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Principal Investigator: Pamela K Woodard
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2019
Award: $624,055
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
This proposal is a first-in-human trial of a newly developed nanoparticle PET radiotracer that targets the
natriuretic peptide receptor C (NPR-C), with the long-term potential to help to determine which asymptomatic
patients with carotid artery stenosis might require surgery. Our research shows that NPR-C is differentially
expressed in the deep intima of maximally diseased and vulnerable plaque segments and is expressed not
only in vascular smooth muscle cells (VSMC) but also uniquely in the macrophages in this deep intimal region.
Our findings show that the VSMC infiltrating into this deep carotid plaque intima and the macrophages
developing there are pathologically unique, with differential expression of NPR-C relative to plaque severity.
The objective of this proposal is to assess the performance of a newly developed PET radiotracer 64Cu-CANF-
Comb 1) to reliably target NPR-C upregulated in atherosclerosis in humans in vivo and 2) to identify features of
vulnerability in human carotid plaque. We will perform carotid PET-MR with 64Cu-CANF-Comb in both
asymptomatic and symptomatic patients scheduled for carotid endarterectomy (CEA) surgery. We chose this
patient population because CEA surgery will permit us to collect the plaque specimen after surgery to allow us
to compare the PET imaging signal with tissue measurements of NPR-C expression and plaque morphology.
To achieve this objective we will address the following Specific Aims: Aim 1. Demonstrate that 64Cu-CANF-
Comb radiotracer can be used to target NPR-C upregulation in human atherosclerosis. After the PET-
MR examination and the CEA surgery, we will collect each patient’s ex vivo CEA specimen. We will compare
PET signal measurements in the diseased artery (plaque to be removed surgically) to NPR-C presence in the
ex vivo specimen by IHC staining for NPR-C and RT-PCR. We will also perform IHC and RT-PCR of the distal
(less diseased) CEA specimen as a control. We will colocalize for macrophages, VSMC and EC to determine
NPR-C expression within cell populations. PET signal between the diseased and non-diseased contralateral
artery and non-diseased portion of the ipsilateral artery will also be compared.
Aim 2. Assess the utility of 64Cu-CANF-Comb to identify plaque with features of vulnerability. We will
compare PET signal in the diseased artery to American Heart Association (AHA) classification for
atherosclerosis vulnerability by grading of H&E stained ex vivo CEA specimens. PET signal will also be
compared to the simultaneously acquired MR images for presence of atherosclerosis and MRI signal
characteristics of fibrous cap, lipid pool and hemorrhage. We will also collect patient demographics, information
regarding symptomatology, and risk factors. The results of this work will provide the necessary information on
the potential of 64Cu-CANF-Comb to detect high-risk atherosclerotic plaque and, thus, will lay the foundation for
larger studies to assess imaging findings in light of patient outcomes.
Terms: <18-FDG><18F- FDG><18FDG><2 Fluoro 2 deoxy D glucose><2-Fluoro-2-deoxyglucose><Address><Affinity><American Heart Association><Anatomic><Anatomic Sites><Anatomic Structure, System, or Substance><Anatomic Structures and Systems><Anatomic structures><Anatomical Sciences><Anatomy><Anatomy Qualifier><Apoplexy><Arterial Fatty Streak><Arterial Fatty Streaks><Arteries><Atheroma><Atheromatous><Atheromatous degeneration><Atheromatous plaque><Atheroscleroses><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Binding><Biodistribution><Biology><Bleeding><Blood Vessels><Body Tissues><Brain Vascular Accident><C-Type Natriuretic Peptide><CAT scan><CNP-22><CT X Ray><CT imaging><CT scan><Caliber><Carotid Arterial Diseases><Carotid Arteries><Carotid Artery Diseases><Carotid Artery Disorders><Carotid Artery Narrowing><Carotid Artery Plaque><Carotid Artery Plaques><Carotid Artery Stenosis><Carotid Atheroscleroses><Carotid Atherosclerotic Disease><Carotid Endarterectomy><Carotid Stenosis><Carotid stent><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Characteristics><Chelating Agents><Chelators><Classification><Clinical><Comb animal structure><Combs><Complex><Complexons><Computed Tomography><Consensus><Contralateral><Detection><Diameter><Disease><Disorder><Distal><EMI scan><Endothelial Cells><Endothelium><Foundations><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G(s), alpha Subunit><G(s), α Subunit><G(s)alpha><G(s)α><G-Protein-Coupled Receptors><GPCR><GTP-Binding Protein alpha Subunits, Gs><GTP-Binding Protein α Subunits, Gs><Goals><Gs alpha Family G-Protein><Gsα><Guidelines><Gαs><Health Care Costs><Health Costs><Healthcare Costs><Hemorrhage><Human><Image><Injury><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Ipsilateral><Leiomyocyte><Length><Ligands><Light><Lipids><MR Imaging><MR Tomography><MRI><Magnetic Resonance Imaging><Manuscripts><Measurement><Medical><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Modern Man><Molecular><Molecular Interaction><Morphology><NMR Imaging><NMR Tomography><Natriuretic Peptide Hormones><Natriuretic Peptides><Nuclear Magnetic Resonance Imaging><Operative Procedures><Operative Surgical Procedures><PET><PET Scan><PET imaging><PETSCAN><PETT><Pathologic><Pathologic Constriction><Pathological Constriction><Patient Schedules><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Peptide Receptor><Performance><Perioperative><Photoradiation><Physiologic><Physiological><Population><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Pre-Clinical Model><Preclinical Models><Procedures><RT-PCR><RTPCR><Rad.-PET><Radiation Dosimetry><Radiometry><Receptor Protein><Regulation><Regulatory Ns Protein><Research><Research Specimen><Reverse Transcriptase Polymerase Chain Reaction><Risk><Risk Factors><Role><Rupture><Safety><Scanning><Severities><Signal Transduction><Signal Transduction Systems><Signaling><Smooth Muscle Cells><Smooth Muscle Myocytes><Smooth Muscle Tissue Cell><Specimen><Staining method><Stains><Stenosis><Stents><Stimulatory Gs G-Protein><Stroke><Surgical><Surgical Interventions><Surgical Procedure><Systematics><Tissues><Tomodensitometry><Tracer><United States><Up-Regulation><Upregulation><Vascular Smooth Muscle><Vascular remodeling><Work><X-Ray CAT Scan><X-Ray Computed Tomography><X-Ray Computerized Tomography><Xray Computed Tomography><Zeugmatography><alpha Subunit Stimulatory GTP-Binding Protein><alpha-Gs><atheromatosis><atherosclerosis plaque><atherosclerotic disease><atherosclerotic lesions><atherosclerotic plaque><atherosclerotic vascular disease><base><biological signal transduction><blood loss><brain attack><carotid artery stent><carotid plaque><carotid stenting><catscan><cerebral vascular accident><cerebrovascular accident><computed axial tomography><computerized axial tomography><computerized tomography><demographics><differential expression><differentially expressed><first in man><first-in-human><fluorodeoxyglucose><high risk><human subject><imaging><in vivo><interventional strategy><macrophage><nano particle><nano-sized particle><nanoparticle><nanosized particle><patient population><patient stratification><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><radioassay><radiolabel><radiotracer><receptor><reverse transcriptase PCR><risk for stroke><risk of stroke><social role><stratified patient><stroke patient><stroke risk><surgery><symptomatology><transcriptional differences><vascular><vascular smooth muscle cell proliferation><vulnerable plaque><α-Gs>