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Principal Investigator: KANG KIM
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $758,510
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
Acute coronary syndromes and strokes together constitute a leading cause of morbidity and mortality in the
United States and Europe, approximately 80% of which are caused by atherosclerotic plaque (AP) rupture.
Over the past decade, extensive efforts have been made to identify a rupture-prone AP. Among others,
infiltration of dense neovascularization arising from vasa vasorum (VV) into the AP core plays a critical role in
AP rupture. Postmortem studies revealed key involvement of VV in AP. However, a persistent lack of a
noninvasive, high-resolution imaging tool to longitudinally assess abnormal microvascular expansion remains a
critical barrier to adequate in-vivo investigation on how VV affects AP progression and contributes to eventual
rupture. To address this dire unmet need, we propose an innovative transcutaneous super resolution
ultrasound (SRU) imaging. The technology development in this project seeks to shift the current US imaging
approach in identifying microvessels of AP from “intravascular” to a “fully noninvasive transcutaneous” imaging
approach. This is only possible by achieving unprecedented high spatial resolution at large depth, breaking
acoustic diffraction limit of the ultrasound frequency that governs spatial resolution. Our group has performed
in-depth feasibility studies where SRU imaging successfully identified neomicrovessels in cholesterol-fed rabbit
AP, evaluated against µCT and histology. Additionally, areas requiring further technical optimization were
identified. Such technology developments and preliminary data thus far rigorously support our overarching
hypothesis that enhanced and optimized SRU will accurately stage plaque progression and identify rupture-
prone plaques by directly measuring VV changes with exquisite detail. To test the hypothesis, we will use a
well-established, clinically relevant cholesterol-fed rabbit AP rupture model, which has shown the most
similarity to human plaque pathology including VV neovascularization, to validate the novel SRU system to 1)
Successfully quantify changes in vessel density and 2) Identify rupture-prone AP. To achieve these goals, we
propose the following specific aims: 1) To develop enhanced SRU at high frequency using a commercial small
animal imaging probe 2) To determine if VV changes estimated by SRU correlate with AP progression and are
predictive of AP rupture. The immediate outcomes of the proposed work are an affordable noninvasive small
animal SRU imaging tool and it’s validation on a clinically relevant rabbit AP model, which also can be used for
other important small animal disease models, which are associated with microvessel abnormality such as
cancer angiogenesis and kidney diseases to name a few. With proper adaptations into a clinical mid frequency
probe and validation in clinical settings in future, this work will lead to our long-term translational goal to
integrate SRU in a facile manner into the current clinical standard of carotid duplex sonography that has shown
poor specificity to plaque vulnerability. This will help to effectively stratify patients at high risk of strokes and
guide adequate intervention/treatment options for stroke prevention, exerting highly influential clinical impact.
Terms: <3-D><3-Dimensional><3D><Acoustics><Address><Affect><Algorithms><Amyloid (Aβ) plaques><Amyloid Plaques><Animal Disease Models><Animals><Apoplexy><Area><Arterial Fatty Streak><Arterial Fatty Streaks><Atheroma><Atheromatous><Atheromatous degeneration><Atheromatous plaque><Autopsy><Blood Vessels><Bolus><Bolus Infusion><Brain Vascular Accident><Cancers><Cardiac infarction><Carotid Atheroscleroses><Carotid Atherosclerotic Disease><Cell Communication and Signaling><Cell Signaling><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Characteristics><Cholesterol><Clinic><Clinical><Confocal Microscopy><Contrast Agent><Contrast Drugs><Contrast Media><Data><Devices><Disease><Disorder><Domestic Rabbit><Echography><Echotomography><Europe><Feasibility Studies><Foundations><Frequencies><Future><Generalized Growth><Goals><Growth><Histology><Human><Image><Imaging Device><Imaging Instrument><Imaging Tool><Imaging technology><In Vitro><Infiltration><Influentials><Injections><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Intravenous><Investigation><Kidney Diseases><Life><Logistic Regressions><Logistics><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Malignant Neoplasms><Malignant Tumor><Measures><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Medical Ultrasound><Microbubbles><Microfluidics><Modeling><Modern Man><Morbidity><Morbidity - disease rate><Myocardial Infarct><Myocardial Infarction><NMR Imaging><NMR Tomography><Names><Nephropathy><Neuritic Plaques><Noise><Non-Invasive Detection><Noninvasive Detection><Nuclear Magnetic Resonance Imaging><Optics><Oryctolagus cuniculus><Outcome><Pathology><Performance><Physiologic><Physiologic pulse><Physiological><Pilot Projects><Play><Population><Preventative treatment><Preventive treatment><Procedures><Pulse><ROC Analyses><ROC Curve><Rabbits><Rabbits Mammals><Radiation><Radiopaque Media><Renal Disease><Resolution><Risk><Role><Rupture><Scanning><Senile Plaques><Signal Transduction><Signal Transduction Systems><Signaling><Specificity><Stroke><Stroke prevention><Surrogate Markers><System><Techniques><Testing><Tissue Growth><Ultrasonic Imaging><Ultrasonogram><Ultrasonography><Ultrasound Diagnosis><Ultrasound Medical Imaging><Ultrasound Test><United States><Validation><Work><X-ray microtomography><Xray microtomography><Zeugmatography><acute coronary syndrome><amyloid beta plaque><amyloid-b plaque><angiogenesis><animal imaging><atherosclerosis plaque><atherosclerotic lesions><atherosclerotic plaque><atherosclerotic plaque rupture><aβ plaques><biological signal transduction><brain attack><cardiac infarct><cerebral vascular accident><cerebrovascular accident><clinical applicability><clinical application><clinical relevance><clinical translation><clinically relevant><clinically translatable><contrast enhanced><cored plaque><coronary attack><coronary infarct><coronary infarction><density><diagnostic ultrasound><diffuse plaque><heart attack><heart infarct><heart infarction><high resolution imaging><high risk><human subject><image construction><image generation><image reconstruction><imaging><imaging approach><imaging based approach><imaging capabilities><imaging probe><in vivo><innovate><innovation><innovative><innovative technologies><interventional strategy><kidney disorder><malignancy><meter><micro CT><micro computed tomography><microCT><microscope imaging><microscopic imaging><microscopy imaging><microtomography><mortality><name><named><naming><necropsy><neoplasm/cancer><neovascularization><novel><ontogeny><optical><patient stratification><pilot study><postmortem><prevent stroke><receiver operating characteristic analyses><receiver operating characteristic curve><renal disorder><resolutions><risk for stroke><risk of stroke><social role><sonogram><sonography><sound measurement><spatiotemporal><stratified patient><stroke risk><stroked><strokes><super high resolution><superresolution><surrogate bio-markers><surrogate biomarkers><tech development><technology development><three dimensional><tomography><tool><translational goal><translational mission><ultra high resolution><ultrasound><ultrasound imaging><ultrasound scanning><uptake><validations><vasa vasorum><vascular><vulnerable plaque><µfluidic>