Electronica Impedance to Access Metabolically Active Plaque

描述（由申请人提供）：电化学阻抗评估代谢活性斑块动脉粥样硬化是一种全身性疾病;然而，其表现往往是局灶性和偏心性的，单个斑块的破裂是心肌梗死和卒中的主要潜在机制。由于氧化脂质和泡沫细胞，易于破裂的斑块含有高水平的炎症活性。流体剪切应力，除了其对血管内皮细胞的机械作用，促进氧化应激和炎症反应的斑块。然而，实时检测动脉粥样硬化病变容易破裂仍然是一个未满足的临床挑战。我们之前的探索性R21资助期的令人鼓舞的结果表明，血管内剪切应力（ISS）和腔内电化学阻抗谱（EIS）的整合区分了脂肪喂养的新西兰白色（NZW）兔中与氧化应激相关的致动脉粥样硬化前病变。具体而言，含有氧化低密度脂蛋白（oxLDL）的血管壁表现出不同的电化学阻抗谱（EIS）幅度，单核细胞和oxLDL一起通过诱导基质金属蛋白酶（MMP）使钙化血管结节不稳定。在这种情况下，我们试图开发一种电化学策略，以确定罪犯（虽然非阻塞性）病变含有oxLDL负载单核细胞-巨噬细胞（泡沫细胞），在诊断血管造影术或经皮冠状动脉介入治疗。我们假设oxLDL富集病变在血管壁中具有不同的电化学性质，可以通过频率依赖性电化学阻抗来测量，以识别代谢活跃的动脉粥样硬化病变。我们的假设将在三个具体目标中得到检验。目的1：确定富含oxLDL病变增加电化学阻抗的机制。将在LDL受体敲除（LDLR-/-）小鼠的斑块中获得EIS。我们推测，这是氧化应激损伤，增加EIS的幅度。目标二：确定EIS对脂肪喂养的NZW兔中oxLDL负载、泡沫细胞丰富的病变的体内灵敏度和特异性，将其作为动脉粥样硬化的已建立模型，其中斑块可用于导管询问。我们还将整合三种血管内传感模式，剪切应力（ISS），超声（IVUS）和电化学阻抗（EIS），用于早期检测代谢不稳定的病变。目的3：确定猪模型中高EIS斑块破裂的体内风险。我们将测试高EIS病变是否易于破裂和栓塞，我们将评估高阻抗和高剪切力的组合是否可预测病变的栓塞倾向。总的来说，我们的跨学科努力旨在整合活性脂质负载病变的电化学特性， 三种动物模型和三种传感模式，以建立早期检测不稳定病变，用于患者特异性干预。

DESCRIPTION (provided by applicant): Electrochemical Impedance to Assess Metabolically Active Plaque Atherosclerosis is a systemic disease; however, its manifestations tend to be focal and eccentric, and rupture of individual plaques is the primary underlying mechanism for myocardial infarction and stroke. Plaques prone to rupture contain high levels of inflammatory activity, due to oxidized lipids and foam cells. Fluid shear stress, in addition to its mechanical effects on vascular endothelial cells, promotes oxidative stress and inflammatory responses in plaque. However, real-time detection of the atherosclerotic lesions prone to rupture remains an unmet clinical challenge. Encouraging results from our previous exploratory R21 funding period demonstrated that integration of intravascular shear stress (ISS) and 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 distinct electrochemical impedance spectroscopy (EIS) magnitude, and that monocytes and oxLDL together destabilize calcific vascular nodules via induction of matrix metalloproteinase (MMP). In this context, we seek to develop an electrochemical strategy to identify culprit (albeit non-obstructive) lesions containing oxLDL-laden monocyte- macrophages (foam cells), during diagnostic angiography or percutaneous coronary intervention. We hypothesize that oxLDL-rich lesions harbor distinct electrochemical properties in the vessel wall that can be measured by frequency-dependent electrochemical impedance to identify metabolically active atherosclerotic lesions. Our hypothesis will be tested in three Specific Aims. Aim 1: Determine the mechanism by which oxLDL-rich lesions increase electrochemical impedance. EIS will be obtained in plaque from LDL receptor-knockout (LDLR-/-) mice. We hypothesize that it is the oxidant stress in the lesions that increases EIS magnitude. Aim 2: Determine in vivo sensitivity and specificity of EIS for oxLDL-laden, foam cell-rich lesions in fat-fed NZW rabbits as an established model of atherosclerosis with plaques accessible to catheter interrogation. We will also integrate three intravascular sensing modalities, shear stress (ISS), ultrasound (IVUS), and electrochemical impedance (EIS), for early detection of metabolically unstable lesions. Aim 3: Determine in vivo risk of rupture in high EIS plaque in a swine model. We will test whether high EIS lesions are prone to rupture and embolization, and we will assess whether the combination of high impedance and high shear predict lesion predisposition to embolization. Overall, our cross-disciplinary efforts aim to integrate electrochemical properties of active lipid-laden lesions with three animal models and three sensing modalities to establish early detection of unstable lesions for patient-specific intervention.