Super Resolution Ultrasound Imaging of Vasa Vasorum to Characterize the Progression of Atherosclerotic Plaques and Predict Rupture Vulnerability

项目摘要 急性冠状动脉综合征和中风一起构成了发病率和死亡率的主要原因， 在美国和欧洲，约80%的动脉粥样硬化斑块（AP）破裂引起。 在过去的十年中，已经做出了广泛的努力来识别易破裂的AP。其中， 由血管（VV）产生的致密新生血管浸润入AP核心，在 前房破裂。尸检研究显示VV在AP中起关键作用。然而，持续缺乏 无创、高分辨率的成像工具，纵向评估异常微血管扩张仍然是一个 充分体内研究VV如何影响AP进展并有助于最终 破裂为了解决这一严重的未满足的需求，我们提出了一种创新的经皮超分辨率 超声（SRU）成像。该项目的技术开发旨在改变目前美国的成像 从“血管内”到“完全无创经皮”成像识别AP微血管的方法 approach.只有在大深度实现前所未有的高空间分辨率，才有可能实现这一目标， 控制空间分辨率的超声频率的声衍射极限。我们的团队已经完成了 深入可行性研究，其中SRU成像成功识别了胆固醇喂养家兔中的新生微血管 AP，根据µCT和组织学进行评价。此外，需要进一步技术优化的领域有 鉴定迄今为止，这些技术发展和初步数据严格支持我们的总体目标。 假设增强和优化的SRU将准确地对斑块进展进行分期并识别破裂- 通过直接测量VV的变化与精致的细节容易斑块。为了验证这个假设，我们将使用 一种成熟的、临床相关的胆固醇喂养兔AP破裂模型，该模型显示了最多的 与人类斑块病理学（包括VV新血管形成）的相似性，以验证新型SRU系统1） 成功量化血管密度变化和2）识别易破裂AP。为了实现这些目标，我们 提出以下具体目标：1）使用商用小型 动物成像探头2）为了确定SRU估计的VV变化是否与AP进展相关， 预测AP破裂。拟议工作的直接成果是一个负担得起的非侵入性小 动物SRU成像工具及其在临床相关兔AP模型上的验证，该模型也可用于 其他重要的小动物疾病模型，其与微血管异常相关，例如 癌症血管生成和肾脏疾病等等。通过适当的调整进入临床中频 在未来的临床环境中进行探索和验证，这项工作将导致我们的长期转化目标， 将SRU以一种简便的方式整合到目前的颈动脉双功超声检查的临床标准中， 对斑块易损性的特异性差。这将有助于有效地对中风高风险患者进行分层， 指导适当的干预/治疗方案，以预防中风，发挥高度影响力的临床影响。

PROJECT SUMMARY Acute coronary syndromes and strokes together constitute a leading cause of morbidity and mortality in the United States and Europe, approximately 80% of which are caused by atherosclerotic plaque (AP) rupture. Over the past decade, extensive efforts have been made to identify a rupture-prone AP. Among others, infiltration of dense neovascularization arising from vasa vasorum (VV) into the AP core plays a critical role in AP rupture. Postmortem studies revealed key involvement of VV in AP. However, a persistent lack of a noninvasive, high-resolution imaging tool to longitudinally assess abnormal microvascular expansion remains a critical barrier to adequate in-vivo investigation on how VV affects AP progression and contributes to eventual rupture. To address this dire unmet need, we propose an innovative transcutaneous super resolution ultrasound (SRU) imaging. The technology development in this project seeks to shift the current US imaging approach in identifying microvessels of AP from “intravascular” to a “fully noninvasive transcutaneous” imaging approach. This is only possible by achieving unprecedented high spatial resolution at large depth, breaking acoustic diffraction limit of the ultrasound frequency that governs spatial resolution. Our group has performed in-depth feasibility studies where SRU imaging successfully identified neomicrovessels in cholesterol-fed rabbit AP, evaluated against µCT and histology. Additionally, areas requiring further technical optimization were identified. Such technology developments and preliminary data thus far rigorously support our overarching hypothesis that enhanced and optimized SRU will accurately stage plaque progression and identify rupture- prone plaques by directly measuring VV changes with exquisite detail. To test the hypothesis, we will use a well-established, clinically relevant cholesterol-fed rabbit AP rupture model, which has shown the most similarity to human plaque pathology including VV neovascularization, to validate the novel SRU system to 1) Successfully quantify changes in vessel density and 2) Identify rupture-prone AP. To achieve these goals, we propose the following specific aims: 1) To develop enhanced SRU at high frequency using a commercial small animal imaging probe 2) To determine if VV changes estimated by SRU correlate with AP progression and are predictive of AP rupture. The immediate outcomes of the proposed work are an affordable noninvasive small animal SRU imaging tool and it’s validation on a clinically relevant rabbit AP model, which also can be used for other important small animal disease models, which are associated with microvessel abnormality such as cancer angiogenesis and kidney diseases to name a few. With proper adaptations into a clinical mid frequency probe and validation in clinical settings in future, this work will lead to our long-term translational goal to integrate SRU in a facile manner into the current clinical standard of carotid duplex sonography that has shown poor specificity to plaque vulnerability. This will help to effectively stratify patients at high risk of strokes and guide adequate intervention/treatment options for stroke prevention, exerting highly influential clinical impact.