Microcalcifications in Atherosclerotic Plaque

摘要 人纤维动脉粥样硬化瘤(FA)帽破裂导致闭塞血栓形成，即心肌梗死 每年有50多万美国人死于心肌梗塞和猝死。易损斑块被定义为 阳性重塑病变，富含血管，以平滑肌细胞凋亡为特征； 含有一个富含脂类的池，其纤维帽被巨噬细胞渗透。当前的模式是一个 盖子厚度65微米(Thin-Cap FA或TCFA)是斑块易损性的关键决定因素，并会发生破裂 当帽状组织承受大于300kpa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动脉粥样硬化的形态、生物环境、组织 组成和机械力。事实上，盖子厚度是否是最重要的单一标准 斑块易损性的预测尚不清楚，动脉粥样硬化帽破裂的潜在机制仍不清楚。 没有被充分理解。 血管钙化是影响斑块破裂稳定性的重要因素之一。 几十年来，心血管钙化一直被认为是一个被动的过程，伴随着 动脉粥样硬化进展与斑块负荷相关，显然对斑块没有主要作用 脆弱性。以前的临床和病理分析都集中在钙化的总量上。 (整个动脉粥样硬化横截面中的钙化区域)，以及钙化越多是否意味着斑块风险越高 不管是不是破裂。然而，在过去十年左右的时间里，这种模式一直在发生变化。最近的研究集中在 关于动脉粥样硬化中是否存在微钙化(微钙化)，更重要的是关于 微钙化位于动脉粥样硬化的盖子内。虽然绝大多数微卡存在于脂质池中或 坏死的核心，它们对脆弱的斑块无关紧要。到目前为止，我们还证明了 数以千计的μCalc主要在未破裂的人类动脉粥样硬化帽中使用µCT成像，并且它们的行为 作为盖子中的背景周向应力的增强器。然而，类似的X射线吸收 血栓和软组织的性质使破裂的FA的μCalcs分析复杂化。要克服这一点 限制，我们开发了一种高分辨率对比度增强µCT(CE？CT)方法来研究 在形成闭塞性血栓的情况下，μCalcs是否与FA帽破裂部位共同定位， 其次是心肌梗塞。工作假设是，足总帽中的μCalcs对 FA帽破裂阈值。为了检验这一假设，我们建议(1)确定以下各项的敏感性和特异性 FA帽中的μCalcs是人类冠状动脉中纤维动脉粥样硬化破裂风险的关键生物标志物，以及(2) 研究载脂蛋白E KO小鼠因μ钙化导致的FA破裂风险增加的特征。如果成功，建议的 研究将增加我们对易损斑块破裂的生物力学的了解，并提供一种替代方案 易损斑块的范例，将考虑μCalcs在人类动脉粥样硬化帽破裂风险中的作用。

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.