Integrating 3-D Intravascular Sensors with Fractional Flow Reserve for Lipid-Rich Plaques

将 3-D 血管内传感器与富脂斑块的血流储备分数相结合

基本信息

批准号：
10436777
负责人：
Rene R.S. Packard
金额：
--
依托单位：
VA GREATER LOS ANGELES HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10436777
关键词：
3-Dimensional Afghanistan American Heart Association Angiography Animal Model Apolipoprotein A-I Area Arterial Fatty Streak Atherosclerosis Cardiometabolic Disease Cardiovascular Diseases Carotid Arteries Cessation of life Clinical Coronary Coronary Arteriosclerosis Coronary artery Detection Diagnostic Disease Electrodes Evaluation Exhibits Family suidae Fatty acid glycerol esters Flowcharts Foam Cells Frequencies Guidelines Gulf War Health High Fat Diet Histologic Individual Inflammatory Intervention Lesion Ligation Lipid-Laden Macrophage Lipids Maps Matrix Metalloproteinases Measurement Measures Medical Metabolic Metabolic Diseases Metabolic syndrome Microelectrodes Middle East Myocardial Infarction New Zealand Nodule Oryctolagus cuniculus Outcome Oxidative Stress Patients Penetration Phase Randomized Clinical Trials Reproducibility Resolution Risk Factors Rupture Sensitivity and Specificity Specimen Spectrum Analysis Stents Stroke Subendothelial Layer Systemic disease Testing Therapeutic Embolization Thinness Time Translations Ultrasonic Transducer Vascular calcification Veterans Visualization base calcification cerebrovascular electric impedance flexibility improved macrophage monocyte multidisciplinary oxidized lipid oxidized low density lipoprotein peptidomimetics percutaneous coronary intervention personalized intervention porcine model pre-clinical pressure pressure sensor response sensor ultrasound

项目摘要

Integrating 3-D Micro-Electrode Sensing with Fractional Flow Reserve for Lipid-Rich Plaques Atherosclerosis and metabolic diseases are on the rise in our veterans returning from battlefields in Afghanistan and the Middle East. Atherosclerosis is a systemic disease; however, its manifestations tend to be focal and eccentric, and rupture of individual plaques is the primary underlying mechanism of myocardial infarction and stroke. Plaques prone to rupture contain high levels of oxidative stress and inflammatory activity in part due to oxidized lipids and foam cells. Based on randomized clinical trials, American Heart Association guidelines recommend the routine measurement of Fraction Flow Reserve (FFR), defined as the ratio of pressure across the stenotic lesions (Pdownstream/Pupstream), to determine the indication for coronary revascularization in patients with coronary artery disease (CAD). For FFR > 0.8, patients are treated with medical optimization; for FFR ≤ 0.8, patients are referred for coronary revascularization, e.g., stent deployment and antiplatelet therapy. Nevertheless, the recent five-year outcomes of the FAME (Fractional Flow Reserve versus Angiography for Multivessel Evaluation) 2 trial revealed no difference in death or myocardial infarction between FFR-guided percutaneous coronary intervention (PCI) and optimal medical therapy in patients with stable CAD. Thus, real-time detection of the metabolically unstable plaque prone to rupture remains an unmet clinical challenge. Our previous studies demonstrated that endoluminal electrochemical impedance spectroscopy (EIS) distinguishes pre-atherogenic lesions associated with oxidative stress in fat-fed New Zealand White (NZW) rabbits. Specifically, vessel walls harboring oxidized low density lipoprotein (oxLDL) exhibit high EIS magnitude. In parallel, intimal monocytes and oxLDL are deleterious at all stages of atherosclerosis, destabilizing calcific vascular nodules via induction of matrix metalloproteinases (MMP). In this context, we seek to develop an electrochemical strategy to identify apparently stable, but metabolically active (with FFR > 0.8) lesions containing oxLDL-laden monocyte-macrophages (foam cells), during diagnostic angiography. We hypothesize that integrating 3-D electrochemical impedance spectroscopy with FFR pressure sensors allows for detection of oxLDL-rich lesions to improve the accuracy of necessary intervention. To test our hypothesis, we have three Specific Aims. In Aim 1, we will integrate a 12-point 3-D electrode array permitting high spatial and angular resolution with pressure sensors to enhance detection of oxLDL-laden plaque. In Aim 2, we will determine the sensitivity and specificity of 3-D EIS mapping for oxLDL- laden, foam cell-rich atherosclerotic lesions in fat-fed vs. D-4F (an apolipoprotein A-I mimetic peptide) + fat-fed NZW rabbits. In Aim 3, we will establish 3-D EIS mapping in rupture-prone plaque in the carotid arteries of a pig model. Overall, establishing 3-D electrochemical mapping of active lipid-laden lesions with animal models of atherosclerosis provides a new strategy to identify metabolically active lesions for personalized intervention, and improve the accuracy of necessary intervention for our veterans.

将3-D微电极传感与富含脂质斑块的分数流储备相结合我们的退伍军人从战场上回来阿富汗和中东。动脉粥样硬化是一种全身性疾病。但是，它的表现往往是焦点和偏心，单个斑块的破裂是心肌的主要基础机制梗塞和中风。容易破裂的斑块含有高水平的氧化应激和炎症活性部分是由于氧化的脂质和泡沫细胞。根据随机临床试验，美国心脏协会指南建议将分数储备（FFR）的常规测量定义为跨狭窄病变的压力（pdownstream/pupstream），以确定冠状动脉的指示冠状动脉疾病（CAD）患者的血运重建。对于FFR> 0.8，患者接受治疗医疗优化；对于FFR≤0.8，请参考患者进行冠状动脉血运重建，例如支架部署和抗血小板疗法。然而，名望的最新成果（分数流储备）多发射评估的血管造影）2试验显示死亡或心肌梗塞没有差异在FFR引导的经皮冠状动脉介入（PCI）和最佳药物治疗之间稳定的CAD。那就是，实时检测代谢不稳定的易于破裂的斑块仍然是未满足的临床挑战。我们先前的研究表明，内肢的电化学阻抗光谱法（EIS）区分了与脂肪喂养的新的氧化应激有关西兰白（NZW）兔子。具体而言，具有氧化的低密度脂蛋白（OXLDL）的容器墙表现出较高的EIS幅度。同时，在所有阶段都删除了内膜单核细胞和OXLDL 动脉粥样硬化，通过诱导基质金属蛋白酶（MMP）诱导钙化血管结节稳定。在这个背景，我们试图制定一种电化学策略，以确定明显稳定但代谢活跃的稳定（带有FFR> 0.8）在诊断期间，含有含有OXLDL的单核细胞（泡沫细胞）的病变血管造影。我们假设将3D电化学阻抗光谱与FFR相结合压力传感器可以检测到富含OXLDL的病变以提高必要的精度干涉。为了检验我们的假设，我们有三个具体目标。在AIM 1中，我们将集成12分3-D 电极阵列允许使用压力传感器高空间和角度分辨率，以增强检测含有OXLDL的牌匾。在AIM 2中，我们将确定3-D EIS映射对OXLDL-的灵敏度和特异性在脂肪喂养中载有泡沫的富含泡沫细胞的动脉粥样硬化病变与D-4F（载脂蛋白A-I模拟肽） +脂肪喂养 NZW兔子。在AIM 3中，我们将在A的颈动脉中建立3-D EIS映射猪模型。总体而言，使用动物模型建立活性脂质病变的3-D电化学映射动脉粥样硬化提供了一种新的策略，可以识别代谢活性病变以进行个性化干预，并提高退伍军人必要干预的准确性。