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

血管超分辨率超声成像可表征动脉粥样硬化斑块的进展并预测破裂脆弱性

• 批准号: 10374343
• 负责人: KANG KIM
• 金额: $ 69.46万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10374343
• 关键词: 3-Dimensional; Acoustics; Address; Affect; Algorithms; Animal Disease Models; Animals; Area; Arterial Fatty Streak; Autopsy; Bolus Infusion; Carotid Atherosclerotic Disease; Characteristics; Cholesterol; Clinic; Clinical; Confocal Microscopy; Contrast Media; Data; Devices; Disease; Europe; Feasibility Studies; Foundations; Frequencies; Future; Goals; Growth; Histology; Human; Image; Imaging Device; Imaging technology; In Vitro; Infiltration; Influentials; Injections; Intervention; Intravenous; Investigation; Kidney Diseases; Lead; Life; Logistic Regressions; Logistics; Magnetic Resonance Imaging; Malignant Neoplasms; Measures; Microbubbles; Microfluidics; Modeling; Morbidity - disease rate; Myocardial Infarction; Names; Noise; Optics; Oryctolagus cuniculus; Outcome; Pathology; Performance; Physiologic pulse; Physiological; Pilot Projects; Play; Population; Preventive treatment; Procedures; ROC Curve; Radiation; Resolution; Risk; Role; Rupture; Scanning; Senile Plaques; Signal Transduction; Specificity; Stroke; Stroke prevention; Surrogate Markers; System; Techniques; Testing; Ultrasonography; United States; Validation; Work; acute coronary syndrome; angiogenesis; animal imaging; atherosclerotic plaque rupture; clinical application; clinical translation; clinically relevant; contrast enhanced; density; high resolution imaging; high risk; human subject; image reconstruction; imaging approach; imaging capabilities; imaging probe; in vivo; innovation; innovative technologies; microCT; microscopic imaging; mortality; neovascularization; novel; patient stratification; spatiotemporal; stroke risk; technology development; tomography; tool; translational goal; ultrasound; uptake; vasa vasorum

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.

项目概要 急性冠状动脉综合征和中风共同构成了发病率和死亡率的主要原因 美国和欧洲，大约80%是由动脉粥样硬化斑块（AP）破裂引起的。 在过去的十年中，人们做出了广泛的努力来识别容易破裂的 AP，其中包括： 滋养管 (VV) 产生的致密新生血管浸润至 AP 核心，在 尸检研究显示 VV 在 AP 中起关键作用，但一直缺乏。 用于纵向评估异常微血管扩张的无创高分辨率成像工具仍然是一个 充分体内研究的关键障碍是 VV 如何影响 AP 进展并有助于最终 为了解决这一未满足的迫切需求，我们提出了一种创新的经皮超分辨率。 该项目的技术开发旨在改变当前的美国成像技术。 从“血管内”到“完全无创经皮”成像识别 AP 微血管的方法 这只有通过在大深度实现前所未有的高空间分辨率才有可能实现。 我们的小组已经研究了控制空间分辨率的超声波频率的声学衍射极限。 SRU 成像成功识别胆固醇喂养兔子体内的新生微血管的深入可行性研究 另外，还根据 µCT 和组织学评估了 AP，需要进一步技术优化的领域。 迄今为止，此类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 - 为了验证这一假设，我们将使用一个通过直接测量 VV 变化来检测易发生斑块的方法。 完善的、临床相关的胆固醇喂养兔 AP 破裂模型，该模型显示了最 与人类斑块病理学相似，包括 VV 新生血管形成，以验证新型 SRU 系统：1) 成功量化血管密度的变化，并 2) 识别容易破裂的 AP。为了实现这些目标，我们。 提出以下具体目标： 1) 使用商用小型芯片开发高频增强型 SRU 动物成像探针 2) 确定 SRU 估计的 VV 变化是否与 AP 进展相关，并且是否与 AP 进展相关 所提出的工作的直接结果是一种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 其他与微血管异常相关的重要小动物疾病模型，例如 癌症血管生成和肾脏疾病等，适当适应临床中频。 未来在临床环境中进行探索和验证，这项工作将实现我们的长期转化目标 以一种简便的方式将 SRU 集成到目前已证实的颈动脉双功超声检查临床标准中 斑块脆弱性的特异性较差，这将有助于有效地对中风和高风险患者进行分层。 指导中风预防的适当干预/治疗方案，发挥高度影响力的临床影响。