Late Vein Graft Failure

Coronary artery bypass grafting (CABG) is a procedure that successfully alleviates angina pectoris and increases life expectancy in patients with coronary artery disease. However, the vein graft undergoes adaptive responses to transplantation into the arterial circulation, with early thrombus formation occurring in 10% of grafts, and patency dropping to 50% at 10 yr postprocedure. Vein graft failure is associated with progressive intimal thickening, atheroma development, and neointima formation (96), with associated affects on morbidity and mortality after CABG. Drug treatments (typically antiplatelet agents) can slow and reduce this process, but can be associated with hemor-rhagic events. However, vein grafting is particularly amenable to gene transfer, as the vein graft itself is isolated and able to undergo genetic modification during the surgical procedure. This concept was demonstrated clearly in a clinical trial in which vein grafts transduced during the procedure with vectors expressing decoy oligodeoxynucleotides against the transcription factor E2F showed significantly reduced postoperative occlusion (6). While research into E2F decoy administration continues, the majority of transgenes investigated in other studies have been chosen for their antiproliferative, antiinflammatory, proapoptotic, or antimigratory agents (97).

A key component in the remodeling of the failing vessel is the migration and proliferation of smooth muscle cells, a feature partly determined by the activity of the matrix metalloproteinases. Adenovirally mediated overexpression of the endogenous tissue inhibitors of MMPs has shown beneficial effects, such as reduction of neointima and inhibition of lesion development in a number of studies of vein graft failure, including porcine in vivo and human ex vivo models (7-9). Other transgenes that have shown promise include nitric oxide synthase (98), p53 (99), retinoblastoma gene product (100) and natriuretic peptide (101). The majority of these studies have examined endpoints measured in days or weeks, although significantly reduced neointima and increased vessel patency at 3 mo was recently demonstrated in a porcine model following adenovirally mediated p53 overexpression (102). However, the long-term nature of vein graft failure requires gene therapy capable of producing long-lasting effects, a feature that remains to be fully demonstrated in this setting.

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