Therapeutics of Vein Graft Intimal Hyperplasia: 100 Years On
2007; Elsevier BV; Volume: 84; Issue: 1 Linguagem: Inglês
10.1016/j.athoracsur.2007.02.035
ISSN1552-6259
AutoresEdward J.W. Wallitt, M Jevon, Philip Hornick,
Tópico(s)Central Venous Catheters and Hemodialysis
ResumoIntimal 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. 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. 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 [1Carrel A.G.C. Uniterminal and biterminal venous transplantations.Surg Gynecol Obstet. 1906; : 266-286Google Scholar]. However, it was not until some 65 years later that this phenomenon was directly linked to vein graft re-stenosis and failure [2Grondin C.M. Meere C. Castonguay Y. Lepage G. Grondin P. Progressive and late obstruction of an aorto-coronary venous bypass graft.Circulation. 1971; 43: 698-702Crossref PubMed Scopus (68) Google Scholar].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 [3Smith S.H. Geer J.C. Morphology of saphenous vein-coronary artery bypass grafts: seven to 116 months after surgery.Arch Pathol Lab Med. 1983; 107: 13-18PubMed Google Scholar]. 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 [4Goldman S. Zadina K. Moritz T. et al.Long-term patency of saphenous vein and left internal mammary artery grafts after coronary artery bypass surgery: results from a Department of Veterans Affairs Cooperative Study.J Am Coll Cardiol. 2004; 44: 2149-2156Abstract Full Text Full Text PDF PubMed Scopus (694) Google Scholar].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 [5Kim D.W. Chung H.J. Nose K. Maruyma I. Tani T. Preventative effects of traditional Chinese formulation, Chaihu-jia-Longgu-Muli-tang, on intimal thickening of carotid artery injured by balloon endothelial denudation in rate.J Pharm Pharmacol. 2002; 54: 571-575Crossref PubMed Scopus (15) Google Scholar]. 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-StenosisIntimal hyperplasia occurs physiologically at closure of the ductus arteriosus [6Slomp J. van Munsteren J.C. Poelmann R.E. de Reeder E.G. Bogers A.J. Gittenberger-de Groot A.C. Formation of intimal cushions in the ductus arteriosus as a model for vascular intimal thickening: an immunohistochemical study of changes in extracellular matrix components.Atherosclerosis. 1992; 93: 25-39Abstract Full Text PDF PubMed Scopus (71) Google Scholar], 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 [7Zubilewicz T. Wronski J. Bourriez A. Injury in vascular surgery—the intimal hyperplastic response.Med Sci Monit. 2001; 7: 316-324PubMed Google Scholar]. 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 [8Anitschkow N. Chalatow S. Ueber experimentelle cholesterinsteatose und ihre bedeutung fur die entstehung einiger pathologischer prozesse.Centrble Allg Pathol Anat. 1913; 24: 1-9Google Scholar] 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 [9Schwartz S.M. deBlois D. O’Brien E.R. The intima: soil for atherosclerosis and restenosis.Circ Res. 1995; 77: 445-465Crossref PubMed Scopus (897) Google Scholar]. Late occlusion of saphenous vein grafts (eg, >5 years after implantation) has been almost always shown to be a result of atherosclerosis [10Ratliff N.B. Myles J.L. Rapidly progressive atherosclerosis in aortocoronary saphenous vein grafts: possible immune-mediated disease.Arch Pathol Lab Med. 1989; 113: 772-776PubMed Google Scholar], and one necroscopic study of 53 patients has shown atherosclerotic changes in almost all saphenous vein grafts implanted for more than 1 year [11Kalan J.M. Roberts W.C. Morphologic findings in saphenous veins used as coronary arterial bypass conduits for longer than 1 year: necropsy analysis of 53 patients, 123 saphenous veins, and 1865 five-millimeter segments of veins.Am Heart J. 1990; 119: 1164-1184Abstract Full Text PDF PubMed Scopus (124) Google Scholar].Glakov remodelling, whereby lumen patency is maintained at the expense of increased vessel wall thickness, has been described for venoarterial grafts in rats [12Tennant M. McGeachie J.K. Adaptive remodelling of smooth muscle in the neo-intima of vein-to-artery grafts in rats: a detailed morphometric analysis.Anat Embryol (Berl). 1993; 187: 161-166Crossref PubMed Scopus (16) Google Scholar]. 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 [13Lau G.T. Ridley L.J. Bannon P.G. Lumen loss in the first year in saphenous vein grafts is predominantly a result of negative remodeling of the whole vessel rather than a result of changes in wall thickness.Circulation. 2006; 114: 435-440Crossref Scopus (45) Google Scholar]. 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 AIHThe endothelium is the primary regulator of vessel wall homeostasis (ie, controlling vascular tone, coagulant state, leukocyte recruitment, and angiogenesis [14Allaire E. Clowes A.W. Endothelial cell injury in cardiovascular surgery: the intimal hyperplastic response.Ann Thorac Surg. 1997; 63: 582-591Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar]). 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 [15Fingerle J. Au Y.P. Clowes A.W. Reidy M.A. Intimal lesion formation in rat carotid arteries after endothelial denudation in absence of medial injury.Arteriosclerosis. 1990; 10: 1082-1087Crossref PubMed Google Scholar]. 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 [16Raja S.G. Haider Z. Ahmad M. Zaman H. Saphenous vein grafts: to use or not to use?.Heart Lung Circ. 2004; 13: 403-409Abstract Full Text Full Text PDF PubMed Google Scholar]. 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 [7Zubilewicz T. Wronski J. Bourriez A. Injury in vascular surgery—the intimal hyperplastic response.Med Sci Monit. 2001; 7: 316-324PubMed Google Scholar]. 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 [17van Beusekom H.M. Whelan D.M. Hofma S.H. et al.Long-term endothelial dysfunction is more pronounced after stenting than after balloon angioplasty in porcine coronary arteries.J Am Coll Cardiol. 1998; 32: 1109-1117Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar]. 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 [18Xu Q. The impact of progenitor cells in atherosclerosis.Nat Clin Pract. 2006; 3: 94-101PubMed Google Scholar]. 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 [19Kipshidze N. Dangas G. Tsapenko M. et al.Role of the endothelium in modulating neointimal formation: vasculoprotective approaches to attenuate restenosis after percutaneous coronary interventions.J Am Coll Cardiol. 2004; 44: 733-739PubMed Google Scholar].In the early 1970s using a canine model, Brody and colleagues [20Brody W.R. Angeli W.W. Kosek J.C. Histologic fate of the venous coronary artery bypass in dogs.Am J Pathol. 1972; 66: 111-130PubMed Google Scholar] 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 [21Angelini G.D. Passani S.L. Breckenridge I.M. Newby A.C. Nature and pressure dependence of damage induced by distension of human saphenous vein coronary artery bypass grafts.Cardiovasc Res. 1987; 21: 902-907Crossref PubMed Scopus (80) Google Scholar].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 [22Leask R.L. Butany J. Johnston K.W. Human saphenous vein coronary artery bypass graft morphology, geometry and haemodynamics.Ann Biomed Eng. 2005; 33: 301-309Crossref PubMed Scopus (26) Google Scholar]. The association between low shear stress and AIH is well documented in vein grafts [14Allaire E. Clowes A.W. Endothelial cell injury in cardiovascular surgery: the intimal hyperplastic response.Ann Thorac Surg. 1997; 63: 582-591Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar], although it has been suggested that high shear stresses are also associated with AIH [23Sterpetti A.V. Cucina A. Lepidi S. et al.Progression and regression of myointimal hyperplasia in experimental vein grafts depends on platelet-derived growth factor and basic fibroblastic growth factor production.J Vasc Surg. 1996; 23: 568-575Abstract Full Text PDF PubMed Scopus (43) Google Scholar]. This leads to the proposal that vessels may require an optimum shear value or gradient, above or below which AIH will occur [24Lemson M.S. Tordoir J.H. Daemen M.J. Kitslaar P.J. Intimal hyperplasia in vascular grafts.Eur J Vasc Endovasc Surg. 2000; 19: 336-350Abstract Full Text PDF PubMed Scopus (155) Google Scholar].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 [25Mitra A.K. Gangahar D.M. Agrawal D.K. Cellular, molecular and immunological mechanisms in the pathophysiology of vein graft hyperplasia.Immunol Cell Biol. 2006; 84: 115-124Crossref PubMed Scopus (134) Google Scholar]. 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 AtherogenesisGiven 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 [24Lemson M.S. Tordoir J.H. Daemen M.J. Kitslaar P.J. Intimal hyperplasia in vascular grafts.Eur J Vasc Endovasc Surg. 2000; 19: 336-350Abstract Full Text PDF PubMed Scopus (155) Google Scholar]. 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 [26Franklin L.R. He G.W. Buxton B.F. Angus J.A. Pharmacology of coronary artery bypass grafts.Ann Thoracic Surg. 1999; 67: 878-888Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar]. Pharmacological relaxation using glyceryl trinitrate and verapamil during harvesting may be an important alternate technique [27He G.W. Rosenfeldt F.L. Angus J.A. Pharmacological relaxation of the saphenous vein during harvesting for coronary artery bypass grafting.Ann Thorac Surg. 1993; 55: 1210-1217Abstract Full Text PDF PubMed Scopus (77) Google Scholar]. 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 [28Souza D.S.R. Johansson B. Bojo L. et al.Harvesting the saphenous vein with surrounding tissue for CABG provides long-term graft patency comparable to the left internal thoracic artery: results of a randomized longitudinal trial.J Thorac Cardiovasc Surg. 2006; 132: 373-378Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar]. External stenting of saphenous vein grafts has also been shown to reduce AIH in the pig [29Mehta D. George S.J. Jeremy J.Y. et al.External stenting reduces long-term medial and neointimal thickening and platelet derived growth factor expression in a pig model of arteriovenous bypass grafting.Nat Med. 1998; 4: 235-239Crossref PubMed Scopus (130) Google Scholar].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 [4Goldman S. Zadina K. Moritz T. et al.Long-term patency of saphenous vein and left internal mammary artery grafts after coronary artery bypass surgery: results from a Department of Veterans Affairs Cooperative Study.J Am Coll Cardiol. 2004; 44: 2149-2156Abstract Full Text Full Text PDF PubMed Scopus (694) Google Scholar]. 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 [30Knatterud G.L. Rosenberg Y. Campeau L. et al.Post CABG InvestigatorsLong-term effects on clinical outcomes of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation in the post coronary artery bypass graft trial.Circulation. 2000; 102: 157-165Crossref PubMed Scopus (243) Google Scholar]. 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 [4Goldman S. Zadina K. Moritz T. et al.Long-term patency of saphenous vein and left internal mammary artery grafts after coronary artery bypass surgery: results from a Department of Veterans Affairs Cooperative Study.J Am Coll Cardiol. 2004; 44: 2149-2156Abstract Full Text Full Text PDF PubMed Scopus (694) Google Scholar].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 PathogenesisThrombosis and CoagulationPlatelet activation occurs rapidly following venoarterial grafting, with the magnitude of the response being related to the extent of injury [31Wilentz J.R. Sanborn T.A. Haudenschild C.C. Valeri C.R. Ryan T.J. Faxon D.P. Platelet accumulation in experimental angioplasty: time course and relation to vascular injury.Circulation. 1987; 75: 636-642Crossref PubMed Scopus (276) Google Scholar]. 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-β, thrombin, and various cytokines (interleukin-1, interleukin-6, interleukin-8) [32Ishiwata S. Tukada T. Nakanishi S. Nishiyama S. Seki A. Postangioplasty restenosis: platelet activation and the coagulation-fibrinolysis system as possible factors in the pathogenesis of restenosis.Am Heart J. 1997; 133: 387-392Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar]. 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 [33Yamaguchi M. Du W. Gould K.E. Dieffenbach C.W. Cruess D.F. Sharefkin J.B. Effects of aspirin, dipyridamole, and dibutyryl cyclic adenosine monophosphate on platelet-derived growth factor A chain mRNA levels in human saphenous vein endothelial cells and smooth muscle cells.Surgery. 1991; 110 (discussion 383–4): 377-383PubMed Google Scholar]. Furthermore, it has been shown in vitro that endothelial and smooth muscle cell PDGF-A mRNA expression is unaffected by aspirin and dipryridamole treatment [34Landymore R.W. MacAulay M.A. Manku M.S. The effects of low, medium and high dose aspirin on intimal proliferation in autologous vein grafts used for arterial reconstruction.Eur J Cardiothorac Surg. 1990; 4: 441-444Crossref PubMed Scopus (8) Google Scholar]. However, interestingly it has recently been reported that topical aspirin delivery does reduce neointimal volume after vein grafting in mice [35Torsney E. Mayr U. Zou Y. Thompson W.D. Hu Y. Xu Q. Thrombosis and neointima formation in vein grafts are inhibited by locally applied aspirin through endothelial protection.Circ Res. 2004; 94: 1466-1473Crossref PubMed Scopus (60) Google Scholar], 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 [36Hermann A. Weber A.A. Schror K. Clopidogrel inhibits platelet adhesion and platelet-dependent mitogenesis in vascular smooth muscle cells.Thromb Res. 2002; 105: 173-175Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar], 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 [37Kulik A. Le May M. Wells G.A. Mesana T.G. Ruel M. The clopidogrel after surgery for coronary artery disease (CASCADE) randomized controlled trial: clopidogrel and aspirin versus aspirin alone after coronary bypass surgery [NCT00228423].Curr Control Trials Cardiovasc Med. 2005; 6: 15Crossref PubMed Scopus (38) Google Scholar].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 [38Wilson N.V. Salisbury J.R. Kakkar V.V. The effect of low molecular weight heparin on intimal hyperplasia in vein grafts.Eur J Vasc Surg. 1994; 8: 60-64Abstract Full Text PDF PubMed Scopus (17) Google Scholar], Lin and colleagues [39Lin P.H. Chen C. Bush R.L. Yao Q. Lumsden A.B. Hanson S.R. Small-caliber heparin-coated ePTFE grafts reduce platelet deposition and neointimal hyperplasia in a baboon model.J Vasc Surg. 2004; 39: 1322-1328Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar] 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 [40Mureebe L. Turnquist S.E. Silver D. Inhibition of intimal hyperplasia by direct thrombin inhibitors in an animal vein bypass model.Ann Vasc Surg. 2004; 18: 147-150Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar].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 [41Huynh T.T. Davies M.G. Thompson M.A. Ezekowitz M.D. Hagen P. Annex B.H. Local treatment with recombinant tissue factor pathway inhibitor reduces the development of intimal hyperplasia in experimental vein grafts.J Vasc Surg. 2001; 33: 400-407Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar]. This, coupled with the observation that tissue factor pathway inhibitor treatment also reduces AIH after arterial injury [42Oltrona L. Speidel C.M. Recchia D. Wickline S.A. Eisenberg P.R. Abendschein D.R. Inhibition of tissue factor-mediated coagulation markedly attenuates stenosis after balloon-induced arterial injury in minipigs.Circulation. 1997; 96: 646-652Crossref PubMed Scopus (110) Google Scholar], indicates that tissue factor pathway inhibitor may be a useful therapeutic tool in the future.InflammationSubendothelial inflammation is central to the pathogenesis of atherosclerosis and has been described as the “hallmark of the re-stenotic process” [43Hoch J.R. Stark V.K. van Rooijen N. Kim J.L. Nutt M.P. Warner T.F. Macrophage depletion alters vein graft intimal hyperplasia.Surgery. 1999; 126: 428-437Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar]. 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 [25Mitra A.K. Gangahar D.M. Agrawal D.K. Cellular, molecular and immunological mechanisms in the pathophysiology of vein graft hyperplasia.Immunol Cell Biol. 2006; 84: 115-124Crossref PubMed Scopus (134) Google Scholar].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 [44Mann M.J. Gibbons G.H. Tsao P.S. et al.Cell cycle inhibition preserves endothelial function in genetically engineered rabbit vein grafts.J Clin Invest. 1997; 99: 1295-1301Crossref PubMed Google Scholar]. In addition, the role of cyclin-dependent kinases in the regulation of transcriptional gene activation by nuclear factor-κB (NF-κB) provides a firm biological link between the coordination of leukocyte recruitment and the cell cycle progression of VSMCs [45Perkins N.D. Felzien L.K. Betts J.C. Leung K. Beach D.H. Nabel G.J. Regulation of NF-kappaB by cyclin-dependent kinases associated with the p300 coactivator.Science. 1997; 275: 523-527Crossref PubMed Scopus (666) Google Scholar].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-β antisense gene therapy reduces intimal thickening and expression of monocyte chemo-attractant protein-1 in rats when delivered virally [46Wolff R.A. Ryomoto M. Stark V.E. et al.Antisense to transforming growth factor-beta1 messenger RNA reduces vein graft intimal hyperplasia and monocyte chemotactic protein 1.J Vasc Surg. 2005; 41: 498-508Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar] and biliverdin, which is a by-product of heme degradation with potent anti-oxidant and anti-inflammatory effects, reduces AIH in rats [47Nakao A. Otterbein L.E. Overhaus M. et al.Biliverdin protects the functional integrity of a transplanted syngeneic small bowel.Gastroenterology. 2004; 127: 595-606Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar].The N
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