Vein grafts are frequently used to bypass extensive infrainguinal arterial occlusive disease, the underlying cause of claudication and limb loss. These grafts, like other forms of vascular reconstruction, exhibit a variable healing response to the trauma of surgery. Severe luminal narrowing, which develops during the first year in approximately 25-30% of all grafts because of pathological remodeling and intimal hyperplasia, is a primary cause of graft thrombosis. Despite decades of research, almost nothing is known about the factors that account for the variability in healing and luminal narrowing, although it is likely, based on animal studies, that the early response to injury determines the long term clinical outcome. In previous work, we have been able to demonstrate that measures of systemic inflammation (serum interleukin-6 (IL-6), blood monocyte-platelet binding) and vascular wall cell proliferation are associated with subsequent vein graft stenosis. Recently our group, in collaboration with Drs. Michael Conte and Carlie de Vries, has discovered that there may be a strong genetic basis for the observed heterogeneity in vascular healing that leads to stenosis and graft failure. We have studied a single nucleotide polymorphism (-838 C>A) in the promoter of the p27Kip1 gene (CDKN1B), an important cyclin-dependent kinase inhibitor, in four separate clinical trials encompassing 3279 subjects undergoing either infrainguinal vein bypass grafting or coronary stent angioplasty. In each of the four trials, subjects with the p27Kip1-838AA genotype demonstrated a markedly decreased risk of developing clinically meaningful stenosis. In preliminary studies, systemic measures of inflammation (e.g. IL-6) are lower in those patients with the AA genotype. In addition, venous cells from patients whose grafts perform well maintain higher levels of p27Kip1 mRNA than cells from patients whose grafts develop stenoses. We therefore propose to determine the underlying mechanisms by which the p27Kip1-838AA genotype is associated with long term vein graft patency by testing the following hypotheses: 1. The p27Kip1-838AA genotype affects graft patency in part by increasing p27Kip1 transcription (Specific Aim 2) and by suppressing the early systemic inflammatory response in the blood monocyte and the proliferation and migration of cells in the vein wall (Specific Aims 1);2. The p27Kip1-838AA genotype is associated with successful arteriovenous fistula maturation or long term patency of an arteriovenous graft for dialysis, historically among the most intractable clinical problems facing vascular surgery (Specific Aim 3). The experiments in Specific Aims 1 and 2 will be conducted in a longitudinal, prospective study of 150 patients undergoing leg bypass surgery, while the studies proposed in Specific Aim 3 will make use of DNA and de-identified, adjudicated clinical outcomes from two seminal NIH-supported randomized clinical trials studying surgical creation of arteriovenous fistulae and grafts.
The proposed research addresses the problem of stenosis in leg vein grafts (25-30% in the first year), a process previously attributed to conventional atherosclerotic risk factors and to the traumatic manipulation of the vein during bypass surgery. Although these factors do influence the clinical outcome, the aggregate effects are weak;our recent observations on p27Kip1 provide a robust genetic explanation for the variability in clinical outcome. Furthermore, these very early studies shift the focus in a fundamental way from atherosclerosis and extent of injury to genetic variation particularly in regard to genes that control cell cycle entry and progression and thereby could transform how we diagnose and manage peripheral vascular disease.
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