Analysis of ¹⁸ F-Sodium Fluoride Positron Emission Tomography Signal Sources in Atherosclerotic Minipigs Shows Specific Binding of ¹⁸ F-Sodium Fluoride to Plaque Calcifications

Abstract

Objective: 18 F-sodium fluoride ( 18 F-NaF) positron emission tomography (PET) imaging is thought to visualize active atherosclerotic plaque calcification. This is supported by the binding of 18 F-NaF to plaque calcification ex vivo, but no prior studies have examined binding of 18 F-NaF to human-like plaque in vivo. Our aim was to validate the specificity of 18 F-NaF PET for plaque calcifications in atherosclerotic minipigs. Approach and Results: Gain-of-function PCSK9 D374Y (proprotein convertase/subtilisin kexin type 9) transgenic Yucatan minipigs (n=4) were fed high-fat diet for 2.5 years to develop atherosclerosis and then subjected to 18 F-NaF PET/computed tomography imaging. The heart, aorta, and iliac arteries were immediately re-scanned ex vivo after surgical extraction. Lesions from the abdominal aorta, iliac arteries, and coronary arteries were cryo-sectioned for autoradiography. Histological plaque characteristics, PET/computed tomography signal, and autoradiography were linked through regression and co-localization analysis. Arterial 18 F-NaF PET signal had intensities comparable to clinical scans and colocalized moderately with calcification detected by computed tomography. Histological analysis showed calcification spanning from microcalcifications near lipid pools and necrotic core to more homogenous macrocalcifications. Comparison with arteries from autopsy cases confirmed the resemblance in localization and appearance with early human plaque calcification. Regression analysis in the abdominal aorta showed correlations with calcified plaque but could not rule out contributions from noncalcified plaque. This was resolved by autoradiography, which showed specific accumulation in plaque calcifications in all examined arteries. In the context of porcine abdominal aorta, 18 F-NaF PET imaging was, however, less accurate than computed tomography for detecting small calcifications. Conclusions: 18 F-NaF accumulates specifically in calcifications of atherosclerotic plaques in vivo.

NaF-PET Imaging of Atherosclerosis Burden

“…Forty-five articles were included in this review [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ] ( Figure 1 ), to which were added selected articles on methodological and other aspects. Findings in the articles are summarized in the following sections and in Tables S1–S6 in the Supplementary Material .…”

“…Several studies dealt with one arterial bed only, i.e., coronary arteries [ 16 , 17 , 18 , 20 , 29 , 30 , 31 , 38 , 39 , 44 ], global heart [ 22 , 23 , 24 , 25 , 27 , 34 ], pulmonary arteries [ 11 ], left carotid artery [ 28 ], aorta [ 26 , 32 , 41 , 42 , 48 , 49 ], abdominal aorta [ 13 , 33 , 45 ], or several arterial beds [ 5 , 6 , 7 , 8 , 9 , 10 , 12 , 14 , 15 , 21 , 35 , 36 , 37 , 40 , 41 , 43 , 46 , 47 ]. Eight reports were experimental animal studies [ 5 , 6 , 32 , 42 , 43 , 45 , 48 , 49 ], and one was an image case report [ 44 <...…”

“…Nogales et al [ 6 ] found in atherosclerotic transgenic Yucutan minipigs moderate co-localization of NaF uptake and CT-calcification in the heart, aorta, and iliac arteries and by autoradiography NaF accumulation in plaque calcifications in all examined arteries, correlating with both non-calcified plaque and thrombotic material. Some vascular segments had a NaF signal despite no CT-detectable calcification, which made the authors state decreased specificity and not increased sensitivity of NaF-PET compared to CT, despite that calcifications of <50 µm in size can be registered by NaF-PET, whereas size 200–500 µm is required for detection by CT [ 50 ].…”

“…Selective concomitant uptake of FDG and NaF in the aortic arc and pulmonary arteries of obese ApoE-/- rats [ 5 ] is an observation not reported elsewhere. The study [ 6 ] in atherosclerotic minipigs could not tell for sure if NaF localizes in microcalcifications, but presence in arterial walls and thrombotic material was observed despite lack of CT detectable calcification. The dissociation between FDG and NaF uptake [ 7 ] in PXE patients suggested chronic ectopic calcification rather than acute inflammation, and the study [ 8 ] of dialysis patients revealed an interesting, but weak, association between bone metabolism and coronary calcification.…”

“…Limitations of animal studies like insufficient spatial PET resolution [ 5 , 6 , 32 , 42 , 43 , 45 ] hamper extrapolation to human conditions. A significant advantage is the use of human-sized animal models that enable NaF-PET/CT imaging of large vessel calcification and microvascular function at multiple time points during atherosclerosis pathogenesis and during prevention and regression studies [ 6 , 75 ]. Human studies had other limitations.…”