Discussion
In this article, we give an overview of what is known about
18F-FDG PET scanning in patients with aortic aneurysms. Only one study reports inclusion of patients with thoracic aneurysms [
12]. Imaging modalities as MRI and CT scanning were excluded, because an earlier search yielded no useful articles to discuss in this review.
18F-FDG PET scanning is an evolving imaging tool in the evaluation of inflammatory disorders and might thus be useful in predicting rupture risk. Indeed, Xu et al. [
29] showed that high wall stress regions, calculated using the finite element method, colocalize with areas of positive
18F-FDG uptake. These results are consistent with the findings of Nchimi et al. [
12].
Contradictory reports on
18F-FDG uptake in AAA patients compared to controls can be found in this review. Patient selection is a possible explanation for these contradictions. For instance, Sakalihasan et al. scanned large, rapidly expanding or symptomatic AAAs [
11]. In addition, some studies scanned patients prior to surgery [
14‐
17,
25,
26], while other studies analyzed
18F-FDG PET scans of AAA patients under routine surveillance, either prospectively [
12,
21‐
23] or retrospectively [
13,
19]. Furthermore, studies investigated both patients and controls with a neoplastic disease [
13,
19], but studies also report on
18F-FDG PET scanning in AAA patients without neoplastic disease and compare this to a control group with neoplastic disease [
16,
17]. As neoplasms display increased
18F-FDG uptake, this might lead to false positive readings. Moreover, two studies did not specify the reason of
18F-FDG PET scanning in their control group [
14,
15].
18F-FDG uptake in AAA patients should be compared to a control group without atherosclerosis: patients without hypertension, hyperlipidemia, and non-smokers. Atherosclerosis is a systemic disease, and results in the control group might be influenced by calcification. While several studies described their control group [
13,
16,
17,
19], others did not [
14,
15]. Currently, not much is known about calcification and
18F-FDG uptake. There are some reports in the literature suggesting that
18F-FDG uptake precedes calcification [
30,
31]. A study reported congruent
18F-FDG uptake with calcification spots on CT in 7 % of calcifications [
32], while there is also a study reporting
18F-FDG uptake in the thoracic aortic wall, distinct from calcification sites at CT [
33]. Rominger et al. retrospectively evaluated 932 patients with
18F-FDG PET/CT and show significant correlation between
18F-FDG uptake and calcifications in the abdominal aorta [
34]. Moreover, increased
18F-FDG uptake and increased calcifications in the arterial system were both established as independent predictors for future vascular events, while both increased
18F-FDG uptake and calcification were identified as being at the highest risk for a vascular event. Four studies in this review investigated whether there was a difference in calcification between AAA patients and controls. While Kotze et al. [
20] and Marini et al. [
17] find no significant differences, Palombo et al. [
16] and Morbelli et al. [
18] report increased arterial calcium load in AAA patients compared to controls. Moreover, an inverse correlation between arterial calcium load and arterial wall metabolism was found.
In addition to patient selection, and incorrect control groups, timing of PET imaging and quantification methods is a possible explanation to contradictory reports in literature. Considerable differences exist in timing of imaging and quantification methodology as reported in studies. Only seven studies specified whether visual uptake of
18F-FDG was seen [
11,
12,
15,
16,
19,
25,
26]. Some studies describe the use of SUV
max or SUV
mean divided by blood pool or liver activity [
12,
16‐
19,
21‐
23,
25‐
27], while others only use SUV
max or SUV
mean without blood pool correction [
13‐
15,
20,
24,
28]. This makes it difficult to compare results in literature, highlighting the importance of standardized techniques and quantification methods. Six studies scanned 60 min after
18F-FDG injection [
11‐
13,
15,
25,
26,
28], four other studies 90 min [
14,
18,
21,
24], and three others [
20,
22,
23] 180 min after
18F-FDG administration. Blomberg et al. showed improvement in atherosclerotic plaque quantification in the carotid arteries and thoracic aorta scanning 180 min after
18F-FDG administration compared to 90 min [
35]. However, Menezes et al. [
21] show that there is no significant difference in SUV
max uptake at 60 min compared to scanning at 180 min.
Correlations between
18F-FDG uptake and pathological weakening of the wall can aid in investigating how effective this imaging tool will be in rupture prediction. Correlation between
18F-FDG PET and histology was first shown in a case report [
36], where
18F-FDG uptake corresponded to an inflammatory infiltrate in the aortic wall. In this review, several studies show correlation between
18F-FDG uptake and histological aneurysm characteristics. Reeps et al. [
14] showed that there is a significant correlation between total inflammatory infiltrate and MMP-9. MMP-9 already has been shown to be significantly upregulated in ruptured sites of AAAs compared to non-ruptured sites [
37]. Moreover, its expression is shown to be decreased in non-ruptured abdominal aneurysms compared to ruptured abdominal aneurysms [
38]. It remains the question whether the inflammatory infiltrate in the AAA wall is an etiological factor responsible for the increase in MMP or merely a reaction to an unknown etiological factor causing this increase in MMP expression.
Remarkably, Truijers et al. [
13], showed the highest
18F-FDG uptake in patients with relatively small AAAs, while the patient with the largest AAA showed very low
18F-FDG uptake. Moreover, studies that compared
18F-FDG uptake in AAA compared to a matched control group reported lower
18F-FDG uptake [
16‐
18]. These observations are most likely the result of a reduction in cell density occurring in large AAAs as documented by Marini et al. [
17]. In contrast to the aneurysmal segment, the arterial tree of patients with AAA display higher
18F-FDG uptake [
18]. The dispersed nature of inflammatory cell islands in larger AAAs causes an underestimation of radioactivity concentration whenever the thickness of the source is less than twice the system spatial resolution. PET scanning has limited spatial resolution, and therefore, it remains a challenge to investigate the arterial wall. While findings of Marini et al. do not label
18F-FDG PET scanning as an inadequate tool for risk stratification in AAA, it is essential to realize that currently, a patient with a negative PET scan should not be considered as low risk for rupture.
Courtois et al. [
25,
26] compared patients with and without
18F-FDG uptake as assessed visually. Interesting results are shown that give insight into the pathophysiology of abdominal aortic aneurysms. The significant reduction in expression of MMP-12 and MMP-15 from regions with no
18F-FDG uptake in PET+ patients may be indicative of a final attempt in the tissue to restore extracellular matrix. This response might be a futile attempt to protect from a yet unknown etiologic factor, leading to more inflammation and thus to a PET+ patient. However, when analyzing remodeling of ECM, it is important to take into account substrates of proteolytic enzymes [
39] and the contribution of the structural protein to tensile strength of the aortic wall.
In humans,
18F-FDG is the most frequently used PET tracer in nuclear investigations of aortic aneurysms and was also shown to have the highest sensitivity in a rat experimental AAA model, compared to two other PET tracers involved in leukocyte activation [
40]. Tegler et al. investigated two other PET tracers targeting proteins involved in chronic inflammation but were not able to show differences in uptake between AAA patients and controls [
41].
Developing effective PET tracers to improve AAA rupture risk stratification should focus on pathophysiological processes in AAA. As AAA walls display a large infiltration of immune cells such as macrophages, PET tracers targeting receptors on macrophages such as integrin αvβ3 might be useful [
42]. The search for novel PET tracers that can be useful in predicting AAA rupture is ongoing. Animal studies are helpful in investigating novel molecular probes that might be useful in predicting AAA rupture. English et al. used a novel abdominal aortic aneurysm model in rats and showed that increased
18F-FDG uptake is predictive of rupture [
43]. Nahrendorf et al. [
44] show, by using macrophage-targeted nanoparticles labeled with fluorine-18 in PET/CT scanning, that macrophages localized in the aneurysmal wall can be visualized. Recently, Shi et al. showed angiogenesis in AAA experimental mice by PET scanning with a (64)Cu-labeled anti-CD105 antibody [
45]. Also, other imaging techniques are being used for rupture prediction in animal models such as non-invasive MR imaging and near-infrared fluorescence [
46,
47]. Future experiments need to prove the ability to use these techniques for rupture risk stratification in AAA patients.
In addition to the aneurysmal wall, improved molecular imaging of the intraluminal thrombus (ILT) not only qualitatively but also quantitatively might provide valuable information helpful in predicting rupture risk. Koole et al. [
48] showed that ILT thickness is associated with higher MMP levels and lower vascular smooth cell numbers, which might implicate that AAA wall adjacent to a thick layer of ILT is significantly weaker than wall in the same AAA adjacent to a thinner or no ILT. Moreover, Nchimi et al. showed that the occurrence of ILT precedes AAA peak growth [
49].
Symptoms in AAA patients point out to an increased rupture risk, but these indicators of increased risk for AAA rupture are not available in asymptomatic AAA patients. In this patient group, there is a need to establish risk percentages for AAA rupture. Studies report subtle differences in
18F-FDG uptake between patients and controls [
14,
15,
18,
50]. As definition of quantitative cutoff values is essential in establishing risk percentages for aneurysm rupture and keeping this little difference in SUV
max in mind between AAA patients and controls, it is essential to correct for partial volume effects observed in the thin aortic wall [
24]. However, in the end, it is unlikely that one single PET scan with a random PET tracer will lead to a reliable single quantitative cutoff value for rupture risk prediction. Serial imaging of AAAs will increase the chance to detect inflammatory activity in the aortic aneurismal wall. Investigating the aneurysm wall metabolism at more than a single time point will give valuable information as formation and expansion of aortic aneurysms takes many years. It is currently unknown whether inflammatory processes lead to expansion of aneurysms. No significant correlation was found between the degree of
18F-FDG uptake and recent AAA growth rate or maximum infrarenal AAA diameter in four studies [
13,
14,
16,
22]. This supports the hypothesis that inflammation precedes expansion instead of expansion preceding inflammation. However, in contradiction with this hypothesis, Kotze et al. report inverse correlation between whole-vessel
18F-FDG uptake and aneurysm expansion at ultrasound after 1 year, indicating that aortic aneurysms with lower metabolic activity may be more likely to expand [
22]. AAA formation and progression is a dynamic process, with repetitive sequences of inflammatory damage and repair. Periods of rapid expansion are followed by periods of quiescence [
51]. It is likely that this dynamic process causes a cyclic variation in
18F-FDG uptake. Indeed, findings published by Morel et al. support evidence of cyclic changes in the metabolism of AAA during growth phases [
21]. Consistent with findings published by Kotze et al. [
22], AAAs with lower
18F-FDG uptake were more likely to expand in this study. It is likely that aneurysms with lower
18F-FDG are at the end of their “period of stasis” and will start with their “period of expansion.” Next to the study published by Morel et al. [
21], solely one case study reports a correlation between aneurysm wall glucose metabolism and inflammatory changes with an increase in SUV
max and aneurysm size over time [
52]. Following AAA patients with repeated PET/CT scans might be useful, but this approach needs to be weighed against higher radiation exposure.