Targeted Endovascular Treatment of Inflammation for Vascular Healing in Humans

 描述（由申请人提供）：外周动脉疾病（PAD）每年影响至少1200万美国人，其中50万人每年需要血管内或外科血运重建手术。不幸的是，只有三分之一的患者在股动脉球囊血管成形术后一年动脉通畅。这一比率在过去20年中没有显著变化，突出了对失败的机械知识的普遍缺乏和缺乏预防性治疗。一个可能的原因是缺乏能够亚毫米分辨率的成像模式来评估血管壁的体内连续变化。磁共振成像（MRI），与黑血成像技术，现在有足够的空间分辨率来检测壁体积的微小变化，并可应用于系列体内研究。可以利用多对比度和动态对比度成像技术来提供对血管壁的进一步了解，所述多对比度和动态对比度成像技术能够提供关于血管壁组成和由外膜血管引起的灌注的信息。认识到再狭窄是炎症的结果，我们最近完成了一项在股动脉血管成形术时通过血管内微输注导管将地塞米松（DEX）输送到外膜的I期研究。动脉外膜是一个免疫丰富的层，积极参与血管对损伤的反应。这项首次人体研究确定了安全性， 局部给药方法的可行性，并提供了良好的临床结果。本申请的基本假设是抑制治疗部位的炎症将导致改善的血管愈合和持续的动脉通畅。为了解决我们的假设，我们提出了一个随机的机制试验，以测试是否DEX可以改善血管成形术的血管愈合反应。在第一个特定目的中，将使用MRI评估药物组与对照组相比经处理动脉节段的壁体积。血管壁将通过测量外膜灌注来进一步表征，该外膜灌注是通过从血浆到血管壁的造影剂的动力学建模来进行的。这提供了对组织炎症的估计。此外，我们将采用计算流体动力学来评估血流动力学描述符及其与血管重塑治疗分配的相互作用。在具体目标#2中，我们将确定围手术期时间点的全身炎症，并将其与治疗分配、血管壁炎症和血管壁体积相关联。在特定目标3中，我们将确定股动脉斑块组成（富含脂质的坏死核心、钙化和致密纤维组织），表示为治疗节段总壁体积的百分比。然后，我们将确定每种组织类型与血管成形术结果的关系，例如壁体积和重塑，以及围手术期炎症反应。总的来说，这些特定的目标将使我们能够确定患者特定的生理参数是否影响血管成形术的结果，DEX是否对血管壁具有生物学效应，以及这种效应是否通过减少炎症来实现。

 DESCRIPTION (provided by applicant): Peripheral artery disease (PAD) affects at least 12 million Americans annually, and half a million of them will require an endovascular or surgical revascularization procedure each year. Unfortunately, only one-third of patients have a patent artery one year after balloon angioplasty of the femoral artery. This rate has not significantly changed in the last 20 years highlighting a general deficit in mechanistic knowledge of failure and lack of adjunctive therapies. One possible reason for this has been the lack of imaging modalities capable of sub-millimeter resolution to assess in vivo serial changes in the vessel wall. Magnetic resonance imaging (MRI), with black-blood imaging techniques, now has sufficient spatial resolution to detect small changes in wall volumes and can be applied to serial in vivo studies. Further insights into the vascular wall can be provided with multi-contrast and dynamic-contrast imaging techniques, which are capable of providing information on vessel wall composition and perfusion arising from adventitial vasa vasorum. Recognizing that restenosis is a consequence of inflammation, we recently completed a Phase 1 study of delivering dexamethasone (DEX) to the adventitia via an endovascular micro-infusion catheter at the time of femoral artery angioplasty. The adventitia of an artery is an immune rich layer that actively participates in the vascular response to injury. This first-in-man study established the safety and feasibility of the local drug delivery method and provided excellent clinical outcomes. The fundamental hypothesis of this application is that inhibition of inflammation at the site of therap will result in improved vascular healing and a sustained patent artery. To address our hypothesis, we propose a randomized mechanistic trial to test whether DEX can improve the vascular healing response to angioplasty. In the first Specific Aim, MRI will be used to assess wall volume of the treated arterial segment in the drug compared to the control group. The vascular wall will be further characterized by measuring adventitial perfusion through kinetic modeling of contrast into the vessel wall from the plasma. This provides an estimate of tissue inflammation. Further we will employ computational fluid dynamics to assess hemodynamic descriptors and their interaction with treatment assignment on vascular remodeling. In Specific Aim #2, we will determine systemic inflammation at peri-operative time points and relate them to treatment assignment, vascular wall inflammation, and wall volume. In Specific Aim #3, we will determine femoral artery plaque composition (lipid rich necrotic core, calcification, and dense fibrous tissue) expressed as a percent of total wall volume of the treated segment. We will then determine each tissue type's relationship with the angioplasty outcomes, such as wall volume and remodeling, as well as the peri-procedural inflammatory response. Collectively, these specific aims will allow us to determine if patient-specific physiological parameters affect angioplasty outcomes, if DEX has a biological effect on the vascular wall, and if this effect is through the reduction of inflammation.