Vein graft failure: current clinical practice and potential for gene therapeutics

Abstract

Autologous saphenous vein is commonly used as a conduit to bypass atherosclerotic lesions in coronary and femoral arteries. Despite the wide use of arterial conduits, which are less susceptible to complications and failure, as alternative conduits, the saphenous vein will continue to be used in coronary artery bypass grafting until acceptable alternative approaches are evaluated. Hence, preservation of vein graft patency is essential for the long-term success. Gene therapy is attractive in this setting as an ex-vivo technology to genetically manipulate the conduit before grafting. The use of safe and efficient vectors for delivery is a necessity as well as a strategy to improve patency in the long term. Here, we review the current clinical practice, the pathogenesis of bypass graft failure and adenovirus-mediated gene therapy strategies designed to improve late vein graft failure by modulation of smooth muscle cells in the vein wall.

External support in preventing vein graft failure

“…8,13 Inhibiting the progression of atherogenesis Emerging evidence has clearly shown that superimposed atherosclerosis is responsible for late vein graft failure after CABG. 2 It is noteworthy that external supports profoundly improve the atherosclerotic resistance of veins by prompting the expression of several antiatherosclerotic mediators such as NO, prostacyclin I 2 , cyclic adenosine monophosphate, and cyclic guanosine monophosphate; 22 and by inhibiting biofactors that are essential for atherogenesis, including a significant reduction of cholesterol and lipid content, as well as a lower expression of VCAM-1 and PDGF in the intima and media of the venous wall. 6,23 The notion that an external prosthesis plays an inhibitory role in atherogenesis was supported by a study in the hypercholesterolemic transgenic mouse model.…”

“…Future translational efforts will definitely focus on combined therapeutic interventions including external support, with novel targets to effectively limit the progress of vein graft failure in patients undergoing CABG. 2,3 Funding This work was supported by the Hong Kong Research Grants Council Earmarked Grant (CUHK 4542/06M).…”

“…Although the exact mechanisms are still incompletely elucidated, neointimal hyperplasia and superimposed atherosclerosis have been recognized as the prime culprits which, logically, become the therapeutic targets. 2 Nonetheless, apart from lipid-lowering and antiplatelet therapy, no other intervention has hitherto been proven to have sustained benefits in preventing vein graft failure in the clinical setting. 2,3 In particular, the beneficial effects of edifoligide treatment, demonstrated in animal models, were inconsistent with those in the clinical arena.…”

“…2 Nonetheless, apart from lipid-lowering and antiplatelet therapy, no other intervention has hitherto been proven to have sustained benefits in preventing vein graft failure in the clinical setting. 2,3 In particular, the beneficial effects of edifoligide treatment, demonstrated in animal models, were inconsistent with those in the clinical arena. 2 Thus recent investigations have focused on exploring novel molecules and pathways.…”

Eph-B4 Mediates Vein Graft Adaptation By Regulation of eNOS

“…4 In some patients, the early adaptive remodeling and inflammatory responses become excessive and lead to neointimal hyperplasia with subsequent late vein graft failure. 5 Understanding the mechanisms of how venous adaptive remodeling is finely regulated to balance adaptation without excessive thickening may improve long-term vein graft patency. 4 The tyrosine kinase receptor Eph-B4, and its cognate ligand Ephrin-B2 determine the molecular distinction between veins and arteries, respectively, in the early embryo.…”