The Impact of Diabetes on Revascularization in BEST-CLI

 描述（由申请人提供）：外周动脉疾病是一种由动脉粥样硬化斑块在远端主动脉下方显著积聚导致下肢动脉灌注减少的疾病。血流量减少可能不足以锻炼肢体并引起缺血性肌肉疼痛，称为间歇性跛行，或者在严重的情况下，减少可能不足以进行基础代谢并引起休息时疼痛，溃疡或坏疽。静息时出现症状或组织坏死是一种医疗紧急情况，代表严重肢体缺血（CLI）状态，在没有血运重建的情况下，截肢的风险很高。人口老龄化和糖尿病患病率的增加确保了这一人口在可预见的未来将继续增长。然而，糖尿病的影响不仅限于PAD的发生率。糖尿病患者是PAD患者中特别脆弱的一个亚群，与非糖尿病患者相比，CLI的风险是非糖尿病患者的四倍。事实上，在以前的CLI研究中，超过一半的患者患有糖尿病。因此，糖尿病和PAD的组合占美国非创伤性截肢的一半以上。糖尿病患者通常表现为足溃疡作为其PAD的第一表现，并且具有挑战性的解剖结构以进行血运重建。血管重建失败，无论是血管内还是外科手术，通常会导致额外的组织损失和经胫骨截肢。尽管存在这些挑战，但对于CLI患者的两种血运重建，再狭窄机制和糖尿病的影响尚未得到充分探索。BEST-CLI试验是一项多中心、随机、有效性比较试验，在CLI患者中比较开放手术旁路治疗与血管内治疗，复合临床终点表示为无严重肢体不良事件生存期（无MALE生存期）。然而，BEST-CLI试验并未研究血运重建可能失败的机制。该提案将通过研究旁路静脉移植物和支架失效的机制来扩展BEST-CLI试验的新临床工作。我们将在中心实验室判定血运重建（静脉移植或支架）的模式，测量糖尿病代谢障碍的全身标志物，并研究蛋白酶激活受体1激活途径的多个步骤，将这些因素与移植失败联系起来。迄今为止，在冠状动脉或外周血运重建方面进行的试验均未确定血运重建失败的机制、糖尿病的影响、PAR 1的作用以及管道通畅性与临床结局之间的关系。因此，本试验为研究糖尿病影响外科和血管内血运重建手术的机制提供了独特的机会。

 DESCRIPTION (provided by applicant): Peripheral artery disease is a condition defined by marked accumulation of atherosclerotic plaque below the distal aorta that reduces lower limb arterial perfusion. Blood flow reductions may be inadequate for exercising limbs and cause ischemic muscle pain, called intermitted claudication, or, in severe cases, the reduction may be inadequate for basal metabolism and cause pain at rest, ulceration, or gangrene. The presence of symptoms at rest or tissue necrosis is a medical urgency and represents a state of critical limb ischemia (CLI) where the risk of amputation, in the absence of revascularization, is high. The ageing of the population and the increasing prevalence of diabetes mellitus ensures this population will continue to grow in the foreseeable future. The impact of diabetes, however, is not limited to PAD incidence. Diabetic patients represent a particularly vulnerable subset of PAD patients and have a four-fold risk of CLI compared to non-diabetic patients. Indeed, in previous studies of CLI, more than half of patients have diabetes. As a result, the combination of diabetes and PAD accounts for more than half of non-traumatic amputations in the United States. Diabetic patients often present with foot ulcerations as their first manifestation of PAD and have challenging anatomy for revascularization. Failed vascular reconstructions, both endovascular or surgical, often result in additional tissue loss and transtibial amputations. Despite these challenges, the mechanisms of restenosis and the impact of diabetes have not been well explored for both types of revascularization in patients with CLI. The BEST-CLI trial is a multi-center, randomized, comparative effectiveness trial comparing open surgical bypass therapy to endovascular therapy in CLI patients with a composite clinical endpoint denoted as Major Adverse Limb Event free survival (MALE-free survival). However, the BEST-CLI trial does not study the mechanisms by which revascularization may fail. This proposal will extend the novel clinical work of the BEST-CLI trial by studying the mechanisms of bypass vein graft and stent failure. We will adjudicate the mode of revascularization (vein graft or stent) in a central core laboratory, measure systemic markers of diabetic dysmetabolism, and study multiple steps along the protease-activated receptor 1 activation pathway, linking these factors with graft failure. No trial conducted to date in either coronary or peripheral revascularization has determined the mechanism of revascularization failure, the impact of diabetes, the contribution of PAR1, nor the relationship between conduit patency and clinical outcomes. Therefore, this trial represents a unique opportunity to investigate the mechanisms by which diabetes affects surgical and endovascular revascularization procedures.