Aggressive venous neointimal hyperplasia in a pig model of arteriovenous graft stenosis

Background. Vascular access dysfunction is the most important cause of morbidity and hospitalization in the hemodialysis population in the United States at a cost of well over one billion dollars per annum. Venous neointimal hyperplasia characterized by stenosis and subsequent thrombosis, is the major cause of polytetrafluoroethylene (PTFE) dialysis graft failure. Despite the magnitude of the problem, there are currently no effective therapies for the prevention or treatment of venous neointimal hyperplasia in PTFE dialysis grafts. We believe that this is partly due to the lack of a validated large animal model of arteriovenous stenosis that could be used to test out novel interventions. Methods. Seven-centimeter PTFE loop grafts were placed between the femoral artery and vein of domestic pigs. The grafts were removed at 2, 4, 7, 14 and 28 days after surgery and subjected to a detailed histological and immunohistochemical examination. Results. Significant neointimal hyperplasia and venous stenosis developed by 28 days at the graft-vein anastomosis. There was minimal neointimal hyperplasia at the graft-artery anastomosis. Venous neointimal hyperplasia (VNH) was characterized by (a) the presence of smooth muscle cells/myofibroblasts; (b) angiogenesis within both the neointima and adventitia; and (c) the presence of an active macrophage cell layer lining the PTFE graft material. These results are very similar to the human lesion previously described by us in dialysis patients. Conclusions. We have developed and validated a pig model of venous neointimal hyperplasia that is very similar to the human lesion. We believe that this is an ideal model in which to test out novel interventions for the prevention and treatment of clinical hemodialysis vascular access dysfunction.