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

项目总结 急性冠脉综合征和中风共同构成了 美国和欧洲，其中约80%是由动脉粥样硬化斑块(AP)破裂引起的。 在过去的十年里，已经做出了广泛的努力来确定易破裂的AP。其中， 来自血管(VV)的致密新生血管渗入AP核心起关键作用 AP破裂。尸检研究揭示了VV在AP中的关键参与。然而，长期缺乏一种 用于纵向评估异常微血管扩张的非侵入性高分辨率成像工具仍然是 在体内充分研究VV如何影响AP进展并最终导致 破裂。为了解决这一迫切的未得到满足的需求，我们提出了一种创新的经皮超分辨率 超声(SRU)成像。该项目中的技术开发寻求将当前的美国成像 从“血管内”到“完全无创”经皮成像识别AP微血管的方法 接近。这只有通过在大深度获得前所未有的高空间分辨率才有可能，打破 决定空间分辨率的超声频率的声衍射极限。我们的团队已经表演了 SRU成像成功识别胆固醇喂养兔新生微血管的深入可行性研究 AP，对照µCT和组织学进行评估。此外，需要进一步优化技术的领域有 已确认身份。到目前为止，这样的技术发展和初步数据严格支持了我们的总体 假设增强和优化的SRU将准确地分期斑块进展并识别破裂- 通过直接测量VV的变化，以精致的细节俯瞰斑块。为了检验这一假设，我们将使用 建立了良好的、临床相关的胆固醇喂养的兔AP破裂模型，该模型显示了 与人类斑块病理包括VV新生血管相似，以验证新的SRU系统为1) 成功地量化血管密度的变化，并2)识别易破裂的AP。为了实现这些目标，我们 提出以下具体目标：1)使用商业小型计算机开发高频增强SRU 动物成像探头2)以确定SRU估计的VV变化是否与AP的进展相关 预示着AP破裂。拟议工作的直接结果是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 其他与微血管异常有关的重要小动物疾病模型，如 癌症、血管生成和肾脏疾病仅举几例。适当地适应到临床中频 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翻译目标 将SRU以方便的方式集成到当前的颈动脉双工超声临床标准中，已显示 斑块易损性的特异性差。这将有助于有效地对中风高危患者和 指导适当的干预/治疗方案预防中风，产生极大的临床影响。

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.