Regional Gene Expression of LOX-1, VCAM-1, and ICAM-1 in Aorta of HIV-1 Transgenic Rats

BACKGROUND: Increased prevalence of atherosclerotic cardiovascular disease in HIV-infected patients has been observed. The cause of this accelerated atherosclerosis is a matter of controversy. As clinical studies are complicated by a multiplicity of risk-factors and a low incidence of hard endpoints, studies in animal models could be attractive alternatives. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated gene expression of lectin-like oxidized-low-density-lipoprotein receptor-1 (LOX-1), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) in HIV-1 transgenic (HIV-1Tg) rats; these genes are all thought to play important roles in early atherogenesis. Furthermore, the plasma level of sICAM-1 was measured. We found that gene expressions of LOX-1 and VCAM-1 were higher in the aortic arch of HIV-1Tg rats compared to controls. Also, the level of sICAM-1 was elevated in the HIV-1Tg rats compared to controls, but the ICAM-1 gene expression profile did not show any differences between the groups. CONCLUSIONS/SIGNIFICANCE: HIV-1Tg rats have gene expression patterns indicating endothelial dysfunction and accelerated atherosclerosis in aorta, suggesting that HIV-infection per se may cause atherosclerosis. This transgenic rat model may be a very promising model for further studies of the pathophysiology behind HIV-associated cardiovascular disease

Feasibility of simultaneous PET/MR of the carotid artery: first clinical experience and comparison to PET/CT

The study aimed at comparing PET/MR to PET/CT for imaging the carotid arteries in patients with known increased risk of atherosclerosis. Six HIV-positive men underwent sequential PET/MR and PET/CT of the carotid arteries after injection of 400 MBq of (18)F-FDG. PET/MR was performed a median of 131 min after injection. Subsequently,PET/CT was performed. Regions of interest (ROI) were drawn slice by slice to include the carotid arteries and standardized uptake values (SUV) were calculated from both datasets independently. Quantitative comparison of (18)F-FDG uptake revealed a high congruence between PET data acquired using the PET/MR system compared to the PET/CT system. The mean difference for SUV(mean) was -0.18 (p < 0.001) and -0.14 for SUV(max) (p < 0.001) indicating a small but significant bias towards lower values using the PET/MR system. The 95% limits of agreement were -0.55 to 0.20 for SUV(mean) and -0.93 to 0.65 for SUV(max). The image quality of the PET/MR allowed for delineation of the carotid vessel wall. The correlations between (18)F-FDG uptake from ROI including both vessel wall and vessel lumen to ROI including only the wall were strong (r = 0.98 for SUV(mean) and r = 1.00 for SUV(max)) indicating that the luminal (18)F-FDG content had minimal influence on the values. The study shows for the first time that simultaneous PET/MR of the carotid arteries is feasible in patients with increased risk of atherosclerosis. Quantification of (18)F-FDG uptake correlated well between PET/MR and PET/CT despite difference in method of PET attenuation correction, reconstruction algorithm, and detector technology

Longitudinal imaging of murine atherosclerosis with 2-deoxy-2-[18F]fluoro-D-glucose and [18F]-sodium fluoride in genetically modified Apolipoprotein E knock-out and wild type mice

Abstract In a longitudinal design, four arterial segments in mice were followed by positron emission tomography/computed tomography (PET/CT) imaging. We aimed to determine how the tracers reflected the development of atherosclerosis via the uptake of 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) for imaging inflammation and [18F]-sodium fluoride (Na[18F]F) for imaging active microcalcification in a murine model of atherosclerosis. Apolipoprotein E knock-out (ApoE) mice and C57 BL/6NtaC (B6) mice were divided into four groups. They received either normal chow (N = 7, ApoE mice and N = 6, B6 mice) for 32 weeks or a high-fat diet (N = 6, ApoEHFD mice and N = 9, B6HFD mice) for 32 weeks. The mice were scanned with [18F]FDG and Na[18F]F using a dedicated small animal PET/CT scanner at three timepoints. The tracer uptakes in four aortic segments (abdominal aorta, aortic arch, ascending aorta, and thoracic aorta) were measured and reported as SUVmax values. The uptake of [18F]FDG (SUVmax: 5.7 ± 0.5 vs 1.9 ± 0.2, 230.3%, p =  < 0.0001) and Na[18F]F (SUVmax: 9.6 ± 1.8 vs 4.0 ± 0.3, 175%, p = 0.007) was significantly increased in the abdominal aorta of ApoEHFD mice at Week 32 compared to baseline abdominal aorta values of ApoEHFD mice. [18F]FDG uptake in the aortic arch, ascending aorta and the thoracic aorta of B6HFD mice at Week 32 showed a robust resemblance to the abdominal aorta uptake whereas the Na[18F]F uptake only resembled in the thoracic aorta of B6HFD mice at Week 32 compared to the abdominal aorta. The uptake of both [18F]FDG and Na[18F]F increased as the disease progressed over time, and the abdominal aorta provided a robust measure across mouse strain and diet. Therefore, it seems to be the preferred region for image readout. For [18F]FDG-PET, both B6 and ApoE mice provide valuable information and either mouse strain may be used in preclinical cardiovascular studies, whereas for Na[18F]F -PET, ApoE mice should be preferred

18F-FDG and 18F-FLT-PET Imaging for Monitoring Everolimus Effect on Tumor-Growth in Neuroendocrine Tumors:Studies in Human Tumor Xenografts in Mice

The mTOR inhibitor everolimus has shown promising results in some but not all neuroendocrine tumors. Therefore, early assessment of treatment response would be beneficial. In this study, we investigated the in vivo and in vitro treatment effect of everolimus in neuroendocrine tumors and evaluated the performance of 18F-FDG and the proliferation tracer 18F-FLT for treatment response assessment by PET imaging.The effect of everolimus on the human carcinoid cell line H727 was examined in vitro with the MTT assay and in vivo on H727 xenograft tumors. The mice were scanned at baseline with 18F-FDG or 18F-FLT and then treated with either placebo or everolimus (5 mg/kg daily) for 10 days. PET/CT scans were repeated at day 1,3 and 10.Everolimus showed significant inhibition of H727 cell proliferation in vitro at concentrations above 1 nM. In vivo tumor volumes measured relative to baseline were significantly lower in the everolimus group compared to the control group at day 3 (126±6% vs. 152±6%; p = 0.016), day 7 (164±7% vs. 226±13%; p<0.001) and at day 10 (194±10% vs. 281±18%; p<0.001). Uptake of 18F-FDG and 18F-FLT showed little differences between control and treatment groups, but individual mean uptake of 18F-FDG at day 3 correlated with tumor growth day 10 (r2 = 0.45; P = 0.034), 18F-FLT mean uptake at day 1 correlated with tumor growth day 7 (r2 = 0.63; P = 0.019) and at day 3 18F-FLT correlated with tumor growth day 7 (r2 = 0.87; P<0.001) and day 10 (r2 = 0.58; P = 0.027).Everolimus was effective in vitro and in vivo in human xenografts lung carcinoid NETs and especially early 18F-FLT uptake predicted subsequent tumor growth. We suggest that 18F-FLT PET can be used for tailoring therapy for neuroendocrine tumor patients through early identification of responders and non-responders