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Ann Thorac Surg 2007;84:317-323
© 2007 The Society of Thoracic Surgeons

Reviews

Therapeutics of Vein Graft Intimal Hyperplasia: 100 Years On

Edward J.W. Wallitt, BSc, Marc Jevon, PhD, Philip I. Hornick, FRCS*

Department of Cardiothoracic Surgery, Imperial College, London, United Kingdom

* Address correspondence to Mr Hornick, Department of Cardiothoracic Surgery, NHLI, Imperial College, Hammersmith Campus, 2nd Floor, B Block, DuCane Rd, London, W12 0NN, United Kingdom (Email: p.hornick{at}imperial.ac.uk).


   Abstract
Top
 Abstract
Introduction
 Intimal Hyperplasia and Vein...
 Pathophysiologic Triggers of AIH
 Therapeutic Approaches to...
 Therapeutic Approaches to AIH...
 Comment
 References
 
Intimal hyperplasia is central to the pathology of vein graft re-stenosis, and despite considerable advances in our understanding of vascular biology since it was first described 100 years ago, it is still a significant clinical problem. Recent decades have seen the development of many new therapeutic agents aimed at treating this condition, but the successes of laboratory studies have not been replicated in the clinic yet. This review discusses these therapeutic agents, how their modes of action relate to the pathogenesis of vein graft intimal hyperplasia, and considerations of ways in which such therapy may be improved in the future.


   Introduction
Top
 Abstract
 Introduction
Intimal Hyperplasia and Vein...
 Pathophysiologic Triggers of AIH
 Therapeutic Approaches to...
 Therapeutic Approaches to AIH...
 Comment
 References
 
This year marks the century since the Nobel-prize winning surgeon Alexis Carrel first alluded to intimal hyperplasia after vein grafting. Noting the "glistening appearance of stitches" in a graft some days after surgery, he famously commented on their similarity to normal endothelium [1]. However, it was not until some 65 years later that this phenomenon was directly linked to vein graft re-stenosis and failure [2].

Although acute bypass failure is typically caused by technical problems and thrombosis, late failure (at least more than 1 month after coronary artery bypass grafting [CABG]) develops as a result of intimal hyperplasia and subsequent accelerated atherogenesis [3]. Therefore treatments meant to bypass vessels are themselves affected by the very malady they are deployed to treat; it would seem that biology is not without a sense of irony.

Intimal hyperplasia represents a substrate for vein graft re-stenosis. Therefore graft failure rates may give us a window into the clinical prevalence. However, precise rates of vein graft failure are difficult to determine. This is primarily because most studies (many of which were undertaken in the 1970s) are retrospective, and since that time, significant changes have occurred in both surgical techniques and patient management (eg, increased lipid control, increased postoperative use of aspirin). The most recent data suggests that after coronary CABG, saphenous vein graft patency at 1 year is 84%, dropping to 61% after 10 years poor compared with an 85%, 10-year patency for internal mammary artery grafts [4].

Fuelled by these figures, and also by the pivotal role intimal hyperplasia plays in other vascular pathologies, a vigorous search for a "magic bullet" has been made in the past 20 years. A wide range of agents have been explored from anti-platelet and anti-proliferative drugs to cod liver oil and traditional Chinese formulations [5]. This review discusses many of these agents, how their modes of action relate to the pathogenesis of vein graft intimal hyperplasia, and considerations of what the future holds for the prevention and treatment of this important problem.


   Intimal Hyperplasia and Vein Graft Re-Stenosis
Top
 Abstract
 Introduction
 Intimal Hyperplasia and Vein...
Pathophysiologic Triggers of AIH
 Therapeutic Approaches to...
 Therapeutic Approaches to AIH...
 Comment
 References
 
Intimal hyperplasia occurs physiologically at closure of the ductus arteriosus [6], as well as pathologically in a variety of disease settings. On a basic level, intimal hyperplasia is a process that involves continued migration and proliferation of smooth muscle cells into the intima, often with associated deposition of extracellular matrix. This results in a highly cellular, subintimal lesion that ultimately reduces the graft lumen and may lead to thrombosis [7]. It is best described in early atherosclerosis where it contributes to initial intimal expansion, fibrous plaque formation, and the constantly evolving lesion described in Anitschkow and Chalatow’s [8] seminal work. However, importantly, intimal hyperplasia also occurs after vein grafting, angioplasty, arteriovenous fistulae formation and transplantation; in these contexts this is now referred to as accelerated intimal hyperplasia (AIH).

A number of risk factors, including trauma, arterial hemodynamics, vasospasm, and ischemia are recognized as being responsible (alone or in combination) for initiating the development of vein graft AIH. As such, these may be regarded as the primary tier of vein graft re-stenosis. However, it is also clear that there exists a secondary tier (accelerated atherogenesis), whereby AIH functions as a nidus for the development of atherosclerotic lesions, possibly through accelerated lipid accumulation and monocyte transmigration [9]. Late occlusion of saphenous vein grafts (eg, >5 years after implantation) has been almost always shown to be a result of atherosclerosis [10], and one necroscopic study of 53 patients has shown atherosclerotic changes in almost all saphenous vein grafts implanted for more than 1 year [11].

Glakov remodelling, whereby lumen patency is maintained at the expense of increased vessel wall thickness, has been described for venoarterial grafts in rats [12]. However, the most recent human data has shown that in the first year after CABG, this is predominantly a negative process, resulting not in the maintenance of luminal patency, but rather the loss of it [13]. As such, the precise balance of intrinsic and extrinsic factors that determine the vessel’s ability to maintain lumen patency have yet to be elucidated.


   Pathophysiologic Triggers of AIH
Top
 Abstract
 Introduction
 Intimal Hyperplasia and Vein...
 Pathophysiologic Triggers of AIH
Therapeutic Approaches to...
 Therapeutic Approaches to AIH...
 Comment
 References
 
The endothelium is the primary regulator of vessel wall homeostasis (ie, controlling vascular tone, coagulant state, leukocyte recruitment, and angiogenesis [14]). Although the precise mechanisms by which resting, healthy endothelial cells prevent AIH is largely unknown, endothelial injury with or without medial damage is associated with its development [15]. It has been proposed that a healthy, nonactivated endothelium may inhibit AIH indirectly through maintenance of vascular homeostasis, and that a wide range of stimuli can disrupt this state, leading to endothelial activation and its consequences.

Mechanical and physical trauma may be associated with endothelial denudation and is a key stimulus for endothelial activation after percutaneous transluminal coronary angioplasty, artery stenting, and vein grafting. The level of AIH is directly linked to the degree of endothelial denudation, which, in vein grafts, has been attributed to luminal distension during surgery, damage at surgical anastamoses, and continued physical trauma under arterial conditions [16]. In humans and animals, such trauma is associated with inflammation, smooth muscle proliferation and migration, and deposition of extracellular matrix, as well as, in some cases, thrombus formation [7]. In the light of this, regeneration of a confluent endothelial layer appears biologically important, although endothelial dysfunction has been shown to continue well after this has taken place [17]. Interestingly, cells involved in endothelial regeneration have been shown to come from a variety of sources, including hematopoietic stem cells, hemangioblast precursor cells, and even monocytes and macrophages [18]. The time course of endothelial regeneration has been described in a variety of models, but variation exists both between models and between similar models in different studies [19].

In the early 1970s using a canine model, Brody and colleagues [20] demonstrated that vein grafts implanted in the arterial circulation developed AIH, whereas those implanted in the venous circulation did not. Subsequently it has been shown that AIH may occur in the absence of endothelial denudation, and although arterial tangential pressure (ie, a force encountered transverse to the arterial wall) is sufficient to cause AIH in veins, as well as medial damage and thickening, the threshold for this is above what is typically encountered in the arterial system [21].

Shear stress, encountered longitudinally to the vessel wall, has also been implicated in the development of AIH. Indeed evidence from in vitro and in vivo studies suggests that large spatial shear gradients lead to both structural and functional changes in vein graft endothelium [22]. The association between low shear stress and AIH is well documented in vein grafts [14], although it has been suggested that high shear stresses are also associated with AIH [23]. This leads to the proposal that vessels may require an optimum shear value or gradient, above or below which AIH will occur [24].

Considerable debate surrounds precisely how altered flow patterns produce their biological effect. It has been shown that flow patterns influence the production of vasoactive compounds, such as nitric oxide and prostacyclin I2, and the expression of receptors involved in leukocyte recruitment, including intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and monocyte chemo-attractant protein-1, which are increased after exposure of endothelial cells to altered shear stress [25]. However, although this does demonstrate a biological link between altered hemodynamics and AIH, the precise mechanisms involved remain unclear. As such, there is a need to develop accurate models to examine flow velocities and shear stresses and their effects on AIH.


   Therapeutic Approaches to Accelerated Atherogenesis
Top
 Abstract
 Introduction
 Intimal Hyperplasia and Vein...
 Pathophysiologic Triggers of AIH
 Therapeutic Approaches to...
Therapeutic Approaches to AIH...
 Comment
 References
 
Given that endothelial denudation is a key element in the development of AIH, attempts have been made since the late 1970s to preserve the endothelium by reducing direct mechanical trauma through the modulation of surgical techniques [24]. Luminal distension procedures, frequently used to overcome graft spasm and to check for leakage, have been well investigated and should be considered as the most important and avoidable cause of intimal damage during surgery [26]. Pharmacological relaxation using glyceryl trinitrate and verapamil during harvesting may be an important alternate technique [27]. In addition, grafting performed using veins harvested with their surrounding tissue reportedly achieve short-term and long-term patencies similar to internal mammary artery grafts [28]. External stenting of saphenous vein grafts has also been shown to reduce AIH in the pig [29].

If AIH forms the primary tier of the re-stenotic process, acting as a substrate for accelerated atherogenesis, then tight control of atherogenic risk factors might be expected to somewhat improve graft patency through a reduction in this secondary process. Surprisingly, recent data suggests that saphenous vein graft patency after CABG is independent of traditional atherogenic risk factors such as race, insulin-controlled diabetes, cigarette smoking, and hypertension [4]. However this evidence does suggest that serum cholesterol levels are predictive of long-term graft patency and that aggressive lipid lowering treatment after arteriovenous grafting can reduce AIH. Indeed, in the Post Coronary Artery Graft Trial, aggressive lipid lowering resulted in significantly less atherosclerosis as assessed by angiography compared with moderate lipid lowering after long-term follow-up [30]. It is reportedly possible to predict the effect of serum cholesterol levels on graft patency based on the calculation of an acceleration factor for a given change in cholesterol, which was determined to be 0.82 per 50 mg/dL. Thus if a man with a serum cholesterol of 200 mg/dL occludes his graft at 5 years, then it is estimated that a man with 250 mg/dL will occlude at 4.1 years, all other variables being equal [4].

Such observations highlight cholesterol as an atherogenic risk factor exerting its effect on vein grafts in a shorter term than smoking, diabetes, or hypertension, and justify the continued tight lipid control after grafting. However, if AIH is considered as a nidus for accelerated, cholesterol-driven atherogenesis, then perhaps even greater vein graft patencies may be achieved with early treatment aimed at its abrogation.


   Therapeutic Approaches to AIH Pathogenesis
Top
 Abstract
 Introduction
 Intimal Hyperplasia and Vein...
 Pathophysiologic Triggers of AIH
 Therapeutic Approaches to...
 Therapeutic Approaches to AIH...
Comment
 References
 
Thrombosis and Coagulation
Platelet activation occurs rapidly following venoarterial grafting, with the magnitude of the response being related to the extent of injury [31]. Clinical experience all too commonly dictates that this can lead directly to thrombosis and early graft failure. However, the function of platelets at sites of vascular damage is complex; involving adhesion to the exposed subendothelial matrix, release of adenosine triphosphate, aggregation by the von Willibrand factor and platelet receptor GpIIb-IIIa, and finally production of pro-proliferative and pro-inflammatory factors such as platelet-derived growth factor (PDGF), transforming growth factor-ß, thrombin, and various cytokines (interleukin-1, interleukin-6, interleukin-8) [32]. It is because many of these vascular mediators have been implicated adversely in AIH that multiple studies have focused on the use of anti-platelet drugs to combat vein graft intimal thickening.

Given their adverse cardiovascular risk profile, oral aspirin is routinely given to CABG patients. In fact evidence from a canine model suggests that systemic administration of aspirin, at either low (75 mg), medium (225 mg), or high (650 mg) doses, does not reduce vein graft AIH [33]. Furthermore, it has been shown in vitro that endothelial and smooth muscle cell PDGF-A mRNA expression is unaffected by aspirin and dipryridamole treatment [34]. However, interestingly it has recently been reported that topical aspirin delivery does reduce neointimal volume after vein grafting in mice [35], although the mechanisms by which aspirin may ablate AIH in this model remain to be elucidated.

Other anti-platelet agents have also been examined for their anti-hyperplastic properties. For example, clopidogrel, which is a thienopyridine family member, has been shown to inhibit platelet adhesion and mitogenic signalling in vitro [36], and the effect of clopidogrel and aspirin together compared with aspirin alone after CABG is currently under investigation in the Clopidogrel After Surgery for Coronary Artery Disease trial [37].

The early use of anti-coagulants after vein grafting is well established. Their beneficial effects are largely assumed to be because of a reduction in coagulative graft occlusion after surgery, although their therapeutic role against AIH and late graft failure remains to be determined. Although heparin has previously failed to suppress graft intimal and medial thickening in a small animal model [38], Lin and colleagues [39] have shown reduced platelet deposition and neointimal hyperplasia with heparin-coated synthetic grafts in baboons. Given their early promise in small animal models, newer anti-coagulants, such as the direct thrombin inhibitors argatroban and lepirudin, offer further therapeutic possibilities [40].

Platelet activation leads to thrombin production, which in turn induces synthesis and release of PDGF from vascular smooth muscle cells (VSMCs). A key component of this pathway is tissue factor, and given the role of PDGF in the evolving intimal lesion, this has appealed as a target. For example, local application of tissue factor pathway inhibitor to experimental vein grafts in rabbits has lead to a reduction in AIH [41]. This, coupled with the observation that tissue factor pathway inhibitor treatment also reduces AIH after arterial injury [42], indicates that tissue factor pathway inhibitor may be a useful therapeutic tool in the future.

Inflammation
Subendothelial inflammation is central to the pathogenesis of atherosclerosis and has been described as the "hallmark of the re-stenotic process" [43]. The earliest stage of this process is leukocyte recruitment, which is a multi-stage and complex process that is driven by a complex array of cytokines, chemokines, and adhesion molecules produced by VSMCs, activated endothelial cells, and leukocytes themselves [25].

More specifically, there appears to be a significant link between subendothelial inflammation and VSMC function. The VSMCs are capable of synthesising a variety of biologically active mediators that regulate vessel contraction and relaxation, proliferation, apoptosis, and inflammation. In one rabbit vein graft study, cell-cycle arrest was able to prevent adhesion molecule expression in vivo, thus maintaining a nonactivated cellular phenotype [44]. In addition, the role of cyclin-dependent kinases in the regulation of transcriptional gene activation by nuclear factor-{kappa}B (NF-{kappa}B) provides a firm biological link between the coordination of leukocyte recruitment and the cell cycle progression of VSMCs [45].

The concept of using anti-inflammatory agents to treat vein graft AIH is relatively new, but data thus far are encouraging. For example, transforming growth factor-ß antisense gene therapy reduces intimal thickening and expression of monocyte chemo-attractant protein-1 in rats when delivered virally [46] and biliverdin, which is a by-product of heme degradation with potent anti-oxidant and anti-inflammatory effects, reduces AIH in rats [47].

The NF-{kappa}B-mediated signalling is involved in the gene regulation of numerous cytokines and adhesion molecules known to be involved in AIH [48], making it an attractive therapeutic target. In fact, recently, intraoperative treatment with NF-{kappa}B decoy oligodeoxynucleotides has suppressed intimal hyperplasia, reduced vessel inflammatory changes, and decreased VSMC proliferation in the vessel intima in rabbits after grafting [49]. However, there are issues regarding the balance between efficacy and safety, as the maintenance of some level of NF-{kappa}B activity is critical for immune responses and cell survival. As a result, the optimum strategy to inhibit NF-{kappa}B activation in intimal hyperplasia is yet to be ascertained, but nonetheless it remains extremely promising [50].

VSMC Proliferation and Migration
The VSMCs form the most prominent cellular element of the neointimal lesion [13], and their proliferation and phenotype switch from contractile to secretory is believed to be stimulated by a variety of growth factors. These include basic fibroblastic growth factor released from damaged platelets and smooth muscle, PDGF from platelets, endothelium, and the VSMCs themselves. Roles for transforming growth factor-ß, angiotensin II, heparinase, and proteases have also been described [24].

There has recently been an increased focus on signalling pathways linking external mitogenic stimuli with pathologic alterations in the cell cycle of VSMC within vein grafts. It is known that VSMC interaction with extracellular matrix through integrins on the cell surface inhibits migration and proliferation, and the protein kinase B/Akt pathway is activated in response to PDGF. Likewise, increased cAMP and cGMP concentrations inhibit VSMC proliferation. In contrast, inhibition of Rho GTPase, mitogen activated protein kinase, and phosphoinositol 3-kinase have been shown to suppress AIH in vein grafts [51]. Thus, VSMC proliferation is regulated by multiple stimuli (eg, mitogen activated protein kinases, phosphoinositol 3-kinase, diacylglycerol/protein kinase C) and inhibitory factors (ie, matrix integrins/heparins, soluble cAMP). The development of improved treatments for the prevention of AIH will be enhanced by better understanding the interplay between these pathways in the context of the regulation of VSMC proliferation and migration.

An intact extracellular matrix prevents VSMC migration by acting as both a physical barrier and an active inhibitor of signalling. Several signalling molecules have all been implicated in VSMC migration [51], including Ca2+-activated calmodulin kinase II, MAPK/small GTPases and focal adhesion kinases, although more is understood about the downstream effectors of migration (ie, matrix metalloproteases and enzymes of the plasmin system). Production of matrix metalloproteases is stimulated by both growth factors and inflammatory cytokines known to be involved in cell proliferation [52] and after balloon injury, tissue plasminogen activator, responsible for the formation of plasmin from plasminogen, is expressed by migrating VSMC [53]. In addition, exposure of cultured VSMC to PDGF or basic fibroblastic growth factor has been shown to increase tissue plasminogen activator production [54].

The pivotal role of VSMC proliferation and migration in this vascular pathology makes it a good therapeutic target. As such, a number of compounds able to specifically target the intracellular and intercellular signalling pathways involved in VSMC proliferation and migration have been investigated, including MAPK inhibitors [55], CDK inhibitors [56], and Gß{gamma} inhibitors [57], as well as endovascular irradiation [58]. However, these treatments are in their early days of development, and while these agents may offer some therapeutic benefit, delivery problems have so far plagued their use.

A number of drugs commonly used in the cardiology clinic have been examined for anti-proliferative and anti-migratory effects, including statins, angiotensin-converting enzyme inhibitors [59], and calcium channel blockers [60]. High serum lipid levels are associated with cardiac and peripheral vascular pathology, and their reduction has been shown to be clinically useful in both a primary and secondary setting. Although the beneficial effects of statins were initially believed to stem wholly from their direct effects on total serum cholesterol levels and subclass balance, more recent data indicates that they may possess a number of additional and desirable "pleiotropic effects," such as suppression of VSMC proliferation [61], restoration of endothelial nitric oxide synthase activity [62], and increased progenitor cell recruitment [63]. This has led to the hope that systemic statin administration could reduce AIH, an idea supported by a recent study of normocholesterolemic rabbits [64]. Furthermore, data from a human vein culture model suggests that statins may be able to significantly reduce AIH if administered topically at high concentrations [65].

Rapamycin, a macrocyclic triene antibiotic, has revolutionized interventional, cardiological, and transplant practice and has been shown to block the proliferative response of VSMCs after mechanical or immune-mediated injury, as well as to inhibit VSMC migration, angiotensin-II induced hypertrophy, and TNF-{alpha} induced expression of ICAM 1 [66]. After the RAVEL [67] and larger SIRIUS [68] trials, rapamycin has now found a firm position in drug stenting and current applications to vein graft intimal hyperplasia have focused on the use of such stents after graft failure. However, the most recent data suggests little benefit of these stents in preventing further graft re-stenosis [69], perhaps reflecting the presence of significant and irreversible intimal hyperplasia in such grafts. Earlier and more effective treatment with rapamycin, perhaps even at the point of graft delivery, may result in reduced AIH and consequential failure.

Oral rapamycin prolongs allograft survival [70] and has held great appeal as a low-cost preventative strategy for re-stenosis. However, despite displaying some promise in small pilot studies [71], it has been shown now to result in no dose-dependent reduction in graft re-stenosis [72]. This factor, coupled with a dose-dependent incidence of adverse side effects, such as abdominal pain, nausea and vomiting, and oral ulcers, underscores the importance of developing local, efficacious drug delivery mechanisms. It is envisioned that such an approach could enable high-tissue concentrations of such agents to be achieved, without the adverse effects often seen at much lower systemic concentrations.

The transcription factor E2F up-regulates a dozen cell-cycle genes [73], theoretically making it an ideal target for anti-proliferative treatment. Indeed, data from a rabbit model showed that intraoperative transfection with E2F decoy oligodeoxynucleotide yielded long-term resistance to vein graft atherosclerosis [74]. This formed the basis for setting up the Project of Ex-vivo Vein Graft Engineering via Transfection I (PREVENT I) study [75], testing the safety and biological efficacy of intraoperative E2F gene therapy in 41 bypass patients. These investigators showed good transfection efficiency (89%) with no increase in the postoperative complication rate. Furthermore, at 1 year, fewer occlusions or revisions were noted in the treatment group. However, the recent conclusion of the Project of Ex-vivo Vein Graft Engineering via Transfection IV (PREVENT IV) study has significantly damped enthusiasm for this treatment [76]. Follow-up of 3,014 patients in multiple centres has revealed that E2F decoy is no more effective than a placebo in preventing angiographic graft failure, acute adverse effects, or major cardiac events 12 to 18 months after CABG. However, the investigators believe that long-term follow-up is needed and may show some benefit yet to come.

Progenitor Cell Recruitment
Asahara and colleagues [77] first demonstrated in 1997 that CD34+ hematopoietic progenitor cells were able to differentiate into an endothelial phenotype, and it has subsequently been shown that these endothelial progenitor cells are capable of homing to sites of vascular damage and contribute to the re-establishment of a confluent and homeostatic endothelium [78]. The homing mechanisms of endothelial progenitor cells are only beginning to be fully explored, but they have been shown to occur at an increased rate in the presence of statins and estrogens, or with physical training [18].

Intimal VSMCs have also been shown to originate from a number of sources, including medial smooth muscle and adventitial fibroblasts, as well as from bone marrow progenitors, pericytes, and pre-existing intimal cells [79]. Bone marrow progenitors are of particular interest, as work in animal models of transplant arteriopathy and post-angioplasty re-stenosis have shown that as much as 86% of lesion VSMCs may be of bone marrow origin [80].

The key role that progenitor cells play in a multitude of vasculopathies clearly represents a paradigm shift in this area. Indeed, Hill and colleagues [81] have even suggested that progenitor function may be an independent marker of vascular function and cardiovascular risk in humans. Although this area of study is clearly in its infancy, some groups believe that progenitors may have important therapeutic applications throughout the field. For example, Werner and colleagues [78] have shown enhanced re-endothelialization in a mouse model of wire injury after endothelial progenitor cell administration, and a number of other groups are looking at the feasibility of enhancing capture of these cells through local drug administration [82]. Although current data is limited for therapeutic applications of these cells to vein graft AIH, they may be an important tool for the future. Our own perspective is that progenitor cells, both endothelial and smooth muscle, may in addition be genetically armed ex-vivo and reintroduced to a post-CABG patient [83]. This would increase potency of the endothelial progenitors and further could allow the vascular smooth muscle cells to act as "Trojan horses" by finding their way into the vessel wall district that exhibits the greatest pathology.


   Comment
Top
 Abstract
 Introduction
 Intimal Hyperplasia and Vein...
 Pathophysiologic Triggers of AIH
 Therapeutic Approaches to...
 Therapeutic Approaches to AIH...
 Comment
References
 
One hundred years after the first description of intimal hyperplasia, vein graft re-stenosis remains a significant problem. Despite considerable strides being made toward reducing the failure rates of these grafts through new and exciting techniques, such as the genetic engineering of native vessel grafts, the problem continues to remain unacceptable to patients and clinicians alike.

It is widely believed that through an increased understanding of the complex cellular and molecular processes involved in vein graft restenosis, novel therapeutic targets may be revealed. However, although a plethora of such targets have been identified and many agents have been directed toward them, few of these agents have reached the clinic. In addition, the hope that aggressive resolution of risk factors associated with accelerated atherogenesis (ie, dyslipidemia, hypertension, and smoking) would effectively prevent graft failure has not been borne out.

Rather than conclude, we would like to propose a two-tiered model of vein graft re-stenosis in which intimal hyperplasia, occurring as a result of exposure of the vein to arterial conditions, forms a fertile soil for subsequent accelerated atherogenesis. Such a model suggests that better vein graft patencies may be achieved through targeting hyperplasia rather than atherogenesis. However, although it has been illustrated herein that many therapeutic agents directed at intimal hyperplasia have been highly successful in a variety of animal models, none have achieved the desired results in humans yet. If the use of vein grafts is to continue for the next 100 years to keep humans, so often crippled by cardiovascular disease, free from the morbidity associated with their use, then the search for improved treatment regimes aimed at reducing or preventing neointima formation must continue. It is probable that some of the agents discussed may be of therapeutic use in the future if suitable delivery mechanisms can be devised or further perfected, thus enabling efficacious local delivery and the avoidance of unwanted side effects at sites remote from grafts.


   References
Top
 Abstract
 Introduction
 Intimal Hyperplasia and Vein...
 Pathophysiologic Triggers of AIH
 Therapeutic Approaches to...
 Therapeutic Approaches to AIH...
 Comment
 References
 

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