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: 8946226
• 负责人: Christopher Dean Owens
• 金额: $ 53.54万
• 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/8946226
• 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; Catheters; Cell Proliferation; Clinical; Computational Geometry; Control Groups; Coronary artery; Descriptor; Dexamethasone; Disease; Drug Delivery Systems; Failure; Glucocorticoids; Growth Factor; Healed; Histocompatibility Testing; Human; Image; Imaging Techniques; Immune; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Injury; Kinetics; Knowledge; Leg; Legal patent; Lipids; Liquid substance; Magnetic Resonance Imaging; Measures; Mechanics; Methods; Modeling; Morphology; Necrosis; Operative Surgical Procedures; Outcome; Patients; Perfusion; Peripheral arterial disease; Pharmaceutical Preparations; Physiological; Plasma; Procedures; Protocols documentation; Randomized; Recording of previous events; Research Project Grants; Resolution; Safety; Site; Specialist; Testing; Therapeutic; Therapy Clinical Trials; Time; Tissues; Toxic effect; Treatment Efficacy; Treatment Failure; Tunica Adventitia; Vascular remodeling; base; calcification; catalyst; contrast enhanced; contrast imaging; cytokine; design; effective therapy; femoral artery; healing; hemodynamics; imaging modality; improved; in vivo; inflammatory marker; insight; local drug delivery; man; millimeter; novel strategies; phase 1 study; public health relevance; quantitative ultrasound; response; response to injury; restenosis; 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（由适用提供）：周围动脉疾病（PAD）每年至少影响1200万美国人，其中一百万将需要每年进行血管内或手术血运重建程序。不幸的是，只有三分之一的患者在股动脉血管血管成形术后一年拥有专利动脉。在过去的20年中，这种速度没有发生显着变化，这突显了失败和缺乏辅助疗法的机械知识的普遍缺陷。造成这种情况的一个可能原因是缺乏能够评估血管壁中体内串行变化的成像方式。磁共振成像（MRI）具有黑血成像技术，现在具有足够的空间分辨率来检测壁量的小变化，并且可以应用于体内研究的串行。可以为血管壁提供进一步的见解，并具有多对比和动态对比度成像技术，这些技术能够提供有关血管壁组成的信息以及由Advance Vasa vasorum引起的灌注。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研究，该研究是在股骨动脉血管成形术时通过血管内微型灌注导管将地塞米松（DEX）传递到院的。动脉的外膜是一种免疫层，积极参与损伤的血管反应。这项人工研究确立了安全性和 局部药物输送方法的可行性，并提供了出色的临床结果。该应用的基本假设是，治疗部位抑制炎症将导致血管愈合的改善和持续的专利动脉。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是否可以改善对血管成形术的血管愈合反应。在第一个特定目的中，与对照组相比，MRI将用于评估药物中治疗的动脉段的壁量。血管壁将进一步特征，是通过将对比度的动力学建模从血浆中测量的灌注。这提供了组织注射的估计值。此外，我们将采用计算流体动力学来评估血液动力学描述符及其与血管重塑的治疗分配的相互作用。在特定的目标＃2中，我们将在围手术期间确定全身性炎症，并将其与治疗分配，血管壁感染和壁量相关。在特定的目标＃3中，我们将确定股动脉斑块组成（富含脂质的坏死核，钙化和密集的纤维组织），其表示为处理片段的总壁量的百分比。然后，我们将确定每种组织类型与血管成形术结局的关系，例如墙壁体积和重塑，以及手术外炎症反应。总的来说，这些特定目标将使我们能够确定患者特异性的物理参数是否影响血管成形术结局，DEX是否对血管壁具有生物学作用，以及这种作用是否通过减少炎症。