On the biology of saphenous vein grafts fitted with external synthetic sheaths and stents

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Biomaterials 28 (2007) 895–908 www.elsevier.com/locate/biomaterials

Leading Opinion

On the biology of saphenous vein grafts fitted with external synthetic sheaths and stents$ Jamie Y. Jeremy, Pat Gadsdon, Nilima Shukla, Vikram Vijayan, Marcella Wyatt, Andrew C. Newby, Gianni D. Angelini Bristol Heart Institute, University of Bristol, UK Received 9 August 2006; accepted 10 October 2006

Abstract Autologous saphenous vein is used as a conduit to bypass atherosclerotic lesions in both the coronary artery (coronary artery bypass graft surgery [CABG]) and in femoral arteries (infrainguinal bypass graft surgery [IIBS]). Despite the undoubted success and benefits of the procedures, graft failure occurs in 50% of cases within 10 years after surgery. A principal cause of late vein graft failure is intimal and medial hyperplasia and superimposed atherogenesis. Apart from lipid lowering therapy, no intervention has hitherto proved clinically effective in preventing late vein graft failure which clearly constitutes a major clinical and economic problem that needs to be urgently resolved. However, we have studied the effect of external synthetic stents and sheaths in pig models of vein into artery interposition grafting and found them to have a profound effect on vein graft remodelling and thickening. In this review, therefore, we will summarise the mechanisms underlying vein graft failure and how these stents influence these processes and the possible mechanisms involved as well as the application of these devices in preventing vein graft failure clinically. r 2006 Elsevier Ltd. All rights reserved. Keywords: Saphenous vein graft failure; Dacron stent; Vicryl sheath

1. Introduction Autologous saphenous vein is used as a conduit to bypass atherosclerotic lesions in both the coronary artery (coronary artery bypass graft surgery [CABG]) and in femoral arteries (infrainguinal bypass graft surgery [IIBS]) [1–4] (Fig. 1). Although arteries (e.g. internal mammary and radial) are widely used as alternative conduits in CABG and have proven less susceptible to complications and failure, the saphenous vein will still be used in CABG $ Editor’s Note: Leading Opinions: This paper is one of a newly instituted series of scientific articles that provide evidence-based scientific opinions on topical and important issues in biomaterials science. They have some features of an invited editorial but are based on scientific facts, and some features of a review paper, without attempting to be comprehensive. These papers have been commissioned by the Editor-inChief and reviewed for factual, scientific content by referees. Corresponding author. Tel.: +44 0117 928 2699; fax: +44 0117 928 3154. E-mail address: [email protected] (J.Y. Jeremy).

0142-9612/$ - see front matter r 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.biomaterials.2006.10.023

in the foreseeable future. In IIBS, autologous saphenous vein is still the treatment of choice for treating critical limb ischaemia and disabling claudication. Despite the undoubted success and benefits of the procedures, early graft failure due to thrombosis occurs in as many as 20% of cases within the first week after surgery [1–4]. Intermediate graft failure (30 days to 2 years after surgery) and late graft failure (42 years after surgery), occurs in 20–50% of cases at 5 years. A principal cause of intermediate to late vein graft failure following bypass is intimal and medial hyperplasia, particularly at the proximal and distal anastamoses (Figs. 1 and 2) [5–7]. Apart from lipid lowering therapy [8], no intervention has hitherto proved clinically effective in preventing late vein graft failure [9,10]. This clearly constitutes a major clinical and economic problem that needs to be urgently resolved. Over the last 10 years or so we have studied the effect of external synthetic stents and sheaths in pig models of vein into artery interposition grafting and found them to have a profound effect on vein graft remodelling and over

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Coronary artery bypass graft

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Fig. 1. Coronary artery bypass graft surgery (CABG) and infrainguinal bypass graft surgery (IIBS). The saphenous vein is removed from the leg of the patient and is then ‘‘surgically prepared’’ which entails distension of the vein graft and the removal of valves. The vein is then anastomosed into the aorta and into the coronary artery which contains atherosclerotic lesions, effectively ‘‘bypassing’’ the lesion [RCA ¼ right coronary artery and LAD ¼ left descending coronary artery] or the femoral artery. One saphenous vein can yield enough material for several bypasses in one patient, which is often the case. Alternative conduits include the internal mammary artery, which is diverted to the coronary artery beneath the lesion, as indicated. Lower panels: Within 1 month after implantation the saphenous vein graft has thickened markedly and a new layer of cells, the neointima, has formed. This process involves the proliferation and migration of vascular smooth muscle cells, the expression of peptide growth factors, remodelling by metalloproteinases and deposition of matrix proteins. The neointima renders the graft susceptible to atherogenesis, macrophages infiltrating this layer to develop into the foam cell and then a plaque, such that as many as 50% of grafts will occlude within 10 years after the procedure.

thickening. In this review, therefore, we will summarise the mechanisms underlying vein graft failure and how these stents influence these processes and the possible application of these devices in preventing vein graft failure clinically. 2. Mechanisms underlying neointima formation and graft thickening 2.1. Surgical trauma Surgical preparation of saphenous veins for bypass graft surgery results in removal of the endothelium [11]. The adhesion of platelets and leucocytes is therefore an immediate occurrence following graft implantation which may not only precipitate thrombosis but also trigger NI

formation [12–18] (Fig. 2). Adherent (activated) platelets generate a large number of substances, including ET-1 [17,20], thromboxane A2 (TXA2), serotonin, plateletderived growth factor (PDGF), platelet factor IV, fibrinogen, fibronectin, thrombospondin, vWF, b thromboglobulin and reactive oxygen species [17], which trigger VSMC proliferation and migration [17–21]. Coagulation factors (and the products of fibrinolysis) are also important instigators of NI formation [17,21] (Fig. 2). Neutrophils and monocytes also promote NI formation [13,14,19–24]. Adherent leucocytes, especially neutrophils, release an array of pro-inflammatory substances, including leukotrienes (LT), interleukins (IL), histamine, tumour necrosing factor, platelet activating factor (PAF), proteases and many more [17]. All these promote VSMC proliferation and migration.

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Fig. 2. Principal events leading to neointima formation and late vein graft failure: (a) early triggers for neointima formation are immediate. Denudation of the endothelium results in adhesion of blood cells which release a battery of factors that trigger the events that lead to the proliferation and migration of VSMCs and neointima formation. These include the endogenous expression of peptide growth factors, MMP activation and oxidative stress. Haemodynamic forces also promote the process, simultaneously. (b) Once the neointima has formed, monocytes infiltrate the layer and become resident macrophages, the progenitor of the foam cell. This in turn is the epicentre of the atherosclerotic plaques which ultimately result in late vein graft failure.

Endothelial removal also results in the loss of vasculoprotective systems that prevent inflammation and thrombosis, these principally being nitric oxide (NO) and prostacyclin (PGI2) as well as ectoADPase, tPA, thrombomodulin, protein S and proteoglycans [25,26]. It follows that the acute loss of these systems may render the graft susceptible to NI formation and atherogenesis. Apart from the inhibition of platelet and leucocyte adhesion, NO, PGI2 and analogues of cAMP and cGMP which mediate the actions of PGI2 and NO, respectively, inhibit various events associated with vein graft failure: VSMC prolifera-

tion and migration, MMP expression, proteoglycan synthesis, tissue plasminogen activator release and cholesterol metabolism [27–30]. The NO-cGMP and PGI2-cAMP axes are impaired in vein grafts [31,32]. Endothelial cells proliferate and migrate to ‘‘reline’’ vein grafts [33], complete coverage occurring within 1–2 weeks [33]. The re-grown endothelium is markedly dysfunctional, however. Grafting of saphenous veins appear to result in a defect at the receptor–NOS coupling level in regrown endothelium [34–36]. Arterial haemodynamic forces, to which the vein graft is subjected, also exert a powerful

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influence on endothelial structure and function [37]. Thus, although there is rapid endothelial regrowth in vein grafts, its functional integrity may be compromised by the impact of arterial haemodynamic forces. The corollary to this is that endothelial regrowth is beneficial in experimental vein grafts. For example, Ohno et al. [38] demonstrated that accelerated re-endothelialisation in rabbit vein grafts reduced both thrombogenicity and NI formation. 2.2. Adhesion molecule expression and vein graft atherogenesis The adhesion of leucocytes to vascular cells, each other and platelets is mediated principally by the selectins, intracellular adhesion molecule (ICAM) and vascular endothelial cell adhesion molecule (VECAM) [39]. A causal link between adhesion molecule expression and NI formation was demonstrated by Stark et al. [40]. Zou et al [41] found that there was reduced neointimal hyperplasia of vein grafts in intercellular adhesion molecule-1 (ICAM-1) deficient mice. Crook et al. [42] established a direct relationship between increased expression of ICAM and neointima formation in human saphenous veins in culture. Other studies have also demonstrated that vein graft surgery is associated with an increased expression of adhesion molecules, including P-selectin, E-selectin, ICAM and VECAM [43,44]. The physical ‘‘environment’’ of vein grafts, including shear stress, is certainly associated with increased adhesion molecule expression [45,46]. Monocyte adhesion is another early event in vein grafts [47]. Monocytes infiltrate the neointima and become resident macrophages which then becomes the foam cell, the epicentre of an atherosclerotic plaque, a process that results ultimately in vein graft failure over the ensuing years [1–4]. In turn there is evidence that the early adhesion of monocytes in vein grafts plays a role in vein graft hyperplasia [48] (Fig. 2). 2.3. Haemodynamic forces Following implantation, the vein graft, which has been subjected only to an internal pressure of 10 mm Hg, is immediately subjected to arterial pressure (100 mm Hg) as well as immediate increases in flow, longitudinal wall (shear) stress, circumferential deformation, circumferential stress, radial deformation, radial stress, pulsatile deformation and pulsatile stress [49]. Haemodynamic forces, principally, excessive high wall shear stresses have been postulated as promoters of intimal hyperplasia since studies have demonstrated that the ratio of luminal radius to wall thickness in grafts tends to adapt to the same value as that in the grafted artery, which suggests that wall thickening occurs to normalise tangential wall stress [49]. These are all associated with increased expression of growth factors, adhesion molecule expression and proliferation. Since the saphenous vein is much thinner than the artery and lacks connective tissue layers that characterises

arteries it adapts to arterial environment by thickening or ‘‘remodelling’’. This effectively involves the proliferation of VSMCs and a concomitant deposition of matrix proteins [50,51] (see section on MMPS later). The process of vein graft remodelling also intrinsically alters intra-graft haemodynamics. Both high and low shear stress are associated with enhanced platelet adhesion [52–54]. The asymmetric growth of the graft may also promote chaotic blood flow patterns [55] which promote platelet and leucocyte adhesion and thrombosis [55]. This in turn would augment the initial triggering of neointima formation as discussed above. 2.4. Peptide growth factors, matrix proteins and metalloproteinases (MMPs) Peptide growth factors and matrix proteins act in concert to promote NI formation [50,51,56]. Peptide growth factors include ET-1, PDGF, basic and acidic fibroblast growth factor (FGF), insulin-like growth factor (IGF-1), epidermal growth factor (EGF) and angiotensin II. All these promote the proliferation and migration of VSMCs in vitro and are rapidly expressed in vein grafts [56]. This led to the concept that factors such as distension, shear stress damage, platelet and leucocyte release substances may promote NI formation through an a priori upregulation of growth factors. In situ, VSMCs are surrounded and embedded in the extracellular matrix (ECM) which functions as a scaffold for cell adhesion and tissue architecture [56]. The ECM comprises of collagen, fibronectin, elastin, vitronectin and proteoglycans and exerts an inhibitory influence on VSMC proliferation in situ [56]. Thus, in vivo, the ECM is ‘‘dissolved’’ and the vessel remodelled by MMPs, principally: interstitial collagenase (MMP-1), gelatinase A (MMP-2), stromelysin-1 (MMP-3), matrilysin (MMP-7) and gelatinase B (MMP-9). MMP activity, in turn, is regulated by tissue inhibitors of MMPs (TIMPs) [56]. Upregulation and activation of certain MMPs has been demonstrated in saphenous vein organ cultures and experimental vein grafts [56]. 2.5. Oxidative stress There is increasing evidence that overproduction of superoxide (O2 ) is an important pathological component of vein graft failure, the principal source being NADPH oxidase [28,29,57]. O2  promotes VSMC proliferation and migration and up-regulates MMPs [28,29]. O2  also reacts with NO to produce reactive nitrogen species reducing NO bioavailability, which is itself associated with vein graft disease [28,29]. Medial/neointimal regions of porcine vein grafts have been shown to contain high levels of nitrated tyrosine (NT), an index of ONOO formation, indicating that both NO and O2  must be present in order for the reaction to occur [58]. Thus, a widely held view is that

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O2  formation compromises vein graft patency through a reduction of NO and direct effects. Platelet and leucocyte release-substances, including ET-1, 5-HT, LT, cytokines and clotting factors have all been shown to promote the expression of O2  generating enzymes, including NADPH oxidase [28,29,59–61]. Since leucocyte and platelet adhesion occurs rapidly after graft implantation as described above, it is reasonable to suggest

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that the vein graft will be rapidly subjected to oxidative stress through up-regulation of these enzymes. 2.6. The vasa vasorum, hypoxia and micovascular repair Hypoxia may also play a key role in mediating vein graft disease [28,29,62]. Surgical removal of the saphenous vein, ipso facto, results in a loss of continuity of the vasa

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Fig. 3. Effect of the external Dacron stent. A loose-fitting, Dacron stent (a) was placed around a saphenous vein into carotid artery interposition graft (b). After 6 months, the graft was excised and studied histologically. In unstented vein grafts (c) there is a marked increase in graft size and neointima (NI) formation (the layer between the internal elastic lamina (IEL) and the lumen) compared to the original ungrafted saphenous vein (inset). It is this thickening that is the basis of vein graft failure. The graft fitted with the external stent (d), however, shows a profound reduction of graft thickening (small arrow IEL and large arrow external elastic lamina [EEL]) and a complete inhibition of the neointima. Lower panels: One month after implantation, the stented vein graft is characterised by the formation of a neoadventitia between the stent and the graft containing large numbers of microvessels which stain positively for VEGF (e) and eNOS (f), two potent angiogenic factors (see also Fig. 4).

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vasorum, a microvessel complex that infiltrates and oxygenates large blood vessels which in turn would result in hypoxia of the tissue. Disruption of the vasa vasorum, per se, is associated with vascular disease [63–66]. In recent studies using an oxygen sensitive probe we found that the pig saphenous vein becomes rapidly hypoxic after excision and remains so after implantation for at least a month (Jeremy et al., unpublished observations). Since the vein graft thickens rapidly, the graft is probably

subject to an increase in oxygen demand which may also increase hypoxia. Hypoxia promotes O2  formation via activation of NADPH oxidase, xanthine oxidase and mitochondrial respiratory chain [67]. Prolonged hypoxia upregulates the expression of literally hundreds of proteins that include those that promote vein graft disease [29,30]. Taken together, these observations indicate that the regeneration of the vasa vasorum may constitute an

Fig. 4. Time course of events that occur with loose-fitting external Dacron stent on porcine vein grafts: [A]: (a) 1 day after, (b) 1 week after and (c) 1 month after implantation. From (a) it can be seen that the stent is loosely fitting. By 1 week after implantation, however, the space between the graft and the stent has filled with a fibrin-rich exudate (b). By 1 month this area has organised into a ‘‘neoadventitia’’ (c) that is rich in microvessels (see right; panel C). We suggest that the fibrin-rich exudate that forms in the space between the graft and the stent promotes the formation of new microvessels that in turn oxygenates the graft thereby preventing hypoxia-induced pathogenesis, including cell proliferation. Panel D represents unstented grafts (trichromes). Note relative lack of microvessels as well as neointima formation and asymmetric growth of the graft (see Fig. 8 for model).

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important adaptation of vein grafts to arterial conditions and to repair and reintegration of the micovascular system. This process involves the angiogenesis and arteriogenesis [68]. Microvessels possess the capacity to rapidly regenerate and re-establish an integrated microcirculation by means of angiogenesis, a process mediated by the proliferation, migration and organisation of endothelial cells into new microvessels [68].

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3. The external Dacron stent and saphenous vein graft thickening The use of an external sheath around vein grafts was first described by Parsonnet et al. [69]. In 1978, Karayannacos et al. [70] described a beneficial effect of an external polyester support on reducing neointimal hyperplasia. In a porcine model, placement of a non-restrictive, porous,

neointima

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IEL

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Fig. 5. Effect of an external biodegradable vicryl sheath on porcine vein graft thickening. As with the Dacron sheath, placement of a vicryl, loose-fitting sheath markedly inhibits vein graft thickening and neointima formation at 6 months after implantation in the pig model (b) compared with unstented grafts (a). As with the Dacron stent, the grafts are characterised by the presence of microvessels closely associated with the media of the graft (lower panel). The difference here, however, is that the vicryl sheath has long been degraded, indicating that long-term presence is not necessary for external prosthetic materials to elicit beneficial effects on vein graft thickening and neointima formation.

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external Dacron stent (used as a prosthetic graft in its own right) around saphenous vein into carotid artery interposition grafts markedly inhibits medial and intimal thickening [71–73] (Fig. 3). These ‘‘stented’’ vein grafts are characterised by a distinct ‘‘neoadventitia’’ in the space between the graft and the stent, that has an abundant microvasculature that extends to the media of the graft [73] (Figs. 3–5). In contrast, the adventitia of unstented vein grafts was sparse and some distance from the graft. These microvessels stain positively for VEGF and eNOS, which generates NO (Fig. 5), both potent angiogenic factors [68], consolidating the view that the stent promotes angiogenesis. It was proposed, therefore, that the action of the Dacron stent is mediated, at least in part, through a promotion of angiogenesis and the formation of a neo-vasa vasorum. In turn, this would promote oxygenation of the graft and obviate hypoxia which, as discussed above, promotes vein graft disease. With regard to the mechanisms underlying this proangiogenic effect of the external stent it was noted that

within 1 week that an exudate has formed in the gap between the stent and the graft, which is rich in fibrin, probably derived from leakage of blood at the anastomoses (Fig. 4). In turn, fibrin and fibrinogen are potent angiogenic factors [68]. At 2 weeks after implantation, microvessels have begun to appear in this space between the graft and the stent (Fig. 4). At 1 month this has organised into a well-defined structure comprising of a dense population of fibroblasts and microvessels (or neo vasa vasorum) (Fig. 4). The formation of this exudate in the graft–stent interface also provides a matrix into which microvessels can grow. Another axiomatic property of the Dacron stent is that it has to be loose-fitting (i.e. 8 mm diameter compared to the saphenous vein graft, which was 5 mm in diameter at implantation) in order for it to elicit inhibitory effects on graft thickening. Restrictive stents (i.e. tight-fitting) do not inhibit neointima formation and indeed can augment graft hyperplasia [74,75]. These restrictive stents do not allow for the formation of a neoadventitia and for an attendant microvessel complex to form [75].

Fig. 6. Effect of microporous PTFE stent on porcine vein graft thickening. In contrast to Dacron (a), the placement of an external loose fitting PTFE stent of identical diameter exacerbated neointima (NI) formation and overall graft thickening (b) 1 month after implantation. Note the complete lack of microvessels and that the tissues have become necrotic (b). As can be seen from panel (d) cells only partially penetrate the PTFE stent whereas Dacron allows for free infiltration of cells (see Fig. 7). At an equivalent time point (1 month), there are abundant microvessels that have infiltrated and have passed through the Dacron stent (c).

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4. Biodegradable sheaths From an interventional perspective, the long-term support of vein grafts with polyester stents may elicit untoward effects that include infection, foreign body/ inflammatory reactions and mechanical complications [76–78]. Furthermore, since neointima formation in vein grafts occurs within the first month after implantation, which is effectively blocked by external stents, then longterm support with a non-degradable stent may not be necessary. One possible means of avoiding these complications is to employ an absorbable external sheath that remains intact for at least 1 month and then is subsequently biodegraded. To test this hypothesis, we studied the effect of biodegradable polyglactin Vicryls sheaths on vein graft thickening in the short and long term [79,80]. Polyglactin is hydrolysed by macrophages and has a reported absorption rate of between 60 and 90 days [81–84]. Biodegradable materials are also associated with a lower incidence of surgical wound infection [85–88]. In order to make as direct a comparison as possible, the polyglactin stent was designed and manufactured to match the structure and dimension of the original polyester Dacrons external stent, such that the only difference between them was biodegradability. Thus, we found that at both one and 6 months after placement of the sheath, there was a marked inhibition of graft thickening and neointima formation (Fig. 5). These sheaths were also characterised by numerous microvessels

a

immediately surrounding the graft. The effective removal of the biodegradable external sheath may therefore reduce the long-term risks for infection, chronic inflammation, and mechanical complications associated with implanted prosthetic material while still eliciting the primary objective of preventing vein graft thickening over the long term. The loose-fitting, macroporous, polyglactin, biodegradable, external sheath may therefore be a safer and more clinically appropriate prosthesis for use in arterial reconstructive surgery. 5. Porosity is crucial for the beneficial effect of external stent Porosity is also an axiomatic determinant in mediating the effect of external stents and sheaths. PTFE (microporous) stents (also 8 mm in diameter) not only promoted neointimal and medial thickening, but also prevented microvessel formation [89] (Fig. 6). Porosity appears to be crucial since it allows the microvessels that form in the neoadventitia to connect with the vasculature outside the stent, allowing a fully integrated blood flow to the graft (Figs. 6 and 7). The micro-porous stent by preventing this connection effectively negates the positive effect of angiogenesis. Thus, in the case of the macroporous Dacron stent, the promotion a fully integrated and functional microvascular system, the graft is supplied with oxygen and therefore hypoxia and its attendant pathological

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Endothelial cells (brown) around giant cells

Fig. 7. Leucocytes, giant cells and external sheaths. External Dacron and Vicryl sheaths are characterised by the accumulation of macrophages, giant cells and other white cells within the stent or sheath material. In (a) macrophages (dark staining) are localised in the stent and to some degree in the adventitial regions but are all but absent from the medial region. In (b) giant cells are clearly visible engulfing stent (Dacron) material. Poylmorphs and lymphocytes (c) and proliferating VSMCs and endothelial cells (b–d) are also present in large numbers. This is indicative of the migration of these cells toward the macrophages and giant cells. They are also replicating which is indicative of the active construction of new microvessels.

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consequences are obviated. This is exemplified by the fact that external PTFE stent elicits marked necrosis in vein grafts (Fig. 6). 6. Inflammatory cells and the external sheaths and stents Another characteristic of the external stents and vicryl sheaths in the porcine vein graft model is that a large number of inflammatory cells infiltrate the prosthetic material, particularly macrophages and giant cells

(Fig. 8). As with any other prosthetic material, polyglactin is inflammogenic, and therefore it is not surprising that the material attracts inflammatory and immune cells [90–92]. These cells release a battery of potent substances that influence VSMC proliferation, migration, NI formation and angiogenesis [17,68]. It was suggested that these release substances, especially cytokines and LT, may create a chemo-attractant gradient such that VSMC migrate towards the stent rather than towards the intima which in turn may contribute to the inhibitory effect of the

exudate in space between graft and stent : provides a matrix for cell migration and microvessel formation

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Angiogenesis and microvascular repair

Microvessels inside sheath anastomose with those outside it

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Fig. 8. Diagrammatic representation of main events leading to the protective effects of external stents and sheaths: (1) firstly an exudate forms in the stent–graft interface where it is contained and retained. Since this is fibrin rich, this may trigger angiogenesis at the saphenous vein adventitial level. The gel also creates a matrix into which cell can migrate and acts as a scaffold for microvessels to grow toward the stent material. (2) Infiltration of macrophages and giant cells create a chemotactic gradient, eliciting migration of VSMCs away from the media toward the stent or sheath. Endothelial cells are also attracted by chemotaxis. Since ECs and VSMCs are the building block for new microvessels this would augment the restoration of a functional vasa vasorum. (3) Macrophages and giant cells secrete angiogenic factors that promote the formation of new microvessels that bio-anastomose which ultimately restores the integrity of the vasa vasorum such that microvascular blood flow to the graft is restored.

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external stent on neointima formation [79,80]. Indeed, VSMCs and endothelial cells and VSMCs accumulate in large numbers within the stent material (Fig. 8). Furthermore, macrophages and giant cells release a battery of growth factors that promote angiogenesis and microvascular repair [68]. Thus, it is tempting to suggest that the macrophages attracted by external cuffs, sheaths or stents may ultimately be axiomatic to the effect of these external prosthetic devices on vascular remodelling. This is further supported by the dense staining for VEGF, a potent

angiogenic factor in and around the sheath area that mirrors the distribution of staining for lectin, a marker for endothelial cells. Similar revascularisation secondary to inflammatory cell accumulation has been observed after implantation of biodegradable disks in mice [93]. 7. Imposition of symmetry Another facet of the external stents or sheaths is that they impose symmetry on the graft when it thickens in

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Fig. 9. Vein graft thickening elicits marked alterations of haemodynamic blood flow which in turn can promote thrombosis and hyperplasia at both the neointimal and medial levels. By contrast, the external sheath or stent imposes symmetry (cylindrical) on the vein graft as it thickens, such that normal laminar blood flow is retained.

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response to arterial haemodynamics. As mentioned earlier, vein grafts thickening is markedly asymmetric (Fig. 9). In turn, these elicit marked alterations of blood flow through the graft which are associated with turbulent blood flow which can elicit thrombosis and hyperplasia [55]. The external stent or sheath, in effect, keeps the graft contained in what one could describe as a ‘‘jelly mold’’ effect (Fig. 9). This in turn prevents turbulent blood flow and imposes laminar and symmetric blood flow, thereby reducing hyperplasia due to asymmetric blood flow. 8. Concluding remarks: future directions In an experimental pig model of vein into artery interposition grafting, it has been clearly demonstrated that external synthetic stents or sheaths elicit a complete inhibition of neiontima formation, an axiomatic lesion in vein graft disease and an overall reduction of graft thickening. These effects appear to be mediated by the promotion of angiogenesis which is mediated by the accumulation of a pro-angiogenic exudate in the space between the graft and the sheath or stent. Macroporosity is also a crucial factor since it allows for a fully integrated and functional microvascular system to develop. Ultimately, we suggest that the profound local accumulation of inflammatory cells, in particular, macrophages and giant cells play a key role in that they initiate accumulation of ECs and VSMCs in and around the material and promote angiogenesis. Another facet of the external stents or sheaths is that they impose symmetry on the graft. From a clinical perspective, therefore, external stents and sheaths clearly constitute a means of preventing vein graft thickening and therefore failure. However, non-degradable stents or sheaths may elicit unpredictable effects in the long term, such as mechanical and inflammatory effects that may ultimately be counter-productive. Biodegradable sheaths may therefore represent the way forward, since they elicit the desired effect of preventing graft thickening and NI formation but then disappear after the graft has had time to adapt to arterial conditions. Another facet that needs to be addressed is the relative rigidity of the external stent or sheath. In all the studies cited, stents and sheaths were quite rigid. It was felt this to be necessary as compression following closure of surgical wounds may defeat the objective of allowing for the formation of a neoadventitia. However, this may constitute a double edged sword as rigid, non-degradable materials may elicit long-term mechanistic damage, particularly in CABG where the beating heart will be directly juxtaposed to an external stent or sheath. This of course may be obviated by the use of degradable external sheath. Further studies are required to explore more flexible or less rigid devices. One facet of most studies in preclinical animal models is that in practice, both CABG and IIBS involve end-to-side anastomoses, not an end-to-end as employed in the studies in the pig model described above. Thus, the pattern of

neointimal hyperplasia and medial thickening occurs not only along the length of the graft but more importantly, at the anastomoses. It is essential to ascertain whether an external stent or sheath exerts a similar effect on the clinically analogous scenario of an end-to-side anastomosis. There are other potential clinical applications for the biodegradable external sheath. It could be used as a means to deliver drugs (e.g., paclitaxel, sirolimus), gene transfer or even stem cells for promotion of angiogenesis, which would have an additive effect to the sheath itself in attenuating vein graft thickening. Acknowledgements We are grateful to Dr. Tim Ashton and Vascutek Sulzer for designing and providing us with all stents and sheaths cited in this review. We are also grateful to the British Heart Foundation for financial support of some of the work cited. References [1] Favaloro R. Critical analysis of coronary artery bypass graft surgery: a 30 year journey. JACC 1998;31:1B–63B. [2] Mortwani JG, Topol EJ. Aortocoronary saphenous vein graft disease. Pathogenesis, predisposition and prevention. Circulation 1998;97:916–31. [3] Fitzgibbon GM, Kafka HP, Leach AJ, Keon WJ, Hooper GD, Burton JR. Coronary bypass graft fate and patient outcome: angiographic follow-up of 5065 grafts related to survival and reoperation in 1388 patients during 25 years. J Am Coll Cardiol 1999;28:616–26. [4] Jackson MR, Belott TP, Dickason T, Kaiser WJ, Modrall JG, Valentine RJ, et al. The consequences of a failed femoropopliteal bypass grafting: comparison of a saphenous vein and PTFE graft. J Vasc Surg 2000;32:498–505. [5] Davies MG, Hagen P-O. Pathobiology of intimal hyperplasia. Br J Surg 1995;81:1254–69. [6] Neitzel GF, Barboriak JJ, Pintar K, et al. Atherosclerosis in aortocoronary bypass grafts. Morphological study and risk factor analysis 6 to 12 years after surgery. Arteriosclerosis 1986;6:594–600. [7] Schwartz SM, deBlois D, O’Brien ERM. The neointima: soil for atherosclerosis and restenosis. Circ Res 1996;77:445–65. [8] Campeau L. Lipid lowering and coronary bypass graft surgery. Curr Opin Cardiol 2000;15:395–9. [9] Jeremy JY, Bryan AJ, Angelini GD. Pathophysiology and treatment of vein graft failure. J Drug Dev 1996;7:309–13. [10] Jeremy JY, Jackson CL, Bryan AJ. Eicosanoids, fatty acids and restenosis following coronary artery bypass graft surgery and balloon angioplasty. Prostag Leukot Essent Fatty Acids 1996;54:385–402. [11] Thatte HS, Khuri SF. The coronary artery bypass conduit: Intraoperative endothelial injury and its implication on graft patency. Ann Thorac Surg 2001;72:S2245–52. [12] Dobrin PB, Golan J, Fareed J. Pre- vs. postoperative pharmacologic inhibition of platelets: effect on intimal hyperplasia in canine autogenous vein grafts. J Cardiovasc Surg 1992;33:705–9. [13] Lerner RG, Moggio RA, Reed GE. Endothelial loss due to leukocytes in canine experimental vein-to-artery grafts. Blood Vessels 1986;23:173–82. [14] Cooper JP, Newby AC. Monocyte adhesion to human saphenous vein in vitro. Atherosclerosis 1991;91:85–95.

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