Electrochemical Impedance Spectroscopy to Assess Metabolically Active Plaque

摘要 心脏代谢紊乱，包括高脂血症、肥胖症和糖尿病前期，构成了不断上升的流行病 在美国。这些沉默的疾病会发展成慢性疾病，包括动脉粥样硬化。代谢活跃 容易破裂的斑块含有高水平的氧化脂质和M1巨噬细胞。而个人的破裂 斑块是心肌梗死和卒中的主要潜在机制，实时检测 容易破裂的脆弱斑块仍然是一个尚未满足的临床挑战。在上一个资金周期中，我们 论证了电化学阻抗谱对氧化态LOW的敏感性和特异性 高脂饮食大鼠斑块内皮下巨噬细胞(泡沫细胞)密度脂蛋白的变化 新西兰白兔(NZW)，基于3种血管内传感模式的整合；即剪切法 应力传感器(SSS)、超声(IVUS)和电化学阻抗谱(EIS)。这一战略 允许在扰动流区进行初始检测，然后通过IVUS进行可视化，然后进行电化学 由EIS进行表征。巨噬细胞或泡沫细胞中含有oxLDL的血管壁显示出显著的 频率依赖的EIS幅度增加，这些巨噬细胞诱导基质金属蛋白酶 (基质金属蛋白酶)，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 通过结扎右颈动脉建立12周高负荷运动后EIS参数的变化。 肥胖饮食。对于下一个资金周期，我们试图证明高3D EIS病变容易破裂和 栓塞术。分数流量储备(FFR)的常规测量，定义为压力比 在冠状动脉插管过程中跨越狭窄病变(P下游/P上游)，决定了 对严重的、由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 内科治疗；对于FFR≤0.8，患者被推荐进行冠状动脉血运重建。然而，预测因素 对于代谢活跃的，尽管是非梗阻性的，容易破裂的病变仍未确定。在这方面，我们的 多学科团队致力于对电化学阻抗谱进行基础翻译 (EIS)在临床前的猪模型中，并检验三维EIS定位的腔内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。为了测试 我们的假设，我们有三个具体目标。在目标1中，我们将在体内测定三维电化学 增强检测携带oxLDL的斑块的性能。在目标2中，我们将在 猪易破裂斑块。在目标3中，我们将比较EIS和近红外光谱分析oxLDL- 拉登牌匾。总之，在猪的脂质损伤模型中建立三维电化学标测。 斑块破裂提供了一种临床前的策略来识别代谢活跃的，尽管是非阻塞性的损害， 提高心脏代谢性疾病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.