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.