R01HL159803

A Receptor-Targeted Nanoparticle PET Tracer in Human Carotid Atherosclerosis - Project Summary

Currently, no consensus exists in clinical guidelines for the management of patients with asymptomatic carotid artery stenosis (ACAS). Some guidelines recommend carotid endarterectomy (CEA) surgery for patients with ACAS of ≥ 60% diameter. However, it is argued that 95% of all surgical interventions for ACAS in the United States may be unnecessary, generating needless healthcare costs of over $2 billion annually.

Our goal in this proposal is to study plaque biology in ACAS patients through PET imaging at the molecular level to help identify individuals who are at 'higher-risk' for ischemic stroke from plaque rupture and may benefit from carotid surgical intervention. We propose a 2-center patient outcomes study that expands upon data and observations from our earlier single-center first-in-human study at Washington University using a nanoparticle PET radiotracer that targets the natriuretic peptide receptor C (NPRC) to determine if it can be used to risk stratify patients with 'higher-risk' ACAS.

We and others have shown that NPRC is expressed at higher levels in complex plaques with features of vulnerability in patients with ACAS. In our most recent NIH R01-funded proof-of-concept study in a cohort of 42 patients with ACAS, we have shown a linear correlation between 64Cu-CANF-COMB PET radiotracer uptake and features of high-risk plaque, as well as correlating 64Cu-CANF-COMB PET uptake to the presence of NPRC in CEA specimens of patients who underwent surgery.

We propose the following specific aims:

Aim 1: To determine the ability of 64Cu-CANF-COMB PET to risk stratify ACAS patients treated with optimal medical therapy (OMT) alone with respect to patient outcomes. In this observational study, 80 patients with ACAS ≥ 60% will undergo 64Cu-CANF-COMB PET/MRI. Patients will be maintained on either OMT alone or receive OMT and CEA as determined by their treating vascular surgeon prior to imaging. OMT will consist of antiplatelet, statin, and hypertension and diabetes management when applicable. All patients will be evaluated with phone interviews every 3 months for a minimum of 18 months to assess for ipsilateral ischemic cerebrovascular events. PET signal will be assessed as a marker of risk for event or progression to CEA in comparison to anatomic features of vulnerable plaque on MRI, with the goal of determining a PET signal threshold which suggests higher risk ACAS.

Aim 2: To further understand the role of NPRC in the evolution of carotid atherosclerosis.
A. Patients treated with OMT alone will undergo repeat PET/MRI at 18 months, or earlier if they develop symptoms. PET/MRI changes over the 18-month interval will be used to further understand the biology of carotid plaque evolution after treatment with OMT.
B. In patients who initially undergo CEA, PET signal will be compared to ex vivo plaque vulnerability and NPRC cellular distribution to facilitate understanding of gene expression using immunohistochemistry (IHC) and cell origin through single-cell RNA/CITE-SEQ transcriptomics.

Results will provide information on the potential of a new imaging approach, 64Cu-CANF-COMB PET, to risk stratify patients with ACAS and reveal mechanistic information about the role of NPRC in plaque vulnerability and inflammation.

Washington University

NOT APPLICABLE

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Missouri United States

State-Wide

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 347% from $766,394 to $3,424,919.