Predicting Cardiovascular Risk in Vulnerable Plaque Rupture

预测易损斑块破裂的心血管风险

• 批准号: 7835191
• 负责人: Sheldon Weinbaum
• 金额: $ 40.81万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7835191
• 关键词: Acute; Address; Algorithms; American; Area; Arterial Fatty Streak; Award; Biomechanics; Blood Pressure; Breast Microcalcification; Cadaver; Calcified; Cardiology; Cardiovascular system; Cereals; Cessation of life; Computer software; Confocal Microscopy; Coronary; Coronary Arteriosclerosis; Coronary artery; Detection; Elements; Event; Exertion; Frequencies; Funding; Grant; Heart; Human; Image; Imaging Techniques; Individual; Lead; Lesion; Life; Location; Magnetic Resonance Imaging; Medical; Modeling; Necrosis; Patients; Prize; Process; Property; Research Personnel; Resolution; Risk; Risk Factors; Role; Rupture; Sampling; Sampling Studies; Shapes; Site; Solid; Solutions; Spatial Distribution; Staining method; Stains; Stress; Structure; System; Thick; Thrombosis; Thrombus; Tissues; Vacuum; Variant; Water; X-Ray Computed Tomography; acute coronary syndrome; base; calcification; cardiovascular risk factor; college; comparative effectiveness; effectiveness research; imaging modality; in vivo; innovation; insight; instrumentation; interfacial; macrophage; meetings; novel; plaque lesion; posters; public health relevance; symposium

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.

描述（由申请人提供）：此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减少中等风险和无症状患者的心血管风险。每年在美国因急性冠状动脉综合征的500,000个冠状动脉死亡中的一半以上是由于薄薄的纤维帽破裂，覆盖了病变的坏死核心和血栓形成。关于某些薄帽破裂和其他帽子的原因，这种机制很可能是威胁性动脉粥样硬化病变的生命中最重要的未解决的问题。我们最近提出了一种新的薄帽纤维瘤（TCFA）破裂的范式，这表明位于CAP本身的微小钙化增加了组织应力浓度和斑块脆弱性。微钙化可能导致空化引起的脱键蛋白，在这种过程中，当由于血压而导致的组织中的拉伸应力变得太大时，盖中的组织将脱离钙化的包含和撕裂。最近使用共聚焦显微镜和高分辨率微计算机断层扫描提供了该新范式的第一个实验证据。在AIM 1中，我们将使用高分辨率的Micro-CT成像系统来检查较广泛的破裂和未破裂的人类薄帽纤维瘤样本，并统计分析细胞级微钙化的频率，大小，形状和空间分布。在AIM 2中，我们使用三维（3D）多级有限元模型（FEM）对盖子的生物力学稳定性的影响进行定量评估，该影响是基于高分辨率的Micro-CT的现实3D几何形状的现实3D几何形状成像。我们将研究由高峰圆向应力（PC）在帽破裂的生物力学上的大小，形状和存在近距离的大小，形状和存在所产生的应力浓度效应。这种基于微观CT的多级方法具有包括在微斑点附近嵌入局部溶液所需的细粒结构，这对于确定PC的扩增至关重要，从而导致纤维运动员破裂。这些研究，如果成功的话，可以解决一些长期存在的谜团，说明为什么某些脆弱的斑块病变比其他易碎的斑块病变更容易破裂，从而为检测和治疗脆弱的斑块提供了至关重要的新标准。 公共卫生相关性：易受伤害斑块的坏死核心的细纤维帽破裂是急性冠状动脉综合征的主要原因。不幸的是，脆弱的斑块破裂机制仍然是一个谜。我们提出，由于组织应力浓度，帽纤维瘤薄纤维瘤的破裂可能是由帽本身的微小钙化引起的，并为这种新范式提供了第一个实验证据。我们将使用基于高分辨率的微分离CCT成像的三维（3D）多级有限元模型来研究微钙化对帽破裂的影响。如果成功，这项研究可能会提供有关纤维帽动脉瘤破裂的重要见解，导致每年美国500,000多名冠状动脉疾病死亡中有一半以上。