Preventing Vein Graft Stenosis in Peripheral Vascular Surgery

预防外周血管手术中移植静脉狭窄

• 批准号: 8331692
• 负责人: MICHAEL SOBEL
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8331692
• 关键词: Accounting; Acute; Affect; Angioplasty; Area; Arteries; Atherosclerosis; Basic Science; Biological; Blood; Blood Cells; Blood Circulation; Blood Clot; Blood Platelets; Blood Vessels; Blood coagulation; Blood flow; Blood specimen; Bypass; Cells; Cessation of life; Cicatrix; Clinical; Coagulation Process; Drug Delivery Systems; Failure; Fibrosis; Gene Expression; Genetic; Genetic Polymorphism; Genotype; Goals; Healed; Health; Health Care Costs; Hospitalization; Hyperplasia; Implant; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Internet; Intervention; Investigation; Leg; Legal patent; Life; Limb structure; Link; Longitudinal Studies; Lower Extremity; Measures; Methods; Observational Study; Operative Surgical Procedures; Outcome; Pathologic; Pathway interactions; Patients; Pattern; Peripheral; Peripheral arterial disease; Pharmaceutical Preparations; Prevention; Procedures; Process; Production; Proteins; RANTES; Regulator Genes; Repeat Surgery; Research; Research Project Grants; Risk; Site; Stenosis; Stents; Stress; Testing; Thrombosis; Time; Veins; Veterans; Work; age group; biological adaptation to stress; cell type; diabetic; disability; emergency service responder; experience; falls; graft failure; healing; high risk; improved; monocyte; prevent; prospective; reconstruction; response; success; trait

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）： 国家健康估计表明，在60-74岁年龄段的人群中，约有26％受外周动脉疾病的影响-DAD。 由于动脉粥样硬化，腿部动脉的逐渐变窄会导致严重的残疾和肢体丧失，尤其是在糖尿病患者中。 在打开这些阻塞的动脉的程序中已经取得了许多进步，但是这些干预措施很容易通过疤痕，纤维化和狭窄而重新堵塞。 使用患者自己的本地静脉旁路移植物特别容易出现移植狭窄和病理血管壁增厚，在手术的第一年内影响了15-35％的旁路。 移植变窄和疤痕是重新手术，移植失败和肢体损失的主要原因，但对因素的理解很少。 大量研究表明，炎症和血栓形成的相互联系途径与这种异常疤痕有关，导致移植物失败。 血小板和单核细胞是血液中循环的两种细胞，PLA在血液凝结和炎症中的关键作用。 当植入新的静脉移植物时，这是将血液凝结和炎症反应联系在一起的两个主要细胞。 如果我们知道哪些患者过度炎症会使他们处于移植失败的危险中，则有可能通过药物或其他干预措施延长其旁路寿命。 我们一直在研究接受PAD腿部旁路的患者血小板和单核细胞的功能，通过测量之前的血液炎症以及手术后的几个月。 我们发现PAD患者的血小板和单核细胞过高。 我们发现，旁路移植物的狭窄患者的血小板 - 单细胞聚集体水平要高于那些伸开的患者。 通常，炎症反应在手术时间左右增加，然后消退，但我们发现，移植物失败的患者在手术后几个月内长期延长了血小板和单核细胞活性升高。 我们还发现了一个遗传特征，似乎影响了旁路的长期成功或失败。 这种遗传特征似乎会影响患者的炎症反应。在该研究项目中，我们建议在多达150名接受腿部腿部的患者中研究血小板和单核细胞功能。 在手术后和手术后长达一年之前，我们将跟踪这些患者以确定其旁路移植物的命运。 从简单的血液样本中，我们将测量其炎症程度以及其血小板和单核细胞的活性。 通过将血小板/单核细胞功能的上升和下降与旁路移植物的结局相关联，我们应该能够确定哪些患者处于最高的移植物衰竭风险。 我们还建议进行基础研究调查，以了解是什么使某些患者的炎症反应更高或更长。 通过了解其遗传特征如何影响炎症反应以及对其他因素的研究，我们可能能够确定药物的新靶标，以延长其旁路的寿命并维持健康的腿部循环。