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Ann Thorac Surg 2003;76:959-966
© 2003 The Society of Thoracic Surgeons

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Review

Preventing saphenous vein graft failure: does gene therapy have a role?

^a Cardiovascular Research Group, The University of Sheffield, Sheffield, United Kingdom
^b Department of Cardiothoracic Surgery, Northern General Hospital, Sheffield, United Kingdom

^* Address reprint requests to Dr Akowuah, Cardiovascular Research Group, Clinical Sciences North, Northern General Hospital, Herries Rd, Sheffield S5 7AU, UK
e-mail: akowuah{at}yahoo.com

	Abstract

Top Abstract Introduction The pathobiology of saphenous... The increasing use of... Conventional methods of... The evolving role of... Viral gene delivery Non-viral approaches Genetic targets for preventing... Progress in gene therapy... Comment References

 
Gene therapy potentially allows local delivery and expression of cytokines, growth factors, and other mediators. In spite of increasing knowledge of the human genome, applications in clinical practice are only just beginning. The main limitations of effective clinical gene therapy are safety and low transfection efficiency. Saphenous vein grafts permit the transfection of the conduit ex vivo. This allows a variety of transfection techniques to be used, enhancing the transfection efficiency while limiting the risk of systemic complications. This review examines the potential mechanisms of gene delivery and genetic targets that may be applied to saphenous vein graft failure.

	Introduction

Top Abstract Introduction The pathobiology of saphenous... The increasing use of... Conventional methods of... The evolving role of... Viral gene delivery Non-viral approaches Genetic targets for preventing... Progress in gene therapy... Comment References

 
Coronary artery bypass graft surgery (CABG) is now one of the most commonly performed surgical procedures worldwide because it is highly effective in relieving symptoms of angina and prolongs life in certain groups of patients. The saphenous vein is the most commonly used conduit during the procedure.

Unfortunately, due to the accelerated arteriosclerosis that develops within the grafted saphenous vein conduits, saphenous vein graft (SVG) failure remains the major limitation of coronary artery bypass graft surgery.

Although an increased usage of arterial conduits has been advocated to overcome this problem, current data indicate that full arterial revascularization is carried out in only a small minority of eligible patients. An alternative approach is to prolong the lifespan of venous grafts. In this regard, the potential for perioperative gene delivery to prevent vein graft failure is the topic of this review.

Up to 15% of vein grafts occlude within the first year after bypass surgery. Thereafter, for the next 5 years, the attrition rate is 1% to 2% per year, accelerating to up to 4% per annum as the graft ages further. As a result, by 10 years after surgery, only 60% of vein grafts are patent and only 50% of these patent vein grafts are free of significant stenoses [1–3] (Fig 1).

View larger version (124K): [in this window] [in a new window]   Fig 1. An occluded human saphenous vein graft removed intraoperatively from a patient having redo surgery.

	The pathobiology of saphenous vein graft failure

Top Abstract Introduction The pathobiology of saphenous... The increasing use of... Conventional methods of... The evolving role of... Viral gene delivery Non-viral approaches Genetic targets for preventing... Progress in gene therapy... Comment References

 
Saphenous vein graft failure, atherogenesis, postangioplasty restenosis, and transplant vasculopathy comprise a spectrum of vasculo-proliferative disorders that are characterized by similar pathologic processes, despite the differing nature of the vascular injury. In the context of SVG failure, the principal modes of injury relate to the process of vein graft harvesting and surgical preparation, the adaptive responses of the conduit to the arterial circulation, and the activation of inflammatory and coagulation pathways. The vascular responses to these insults include medial vascular smooth muscle cell (VSMC) proliferation and migration, neointimal hyperplasia, and deposition of extracellular matrix (ECM). For reasons that are not entirely clear, the remodeled vessel appears prone to accelerated atherogenesis.

Surgical preparation of the graft disturbs endothelial cells (EC) on the luminal surface of vessels [6, 7], which usually provide an effective barrier to circulating blood cells and platelets, and are thought to have a modulatory role in hemostasis and cellular proliferation within the vessel wall. The consequent reduction in EC-derived nitric oxide (NO) [8] and prostacycline [9] encourages platelet adhesion and aggregation. Platelet activation leads to the release of procoagulant factors, vasoconstrictors, and platelet-derived growth factor (PDGF), which stimulate medial VSMC proliferation and the migration of a subpopulation of cells to the neointima [10]. Additionally, medial VSMC necrosis, perhaps arising from the high hydrostatic pressures [6] applied during vein preparation or the ischemia/reperfusion injury incurred with implantation [11], promotes the infiltration of inflammatory cells. These inflammatory cells in turn secrete cytokines and growth factors, further stimulating medial VSMC proliferation and migration.

The SMCs migrating to the neointima at later time points when medial proliferation has reduced exhibit a "synthetic" phenotype. These cells synthesize ECM and also release PDGF and proteases, including metalloproteinases and plasminogen activators, both of which further facilitate migration by digestion of the extracellular matrix surrounding medial and endothelial VSMCs [12, 13]. The presence of VSMCs in the neointima has traditionally been considered evidence of migration from the media. Recently, in vivo models of vasculoproliferative disease have suggested circulating stem cells can also migrate and differentiate into VSMCs [14].

Although loss of endothelial integrity appears pivotal to the processes discussed, even after reendothelialization, the remodeling process continues, albeit at lower rate [13]. The reason for this is not clear, but continued endothelial dysfunction, the innate response of venous VSMC to mitogens [15], and the arterial circulation have all been proposed. The grafts also exhibit abnormalities of lipid handling [16], which in the longer term renders them prone to accelerated, diffuse, concentric, and friable atherosclerotic disease.

Many or all of the maladaptive responses described represent temporally indistinct phases of SVG failure, resulting in the formation of an obstructive neointima and a reduction in flow through the graft.

	The increasing use of arterial grafts

Top Abstract Introduction The pathobiology of saphenous... The increasing use of... Conventional methods of... The evolving role of... Viral gene delivery Non-viral approaches Genetic targets for preventing... Progress in gene therapy... Comment References

 
The use of the left internal mammary artery (LIMA) for anastamoses to the left anterior descending artery results in excellent long-term patency rates: 90% at 10 years [17]. Perhaps reflecting this improved patency is a considerable body of retrospective evidence that shows that this improved patency is associated with prolonged overall survival, a reduction in late myocardial infarction and other nonfatal cardiac events, and a lower rate of reoperation [18, 19].

Most patients undergoing CABG need three or more grafts. The use of both internal mammary arteries remains controversial. Several studies have failed to show any benefits over the use of only the left internal mammary alone [20, 21]. However, recent studies have suggested that the use of bilateral internal mammary arteries may decrease the risk of death, percutaneous transluminal coronary angioplasty (PTCA), and reoperation compared with use of a single IMA graft. The greatest advantage of bilateral internal mammary arteries grafts was seen in patients who have the longest life expectancy, that is, younger patients [22–24].

Other arterial conduits, like the radial artery, the right gastroepiploic artery, or the inferior epigastric artery, have also been used. Current studies suggest that radial artery use may lead to a decrease in the incidence of perioperative myocardial infarction and late reintervention compared with saphenous vein grafts [25] However, only 5-year angiographic data are currently available in patients receiving the radial artery with patency rates of 90% [26].

Arterial grafting is limited by several factors. The technical difficulty and the duration of the operation are increased, particularly with right internal thoracic artery harvest. Also, the length of the available arterial conduits limits the coronary vessels and the position on the vessel that can be grafted by each conduit independently, necessitating the use of composite Y or T grafts to increase length and provide flexibilty. However, in a recent study, arterial composit Y grafts have been shown to be inferior to independent grafts in terms of coronary blood flow after dipyridamole infusion [27].

Also, there are continuing concerns about increased morbidity, particularly sternal wound healing for bilateral internal thoracic artery and vascular and neurogical complications after radial artery harvest. Finally, arterial spasm remains a problem, particularly with the radial artery.

As a result of these limitations, the use of arterial grafts other than the LIMA is still not common practice in the UK. In 1999, fewer than 20% of patients having first-time CABG in the UK had more than one arterial graft. Fewer than 5% of patients had three or more arterial grafts (The Society of Cardiothoracic Surgeons of Great Britain and Ireland, United Kingdom Cardiac Surgical Register) [28].

	Conventional methods of preventing SVG failure

Top Abstract Introduction The pathobiology of saphenous... The increasing use of... Conventional methods of... The evolving role of... Viral gene delivery Non-viral approaches Genetic targets for preventing... Progress in gene therapy... Comment References

 
Of the conventional approaches to limit SVG failure, cessation of smoking is perhaps the most important. Smoking causes accelerated SVG failure. Angiographic follow-up of 340 males with 1,160 grafts showed that, after exclusion of 112 grafts for early occlusion, 52% of grafts remained disease free in nonsmokers compared with 39% in smokers [28].

This in turn leads to a worse clinical outcome. In a prospective follow-up study of 415 patients for 15 years after venous bypass surgery, compared with patients who stopped smoking since surgery, persistent smokers had 2.3 times increased risk of myocardial infarction and 2.5 times increased risk of reoperation 1 year after surgery. Five to 15 years after surgery, the risk of myocardial infarction, reoperation, and return of angina in patients continuing to smoke were 2.5, 3.3, and 2 times, respectively, greater than patients who had stopped smoking [29, 30].

Antiplatelet therapy with aspirin is the most established medical therapy for preventing SVG failure. The Veterans Administration Cooperative Studies have shown that aspirin at a dose of 325 mg per day or higher increased graft patency at 60 days compared with placebo [31]. At 1 year, the graft occlusion rate for patients on daily aspirin was 3.2% compared with 22.6% for placebo [32]. Furthermore, early initiation of aspirin therapy, within 48 hours of surgery, compared with commencing therapy after 48 hours, has recently been shown to be associated with reduced mortality (1.3% vs 4%), a reduction in early postoperative myocardial infarction (2.8 vs 5.4%), stroke (1.3% vs 2.6%), renal failure (0.9% vs 3.4%), and bowel infarction (0.3% vs 0.8%) [33].

Finally, lipid-lowering agents have a role. Recently, simvastatin has been shown to reduce neointima formation in organ-cultured human saphenous vein by the inhibition of smooth muscle cell proliferation and migration, probably mediated by the downregulation of mixed metalloprotease 9 [34].

Several clinical trials on the role of lipid lowering therapy have been published. The post-CABG study investigated this question specifically in patients after coronary artery bypass surgery and used both clinical and angiographic endpoints. Follow-up angiograpghy performed in 1,192 patients at a mean of 4.3 years after recruitment showed that aggressive lowering of LDL cholesterol reduced progression of vein graft disease (defined as per patient percentage of grafts with a decrease of 0.6 mm or more in lumen diameter), the rate of vein graft occlusion, and the number of new vein graft lesions as compared with moderate lowering of LDL cholesterol. The observed angiographic benefits were reflected in a reduction in the need for further revascularization in the aggressively treated group compared with the moderately treated group [35].

These conventional approaches, while important, have failed to prevent SVG failure.

	The evolving role of gene therapy

Top Abstract Introduction The pathobiology of saphenous... The increasing use of... Conventional methods of... The evolving role of... Viral gene delivery Non-viral approaches Genetic targets for preventing... Progress in gene therapy... Comment References

 
Greater understanding of the pathogenesis of SVG failure has stimulated interest in new therapeutic approaches directed at the biological mechanisms that control the vasculo-proliferative process. In this regard, the first descriptions of site-directed transfer of exogenous genetic material into the vascular system were published more than a decade ago [36] [37]. Thus, gene therapy offers, at least in theory, an alternative and novel approach to the treatment of SVG failure. However, the translation of gene therapy to the clinical arena has been hampered by the technical challenges.

There are two general approaches to gene therapy. One is to introduce a gene so that the transfected cell will make a protein. The other is to introduce antisense oligonucleotides, which act as decoys and block the production of a protein.

Successful gene therapy will depend on the following [1]: the appropriate choice of therapeutic gene and gene product to express in the vascular wall [2], a safe and efficacious vector mechanism for the introduction of these genes into the cell, and [3] a practical and easy approach for the delivery of vectors to the target cell [38]. Saphenous vein grafting presents a unique opportunity to maximize gene transfection ex vivo, immediately after harvesting and before implantation, and may therefore become a forerunner for future progress in this field as well as being an important application in its own right.

	Viral gene delivery

Top Abstract Introduction The pathobiology of saphenous... The increasing use of... Conventional methods of... The evolving role of... Viral gene delivery Non-viral approaches Genetic targets for preventing... Progress in gene therapy... Comment References

 
Early studies demonstrating high-efficiency in vivo gene delivery by viral vectors, particularly those based on the adenovirus, were heralded as a major landmark in cardiovascular gene therapy. It led to an intense period of research in the field. The important biological and preclinical vascular gene transfer studies performed with viral vectors would not have been possible using other less efficient vector systems [39–41].

Despite the high efficiency of viral vectors, there are three main limitations to their widespread use in human vascular gene therapy. They are limited by: (1) high prevalence of preexisting immunity to adenovirus; (2) the profound destructive immune response generated to adenoviral transduced cells; and (3) direct tissue toxicity [42, 43].

Because they are uniformly seronegative for human adenovirus exposure, laboratory animals are highly susceptible to gene transfection on a first exposure to adenoviral vectors. However, once immunized with adenoviral vectors, they essentially cannot undergo successful vascular gene delivery [44]. Adult humans have a high prevalence, approximately 60%, of seroposivisity to adenovirus [44], and an even higher prevalence of memory T-cells responsive to adenoviral infection. In the absence of concurrent immunosuppressant agents, vascular gene delivery with adenoviral vectors in the vast majority of coronary artery disease patients may therefore be unsuccessful. Furthermore, transduced cells that express low amounts of adenoviral proteins are eliminated by the host immune response. This may result not only in the death of the cell and the cessation of recombinant gene expression, but also in the development of inflammatory cell infiltrates and vascular cell activation in the artery wall. In addition, direct toxicity of high concentrations of adenoviral vectors results in smooth muscle cell death and endothelial denudation [42]. Specifically, a recent report demonstrating abnormal vascular reactivity after adenoviral gene delivery suggests that sublethal forms of vascular toxicity may also exist [45].

These three major shortcomings, coupled with the potential generation of replication competence, raise legitimate questions about the safety and efficacy of viral gene transfection. The death of a patient during an adenoviral clinical trial in the US lends legitimacy to these concerns [46].

	Non-viral approaches

Top Abstract Introduction The pathobiology of saphenous... The increasing use of... Conventional methods of... The evolving role of... Viral gene delivery Non-viral approaches Genetic targets for preventing... Progress in gene therapy... Comment References

 
The limitations of viral vectors discussed above, particularly the ongoing safety concerns and difficulty in targeting to specific cell types, have led to the evaluation and development of nonviral gene transfection techniques.

The main alternatives to viruses are direct naked DNA transfection, liposome- mediated transfection, the use of liposome-polycation complexes, and synthetic cationic polymers. To date, however, all these nonviral methods have relatively low efficiency of transfection, particularly in vivo.

In an attempt to overcome these problems, we have explored the use of ultrasound to enhance naked plasmid delivery in vascular cells. Ultrasound has the particular advantage of a strong safety record in vivo and the ability to target virtually any organ by focused external ultrasound. In our initial proof-of-concept experiments, we used very low-intensity ultrasound to transfect porcine vascular smooth muscle cells (VSMC) and endothelial cells (EC) after transfection with a plasmid expressing the luciferase reporter gene [47]. This achieved a tenfold increase in reporter gene expression compared with naked DNA alone in VSMC. In subsequent experiments, we have shown up to 300-fold enhancements when ultrasound is combined with the use of microbubble echocontrast agents in vitro. This approach also enhances by fourfold the efficiency of synthetic cationic polymer transfection, yielding luciferase transgene expression levels 3,000-fold higher than after naked DNA transfection alone in vitro [48]. In the in vivo situation, we have recently demonstrated significant enhancements in gene expression in porcine coronary artery after endoluminal ultrasound-enhanced, stent-based gene delivery [49]. Furthermore, we have achieved significant ultrasound-enhanced transgene expression in ex vivo saphenous vein organ culture, and in vivo studies involving porcine carotid interposition vein grafts are currently under way. Other groups have also demonstrated ultrasound-enhanced gene transfection in a variety of in vivo models [50, 51].

Whatever the success of gene delivery using ultrasound or other gene delivery techniques, translation to clinical gene delivery will depend upon the choice of an appropriate gene target, the focus of the next section of this review.

	Genetic targets for preventing SVG failure

Top Abstract Introduction The pathobiology of saphenous... The increasing use of... Conventional methods of... The evolving role of... Viral gene delivery Non-viral approaches Genetic targets for preventing... Progress in gene therapy... Comment References

 
Based on the pathologic processes involved in SVG disease, several approaches can potentially be used for treatment (Table 1) . Many of the pathobiological processes are mediated through the cell cycle, including cell growth, death, apoptosis, and migration. The proliferative and synthetic capacity of VSMC will profoundly effect extracellular matrix deposition. Consequently, investigators have studied the potential of genes that regulate the cell cycle to modify the disease process. The cytostatic approach has been used to inhibit smooth muscle cell proliferation. For example, antisense oligodeoxynucleotides to block expression of proliferating cell nuclear antigen (PCNA) and cell division cycle 2 (CDC2) kinase have been used to prevent vascular smooth muscle proliferation in an arterialised jugular vein graft in the rabbit [52].

Marked endothelial dysfunction and loss occurs in a saphenous vein graft, which reduces the availability of endothelial factors responsible for preventing inflammatory cell adhesion, thrombosis, and smooth muscle cell proliferation. These factors include prostacyclin, adenosine, and NO [54]. Successful transfection of the endothelial NO synthase gene in human saphenous vein grafts preserves vascular nitric oxide production and attenuates the extent of endothelial dysfunction over time [55]. In organ-cultured human saphenous vein, adenoviral-mediated gene transfer of endothelial NO synthase significantly decreased neointima formation after 14 days, compared with viral-mediated transfer of the nontherapeutic gene lac Z [56].

Another approach has been to inhibit smooth muscle cell migration. A key element in the formation of the neointima is the migration of smooth muscle cells from the media to the intima [57]. Crucial to this process is the expression and activation of a variety of proteases, directed to facilitating migration through the extracellular matrix. The family of mixed metalloproteases (MMP) is the most important group of proteases described [58]. Overexpression of the protease inhibitors, tissue inhibitors of matrix metalloproteases (TIMPs) TIMP-1, inhibits smooth muscle cell migration and decreases neointimal formation in a saphenous vein graft [59]. TIMP-3 has also been shown to decrease neointimal formation in saphenous vein graft models in vitro and in vivo [60].

Neointima formation after vein graft surgery is a relatively early event that is followed by the development or more "classic" artherosclerosis. Whatever the genetic approach, the hope is that prevention or amelioration of neointima formation will remove the substrate for this latter development of artherosclerotic plaque, and hence prevent late graft failure.

	Progress in gene therapy for SVG failure in vivo

Top Abstract Introduction The pathobiology of saphenous... The increasing use of... Conventional methods of... The evolving role of... Viral gene delivery Non-viral approaches Genetic targets for preventing... Progress in gene therapy... Comment References

 
Despite the excellent results so far achieved with adenoviral transfection of therapeutic genes, concerns over the safety of this approach have prevented human gene therapy trials for SVG failure. Table 2 summarizes the first few trials aimed at modifying the pathologic changes of vein grafts placed in an arterial system.

George and associates demonstrated that upregulation of TIMP 1 activity led to inhibition of smooth muscle cell migration and a reduction in neointimal formation in human saphenous vein organ culture model [59]. Subsequently, they showed that upregulation of TIMP- 3 in an in vivo porcine carotid artery/saphenous vein graft interposition model led to a reduction of neointimal formation at 28 days [60]. A significant reduction in neointima formation after adenoviral mediated transfer on the NO synthase gene, eNOS, has also been reported [56].

The data discussed so far all employ viral gene delivery mechanisms. However, the most recent paper on in vivo gene therapy for SVG described a nonviral gene delivery method, perhaps highlighting the increasing realization of the problems associated with viruses and the potential of nonviral gene delivery [62].

The authors investigated the effect of pressure-mediated transfection of cis element decoy oligonucleotides of NF_kB in a canine aortocoronary SVG model. NF_kB is a nuclear transcription factor that controls the expression of genes involved in cell cycle regulation, as well as genes that mediate the expression of adhesion molecules after external stimulation of a cell. After 4 weeks, the ratio of neointimal area to medial area in the treatment group was approximately half that of the treatment group.

To date, there has been one human gene therapy trial to modify SVG failure [63]. It involved the use of decoy oligodeoxynucleotides, which bind to and inactivate the pivotal cell cycle transcription factor, E2F. Oligonucleotides were delivered to infrainguinal saphenous vein grafts intraoperatively by ex vivo nondistending pressure mediated transfection (300 mm Hg). Primary graft failure was defined as graft occlusion requiring graft revision or evidence on ultrasonography of a stenosis of more than 75% at 12 months after surgery in patients who were not candidates for reoperation. At 12 months, 29% of patients in the treatment group had suffered primary graft failure compared with 69% in the control group.

	Comment

Top Abstract Introduction The pathobiology of saphenous... The increasing use of... Conventional methods of... The evolving role of... Viral gene delivery Non-viral approaches Genetic targets for preventing... Progress in gene therapy... Comment References

 
The substantial advances over the past decade have allowed a clear definition of the challenges that must be met in order to bring gene therapy for SVG failure into the clinical arena. The issues of gene delivery, genetic targets, and safety remain the main hurdles for this technique.

An ideal vector should be able to achieve highly efficient transfection and sustained recombinant gene expression with minimal toxicity, which no currently available vector system achieves. Viruses are highly efficient but may be toxic, and nonviral gene delivery methods, while safe, are inefficient.

Saphenous vein graft disease results from several pathologic and physiologic processes acting in concert. Present studies, by necessity, usually focus on local overexpression of single molecules. It is likely that any successful gene therapy must influence several of these processes, in different parts of the vessel at different times.

Finally, the safety of gene therapy has been thrown into question by recent events [64]. The death of teenager in a gene therapy trial in the US raised concerns about adenoviral gene therapy. Recently, a trial using adeno-associated viruses, was "put on hold" due to concerns about a germ line mutation in a patient [64]. It is clear that because of worries about safety of viral gene transfection, the focus should shift to improving the efficiency of nonviral gene transfer systems.

Saphenous vein grafts permits the transfection of the conduit ex vivo, enhancing the transfection efficiency and limitting the risk of systemic complications. Gene therapy raises the prospect of a renaissance in the use of the saphenous vein as a conduit for bypass surgery.

	References

Top Abstract Introduction The pathobiology of saphenous... The increasing use of... Conventional methods of... The evolving role of... Viral gene delivery Non-viral approaches Genetic targets for preventing... Progress in gene therapy... Comment References

 

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