National health estimates show that about 26% of people in the 60-74 age group are affected by Peripheral Arterial Disease - PAD. Progressive narrowing of the arteries of the legs, due to atherosclerosis, causes major disability and limb loss, especially in diabetics. Many advances have been made in procedures to open these obstructed arteries, but these interventions are prone to becoming re-clogged by scarring, fibrosis and narrowing. Bypass grafts using a patient's own, native veins are especially prone to graft stenosis and pathologic vascular wall thickening, affecting 15-35% of bypasses within the first year of surgery. Graft narrowing and scarring is a leading cause of reoperation, graft failure and limb loss, and yet the contributory factors are poorly understood. A wealth of research suggests that the inter-connected pathways of inflammation and thrombosis are involved in this abnormal scarring that leads to graft failure. Platelets and monocytes are two types of cells that circulate in the blood, and pla key roles in blood clotting and inflammation. When a new vein graft is implanted, these are the two main cells that link together the blood clotting and inflammatory responses. If we know which patients have excessive inflammation putting them at risk of graft failure, it may be possible to prolong the life of their bypasses with drugs or other interventions. We have been studying the function of blood platelets and monocytes in patients undergoing leg bypasses for PAD, by measuring inflammation in their blood before, and for months after surgery. We have found that patients with PAD have excessively active platelets and monocytes. We found that patients with narrowing of their bypass grafts had much higher levels of platelet-monocyte aggregates than those patients whose grafts were wide open. Normally, the inflammatory response rises around the time of surgery, and then subsides, but we found that patients whose grafts failed have prolonged, elevated activity of their platelets and monocytes for months after surgery. We also have discovered a genetic trait that appears to affect the long term success or failure of the bypass. This genetic trait appears to influence a patient's inflammatory response. In this research project, we propose to study platelet and monocyte function in up to 150 patients undergoing leg bypass for PAD. Before, and up to one year after surgery we will track these patients to determine the fate of their bypass grafts. From simple blood samples, we will measure their degree of inflammation, and the activity of their platelets and monocytes. By correlating the rise and fall of platelet/monocyte function and inflammation with the outcomes of their bypass grafts, we should be able to identify which patients are at highest risk of graft failure. We also propose to do basic research investigations to understand what makes some patient's inflammatory response higher or more prolonged. Through an understanding of how their genetic traits influence the inflammatory response, and the study of other factors, we may be able to identify new targets for drugs to prolong the life of their bypass and maintain healthy circulation to the leg.
Peripheral arterial disease is a significant cause of Veteran disability and limb loss, affecting 12% of people in the 40-59 age group, and 26% in the 60-74 age group. Diabetic Veterans are especially prone to peripheral arterial disease, and it is a major cause for their hospitalization and limb loss. Although there are many successful procedures to improve blood flow in clogged arteries, over time the arteries and bypass grafts are prone to scar down and become blocked again. Excessive activity of blood cells involved in clotting and inflammation are involved. We propose to identify which patients are more prone to this scarring or stenosis, by discovering the biological links between their genetic traits, inflammation, and blood clotting. These advances could result in important reductions in limb loss, disability, death, and health care costs for our Veterans.