5 vs. 0.7 +/- 0.2 mm, p less than 0.007); this finding correlated histologically with vein wall fibrosis. There was good correlation between ultrasound imaging and histologic analysis, with the ability to distinguish among normal intima, intimal hyperplasia, vein wall fibrosis and atheromatous plaque. Thus, this preliminary study demonstrates the ability of intravascular ultrasound to provide real-time cross-sectional images of saphenous veins and morphologic characterization of their walls. This modality may have important clinical applications, including the ability to detect serial changes in vein graft intimal hyperplasia and atherosclerosis.     

在冠状动脉移植术中他汀类药物应用于静脉移植后狭窄机制研究进展

相比于左侧乳内动脉及桡动脉,大隐静脉在冠状动脉移植后的长期通畅率较低。一系列的临床试验和观察研究表明他汀类药物在静脉移植通畅率治疗上有显著的益处。除了能降低血脂外,他汀类药物可以在移植静脉的血管壁上直接抑制甲羟戊酸途径发挥多效性,并且可以降低小GTP酶比如Rho和Rac的香叶酰化。他汀类药物能够改善内皮功能的同时减少血管炎性反应及氧化应激,并且抑制平滑肌细胞的增殖与迁移。为了能将这些机制安全地运用到临床实践中,更多的临床试验需要聚焦于他汀类药物对静脉移植通畅率的干预作用,文章将对上述问题做一综述。     

Choice of internal mammary artery or saphenous vein graft for myocardial revascularization

The saphenous vein has been the traditional conduit for elective myocardial revascularization. Although readily available and adaptable to many configurations around the heart, it is prone to intimal hyperplasia and vein graft atherosclerosis, which diminish long-term patency and relief of symptoms. The internal mammary artery graft represents a marked improvement over the saphenous vein graft in many respects. Data are presented comparing saphenous vein graft patency with that of the internal mammary artery, bilateral internal mammary artery, free internal mammary artery, and sequential internal mammary artery grafts.     

Pathologic findings in the aortocoronary vein grafts. A scanning electron microscope study.

Examination of totally or partially obstructed human aortocoronary vein grafts, obtained at different time intervals after the bypass operation, has shown that the initial occlusive process is due to thrombosis and may appear a few hours or days after surgery. The cellular phase of intimal proliferation affecting most of the grafts becomes apparent about 4 weeks after the operation. After 1 year the intimal hyperplasia acquires a cell-poor, fibrotic character; the graft usually remains patent. About one-half of the vein grafts obtained 3 or more years after the operation show complicated atherosclerotic lesions. These findings indicate that most of the vein grafts undergo extensive structural changes and some may show similar degenerative lesions as they develop in the coronary arteries.     

Gene therapy for vein grafts

Bypass vein graft failure represents the greatest limitation to the current surgical therapy of myocardial and lower extremity ischemia. Elucidation of the molecular and cellular biology of neointimal hyperplasia and subsequent vein graft atherosclerosis has formed a basis for the design and implementation of gene-based therapies to prevent vein graft disease. Manipulation of the genetic regulation of vascular cell cycle progression has been shown to effectively redirect vein graft biology away from neointimal disease and toward medial hypertrophy as a more adaptive form of remodeling in response to stresses of the arterial circulation, and has prevented experimental graft atherosclerosis. Early clinical experience suggests that this approach may provide an early avenue for translation of such a gene-based therapy in humans. Other experimental gene transfer strategies have also been explored in animal models of vein grafts, which may be particularly well suited to the application of genetic manipulation given the direct access to the tissue at the time of disease initiation.     

凝集素样氧化低密度脂蛋白受体1在兔自体静脉移植物及其粥样硬化病变中的分布表达

目的自体静脉移植物粥样硬化的产生机制有其特殊性,我们研究了一种新的氧化低密度脂蛋白(OXLDL)的受体,即凝集素样氧化低密度脂蛋白受体1(LOX1)在兔自体静脉移植物及其粥样硬化病变中的表达,探讨其在静脉移植物粥样硬化形成中的作用。方法将30只新西兰大白兔随机分为正常对照组、单纯移植组和高脂移植组3组,分别给予普通饲料喂养(N=10)、单纯自体颈外静脉移植(N=10)和自体颈外静脉移植加高脂饲料喂养(N=10)。在实验12周末处死动物,静脉移植段行免疫组化染色检测LOX1的表达及分布,用半定量逆转录聚合酶链反应(RTPCR)检测LOX1MRNA表达的情况,并且统计分析血清总胆固醇水平、内膜厚度与LOX1的表达之间的关系。结果正常对照组的颈外静脉组织中仅见极少量LOX1表达于静脉内皮细胞表面;而单纯移植组的静脉移植物的新生内膜和内皮细胞层,可见LOX1的表达明显升高(0.31±0.14比0.09±0.04,P<0.01),其中LOX1表达最强的是内皮细胞;高脂移植组静脉移植物的内皮和粥样硬化部位,可见LOX1的表达更加显著上调(0.93±0.34比0.31±0.14,P<0.01),在粥样硬化部位,内皮细胞和泡沫细胞LOX1染色均阳性,而表达最强的也是内皮细胞。并且LOX1的表达和血清总胆固醇水平、内膜厚度均显著正相关(P=0.00和0.02),偏相关系数分别为0.78和0.42。结论LOX1表达于兔自体静脉移植物的内皮和新生内膜,表达量较正常静脉组织明显上调,高胆固醇血症可以上调静脉移植物粥样硬化部位LOX1的表达,提示LOX1可能参与了静脉移植物粥样硬化的发生发展。     

Bypass Surgery in Limb Salvage: Polytetrafluoroethylene Prosthetic Bypass

Polytetrafluoroethylene (PTFE) grafts have proven to be an adequate alternative conduit for peripheral bypass operations. Whether or not one uses PTFE depends on several factors: surgeon preference, individual patient circumstances, or when autologous greater saphenous vein is not available or adequate. These conventional grafts have evolved and undergone modification. The intraluminal surface has been coated with carbon or bonded with heparin. The structure of grafts has been modified with the creation of a hood or cuff, with the incorporation of a stent-graft segment for a sutureless anastomosis, or the fusion of PTFE with an outer polyester layer to minimize suture hole bleeding. This evolution intends to limit graft thrombogenicity, ameliorate the formation of intimal hyperplasia, decrease complications, and improve overall graft patency.