Effect of lipid modification on peripheral arterial dis*

描述(由申请人提供)：积极的脂类修饰在预防动脉粥样硬化进展和下肢再狭窄方面的益处尚不清楚。由于缺乏对血管病变病理学的定量测量，这一领域受到严重阻碍。手术干预后再狭窄的完整自然病史尚不清楚。我们将结合我们在贝勒医学院的专业知识和资源，以多学科的方式解决这些重要问题。我们假设，积极的血脂调节方案将通过减少血栓形成和炎症来抑制股动脉粥样硬化的进展，并减少血管内支架术后股动脉再狭窄的发生率。我们将招募120名有症状的单腿股动脉闭塞症患者。这些患者将接受血管内支架治疗，并被随机分为两组：1)标准医疗和2)积极的调脂治疗，可升高高密度脂蛋白(40 mg/dl)，降低低密度脂蛋白(80 mg/dl)和甘油三酯(CL50 mg/dl)。我们将对这些患者进行为期2年的随访。我们的具体目的是：1)确定积极的血脂调节对动脉粥样硬化进展和股动脉再狭窄的影响。最近，我们采用高分辨率磁共振成像(MRI)来研究肢体血管病理，包括病变的大小、成分和形态。这项技术将用于检查支架内再狭窄的支架股动脉和动脉粥样硬化进展或消退的对侧股动脉。2)确定积极的血脂调节方案对股动脉血管成形术和/或支架术后临床适用的血流动力学测量的影响，以及对减少系统性重大心血管事件的影响。贝勒的庞大临床工作量和出色的血管内治疗专业知识将使我们能够评估临床结果，包括踝臂指数(ABI)、步行距离、绝对跛行和在PAD显著人群中的双功超声。3)。研究积极的三联药物治疗对脂蛋白、炎症的影响，以及与PAD进展、再狭窄和临床事件的关系。低密度脂蛋白、高密度脂蛋白、甘油三酯、脂蛋白(A)、颗粒大小和数量、超敏C反应蛋白、肿瘤坏死因子α、IL-8、单核细胞趋化蛋白-1、P-选择素、S-细胞间黏附分子-1、S-血管细胞黏附分子-1和可溶性CD40L的检测将使我们能够从机制上深入了解PAD的进展和临床事件。4)。研究积极的三联药物治疗对血栓形成的影响，以及与PAD进展、再狭窄和临床事件的关系。将这些研究与临床结果和定量的股骨磁共振图像相关联，将使我们能够从机械上深入了解PAD的进展和临床事件。本研究将为延缓或预防动脉血运重建术后动脉粥样硬化和再狭窄的进展提供一种新的策略。重要的是，我们的MRI研究将首次提供关于血管病变的定量数据。最后，这些研究将促进我们对与激进的脂质修饰相关的炎症和血栓形成的分子机制的理解。

DESCRIPTION (provided by applicant): The benefit of aggressive lipid modification on the prevention of progression of atherosclerosis and restenosis in the lower extremity is unknown. This field is severely hampered by the lack of quantitative measurement of vascular lesion pathology. Complete natural history of restenosis following surgical intervention is not clear. We will combine our expertise and resources at Baylor College of Medicine in a multidisciplinary approach to address these important questions. We hypothesize that an aggressive regimen of serum lipid modification will inhibit the progression of atherosclerosis in femoral arteries and reduce the incidence of restenosis of femoral arteries following endovascular stenting by decreasing thrombosis and inflammation. We will recruit a total of 120 patients with symptomatic femoral artery occlusive disease in one leg. These patients will be treated with endovascular stenting, and randomized into two groups: 1) standard medical care and 2) aggressive lipid modification therapy which increases HDL (>40mg/dl) and decreases LDL (<80 mg/dl) and TG (cl50 mg/dl). We will follow these patients for 2 years. Our Specific Aims are to: 1) Determine the effect of aggressive lipid modification on progression of atherosclerosis and restenosis of femoral arteries. Recently, we have adapted high resolution magnetic resonance imaging (MRI) to study extremity vascular pathology including lesion size, composition, and morphology. This technology will be used to examine both the stented femoral artery for in-stent restenosis and the contralateral femoral artery for atherosclerosis progression or regression. 2) Determine the effects of an aggressive regimen of serum lipid modification on the clinically applicable hemodynamic measurements following femoral artery angioplasty and/or stenting and on the reduction of systemic major cardiovascular events. Large clinical volume and excellent endovascular therapy expertise at Baylor will enable us to evaluate the clinical outcomes, including ankle brachial index (ABI), walking distance, absolute claudication, and duplex ultrasound in a population with significant PAD. 3). Investigate effects of aggressive triple-drug therapy on lipoproteins, inflammation, and relationship to PAD progression, restenosis, and clinical events. Assays of LDL, HDL, TG, Lp(a), particle size and number, hsCRP, TNFalpha, IL-8, MCP-1, sP-selectin, s-ICAM-1, s-VCAM-1, and sCD40L will permit mechanistic insights into PAD progression and clinical events. 4). Investigate the effects of aggressive triple-drug therapy on thrombosis, and relationship to PAD progression, restenosis and clinical events. Association of these studies with clinical outcomes and quantitative femoral MR images will permit mechanistic insights into PAD progression and clinical events. This study will provide a novel strategy to retarding or preventing progression of atherosclerosis and restenosis following arterial revascularization procedures. Importantly, our MRI studies will, for the first time, provide quantitative data on the vascular lesions. Finally, these studies will advance our understanding of the molecular mechanisms of inflammation and thrombosis associated with aggressive lipid modification.