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Active calcification is a marker of plaque vulnerability. [18F]-sodium fluoride (NaF) positron emission tomography (PET) uptake may serve as a biomarker of active calcification. NaF binds to hydroxyapatite molecules that are expressed in regions with active calcification. Osteopontin is a phosphorylated glycoprotein that regulates mineralization and calcification. Extensively expressed at sites of calcification in plaque, osteopontin has high affinity for hydroxyapatite. Positive plaque remodeling is another marker of plaque vulnerability that is associated with future cerebrovascular events. We hypothesized that active calcification within carotid plaque, as determined by NaF PET/CT uptake, is associated with intraplaque expression of osteopontin and positive plaque remodeling.
Eleven patients (69±5 years, 3 female) scheduled for carotid endarterectomy were prospectively recruited. Patients underwent NaF PET imaging of carotid vasculature (images were 3.27mm thick). Contrast-enhanced CT angiography of the carotid was performed; contiguous slices were acquired at 0.625mm intervals. Bifurcation of the common carotid was used as the reference point; maximum NaF uptake normalized to blood (tissue to blood ratio - TBR) was measured at every PET slice extending 2 cm above and below the bifurcation.
Using NASCET criteria, cross-sectional vessel area was measured and related to proximal and distal segments without evidence of disease, to generate a plaque remodeling index (RI) for every PET slice. Regions with a RI greater than 1.0 were classified as positive remodeling.
Following endarterectomy, excised plaque was fixed, sectioned and immunostained for osteopontin. An electronic algorithm was applied on whole-slide digitized images to quantify osteopontin expression.
Using the distance from the bifurcation, pathology slices at an interval of 2000 microns were aligned with CT and co-registered with PET.
Carotid endarterectomy was performed in 11 patients; one patient received a 2nd carotid endarterectomy due to bilateral disease. 2 patients were excluded (intolerance to CT contrast agent and PET/CT misalignment). Immunohistology was available for 8 excised plaques.
Due to within plaque clustering, a meta-analysis was performed and demonstrated that maximum NaF uptake was related to intraplaque osteopontin expression (r=0.37, p=0.03) (Figure 1). NaF uptake was greater in regions with positive plaque remodeling (TBR=2.6±0.9 with positive remodeling (n=185) vs. 1.6±0.6 (n=46) without positive remodeling, p<0.001).
NaF uptake imaged with PET/CT correlates significantly with osteopontin immunohistochemistry and is greater in regions with positive plaque remodeling. NaF PET/CT may serve as a novel biomarker of active calcification and enable identification of high-risk patients. Larger outcome based follow-up studies are underway.