**7. Upregulation of innate inflammatory markers and graft failure**

Studies have shown that patients who present with unstable angina after revascularization by previous bypass procedures do so because of an obstructive atherosclerotic lesion in the saphenous vein conduit, and graft stenosis. These plaques have been seen as early as 1 year after bypass procedures [35]. When the vein conduit plaque is viewed histologically, it is found to have an increased number of foam cells than in arterial atheromatous plaques. Recent studies support the theory that a stimulus must exist that induces the expression of inflammatory mediators and may be the inciting factor leading to intimal hyperplasia and eventual graft failure [15].

Scavenger receptor proteins play a vital early role in vascular inflammation. Scavenger receptor proteins on the surface of vascular endothelial cells and macrophage have been shown to upregulate NF-kappaB inflammatory pathways. Studies focusing on upregulation of inflammatory markers following distention compared to non distended vein segments have shown that expression of scavenger receptor-A, scavenger receptor- B, and CD36 are upregu‐ lated in the distended saphenous vein tissue [15]. This suggests that the process of distention is an inciting event that allows for the upregulation of scavenger receptors, leading to graft failure through atherosclerotic lesion progression initiated by the formation of foam cells in these saphenous vein grafts.

Pressure distention of saphenous vein conduits has been part of the standard vein preparation procedure for decades. The longer the vein is exposed to pressure distention the higher the expression of biomarkers. These biomarkers include; toll like receptors (TLRs), intracellular adhesion molecules (ICAM), vascular cell adhesion molecule-1 (VCAM-1), and platelet endothelial cell adhesion molecule-1 (PECAM-1). An upregulation of ICAM, VCAM-1, and PECAM-1 was seen in veins that had undergone distention when compared with the nondis‐ tended vein [15]. The expression of these cell adhesion molecules is important because an interaction of VCAM-1 and ICAM-1 with monocytes facilitates the monocytes' recruitment to the vein [36]. Additionally, interactions of ICAM-1 and VCAM-1 with PECAM-1 mediate the process of diapedesis of the monocytes into the vessel wall. These initial cell-mediated events facilitate recruitment of more inflammatory cytokines to the area of injury caused by the damage from distention. PECAM-1 is constitutively expressed on all endothelium regardless of cytokine activation.

Vascular smooth muscle cells, monocytes/macrophages, and endothelial cells have all been shown to express MMPs. Vein graft stenosis appears to be associated with increased expression of MMP-9 and increased activation of MMP-2 [32]. Pharmacological inhibitor studies demon‐ strate that MMPs are, indeed, involved in the formation of the neointima. Therefore, with this data it appears that MMPs are critical for smooth muscle cell migration and proliferation, which serve as the cellular basis for neointimal proliferation *in vivo*. Tissue inhibitors of metalloprotienases (TIMPs) are four naturally occurring proteins that inactive MMP's by binding to them. Kranzhofer et al showed that three of these TIMPs are found on saphenous vein grafts [33]. Several regulatory mechanisms exist to keep a precise balance between enzymes that degrade matrix and proteins that inhibit their action. Cytokines and growth factors, specifically platelet derived growth factor BB act together through a protein kinase C dependent mechanism to increase the expression of MMP-9, whereas transforming growth factor-beta and platelet derived growth factor BB induce TIMP-3 expression in vascular smooth muscle cells [31]. However, they do not have any influence on TIMP-1, or TIMP-2 expression. Baker et al. transfected grafts with a gene for TIMP-3 and observed an 84% reduction in neointima at 14 days and 58% reduction at 28 days in porcine vein grafts [34]. This shows promise for a potential preventative treatment of neointimal hyperplasia, but problems such as weakening of pre-existing atherosclerotic plaques need to be addressed and the longer-term

**7. Upregulation of innate inflammatory markers and graft failure**

Studies have shown that patients who present with unstable angina after revascularization by previous bypass procedures do so because of an obstructive atherosclerotic lesion in the saphenous vein conduit, and graft stenosis. These plaques have been seen as early as 1 year after bypass procedures [35]. When the vein conduit plaque is viewed histologically, it is found to have an increased number of foam cells than in arterial atheromatous plaques. Recent studies support the theory that a stimulus must exist that induces the expression of inflammatory mediators and may be the inciting factor leading to intimal hyperplasia and eventual graft

Scavenger receptor proteins play a vital early role in vascular inflammation. Scavenger receptor proteins on the surface of vascular endothelial cells and macrophage have been shown to upregulate NF-kappaB inflammatory pathways. Studies focusing on upregulation of inflammatory markers following distention compared to non distended vein segments have shown that expression of scavenger receptor-A, scavenger receptor- B, and CD36 are upregu‐ lated in the distended saphenous vein tissue [15]. This suggests that the process of distention is an inciting event that allows for the upregulation of scavenger receptors, leading to graft failure through atherosclerotic lesion progression initiated by the formation of foam cells in

Pressure distention of saphenous vein conduits has been part of the standard vein preparation procedure for decades. The longer the vein is exposed to pressure distention the higher the

benefits of this therapy remain unknown.

failure [15].

154 Artery Bypass

these saphenous vein grafts.

Toll-like receptors play a very important role in the signaling pathway of inflammation. Traditionally, TLR4 costimulates with CD14 in chronic conditions. Interestingly TLR4 has also been shown to bind directly to lipopolysaccharide without CD14 costimulation, leading to subsequent NF-kappa B activation. Studies in TLR4-deficient mice have shown that despite the presence of lipopolysaccharide, these mice do not develop neointima, suggesting that neointimal hyperplasia is a TLR4-dependent process [15], [37]. TLR4 in cooperation with interleukin-1 receptor plays a significant role in the formation of neointima. TLR4 signaling also promotes a proinflammatory phenotype and plays a role in the early response to vascular injury. Therefore, the upregulation of TLR4 may play a role in the development of graft failure in terms of neointimal hyperplasia. TLR2 activation with MYD88 leads to cytokine production through NF-kappa B pathways. Thus, these data suggest that vein graft failure is likely a multifactorial process that includes neointimal hyperplasia and inflammation. Immediate vein graft failure is most probably due to inflammatory cytokines whereas late failure (1 year after CABG) is due to neointimal hyperplasia. However, the common cause of both of these processes is quite possibly exacerbated by SV pressure distention [15].
