Abstract
Vascular calcification is a complex biological process that is a hallmark of atherosclerosis. While macrocalcification confers plaque stability, microcalcification is a key feature of high-risk atheroma and is associated with increased morbidity and mortality. Positron emission tomography and X-ray computed tomography (PET/CT) imaging of atherosclerosis using 18F-sodium fluoride (18F-NaF) has the potential to identify pathologically high-risk nascent microcalcification. However, the precise molecular mechanism of 18F-NaF vascular uptake is still unknown. Here we use electron microscopy, autoradiography, histology and preclinical and clinical PET/CT to analyse 18F-NaF binding. We show that 18F-NaF adsorbs to calcified deposits within plaque with high affinity and is selective and specific. 18F-NaF PET/CT imaging can distinguish between areas of macro- and microcalcification. This is the only currently available clinical imaging platform that can non-invasively detect microcalcification in active unstable atherosclerosis. The use of 18F-NaF may foster new approaches to developing treatments for vascular calcification.
Highlights
Vascular calcification is a complex biological process that is a hallmark of atherosclerosis
Vessel mineralization is first marked by the appearance of calcified micro nodules which grow and coalesce into much larger macroscopic deposits[8]. The genesis of these micro nodules is principally mediated by a coordinated cellular pathway that shares similarities to active skeletal osteogenesis but may involve a more passive process where a combination of high local concentrations of phosphates and phosphatidylserines from necrotic cells and an absence of calcification inhibitors results in the precipitation of calcium phosphate particles
This distinction is important because macrocalcification imparts plaque stability, microcalcification heralds the onset of vessel mineralization triggered by cell death and inflammation[8,12] and may itself be implicated in the aetiology of plaque rupture and major adverse cardiovascular events[13,14]
Summary
Vascular calcification is a complex biological process that is a hallmark of atherosclerosis. Positron emission tomography and X-ray computed tomography (PET/CT) imaging of atherosclerosis using 18F-sodium fluoride (18F-NaF) has the potential to identify pathologically high-risk nascent microcalcification. There is no universal size convention, emerging consensus categorizes micro- and macrocalcification based on nodules of o50 and Z50 mm, respectively[11] This distinction is important because macrocalcification imparts plaque stability, microcalcification heralds the onset of vessel mineralization triggered by cell death and inflammation[8,12] and may itself be implicated in the aetiology of plaque rupture and major adverse cardiovascular events[13,14]. Positron emission tomography (PET)/CT imaging of atherosclerosis using 18F-sodium fluoride (18F-NaF) has recently been reported and, for the first time, has the potential to non-invasively identify high-risk microcalcification[18,19,20,21]. We compared clinical 18F-NaF PET/CT images with mPET/mCT images of excised carotid endarterectomy specimens to develop a translational model of 18F-NaF vascular uptake from bedside to bench and back and understand 18F-NaF adsorption to vascular calcification on all three levels studied
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