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The usefulness of perfluorocarbon nanoemulsions for the imaging of experimental myocarditis has been demonstrated in a high-field 9.4 Tesla MRI scanner. Our proof-of-concept study investigated the imaging capacity of PFC-based 19F/1H MRI in an animal myocarditis model using a clinical field strength of 1.5 Tesla. To induce experimental myocarditis, five male rats (weight ~300 g, age ~50 days) were treated with one application per week of doxorubicin (2 mg/kg BW) over a period of six weeks. Three control animals received the identical volume of sodium chloride 0.9% instead. Following week six, all animals received a single 4 ml injection of an 20% oil-in-water perfluorooctylbromide nanoemulsion 24 hours prior to in vivo1H/19F imaging on a 1.5 Tesla MRI. After euthanasia, cardiac histology and immunohistochemistry using CD68/ED1 macrophage antibodies were performed, measuring the inflamed myocardium in μm2 for further statistical analysis to compare the extent of the inflammation with the 19F-MRI signal intensity. All animals treated with doxorubicin showed a specific signal in the myocardium, while no myocardial signal could be detected in the control group. Additionally, the doxorubicin group showed a significantly higher SNR for 19F and a stronger CD68/ED1 immunhistoreactivity compared to the control group. This proof-of-concept study demonstrates that perfluorocarbon nanoemulsions could be detected in an in vivo experimental myocarditis model at a currently clinically relevant field strength.

BackgroundLigands of peroxisome-proliferator activated receptors (PPARs), such as non-esterified fatty acids (NEFAs), induce expression of angiopoietin-like protein 4 (ANGPTL4). Recently ANGPTL4 has been reported to be a mediator of intracellular adipose lipolysis induced by glucocorticoids.ObjectiveTo determine the concentrations of ANGPTL4 in cord serum of neonates born by spontaneous vaginal delivery (SVD) and by pre-labor cesarean section (CS) from healthy women, and to relate them to parameters of neonatal lipolytic activity at birth.MeasurementsIn 54 neonates born by SVD and in 56 neonates born by CS, arterial cord blood was drawn to determine insulin, cortisol, triacylglycerols (TAGs), glycerol, non-esterified fatty acids (NEFAs), individual fatty acids, ANGPTL4, adiponectin, retinol binding protein 4 (RBP4) and leptin.ResultsBirth weight and neonatal fat mass in SVD and CS showed no difference, but the concentrations of glycerol, adiponectin, RBP4, NEFAs and most individual fatty acids were higher in cord serum of neonates born by SVD compared to CS, indicating a higher adipose tissue breakdown in the SVD group. The concentrations of TAG and cortisol were also higher and that of insulin was lower in cord serum of SVD compared to the CS group. However, the concentration in cord serum of ANGPTL4 did not differ between the two groups and no positive correlation with either NEFA or glycerol concentrations were detected.ConclusionANGPTL4 is known to stimulate lipolysis in adults, but does not appear to mediate the increased activity in SVD, indicating the presence of different regulatory inputs.

Ezetimibe (EZE), an inhibitor of cholesterol absorption, reduces atherosclerosis in apolipoprotein E–deficient (apo –/– ) mice. The matrix protein ED-B fibronectin (ED-B) is upregulated in atherosclerotic lesions. Using a novel conjugate for near-infrared fluorescence (NIRF) imaging targeting ED-B, we studied the effect of EZE on plaque lesion formation in apoE –/– mice. ApoE –/– mice received EZE (5 μg/kg/d) or chow up to the age of 4, 6, and 8 months. NIRF imaging of aortic lesions was performed 24 hours after intravenous application ex vivo and in vivo. Plaque lesion formation was analyzed by histology and immunohistochemistry. Aortic lesion formation detected by Sudan staining and NIRF imaging was significantly reduced at 6 and 8 months ( p < .001). Plaque areas determined by NIRF imaging significantly correlated with Sudan staining ( p < .001). EZE treatment resulted in a significant reduction in plaque macrophage and ED-B immunoreactivity (both p < .05) in brachiocephalic lesions. There was a significant reduction in plaque size in brachiocephalic arteries in 8-month-old mice treated with EZE compared with mice during short-term treatment ( p < .05), indicating EZE plaque regression. Targeted NIRF imaging showed a correlation to histologic lesion extension during therapeutical intervention in experimental atherosclerosis.

Abstract   Background To evaluate the ability of ultrahigh-field magnetic resonance imaging (MRI) to accurately depict the composition of the human arterial vessel wall ex vivo and to detect early atherosclerotic lesion formation in comparison to histology. Methods Eight iliac artery specimens with low-grade atherosclerotic lesions obtained from human organ donors were studied. Three-dimensional, high-resolution MRI (spatial resolution: 79 � 79 � 109 μm) was performed using T1-, T2- and proton density (PD)-weightings (7.0 Tesla MR system, Bruker Pharmascan). A total of 36 MR slices and corresponding histological sections were matched for comparative evaluation of area measurements of lumen, media and adventitia and—if present—plaque size. Statistical correlation between histology and MR measurements was tested and a ROC-analysis was performed to determine the plaque size being predictive of correctly identifying atherosclerotic lesions with MRI. Results The areas of vessel lumen and media as measured on T1-, T2- and PD-weighted MR images showed a strong correlation with the corresponding histological measurements (r = 0.84 to r = 0.89; P r = 0.55 to r = 0.62; P  4.0 mm2 were 79% and 91%, respectively. With T2- and PD-weighted MRI, however, sensitivity and specificity for the detection of plaques > 0.4 mm2 were 93% and 89%. Conclusions In an experimental ex vivo setting, ultrahigh-field MRI of the human arterial vessel wall resulted in an accurate visualization of vessel wall composition when compared to histology and, thus, allowed for a quantitative assessment. T2- and PD-weighted MRI proved capable of reliably detecting submillimeter atherosclerotic lesions. [ABSTRACT FROM AUTHOR]

Abstract Integrins are heterodimeric a/ß receptors that link the cytoskeleton with the extracellular matrix, thereby regulating several cell functions important in atherosclerosis. In vitro, the subtilisin/kexin-like proprotein convertases (PCs), namely PC5 and furin, have been shown to be responsible for the endoproteolytic activation of the av integrin subunit. Based on their cleavage activity, these PCs are potential targets in atherosclerosis. In the present study, we investigated the localization of furin and PC5 in different stages of human atherosclerosis. Immunohistochemical analysis of furin and PC5 revealed their presence in vascular smooth-muscle cells and endothelial cells in atherosclerotic and non-atherosclerotic lesions. However, in the more advanced lesions, furin and PC5 staining was significantly expressed in macrophages/foam cells. In vitro, THP-1 derived macrophages contained furin and PC5, and maturation of monocytes to macrophages was accompanied by enhanced avß3 cell-surface expression. Inhibition of furin/PC5 with the specific pharmacological furin-like PC-inhibitor dec-CMK inhibited av endoproteolytic activation but did not abolish avß3 cell-surface expression. This indicates that furin/PC5 is required for av endoproteolytic activation but not for av routing and sorting to the cell surface. In conclusion, our study demonstrates that furin and PC5 are significantly expressed in mononuclear cells in advanced human atherosclerotic lesions, where they regulate av endoproteolytic activation. [ABSTRACT FROM AUTHOR]