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

83 Scopus citations


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 (US)
Article numbere007835
JournalCirculation: Cardiovascular Imaging
Issue number1
StatePublished - 2019
Externally publishedYes


  • Atherosclerosis
  • Fluoride
  • Microcalcification
  • Molecular imaging
  • Positron emission tomography

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Cardiology and Cardiovascular Medicine


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