Predicting Cardiovascular Risk in Vulnerable Plaque Rupture

描述(由申请人提供)：本申请涉及广泛的挑战领域(05)：比较有效性研究；挑战主题05-HL-104降低中等风险和无症状患者的心血管风险。在美国，每年有500,000人死于急性冠状动脉综合征，其中一半以上是由于覆盖在病变坏死核心上的薄纤维帽破裂和血栓形成。一些薄帽破裂而另一些不破裂的机制很可能是威胁生命的动脉粥样硬化血栓病变中最重要的未解问题。我们最近提出了一种新的薄帽纤维动脉粥样硬化瘤(TCFA)破裂模式，认为位于薄帽内的微小钙化增加了组织应力集中和斑块易损性。微钙化可导致空化诱导脱粘，这是一个过程，在这个过程中，由于血压导致组织中的拉应力变得太大，帽子中的组织将从钙化的包裹物中拉出并撕裂。这一新模式的第一个实验证据是最近使用共聚焦显微镜和高分辨率显微计算机断层成像提供的。在目标1中，我们将使用高分辨率的Micro-CT成像系统来检查更广泛的破裂和未破裂的人类薄帽纤维动脉粥样硬化瘤样本，并统计分析细胞水平的微钙化的频率、大小、形状和空间分布。在目标2中，我们使用基于高分辨率Micro-CT成像的人体冠状动脉病变的真实三维几何形状的三维(3D)多层有限元模型来定量评估微钙化对盖子生物力学稳定性的影响。我们将研究在高峰值周向应力(PCS)区域附近的多个微钙化的大小、形状和存在所产生的应力集中对帽裂的生物力学的影响。这种基于多层次微CT的方法能够包含将局部溶液嵌入到微包裹体附近所需的细小颗粒结构，这对于确定导致纤维动脉粥样硬化破裂的PCS扩增至关重要。如果这些研究成功，可能会解开长期存在的谜团，即为什么一些脆弱的斑块病变比其他斑块更容易破裂，因此，为检测和治疗脆弱斑块提供了至关重要的新标准。 公共卫生相关性：易损斑块坏死核心上覆盖的薄纤维帽破裂是急性冠脉综合征的主要原因。不幸的是，易损斑块破裂的机制仍然是个谜。我们提出薄帽纤维动脉粥样硬化瘤的破裂可能是由于组织应力集中导致帽盖本身的微小钙化所致，并为这一新的范式提供了第一个实验证据。我们将使用基于高分辨率Micro-CT成像的人体冠状动脉病变的真实3D几何的三维(3D)多层有限元模型来研究微钙化对帽状破裂的影响。如果成功，这项研究可能会为纤维帽状动脉粥样硬化的破裂提供重要的见解，纤维帽动脉粥样硬化是导致美国每年50万冠状动脉疾病死亡的一半以上的原因。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (05): Comparative Effectiveness Research; Challenge Topic 05-HL-104 Reducing cardiovascular risk in moderate-risk and asymptomatic patients. More than half of the 500,000 coronary artery deaths each year in the U.S. from acute coronary syndrome are due to the rupture of the thin fibrous cap overlying the necrotic core of the lesion and the formation of a thrombus. The mechanism as to why some thin caps rupture and others do not is very likely the single most important unanswered question in life threatening atherothrombotic lesions. We recently proposed a new paradigm of thin cap fibroatheroma (TCFA) rupture, suggesting that minute calcifications located in the cap itself increase tissue stress concentration and plaque vulnerability. Microcalcifications can lead to cavitation induced debonding, a process in which the tissue in the cap will pull away from the calcified inclusion and tear when tensile stress in the tissue due to blood pressure becomes too large. The first experimental evidence for this new paradigm was recently provided using confocal microscopy and high resolution micro computed tomography. In Aim 1 we will use a high resolution micro-CT imaging system to examine a much broader sample of ruptured and non-ruptured human thin cap fibroatheroma and statistically analyze the frequency, size, shape and spatial distribution of the cellular-level microcalcifications. In Aim 2 we quantitatively evaluate the impact of the microcalcifications on the biomechanical stability of the cap using a three-dimensional (3D) multi-level finite element model (FEM) of realistic 3D geometries of human coronary lesions based on high resolution micro-CT imaging. We will investigate the stress concentration effect produced by the size, shape and presence of multiple microcalcifications in close proximity within a region of high peak circumferential stress (PCS), on the biomechanics of cap rupture. This multi-level micro-CT based approach has the ability to include the fine grain structure required to imbed local solutions in the vicinity of the microinclusions, which is critical to determine the PCS amplification leading to fibroatheroma rupture. These studies, if successful, could resolve the long-standing mystery as to why some vulnerable plaque lesions are more prone to rupture than others and, as a result, provide vital new criteria for the detection and treatment of vulnerable plaque. PUBLIC HEALTH RELEVANCE: The rupture of the thin fibrous cap overlying the necrotic core of a vulnerable plaque is the principal cause of acute coronary syndrome. Unfortunately, the mechanism of vulnerable plaque rupture has remained a mystery. We proposed that the rupture of thin cap fibroatheroma may be caused by minute calcifications in the cap itself due to tissue stress concentration and provided the first experimental evidence for this new paradigm. We will investigate the impact of microcalcifications on cap rupture using a three-dimensional (3D) multi-level finite element model of realistic 3D geometries of human coronary lesions based on high resolution micro-CT imaging. If successful, this study may provide important insights on the rupture of fibrous cap atheromas responsible for more than half of the 500,000 coronary artery disease deaths in US every year.