3D Subharmonic Pressure Maps of Vulnerable Plaques

描述(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记物。斑块内新生血管(从血管萌发)、斑块内出血(IPH)、坏死核的大小和斑块易损性之间存在关联。因此，临床上非常需要一种非侵入性的成像工具，以便能够及早发现和评估被认为有可能发生未来心血管事件的个体的易损斑块。使用微泡的超声造影(US)就是这样一种潜在的工具，它已经被用来成像斑块内的新生血管。我们建议扩展这一概念，利用造影剂微泡作为非线性显像剂和传感器，无创评估动脉粥样硬化斑块的压力。我们的团队已经证明，微泡超声造影剂(UCAS)产生的非线性亚谐信号可以用于一种新的亚谐成像(SHI)模式。此外，这些信号还提供了很好的静液压指示(误差&lt；4 mm Hg)。在此基础上，提出了一种创新的定量方法--亚谐辅助压力估计(SHAPE)，并对其进行了初步研究。本项目旨在开发3D SHI和SHAPE，用于非侵入性、实时在体评估斑块新生血管和斑块内压力(包括斑块顶端的压力梯度)，作为早期检测易损斑块的新生物标志物。我们还将调查不同大小的UCA的斑块SHI和SHAPE。首先，将在体外测试静水压力对微米和纳米气泡的亚谐性能的影响，以选择最适合形状的UCA(特定目标1)。接下来，3D SHI/SHAPE算法的改进版本将在最先进的US扫描仪(Logiq 9，GE Healthcare，密尔沃基，威斯康星州密尔沃基)上实施，可用于实时、斑块新生血管成像和动态压力测量(特定目标2)。这些新的实施将在渡边遗传性高脂血症(WHHL)兔体内进行测试。最后，我们将使用有创压力监测技术和组织学作为参考标准来评估WHHL兔动脉粥样硬化病变的在体3D SHI/SHAPE是否能够跟踪新生血管和斑块内压力随时间的差异(特定目标3)。总之，该项目旨在通过开发一种新的、定量的、创新的基于超声的方法(即3D SHI/SHAPE)来非侵入性地、实时地评估斑块新生血管以及估计斑块内压力，从而从根本上改变易损斑块早期检测的临床范式，作为将该方法转化为对出现颈动脉斑块的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.