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

Abstract

Background: Microcalcifications in atherosclerotic plaques are destabilizing, predict adverse cardiovascular events, and are associated with increased morbidity and mortality. 18F-fluoride PET/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 and Results: 18F-fluoride signal amplification derived from microcalcifications was validated against near infrared fluorescence (NIRF) molecular imaging and histology using an in vitro 3D hydrogel collagen platform, ex vivo human specimens, and a mouse model of atherosclerosis. 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 3D collagen system and exhibited an increasing signal with an increase in collagen concentration (0.25mg/ml collagen - 33.8×102±12.4×102 CPM; 0.5 mg/ml collagen - 67.7×102±37.4×102 CPM, 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, NIRF and histological analysis. Additionally, the 18F-fluoride ligand identified micro- and macrocalcifications in atherosclerotic aortas obtained from LDLr-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.

Atherosclerosis Imaging with 18F-Sodium Fluoride PET

“…We found 35 eligible articles. Three on the aortic valve ( n = 3) and seven on methodology ( n = 7) were excluded based on the abovementioned criteria, leaving 25 dealing with the coronary arteries [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ], femoral artery [ 12 , 13 , 14 , 15 ], abdominal aorta [ 16 , 17 , 18 ], carotid arteries [ 19 , 20 ], thoracic aorta [ 21 ], and intracranial [ 22 ], renal [ 23 ], and penile arteries [ 24 ]. One study focused on the carotid and cerebral arteries [ 25 ], another on the carotids, the aortic arch, and coronary arteries [ 26 ], and a third on several major arteries [ 27 ].…”

Atherosclerosis imaging with 18F-sodium fluoride PET: state-of-the-art review

“…Nonetheless, a number of observations, listed below, may hold true, whereas other questions remain unanswered. Most 2019 papers on NaF-PET imaging focus on unstable or what is designated vulnerable plaque morphology and detection in predominantly the coronary arteries often employing advanced methodologies [49,56,[58][59][60][61][62][63]. In August 2019, the first study on the efficacy of therapy judged by NaF-PET imaging appeared.…”

Coronary Artery Microcalcification: Imaging and Clinical Implications

“…Coronary atherosclerosis is directly connected to macrophages osteogenic activity in the early stages of atherosclerosis, which results in microcalcifications [42]. This allows 18 F-NaF to detect active microcalcification area beyond the resolution of CT scan [128][129][130][131]. The stronger affinity of the radioligand with newly formed hydroxyapatite compared to the old crystals makes it possible to distinguish between actively inflamed coronary calcifications from stable ones.…”