3D Subharmonic Pressure Maps of Vulnerable Plaques

描述（由申请人提供）：新生血管形成已被描述为临床前心血管疾病，特别是动脉粥样硬化的早期和敏感标志物。斑块内新血管形成（从血管中萌发）、斑块内出血（IPH）、坏死核心的大小和斑块易损性之间存在相关性。因此，临床上非常需要一种非侵入性成像工具，以能够早期检测和评估被认为处于未来心血管事件风险中的个体中的易损斑块。使用微泡的对比增强超声成像（US）是这样一种潜在的工具，其已被用于对斑块内新生血管进行成像。我们建议扩大这一概念，利用造影剂微泡作为非线性成像剂和传感器的非侵入性压力估计动脉粥样硬化斑块。我们的小组已经证明，非线性次谐波信号从微泡为基础的美国造影剂（UCA）可以用于一种新的次谐波成像（SHI）模式。此外，这些信号提供了流体静压的良好指示（误差<4 mmHg）。基于这些结果，提出了一种创新的和定量的技术，称为次谐波辅助压力估计（SHAPE），并在试点研究中进行了调查。该项目旨在开发3D SHI和SHAPE，用于斑块新生血管的非侵入性、真实的时间体内评价以及斑块内压力（包括穿过斑块帽的压力梯度）作为早期检测易损斑块的新型生物标志物。我们还将研究不同大小的UCA的斑块SHI和SHAPE。最初，将在体外测试流体静压对微米和纳米气泡的次谐波性能的影响，以选择用于SHAPE的最佳UCA（特定目标1）。接下来，将在最先进的US扫描仪（Logiq 9，GE Healthcare，密尔沃基，WI）上实施3D SHI/SHAPE算法的改进版本，该扫描仪可用于真实的时间、斑块新生血管成像和动态压力测量（特定目标2）。这些新的实现将在Watanabe遗传性高脂血症（WHHL）兔体内进行测试。最后，我们将评估WHHL兔动脉粥样硬化病变的体内3D SHI/SHAPE是否可以使用有创压力监测技术和组织学作为参考标准（特定目标3）来跟踪新生血管和斑块内压力随时间的差异。总之，该项目旨在通过开发一种新颖的、定量的和创新的基于超声的方法（即，3D SHI/SHAPE）用于斑块新生血管的非侵入性、真实的时间评估以及斑块内压力的估计，作为将该方法转化为颈动脉斑块受试者的临床试验的长期目标的第一步。

DESCRIPTION (provided by applicant): Neovascularization has been described as an early and sensitive marker for pre-clinical cardiovascular disease and, in particular, atherosclerosis. There is an association between intra-plaque neovascularization (sprouting from the vasa vasorum), intra-plaque hemorrhage (IPH), the size of the necrotic core and plaque vulnerability. Hence, there is a great clinical need for a non-invasive imaging tool to enable early detection and assessment of vulnerable plaques in individuals considered to be at risk for a future cardiovascular event. Contrast-enhanced ultrasound imaging (US) using microbubbles is one such potential tool, which has been used to image intra-plaque neovascularity. We propose to expand on this concept by utilizing contrast microbubbles as both nonlinear imaging agents and as sensors for non-invasive pressure estimation in atherosclerotic plaques. Our group has demonstrated that the nonlinear subharmonic signals from microbubble-based US contrast agents (UCAs) can be used in a new subharmonic imaging (SHI) mode. Moreover, these signals provide an excellent indication of hydrostatic pressures (errors<4 mmHg). Based on such results, an innovative and quantitative technique called subharmonic-aided pressure estimation (SHAPE) was proposed and investigated in pilot studies. This project aims to develop 3D SHI and SHAPE for the non-invasive, real time in vivo evaluation of plaque neovascularity as well as intra-plaque pressures (including the pressure gradient across the plaque cap) as novel biomarkers for the early detection of vulnerable plaques. We will also investigate different sized UCAs for plaque SHI and SHAPE. Initially, the effects of hydrostatic pressure on the subharmonic performance of micro- as well as nano-bubbles will be tested in vitro to select the best UCA for SHAPE (Specific Aim 1). Next, an improved version of the 3D SHI/SHAPE algorithm will be implemented on a state-of-the-art US scanner (Logiq 9, GE Healthcare, Milwaukee, WI) that can be used for real time, plaque neovascularity imaging and dynamic pressure measurements (Specific Aim 2). These new implementations will be tested in vivo in Watanabe Heritable Hyperlipidemic (WHHL) rabbits. Finally, we will assess whether in vivo 3D SHI/SHAPE of atherosclerotic lesions in WHHL rabbits can track differences in neovascularity and intra-plaque pressures over time using invasive pressure monitoring techniques and histology as the reference standards (Specific Aim 3). In conclusion, this project aims to fundamentally shift the clinical paradigm on early detection of vulnerable plaques by developing a novel, quantitative and innovative ultrasound based method (i.e., 3D SHI/SHAPE) for the non-invasive, real time evaluation of plaque neovascularity as well as estimates of intra-plaque pressures, as a first step towards the long-term goal of translating this method into a clinical trial of subjects presenting with carotid plaque.