VALIDATION OF [18F]-SODIUM FLUORIDE AS A MARKER OF ACTIVE CALCIFICATION AND HIGH-RISK CAROTID PLAQUE: A SUB-STUDY OF THE CANADIAN ATHEROSCLEROSIS IMAGING NETWORK (CAIN-2)

Abstract

[18F]-sodium fluoride (NaF) positron emission tomography (PET) uptake may serve as an imaging-derived biomarker of active calcification. It is postulated that NaF binds to hydroxyapatite molecules that are expressed in regions with active calcification. We aimed to: 1. Validate NaF uptake imaged with PET/CT, as a direct marker of active calcification within carotid plaque, as determined by its association with intraplaque expression of hydroxyapatite; and 2. Determine whether NaF uptake is related to cerebrovascular events. Eleven patients (69 ± 5 years, 3 females) scheduled for carotid endarterectomy were prospectively recruited. Patients underwent NaF PET and contrast-enhanced CTA imaging of carotid vasculature. The bifurcation of the common carotid was used as a 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. Following endarterectomy, excised carotid plaque was fixed, sectioned and stained with Goldner’s Trichrome (marker of hydroxyapatite expression). An electronic algorithm was applied to quantify hydroxyapatite expression on whole-slide digitized images. Using the distance from the bifurcation, pathology was aligned with CTA and co-registered with PET. To determine the relationship between NaF uptake and cerebrovascular events, bilateral carotid plaque was classified as either symptomatic (associated with cerebrovascular events) or clinically silent, asymptomatic plaque. Carotid endarterectomy was performed in 11 patients; one patient received a 2nd carotid endarterectomy due to bilateral disease. Two patients were excluded (intolerance to CT contrast agent and PET/CT misalignment). Staining was available for 8 excised plaques. NaF uptake was related to intraplaque hydroxyapatite expression (r=0.45, p<0.001) (Figure 1). NaF uptake was greater at the side of carotid endarterectomy (endarterectomy: 3.73±1.1 TBR vs. contralateral: 2.82±0.6 TBR, p=0.030). Symptomatic carotid plaque had evidence for greater NaF uptake (symptomatic plaque: 3.75±1.1 TBR vs. asymptomatic plaque: 2.79±0.6 TBR p=0.04) NaF uptake imaged with PET/CT is related to intraplaque expression of hydroxyapatite, which is expressed in regions with active calcific activity. NaF uptake was greater in plaque that was scheduled for endarterectomy, as well as symptomatic plaque associated with cerebrovascular events. 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.