Microcalcifications in Atherosclerotic Plaque

动脉粥样硬化斑块中的微钙化

• 批准号: 10411607
• 负责人: Luis Cardoso
• 金额: $ 15.7万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-05 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10411607
• 关键词: 3-Dimensional; Agreement; American; Apolipoprotein E; Apoptosis; Area; Arterial Fatty Streak; Arteries; Biological; Biological Markers; Biomechanics; Breast Microcalcification; Cardiovascular system; Cessation of life; Clinical; Collagen; Coronary; Coronary Vessels; Descending aorta; Elements; Environment; Frequencies; Geometry; Histologic; Human; Hypertension; Image; Inflammation; Intrinsic factor; Intuition; Knockout Mice; Lead; Lesion; Lipids; Logistic Regressions; Maps; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mechanical Stress; Mechanics; Modeling; Morphology; Mus; Myocardial Infarction; Necrosis; Pathologic; Play; Process; Property; Regression Analysis; Research; Resolution; Risk; Risk Factors; Roentgen Rays; Role; Rupture; Sampling; Scanning; Sensitivity and Specificity; Shapes; Site; Smooth Muscle Myocytes; Spatial Distribution; Stenosis; Stress; Sudden Death; Testing; Thick; Thinness; Thrombus; Tissues; Vascular calcification; absorption; acute coronary syndrome; aortic arch; base; calcification; contrast enhanced; coronary artery calcification; density; digital; experience; high risk; histological image; human tissue; in vivo; macrophage; mechanical force; prevent; soft tissue; specific biomarkers; tissue stress; vasa vasorum

SUMMARY Human fibroatheroma (FA) cap rupture leads to the formation of an occluding thrombus, myocardial infarction (MI) and sudden death in more than half a million Americans every year. A vulnerable plaque is defined as a positively remodeled lesion, rich in vasa-vasorum, characterized by smooth muscle cell apoptosis, and containing a lipid rich pool with a fibrous cap that is infiltrated by macrophages. The current paradigm is that a cap thickness < 65 µm (thin-cap FA or TCFA) is the key determinant of plaque vulnerability, and rupture occurs when the cap tissue experiences a peak stress greater than 300 kPa. However, there are several other factors that play an important role in the FA cap rupture, including atheroma morphology, biological environment, tissue composition and mechanical forces. Indeed, whether the cap thickness is the single most important criterion predicting plaque vulnerability is unclear, and the underlying mechanisms for atheroma cap rupture are still insufficiently understood. Vascular calcification has emerged among the factors that play an important role in the stability of plaque rupture. For many decades, cardiovascular calcification has been considered as a passive process, accompanying atheroma progression, correlated with plaque burden, and apparently without a major role on plaque vulnerability. Clinical and pathological analyses have previously focused on the total amount of calcification (calcified area in a whole atheroma cross section), and whether more calcification means higher risk of plaque rupture or not. However, this paradigm has been changing in the last decade or so. Recent research has focused on the presence of microcalcifications (µCalcs) in the atheroma, and more importantly on whether clusters of µCalcs are located in the cap of the atheroma. While the vast majority of µCalcs are found in the lipid pool or necrotic core, they are inconsequential to vulnerable plaque. We have also demonstrated to date the existence of thousands of μCalcs primarily in non-ruptured human atheroma caps using µCT imaging, and that they behave as an intensifier of the background circumferential stress in the cap. However, the similar X-ray absorption properties of a thrombus and soft tissue complicates the analysis of μCalcs in ruptured FAs. To overcome this limitation, we have developed a high-resolution contrast-enhanced µCT (CEµCT) approach to investigate whether μCalcs co-localize with the site of FA cap rupture, in cases where an occluding thrombus is formed, followed by myocardial infarction. The working hypothesis is that μCalcs in the FA cap has a major effect on the FA cap rupture threshold. To test this hypothesis we propose to (1) determine the sensitivity and specificity of μCalcs in the FA cap as a key biomarker of fibroatheroma rupture risk in human coronary vessels, and (2) to characterize the increase in FA rupture risk due to μCalcs in the ApoE KO mice. If successful, the proposed study will increase our understanding on vulnerable plaque rupture biomechanics and provide an alternative paradigm for vulnerable plaque that will consider the effect of μCalcs in human atheroma cap rupture risk.

概括 人纤维粥样斑块 (FA) 帽破裂导致闭塞血栓、心肌梗死的形成 (MI) 和每年超过 50 万美国人猝死。易损斑块定义为 病变正向重塑，富含滋养血管，以平滑肌细胞凋亡为特征， 含有富含脂质的池和被巨噬细胞渗透的纤维帽。当前的范式是 帽厚度 < 65 µm（薄帽 FA 或 TCFA）是斑块脆弱性和发生破裂的关键决定因素 当帽组织承受大于 300 kPa 的峰值应力时。然而，还有其他几个因素 在 FA 帽破裂中起重要作用的因素包括粥样斑块形态、生物环境、组织 成分和机械力。事实上，盖子厚度是否是最重要的标准 预测斑块易损性尚不清楚，动脉粥样硬化帽破裂的潜在机制仍不清楚 理解不够。 血管钙化已成为对斑块破裂稳定性起重要作用的因素之一。 几十年来，心血管钙化一直被认为是一个被动过程，伴随着 动脉粥样硬化进展，与斑块负荷相关，并且显然对斑块没有主要作用 脆弱性。临床和病理分析以前集中于钙化总量 （整个粥样斑块横截面中的钙化区域），以及更多的钙化是否意味着更高的斑块风险 是否破裂。然而，这种范式在过去十年左右的时间里一直在发生变化。最近的研究重点 动脉粥样硬化斑块中微钙化 (μCalcs) 的存在，更重要的是，是否存在微钙化簇 µCalcs 位于粥样斑块的顶部。虽然绝大多数 µCalc 存在于脂质库或 坏死核心，它们对易损斑块无关紧要。我们还证明了迄今为止的存在 使用 µCT 成像，主要在未破裂的人类动脉粥样硬化帽中收集了数千个 µCalc，并且它们的行为 作为盖中背景周向应力的增强器。然而，类似的 X 射线吸收 血栓和软组织的特性使破裂 FA 中 μCalcs 的分析变得复杂。为了克服这个 为了克服这些限制，我们开发了一种高分辨率对比增强 µCT (CEµCT) 方法来研究 在形成闭塞血栓的情况下，μCalcs 是否与 FA 帽破裂部位共定位， 其次是心肌梗塞。工作假设是 FA 上限中的 μCalcs 对 FA 帽破裂阈值。为了检验这一假设，我们建议 (1) 确定以下因素的敏感性和特异性： FA 帽中的 μCalcs 作为人类冠状血管中纤维粥样斑块破裂风险的关键生物标志物，以及 (2) 描述 ApoE KO 小鼠中 μCalcs 导致 FA 破裂风险增加的特征。如果成功的话，建议 研究将增加我们对易损斑块破裂生物力学的理解并提供替代方案 易损斑块的范例，将考虑 μCalcs 对人类动脉粥样硬化帽破裂风险的影响。