Electrochemical Impedance Spectroscopy to Assess Metabolically Active Plaque

摘要 包括高脂血症、肥胖症和糖尿病前期在内的心脏代谢紊乱构成了不断上升的流行病 在美国.这些沉默的疾病进展为慢性疾病，包括动脉粥样硬化。代谢活性 易于破裂的斑块含有高水平的氧化脂质和M1巨噬细胞。当个体的破裂 斑块是心肌梗死和中风的主要潜在机制，实时检测斑块的变化， 易破裂的易损斑块仍然是一个未解决的临床挑战。在上一个融资周期，我们 证明了电化学阻抗谱的灵敏度和特异性的氧化低 高脂饮食大鼠动脉粥样硬化斑块内皮层下的高密度脂蛋白（oxLDL）巨噬细胞（泡沫细胞） 新西兰白色（NZW）家兔，基于3种血管内感知模式的集成;即剪切 应力传感器（SSS）、超声（IVUS）和电化学阻抗谱（EIS）。这一战略 允许在扰动流区域进行初始检测，然后通过IVUS进行可视化，然后进行电化学 通过EIS表征。巨噬细胞或泡沫细胞中含有oxLDL的血管壁表现出显著的 频率依赖性EIS幅度增加，这些巨噬细胞诱导基质金属蛋白酶 (MMP)使钙化的纤维帽不稳定。我们进一步在尤卡坦小型猪身上部署了3D EIS传感器 进行右颈动脉结扎，以确定12周高血压引起的EIS参数变化， 高脂肪饮食。对于下一个资助周期，我们试图证明高三维EIS病变容易破裂， 栓塞血流储备分数（FFR）的常规测量，定义为压力与血流储备的比值。 在冠状动脉导管插入术期间，狭窄病变的跨瓣血流（P下游/P上游），确定了 在严重的，缺血引起的冠状动脉狭窄的干预。对于FFR ≥ 0.8，患者接受以下治疗 药物治疗;对于FFR ≤ 0.8的患者，转诊进行冠状动脉血运重建。然而，预测者 对于代谢活性的，尽管是非阻塞性的，但易于破裂的病变仍然不确定。在这方面，我们 一个多学科的团队旨在使电化学阻抗谱的基本翻译 (EIS)在临床前的猪模型，并测试假设，3-D EIS映射的腔内oxLDL- 负载巨噬细胞提高了我们检测易于栓塞的人类动脉粥样硬化病变的能力。测试 我们的假设，我们有三个具体目标。在目标1中，我们将确定在体内的三维电化学 性质，以增强载oxLDL的斑块的检测。在目标2中，我们将建立三维EIS映射， 猪的易破裂斑块。在目标3中，我们将比较电化学阻抗谱与近红外光谱对氧化低密度脂蛋白- 满载斑块。总之，在猪模型中建立含脂质病变的3-D电化学标测， 斑块破裂提供了一种临床前策略，以识别代谢活性的，尽管是非阻塞性的，病变， 提高心血管代谢紊乱个性化干预的准确性。

ABSTRACT Cardiometabolic disorders, including hyperlipidemia, obesity, and pre-diabetes, constitute the rising epidemic in the US. These silent disorders progress to chronic diseases, including atherosclerosis. Metabolically active plaques prone to rupture contain high levels of oxidized lipids and M1 macrophages. While rupture of individual plaques is the primary underlying mechanism of myocardial infarction and stroke, real-time detection of the vulnerable plaques prone to rupture remains an unmet clinical challenge. During the previous funding cycle, we demonstrated the sensitivity and specificity of electrochemical impedance spectroscopy for oxidized low density lipoprotein (oxLDL)-laden macrophages (foam cells) in the subendothelial layers of plaques in fat-fed New Zealand White (NZW) rabbits, based on integration of 3 intravascular sensing modalities; namely, shear stress sensor (SSS), ultrasound (IVUS), and electrochemical impedance spectroscopy (EIS). This strategy allowed initial detection in area of disturbed flow, then visualization by IVUS, and then electrochemical characterization by EIS. Vessel walls harboring oxLDL in the macrophages or foam cells exhibit a significant increase in the frequency-dependent EIS magnitude, and these macrophages induce matrix metalloproteinase (MMP) which destabilizes the calcified fibrous cap. We further deployed 3-D EIS sensors in Yucatan mini-pigs undergoing right carotid artery ligation to establish the changes in EIS parameters caused by 12 weeks of high- fat diet. For the next funding cycle, we seek to demonstrate that high 3-D EIS lesions are prone to rupture and embolization. The routine measurement of Fraction Flow Reserve (FFR), defined as the ratio of pressure across the stenotic lesions (Pdownstream/Pupstream) during coronary catheterization, determines the indication for intervention in the significant, ischemia-causing coronary stenoses. For FFR ≥ 0.8, patients are treated with medical therapy; for FFR ≤ 0.8, patients are referred for coronary revascularization. However, the predictors for metabolically active, albeit non-obstructive, lesions prone to rupture remain undefined. In this context, our multi-disciplinary team aims to make the fundamental translation of electrochemical impedance spectroscopy (EIS) in the pre-clinical swine models and to test the hypothesis that 3-D EIS mapping of endoluminal oxLDL- laden macrophages advances our ability to detect human atherosclerotic lesions prone to embolization. To test our hypothesis, we have three Specific Aims. In Aim 1, we will determine in vivo 3-D electrochemical properties to enhance detection of oxLDL-laden plaque. In Aim 2, we will establish 3-D EIS mapping in rupture-prone plaque in swine. In Aim 3, we will compare EIS with near-infrared spectroscopy for oxLDL- laden plaque. Overall, establishing 3-D electrochemical mapping of lipid-laden lesions in a swine model of plaque rupture provides a pre-clinical strategy to identify metabolically active, albeit non-obstructive, lesions, and improve the accuracy of personalized intervention for cardiometabolic disorders.