18F-FDG PET Imaging of Murine Atherosclerosis: Association with Gene Expression of Key Molecular Markers

Hag, Anne Mette Fisker; Pedersen, Sune Folke; Christoffersen, Christina; Binderup, Tina; Jensen, Mette Munk; Jørgensen, Jesper Tranekjær; Skovgaard, Dorthe; Ripa, R; Kjær, Andreas

doi:10.1371/journal.pone.0050908

Cited by 43 publications

(32 citation statements)

References 44 publications

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“…The first clinical study with PET imaging of atherosclerosis, published in 2002 (17), was consequently performed using 18 F-FDG, which is a marker for uptake of glucose and hereby metabolism in tissue. The uptake of 18 F-FDG was later shown to correlate significantly with plaque macrophage content, with other circulating inflammatory biomarkers (18)(19)(20)(21) and known cardiovascular risk factors (6,22). Therefore, hope has risen that 18 F-FDG might be used to evaluate therapeutic intervention (23).…”

Section: Discussionmentioning

confidence: 99%

⁶⁴Cu-DOTATATE for Noninvasive Assessment of Atherosclerosis in Large Arteries and Its Correlation with Risk Factors: Head-to-Head Comparison with ⁶⁸Ga-DOTATOC in 60 Patients

et al. 2015

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The somatostatin receptor subtype 2 is expressed on macrophages, an abundant cell type in the atherosclerotic plaque. Visualization of somatostatin receptor subtype 2, for oncologic purposes, is frequently made using the DOTA-derived somatostatin analogs DOTATOC or DOTATATE for PET. We aimed to compare the uptake of the PET tracers 68 Ga-DOTATOC and 64 Cu-DOTATATE in large arteries, in the assessment of atherosclerosis by noninvasive imaging technique, combining PET and CT. Further, the correlation of uptake and cardiovascular risk factors was investigated. Methods: Sixty consecutive patients with neuroendocrine tumors underwent both 68 Ga-DOTATOC and 64 Cu-DOTATATE PET/CT scans, in random order. For each scan, the maximum and mean standardized uptake values (SUVs) were calculated in 5 arterial segments. In addition, the blood-pool-corrected target-to-background ratio was calculated. Uptake of the tracers was correlated with cardiovascular risk factors collected from medical records. Results: We found detectable uptake of both tracers in all arterial segments studied. Uptake of 64 Cu-DOTATATE was significantly higher than 68 Ga-DOTATOC in the vascular regions both when calculated as maximum and mean uptake. There was a significant association between Framingham risk score and the overall maximum uptake of 64 Cu-DOTATATE using SUV (r 5 0.4; P 5 0.004) as well as target-to-background ratio (r 5 0.3; P 5 0.04), whereas no association was found with 68 Ga-DOTATOC. The association of risk factors and maximum SUV of 64 Cu-DOTATATE was found driven by body mass index, smoking, diabetes, and coronary calcium score (P , 0.001, P 5 0.01, P 5 0.005, and P 5 0.03, respectively). Conclusion: In a series of oncologic patients, vascular uptake of 68 Ga-DOTATOC and 64 Cu-DOTATATE was found, with highest uptake of the latter. Uptake of 64 Cu-DOTATATE, but not of 68 Ga-DOTATOC, was correlated with cardiovascular risk factors, suggesting a potential role for 64 Cu-DOTATATE in the assessment of atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

⁶⁴Cu-DOTATATE for Noninvasive Assessment of Atherosclerosis in Large Arteries and Its Correlation with Risk Factors: Head-to-Head Comparison with ⁶⁸Ga-DOTATOC in 60 Patients

et al. 2015

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“…[23][24][25] Thus, the evaluation of 18 F-FDG signal may be a useful approach to noninvasively monitor plaque inflammation and the effectiveness of therapies intended to alleviate inflammation in atherosclerosis. This method has successfully been adopted to murine atherosclerosis models, 18,26 although certain limitations still exist in terms of its feasibility for in vivo positron emission tomographic imaging. 27 Therefore, we focused on investigating the effects of MT-II on 18 F-FDG uptake by ex vivo analyses.…”

Section: F-fdg Uptake By Mt-ii 1351mentioning

confidence: 99%

Pharmacological Activation of the Melanocortin System Limits Plaque Inflammation and Ameliorates Vascular Dysfunction in Atherosclerotic Mice

Rinne

Silvola

Hellberg

et al. 2014

ATVB

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A therosclerosis is a chronic inflammatory disease causing progressive lesion formation and luminal narrowing of arteries. The underlying pathology is initiated by endothelial dysfunction and structural alterations after an imbalanced lipid metabolism and trapping of low-density lipoprotein (LDL) particles in the intima of arteries.1,2 Subsequently, intimal lipid accumulation triggers the release of various chemokines by activated endothelial cells, inducing a multiphase cascade of leukocyte infiltration and inflammatory responses in the arterial walls. As the knowledge of these inflammatory pathways has been growing during the past years, it has also uncovered new druggable targets that could complement the current treatment options, which do not directly interfere with the central inflammatory mechanisms driving atheroprogression. One endogenous pathway that has gained increasing attention for its wide-ranging and potent actions in suppressing maladaptive inflammatory responses is the melanocortin system consisting of melanocortin peptides and their cellular receptors. 3,4 However, the role of melanocortin signaling and its promise as a therapeutic target in atherosclerosis remain fully unexplored.Melanocortins are a family of peptides that are proteolytically cleaved from the common precursor molecule pro-opiomelanocortin. These peptides include melanocyte-stimulating hormones (α-, β-, and γ-MSH) and adrenocorticotropic hormone. They regulate important physiological functions by acting via G-protein-coupled melanocortin receptors (MC-Rs), named from MC1-R to MC5-R. 5,6 Our recent findings indicate that α-MSH serves as a protective regulator in the vasculature by enhancing endothelium-dependent control of blood vessel tone. 7 Mechanistically, α-MSH was shown to augment vascular nitric oxide (NO) availability by activating MC1-R in the endothelium. Besides promoting endothelial function, mounting evidence indicates that α-MSH, through the activation of © 2014 American Heart Association, Inc. Objective-Melanocortin peptides have been shown to elicit anti-inflammatory actions and to promote vascular endothelial function by activating type 1 and 3 melanocortin receptors. Here, we addressed whether these favorable properties of melanocortins could reduce atherosclerotic plaque inflammation and improve vasoreactivity in atherosclerotic mice. Approach and Results-Low-density lipoprotein receptor-deficient mice expressing only apolipoprotein B100 were fed a high-fat diet for 8 or 16 weeks and treated with either vehicle or a stable melanocortin analog, melanotan II (MT-II, 0.3 mg/kg per day, 4 weeks). We determined plaque uptake of fluorine-18-labeled fluorodeoxyglucose as a surrogate marker for atherosclerotic plaque inflammation and vascular function of the aorta by ex vivo analyses. MT-II had no effect on body weight or composition, or plasma cholesterol levels in atherosclerotic mice. Without attenuating atherosclerotic lesion size or lesional macrophage accumulation, MT-II treatment reduced fluorine-18-labeled...

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“…In murine experiments, a strong correlation between FDG uptake and gene expression of inflammatory molecular markers has been demonstrated (21). Building on these early findings, in rabbits, it has been shown that inflamed aortic lesions accumulate up to 20 times more FDG than non-inflamed arterial lesions, thereby enabling reliable noninvasive detection of inflamed loci within arterial wall with FDG-PET (20).…”

Section: Basis For Arterial Fluorine-2-deoxy-d-glucose (Fdg) Uptake Fmentioning

confidence: 88%

Role of molecular imaging with positron emission tomographic in aortic aneurysms

et al. 2017

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Aortic aneurysms (AA) are often asymptomatic before the occurrence of acute, potentially fatal complications including dissection and/or rupture. Beyond aortic size, the ability to assess aortic wall characteristics and processes contributing to aneurysm development may allow improved selection of patients who may benefit from prophylactic surgical intervention. Current risk stratification for aneurysms relies upon routine noninvasive imaging of aortic size without assessing the underlying pathophysiologic processes, including features such as inflammation, which may be associated with aneurysm development and progression. The use of molecular imaging modalities with positron emission tomographic (PET) scan allows characterization of aortic wall inflammatory activity. Elevated uptake of Fuorine-2-deoxy-D-glucose (FDG), a radiotracer with elevated avidity in highly-metabolic cells, has been correlated with the development and progression of both abdominal and thoracic AA in a number of animal models and clinical studies. Other novel PET radiotracers targeting matrix metalloproteinases (MMPs), mitochondrial translocator proteins (TSPO) and endothelial cell adhesion molecules are being investigated for clinical utility in identifying progression of disease in AA. By further defining the activation of molecular pathways in assessing aortic regions at risk for dilatation, this imaging modality can be integrated into future clinical decision-making models.

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18F-FDG PET Imaging of Murine Atherosclerosis: Association with Gene Expression of Key Molecular Markers

Cited by 43 publications

References 44 publications

⁶⁴Cu-DOTATATE for Noninvasive Assessment of Atherosclerosis in Large Arteries and Its Correlation with Risk Factors: Head-to-Head Comparison with ⁶⁸Ga-DOTATOC in 60 Patients

⁶⁴Cu-DOTATATE for Noninvasive Assessment of Atherosclerosis in Large Arteries and Its Correlation with Risk Factors: Head-to-Head Comparison with ⁶⁸Ga-DOTATOC in 60 Patients

Pharmacological Activation of the Melanocortin System Limits Plaque Inflammation and Ameliorates Vascular Dysfunction in Atherosclerotic Mice

Role of molecular imaging with positron emission tomographic in aortic aneurysms

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18F-FDG PET Imaging of Murine Atherosclerosis: Association with Gene Expression of Key Molecular Markers

Cited by 43 publications

References 44 publications

64Cu-DOTATATE for Noninvasive Assessment of Atherosclerosis in Large Arteries and Its Correlation with Risk Factors: Head-to-Head Comparison with 68Ga-DOTATOC in 60 Patients

64Cu-DOTATATE for Noninvasive Assessment of Atherosclerosis in Large Arteries and Its Correlation with Risk Factors: Head-to-Head Comparison with 68Ga-DOTATOC in 60 Patients

Pharmacological Activation of the Melanocortin System Limits Plaque Inflammation and Ameliorates Vascular Dysfunction in Atherosclerotic Mice

Role of molecular imaging with positron emission tomographic in aortic aneurysms

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⁶⁴Cu-DOTATATE for Noninvasive Assessment of Atherosclerosis in Large Arteries and Its Correlation with Risk Factors: Head-to-Head Comparison with ⁶⁸Ga-DOTATOC in 60 Patients

⁶⁴Cu-DOTATATE for Noninvasive Assessment of Atherosclerosis in Large Arteries and Its Correlation with Risk Factors: Head-to-Head Comparison with ⁶⁸Ga-DOTATOC in 60 Patients