Intravascular NIRF-IVUS imaging of inflammation-guided arterial therapy

摘要 本R 01申请的目的是改善动脉粥样硬化和血管内 支架植入术，通过可平移的血管内成像阐明其潜在的病理生物学， 动脉炎症和结构。为了实现这一目标，我们将设计下一代血管内 近红外荧光血管内超声成像系统 动脉然后，我们将利用NIRF-IVUS来阐明炎症在评估和指导 动脉粥样硬化和支架再狭窄的药物治疗策略。冠状动脉疾病（CAD）是一种 冠状动脉粥样硬化是世界范围内死亡和残疾的主要原因，通常需要冠状动脉支架植入术进行治疗。生物 和分子过程，如炎症驱动毁灭性的CAD和支架并发症，但在很大程度上是 现代临床成像方法无法检测到。能够对冠状动脉进行成像和量化 炎症等分子过程将改善患者风险分层，指导CAD的选择 和支架药物治疗，并帮助简化CAD和支架治疗的发展，从0期 /临床前至IV期/批准后阶段。 我们的实验室共同开发了新颖的创新性血管内成像系统，该系统结合了联合收割机的高 分辨率IVUS，主要的冠状动脉内结构成像方法，与NIRF分子成像， 强大的新的分子成像方法在快速临床翻译。在这个应用程序中，我们将 显著提高血管内NIRF-IVUS检测高风险斑块的平移潜力， 支架并发症的风险，并进一步指导动脉药物治疗的个性化选择。的 本提案的具体目标是：目标1：开发下一代NIRF-IVUS v2.0系统，针对以下方面进行优化： 体内冠状动脉内成像，并在猪连续冠状动脉支架炎症模型中进行体内测试。目标二： 证明NIRF-IVUS炎症指标驱动动脉粥样硬化进展和动脉粥样硬化血栓形成， 体内，并预测依折麦布，FDA批准的动脉粥样硬化剂的反应。目标3：展示 NIRF-IVUS测量体内炎症驱动支架再狭窄，并预测对 秋水仙碱，一种FDA批准的有可能减少再狭窄的疗法。 本研究的长期目标是为临床NIRF-IVUS提供转化基础， 提供一种新的、个性化的用药方法，选择患者进行抗炎治疗， 斑块进展、动脉粥样硬化和支架并发症。这些知识的临床转化可能 提供了一种使用血管内NIRF-IVUS改善CAD患者结局的新范例。

ABSTRACT The goal of this R01 application is to improve the treatment of atherosclerosis and endovascular stenting by illuminating their underlying pathobiology through translatable intravascular imaging of arterial inflammation and structure. To achieve this goal, we will engineer a next-generation intravascular near-infrared fluorescence-intravascular ultrasound (NIRF-IVUS) imaging system targeted to human coronary arteries. We will then harness NIRF-IVUS to elucidate the role of inflammation in assessing and guiding atherosclerosis and stent restenosis pharmacotherapeutic strategies. Coronary artery disease (CAD) is a worldwide leading cause of death and disability, and often requires coronary stenting for treatment. Biological and molecular processes such as inflammation drive devastating CAD and stent complications, but are largely invisible to contemporary clinical imaging methods. The ability to image and quantify coronary arterial molecular processes such as inflammation would improve patient risk stratification, guide the selection CAD and stent pharmacotherapies, and help streamline CAD and stent therapeutics development from phase 0 /preclinical to phase IV/post-approval stages. Our laboratory has co-developed novel and innovative intravascular imaging systems that combine high- resolution IVUS, the dominant intracoronary structural imaging method, with NIRF molecular imaging, a powerful new molecular imaging approach under rapid clinical translation. In this application, we will substantially improve the translational potential of intravascular NIRF-IVUS to detect high-risk plaques and stents at risk of complications, and further guide the personalized selection of arterial pharmacotherapy. The Specific Aims of this proposal are: Aim 1: Develop a next generation NIRF-IVUS v2.0 system optimized for in vivo intracoronary imaging, and test in vivo in a swine serial coronary stent inflammation model. Aim 2: Demonstrate that NIRF-IVUS measures of inflammation drive atheroma progression and atherothrombosis in vivo, and predict the response to ezetimibe, an FDA-approved atherosclerosis agent. Aim 3: Demonstrate that NIRF-IVUS measures of inflammation drive stent restenosis in vivo, and predict the response to colchicine, an FDA-approved therapy with the potential to reduce restenosis. The long-term objectives of this research are to provide a translational foundation for clinical NIRF-IVUS, and to provide a new, personalized medicine approach to select patients for anti-inflammatory therapy to reduce plaque progression, atherothrombosis, and stent complications. Clinical translation of this knowledge may provide a new paradigm using intravascular NIRF-IVUS to improve outcomes in patients with CAD.