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Unlabelled: (18)F-FDG accumulates in glycolytically active tissues and is known to concentrate in tissues that are rich in activated macrophages. In this study, we tested the hypotheses that human granulocyte-macrophage colony-stimulating factor (GM-CSF), a clinically used cytokine, increases macrophage glycolysis and deoxyglucose uptake in vitro and acutely enhances (18)F-FDG uptake within inflamed tissues such as atherosclerotic plaques in vivo., Methods: In vitro experiments were conducted on human macrophages whereby inflammatory activation and uptake of radiolabeled 2-deoxyglucose was assessed before and after GM-CSF exposure. In vivo studies were performed on mice and New Zealand White rabbits to assess the effect of GM-CSF on (18)F-FDG uptake in normal versus inflamed arteries, using PET., Results: Incubation of human macrophages with GM-CSF resulted in increased glycolysis and increased 2-deoxyglucose uptake (P < 0.05). This effect was attenuated by neutralizing antibodies against tumor necrosis factor-α or after silencing or inhibition of 6-phosphofructo-2-kinase. In vivo, in mice and in rabbits, intravenous GM-CSF administration resulted in a 70% and 73% increase (P < 0.01 for both), respectively, in arterial (18)F-FDG uptake in atherosclerotic animals but not in nonatherosclerotic controls. Histopathologic analysis demonstrated a significant correlation between in vivo (18)F-FDG uptake and macrophage staining (R = 0.75, P < 0.01)., Conclusion: GM-CSF substantially augments glycolytic flux in vitro (via a mechanism dependent on ubiquitous type 6-phosphofructo-2-kinase and tumor necrosis factor-α) and increases (18)F-FDG uptake within inflamed atheroma in vivo. These findings demonstrate that GM-CSF can be used to enhance detection of inflammation. Further studies should explore the role of GM-CSF stimulation to enhance the detection of inflammatory foci in other disease states., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Unlabelled: Chronic obstructive pulmonary disease (COPD) patients exhibit increased cardiovascular risk, even after controlling for smoking. Inflammation may underlie this observation., Methods: We measured vascular inflammation in both COPD patients and controls using (18)F-FDG PET/CT. Aortic inflammation was expressed as the target-to-background ratio (TBR) of the standardized uptake value in 7 COPD patients, 5 metabolic syndrome patients, and 7 ex-smokers., Results: Abdominal aortic mean TBR (+/-SD) was greater in COPD patients than in ex-smoker controls (1.60 +/- 0.13 vs. 1.34 +/- 0.15, P = 0.0001). Aortic arch and abdominal aorta mean TBRs were higher in metabolic syndrome patients than in COPD patients (aortic arch, 1.80 +/- 0.18 vs. 1.53 +/- 0.18, P = 0.001, and abdominal aorta, 1.71 +/- 0.14 vs. 1.60 +/- 0.13, P = 0.001)., Conclusion: COPD patients exhibited aortic inflammation that fell between the aortic inflammation exhibited by ex-smokers and that by metabolic syndrome patients. This may in part explain the increased risk of cardiovascular disease in COPD patients.

Unlabelled: Macrophages play a key role in atherosclerotic plaque rupture. The iodine-based contrast agent N1177 accumulates in macrophages, allowing for their detection with CT. In this study, we tested whether the intensity of enhancement detected with CT in the aortic wall of rabbits injected with N1177 correlated with inflammatory activity evaluated with (18)F-FDG PET/CT and macrophage density on histology., Methods: Atherosclerotic plaques were induced in the aorta of New Zealand White rabbits (n = 7) by a repeated balloon injury (4 wk apart) and 4 mo of hyperlipemic diet. Noninjured rabbits, fed a chow diet, were used as controls (n = 3). A CT scan of the aorta (n = 10) was acquired in each rabbit before, during, and at 2 h after intravenous injection of N1177 (250 mg of iodine/kg). One week later, the same rabbits underwent PET/CT 3 h after injection of (18)F-FDG (37 MBq/kg [1 mCi/kg]). CT enhancement was calculated as the difference in aortic wall densities between images obtained before and images obtained at 2 h after injection of N1177. Mean standardized uptake values were measured on PET axial slices of the aorta in regions of interest encompassing the vessel wall. Macrophage density was measured by immunohistology (anti-RAM-11 antibody) on corresponding aortic cross-sections., Results: N1177-enhanced CT measured stronger enhancement in the aortic wall of atherosclerotic rabbits than in control rabbits (10.0 +/- 5.2 vs. 2.0 +/- 2.1 Hounsfield units, respectively; P < 0.05). After the injection of (18)F-FDG, PET detected higher standardized uptake values in the aortic wall of atherosclerotic rabbits than in control rabbits (0.61 +/- 0.12 vs. 0.21 +/- 0.02; P < 0.05). The intensity of enhancement in the aortic wall measured with CT after injection of N1177 correlated with (18)F-FDG uptake on PET/CT (r = 0.61, P < 0.001) and macrophage density on immunohistology (r = 0.63, P < 0.001)., Conclusion: The intensity of enhancement detected with CT in the aortic wall of rabbits injected with N1177 correlates with intense uptake of (18)F-FDG measured with PET and with macrophage density on histology, suggesting a role for N1177 in noninvasive identification of high-risk atherosclerotic plaques with CT.

Unlabelled: Atherosclerosis imaging with 18F-FDG PET is useful for tracking inflammation within plaque and monitoring the response to drug therapy. Short-term reproducibility of this technique in peripheral artery disease has not been assessed, and the optimal method of 18F-FDG quantification is still debated. We imaged 20 patients with vascular disease using 18F-FDG PET twice, 14 d apart, and used these data to assess reproducibility measures and compare 2 methods of 18F-FDG uptake measurement. We also reviewed the literature on quantification methods to determine the optimal measures of arterial 18F-FDG uptake for future studies., Methods: Twenty patients with vascular disease underwent PET/CT of the iliac, femoral, and carotid arteries 90 min after 18F-FDG administration. In 19 patients, repeat testing was performed at 2 wk. Coregistration and attenuation correction were performed with CT. Vessel 18F-FDG uptake was measured as both the mean and maximum blood-normalized standardized uptake value (SUV), known as the target-to-background ratio (TBR). We assessed interscan, interobserver, and intraobserver agreement., Results: Nineteen patients completed both imaging sessions. The carotid and peripheral arteries all have excellent short-term reproducibility of the 18F-FDG signal, with intraclass correlation coefficients all greater than 0.8 for all measures of reproducibility. Both mean and maximum TBR measurements for quantifying 18F-FDG uptake are equally reproducible. 18F-FDG uptake was significantly higher in the carotid arteries than in both iliac and femoral vessels (P < 0.001 for both)., Conclusion: We found that both mean and maximum TBR in the carotid, iliac, and femoral arteries were highly reproducible. We suggest the mean TBR be used for tracking systemic arterial therapies, whereas the maximum TBR is optimal for detecting and monitoring local, plaque-based therapy.

Atherosclerosis is a systemic disease that affects most major arteries of the body and is the most common cause of premature death in the western world. It develops slowly and often asymptomatically, so that for many patients its first manifestation is sudden cardiac death, stroke, or myocardial infarction. The current gold standard for imaging atherosclerosis is x-ray angiography. However, recent advances in understanding of the pathobiology of atherosclerosis have highlighted the inadequacies of this technique and the need for better imaging approaches. The purpose of this article is to briefly outline the biology of atherosclerosis and to review the techniques available to image it, concentrating specifically on those that detect metabolic or inflammatory changes within the atherosclerotic plaque.