18 F – Sodium Fluoride Uptake in Abdominal Aortic Aneurysms

BACKGROUND Fluorine-18 – sodium ﬂ uoride ( 18 F-NaF) uptake is a marker of active vascular calci ﬁ cation associated with high-risk atherosclerotic plaque. OBJECTIVES In patients with abdominal aortic aneurysm (AAA), the authors assessed whether 18 F-NaF positron emission tomography (PET) and computed tomography (CT) predicts AAA growth and clinical outcomes. METHODS In prospective case-control (n ¼ 20 per group) and longitudinal cohort (n ¼ 72) studies, patients with AAA (aortic diameter > 40 mm) and control subjects (aortic diameter < 30 mm) underwent abdominal ultrasound, 18 F-NaF PET-CT, CT angiography, and calcium scoring. Clinical endpoints were aneurysm expansion and the composite of AAA repair or rupture.

A bdominal aortic aneurysm (AAA) disease affects up to 5% of men aged 64 to 75 years, and its prevalence is increasing in more elderly populations (1). With progressive AAA expansion over time, there is an increasing risk for often fatal rupture, representing the 12th commonest cause of death among older men (2). Consequently, patients with AAA enter an ultrasound-based surveillance program, with the aim of facilitating preemptive elective aneurysm repair to avoid fatal rupture. AAA surveillance relies on serial measurements of aneurysm diameter, which is currently the best clinical predictor of further expansion and rupture (3,4). However, AAA growth is nonlinear, unpredictable, and influenced by biomechanical processes that cannot be predicted by conventional anatomic imaging alone (5). Indeed, aneurysms not infrequently rupture below the current threshold (55 mm in diameter) for elective repair, and many patients with aneurysms >70 mm never experience rupture (6). There is therefore a need to develop more reliable methods to identify patients who are at particular risk for AAA expansion and rupture (7).
In AAA disease, degradation of the extracellular matrix occurs in response to the accumulation of inflammatory cells, such as macrophages and lymphocytes, and the activation of matrix metalloproteinases. The resulting milieu of cellular inflammation, tissue destruction, and necrosis can lead to cycles of further inflammation (8). Focal "hotspots" of such intense biological activity have been identified in active aneurysm disease and can occur at the site of rupture (9). We have recently demonstrated that the positron-emitting radiotracer 18 F-sodium fluoride ( 18 F-NaF) can identify areas of early microcalcification (10) that occur in response to necrotic inflammation in ruptured or high-risk human carotid (11) and coronary (12) atherosclerotic plaques. This tracer has not been assessed in patients with AAA, although loss of tissue integrity and necrotic inflammation may be central to its pathophysiology, underlie aneurysm expansion, and ultimately predict disease progression and outcome (7). We hypothesized that 18 F-NaF uptake on positron emission tomography (PET) would highlight areas of microcalcification and AAA disease activity, representing regions prone to expansion and rupture. The main aims of this study were to determine whether 18 F-NaF uptake on combined PET and computed tomography (CT) is increased in AAA and whether this is associated with aneurysm growth (the primary endpoint) and subsequent rates of AAA repair or rupture. Ultrasound scans were carried out in an accredited clinical vascular science laboratory using a standardized protocol with known interobserver variability of 3.4% (14). The AAA growth rate was determined using the AAA maximum anteroposterior diameter obtained   Maximum tissue-to-background ratios (TBRs) were then calculated, after correction for blood pool activity using the averaged mean SUVs of 3 consecutive regions of interest from the right atrium, according to our previously described technique (16). Although TBR max was used for our primary analysis (12), we also investigated other methods for quantification, including SUV max and corrected SUV max (calculated by subtracting the blood pool activity from SUV max ) (17). Finally, we adopted the "most diseased segment" (MDS) approach, as suggested by others (11,16,(18)(19)(20). The MDS TBR max was calculated as the average TBR max across 3 axial slices centered on the region of the aneurysm with the highest tracer activity (11).       Table 1).

METHODS
In contrast to control aortic tissue, AAA tissue demonstrated ex vivo 18 F-NaF uptake that correlated with areas of tissue disruption with necrotic debris and active calcification (r ¼ 0.808, p ¼ 0.015) ( Figure 3). Areas of 18  Although there appeared to be some differences with respect to diastolic blood pressure, body mass index, and peripheral arterial disease, the trend was inconsistent across the tertiles ( Table 1). 18  The 20 patients for the case-control study were selected from within the cohort study population. AAA ¼ abdominal aortic aneurysm; CT ¼ computed tomography; PET ¼ positron emission tomography.  Patients with aneurysms in the highest tertile of 18 F-NaF uptake were more likely to experience AAA repair or rupture during follow-up (15.3% vs. 5.6%; log-rank p ¼ 0.043) ( Table 2). They also had a reduced time to AAA event: 572 days versus 735 days for AAA repair (log-rank p ¼ 0.014) and 572 days versus 709 days for the composite of AAA repair or rupture (log-rank p ¼ 0.043) (Figure 4). In those patients who experienced AAA events, 18 Table 2). Fourth, this is the largest dedicated study using PET-CT in AAA disease to date and the first clinical study to investigate 18 F-NaF PET-CT in AAA disease progression (21). Finally, this was a prospective clinical cohort study, in contrast with many previous studies of PET-CT in patients with AAA that are based on retrospective data, often obtained from cohorts derived from oncological imaging practice.

DISCUSSION
We previously demonstrated that 18 F-NaF selectively binds to microcalcification in coronary (11) and carotid atherosclerotic (10,11) plaques and that this is associated with plaque vulnerability and rupture. We (11,12) and others (22) have also shown that 18 F-NaF binds to areas of tissue necrosis-associated myocardial and cerebral infarction. In our present study, data from histology and micro-PET-CT indicate that this tracer behaves in a similar fashion in AAA. Increased 18 F-NaF uptake was most marked in AAA tissue with advanced disease and active calcification. We suggest that 18 F-NaF uptake again relates to microcalcification and is particular to the most diseased areas associated with tissue disruption and loss of integrity. Interestingly, we also showed that 18

CONCLUSIONS
This novel proof-of-concept PET-CT study of patients with asymptomatic AAA demonstrates that 18  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.