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既往无症状患者中心肌梗死的高患病率。其主要原因是易损斑块的急性破裂，但目前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转变为不稳定状态的关键因素。因此，红细胞的主要成分铁在动脉壁中积聚，它的存在表明即将破裂。使用铁作为易损斑块的成像标记物的主要挑战是钙的同时存在。与铁不同，冠状动脉钙化代表整体斑块负担，而不是脆弱性。由铁和钙在单个斑块中的共定位引起的大问题是它们在磁共振成像和X射线计算机断层扫描（CT）上都是不可区分的，这两种是用于冠状动脉的非侵入性成像的两种最被接受的方式。为了解决这个问题，我们最近应用了双能量CT，它减去了用实质上不同的能量谱获得的图像，以区分在传统CT上看起来相似的材料，如铁和钙。 基于我们成功的初步工作，我们的中心假设是，因此，双能量CT可以直接检测体内脆弱的斑块凭借铁积累在动脉壁。我们在量子计划的第一阶段的目标是检测铁作为易损斑块的标志物，尽管存在钙。具体目标是：（1）发展一种能检测铁并区分铁和钙的成像技术。我们的工作假设是，CT图像同时收购使用一种新的双源CT系统在两个不同的X射线管电位可以结合起来，明确区分铁钙。我们将使用铁和钙溶液的混合物和亚毫米颗粒，以及患病血管的冷冻标本。目的（2）测定动脉易损斑块和活体动脉壁内铁含量。a）使用高分辨率双能量显微CT（micro-CT），我们将量化易损斑块中铁沉积的患病率，浓度和分布。B）最后，我们将使用糖尿病猪模型在体内验证我们的双能量技术，该模型产生与患者相似的不稳定动脉粥样硬化病变。将使用组织学技术对斑块阶段进行分类。 在第二阶段，我们将建立新一代的CT技术，其性能特征是准确检测人体出血斑块所必需的。该建议的意义在于，通过在易损斑块破裂之前检测和治疗症状前易损斑块，可以显著减少过早死亡、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.