Identifying active vascular microcalcification by 18F-sodium fluoride positron emission tomography

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.

Imaging Cardiovascular Calcification

“…22, 98, 106 Dweck et al106 investigated histological markers of active calcification (ie, tissue nonspecific alkaline phosphatase and osteocalcin) in aortic stenosis and found a strong correlation between 18 F‐NaF uptake and these markers, thus confirming that 18 F‐NaF PET imaging provides information about the activity of calcification and might differentiate biologically active calcification from stable calcification. Alizarin Red staining also confirmed 18 F‐NaF uptake in areas of microcalcification17 (Figure 4). As calcium density gradually increases and becomes quiescent without further precipitation of extracellular calcium,107 it becomes visible on CT imaging,108 and its hydroxyapatite core becomes hidden from 18 F‐NaF 106.…”

“…The preferential binding of 18 F‐NaF to microcalcification is because of the high surface area of hydroxyapatite in these nanocrystalline areas 16. Irkle et al17 used autoradiography, whereby dispersion in large tissues and the lack of physical barriers increased adsorption of 18 F‐NaF to microcalcifications.…”

“…Macrocalcifications have a large volume but small surface area; much of the hydroxyapatite is internalized and not available for binding with 18 F‐fluoride 16. Moreover, 18 F‐NaF cannot penetrate into its deeper layers 14, 17…”

“…Irkle et al17 studied the mechanism of 18 F‐NaF vascular uptake by performing comprehensive examinations of carotid artery plaques in vivo and in vitro. In this study, pharmacodynamic and pharmacokinetic analysis confirmed the beneficial properties of 18 F‐NaF for plaque assessment (eg, high affinity for calcification, stability before scanning, low plasma activity at the time of scanning with minimal myocardial uptake) and showed that the tracer is more specific to microcalcification than macrocalcification.…”

“…As a consequence of this effect, 18 F‐NaF binds preferentially to regions of microcalcification compared with macroscopic deposits. Reprinted from Irkle et al17 with permission. Copyright ©2015, Nature Publishing Group, a division of Macmillan Publishers Limited.…”