Targeted Endovascular Treatment of Inflammation for Vascular Healing in Humans

 描述(申请人提供)：外周动脉疾病(PAD)每年至少影响1200万美国人，其中50万人每年需要血管内或外科血管重建术。不幸的是，在股动脉球囊血管成形术一年后，只有三分之一的患者有动脉未闭。这一比率在过去20年中没有显着变化，突显出对失败和缺乏辅助治疗的机械性知识的普遍缺失。一个可能的原因是缺乏能够达到亚毫米分辨率的成像设备来评估体内血管壁的一系列变化。核磁共振成像(MRI)与黑血成像技术相结合，现在具有足够的空间分辨率来检测室壁体积的微小变化，并可应用于连续的活体研究。多对比和动态对比成像技术可以提供对血管壁的进一步了解，这些成像技术能够提供关于血管外膜血管产生的血管壁成分和血流灌注的信息。认识到再狭窄是炎症的结果，我们最近完成了一项第一阶段的研究，即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。动脉外膜是一个免疫富集层，积极参与血管对损伤的反应。这项首个人的研究确定了安全性和 证明了局部给药方法的可行性，并提供了良好的临床效果。这项应用的基本假设是，抑制血管局部的炎症将导致血管愈合的改善和持续的动脉通畅。为了解决我们的假设，我们提出了一项随机机械试验，以测试DEX是否可以改善血管成形术的血管愈合反应。在第一个特定目标中，将使用MRI来评估药物中治疗的动脉节段的壁体积与对照组的比较。通过从血浆到血管壁的对比剂的动力学建模来测量外膜的血流灌注，从而进一步表征血管壁。这提供了对组织炎症的估计。此外，我们将使用计算流体力学来评估血流动力学描述符以及它们与血管重塑治疗任务之间的相互作用。在特定的目标2中，我们将确定围手术期的全身性炎症，并将其与治疗任务、血管壁炎症和血管壁体积联系起来。在具体目标#3中，我们将确定股动脉斑块成分(富含脂质的坏死核、钙化和致密的纤维组织)，以处理节段总壁容的百分比表示。然后，我们将确定每种组织类型与血管成形术结果的关系，例如血管壁体积和重塑，以及围手术期炎症反应。总而言之，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是否对血管壁产生生物学效应，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.