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Eur J Cardiothorac Surg 2002;22:387-396
© 2002 Elsevier Science NL

Review

Mechanisms and future directions for prevention of vein graft failure in coronary bypass surgery

Division of Cardiothoracic Surgery, Department of Surgery, The University of Illinois at Chicago, 840 South Wood Street, CSB Suite 417 (MC 958), Chicago, IL 60612, USA

Received 10 January 2002; received in revised form 21 March 2002; accepted 18 April 2002.

* Corresponding author. Tel.: +1-312-996-6215; fax: +1-312-996-2013
e-mail: mmassad{at}uic.edu

	Abstract

Top Abstract 1. Introduction 2. Reperfusion injury and... 3. Neointimal hyperplasia (NIH) 4. Adhesion molecules 5. Effects of nitric... 6. Influence of pulsatile... 7. Preventing vein graft... 8. Conclusions References

 
Coronary artery bypass grafting has been utilized as a beneficial treatment for myocardial ischemic disease for over three decades. Failure of coronary artery venous grafts occurs at a substantial rate and has a large impact on two main endpoints, survival and quality of life. An exhaustive amount of basic research has been generated to delineate possible mechanisms responsible for graft failure and modalities to prevent its occurrence. Although pharmacotherapy exists, insufficient translation has emerged from the bench to the operating room. In this article, we review the literature regarding the current mechanisms and mediators including growth factors, nitric oxide and genetics leading to saphenous vein graft occlusion. The review addresses the current state of affairs and modes for prevention of vein graft failure perioperatively and newer technologies that may help ameliorate this problem in the future.

Key Words: Vein graft failure • Mechanisms • Future directions • Prevention • Coronary artery bypass

	1. Introduction

Top Abstract 1. Introduction 2. Reperfusion injury and... 3. Neointimal hyperplasia (NIH) 4. Adhesion molecules 5. Effects of nitric... 6. Influence of pulsatile... 7. Preventing vein graft... 8. Conclusions References

 
Coronary artery bypass grafting using saphenous vein conduits, with and without arterial conduits, remains the standard for treatment of intractable angina due to coronary artery occlusive disease. From its beginning in the late sixties [1,2], this procedure has been championed as the answer to coronary artery disease. However it was soon evident that coronary artery bypass grafting provides only palliation to an ongoing process that is further complicated by the rapid development of vein graft atherosclerosis. It is estimated that during the first year after coronary bypass surgery, between 10 and 15% of venous grafts occlude [3–5]. The graft attrition rate has been estimated at 1–2% per year between 1 and 6 years, and at 4% per year between 6 and 10 years after surgery. By 10 years after surgery, about 60% of the vein grafts are patent; only 50% of these patent vein grafts remain free of significant stenosis [3–5].

Evaluation of the saphenous vein graft used in coronary artery bypass grafting has had a long history, and began in response to the high rate of graft failure. Early thrombosis and neointimal hyperplasia (NIH) with subsequent atherosclerosis are long thought to be the primary causes of graft failure [3,4]. The cause of this failure may stem from thrombosis within the vein graft caused by a combination of structural and physiologic alterations in the vessel wall (Table 1). NIH, defined as the accumulation of smooth muscle cells (SMC) and extracellular matrix in the intimal compartment of the vein, is the major disease process in venous grafts within the first year. Nearly all veins implanted into the arterial circulation develop some intimal wall thickening within 4–6 weeks thereby reducing the lumen size. SMC in the media of normal adult arteries proliferate at a very low rate (<0.1%/d) but can switch very rapidly from quiescence to a proliferative state in response to appropriate stimuli [6]. Injury to the intima results in migration and proliferation of SMCs from the media to the intima 3 days after. A transition of arterial SMCs to an active state has been implicated in the failure of human vascular reconstructions after arterial bypass grafting as well as following angioplasty. To proliferate and migrate, SMCs must be able to detach as a cell by breaking down intercellular junctions yet preserve the geometry of the vessel. It is likely that SMCs accomplish this task in the same way as other cells by simultaneously expressing matrix metalloproteinases and their inhibitors. This relative proteolytic balance may be of great importance [7]. The resulting luminal narrowing of the vein graft, in itself, is not usually flow-limiting. However, after a period of time, the area of NIH may become an atherosclerosis-prone region that may lead to subsequent stenosis [8].

	2. Reperfusion injury and thrombosis

Top Abstract 1. Introduction 2. Reperfusion injury and... 3. Neointimal hyperplasia (NIH) 4. Adhesion molecules 5. Effects of nitric... 6. Influence of pulsatile... 7. Preventing vein graft... 8. Conclusions References

 
Acute thrombosis of the saphenous vein graft within 30 days of the coronary bypass procedure occurs in up to 12% of the cases [3,4]. It has now been established that the ischemic period of the vein graft prior to implantation plays a significant role in endothelial cell injury [9]. It is known that when ischemic vascular tissue is re-perfused with oxygenated blood, neutrophils accumulate and rapidly adhere to the hypoxically injured endothelium [10]. Once this occurs, leukocyte-mediated injury appears as a result of the release of a variety of substances such as oxygen free radicals, thromboxanes, leukotrienes, and proteases [11]. Shreeniwas and colleagues, among others, have demonstrated that when the endothelial cells are rendered hypoxic and then re-oxygenated, induction of adhesion molecules on the surface causes neutrophil adherence and leads to endothelial damage and possible activation of the coagulation cascade [9,12].

Furthermore, the coronary bypass operation, in itself, disturbs the local production of factors influencing hemostasis and alters their circulating levels. There is known to be a marked elevation of plasma fibrinogen during cardiopulmonary bypass, which, in turn, favors a prothrombic response [13]. In contrast, there are several other mechanisms after cardiopulmonary bypass that could have protective effects or potential on the vein endothelium such as low platelet levels, low prothrombin time and prolonged partial thromboplastin time. In addition, saphenous vein grafts, particularly when denuded or skeletonized, are highly sensitive to circulating vasoconstrictors, including endothelin-1 [10]. Although the predominant vasomotor response to thrombin is constriction, when the endothelium is intact, thrombin mediated vasorelaxation also occurs through endothelial receptors [9,14]. Hence, the thrombotic potential of the vein graft is quite compounded.

	3. Neointimal hyperplasia (NIH)

Top Abstract 1. Introduction 2. Reperfusion injury and... 3. Neointimal hyperplasia (NIH) 4. Adhesion molecules 5. Effects of nitric... 6. Influence of pulsatile... 7. Preventing vein graft... 8. Conclusions References

 
NIH poses a significant clinical problem in the coronary artery bypass graft. It is a process by which the intima becomes thickened due to ingrowth of SMCs from the media with subsequent extracellular matrix deposition and narrowing of the lumen. It has been strongly suggested that NIH is associated with extensive endothelial denudation and destruction [15]. In saphenous vein grafts, NIH has also been related to vigorous distension, the degree of spasm, and use of vein dilators. In the endothelium of experimental rat models, denuded surfaces are first covered with platelets and then displaced by an advancing front of regenerating endothelium over days. This growth is stimulated by several growth factors including platelet derived growth factor (PDGF), transforming growth factor-beta and epidermal growth factor (EGF) [16]. These growth factors, in turn, stimulate the proliferation and invasion of the SMC into the intima. Endothelial cells, SMCs, and macrophages in culture synthesize several growth factors, one of which resembles PDGF. Another important factor that is involved in this process is basic fibroblast growth factor. Stored in endothelial and smooth muscle cells, it is released in response to injury. It is a potent mitogen for the endothelium as well as the SMCs [17]. A cascade of events occurs at the level of the cell cycle. The progression of the mammalian SMC through the G1, G2, S and M phases is governed by the sequential activation and inactivation of a highly conserved family of regulatory proteins, namely, cyclin-dependent kinases (Cdks) [18]. Cdk activation requires the binding of a ligand controlled by both positive and negative phosphorylation. Each cyclin exhibits a cell cycle-phase specific pattern of expression. A number of checkpoints exists regulated by Cdks, especially at the G1/S by Cdk 4/6 and 2 interacting with cyclin D and E respectively. The subsequent activation of Cdk 1 by cyclin B is essential for transition from the G2 to the M phase of the cell cycle. The inhibitory Cdk proteins include the CIP/KIP family and the INK family. Moreover, the key target of the G1 Cdks is the retinoblastoma tumor suppressor protein (pRb), that belongs to the Rb family of pocket proteins. In their hypophosphorylated form, pocket proteins can sequester cell cycle regulatory transcription factors, including heterodimers of E2F and DP families of proteins [19]. Phosphorylation of pRb, first by cyclin D-dependent kinases and then by cyclin E/Cdk2 during late G1, leads to release of E2F/DP and subsequent activation of genes that participate in DNA synthesis [20]. E2F binds to its target on the cell chromosome initiating a complex cascade of cellular activities leading to the proliferation of SMCs [21]. In addition to serving as a mitogenic stimulus for the initiation of SMC growth, these above factors promote cell proliferation. Thus, the process of neointimal hyperplasia seems to begin with endothelial injury.

More recent evidence from a porcine model of saphenous vein grafting indicates that additional mechanisms for graft neointima formation may involve perivascular fibroblasts [22]. These fibroblasts translocate through the media of newly placed vein grafts and differentiate into myofibroblasts, acquiring alpha-smooth muscle actin. Intima of human saphenous vein grafts retrieved during repeat coronary bypass graft operations exhibits a profile of cytoskeletal proteins that is similar to that of myofibroblasts in the porcine vein grafts, also suggesting a possible role for these cells in NIH [9].

There is now accumulating evidence that matrix metalloproteinases (MMPs), the physiological mediators of matrix deposition and degradation, play an important role in the development of NIH following arterial bypass. A specific oral MMP inhibitor of neointima formation in cultured human saphenous vein has been demonstrated [23]. This observation was paralleled by a significant reduction in the levels of MMP-2 and -9 in the tissues. By themselves, MMP inhibitors may offer a potential therapeutic strategy in the prevention of NIH.

	4. Adhesion molecules

Top Abstract 1. Introduction 2. Reperfusion injury and... 3. Neointimal hyperplasia (NIH) 4. Adhesion molecules 5. Effects of nitric... 6. Influence of pulsatile... 7. Preventing vein graft... 8. Conclusions References

 
The adhesion molecules primarily consist of selectins, integrins and the immunoglobulin supergene family. These molecules are expressed on the activated endothelial and leucocyte cell surface in the context of a chemotaxin gradient from the site of the vessel injury to the local circulation. The differential expression allows for rolling of the leucocyte (selectins) and adhesion (integrins and immunoglobulins) to the endothelial cell. The latter triggers the cytoskeleton diapedesis machinery leading to leucocyte migration through the vessel wall layers. The migrated leucocytes are usually neutrophils that release a respiratory burst complex and cytokines with paracrine and autocrine effects. These neutrophils can mature to macrophages and lipid laden foam cells while recruited lymphocytes will transform into monocytes. This cellular constellation forms the fatty streak; the earliest appearance of an atherosclerotic plaque. In the discussion hereafter, we shall describe the biology of these peculiar molecules while in action.

Selectins are molecules with an amino-terminal calcium-binding lectin domain followed by an EGF-like domain, a short series of consensus repeats, a transmembrane domain, and a short cytoplasmic tail that interact with carbohydrate groups on highly glycosylated protein ligands. During inflammation or injury, they mediate the first step in leukocyte adhesion. Selectins are of three types; E-selectin from endothelial cells, P-selectin from endothelial and platelet cells, and L-selectin from leucocytes. P-selectins are usually stored and become expressed upon exposure to tumor necrosis factor-alpha or interleukin-1 (IL-1) which are released in response to injury.

Integrins are receptor proteins that reside on the surface of the cell and are critically important to cellular communication. They are the main pathway through which cells both bind and respond to the extracellular matrix. Integrins are heterodimeric molecules consisting of non-covalently bound alpha and beta subunits. Integrins are not constitutively active and require conformational changes to modulate their affinity for ligands. These molecules mediate a broad distribution of interactions between cells and extracellular matrix components. Integrins comprise three families based on their beta subunits; beta-1, -2 and -3. They usually have binding sites that recognize a short sequence of amino acids, such as the tripeptide L-arginyl-L-glycyl-L-aspartate. This sequence is found in a number of structural proteins, including vitronectin, fibronectin, collagen, laminin, and fibrinogen. With respect to their vascular pathophysiology, the beta-1 integrins appear to mediate cell adhesion to the extra-cellular matrix proteins, such as collagen and others stated earlier. The beta-2 integrins, found exclusively on leucocytes along with very late activation antigen-4 (VLA-4), interact with the super immunoglobulin family and with fibrinogen. Glycoprotein IIb/IIIa, a beta-3 integrin found on megakaryocytes and platelets, is in itself important in fibrinogen binding and platelet aggregation, as well as binding of the platelet to fibronectin and to von Willebrand factor.

The immunoglobulin supergene family contains a series of immunoglobulin-like domains of 90–100 amino acids that function as endothelial ligands for the integrins expressed on leukocytes and platelets; they may also mediate homotypic cell-cell associations. These molecules also participate in signal transduction and cell migration from the intravascular compartment [24]. The prototypic members of this superfamily, vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 and -2 (ICAM-1, -2), and platelet-endothelial cell adhesion molecule (PECAM), have all been implicated in atherogenesis. VCAM-1 binds circulating monocytes and lymphocytes expressing the integrins alpha-4 beta-1 and alpha-4 beta-7 [25,26], whereas ICAM-1 is the counter-receptor for several leukocyte beta-2 integrins, such as lymphocyte function-associated antigen (CD11a/CD18) and Mac-1 (CD11b/CD18). The interaction of ICAM-1 with leukocyte integrins also plays an important role in leukocyte trafficking and in the initiation of antigen-specific immune responses [27]. Gene expression of adhesion molecules is up regulated in inflammatory states such as ischemia-reperfusion. Elevated CAM expression is temporally associated with leukocyte sequestration and infiltration into the tissues. Direct cell-cell adhesions facilitate neutrophil uptake by the activated endothelial cells [28]. These neutrophils, in turn, induce the release of an immunologically related molecule similar to PDGF, that may cause SMC proliferation and NIH.

The role of leukocyte migration during inflammation and its relationship to atherosclerosis has been well established. It is also known that long-term graft failure in conjunction with NIH, occurs in part as a result of accelerated atherosclerosis within the vein graft. Recent evidence indicates that up regulation of adhesion molecules helps to facilitate this process of atherosclerosis [29]. Observations in experimentally induced hypercholesterolemic animals demonstrate that adherence of leukocytes, predominantly monocytes and a small number of lymphocytes, to the endothelium is an early inflammatory response [30]. The leukocytes then migrate into the subendothelial space in response to chemotactic proteins where they become engorged with lipids, leading to the formation of activated lipid-laden macrophages or ‘foam’ cells. Foam cells produce a wealth of growth factors that, in turn, promote neointimal proliferation [29,31]. As leukocyte infiltration continues, the SMCs are stimulated to migrate into the intima and proliferate.

	5. Effects of nitric oxide (NO)

Top Abstract 1. Introduction 2. Reperfusion injury and... 3. Neointimal hyperplasia (NIH) 4. Adhesion molecules 5. Effects of nitric... 6. Influence of pulsatile... 7. Preventing vein graft... 8. Conclusions References

 
NO is another important player in the prevention of vein graft failure. It has an important role in vasodilation, anti-platelet activity, NIH, and atherosclerosis. It is formed as a by-product of the stepwise conversion of L-arginine, an essential amino acid, to citrulline. This process involves hydroxylation of one of the guinidino nitrogens [32]. Nitric oxide synthase (NOS) has been identified as the synthetic enzyme [33]. However, the enzyme exists in more than one form (isozyme) characteristic of the tissue within which it is produced (example: endothelial, neuronal). The enzyme can synthesize NO constitutively and is, hence, referred to as constitutive nitric oxide synthase (cNOS), or can be induced to synthesize NO under certain conditions (i.e. inflammation). The inducible form is called inducible nitric oxide synthase (iNOS). The synthesis involves transcription of gene(s) present within the chromosome and is under tight control by gene regulatory mechanisms. In biological systems, NO has a half-life of less than 5 s, within which time it is oxidized to nitrite and nitrate. In vitro, NO is degraded by interaction with the superoxide anion which is terminated by superoxide dismutase within the cell [34]. Hemoglobin also binds and inactivates the NO complex [35].

The main target of NO is stimulation of soluble guanylate cyclase (sGC) by interacting with the ferroheme center of the enzyme. This results in the generation of guanosine 3 prime: 5 prime-cyclic monophosphate (cGMP). The increase in cGMP then leads to vasodilation and inhibition of platelet aggregation [36]. In addition to producing smooth muscle relaxation, NO has also been shown to interfere with white cell migration through reducing the adhesion of neutrophils to the endothelial surface.

NO has been shown both in vivo and in vitro to have both cytoprotective and cytotoxic properties depending on a number of factors in which the synthesizing environment is a crucial element. Cytoprotective effects include scavenging oxygen free radicals; and blocking release of prostaglandin E2 and prostaglandin F2 alpha [37,38]. Research studies have shown that the anti-inflammatory effects of NO are complex and are seen in the attenuation of endothelial cell activation and expression of adhesion molecules [39,40]. These effects are partly based on regulation of transcription; however, modulation of cytokine production, and the direct inhibition of neutrophil functions are all products of NO activity. The cytotoxic effects of NO are numerous and include: (1) decreasing protein synthesis; (2) increasing lipid peroxidation by generating highly reactive hydroxyl radicals such as ONOOH; and (3) decreasing acute phase proteins [41,42].

Along with altering endothelial cell function, the injury caused by ischemia-reperfusion causes a reduction in both the basal and stimulated NO release, and an attenuation of the vasorelaxation responses to agonist stimulators of endothelial nitric oxide (eNOS) such as acetylcholine and bradykinin [42–45]. All these lead to impairment of the release of iNOS and a down regulation of the constitutional form secondary to ischemic injury. With respect to initial vein graft injury, biological effects of NO will be lost with traumatic endothelial cell loss caused by manipulation, yet its synthesis will increase with the transient ischemia followed by reperfusion after grafting. No data exists about the effect of increased wall stresses incurred by arterial pressures on NO synthesis. All of these lead to the liberation of growth factors and cytokines that influence the migration and proliferation of vascular SMCs, as well as the deposition of extracellular matrix into the intimal compartment of the affected vessels [9]. NO is an important vasoactive molecule that limits NIH by inhibiting SMC proliferation and induces cellular death by apoptosis [46,47]. Kown et al. have shown that by treating vein grafts with L-arginine to increase NO levels, NIH was reduced [48]. These investigators were able to effectively show that elevated levels of NO were associated with reduced incidence of NIH.

It is well established that the endothelial cell injury is one of the initiating events in the development of atherosclerosis [34,49]. In addition to the negative effects of NO on NIH, the developing atherosclerosis can impair the NO mediated effects that normally occur within the vessel wall [50]. In vitro studies with atherosclerotic models using a cholesterol-enhanced diet, show a decrease in NO release from the endothelium [50]. This decrease in NO production occurs through alterations in certain receptor-mediated functions and an associated interaction of NO with oxidized low-density lipoprotein [50]. Interestingly, women appear to have greater resistance to atherosclerosis in the premenopausal years than the postmenopausal years. Higher basal levels of estrogen have been suspected as the etiological factor accounting in part for the resistance through an estrogen-dependent increase in basal NO synthesis [51]. In addition, long-term smoking has been associated with a diminished nitric oxide-dependent component of basal vascular tone and an impaired endothelium [52]. This may reflect impairment of the normal anti-atherosclerotic endothelial functions among smokers and suggests that the cellular effects of nitric oxide are altered [52]. In the context of this experiment, the relevance of smoking-induced enhancement of endothelin-1 vasoconstriction remains to be determined, although the notion of advising a patient to stop smoking can only be universalized. Other targets of NO, in addition to stimulation of sGC, include inhibiting CDK 2 expression level, threonine phosphorylation and kinase activity and blunting the expression of cyclin [53]. Nonetheless, administration of arginine normalizes vascular dysfunction in patients and animals with hypercholesterolemia [54]. A genetic etiology has been demonstrated in a study documenting the population distribution of an endothelial (cNOS) gene polymorphism showing that patients with a specific cNOS genotype are at a greater risk of developing coronary heart disease when smoking [55].

	6. Influence of pulsatile stretch and arterialization

Top Abstract 1. Introduction 2. Reperfusion injury and... 3. Neointimal hyperplasia (NIH) 4. Adhesion molecules 5. Effects of nitric... 6. Influence of pulsatile... 7. Preventing vein graft... 8. Conclusions References

 
Response of the vein graft to cyclic stretching and pressure loading underlies some of the pathologic changes that are seen within the vessel wall during and after coronary bypass. Several mechanical factors are identified when exposing the vein graft to arterial pressure [56]. Static, high-pressure stretching may be inadvertently applied during vein preparation. In addition, the vein is subject to cyclical, high-pressure stretching as soon as it is implanted into the arterial circulation. This circumferential stretching is appreciated as a trigger for a cascade of molecular events occurring in endothelial and SMCs. A rise in intracellular calcium is the lead conductor in signaling pathways and gene expression. The human saphenous vein has myogenic tone regulated by voltage-gated and calcium regulated potassium channels and stretch regulated cation channels. The effect of circumferential deformation or stretch has also been shown to up regulate ICAM-1 and VCAM-1 expression on the saphenous vein endothelium while thrombomodulin is down regulated [57]. The cyclic strain effect is transmitted to the genome as exhibited by expression of monocyte chemoattractant protein in umbilical vein endothelial cells and up regulation of NOS. This mechanical-biological energy transfer across the cells is important when designing models of NIH or atherosclerosis as it appears to be pivotal in a dynamic tissue such as the heart. There are several experimental and clinical studies on the effects of external wall support on reducing the wall stress and inhibiting NIH formation [58,59]. Four weeks after graft implantation, externally stented grafts had a larger lumen and an almost fourfold thinner media and neointima than paired unstented grafts in the same animals [58]. Cell proliferation was also greatly reduced by stenting in the neointimal and medial layers [58]. Furthermore, application of an external polyester stent to the outer surface of carotid interposition vein grafts reduced medial thickening, neointima formation, and cell proliferation along with a significant reduction in PDGF expression. It is not known whether the benefits of the stent are maintained on the long term [59].

	7. Preventing vein graft failure

Top Abstract 1. Introduction 2. Reperfusion injury and... 3. Neointimal hyperplasia (NIH) 4. Adhesion molecules 5. Effects of nitric... 6. Influence of pulsatile... 7. Preventing vein graft... 8. Conclusions References

 
Most graft stenosis occurs asymptomatically and early recognition would help prevent further myocardiac cell ischemia and damage [60]. It is, therefore, important to identify the key mechanisms leading to graft failure in order to delay this disease process. We extrapolate these epidemiological terms to primary and secondary prevention of vein graft failure in coronary bypass operations. Primary prevention focuses on preventing the initial pathophysiologic processes that occur in the first place. Its role extends to both the intraoperative and immediate postoperative period. Secondary prevention includes further intervention that is undertaken based on the assumption that renewed or continued intimal thickening in the context of atherosclerosis is the likely cause of future vein graft failure [9]. Asymptomatic detection of NIH/atherosclerosis has important clinical significance. The application of modalities to modify these disease processes is still evolving. Other than angioscopy, intraoperative coronary ultrasound provides 3D reconstruction of the arteriopathy. It may allow further information regarding vein graft stenosis to be obtained especially in some patients where arteriopathy is not clearly apparent on angiography [61]. This technology can potentially allow more accurate estimation of the target anastomosis site. Use of this ultrasound technology can offer better estimation of the rate and extent of progression of the arteriopathy in the context of modern pharmacotherapy.

7.1. Intra-operative prevention
In the operating room, tissue manipulation and the role of the surgeon or surgical assistant is quite essential. The ‘no touch technique‘ of handling tissues during harvesting should be adopted in order to preserve the endothelial integrity and function [62]. After harvesting, meticulous care should be taken to avoid distention of the vein graft. An infusion pressure of no more than 100 mmHg is recommended for minimal endothelial damage [63]. The preservation solution in which the vein graft is kept until the time of implantation has been a major area of controversy in regard to its contents and also in regard to the duration of storage so as to minimize or prevent thrombosis and NIH. Several authors have documented morphologic and functional impairment of the endothelial cells caused by preservation in heparinized autologous whole blood and in electrolyte solutions such as normal saline or Ringer's lactate; this functional impairment seems to persist indefinitely [15,64–66]. Autologous blood, though may seem to be optimal for short-term preservation, contains platelets, fibrin, and leukocytes along with many other pro-thrombotic substances that would be detrimental. On the other hand, normal saline and other crystalloid solutions have repeatedly been proven to cause significant irreparable damage to the endothelial surface of the saphenous vein graft [64,67]. The University of Wisconsin (UW) solution, a colloid that has been used for well over a decade in the preservation of solid organs during transplantation, has been evaluated for preservation of saphenous vein grafts prior to implantation [66,69]. Cavallari and associates found that veins stored in UWs maintained smooth muscle cell function when compared to veins stored in normal saline or autologous whole blood [65]. These investigators used the intimal thickness and response to norepinephrine, acetylcholine, and sodium nitroprusside in their evaluations. Other investigations showed attenuation of endothelium-dependent relaxations to acetylcholine and enhancement of the response to 5-HT with UWs [68]. When UWs was compared with Euro-Collins solution as a preservative for the vascular endothelium, the difference in maintaining cell integrity was very significant. UWs maintained more than 99% of the cell viability after 24 h of storage followed by rewarming, with no structural or intracellular changes up to 72 h of preservation [69]. Mankad et al., however, were able to demonstrate a temperature-dependent endothelial dysfunction in the isolated rat heart and hypothesized that this effect may have been partly in response to the high potassium concentration [65]. Variations in the temperature of the preservation solution have been evaluated even in much greater detail. It has been demonstrated that preservation at 4°C promoted significant endothelial disruption [70]. Solberg et al. showed that veins stored in cell culture media at 4°C demonstrated a marked increase in endothelial cell disjunction [70]. They observed an 18% loss of endothelial cells at 4°C compared to only 4% at 20°C and noted that cooling caused a breakdown of the endothelial cytoskeleton. Thus, it seems that the use of normothermic solutions may produce less endothelial damage. Our initial laboratory results with the use of normothermic pyruvate based anaerobic medium for vein preservation seem quite encouraging and may lead to a future direction in this area.

With the recent re-introduction of off-pump beating heart surgery for coronary revascularization, some of the factors that may impact vein graft patency may be ameliorated. Cardiopulmonary bypass (CPB) during standard coronary bypass operations can trigger a cascade of inflammatory mediators that mediate systemic inflammation of which endothelial injury is an end-result [71]. The complement cascade's main switch is turned on during CPB causing neutrophil and cytokine production. The latter up-regulates adhesion molecules, mainly ICAM, resulting in neutrophil migration and release of complex-proteolytic enzymes or oxygen-derived free radicals [72]. Nonetheless, CPB's effect on NIH is not an all or none phenomenon. The balance between the IL-8/IL-6 ratio in the context of other anti-NIH factors may be the valid answer that is far from wrong and right.

7.2. The gene deliver vehicle
Much interest in reducing NIH by blocking gene expression is arising given the better understanding of the cell cycle of endothelial and smooth muscle cells. Understanding this background has allowed applied genetics to tackle aspects of coronary graft failure such as stenosis, thrombosis and ischemia. Genes that could influence these processes will ultimately influence coronary graft patency and in turn determine the long-term morbidity and outcome. A promising application of gene therapy for vein grafts entails the use of anti-sense oligonucleotides to block the expression of genes encoding cell cycle regulatory proteins in SMCs [9,73]. Cell-cycle blockade by ex-vivo gene therapy of experimental vein grafts has been shown to inhibit the NIH and subsequent accelerated atherosclerosis that lead to bypass graft failure.

Delivery of genes into cells of interest (example: SMCs) may occur either by direct injection of naked plasmid DNA or liposomes or through a hemagglutinating virus vector. Given the poor uptake of naked genes and the limited time expression, viral mediated gene delivery is preferred. Three main classes of viral vectors have been be utilized: an adeno-associated virus, a herpes simplex virus and the retroviral family vector (murine leukemia virus and lenti-virus HIV-1) [74]. The adenovirus vector is one of the most commonly used vectors for vascular disease given its ease of high titer generation, easy handling, large insert capacity and extensive characterization [75]. It is becoming more favored as a gene therapy vector because of its ability to infect a large number of both dividing and non-dividing cell types and to integrate non-pathogenically into chromosome 19 [76]. The major limitation with retroviruses is random insertion causing mutations and the difficulty establishing their safety and efficacy [77]. The rate limiting step for stenosis is inhibiting the cell entry into the cell cycle. Genes delivered via hemagglutinin virus vectors carrying antisense oligonucleotides to cyclin B1 and Cdk 2 encoding genes have been shown to inhibit NIH following balloon injury [78]. Other approaches include: (1) delivery of mutated retinoblastoma protein that prevents cell cycling by forming a complex with E2F; (2) fusion of the active sites of the Cdk inhibitors; or (3) construction of a hybrid protein consisting of the amino-terminal fragment of a urokinase-type plasminogen activator linked to a protease inhibitor [79–81]. This latter hybrid binds to the urokinase plasminogen activator receptor to inhibit plasmin activity, a potent cell migration promoter.

More recent studies using decoy oligodeoxynucleotide, which binds and inactivates the pivotal cell-cycle transcription factor E2F have shown that intraoperative transfection of human bypass vein grafts with E2F-decoy is safe, feasible, and can achieve sequence-specific inhibition of cell-cycle gene expression and DNA replication. Future application of this bioengineering technology may lower the rate of failure of human vein grafts [82].

There had been no studies that directly addressed the use of gene therapy for prevention of thrombosis in coronary grafts, but extrapolation of results from balloon mediated injury to the femoral artery in rabbits has been encouraging. From these early experiments, one can conclude that adenovirus mediated transfer of tissue-type plasminogen activator that converts plasminogen to plasmin prevents the local formation of fibrin [83]. In addition, artificial expression of thrombomodulin and tissue factor pathway inhibitor have been shown to prevent thrombosis and stenosis after balloon injury [84,85].

An ample amount of literature illustrates the role of genes in preventing ischemia through other modalities such as delivery of angiogenic factors such as basic Fibroblast growth factor, vascular endothelial growth factor, eNOS, and decoy nuclear factor KB. Gene vectors for NOS are now being examined to introduce the NOS gene into the endothelium of the saphenous vein in order to prevent NIH. Cable and colleagues showed a significant reduction in the intima to media ratio when using adenoviral-mediated gene transfer [86]. Their results correlate with other studies showing that local administration of nitric oxide analogues may cause local vasodilatation of the vein graft and may suppress intimal thickening, all of which result in the prevention of vasospasm and the morphological changes within the vessel wall [87].

7.3. Postoperative prevention
Antiplatelet therapy and anticoagulants have been administered postoperatively based on the assumption that accumulation of platelets and clotting factors plays a significant role in the development of early and late thrombosis and may play an additional role in the development of intimal thickening. At the sixth annual meeting of the American College of Chest physicians, a panel of experts drew a set of recommendations regarding antithrombotic use perioperatively from the evidence-based existing literature [88]. In saphenous venous graft bypass, aspirin is recommended to start as soon as 6 h after surgery. In several clinical series, aspirin and dipyridamole have both been effective in reducing coronary bypass graft failure when administered within 12–24 h after surgery [89]. These drugs did not prove effective in preventing NIH when administered after that period. Newer forms of antithrombotic therapy, such as inhibitors of platelet glycoprotein IIb/IIIa receptors, appear to provide long-term benefit in coronary arteries subjected to angioplasty and may have potential applications in coronary bypass operations [90].

Specific inhibitors of smooth muscle cell proliferation have also been investigated. Although many such drugs have been shown to be inhibitory in animal models, none has proved successful in preventing coronary graft stenosis in humans [91]. Cytotoxic and cytostatic strategies are being developed to destroy or suppress the proliferation of SMCs and limit NIH. Illustration of this ingenious pharmacotherapy is worthwhile. Extrapolations from cancer therapy that targets the SMC and angiogenesis may provide some new light on this subject. It has been shown that an antiangiogenic agent AGM-1470 suppressed SMC migratory activity in a cyotstatic but not cytotoxic dose-response manner. AGM -1470 suppressed new capillary formation around the anastomses [92]. All four antineoplastic drugs, cytarabin, doxorubicin, vincristin and etoposide, had strong dose-dependent antiproliferative effect on cultured SMC. None of these experiments have been reported in clinical experiments, and therefore the true side effects of these interactions remain unknown [93,94].

Local irradiation, or brachytherapy, has been used in animals and to a limited extent in humans to alter vein graft stenosis. The long-term impact of brachytherapy on the diseased vein graft segment is not known [95]. Veins treated in this manner might remain patent, or they might develop fibroproliferative lesions. Local radiotherapy has been used for several decades to reduce the post-operative recurrence of the fibrovascular proliferations of pterygia and keloids. Similarly, in animal and human experiments, endovascular radiotherapy has been shown to reduce arterial smooth muscle proliferation [96]. An ingenious application within the radiation theme is photodynamic therapy with motexan lutetium. This photosensitizer accumulates in atherosclerotic plaques and, activated by far-red light, can induce apoptosis [97]. The goal of such treatment is to achieve a clinically significant decrease in the morbidity and mortality resulting from vein graft stenosis. The potential for a large reduction in the consequences of SVG occlusion, the very large number of patients at risk, and the simplicity of the proposed intervention all encourage prompt scientific evaluation of this technique [98].

	8. Conclusions

Top Abstract 1. Introduction 2. Reperfusion injury and... 3. Neointimal hyperplasia (NIH) 4. Adhesion molecules 5. Effects of nitric... 6. Influence of pulsatile... 7. Preventing vein graft... 8. Conclusions References

 
Thrombosis, NIH and atherosclerosis are three interrelated entities that contribute to the current understanding of vein graft failure in coronary artery bypass graft operations. Each occurs along a spectrum of time frames triggered by endothelial injury and perpetuated by a cascade of inflammatory mediators from the vascular matrix and leucocytes acting primarily on endothelial and smooth muscle cells. Although the biology of this process is complex, there has been several initiatives for better defining these disease processes and for interventions to prevent them. It appears that certain treatments centered on the time of vessel grafting are able to influence cell migration, matrix production, and other variables associated with vascular remodeling, such that there are long-term inhibitory effects on neointima formation. The overall picture for the pathophysiology of coronary graft failure is riddled with many isolated experiments providing more information. Their contribution remains vital to continue to search for clues, yet their exact role in the overall context is still to be understood.

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Top Abstract 1. Introduction 2. Reperfusion injury and... 3. Neointimal hyperplasia (NIH) 4. Adhesion molecules 5. Effects of nitric... 6. Influence of pulsatile... 7. Preventing vein graft... 8. Conclusions References

 

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