Our study was aimed at investigating the potential of 68Ga-DOTATATE PET/CT to detect macrophage density at inflammatory lesions of large arteries. In addition, we compared the tracer uptake with that of 18F-FDG regarding colocalization and intensity of the uptake in correlation to commonly accepted risk factors for cardiovascular disease. To our knowledge, this is the first investigation to compare 18F-FDG and 68Ga-DOTATATE in atherosclerosis imaging.
18F-FDG has already been established as a useful tool to identify inflammatory processes, e.g., in large arteries
[17–22]. In general, it is taken up by cells in proportion to their metabolic activity. Rudd et al. and Tawakol et al. reported that carotid atherosclerotic plaques with high 18F-FDG uptake have a high macrophage density
[20, 21], indicating that 18F-FDG might be a useful tool to detect inflammatory plaques. 68Ga-DOTATATE has also been demonstrated to detect activated macrophages
 due to a specific overexpression of the SSTR-2, the specific molecular target of 68Ga-DOTATATE, on the cell surface of activated macrophages. Although the potential for macrophage detection has been demonstrated on both 18F-FDG and 68Ga-DOTATATE, a concordant focally increased uptake was only found in the minority of cases in this study (Figure
When comparing patients with and without risk factors for cardiovascular disease, many sites of tracer uptake could be detected both in high-risk and low-risk patients with 18F-FDG. In most arterial segments (apart from the ascending aorta), the maximum TBR values of the high-risk group were higher than those of the low-risk group. However, this difference did not reach statistical significance except for the left iliac artery (Figure
There were few significant differences between the two tracers in the low-risk group. In the high-risk group, however, TBR for 68Ga-DOTATATE showed significantly higher values than that for 18F-FDG.
Additionally, significant correlations between the mean uptake of both tracers and the patients' score of risk factors were found. In the literature, several studies reported significant correlations between focally increased 18F-FDG uptake in the walls of large arteries and the presence of cardiovascular risk factors, such as hypercholesterolemia, hypertension, age, and diabetes
. Other study groups found associations between the plaque burden of the left anterior descending coronary artery and cardiovascular risk factors
[22, 31]. In our study, only a significant correlation between the mean TBR in the abdominal aorta with hypertension was found. The lack of further correlations might be due to the small size of our sample. For 68Ga-DOTATATE, tracer uptake correlated significantly with hypertension, age, and the presence of calcifications.
18F-FDG uptake in inflammatory cells is influenced by macrophage differentiation and cell activation
 since immune cell activation is associated with increased oxidative metabolism and, consequently, increased use of glucose
. In our investigation, we found many 18F-FDG-positive sites both in the low- and high-risk groups, whereas very few 68Ga-DOTATATE-positive foci could be found in low-risk individuals. This raises doubt whether all accumulations of 18F-FDG within the arteries are due to macrophage-mediated inflammatory activity.
In contrast to 18F-FDG, 68Ga-DOTATATE visualizes the distribution of SSTR-2. As mentioned above, the specific expression of SSTR-2 on the surface of macrophages, as well as the significant upregulation of this receptor upon stimulation (e.g. with lipopolysaccharide), has been reported
. Furthermore, another research group observed that the expression of SSTR-2 in human coronary endothelial cells is decreased by treatment with the inflammatory cytokine TNF-α, which is mainly produced and secreted by activated macrophages
. Therefore, in the pro-inflammatory setting, SSTR-2 expression is upregulated for macrophages, whereas on the other hand, it is downregulated in endothelial cells. In coronary heart disease, this idea could support the use of 68Ga-DOTATATE for the detection of vulnerable plaques.
SSTR-2 also plays another role in atherosclerotic plaques. Adams et al. demonstrated the increased expression of SSTR-2 when human umbilical vein endothelial cells are proliferating, thereby suggesting its active role in angiogenesis, which has been described in the context of unstable plaques
. Consequently, 68Ga-DOTATATE PET could be used to visualize unstable plaques in two different ways: detection of activated macrophages as well as angiogenesis within the atherosclerotic lesion
. Our results indicate that 68Ga-DOTATATE PET detects a higher number of increased focal uptakes in patients with high cardiovascular risk; this may be used as a complementary imaging modality in the detection of inflammatory plaque by identifying somatostatin receptor-positive sites within the arteries.
In this study, risk factors for CAD correlated less strongly with foci of increased 18F-FDG uptake as compared to those of 68Ga-DOTATATE. This might be interpreted as an indication that 68Ga-DOTATATE is more specific for the inflamed plaque. However, due to the small sample size of our investigation, it is difficult to draw firm conclusions. For example, another reason for the observed difference between the two tracers could be tracer kinetics. DOTATATE binds to the SSTR-2, and thus, the uptake is potentially limited by the number of saturated SSTR-2 receptors. This is not the case with FDG, which is continuously metabolized by activated macrophages. Otherwise, FDG as the smaller molecule is potentially more vulnerable to unspecific uptake mechanisms like increased vascular permeability due to inflammation. So, in theory, FDG should be more sensitive than DOTATATE but potentially less specific, which could explain the better correlation with different risk groups.
Another important limitation is the lack of histological validation of 68Ga-DOTATATE uptake. Due to the retrospective design, a selection bias cannot be excluded. Also, this study was performed in cancer patients; therefore, our findings may be not generalizable to studies in vascular disease. Especially, we cannot exclude the influence of anticancer therapies or the hormone action of neuroendocrine tumors (Table
3). So far, no influence of TSH-suppressive therapy or peptide receptor radionuclide therapy (PRRT) on atherosclerosis has been published. In the only patient with PRRT, the interval to the PET scans was at least 8 weeks, so we do not expect any interference. Also, none of the two patients on chemotherapy was immunodeficient, according to their white blood cell count. However, further prospective studies in a higher number of non-oncological patients are warranted.