Targeted Endovascular Treatment of Inflammation for Vascular Healing in Humans

靶向血管内炎症治疗促进人类血管愈合

• 批准号: 9265509
• 负责人: David A Saloner
• 金额: $ 53.07万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-18 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9265509
• 关键词: Address; Affect; American; Angiography; Angioplasty; Anti-Inflammatory Agents; Anti-inflammatory; Arteries; Balloon Angioplasty; Biological; Biological Monitoring; Blood; Blood Vessels; Blood flow; CCL2 gene; Calcified; Catheters; Cell Proliferation; Clinical; Control Groups; Coronary artery; Descriptor; Dexamethasone; Disease; Drug Delivery Systems; Failure; Geometry; Glucocorticoids; Growth Factor; Human; Image; Imaging Techniques; Immune; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Injury; Interleukin-1 beta; Kinetics; Knowledge; Leg; Legal patent; Lipids; Liquid substance; Magnetic Resonance Imaging; Measures; Mechanics; Methods; Modeling; Modernization; Morphology; Necrosis; Operative Surgical Procedures; Outcome; Patients; Perfusion; Perioperative; Peripheral arterial disease; Pharmaceutical Preparations; Physiological; Plasma; Procedures; Protocols documentation; Randomized; Recording of previous events; Research Project Grants; Resolution; Site; Specialist; Testing; Therapeutic; Therapy Clinical Trials; Time; Tissues; Toxic effect; Treatment Efficacy; Treatment Failure; Tunica Adventitia; Ultrasonography; Vascular remodeling; base; calcification; catalyst; contrast enhanced; contrast imaging; cytokine; design; effective therapy; femoral artery; healing; hemodynamics; imaging modality; improved; improved outcome; in vivo; inflammatory marker; insight; local drug delivery; man; novel strategies; phase 1 study; public health relevance; response; response to injury; restenosis; safety and feasibility; shear stress; treatment site; vasa vasorum; vascular bed; vascular inflammation

 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.

 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，其中每年有 50 万人需要进行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拥有未闭动脉。股动脉球囊血管成形术一年后，这一比率在过去 20 年中没有显着变化，突显了失败的机械知识普遍缺乏和缺乏辅助治疗的一个可能原因。一直以来，缺乏能够进行亚毫米分辨率的成像方式来评估体内血管壁的连续变化，而采用黑血成像技术的磁共振成像 (MRI) 现在具有足够的空间分辨率来检测血管壁的微小变化。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，这些技术能够提供有关血管壁组成和外膜滋养管灌注的信息。认识到再狭窄是炎症的结果，我们最近完成了一项一期研究，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。动脉的外膜是一个免疫丰富的层。积极参与血管对损伤的反应。这项首次人体研究证实了其安全性和有效性。 局部药物输送方法的可行性并提供了良好的临床结果，该应用的基本假设是抑制治疗部位的炎症将改善血管愈合和持续的动脉开放。测试 DEX 是否可以改善血管成形术的血管愈合反应的机制试验在第一个具体目标中，将使用 MRI 来评估药物中治疗的动脉段的壁体积，并与对照组进行比较。通过测量通过对血浆中的血管壁进行动力学建模，我们将进一步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。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（富含脂质的坏死核心、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，这些具体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作用，以及这种作用是否是通过减少炎症来实现的。