Non-Invasive Localization of Vulnerable Plaques

描述(由申请人提供)：当今美国的主要公共卫生问题之一是在以前没有症状的患者中心肌梗死的高患病率。最主要的原因是易损动脉粥样硬化斑块的急性破裂，但目前还没有检测方法可以在无症状阶段非侵入性地识别易损斑块。解决这一深刻的健康问题所需的巨大飞跃，这项提案的目标是开发一种非侵入性技术，在破裂之前检测脆弱的斑块。红细胞外渗和斑块内出血被认为是斑块从稳定状态向不稳定状态转变的关键因素。因此，红细胞的主要成分铁在动脉壁中积聚，它的存在预示着即将破裂。使用铁作为易损斑块的成像标记物的一个主要挑战是同时存在钙。与铁不同，冠状动脉钙化代表的是整体斑块负担，而不是脆弱性。铁和钙在单个斑块中共存的最大问题是，它们在磁共振成像和X射线计算机断层扫描(CT)上都无法区分，这两种方法是最被接受的冠状动脉非侵入性成像方法。为了解决这个问题，我们最近应用了双能量CT，它减去用显著不同的能量谱获取的图像，以区分在常规CT上看起来相似的材料，如铁和钙。 因此，基于我们成功的初步工作，我们的中心假设是，双能量CT可以通过动脉壁铁的积聚直接在体内检测易受攻击的斑块。我们在量子计划第一阶段的目标是检测铁作为易损斑块的标志，尽管存在钙。具体目标是(1)：开发一种可以检测铁并区分铁和钙的成像技术。我们的工作假设是，使用一种新的双源CT系统在两个不同的X射线管电位下同时采集的CT图像可以组合在一起，明确区分铁和钙。我们将使用铁和钙溶液和亚毫米颗粒的混合物，以及病变血管的移植标本。目的(2)是为了测量动脉标本和活体内易损斑块中的铁离子。A)使用高分辨率、双能显微CT(Micro-CT)，我们将量化易损斑块中铁沉积的患病率、密度和分布。B)最后，我们将在体内使用糖尿病猪模型来验证我们的双能量技术，该模型与患者类似，会出现不稳定的动脉粥样硬化病变。组织学技术将用于对斑块分期进行分类。 在第二阶段，我们将建立新一代CT技术，具有准确检测人类出血性斑块所需的性能特征。这一建议的意义在于，通过在症状前期易损斑块破裂之前对其进行检测和治疗，可以显著降低过早死亡、生产力损失、住院和社会治疗成本。

DESCRIPTION (provided by applicant): One of the major public health issues in the United States today is the high prevalence of myocardial infarction in previously asymptomatic patients. The dominant cause is acute rupture of vulnerable atherosclerotic plaques, but no test is currently available to non-invasively identify vulnerable plaques during the asymptomatic stage. The quantum leap needed to address this profound health issue and the goal of this proposal is to develop a non-invasive technique that detects vulnerable plaques prior to rupture. Extravasation of erythrocytes and intra-plaque hemorrhage are considered critical factors in the transition of a plaque from the stable to unstable state. As a consequence, iron, a main component of red blood cells, accumulates in the artery wall and its presence indicates impending rupture. A major challenge in using iron as an imaging marker of vulnerable plaque is the concurrent presence of calcium. Unlike iron, coronary calcifications represent overall plaque burden rather than vulnerability. The great problem resulting from the co-localization of iron and calcium in individual plaques is that they are indistinguishable on both magnetic resonance imaging and x-ray computed tomography (CT), the two most accepted modalities for non-invasive imaging of coronary arteries. To solve this problem, we have recently applied dual-energy CT, which subtracts images acquired with substantially different energy spectra to discriminate materials that appear similar on conventional CT, such as iron and calcium. Based on our successful preliminary work, our central hypothesis is, therefore, that dual-energy CT can directly detect vulnerable plaques in vivo by virtue of iron accumulation in the artery wall. Our objective during Phase I of this Quantum Program is to detect iron as a marker of vulnerable plaques despite the presence of calcium. The specific aims are (1): To develop an imaging technique that can detect iron and discriminate iron from calcium. Our working hypothesis is that CT images simultaneously acquired using a new dual-source CT system at two different x-ray tube potentials can be combined to unequivocally differentiate iron from calcium. We will use mixtures of iron and calcium solutions and sub-mm particles, as well as explanted specimens of diseased vessels. Aim (2) is designed to measure intramural iron in vulnerable plaques of arterial specimens and in vivo. a) Using high resolution, dual-energy microscopic CT (micro-CT), we will quantify the prevalence, concentration, and distribution of iron deposits in vulnerable plaques. b) Finally, we will validate our dual-energy techniques in vivo using a diabetic pig model that develops unstable atherosclerotic lesions similar to patients. Histological techniques will be used to classify plaque stages. In Phase II, we will build a new generation of CT technology with the performance characteristics necessary to accurately detect hemorrhagic plaque in humans. The significance of this proposal is that by detecting and treating pre-symptomatic vulnerable plaques before they rupture, the premature death, loss of productivity, hospitalization and treatment cost to society can be markedly reduced.