18F-Fluoride Signal Amplification Identifies Microcalcifications Associated With Atherosclerotic Plaque Instability in Positron Emission Tomography/Computed Tomography Images

Michael D. Creager, Tobias Hohl, Joshua D. Hutcheson, Alastair J. Moss, Florian Schlotter, Mark C. Blaser, Mi-Ae Park, Lang Ho Lee, Sasha A. Singh, Carlos J. Alcaide-Corral, Adriana A.S. Tavares, David E. Newby, Marie F. Kijewski, Masanori Aikawa, Marcelo Di Carli, Marc R. Dweck, Elena Aikawa

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Microcalcifications in atherosclerotic plaques are destabilizing, predict adverse cardiovascular events, and are associated with increased morbidity and mortality.18F-fluoride positron emission tomography (PET)/computed tomography (CT) imaging has demonstrated promise as a useful clinical diagnostic tool in identifying high-risk plaques; however, there is confusion as to the underlying mechanism of signal amplification seen in PET-positive, CT-negative image regions. This study tested the hypothesis that 18F-fluoride PET/CT can identify early microcalcifications.

Methods: 18F-fluoride signal amplification derived from microcalcifications was validated against near-infrared fluorescence molecular imaging and histology using an in vitro 3-dimensional hydrogel collagen platform, ex vivo human specimens, and a mouse model of atherosclerosis.

Results: Microcalcification size correlated inversely with collagen concentration. The 18F-fluoride ligand bound to microcalcifications formed by calcifying vascular smooth muscle cell derived extracellular vesicles in the in vitro 3-dimensional collagen system and exhibited an increasing signal with an increase in collagen concentration (0.25 mg/mL collagen −33.8×102±12.4×102 counts per minute; 0.5 mg/mL collagen −67.7×102±37.4×102 counts per minute; P=0.0014), suggesting amplification of the PET signal by smaller microcalcifications. We further incubated human atherosclerotic endarterectomy specimens with clinically relevant concentrations of 18F-fluoride. The 18F-fluoride ligand labeled microcalcifications in PET-positive, CT-negative regions of explanted human specimens as evidenced by 18F-fluoride PET/CT imaging, near-infrared fluorescence, and histological analysis. Additionally, the 18F-fluoride ligand identified micro and macrocalcifications in atherosclerotic aortas obtained from low-density lipoprotein receptor-deficient mice.

Conclusions: Our results suggest that 18F-fluoride PET signal in PET-positive, CT-negative regions of human atherosclerotic plaques is the result of developing microcalcifications, and high surface area in regions of small microcalcifications may amplify PET signal.
Original languageEnglish
Article numbere007835
JournalCirculation: Cardiovascular Imaging
Volume12
Issue number1
DOIs
Publication statusPublished - 15 Jan 2019

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