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.

Public Health Relevance

More than 18 million North Americans have atherosclerotic disease, and both morbidity and mortality remain appreciable in the Western world. Despite the advent of intravascular modalities, identifying mechanically and metabolically unstable lesions remains an unmet clinical need. We hereby seek to provide new insights into the early detection of unstable plaque for patient-specific intervention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL118650-01A1
Application #
8696711
Study Section
Special Emphasis Panel (ZRG1-SBIB-V (02))
Program Officer
Lee, Albert
Project Start
2014-07-10
Project End
2018-05-31
Budget Start
2014-07-10
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$408,978
Indirect Cost
$108,387
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095