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降低中度风险和无症状患者的心血管风险。在美国每年50万例急性冠状动脉综合征的冠状动脉死亡中，超过一半是由于覆盖病变坏死核心的薄纤维帽破裂和血栓形成。为什么一些薄帽破裂而另一些不破裂的机制很可能是危及生命的动脉粥样硬化血栓病变中最重要的一个未回答的问题。我们最近提出了一个新的范例薄帽纤维粥样硬化（TCFA）破裂，表明位于帽本身的微小钙化增加组织应力集中和斑块的脆弱性。微钙化可导致空化诱导的脱粘，在该过程中，当由于血压导致的组织中的拉伸应力变得过大时，帽中的组织将从钙化的内含物拉开并撕裂。最近，使用共聚焦显微镜和高分辨率显微计算机断层扫描提供了这种新模式的第一个实验证据。在目标1中，我们将使用高分辨率显微CT成像系统来检查破裂和非破裂的人类薄帽纤维粥样硬化的更广泛的样本，并统计分析细胞水平微钙化的频率、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真实三维几何形状的三维（3D）多级有限元模型（FEM）定量评价微钙化对帽生物力学稳定性的影响。我们将研究在高峰周向应力（PCS）区域内多个微钙化的大小、形状和存在对帽断裂生物力学的应力集中效应。这种基于多级显微CT的方法能够包括在微内含物附近嵌入局部溶液所需的细粒结构，这对于确定导致纤维粥样硬化破裂的PCS放大是至关重要的。这些研究如果成功，可以解决长期存在的谜团，即为什么一些易损斑块病变比其他病变更容易破裂，从而为易损斑块的检测和治疗提供重要的新标准。 公共卫生相关性：覆盖在易损斑块坏死核心上的薄纤维帽破裂是急性冠状动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一个谜。我们提出薄帽纤维粥样硬化的破裂可能是由于组织应力集中引起的帽本身的微小钙化引起的，并为这种新的范例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三维几何形状的三维（3D）多级有限元模型研究微钙化对冠状动脉帽破裂的影响。如果成功，这项研究可能会提供重要的见解，纤维帽动脉粥样硬化破裂负责超过一半的500，000冠状动脉疾病死亡在美国每年。

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.