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 人纤维瘤（FA）帽破裂导致形成闭塞血栓，心肌梗死 （MI）每年有超过一百万美国人的突然死亡。脆弱的牌匾被定义为 积极去除病变，富含Vasa-vasorum，其特征是平滑肌细胞凋亡和 包含一个富含脂质的池，上面有纤维帽，该纤维被巨噬细胞浸润。当前的范式是 盖厚度<65 µm（薄盖FA或TCFA）是牙菌斑脆弱性的关键决定器，发生破裂 当帽组织的峰值应力大于300 kPa时。但是，还有其他几个因素 该在FA CAP破裂中起着重要作用，包括动脉瘤形态，生物学环境，组织 组成和机械力。确实，盖厚度是否是最重要的标准 预测斑块脆弱性尚不清楚，并且动脉瘤帽破裂的潜在机制仍然 不足以理解。 血管计算在斑块破裂的稳定性中起着重要作用的因素中出现了。 数十年来，心血管计算被认为是一个被动过程，参与 动脉瘤进展，与斑块伯嫩相关，显然在斑块上没有主要作用 脆弱性。临床和病理分析以前已集中在钙化总量上 （整个动脉瘤横截面中的钙化面积）以及更多的钙化是否意味着更高的斑块风险 是否破裂。但是，在过去十年左右的时间里，这种范式一直在发生变化。最近的研究重点 关于动脉瘤中的微钙化（µCALCS）的存在，更重要的是 µCALC位于动脉瘤的瓶盖中。而绝大多数µCALC在脂质池中发现或 坏死的核心，它们与脆弱的牌匾无关紧要。我们还展示了到期 使用µCT成像中未破裂的人类动脉瘤帽中数千CALC的主要量 作为盖中背景圆周应力的强度。但是，类似的X射线滥用 血栓和软组织的特性使对FAS破裂的μCALC的分析变得复杂。克服这一点 限制，我们已经开发了一种高分辨率对比增强µCT（CEµCT）来研究 μCALC是否与FA帽破裂部位共定位，如果形成遮挡血栓， 其次是心肌梗塞。工作假设是FA帽中的μCALC对 FA帽破裂阈值。为了检验这一假设，我们建议（1）确定 FA帽中的μCALC是人冠状动脉血管破裂风险的关键生物标志物，（2）至 表征由于APOE KO小鼠中μCALC引起的FA破裂风险的增加。如果成功，提议 研究将提高我们对脆弱的斑块破裂生物力学的理解，并提供替代方案 易损害斑块的范例将考虑μCALC在人动脉粥样硬化帽破裂风险中的影响。