18F-Sodium Fluoride Uptake in Abdominal Aortic Aneurysms: The SoFIA3 Study

Rachael O Forsythe, Marc R Dweck, Olivia M B McBride, Alex T Vesey, Scott I Semple, Anoop S V Shah, Philip D Adamson, William A Wallace, Jakub Kaczynski, Weiyang Ho, Edwin J R van Beek, Calum D Gray, Alison Fletcher, Christophe Lucatelli, Aleksander Marin, Paul Burns, Andrew Tambyraja, Roderick T A Chalmers, Graeme Weir, Neil Mitchard, Adriana Tavares, Jennifer M J Robson, David E Newby, Rachael O Forsythe, Marc R Dweck, Olivia M B McBride, Alex T Vesey, Scott I Semple, Anoop S V Shah, Philip D Adamson, William A Wallace, Jakub Kaczynski, Weiyang Ho, Edwin J R van Beek, Calum D Gray, Alison Fletcher, Christophe Lucatelli, Aleksander Marin, Paul Burns, Andrew Tambyraja, Roderick T A Chalmers, Graeme Weir, Neil Mitchard, Adriana Tavares, Jennifer M J Robson, David E Newby

Abstract

Background: Fluorine-18-sodium fluoride (18F-NaF) uptake is a marker of active vascular calcification associated with high-risk atherosclerotic plaque.

Objectives: In patients with abdominal aortic aneurysm (AAA), the authors assessed whether 18F-NaF positron emission tomography (PET) and computed tomography (CT) predicts AAA growth and clinical outcomes.

Methods: In prospective case-control (n = 20 per group) and longitudinal cohort (n = 72) studies, patients with AAA (aortic diameter >40 mm) and control subjects (aortic diameter <30 mm) underwent abdominal ultrasound, 18F-NaF PET-CT, CT angiography, and calcium scoring. Clinical endpoints were aneurysm expansion and the composite of AAA repair or rupture.

Results: Fluorine-18-NaF uptake was increased in AAA compared with nonaneurysmal regions within the same aorta (p = 0.004) and aortas of control subjects (p = 0.023). Histology and micro-PET-CT demonstrated that 18F-NaF uptake localized to areas of aneurysm disease and active calcification. In 72 patients within the longitudinal cohort study (mean age 73 ± 7 years, 85% men, baseline aneurysm diameter 48.8 ± 7.7 mm), there were 19 aneurysm repairs (26.4%) and 3 ruptures (4.2%) after 510 ± 196 days. Aneurysms in the highest tertile of 18F-NaF uptake expanded 2.5× more rapidly than those in the lowest tertile (3.10 [interquartile range (IQR): 2.34 to 5.92 mm/year] vs. 1.24 [IQR: 0.52 to 2.92 mm/year]; p = 0.008) and were nearly 3× as likely to experience AAA repair or rupture (15.3% vs. 5.6%; log-rank p = 0.043).

Conclusions: Fluorine-18-NaF PET-CT is a novel and promising approach to the identification of disease activity in patients with AAA and is an additive predictor of aneurysm growth and future clinical events. (Sodium Fluoride Imaging of Abdominal Aortic Aneurysms [SoFIA3]; NCT02229006; Magnetic Resonance Imaging [MRI] for Abdominal Aortic Aneurysms to Predict Rupture or Surgery: The MA3RS Trial; ISRCTN76413758).

Keywords: abdominal aortic aneurysm; positron emission tomography; repair; rupture.

Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Positron Emission Tomographic and Computed Tomographic Images of Abdominal Aortic Aneurysms (A) Structural image of computed tomographic angiography, (B)18F–sodium fluoride uptake on positron emission tomography, and (C) fused positron emission tomographic–computed tomographic images colocalizing 18F–sodium fluoride uptake with the skeleton and abdominal aortic aneurysm.
Figure 2
Figure 2
Study Populations The 20 patients for the case-control study were selected from within the cohort study population. AAA = abdominal aortic aneurysm; CT = computed tomography; PET = positron emission tomography.
Figure 3
Figure 3
Correlation of Histology With Micro–Positron Emission Tomography and Computed Tomography of Abdominal Aortic Tissue Ex vivo micro–positron emission tomography and computed tomography (left) and histology (right) of aortic wall excised (A) at postmortem in a patient without an aneurysm and (B) during open abdominal aortic aneurysm repair. Regions of interest (dashed circle) of 18F–sodium fluoride (18F-NaF) uptake demonstrate atheromatous disease with necrosis (hematoxylin and eosin stain, magnification ×100 [Online Video 1]; B1) and calcification (black, Von Kossa stain, magnification ×200; B2) in the aortic aneurysm tissue that is not apparent in control aorta (A1, A2).
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5800891/bin/grv1.jpg
Online Video 1 Micro-positron emission tomography and computed tomography of aortic aneurysm tissue following ex vivo incubation with 18F-sodium fluoride. Note 18F-sodium fluoride uptake (red) by positron emission tomography is distinct from the macrocalcification (white) identified with computed tomography. Some areas of macrocalcification show little or no associated 18F-sodium fluoride whereas other areas have avid 18F-sodium fluoride uptake in the absence of macrocalcification.
Figure 4
Figure 4
Prediction of Disease Progression and Clinical Outcome by 18F–Sodium Fluoride Positron Emission Tomography Association of 18F–sodium fluoride (18F-NaF) uptake with disease progression and clinical outcome. (A) Rate of aneurysm expansion (millimeters per year, log2 transformed) across the tertiles of 18F-NaF uptake. The highest tertile expanded more rapidly than those in the lowest tertile (3.10 vs. 1.24 mm/year, respectively, p = 0.008). Cumulative event rate (censored at date of death) across the tertiles of 18F-NaF uptake for (B) abdominal aortic aneurysm repair or rupture (log-rank p = 0.043) and (C) abdominal aortic aneurysm repair (log-rank p = 0.014).
Central Illustration
Central Illustration
Fluorine-18–Sodium Fluoride Uptake in Abdominal Aortic Aneurysms Fluorine-18–sodium fluoride uptake is specific to abdominal aortic aneurysm tissue, is proportional to the rate of aneurysm expansion, and predicts the risk for repair or rupture independent of aneurysm diameter.

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