3D Subharmonic Pressure Maps of Vulnerable Plaques

描述（由申请人提供）：新生血管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。斑块内新生血管（从血管血管萌发）、斑块内出血（IPH）、坏死核心的大小和斑块易损性之间存在关联。因此，临床非常需要一种非侵入性成像工具，以便早期发现和评估被认为有未来心血管事件风险的个体的易损斑块。利用微泡造影增强超声成像（US）就是这样一种潜在的工具，它已被用于成像斑块内的新血管。我们建议通过利用对比微泡作为非线性显像剂和传感器来扩展这一概念，用于动脉粥样硬化斑块的非侵入性压力估计。我们的团队已经证明了基于微泡的US造影剂（UCAs）的非线性次谐波信号可以用于新的次谐波成像（SHI）模式。此外，这些信号还能很好地指示静水压力（误差<4 mmHg）。基于这些结果，提出了一种称为次谐波辅助压力估计（SHAPE）的创新定量技术，并在试点研究中进行了研究。该项目旨在开发3D SHI和SHAPE，用于无创，实时体内评估斑块新生血管以及斑块内压力（包括斑块帽上的压力梯度），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对斑块SHI和SHAPE的影响。首先，静水压力对微泡和纳米泡亚谐波性能的影响将在体外进行测试，以选择最佳的UCA用于SHAPE （Specific Aim 1）。接下来，3D SHI/SHAPE算法的改进版本将在最先进的美国扫描仪（Logiq 9, GE Healthcare, Milwaukee， WI）上实施，该扫描仪可用于实时、斑块新生血管成像和动态压力测量（Specific Aim 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，我们将利用侵入性压力监测技术和组织学作为参考标准，评估WHHL兔动脉粥样硬化病变的体内3D SHI/SHAPE是否可以追踪新血管和斑块内压力随时间的变化（Specific Aim 3）。总之，本项目旨在通过开发一种新颖、定量和创新的基于超声的方法（即3D SHI/SHAPE），从根本上改变易损斑块早期检测的临床模式，用于无创、实时评估斑块新生血管以及估计斑块内压力，作为将该方法转化为颈动脉斑块患者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.